Michele G. Sullivan

SAN ANTONIO – An analysis from 2 decades of follow-up in women who took tamoxifen or placebo for breast cancer prevention showed the benefit in prevention persists, but no benefit in survival has yet to emerge.

Dr. Erica Mayer of the Dana-Farber Cancer Institute, Boston, discusses IBIS-1 results in an interview and details what those results will mean in the clinic, at the San Antonio Breast Cancer Symposium.

[email protected]

On Twitter @alz_gal

SAN ANTONIO – An analysis from 2 decades of follow-up in women who took tamoxifen or placebo for breast cancer prevention showed the benefit in prevention persists, but no benefit in survival has yet to emerge.

Dr. Erica Mayer of the Dana-Farber Cancer Institute, Boston, discusses IBIS-1 results in an interview and details what those results will mean in the clinic, at the San Antonio Breast Cancer Symposium.

[email protected]

On Twitter @alz_gal

SAN ANTONIO – An analysis from 2 decades of follow-up in women who took tamoxifen or placebo for breast cancer prevention showed the benefit in prevention persists, but no benefit in survival has yet to emerge.

Dr. Erica Mayer of the Dana-Farber Cancer Institute, Boston, discusses IBIS-1 results in an interview and details what those results will mean in the clinic, at the San Antonio Breast Cancer Symposium.

[email protected]

On Twitter @alz_gal

SAN ANTONIO – Five years of tamoxifen provided 20 years of breast cancer prevention to some at-risk women who took it prophylactically.

However, their 20-year all-cause mortality was no different from those taking placebo (182 vs. 166 deaths), nor was their mortality from breast cancer (31 vs. 26, respectively), Jack Cuzick, Ph.D., said at the San Antonio Breast Cancer Symposium.

“While we saw clear, lasting benefits of tamoxifen in reducing breast cancer incidence, uncertainty with respect to mortality remains,” said Dr. Cuzick, the John Snow professor of epidemiology at Wolfson Institute of Preventive Medicine at Queen Mary University, London.

He suggested that, in light of the small number of deaths, the study was not sufficiently powered to detect any significant survival difference. But women in the IBIS-1 trial will continue to be observed, and future analyses could clarify the issue, he added.

“Although 20 years seems like a long follow-up time, it is actually too early to make any clear statement about mortality,” he said. “However, we are concerned about an excess emergence of ER-negative tumors, which we saw after 10 years.”

The study was simultaneously published on Dec. 13 in Lancet Oncology

IBIS-1 randomized 7,154 healthy pre- and postmenopausal women to 5 years of either 20 mg daily tamoxifen or placebo. These women were aged 35-70 years at baseline and presented with an increased breast cancer risk attributable to a family history.

IBIS-1 was first reported in 2002, when 4-year follow-up found a 32% reduction in breast cancer risk associated with tamoxifen. But it also found a significant increase in deaths among that group (25 vs.11 in placebo), many of which were attributable to more endometrial cancer (11 vs. 5).

In 2007, the investigators published the trial’s 8-10 year findings. At that time, tamoxifen was associated with a 27% decreased risk of any breast cancer, and a 34% decreased risk of developing an ER-positive cancer. It found a consistent prophylactic benefit for tamoxifen; most of the risk reduction, however, occurred in the 5-year active treatment phase.

The significant increase in death had continued (25 vs. 11), although that report indicated that no specific cause, including endometrial cancer, drove that finding.

At the meeting, Dr. Cuzick discussed the latest findings of IBIS-1, which has now followed the cohort for up to 20 years (median, 16 years).

“We have seen a continued separation of the cancer incidence curves, with a 20-year incidence of 7.8% vs. 12.3%,” Dr. Cuzick said. “We saw that the 30% overall reduction was maintained; the number needed to treat to prevent one breast cancer was 22, which is very favorable when compared to prevention strategies for other diseases.”

The incidence of ER-positive tumors was reduced, compared with placebo, he added (4.9% vs. 8.3%), with a number needed to treat of 29. However, Dr. Cuzick said, there was a slight increase in the incidence of ER-negative tumors after 10 years.

“This is likely because these are tumors that would have appeared earlier as ER-positive tumors, but under tamoxifen, they were held back for some time and eventually broke out as ER-negative tumors.”

Hormone therapy was allowed in IBIS-1, and about 50% of women were taking hormones during at least part of the study. They did not experience the same level of benefit form tamoxifen as those who were not taking hormone therapy (12% vs. 38%). “This is very clear evidence that the benefits are substantially greater in those who are not using concurrent [hormone therapy] when on tamoxifen,” he said.

However, tamoxifen was associated with side effects and risks, including an increased risk of developing other cancers. Most concerning was the 45% increase in the risk of endometrial cancer, which accounted for five deaths in the treatment group; there were no deaths from endometrial cancer in the placebo group.

“We had hoped that endometrial cancer might not translate into such a large morality increase as there were no deaths due to this in the 8-year follow-up. We do need to be aware of this.”

Recurrent breast cancer was the single largest cause of death, but the between-group difference was not significant (26 vs. 31). Cardiovascular deaths were similar between the groups, and all that did occur, did so during the treatment period.

Nonmelanoma skin cancers were 39% more likely in the tamoxifen group, although they caused no deaths. “This was a very large increase and a surprise; we really don’t understand it,” Dr. Cuzick said.

There were 12 fewer colorectal cancers in the tamoxifen group. “That there was a slight reduction here is of some interest, as we did not see at all with placebo.”

The tamoxifen-associated risk of any other cancers was nonsignificant.

The IBIS-I trial was supported by Cancer Research UK. Dr. Cuzick has received funding for other trials from AstraZeneca and is a consultant for AstraZeneca. The company also provided both the study drug and placebo.

[email protected]

On Twitter @alz_gal

SAN ANTONIO – Five years of tamoxifen provided 20 years of breast cancer prevention to some at-risk women who took it prophylactically.

However, their 20-year all-cause mortality was no different from those taking placebo (182 vs. 166 deaths), nor was their mortality from breast cancer (31 vs. 26, respectively), Jack Cuzick, Ph.D., said at the San Antonio Breast Cancer Symposium.

“While we saw clear, lasting benefits of tamoxifen in reducing breast cancer incidence, uncertainty with respect to mortality remains,” said Dr. Cuzick, the John Snow professor of epidemiology at Wolfson Institute of Preventive Medicine at Queen Mary University, London.

He suggested that, in light of the small number of deaths, the study was not sufficiently powered to detect any significant survival difference. But women in the IBIS-1 trial will continue to be observed, and future analyses could clarify the issue, he added.

“Although 20 years seems like a long follow-up time, it is actually too early to make any clear statement about mortality,” he said. “However, we are concerned about an excess emergence of ER-negative tumors, which we saw after 10 years.”

The study was simultaneously published on Dec. 13 in Lancet Oncology

IBIS-1 randomized 7,154 healthy pre- and postmenopausal women to 5 years of either 20 mg daily tamoxifen or placebo. These women were aged 35-70 years at baseline and presented with an increased breast cancer risk attributable to a family history.

IBIS-1 was first reported in 2002, when 4-year follow-up found a 32% reduction in breast cancer risk associated with tamoxifen. But it also found a significant increase in deaths among that group (25 vs.11 in placebo), many of which were attributable to more endometrial cancer (11 vs. 5).

In 2007, the investigators published the trial’s 8-10 year findings. At that time, tamoxifen was associated with a 27% decreased risk of any breast cancer, and a 34% decreased risk of developing an ER-positive cancer. It found a consistent prophylactic benefit for tamoxifen; most of the risk reduction, however, occurred in the 5-year active treatment phase.

The significant increase in death had continued (25 vs. 11), although that report indicated that no specific cause, including endometrial cancer, drove that finding.

At the meeting, Dr. Cuzick discussed the latest findings of IBIS-1, which has now followed the cohort for up to 20 years (median, 16 years).

“We have seen a continued separation of the cancer incidence curves, with a 20-year incidence of 7.8% vs. 12.3%,” Dr. Cuzick said. “We saw that the 30% overall reduction was maintained; the number needed to treat to prevent one breast cancer was 22, which is very favorable when compared to prevention strategies for other diseases.”

The incidence of ER-positive tumors was reduced, compared with placebo, he added (4.9% vs. 8.3%), with a number needed to treat of 29. However, Dr. Cuzick said, there was a slight increase in the incidence of ER-negative tumors after 10 years.

“This is likely because these are tumors that would have appeared earlier as ER-positive tumors, but under tamoxifen, they were held back for some time and eventually broke out as ER-negative tumors.”

Hormone therapy was allowed in IBIS-1, and about 50% of women were taking hormones during at least part of the study. They did not experience the same level of benefit form tamoxifen as those who were not taking hormone therapy (12% vs. 38%). “This is very clear evidence that the benefits are substantially greater in those who are not using concurrent [hormone therapy] when on tamoxifen,” he said.

However, tamoxifen was associated with side effects and risks, including an increased risk of developing other cancers. Most concerning was the 45% increase in the risk of endometrial cancer, which accounted for five deaths in the treatment group; there were no deaths from endometrial cancer in the placebo group.

“We had hoped that endometrial cancer might not translate into such a large morality increase as there were no deaths due to this in the 8-year follow-up. We do need to be aware of this.”

Recurrent breast cancer was the single largest cause of death, but the between-group difference was not significant (26 vs. 31). Cardiovascular deaths were similar between the groups, and all that did occur, did so during the treatment period.

Nonmelanoma skin cancers were 39% more likely in the tamoxifen group, although they caused no deaths. “This was a very large increase and a surprise; we really don’t understand it,” Dr. Cuzick said.

There were 12 fewer colorectal cancers in the tamoxifen group. “That there was a slight reduction here is of some interest, as we did not see at all with placebo.”

The tamoxifen-associated risk of any other cancers was nonsignificant.

The IBIS-I trial was supported by Cancer Research UK. Dr. Cuzick has received funding for other trials from AstraZeneca and is a consultant for AstraZeneca. The company also provided both the study drug and placebo.

[email protected]

On Twitter @alz_gal

SAN ANTONIO – Five years of tamoxifen provided 20 years of breast cancer prevention to some at-risk women who took it prophylactically.

However, their 20-year all-cause mortality was no different from those taking placebo (182 vs. 166 deaths), nor was their mortality from breast cancer (31 vs. 26, respectively), Jack Cuzick, Ph.D., said at the San Antonio Breast Cancer Symposium.

“While we saw clear, lasting benefits of tamoxifen in reducing breast cancer incidence, uncertainty with respect to mortality remains,” said Dr. Cuzick, the John Snow professor of epidemiology at Wolfson Institute of Preventive Medicine at Queen Mary University, London.

He suggested that, in light of the small number of deaths, the study was not sufficiently powered to detect any significant survival difference. But women in the IBIS-1 trial will continue to be observed, and future analyses could clarify the issue, he added.

“Although 20 years seems like a long follow-up time, it is actually too early to make any clear statement about mortality,” he said. “However, we are concerned about an excess emergence of ER-negative tumors, which we saw after 10 years.”

The study was simultaneously published on Dec. 13 in Lancet Oncology

IBIS-1 randomized 7,154 healthy pre- and postmenopausal women to 5 years of either 20 mg daily tamoxifen or placebo. These women were aged 35-70 years at baseline and presented with an increased breast cancer risk attributable to a family history.

IBIS-1 was first reported in 2002, when 4-year follow-up found a 32% reduction in breast cancer risk associated with tamoxifen. But it also found a significant increase in deaths among that group (25 vs.11 in placebo), many of which were attributable to more endometrial cancer (11 vs. 5).

In 2007, the investigators published the trial’s 8-10 year findings. At that time, tamoxifen was associated with a 27% decreased risk of any breast cancer, and a 34% decreased risk of developing an ER-positive cancer. It found a consistent prophylactic benefit for tamoxifen; most of the risk reduction, however, occurred in the 5-year active treatment phase.

The significant increase in death had continued (25 vs. 11), although that report indicated that no specific cause, including endometrial cancer, drove that finding.

At the meeting, Dr. Cuzick discussed the latest findings of IBIS-1, which has now followed the cohort for up to 20 years (median, 16 years).

“We have seen a continued separation of the cancer incidence curves, with a 20-year incidence of 7.8% vs. 12.3%,” Dr. Cuzick said. “We saw that the 30% overall reduction was maintained; the number needed to treat to prevent one breast cancer was 22, which is very favorable when compared to prevention strategies for other diseases.”

The incidence of ER-positive tumors was reduced, compared with placebo, he added (4.9% vs. 8.3%), with a number needed to treat of 29. However, Dr. Cuzick said, there was a slight increase in the incidence of ER-negative tumors after 10 years.

“This is likely because these are tumors that would have appeared earlier as ER-positive tumors, but under tamoxifen, they were held back for some time and eventually broke out as ER-negative tumors.”

Hormone therapy was allowed in IBIS-1, and about 50% of women were taking hormones during at least part of the study. They did not experience the same level of benefit form tamoxifen as those who were not taking hormone therapy (12% vs. 38%). “This is very clear evidence that the benefits are substantially greater in those who are not using concurrent [hormone therapy] when on tamoxifen,” he said.

However, tamoxifen was associated with side effects and risks, including an increased risk of developing other cancers. Most concerning was the 45% increase in the risk of endometrial cancer, which accounted for five deaths in the treatment group; there were no deaths from endometrial cancer in the placebo group.

“We had hoped that endometrial cancer might not translate into such a large morality increase as there were no deaths due to this in the 8-year follow-up. We do need to be aware of this.”

Recurrent breast cancer was the single largest cause of death, but the between-group difference was not significant (26 vs. 31). Cardiovascular deaths were similar between the groups, and all that did occur, did so during the treatment period.

Nonmelanoma skin cancers were 39% more likely in the tamoxifen group, although they caused no deaths. “This was a very large increase and a surprise; we really don’t understand it,” Dr. Cuzick said.

There were 12 fewer colorectal cancers in the tamoxifen group. “That there was a slight reduction here is of some interest, as we did not see at all with placebo.”

The tamoxifen-associated risk of any other cancers was nonsignificant.

The IBIS-I trial was supported by Cancer Research UK. Dr. Cuzick has received funding for other trials from AstraZeneca and is a consultant for AstraZeneca. The company also provided both the study drug and placebo.

[email protected]

On Twitter @alz_gal

SAN ANTONIO – The combination of capecitabine plus the bisphosphonate ibandronate didn’t improve disease-free survival in elderly women with moderate- or high-risk breast cancers.

After 5 years, there was an absolute – but nonsignificant – difference of 3.8% in favor of the combination treatment, Dr. Gunter von Minckwitz said at the San Antonio Breast Cancer Symposium. “But thereafter, the survival curves crossed and there was no statistically significant difference between the groups.”

But the results of the 5-year Ibandronate with or without Capecitabine for Elderly Patients with Early Breast Cancer (ICE) trial do suggest that women older than 65 years can tolerate a complete chemotherapy regimen quite well, and shouldn’t be denied the chance to receive such treatment, Dr. von Minckwitz, chair of the German Breast Group , said during his presentation.

Michele G. Sullivan/Frontline Medical News

“We still see a large fraction of elderly patients who are not getting appropriate treatment. These women were about 71 years old at the beginning of this study, and after 5 years, 90% are still surviving. This shows us that the life expectancy of these patients is long. This is important information when treatment decisions are being made in these patients, who have perhaps not been considered fit enough to receive adjuvant chemotherapy, including endocrine treatment,” he said.

Investigators randomized 1,358 women aged 65 years or older to either ibandronate alone or ibandronate plus capecitabine. In each arm, patients and their physicians could decide on the ibandronate delivery mode – either 50 mg daily or 6 mg intravenously, delivered every 4 weeks. Capecitabine was delivered in six cycles of 2,000 mg/m² daily on days 1 and 4, followed by thrice weekly for six cycles in conjunction with the preferred ibandronate schedule. Both treatments continued for 2 years.

The patients were a mean of 71 years, with 25% being at least 75 years. About 10% had a Charlson comorbidity score of at least 2. About 20% of the tumors were HER2-positive, and 15%, triple negative. Most (80%) were hormone-receptor positive. About 3/4 of the cohort had only been treated with an aromatase inhibitor.

At 3 years, there was no difference in disease-free survival, with an 85% rate in the combination group and 84% in the ibandronate-only group. At 5 years, disease-free survival was 79% and 75%, respectively. Nor was there any difference in overall survival at 3 years; in fact, survival was quite good, Dr. von Minckwitz said, with 95% still alive in the combination group and 94% in the ibandronate-only group. At 5 years, patients continued to do very well, with an overall survival of 90% in the combination group and 88% in the ibandronate-only group.

There were no significant between-group differences in any subgroup analyzed, including separation by age; pN status; hormone-receptor status; hemoglobin, albumin, and creatinine clearance; comorbidity status; or body mass index.

Adverse events of grades 3 or 4 were significantly more common in the combination group (31% vs. 9%). Two individual events drove that finding – gastrointestinal problems (6.7% vs. 1%), and skin disorders, especially hand-foot syndrome (14.6% vs. 0.6%).

Other adverse events more common in the combination group included blood and lymphatic disorders (1.2% vs 0.7%); neuropathy and dizziness (2.5% vs. 0.7%) arrhythmias and cardiac ischemia (1.8% vs. 0.4%); and thromboembolic events (2.8% vs.1.3%).

Ibandronate completion was virtually identical – about 76% in each group. Most patients in the combination group (83%) also completed the treatment.

A quarter of patients in each group experienced a bone-related adverse event, excluding metastasis. These included fractures, surgery, and new osteoporosis. Because these were so frequent, Dr. von Minckwitz suggested that bisphosphonates should be part of any treatment regimen for this population.

The ICE survival curves are so good, Dr. Minckwitz said, that they raise a bit of a question, which only time can answer. “Due to the excellent survival data, we need longer follow-up to observe any potential late effect of capecitabine.”

He had no relevant financial disclosures. The German Breast Group has no financial ties with any pharmaceutical company.

[email protected]

On Twitter @alz_gal

SAN ANTONIO – The combination of capecitabine plus the bisphosphonate ibandronate didn’t improve disease-free survival in elderly women with moderate- or high-risk breast cancers.

After 5 years, there was an absolute – but nonsignificant – difference of 3.8% in favor of the combination treatment, Dr. Gunter von Minckwitz said at the San Antonio Breast Cancer Symposium. “But thereafter, the survival curves crossed and there was no statistically significant difference between the groups.”

But the results of the 5-year Ibandronate with or without Capecitabine for Elderly Patients with Early Breast Cancer (ICE) trial do suggest that women older than 65 years can tolerate a complete chemotherapy regimen quite well, and shouldn’t be denied the chance to receive such treatment, Dr. von Minckwitz, chair of the German Breast Group , said during his presentation.

Michele G. Sullivan/Frontline Medical News

“We still see a large fraction of elderly patients who are not getting appropriate treatment. These women were about 71 years old at the beginning of this study, and after 5 years, 90% are still surviving. This shows us that the life expectancy of these patients is long. This is important information when treatment decisions are being made in these patients, who have perhaps not been considered fit enough to receive adjuvant chemotherapy, including endocrine treatment,” he said.

Investigators randomized 1,358 women aged 65 years or older to either ibandronate alone or ibandronate plus capecitabine. In each arm, patients and their physicians could decide on the ibandronate delivery mode – either 50 mg daily or 6 mg intravenously, delivered every 4 weeks. Capecitabine was delivered in six cycles of 2,000 mg/m² daily on days 1 and 4, followed by thrice weekly for six cycles in conjunction with the preferred ibandronate schedule. Both treatments continued for 2 years.

The patients were a mean of 71 years, with 25% being at least 75 years. About 10% had a Charlson comorbidity score of at least 2. About 20% of the tumors were HER2-positive, and 15%, triple negative. Most (80%) were hormone-receptor positive. About 3/4 of the cohort had only been treated with an aromatase inhibitor.

At 3 years, there was no difference in disease-free survival, with an 85% rate in the combination group and 84% in the ibandronate-only group. At 5 years, disease-free survival was 79% and 75%, respectively. Nor was there any difference in overall survival at 3 years; in fact, survival was quite good, Dr. von Minckwitz said, with 95% still alive in the combination group and 94% in the ibandronate-only group. At 5 years, patients continued to do very well, with an overall survival of 90% in the combination group and 88% in the ibandronate-only group.

There were no significant between-group differences in any subgroup analyzed, including separation by age; pN status; hormone-receptor status; hemoglobin, albumin, and creatinine clearance; comorbidity status; or body mass index.

Adverse events of grades 3 or 4 were significantly more common in the combination group (31% vs. 9%). Two individual events drove that finding – gastrointestinal problems (6.7% vs. 1%), and skin disorders, especially hand-foot syndrome (14.6% vs. 0.6%).

Other adverse events more common in the combination group included blood and lymphatic disorders (1.2% vs 0.7%); neuropathy and dizziness (2.5% vs. 0.7%) arrhythmias and cardiac ischemia (1.8% vs. 0.4%); and thromboembolic events (2.8% vs.1.3%).

Ibandronate completion was virtually identical – about 76% in each group. Most patients in the combination group (83%) also completed the treatment.

A quarter of patients in each group experienced a bone-related adverse event, excluding metastasis. These included fractures, surgery, and new osteoporosis. Because these were so frequent, Dr. von Minckwitz suggested that bisphosphonates should be part of any treatment regimen for this population.

The ICE survival curves are so good, Dr. Minckwitz said, that they raise a bit of a question, which only time can answer. “Due to the excellent survival data, we need longer follow-up to observe any potential late effect of capecitabine.”

He had no relevant financial disclosures. The German Breast Group has no financial ties with any pharmaceutical company.

[email protected]

On Twitter @alz_gal

SAN ANTONIO – The combination of capecitabine plus the bisphosphonate ibandronate didn’t improve disease-free survival in elderly women with moderate- or high-risk breast cancers.

After 5 years, there was an absolute – but nonsignificant – difference of 3.8% in favor of the combination treatment, Dr. Gunter von Minckwitz said at the San Antonio Breast Cancer Symposium. “But thereafter, the survival curves crossed and there was no statistically significant difference between the groups.”

But the results of the 5-year Ibandronate with or without Capecitabine for Elderly Patients with Early Breast Cancer (ICE) trial do suggest that women older than 65 years can tolerate a complete chemotherapy regimen quite well, and shouldn’t be denied the chance to receive such treatment, Dr. von Minckwitz, chair of the German Breast Group , said during his presentation.

Michele G. Sullivan/Frontline Medical News

“We still see a large fraction of elderly patients who are not getting appropriate treatment. These women were about 71 years old at the beginning of this study, and after 5 years, 90% are still surviving. This shows us that the life expectancy of these patients is long. This is important information when treatment decisions are being made in these patients, who have perhaps not been considered fit enough to receive adjuvant chemotherapy, including endocrine treatment,” he said.

Investigators randomized 1,358 women aged 65 years or older to either ibandronate alone or ibandronate plus capecitabine. In each arm, patients and their physicians could decide on the ibandronate delivery mode – either 50 mg daily or 6 mg intravenously, delivered every 4 weeks. Capecitabine was delivered in six cycles of 2,000 mg/m² daily on days 1 and 4, followed by thrice weekly for six cycles in conjunction with the preferred ibandronate schedule. Both treatments continued for 2 years.

The patients were a mean of 71 years, with 25% being at least 75 years. About 10% had a Charlson comorbidity score of at least 2. About 20% of the tumors were HER2-positive, and 15%, triple negative. Most (80%) were hormone-receptor positive. About 3/4 of the cohort had only been treated with an aromatase inhibitor.

At 3 years, there was no difference in disease-free survival, with an 85% rate in the combination group and 84% in the ibandronate-only group. At 5 years, disease-free survival was 79% and 75%, respectively. Nor was there any difference in overall survival at 3 years; in fact, survival was quite good, Dr. von Minckwitz said, with 95% still alive in the combination group and 94% in the ibandronate-only group. At 5 years, patients continued to do very well, with an overall survival of 90% in the combination group and 88% in the ibandronate-only group.

There were no significant between-group differences in any subgroup analyzed, including separation by age; pN status; hormone-receptor status; hemoglobin, albumin, and creatinine clearance; comorbidity status; or body mass index.

Adverse events of grades 3 or 4 were significantly more common in the combination group (31% vs. 9%). Two individual events drove that finding – gastrointestinal problems (6.7% vs. 1%), and skin disorders, especially hand-foot syndrome (14.6% vs. 0.6%).

Other adverse events more common in the combination group included blood and lymphatic disorders (1.2% vs 0.7%); neuropathy and dizziness (2.5% vs. 0.7%) arrhythmias and cardiac ischemia (1.8% vs. 0.4%); and thromboembolic events (2.8% vs.1.3%).

Ibandronate completion was virtually identical – about 76% in each group. Most patients in the combination group (83%) also completed the treatment.

A quarter of patients in each group experienced a bone-related adverse event, excluding metastasis. These included fractures, surgery, and new osteoporosis. Because these were so frequent, Dr. von Minckwitz suggested that bisphosphonates should be part of any treatment regimen for this population.

The ICE survival curves are so good, Dr. Minckwitz said, that they raise a bit of a question, which only time can answer. “Due to the excellent survival data, we need longer follow-up to observe any potential late effect of capecitabine.”

He had no relevant financial disclosures. The German Breast Group has no financial ties with any pharmaceutical company.

[email protected]

On Twitter @alz_gal

SAN ANTONIO – In the FERGI trial, the combination of pictilisib and fulvestrant nearly doubled progression-free survival in a subset of patients with ER+/PR+ breast cancer, increasing the duration of response by almost 3 months, Dr. Eric Winer said at the San Antonio Breast Cancer Symposium.

But in the entire study cohort, the combination conferred no advantage over fulvestrant alone, with less than a 2-month survival advantage going to the combination therapy arm, said Dr. Winer of the Dana-Farber Cancer Institute, Boston.

The findings raise the question of whether pictilisib, a general inhibitor of the PI3 kinase pathway, confers any meaningful clinical results, especially in light of the excess of associated adverse events (31% with combined therapy vs. 20% with fulvestrant alone), according to Dr. Jennifer Litton of the University of Texas MD Anderson Cancer Center, Houston.

In this video interview, she shared her views on the study results, the drug’s mechanism, and its possible future – especially in light of the more effective and more selective PI3k inhibitors that are now in early clinical trials.

[email protected]

SAN ANTONIO – In the FERGI trial, the combination of pictilisib and fulvestrant nearly doubled progression-free survival in a subset of patients with ER+/PR+ breast cancer, increasing the duration of response by almost 3 months, Dr. Eric Winer said at the San Antonio Breast Cancer Symposium.

But in the entire study cohort, the combination conferred no advantage over fulvestrant alone, with less than a 2-month survival advantage going to the combination therapy arm, said Dr. Winer of the Dana-Farber Cancer Institute, Boston.

The findings raise the question of whether pictilisib, a general inhibitor of the PI3 kinase pathway, confers any meaningful clinical results, especially in light of the excess of associated adverse events (31% with combined therapy vs. 20% with fulvestrant alone), according to Dr. Jennifer Litton of the University of Texas MD Anderson Cancer Center, Houston.

In this video interview, she shared her views on the study results, the drug’s mechanism, and its possible future – especially in light of the more effective and more selective PI3k inhibitors that are now in early clinical trials.

[email protected]

SAN ANTONIO – In the FERGI trial, the combination of pictilisib and fulvestrant nearly doubled progression-free survival in a subset of patients with ER+/PR+ breast cancer, increasing the duration of response by almost 3 months, Dr. Eric Winer said at the San Antonio Breast Cancer Symposium.

But in the entire study cohort, the combination conferred no advantage over fulvestrant alone, with less than a 2-month survival advantage going to the combination therapy arm, said Dr. Winer of the Dana-Farber Cancer Institute, Boston.

The findings raise the question of whether pictilisib, a general inhibitor of the PI3 kinase pathway, confers any meaningful clinical results, especially in light of the excess of associated adverse events (31% with combined therapy vs. 20% with fulvestrant alone), according to Dr. Jennifer Litton of the University of Texas MD Anderson Cancer Center, Houston.

In this video interview, she shared her views on the study results, the drug’s mechanism, and its possible future – especially in light of the more effective and more selective PI3k inhibitors that are now in early clinical trials.

[email protected]

SAN ANTONIO – The combination of pictilisib and fulvestrant improved progression-free survival in some women with advanced hormone receptor–positive breast cancer – but the jury is out on whether that benefit is clinically meaningful.

At 17 months, women taking the dual regimen were 26% less likely to experience disease progression, but that progression-free survival difference amounted to only about 2 months, Dr. Eric Winer said at the San Antonio Breast Cancer Symposium.

Results were slightly better in those with both progesterone and estrogen receptor–positive tumors, and in the small subgroup of patients with a confirmed PIK3CA mutation tumor, Dr. Winer, a coinvestigator on the study, said during a press briefing.

“There was enough action here that there is interest in pursuing research on this [investigational] drug,” said Dr. Winer of the Dana Farber Cancer Institute, Boston. “Whether or not this is the right drug remains to be seen. ... We will see if there is a stronger signal in the ongoing phase III trial.”

Pictilisib is a PI3 kinase inhibitor, under development by Genentech. PI3 kinase is an oncogene commonly mutated in cancer. The PI3k/Akt/mTOR pathway regulates cell growth and survival. However, pictilisib is a nonselective pan-inhibitor of this pathway, so concern remains about side effects involving normal PI3k processes.

The FERGI study randomized 168 women (89 in the combination arm) with estrogen receptor–positive and/or progesterone receptor–positive tumors to either fulvestrant 500 mg plus placebo or fulvestrant 500 mg plus pictilisib 340 mg. All patients had failed prior treatment with an aromatase inhibitor, relapsing within 6 months of beginning or completing AI treatment, or by having disease progression while on AI treatment. They were stratified by both hormone receptor and PIK3CA tumor status. The study’s primary endpoint was progression-free survival duration in the entire group, and within both subgroups.

Fulvestrant was administered on day 1 of each 28-day cycle and pictilisib or placebo every day. Tumor assessments were performed every 8 weeks of the 24-week trial.

At a mean follow-up of 17 months, 120 patients had progressed – 59 in the combination group and 61 in the placebo group – a nonsignificant difference (P = .096). Time to progression was 6.6 months in the combination arm vs. 5.1 months in the placebo arm.

Combination therapy conferred a significant advantage, however, upon women whose tumors were both ER+ and PR+. Among this group of 116, there were 57 progression events. The median time to progression was significantly longer in the combination arm than in the placebo arm (7.4 months vs. 3.7 months), representing a 56% risk reduction (P = .002).

The combination conferred no survival benefit on women whose tumors were positive for the PIK3CA mutation. “This was a surprise because the PIK3CA gene is a central component of the PI3k signaling pathway. It may be that PIK3CA mutation is not the only way to activate PI3k signaling,” Dr. Winer said.

Adverse events were significantly more common among those taking combination therapy. (31% vs. 20%).

Among these were diarrhea (63% vs. 9%); nausea (48% vs. 19%); rash (43% vs. 6%); fatigue (27% vs. 20%); vomiting (20% vs. 4%); decreased appetite (19% vs. 6%); and hyperglycemia (17% vs. 5%). Dysgeusia occurred in 35% of those in the combination arm and in none of those in the placebo arm. There appeared to be no drug-drug interaction between fulvestrant and pictilisib; there were no treatment-related deaths.

“The bottom line is we had hoped for a somewhat more active improvement seen in progression-free survival, but the exploratory subgroup [of ER+ PR+ tumors] is worth looking into further,” Dr. Winer said.

In an interview, moderator Dr. Jennifer Litton of the University of Texas MD Anderson Cancer Center, Houston, questioned what the statistically significant progression-free survival differences would really mean clinically. By 21 months, the median overall survival difference had declined to 6.6 months vs. 5.1 months for the intention-to-treat group. “You have to wonder if it’s really worth it, considering the side effects.”

At any rate, Dr. Winer wondered aloud if pictilisib has much of a future. While Genentech continues to test the drug in phase III trials, several other PI3k inhibitors are in early studies. These look to be both more effective and more selectively targeted than pictilisib – a combination that would theoretically decrease side effects while improving survival.

“There are more data to be analyzed,” he said. “But I predict that in the wake of these newer drugs, pictilisib will not go forward after they are.”

The study was funded by Genentech. Dr. Winer had no financial disclosures. The principal investigator, Dr. Ian Krop of the Dana-Farber Cancer Institute, receives research funding from the company.

[email protected]

SAN ANTONIO – The combination of pictilisib and fulvestrant improved progression-free survival in some women with advanced hormone receptor–positive breast cancer – but the jury is out on whether that benefit is clinically meaningful.

At 17 months, women taking the dual regimen were 26% less likely to experience disease progression, but that progression-free survival difference amounted to only about 2 months, Dr. Eric Winer said at the San Antonio Breast Cancer Symposium.

Results were slightly better in those with both progesterone and estrogen receptor–positive tumors, and in the small subgroup of patients with a confirmed PIK3CA mutation tumor, Dr. Winer, a coinvestigator on the study, said during a press briefing.

“There was enough action here that there is interest in pursuing research on this [investigational] drug,” said Dr. Winer of the Dana Farber Cancer Institute, Boston. “Whether or not this is the right drug remains to be seen. ... We will see if there is a stronger signal in the ongoing phase III trial.”

Pictilisib is a PI3 kinase inhibitor, under development by Genentech. PI3 kinase is an oncogene commonly mutated in cancer. The PI3k/Akt/mTOR pathway regulates cell growth and survival. However, pictilisib is a nonselective pan-inhibitor of this pathway, so concern remains about side effects involving normal PI3k processes.

The FERGI study randomized 168 women (89 in the combination arm) with estrogen receptor–positive and/or progesterone receptor–positive tumors to either fulvestrant 500 mg plus placebo or fulvestrant 500 mg plus pictilisib 340 mg. All patients had failed prior treatment with an aromatase inhibitor, relapsing within 6 months of beginning or completing AI treatment, or by having disease progression while on AI treatment. They were stratified by both hormone receptor and PIK3CA tumor status. The study’s primary endpoint was progression-free survival duration in the entire group, and within both subgroups.

Fulvestrant was administered on day 1 of each 28-day cycle and pictilisib or placebo every day. Tumor assessments were performed every 8 weeks of the 24-week trial.

At a mean follow-up of 17 months, 120 patients had progressed – 59 in the combination group and 61 in the placebo group – a nonsignificant difference (P = .096). Time to progression was 6.6 months in the combination arm vs. 5.1 months in the placebo arm.

Combination therapy conferred a significant advantage, however, upon women whose tumors were both ER+ and PR+. Among this group of 116, there were 57 progression events. The median time to progression was significantly longer in the combination arm than in the placebo arm (7.4 months vs. 3.7 months), representing a 56% risk reduction (P = .002).

The combination conferred no survival benefit on women whose tumors were positive for the PIK3CA mutation. “This was a surprise because the PIK3CA gene is a central component of the PI3k signaling pathway. It may be that PIK3CA mutation is not the only way to activate PI3k signaling,” Dr. Winer said.

Adverse events were significantly more common among those taking combination therapy. (31% vs. 20%).

Among these were diarrhea (63% vs. 9%); nausea (48% vs. 19%); rash (43% vs. 6%); fatigue (27% vs. 20%); vomiting (20% vs. 4%); decreased appetite (19% vs. 6%); and hyperglycemia (17% vs. 5%). Dysgeusia occurred in 35% of those in the combination arm and in none of those in the placebo arm. There appeared to be no drug-drug interaction between fulvestrant and pictilisib; there were no treatment-related deaths.

“The bottom line is we had hoped for a somewhat more active improvement seen in progression-free survival, but the exploratory subgroup [of ER+ PR+ tumors] is worth looking into further,” Dr. Winer said.

In an interview, moderator Dr. Jennifer Litton of the University of Texas MD Anderson Cancer Center, Houston, questioned what the statistically significant progression-free survival differences would really mean clinically. By 21 months, the median overall survival difference had declined to 6.6 months vs. 5.1 months for the intention-to-treat group. “You have to wonder if it’s really worth it, considering the side effects.”

At any rate, Dr. Winer wondered aloud if pictilisib has much of a future. While Genentech continues to test the drug in phase III trials, several other PI3k inhibitors are in early studies. These look to be both more effective and more selectively targeted than pictilisib – a combination that would theoretically decrease side effects while improving survival.

“There are more data to be analyzed,” he said. “But I predict that in the wake of these newer drugs, pictilisib will not go forward after they are.”

The study was funded by Genentech. Dr. Winer had no financial disclosures. The principal investigator, Dr. Ian Krop of the Dana-Farber Cancer Institute, receives research funding from the company.

[email protected]

SAN ANTONIO – The combination of pictilisib and fulvestrant improved progression-free survival in some women with advanced hormone receptor–positive breast cancer – but the jury is out on whether that benefit is clinically meaningful.

At 17 months, women taking the dual regimen were 26% less likely to experience disease progression, but that progression-free survival difference amounted to only about 2 months, Dr. Eric Winer said at the San Antonio Breast Cancer Symposium.

Results were slightly better in those with both progesterone and estrogen receptor–positive tumors, and in the small subgroup of patients with a confirmed PIK3CA mutation tumor, Dr. Winer, a coinvestigator on the study, said during a press briefing.

“There was enough action here that there is interest in pursuing research on this [investigational] drug,” said Dr. Winer of the Dana Farber Cancer Institute, Boston. “Whether or not this is the right drug remains to be seen. ... We will see if there is a stronger signal in the ongoing phase III trial.”

Pictilisib is a PI3 kinase inhibitor, under development by Genentech. PI3 kinase is an oncogene commonly mutated in cancer. The PI3k/Akt/mTOR pathway regulates cell growth and survival. However, pictilisib is a nonselective pan-inhibitor of this pathway, so concern remains about side effects involving normal PI3k processes.

The FERGI study randomized 168 women (89 in the combination arm) with estrogen receptor–positive and/or progesterone receptor–positive tumors to either fulvestrant 500 mg plus placebo or fulvestrant 500 mg plus pictilisib 340 mg. All patients had failed prior treatment with an aromatase inhibitor, relapsing within 6 months of beginning or completing AI treatment, or by having disease progression while on AI treatment. They were stratified by both hormone receptor and PIK3CA tumor status. The study’s primary endpoint was progression-free survival duration in the entire group, and within both subgroups.

Fulvestrant was administered on day 1 of each 28-day cycle and pictilisib or placebo every day. Tumor assessments were performed every 8 weeks of the 24-week trial.

At a mean follow-up of 17 months, 120 patients had progressed – 59 in the combination group and 61 in the placebo group – a nonsignificant difference (P = .096). Time to progression was 6.6 months in the combination arm vs. 5.1 months in the placebo arm.

Combination therapy conferred a significant advantage, however, upon women whose tumors were both ER+ and PR+. Among this group of 116, there were 57 progression events. The median time to progression was significantly longer in the combination arm than in the placebo arm (7.4 months vs. 3.7 months), representing a 56% risk reduction (P = .002).

The combination conferred no survival benefit on women whose tumors were positive for the PIK3CA mutation. “This was a surprise because the PIK3CA gene is a central component of the PI3k signaling pathway. It may be that PIK3CA mutation is not the only way to activate PI3k signaling,” Dr. Winer said.

Adverse events were significantly more common among those taking combination therapy. (31% vs. 20%).

Among these were diarrhea (63% vs. 9%); nausea (48% vs. 19%); rash (43% vs. 6%); fatigue (27% vs. 20%); vomiting (20% vs. 4%); decreased appetite (19% vs. 6%); and hyperglycemia (17% vs. 5%). Dysgeusia occurred in 35% of those in the combination arm and in none of those in the placebo arm. There appeared to be no drug-drug interaction between fulvestrant and pictilisib; there were no treatment-related deaths.

“The bottom line is we had hoped for a somewhat more active improvement seen in progression-free survival, but the exploratory subgroup [of ER+ PR+ tumors] is worth looking into further,” Dr. Winer said.

In an interview, moderator Dr. Jennifer Litton of the University of Texas MD Anderson Cancer Center, Houston, questioned what the statistically significant progression-free survival differences would really mean clinically. By 21 months, the median overall survival difference had declined to 6.6 months vs. 5.1 months for the intention-to-treat group. “You have to wonder if it’s really worth it, considering the side effects.”

At any rate, Dr. Winer wondered aloud if pictilisib has much of a future. While Genentech continues to test the drug in phase III trials, several other PI3k inhibitors are in early studies. These look to be both more effective and more selectively targeted than pictilisib – a combination that would theoretically decrease side effects while improving survival.

“There are more data to be analyzed,” he said. “But I predict that in the wake of these newer drugs, pictilisib will not go forward after they are.”

The study was funded by Genentech. Dr. Winer had no financial disclosures. The principal investigator, Dr. Ian Krop of the Dana-Farber Cancer Institute, receives research funding from the company.

[email protected]

PHILADELPHIA – A combination drug of dextromethorphan and quinidine significantly reduced aggression and agitation in patients with Alzheimer’s disease.

Associated with those improvements were significant reductions in measures of caregiver strain and distress, Dr. Erik Pioro said at the Clinical Trials Conference on Alzheimer’s Disease.

“These were very clear, stable, and statistically and clinically meaningful differences,” when compared with patients who received placebo, said Dr. Pioro, director of the Section of Amyotrophic Lateral Sclerosis and Related Disorders at the Cleveland Clinic.

The drug, Nuedexta, is already approved for pseudobulbar affect and is being investigated as AVP-923 for several other indications, including depression, migraine, neuropathic pain, autism, and Parkinson’s disease dyskinesia.

This phase II trial comprised 220 patients with moderate Alzheimer’s who displayed clinically significant agitation or aggression as measured by the Neuropsychiatric Inventory (NPI) and the Clinical Global Impressions Scale.

Most (87%) were living at home, about 5% were in nursing homes, and the remainder were in assisted living facilities. At baseline, 74% were taking cholinesterase inhibitors; 50%, memantine; 56%, an antidepressant (including trazodone); 21%, an antipsychotic; and 8%, a benzodiazepine.

As measured by scores on the NPI, 92% displayed clinically significant aggression; 70%, irritability/lability; 52%, apathy/indifference; and 47%, anxiety and aberrant motor behaviors. About a third of the group had nighttime behavioral disorders, depression, dysphoria, delusions, disinhibition, elation, and hallucinations.

“These symptoms had to be severe enough that their physician would normally consider pharmacological treatment for them even if they were not enrolled in this trial,” Dr. Pioro said.

They were randomized to dextromethorphan hydrobromide and quinidine sulfate (20 mg/10 mg) or placebo for 10 weeks. Patients in the active group stayed on the study drug for the entire time. Those in the placebo group were assessed for response; 30 of these had improved on placebo. These were rerandomized to active and placebo groups. Placebo nonresponders were also rerandomized to the drug or placebo.

This allowed not only for a comparison of groups who had taken the drug or placebo for the full study, but also for the investigators to accurately tease out any placebo effects.

Continued on next page >>

By the end of the first 5-week phase, patients in the active group experienced a mean improvement of 3.3 points on the NPI aggression subscale, which was significantly better than the 1.7-point improvement seen among those taking placebo.

After the placebo nonresponders had been rerandomized and treated for another 5 weeks, those taking the study drug had a mean 2-point improvement, compared with a 0.8-point improvement among those taking placebo.

In the group that been on their originally assigned treatment for the entire 10 weeks, those taking the study drug again fared significantly better (a mean improvement of about 4.5 points vs. 1.5 points with placebo).

In all randomization schemes, the clinical and physicians’ global impression improved significantly more in the active group than in the placebo group.

The total NPI score improved significantly more in the active group (13.5 vs. 8.5 points for those who had been on the same treatments for 10 weeks). NPI symptom clusters showed the same pattern of improvement favoring the study drug.

Measurements of caregiver response based on the Caregivers Strain Index and the NPI Caregiver Distress Score both significantly improved more for caregivers of patients taking the study drug for 10 weeks, compared to those taking placebo.

Treatment-emergent adverse events were significantly more common among the patients who took the study drug (61% vs. 43%). The most common were falls (9% vs. 4%), diarrhea (6% vs. 3%), urinary tract infection (5% vs. 4%), and dizziness (5% vs. 2.5%). These caused 5% of patients taking the drug and 3% taking placebo to discontinue treatment.

Dr. Pioro is a consultant for Avanir, which manufactures Nuedexta.

PHILADELPHIA – A combination drug of dextromethorphan and quinidine significantly reduced aggression and agitation in patients with Alzheimer’s disease.

Associated with those improvements were significant reductions in measures of caregiver strain and distress, Dr. Erik Pioro said at the Clinical Trials Conference on Alzheimer’s Disease.

“These were very clear, stable, and statistically and clinically meaningful differences,” when compared with patients who received placebo, said Dr. Pioro, director of the Section of Amyotrophic Lateral Sclerosis and Related Disorders at the Cleveland Clinic.

The drug, Nuedexta, is already approved for pseudobulbar affect and is being investigated as AVP-923 for several other indications, including depression, migraine, neuropathic pain, autism, and Parkinson’s disease dyskinesia.

This phase II trial comprised 220 patients with moderate Alzheimer’s who displayed clinically significant agitation or aggression as measured by the Neuropsychiatric Inventory (NPI) and the Clinical Global Impressions Scale.

Most (87%) were living at home, about 5% were in nursing homes, and the remainder were in assisted living facilities. At baseline, 74% were taking cholinesterase inhibitors; 50%, memantine; 56%, an antidepressant (including trazodone); 21%, an antipsychotic; and 8%, a benzodiazepine.

As measured by scores on the NPI, 92% displayed clinically significant aggression; 70%, irritability/lability; 52%, apathy/indifference; and 47%, anxiety and aberrant motor behaviors. About a third of the group had nighttime behavioral disorders, depression, dysphoria, delusions, disinhibition, elation, and hallucinations.

“These symptoms had to be severe enough that their physician would normally consider pharmacological treatment for them even if they were not enrolled in this trial,” Dr. Pioro said.

They were randomized to dextromethorphan hydrobromide and quinidine sulfate (20 mg/10 mg) or placebo for 10 weeks. Patients in the active group stayed on the study drug for the entire time. Those in the placebo group were assessed for response; 30 of these had improved on placebo. These were rerandomized to active and placebo groups. Placebo nonresponders were also rerandomized to the drug or placebo.

This allowed not only for a comparison of groups who had taken the drug or placebo for the full study, but also for the investigators to accurately tease out any placebo effects.

Continued on next page >>

By the end of the first 5-week phase, patients in the active group experienced a mean improvement of 3.3 points on the NPI aggression subscale, which was significantly better than the 1.7-point improvement seen among those taking placebo.

After the placebo nonresponders had been rerandomized and treated for another 5 weeks, those taking the study drug had a mean 2-point improvement, compared with a 0.8-point improvement among those taking placebo.

In the group that been on their originally assigned treatment for the entire 10 weeks, those taking the study drug again fared significantly better (a mean improvement of about 4.5 points vs. 1.5 points with placebo).

In all randomization schemes, the clinical and physicians’ global impression improved significantly more in the active group than in the placebo group.

The total NPI score improved significantly more in the active group (13.5 vs. 8.5 points for those who had been on the same treatments for 10 weeks). NPI symptom clusters showed the same pattern of improvement favoring the study drug.

Measurements of caregiver response based on the Caregivers Strain Index and the NPI Caregiver Distress Score both significantly improved more for caregivers of patients taking the study drug for 10 weeks, compared to those taking placebo.

Treatment-emergent adverse events were significantly more common among the patients who took the study drug (61% vs. 43%). The most common were falls (9% vs. 4%), diarrhea (6% vs. 3%), urinary tract infection (5% vs. 4%), and dizziness (5% vs. 2.5%). These caused 5% of patients taking the drug and 3% taking placebo to discontinue treatment.

Dr. Pioro is a consultant for Avanir, which manufactures Nuedexta.

PHILADELPHIA – A combination drug of dextromethorphan and quinidine significantly reduced aggression and agitation in patients with Alzheimer’s disease.

Associated with those improvements were significant reductions in measures of caregiver strain and distress, Dr. Erik Pioro said at the Clinical Trials Conference on Alzheimer’s Disease.

“These were very clear, stable, and statistically and clinically meaningful differences,” when compared with patients who received placebo, said Dr. Pioro, director of the Section of Amyotrophic Lateral Sclerosis and Related Disorders at the Cleveland Clinic.

The drug, Nuedexta, is already approved for pseudobulbar affect and is being investigated as AVP-923 for several other indications, including depression, migraine, neuropathic pain, autism, and Parkinson’s disease dyskinesia.

This phase II trial comprised 220 patients with moderate Alzheimer’s who displayed clinically significant agitation or aggression as measured by the Neuropsychiatric Inventory (NPI) and the Clinical Global Impressions Scale.

Most (87%) were living at home, about 5% were in nursing homes, and the remainder were in assisted living facilities. At baseline, 74% were taking cholinesterase inhibitors; 50%, memantine; 56%, an antidepressant (including trazodone); 21%, an antipsychotic; and 8%, a benzodiazepine.

As measured by scores on the NPI, 92% displayed clinically significant aggression; 70%, irritability/lability; 52%, apathy/indifference; and 47%, anxiety and aberrant motor behaviors. About a third of the group had nighttime behavioral disorders, depression, dysphoria, delusions, disinhibition, elation, and hallucinations.

“These symptoms had to be severe enough that their physician would normally consider pharmacological treatment for them even if they were not enrolled in this trial,” Dr. Pioro said.

They were randomized to dextromethorphan hydrobromide and quinidine sulfate (20 mg/10 mg) or placebo for 10 weeks. Patients in the active group stayed on the study drug for the entire time. Those in the placebo group were assessed for response; 30 of these had improved on placebo. These were rerandomized to active and placebo groups. Placebo nonresponders were also rerandomized to the drug or placebo.

This allowed not only for a comparison of groups who had taken the drug or placebo for the full study, but also for the investigators to accurately tease out any placebo effects.

Continued on next page >>

By the end of the first 5-week phase, patients in the active group experienced a mean improvement of 3.3 points on the NPI aggression subscale, which was significantly better than the 1.7-point improvement seen among those taking placebo.

After the placebo nonresponders had been rerandomized and treated for another 5 weeks, those taking the study drug had a mean 2-point improvement, compared with a 0.8-point improvement among those taking placebo.

In the group that been on their originally assigned treatment for the entire 10 weeks, those taking the study drug again fared significantly better (a mean improvement of about 4.5 points vs. 1.5 points with placebo).

In all randomization schemes, the clinical and physicians’ global impression improved significantly more in the active group than in the placebo group.

The total NPI score improved significantly more in the active group (13.5 vs. 8.5 points for those who had been on the same treatments for 10 weeks). NPI symptom clusters showed the same pattern of improvement favoring the study drug.

Measurements of caregiver response based on the Caregivers Strain Index and the NPI Caregiver Distress Score both significantly improved more for caregivers of patients taking the study drug for 10 weeks, compared to those taking placebo.

Treatment-emergent adverse events were significantly more common among the patients who took the study drug (61% vs. 43%). The most common were falls (9% vs. 4%), diarrhea (6% vs. 3%), urinary tract infection (5% vs. 4%), and dizziness (5% vs. 2.5%). These caused 5% of patients taking the drug and 3% taking placebo to discontinue treatment.

Dr. Pioro is a consultant for Avanir, which manufactures Nuedexta.

PHILADELPHIA – A combination drug of dextromethorphan and quinidine significantly reduced aggression and agitation in patients with Alzheimer’s disease.

Associated with those improvements were significant reductions in measures of caregiver strain and distress, Dr. Erik Pioro said at the Clinical Trials Conference on Alzheimer’s Disease.

“These were very clear, stable, and statistically and clinically meaningful differences,” when compared with patients who received placebo, said Dr. Pioro, director of the Section of Amyotrophic Lateral Sclerosis and Related Disorders at the Cleveland Clinic.

The drug, Nuedexta, is already approved for pseudobulbar affect and is being investigated as AVP-923 for several other indications, including depression, migraine, neuropathic pain, autism, and Parkinson’s disease dyskinesia.

This phase II trial comprised 220 patients with moderate Alzheimer’s who displayed clinically significant agitation or aggression as measured by the Neuropsychiatric Inventory (NPI) and the Clinical Global Impressions Scale.

Most (87%) were living at home, about 5% were in nursing homes, and the remainder were in assisted living facilities. At baseline, 74% were taking cholinesterase inhibitors; 50%, memantine; 56%, an antidepressant (including trazodone); 21%, an antipsychotic; and 8%, a benzodiazepine.

As measured by scores on the NPI, 92% displayed clinically significant aggression; 70%, irritability/lability; 52%, apathy/indifference; and 47%, anxiety and aberrant motor behaviors. About a third of the group had nighttime behavioral disorders, depression, dysphoria, delusions, disinhibition, elation, and hallucinations.

“These symptoms had to be severe enough that their physician would normally consider pharmacological treatment for them even if they were not enrolled in this trial,” Dr. Pioro said.

They were randomized to dextromethorphan hydrobromide and quinidine sulfate (20 mg/10 mg) or placebo for 10 weeks. Patients in the active group stayed on the study drug for the entire time. Those in the placebo group were assessed for response; 30 of these had improved on placebo. These were rerandomized to active and placebo groups. Placebo nonresponders were also rerandomized to the drug or placebo.

This allowed not only for a comparison of groups who had taken the drug or placebo for the full study, but also for the investigators to accurately tease out any placebo effects.

By the end of the first 5-week phase, patients in the active group experienced a mean improvement of 3.3 points on the NPI aggression subscale, which was significantly better than the 1.7-point improvement seen among those taking placebo.

After the placebo nonresponders had been rerandomized and treated for another 5 weeks, those taking the study drug had a mean 2-point improvement, compared with a 0.8-point improvement among those taking placebo.

In the group that been on their originally assigned treatment for the entire 10 weeks, those taking the study drug again fared significantly better (a mean improvement of about 4.5 points vs. 1.5 points with placebo).

In all randomization schemes, the clinical and physicians’ global impression improved significantly more in the active group than in the placebo group.

The total NPI score improved significantly more in the active group (13.5 vs. 8.5 points for those who had been on the same treatments for 10 weeks). NPI symptom clusters showed the same pattern of improvement favoring the study drug.

Measurements of caregiver response based on the Caregivers Strain Index and the NPI Caregiver Distress Score both significantly improved more for caregivers of patients taking the study drug for 10 weeks, compared to those taking placebo.

Treatment-emergent adverse events were significantly more common among the patients who took the study drug (61% vs. 43%). The most common were falls (9% vs. 4%), diarrhea (6% vs. 3%), urinary tract infection (5% vs. 4%), and dizziness (5% vs. 2.5%). These caused 5% of patients taking the drug and 3% taking placebo to discontinue treatment.

Dr. Pioro is a consultant for Avanir, which manufactures Nuedexta.

[email protected]

On Twitter @alz_gal

PHILADELPHIA – A combination drug of dextromethorphan and quinidine significantly reduced aggression and agitation in patients with Alzheimer’s disease.

Associated with those improvements were significant reductions in measures of caregiver strain and distress, Dr. Erik Pioro said at the Clinical Trials Conference on Alzheimer’s Disease.

“These were very clear, stable, and statistically and clinically meaningful differences,” when compared with patients who received placebo, said Dr. Pioro, director of the Section of Amyotrophic Lateral Sclerosis and Related Disorders at the Cleveland Clinic.

The drug, Nuedexta, is already approved for pseudobulbar affect and is being investigated as AVP-923 for several other indications, including depression, migraine, neuropathic pain, autism, and Parkinson’s disease dyskinesia.

This phase II trial comprised 220 patients with moderate Alzheimer’s who displayed clinically significant agitation or aggression as measured by the Neuropsychiatric Inventory (NPI) and the Clinical Global Impressions Scale.

Most (87%) were living at home, about 5% were in nursing homes, and the remainder were in assisted living facilities. At baseline, 74% were taking cholinesterase inhibitors; 50%, memantine; 56%, an antidepressant (including trazodone); 21%, an antipsychotic; and 8%, a benzodiazepine.

As measured by scores on the NPI, 92% displayed clinically significant aggression; 70%, irritability/lability; 52%, apathy/indifference; and 47%, anxiety and aberrant motor behaviors. About a third of the group had nighttime behavioral disorders, depression, dysphoria, delusions, disinhibition, elation, and hallucinations.

“These symptoms had to be severe enough that their physician would normally consider pharmacological treatment for them even if they were not enrolled in this trial,” Dr. Pioro said.

They were randomized to dextromethorphan hydrobromide and quinidine sulfate (20 mg/10 mg) or placebo for 10 weeks. Patients in the active group stayed on the study drug for the entire time. Those in the placebo group were assessed for response; 30 of these had improved on placebo. These were rerandomized to active and placebo groups. Placebo nonresponders were also rerandomized to the drug or placebo.

This allowed not only for a comparison of groups who had taken the drug or placebo for the full study, but also for the investigators to accurately tease out any placebo effects.

By the end of the first 5-week phase, patients in the active group experienced a mean improvement of 3.3 points on the NPI aggression subscale, which was significantly better than the 1.7-point improvement seen among those taking placebo.

After the placebo nonresponders had been rerandomized and treated for another 5 weeks, those taking the study drug had a mean 2-point improvement, compared with a 0.8-point improvement among those taking placebo.

In the group that been on their originally assigned treatment for the entire 10 weeks, those taking the study drug again fared significantly better (a mean improvement of about 4.5 points vs. 1.5 points with placebo).

In all randomization schemes, the clinical and physicians’ global impression improved significantly more in the active group than in the placebo group.

The total NPI score improved significantly more in the active group (13.5 vs. 8.5 points for those who had been on the same treatments for 10 weeks). NPI symptom clusters showed the same pattern of improvement favoring the study drug.

Measurements of caregiver response based on the Caregivers Strain Index and the NPI Caregiver Distress Score both significantly improved more for caregivers of patients taking the study drug for 10 weeks, compared to those taking placebo.

Treatment-emergent adverse events were significantly more common among the patients who took the study drug (61% vs. 43%). The most common were falls (9% vs. 4%), diarrhea (6% vs. 3%), urinary tract infection (5% vs. 4%), and dizziness (5% vs. 2.5%). These caused 5% of patients taking the drug and 3% taking placebo to discontinue treatment.

Dr. Pioro is a consultant for Avanir, which manufactures Nuedexta.

[email protected]

On Twitter @alz_gal

PHILADELPHIA – A combination drug of dextromethorphan and quinidine significantly reduced aggression and agitation in patients with Alzheimer’s disease.

Associated with those improvements were significant reductions in measures of caregiver strain and distress, Dr. Erik Pioro said at the Clinical Trials Conference on Alzheimer’s Disease.

“These were very clear, stable, and statistically and clinically meaningful differences,” when compared with patients who received placebo, said Dr. Pioro, director of the Section of Amyotrophic Lateral Sclerosis and Related Disorders at the Cleveland Clinic.

The drug, Nuedexta, is already approved for pseudobulbar affect and is being investigated as AVP-923 for several other indications, including depression, migraine, neuropathic pain, autism, and Parkinson’s disease dyskinesia.

This phase II trial comprised 220 patients with moderate Alzheimer’s who displayed clinically significant agitation or aggression as measured by the Neuropsychiatric Inventory (NPI) and the Clinical Global Impressions Scale.

Most (87%) were living at home, about 5% were in nursing homes, and the remainder were in assisted living facilities. At baseline, 74% were taking cholinesterase inhibitors; 50%, memantine; 56%, an antidepressant (including trazodone); 21%, an antipsychotic; and 8%, a benzodiazepine.

As measured by scores on the NPI, 92% displayed clinically significant aggression; 70%, irritability/lability; 52%, apathy/indifference; and 47%, anxiety and aberrant motor behaviors. About a third of the group had nighttime behavioral disorders, depression, dysphoria, delusions, disinhibition, elation, and hallucinations.

“These symptoms had to be severe enough that their physician would normally consider pharmacological treatment for them even if they were not enrolled in this trial,” Dr. Pioro said.

They were randomized to dextromethorphan hydrobromide and quinidine sulfate (20 mg/10 mg) or placebo for 10 weeks. Patients in the active group stayed on the study drug for the entire time. Those in the placebo group were assessed for response; 30 of these had improved on placebo. These were rerandomized to active and placebo groups. Placebo nonresponders were also rerandomized to the drug or placebo.

This allowed not only for a comparison of groups who had taken the drug or placebo for the full study, but also for the investigators to accurately tease out any placebo effects.

By the end of the first 5-week phase, patients in the active group experienced a mean improvement of 3.3 points on the NPI aggression subscale, which was significantly better than the 1.7-point improvement seen among those taking placebo.

After the placebo nonresponders had been rerandomized and treated for another 5 weeks, those taking the study drug had a mean 2-point improvement, compared with a 0.8-point improvement among those taking placebo.

In the group that been on their originally assigned treatment for the entire 10 weeks, those taking the study drug again fared significantly better (a mean improvement of about 4.5 points vs. 1.5 points with placebo).

In all randomization schemes, the clinical and physicians’ global impression improved significantly more in the active group than in the placebo group.

The total NPI score improved significantly more in the active group (13.5 vs. 8.5 points for those who had been on the same treatments for 10 weeks). NPI symptom clusters showed the same pattern of improvement favoring the study drug.

Measurements of caregiver response based on the Caregivers Strain Index and the NPI Caregiver Distress Score both significantly improved more for caregivers of patients taking the study drug for 10 weeks, compared to those taking placebo.

Treatment-emergent adverse events were significantly more common among the patients who took the study drug (61% vs. 43%). The most common were falls (9% vs. 4%), diarrhea (6% vs. 3%), urinary tract infection (5% vs. 4%), and dizziness (5% vs. 2.5%). These caused 5% of patients taking the drug and 3% taking placebo to discontinue treatment.

Dr. Pioro is a consultant for Avanir, which manufactures Nuedexta.

[email protected]

On Twitter @alz_gal

PHILADELPHIA – An investigational 5-HT6 inhibitor in combination with donepezil significantly boosted cognition in patients with moderate Alzheimer’s disease and has advanced into three placebo-controlled phase III trials.

The investigational drug, idalopirdine, is a potent antagonist of the 5-HT6 receptor, which plays a key part in neurotransmission in the cerebral cortex and hippocampus. When activated, it inhibits glutamatergic, noradrenergic, and dopaminergic transmission, and it inhibits cholinergic function when blocked. The drug seems to enhance acetylcholine and glutamate signaling by blocking this system, Dr. Alireza Atri said at the Clinical Trials Conference on Alzheimer’s Disease.

Rat studies showed that combining idalopirdine with the acetylcholinesterase inhibitor improved cognition. The effect seen only when the two drugs were combined, said Dr. Atri of Massachusetts General Hospital, Boston. “Vehicle/vehicle and vehicle/ idalopirdine effected no change at all. But the combination gave us a nice augmentation of potentiation that lasted quite a long time.”

However, idalopirdine’s lack of an effect when not used in combination with donepezil may signal that it’s inhibitory effect on CYP206 just serves to increase the bioavailability of donepezil, which is metabolized by CYP206, according to Dr. Lon Schneider, director of the California Alzheimer’s Disease Center, Los Angeles.

The preclinical experiments with idalopirdine were sufficient to launch the phase II trial, Dr. Atri said. It comprised 278 patients with moderate Alzheimer’s; all were already taking donepezil 10 mg. They were randomized to placebo plus their donepezil or to idalopirdine 90 mg/day plus donepezil. Treatment lasted 24 weeks, which included a 2-week donepezil run-in and a 2-week washout. The trial was published in the November issue of Lancet Neurology (2014;13:1092-9).

The primary endpoints were cognitive change as measured by the Alzheimer’s Disease Assessment Scale-Cognition (ADAS-Cog) and safety and tolerability. Secondary endpoints were the clinical outcomes on the Alzheimer’s Disease Cooperative Study measures, including clinical global impression (ADCS-CGI), activities of daily living (ADCS-ADL), and behavioral symptoms.

Mean age of the patients was 74.5 years, and about 70% were women. They had been diagnosed about 2 years prior to the start of the study and had used donepezil for about 1.5 years. Their mean Mini Mental State Exam score was 17, and their mean ADAS-Cog score was 28.

At week 24, scores in the placebo group worsened by about 1.4 points from baseline (indicating cognitive decline) while those in the idalopirdine group had improved by about 1 point from baseline. The 24-week score spread was slightly more than 2 points, which is a statistically and clinically significant difference, Dr. Atri said. None of the changes on the secondary endpoints were significant.

Adverse events caused 25 patients to discontinue treatment (18 taking the study drug and 7 taking placebo). The most common were increased liver enzymes, which were transient and discovered incidentally during routine blood work (10% with idalopirdine vs. 2% with placebo); diarrhea (4% vs. 7%); urinary tract infection (2% vs. 7%); falls (2% vs. 6%); and benign prostatic hyperplasia (5% vs. 0%). One death occurred in each treatment group; neither was regarded as being related to treatment.

The analysis included 12 measures of behavior. “On eight of these, there was not even a whiff of a signal,” Dr. Atri said. “On two – depression and dysphoria/appetite – there was maybe a hint of an effect, at least enough to keep and eye on.” The other measures showed nonsignificant differences.

The codevelopers of idalopirdine, Lundbeck and Otsuka, will continue to study the drug in three phase III trials, he said.

STARSHINE will randomize an estimated 930 patients to 30 mg or 60 mg idalopirdine plus donepezil or placebo for 20 weeks followed by a 4-week donepezil washout.

STARBEAM will randomize 840 patients to donepezil plus 10 mg or 30 mg idalopirdine for 20 weeks, followed by a 4-week donepezil washout.

STARBRIGHT will randomize 720 patients to any acetylcholinesterase inhibitor plus 60 mg idalopirdine for 20 weeks, plus a 4-week acetylcholinesterase inhibitor washout.

A 24-week open-label extension of donepezil plus 60 mg idalopirdine is also planned.

While Dr. Atri suggested that the drug exerts a direct effect on neurotransmission, Dr. Schneider suggested that it could simply be potentiating the effect of donepezil.

Idalopirdine is a potent inhibitor of CYP206 and its use will probably increase the bioavailability of the many drugs that depend on CYP206 for their clearance, including donepezil. In this trial, bioavailability of donepezil increased by 10%. A pharmacokinetic action could have been the real driver of results, Dr. Schneider said in an interview.

He questioned the wisdom of pursuing a drug that may have little inherent action.

“If as a hypothetical, the drug is inactive itself, but blocks an enzyme responsible for metabolizing donepezil, and donepezil levels rise and cause improvement, then one can’t say that the drug in question is effective. One can’t even say that the ‘combination’ is effective. Would you take a drug that may have side effects such as liver toxicity and others, just so it can block an enzyme to raise the level of another drug, and especially when several marketed drugs may do the same? What would likely happen if the drug group showed advantageous effects in these STAR trials is that sensitivity analyses would be done to help assess whether the drug also had an effect or what the contribution of donepezil levels was to the effect.”

Dr. Atri is on advisory board for several pharmaceutical companies, but has no financial ties with Lundbeck or Otsuka. Dr. Schneider has financial relationships with a number of pharmaceutical companies.

[email protected]

On Twitter @alz_gal

PHILADELPHIA – An investigational 5-HT6 inhibitor in combination with donepezil significantly boosted cognition in patients with moderate Alzheimer’s disease and has advanced into three placebo-controlled phase III trials.

The investigational drug, idalopirdine, is a potent antagonist of the 5-HT6 receptor, which plays a key part in neurotransmission in the cerebral cortex and hippocampus. When activated, it inhibits glutamatergic, noradrenergic, and dopaminergic transmission, and it inhibits cholinergic function when blocked. The drug seems to enhance acetylcholine and glutamate signaling by blocking this system, Dr. Alireza Atri said at the Clinical Trials Conference on Alzheimer’s Disease.

Rat studies showed that combining idalopirdine with the acetylcholinesterase inhibitor improved cognition. The effect seen only when the two drugs were combined, said Dr. Atri of Massachusetts General Hospital, Boston. “Vehicle/vehicle and vehicle/ idalopirdine effected no change at all. But the combination gave us a nice augmentation of potentiation that lasted quite a long time.”

However, idalopirdine’s lack of an effect when not used in combination with donepezil may signal that it’s inhibitory effect on CYP206 just serves to increase the bioavailability of donepezil, which is metabolized by CYP206, according to Dr. Lon Schneider, director of the California Alzheimer’s Disease Center, Los Angeles.

The preclinical experiments with idalopirdine were sufficient to launch the phase II trial, Dr. Atri said. It comprised 278 patients with moderate Alzheimer’s; all were already taking donepezil 10 mg. They were randomized to placebo plus their donepezil or to idalopirdine 90 mg/day plus donepezil. Treatment lasted 24 weeks, which included a 2-week donepezil run-in and a 2-week washout. The trial was published in the November issue of Lancet Neurology (2014;13:1092-9).

The primary endpoints were cognitive change as measured by the Alzheimer’s Disease Assessment Scale-Cognition (ADAS-Cog) and safety and tolerability. Secondary endpoints were the clinical outcomes on the Alzheimer’s Disease Cooperative Study measures, including clinical global impression (ADCS-CGI), activities of daily living (ADCS-ADL), and behavioral symptoms.

Mean age of the patients was 74.5 years, and about 70% were women. They had been diagnosed about 2 years prior to the start of the study and had used donepezil for about 1.5 years. Their mean Mini Mental State Exam score was 17, and their mean ADAS-Cog score was 28.

At week 24, scores in the placebo group worsened by about 1.4 points from baseline (indicating cognitive decline) while those in the idalopirdine group had improved by about 1 point from baseline. The 24-week score spread was slightly more than 2 points, which is a statistically and clinically significant difference, Dr. Atri said. None of the changes on the secondary endpoints were significant.

Adverse events caused 25 patients to discontinue treatment (18 taking the study drug and 7 taking placebo). The most common were increased liver enzymes, which were transient and discovered incidentally during routine blood work (10% with idalopirdine vs. 2% with placebo); diarrhea (4% vs. 7%); urinary tract infection (2% vs. 7%); falls (2% vs. 6%); and benign prostatic hyperplasia (5% vs. 0%). One death occurred in each treatment group; neither was regarded as being related to treatment.

The analysis included 12 measures of behavior. “On eight of these, there was not even a whiff of a signal,” Dr. Atri said. “On two – depression and dysphoria/appetite – there was maybe a hint of an effect, at least enough to keep and eye on.” The other measures showed nonsignificant differences.

The codevelopers of idalopirdine, Lundbeck and Otsuka, will continue to study the drug in three phase III trials, he said.

STARSHINE will randomize an estimated 930 patients to 30 mg or 60 mg idalopirdine plus donepezil or placebo for 20 weeks followed by a 4-week donepezil washout.

STARBEAM will randomize 840 patients to donepezil plus 10 mg or 30 mg idalopirdine for 20 weeks, followed by a 4-week donepezil washout.

STARBRIGHT will randomize 720 patients to any acetylcholinesterase inhibitor plus 60 mg idalopirdine for 20 weeks, plus a 4-week acetylcholinesterase inhibitor washout.

A 24-week open-label extension of donepezil plus 60 mg idalopirdine is also planned.

While Dr. Atri suggested that the drug exerts a direct effect on neurotransmission, Dr. Schneider suggested that it could simply be potentiating the effect of donepezil.

Idalopirdine is a potent inhibitor of CYP206 and its use will probably increase the bioavailability of the many drugs that depend on CYP206 for their clearance, including donepezil. In this trial, bioavailability of donepezil increased by 10%. A pharmacokinetic action could have been the real driver of results, Dr. Schneider said in an interview.

He questioned the wisdom of pursuing a drug that may have little inherent action.

“If as a hypothetical, the drug is inactive itself, but blocks an enzyme responsible for metabolizing donepezil, and donepezil levels rise and cause improvement, then one can’t say that the drug in question is effective. One can’t even say that the ‘combination’ is effective. Would you take a drug that may have side effects such as liver toxicity and others, just so it can block an enzyme to raise the level of another drug, and especially when several marketed drugs may do the same? What would likely happen if the drug group showed advantageous effects in these STAR trials is that sensitivity analyses would be done to help assess whether the drug also had an effect or what the contribution of donepezil levels was to the effect.”

Dr. Atri is on advisory board for several pharmaceutical companies, but has no financial ties with Lundbeck or Otsuka. Dr. Schneider has financial relationships with a number of pharmaceutical companies.

[email protected]

On Twitter @alz_gal

PHILADELPHIA – An investigational 5-HT6 inhibitor in combination with donepezil significantly boosted cognition in patients with moderate Alzheimer’s disease and has advanced into three placebo-controlled phase III trials.

The investigational drug, idalopirdine, is a potent antagonist of the 5-HT6 receptor, which plays a key part in neurotransmission in the cerebral cortex and hippocampus. When activated, it inhibits glutamatergic, noradrenergic, and dopaminergic transmission, and it inhibits cholinergic function when blocked. The drug seems to enhance acetylcholine and glutamate signaling by blocking this system, Dr. Alireza Atri said at the Clinical Trials Conference on Alzheimer’s Disease.

Rat studies showed that combining idalopirdine with the acetylcholinesterase inhibitor improved cognition. The effect seen only when the two drugs were combined, said Dr. Atri of Massachusetts General Hospital, Boston. “Vehicle/vehicle and vehicle/ idalopirdine effected no change at all. But the combination gave us a nice augmentation of potentiation that lasted quite a long time.”

However, idalopirdine’s lack of an effect when not used in combination with donepezil may signal that it’s inhibitory effect on CYP206 just serves to increase the bioavailability of donepezil, which is metabolized by CYP206, according to Dr. Lon Schneider, director of the California Alzheimer’s Disease Center, Los Angeles.

The preclinical experiments with idalopirdine were sufficient to launch the phase II trial, Dr. Atri said. It comprised 278 patients with moderate Alzheimer’s; all were already taking donepezil 10 mg. They were randomized to placebo plus their donepezil or to idalopirdine 90 mg/day plus donepezil. Treatment lasted 24 weeks, which included a 2-week donepezil run-in and a 2-week washout. The trial was published in the November issue of Lancet Neurology (2014;13:1092-9).

The primary endpoints were cognitive change as measured by the Alzheimer’s Disease Assessment Scale-Cognition (ADAS-Cog) and safety and tolerability. Secondary endpoints were the clinical outcomes on the Alzheimer’s Disease Cooperative Study measures, including clinical global impression (ADCS-CGI), activities of daily living (ADCS-ADL), and behavioral symptoms.

Mean age of the patients was 74.5 years, and about 70% were women. They had been diagnosed about 2 years prior to the start of the study and had used donepezil for about 1.5 years. Their mean Mini Mental State Exam score was 17, and their mean ADAS-Cog score was 28.

At week 24, scores in the placebo group worsened by about 1.4 points from baseline (indicating cognitive decline) while those in the idalopirdine group had improved by about 1 point from baseline. The 24-week score spread was slightly more than 2 points, which is a statistically and clinically significant difference, Dr. Atri said. None of the changes on the secondary endpoints were significant.

Adverse events caused 25 patients to discontinue treatment (18 taking the study drug and 7 taking placebo). The most common were increased liver enzymes, which were transient and discovered incidentally during routine blood work (10% with idalopirdine vs. 2% with placebo); diarrhea (4% vs. 7%); urinary tract infection (2% vs. 7%); falls (2% vs. 6%); and benign prostatic hyperplasia (5% vs. 0%). One death occurred in each treatment group; neither was regarded as being related to treatment.

The analysis included 12 measures of behavior. “On eight of these, there was not even a whiff of a signal,” Dr. Atri said. “On two – depression and dysphoria/appetite – there was maybe a hint of an effect, at least enough to keep and eye on.” The other measures showed nonsignificant differences.

The codevelopers of idalopirdine, Lundbeck and Otsuka, will continue to study the drug in three phase III trials, he said.

STARSHINE will randomize an estimated 930 patients to 30 mg or 60 mg idalopirdine plus donepezil or placebo for 20 weeks followed by a 4-week donepezil washout.

STARBEAM will randomize 840 patients to donepezil plus 10 mg or 30 mg idalopirdine for 20 weeks, followed by a 4-week donepezil washout.

STARBRIGHT will randomize 720 patients to any acetylcholinesterase inhibitor plus 60 mg idalopirdine for 20 weeks, plus a 4-week acetylcholinesterase inhibitor washout.

A 24-week open-label extension of donepezil plus 60 mg idalopirdine is also planned.

While Dr. Atri suggested that the drug exerts a direct effect on neurotransmission, Dr. Schneider suggested that it could simply be potentiating the effect of donepezil.

Idalopirdine is a potent inhibitor of CYP206 and its use will probably increase the bioavailability of the many drugs that depend on CYP206 for their clearance, including donepezil. In this trial, bioavailability of donepezil increased by 10%. A pharmacokinetic action could have been the real driver of results, Dr. Schneider said in an interview.

He questioned the wisdom of pursuing a drug that may have little inherent action.

“If as a hypothetical, the drug is inactive itself, but blocks an enzyme responsible for metabolizing donepezil, and donepezil levels rise and cause improvement, then one can’t say that the drug in question is effective. One can’t even say that the ‘combination’ is effective. Would you take a drug that may have side effects such as liver toxicity and others, just so it can block an enzyme to raise the level of another drug, and especially when several marketed drugs may do the same? What would likely happen if the drug group showed advantageous effects in these STAR trials is that sensitivity analyses would be done to help assess whether the drug also had an effect or what the contribution of donepezil levels was to the effect.”

Dr. Atri is on advisory board for several pharmaceutical companies, but has no financial ties with Lundbeck or Otsuka. Dr. Schneider has financial relationships with a number of pharmaceutical companies.

[email protected]

On Twitter @alz_gal

PHILADELPHIA – A covered nitinol stent graft effectively restored and maintained patency of hemodialysis access routes that had been impaired by in-stent restenosis.

The combination of a stent graft plus angioplasty was significantly more effective than angioplasty alone at keeping the access routes open, Dr. Alexander Yevzlin reported at Kidney Week 2014.

Maintaining healthy vascular access is key for effective dialysis; this is usually accomplished by bare metal stenting. However, in-stent restenosis is so common that patients may need angioplasty every 3-6 months to maintain access patency.

In comparison, coronary angioplasty is usually sustained for at least 5 years, said Dr. Yevzlin, director of interventional nephrology at the University of Wisconsin, Madison. “This places a very large extra burden of morbidity on patients, and a large burden of cost on society.”

The ongoing RESCUE study is examining the Fluency Plus cardiovascular stent graft for in-stent restenosis. Fluency is a nitinol stent covered with a plastic graft of expanded polytetrafluoroethylene. Dr. Yevzlin reported preliminary 6-month data.

The study has randomized 265 patients with in-stent restenosis of a dialysis access circuit to treatment with either balloon angioplasty alone, or angioplasty plus the stent graft. The primary endpoints are access circuit primary patency at 6 months and 30-day safety. Safety endpoints are any additional interventions including surgery, hospitalization, or prolongation of an existing hospitalization; or death. The secondary endpoint is postintervention lesion patency (defined as the interval after the index intervention until the next reintervention at the original treatment site or until the extremity is abandoned for permanent access).

There were no safety issues, Dr. Yevzlin said; by 30 days, 97% of patients in both groups were still free of any adverse event.

By 6 months, access circuit patency was significantly higher among those who received stent grafts than those who had angioplasties alone. Postintervention lesion patency was 65% in the stent graft group and 10% in the angioplasty group – a significant difference.

The stent graft performed well in both arteriovenous grafts and fistulas. In a subgroup of those with an arteriovenous graft, the postinterventional lesion patency rate was 58% in the stent graft group and 5% in the angioplasty group. In the fistula subgroup, the rates were 72% and 15%, respectively.

The meeting was sponsored by the American Society of Nephrology. Dr. Yevzlin disclosed financial relationships with Bard Peripheral Vascular, the manufacturer of the stent graft; Phraxis; CytoPherx; and Covidien.

[email protected]

PHILADELPHIA – A covered nitinol stent graft effectively restored and maintained patency of hemodialysis access routes that had been impaired by in-stent restenosis.

The combination of a stent graft plus angioplasty was significantly more effective than angioplasty alone at keeping the access routes open, Dr. Alexander Yevzlin reported at Kidney Week 2014.

Maintaining healthy vascular access is key for effective dialysis; this is usually accomplished by bare metal stenting. However, in-stent restenosis is so common that patients may need angioplasty every 3-6 months to maintain access patency.

In comparison, coronary angioplasty is usually sustained for at least 5 years, said Dr. Yevzlin, director of interventional nephrology at the University of Wisconsin, Madison. “This places a very large extra burden of morbidity on patients, and a large burden of cost on society.”

The ongoing RESCUE study is examining the Fluency Plus cardiovascular stent graft for in-stent restenosis. Fluency is a nitinol stent covered with a plastic graft of expanded polytetrafluoroethylene. Dr. Yevzlin reported preliminary 6-month data.

The study has randomized 265 patients with in-stent restenosis of a dialysis access circuit to treatment with either balloon angioplasty alone, or angioplasty plus the stent graft. The primary endpoints are access circuit primary patency at 6 months and 30-day safety. Safety endpoints are any additional interventions including surgery, hospitalization, or prolongation of an existing hospitalization; or death. The secondary endpoint is postintervention lesion patency (defined as the interval after the index intervention until the next reintervention at the original treatment site or until the extremity is abandoned for permanent access).

There were no safety issues, Dr. Yevzlin said; by 30 days, 97% of patients in both groups were still free of any adverse event.

By 6 months, access circuit patency was significantly higher among those who received stent grafts than those who had angioplasties alone. Postintervention lesion patency was 65% in the stent graft group and 10% in the angioplasty group – a significant difference.

The stent graft performed well in both arteriovenous grafts and fistulas. In a subgroup of those with an arteriovenous graft, the postinterventional lesion patency rate was 58% in the stent graft group and 5% in the angioplasty group. In the fistula subgroup, the rates were 72% and 15%, respectively.

The meeting was sponsored by the American Society of Nephrology. Dr. Yevzlin disclosed financial relationships with Bard Peripheral Vascular, the manufacturer of the stent graft; Phraxis; CytoPherx; and Covidien.

[email protected]

PHILADELPHIA – A covered nitinol stent graft effectively restored and maintained patency of hemodialysis access routes that had been impaired by in-stent restenosis.

The combination of a stent graft plus angioplasty was significantly more effective than angioplasty alone at keeping the access routes open, Dr. Alexander Yevzlin reported at Kidney Week 2014.

Maintaining healthy vascular access is key for effective dialysis; this is usually accomplished by bare metal stenting. However, in-stent restenosis is so common that patients may need angioplasty every 3-6 months to maintain access patency.

In comparison, coronary angioplasty is usually sustained for at least 5 years, said Dr. Yevzlin, director of interventional nephrology at the University of Wisconsin, Madison. “This places a very large extra burden of morbidity on patients, and a large burden of cost on society.”

The ongoing RESCUE study is examining the Fluency Plus cardiovascular stent graft for in-stent restenosis. Fluency is a nitinol stent covered with a plastic graft of expanded polytetrafluoroethylene. Dr. Yevzlin reported preliminary 6-month data.

The study has randomized 265 patients with in-stent restenosis of a dialysis access circuit to treatment with either balloon angioplasty alone, or angioplasty plus the stent graft. The primary endpoints are access circuit primary patency at 6 months and 30-day safety. Safety endpoints are any additional interventions including surgery, hospitalization, or prolongation of an existing hospitalization; or death. The secondary endpoint is postintervention lesion patency (defined as the interval after the index intervention until the next reintervention at the original treatment site or until the extremity is abandoned for permanent access).

There were no safety issues, Dr. Yevzlin said; by 30 days, 97% of patients in both groups were still free of any adverse event.

By 6 months, access circuit patency was significantly higher among those who received stent grafts than those who had angioplasties alone. Postintervention lesion patency was 65% in the stent graft group and 10% in the angioplasty group – a significant difference.

The stent graft performed well in both arteriovenous grafts and fistulas. In a subgroup of those with an arteriovenous graft, the postinterventional lesion patency rate was 58% in the stent graft group and 5% in the angioplasty group. In the fistula subgroup, the rates were 72% and 15%, respectively.

The meeting was sponsored by the American Society of Nephrology. Dr. Yevzlin disclosed financial relationships with Bard Peripheral Vascular, the manufacturer of the stent graft; Phraxis; CytoPherx; and Covidien.

[email protected]

PHILADELPHIA – Extended time on hemodialysis each week produced some modest improvement in lab values but didn’t result in any overall increases in quality of life for patients.

A dialysis regimen of at least 24 hours weekly failed to confer any significant benefits on blood pressure, weight, or 12-month cardiovascular outcomes, Dr. Meg Jardine said at Kidney Week 2014, which was sponsored by the American Society of Nephrology.

A follow-up period of 12 months, however, probably isn’t long enough to detect any potential cardiovascular benefits, noted Dr. Jardine of the George Institute of Global Health of Sydney.

The ACTIVE Dialysis Multinational Trial was conducted at 40 centers in Australia, China, New Zealand, and the U.K. It randomized 200 patients with end-stage renal disease to either standard dialysis (12-18 hours weekly) or the extended regimen (24-28 hours). Dialysis could be carried out at home or in a center. The primary endpoint was any change in health-related quality of life as measured on the EQ-5D, an internationally validated health quality of life measure, which was administered every 3 months. The EQ-5D score ranges from 0-1, with 0 being death and 1 being perfect health.

Secondary outcomes included overall survival, changes in biochemical and hematological markers, and safety including vascular access issues. A prespecified subanalysis examined changes in left ventricular mass index.

Patients were a mean of 52 years old. Most (70%) were male. At baseline, they received dialysis for a mean of 14 hours per week; 88% of dialysis was performed at a dialysis center. Access was via a native arteriovenous fistula in 84% of patients. The baseline EQ-5D score was 0.76 in the standard-dialysis group and 0.79 in the extended-dialysis group.

After 12 months, neither of the groups experienced any significant improvements in overall quality of life measures, Dr. Jardine said. There was a nonsignificant indication that the physical health subscale improved among patients who had the extended dialysis. There was no change in the mental health subscale in either group.

Patients in the extended-dialysis group did experience some significant improvements in laboratory measures. Potassium and phosphate levels declined significantly from baseline – enough to eliminate the need for a phosphate binder for many, she said. Calcium increased significantly, as did hemoglobin.

Both diastolic and systolic blood pressure improved somewhat, and although those improvements were not statistically significant, they did confer a significant decrease in the need for antihypertensive therapy.

At the 12-month follow up, imaging revealed that patients in the extended-dialysis group had a greater left ventricular mass – a mean of 2.84 g/m² more than that seen in the standard-dialysis group. The short follow-up time, however, makes interpretation of this finding difficult, Dr. Jardine said.

There were no significant differences in serious adverse effects between the groups. There were two deaths and three transplants in the standard arm, compared with five deaths and two transplants in the extended dialysis arm – not a significant difference.

Dr. Jardine disclosed that she has received honoraria from Servier Laboratories and Amgen.

[email protected]

PHILADELPHIA – Extended time on hemodialysis each week produced some modest improvement in lab values but didn’t result in any overall increases in quality of life for patients.

A dialysis regimen of at least 24 hours weekly failed to confer any significant benefits on blood pressure, weight, or 12-month cardiovascular outcomes, Dr. Meg Jardine said at Kidney Week 2014, which was sponsored by the American Society of Nephrology.

A follow-up period of 12 months, however, probably isn’t long enough to detect any potential cardiovascular benefits, noted Dr. Jardine of the George Institute of Global Health of Sydney.

The ACTIVE Dialysis Multinational Trial was conducted at 40 centers in Australia, China, New Zealand, and the U.K. It randomized 200 patients with end-stage renal disease to either standard dialysis (12-18 hours weekly) or the extended regimen (24-28 hours). Dialysis could be carried out at home or in a center. The primary endpoint was any change in health-related quality of life as measured on the EQ-5D, an internationally validated health quality of life measure, which was administered every 3 months. The EQ-5D score ranges from 0-1, with 0 being death and 1 being perfect health.

Secondary outcomes included overall survival, changes in biochemical and hematological markers, and safety including vascular access issues. A prespecified subanalysis examined changes in left ventricular mass index.

Patients were a mean of 52 years old. Most (70%) were male. At baseline, they received dialysis for a mean of 14 hours per week; 88% of dialysis was performed at a dialysis center. Access was via a native arteriovenous fistula in 84% of patients. The baseline EQ-5D score was 0.76 in the standard-dialysis group and 0.79 in the extended-dialysis group.

After 12 months, neither of the groups experienced any significant improvements in overall quality of life measures, Dr. Jardine said. There was a nonsignificant indication that the physical health subscale improved among patients who had the extended dialysis. There was no change in the mental health subscale in either group.

Patients in the extended-dialysis group did experience some significant improvements in laboratory measures. Potassium and phosphate levels declined significantly from baseline – enough to eliminate the need for a phosphate binder for many, she said. Calcium increased significantly, as did hemoglobin.

Both diastolic and systolic blood pressure improved somewhat, and although those improvements were not statistically significant, they did confer a significant decrease in the need for antihypertensive therapy.

At the 12-month follow up, imaging revealed that patients in the extended-dialysis group had a greater left ventricular mass – a mean of 2.84 g/m² more than that seen in the standard-dialysis group. The short follow-up time, however, makes interpretation of this finding difficult, Dr. Jardine said.

There were no significant differences in serious adverse effects between the groups. There were two deaths and three transplants in the standard arm, compared with five deaths and two transplants in the extended dialysis arm – not a significant difference.

Dr. Jardine disclosed that she has received honoraria from Servier Laboratories and Amgen.

[email protected]

PHILADELPHIA – Extended time on hemodialysis each week produced some modest improvement in lab values but didn’t result in any overall increases in quality of life for patients.

A dialysis regimen of at least 24 hours weekly failed to confer any significant benefits on blood pressure, weight, or 12-month cardiovascular outcomes, Dr. Meg Jardine said at Kidney Week 2014, which was sponsored by the American Society of Nephrology.

A follow-up period of 12 months, however, probably isn’t long enough to detect any potential cardiovascular benefits, noted Dr. Jardine of the George Institute of Global Health of Sydney.

The ACTIVE Dialysis Multinational Trial was conducted at 40 centers in Australia, China, New Zealand, and the U.K. It randomized 200 patients with end-stage renal disease to either standard dialysis (12-18 hours weekly) or the extended regimen (24-28 hours). Dialysis could be carried out at home or in a center. The primary endpoint was any change in health-related quality of life as measured on the EQ-5D, an internationally validated health quality of life measure, which was administered every 3 months. The EQ-5D score ranges from 0-1, with 0 being death and 1 being perfect health.

Secondary outcomes included overall survival, changes in biochemical and hematological markers, and safety including vascular access issues. A prespecified subanalysis examined changes in left ventricular mass index.

Patients were a mean of 52 years old. Most (70%) were male. At baseline, they received dialysis for a mean of 14 hours per week; 88% of dialysis was performed at a dialysis center. Access was via a native arteriovenous fistula in 84% of patients. The baseline EQ-5D score was 0.76 in the standard-dialysis group and 0.79 in the extended-dialysis group.

After 12 months, neither of the groups experienced any significant improvements in overall quality of life measures, Dr. Jardine said. There was a nonsignificant indication that the physical health subscale improved among patients who had the extended dialysis. There was no change in the mental health subscale in either group.

Patients in the extended-dialysis group did experience some significant improvements in laboratory measures. Potassium and phosphate levels declined significantly from baseline – enough to eliminate the need for a phosphate binder for many, she said. Calcium increased significantly, as did hemoglobin.

Both diastolic and systolic blood pressure improved somewhat, and although those improvements were not statistically significant, they did confer a significant decrease in the need for antihypertensive therapy.

At the 12-month follow up, imaging revealed that patients in the extended-dialysis group had a greater left ventricular mass – a mean of 2.84 g/m² more than that seen in the standard-dialysis group. The short follow-up time, however, makes interpretation of this finding difficult, Dr. Jardine said.

There were no significant differences in serious adverse effects between the groups. There were two deaths and three transplants in the standard arm, compared with five deaths and two transplants in the extended dialysis arm – not a significant difference.

Dr. Jardine disclosed that she has received honoraria from Servier Laboratories and Amgen.

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