HT Staff

Changing the route of administration has significantly improved the efficacy of an investigational malaria vaccine, according to a study published in Science.

The vaccine, called PfSPZ, is composed of live but weakened sporozoites of Plasmodium falciparum.

In a previous clinical trial, the vaccine proved largely ineffective at preventing malaria. But in that study, PfSPZ was administered either intradermally or subcutaneously.

In a new phase 1 study, researchers administered the vaccine intravenously at varying doses. And they found that, at high doses, PfSPZ offered protection against malaria in most subjects.

“In this trial, we showed, in principle, that sporozoites can be developed into a malaria vaccine that confers high levels of protection . . . ,” said study author Robert A. Seder, MD, chief of the Cellular Immunology Section of the NIAID Vaccine Research Center in Bethesda, Maryland.

Dr Seder and his colleagues tested the vaccine in 57 healthy adult volunteers, aged 18 to 45 years, who never had malaria. Forty of the subjects received the vaccine, and 17 did not.

Adverse reactions

To evaluate safety, the researchers divided recipients into groups receiving 2 to 6 intravenous doses of PfSPZ vaccine at increasing dosages. After vaccination, the team monitored subjects closely for 7 days.

There were no malaria infections related to vaccination. However, there were a number of adverse events.

Nine subjects had mild pain/tenderness or bruising, and 1 had moderate bruising at the injection site. Sixteen participants had mild solicited systemic reactogenicity, 4 had moderate, and 1 had severe reactogenicity.

Sixteen subjects also had transient, asymptomatic increases in aspartate aminotransferase and/or alanine aminotransferase that was possibly related to vaccination.

Response and protection

Based on blood measurements, the researchers found that subjects who received a higher total dosage of PfSPZ vaccine generated more antibodies against malaria and more T cells specific to the vaccine.

To evaluate whether and how well the PfSPZ vaccine prevented malaria infection, each participant—both vaccinated individuals and the control group—was exposed to bites by 5 mosquitoes carrying the P falciparum strain.

This took place 3 weeks after participants received their final vaccination. The researchers monitored the subjects as outpatients for 7 days and then admitted them to the clinic, where they stayed until they were diagnosed with malaria, treated with antimalarial drugs and cured of infection, or shown to be free of infection.

The researchers found that higher dosages of PfSPZ vaccine were associated with protection against malaria infection. Three of the 15 participants who received higher dosages of the vaccine became infected, compared to 16 of 17 subjects in the lower-dosage group.

Among the 12 participants who received no vaccine, 11 became infected with malaria after the mosquito challenge.

“[T]hese trial results are a promising first step in generating high-level protection against malaria, and they allow for future studies to optimize the dose, schedule, and delivery route of the candidate vaccine,” Dr Seder said.

A number of follow-up studies are planned, including research to evaluate the vaccine’s different dose schedules, possible protection against other Plasmodium strains, and the durability of protection.

The researchers may also evaluate whether higher doses administered subcutaneously or intradermally provide the same level of protection as that found in this study.

The PfSPZ vaccine was developed by scientists at Sanaria Inc., of Rockville, Maryland.

Changing the route of administration has significantly improved the efficacy of an investigational malaria vaccine, according to a study published in Science.

The vaccine, called PfSPZ, is composed of live but weakened sporozoites of Plasmodium falciparum.

In a previous clinical trial, the vaccine proved largely ineffective at preventing malaria. But in that study, PfSPZ was administered either intradermally or subcutaneously.

In a new phase 1 study, researchers administered the vaccine intravenously at varying doses. And they found that, at high doses, PfSPZ offered protection against malaria in most subjects.

“In this trial, we showed, in principle, that sporozoites can be developed into a malaria vaccine that confers high levels of protection . . . ,” said study author Robert A. Seder, MD, chief of the Cellular Immunology Section of the NIAID Vaccine Research Center in Bethesda, Maryland.

Dr Seder and his colleagues tested the vaccine in 57 healthy adult volunteers, aged 18 to 45 years, who never had malaria. Forty of the subjects received the vaccine, and 17 did not.

Adverse reactions

To evaluate safety, the researchers divided recipients into groups receiving 2 to 6 intravenous doses of PfSPZ vaccine at increasing dosages. After vaccination, the team monitored subjects closely for 7 days.

There were no malaria infections related to vaccination. However, there were a number of adverse events.

Nine subjects had mild pain/tenderness or bruising, and 1 had moderate bruising at the injection site. Sixteen participants had mild solicited systemic reactogenicity, 4 had moderate, and 1 had severe reactogenicity.

Sixteen subjects also had transient, asymptomatic increases in aspartate aminotransferase and/or alanine aminotransferase that was possibly related to vaccination.

Response and protection

Based on blood measurements, the researchers found that subjects who received a higher total dosage of PfSPZ vaccine generated more antibodies against malaria and more T cells specific to the vaccine.

To evaluate whether and how well the PfSPZ vaccine prevented malaria infection, each participant—both vaccinated individuals and the control group—was exposed to bites by 5 mosquitoes carrying the P falciparum strain.

This took place 3 weeks after participants received their final vaccination. The researchers monitored the subjects as outpatients for 7 days and then admitted them to the clinic, where they stayed until they were diagnosed with malaria, treated with antimalarial drugs and cured of infection, or shown to be free of infection.

The researchers found that higher dosages of PfSPZ vaccine were associated with protection against malaria infection. Three of the 15 participants who received higher dosages of the vaccine became infected, compared to 16 of 17 subjects in the lower-dosage group.

Among the 12 participants who received no vaccine, 11 became infected with malaria after the mosquito challenge.

“[T]hese trial results are a promising first step in generating high-level protection against malaria, and they allow for future studies to optimize the dose, schedule, and delivery route of the candidate vaccine,” Dr Seder said.

A number of follow-up studies are planned, including research to evaluate the vaccine’s different dose schedules, possible protection against other Plasmodium strains, and the durability of protection.

The researchers may also evaluate whether higher doses administered subcutaneously or intradermally provide the same level of protection as that found in this study.

The PfSPZ vaccine was developed by scientists at Sanaria Inc., of Rockville, Maryland.

Changing the route of administration has significantly improved the efficacy of an investigational malaria vaccine, according to a study published in Science.

The vaccine, called PfSPZ, is composed of live but weakened sporozoites of Plasmodium falciparum.

In a previous clinical trial, the vaccine proved largely ineffective at preventing malaria. But in that study, PfSPZ was administered either intradermally or subcutaneously.

In a new phase 1 study, researchers administered the vaccine intravenously at varying doses. And they found that, at high doses, PfSPZ offered protection against malaria in most subjects.

“In this trial, we showed, in principle, that sporozoites can be developed into a malaria vaccine that confers high levels of protection . . . ,” said study author Robert A. Seder, MD, chief of the Cellular Immunology Section of the NIAID Vaccine Research Center in Bethesda, Maryland.

Dr Seder and his colleagues tested the vaccine in 57 healthy adult volunteers, aged 18 to 45 years, who never had malaria. Forty of the subjects received the vaccine, and 17 did not.

Adverse reactions

To evaluate safety, the researchers divided recipients into groups receiving 2 to 6 intravenous doses of PfSPZ vaccine at increasing dosages. After vaccination, the team monitored subjects closely for 7 days.

There were no malaria infections related to vaccination. However, there were a number of adverse events.

Nine subjects had mild pain/tenderness or bruising, and 1 had moderate bruising at the injection site. Sixteen participants had mild solicited systemic reactogenicity, 4 had moderate, and 1 had severe reactogenicity.

Sixteen subjects also had transient, asymptomatic increases in aspartate aminotransferase and/or alanine aminotransferase that was possibly related to vaccination.

Response and protection

Based on blood measurements, the researchers found that subjects who received a higher total dosage of PfSPZ vaccine generated more antibodies against malaria and more T cells specific to the vaccine.

To evaluate whether and how well the PfSPZ vaccine prevented malaria infection, each participant—both vaccinated individuals and the control group—was exposed to bites by 5 mosquitoes carrying the P falciparum strain.

This took place 3 weeks after participants received their final vaccination. The researchers monitored the subjects as outpatients for 7 days and then admitted them to the clinic, where they stayed until they were diagnosed with malaria, treated with antimalarial drugs and cured of infection, or shown to be free of infection.

The researchers found that higher dosages of PfSPZ vaccine were associated with protection against malaria infection. Three of the 15 participants who received higher dosages of the vaccine became infected, compared to 16 of 17 subjects in the lower-dosage group.

Among the 12 participants who received no vaccine, 11 became infected with malaria after the mosquito challenge.

“[T]hese trial results are a promising first step in generating high-level protection against malaria, and they allow for future studies to optimize the dose, schedule, and delivery route of the candidate vaccine,” Dr Seder said.

A number of follow-up studies are planned, including research to evaluate the vaccine’s different dose schedules, possible protection against other Plasmodium strains, and the durability of protection.

The researchers may also evaluate whether higher doses administered subcutaneously or intradermally provide the same level of protection as that found in this study.

The PfSPZ vaccine was developed by scientists at Sanaria Inc., of Rockville, Maryland.

Photo by Rhoda Baer

Results of a nationwide poll indicate that many Americans believe participation in clinical trials is important.

And most of the individuals surveyed said they would participate in a trial if their doctor recommended it.

However, many respondents said they learned of clinical trials via the Internet, not from discussions with their physician. And most said a physician’s recommendation was an important factor in the decision to enroll in a clinical trial.

This poll was conducted online by Zogby Analytics. The results are available on the Research!America website.

The goal of the survey was to evaluate respondents’ perceptions about clinical trials and determine if perceptions differed according to racial groups. The survey included 684 non-Hispanic whites, 406 Hispanics, 403 African-Americans, and 300 Asians.

A willingness to participate

Most of the African-Americans (62%) and Hispanics (57%) polled said it’s very important to participate in a clinical trial to improve the health of others. Fifty percent of Asians agreed, as did 49% of non-Hispanic whites.

Furthermore, 75% of Hispanics, 72% of African-Americans, 71% of non-Hispanic whites, and 65% of Asians said they would likely participate in a clinical trial if it was recommended by a doctor.

And about three-quarters of all respondents said, assuming the correct privacy protections were in place, they would be willing to share personal health information to advance medical research.

“The poll reveals a willingness among minorities to participate in clinical trials to improve the quality of healthcare, but enrollment remains stubbornly low,” said Mary Woolley, president and CEO of Research!America.

Among those individuals surveyed, only 17% of Hispanics, 15% of African-Americans, 15% of non-Hispanic whites, and 11% of Asians said they or a family member had participated in a clinical trial.

When asked to give a reason for low enrollment in clinical trials, most respondents cited a lack of trust—61% of African-Americans, 54% of non-Hispanic whites, 52% of Hispanics, and 51% of Asians.

The importance of physicians, institutions

Many of the individuals surveyed said they had learned of clinical trials via the Internet—56% of Asians, 52% of non-Hispanic whites, 50% of African-Americans, and 45% of Hispanics.

Far fewer said they had heard of trials during discussions with their doctors—22% of Hispanics, 22% of non-Hispanic whites, 20% of Asians, and 17% of African-Americans.

And most respondents said a doctor’s recommendation is a “very” or “somewhat” important factor in the decision to participate in a clinical trial—81% of Hispanics, 81% of non-Hispanic whites, 80% of Asians, and 78% of African-Americans.

Institutional reputation was also deemed an important factor by 74% of African-Americans, 72% of non-Hispanic whites, 66% of Hispanics, and 66% of Asians.

And many respondents said healthcare providers should play a major role in raising awareness of clinical trials. In fact, 42% of non-Hispanic whites, 38% of Hispanics, 36% of Asians, and 33% of African-Americans said providers have the greatest responsibility in educating the public about clinical trials.

“It’s imperative that healthcare providers and others help patients gain a deeper knowledge of clinical trials so all Americans can benefit from life-saving treatments,” Woolley said.

This survey was conducted by Zogby Analytics for Research!America, the Association of Clinical Research Organizations, the Clinical Research Forum, the Friends of the National Library of Medicine, and the Clinical Trials Transformation Initiative.

Photo by Rhoda Baer

Results of a nationwide poll indicate that many Americans believe participation in clinical trials is important.

And most of the individuals surveyed said they would participate in a trial if their doctor recommended it.

However, many respondents said they learned of clinical trials via the Internet, not from discussions with their physician. And most said a physician’s recommendation was an important factor in the decision to enroll in a clinical trial.

This poll was conducted online by Zogby Analytics. The results are available on the Research!America website.

The goal of the survey was to evaluate respondents’ perceptions about clinical trials and determine if perceptions differed according to racial groups. The survey included 684 non-Hispanic whites, 406 Hispanics, 403 African-Americans, and 300 Asians.

A willingness to participate

Most of the African-Americans (62%) and Hispanics (57%) polled said it’s very important to participate in a clinical trial to improve the health of others. Fifty percent of Asians agreed, as did 49% of non-Hispanic whites.

Furthermore, 75% of Hispanics, 72% of African-Americans, 71% of non-Hispanic whites, and 65% of Asians said they would likely participate in a clinical trial if it was recommended by a doctor.

And about three-quarters of all respondents said, assuming the correct privacy protections were in place, they would be willing to share personal health information to advance medical research.

“The poll reveals a willingness among minorities to participate in clinical trials to improve the quality of healthcare, but enrollment remains stubbornly low,” said Mary Woolley, president and CEO of Research!America.

Among those individuals surveyed, only 17% of Hispanics, 15% of African-Americans, 15% of non-Hispanic whites, and 11% of Asians said they or a family member had participated in a clinical trial.

When asked to give a reason for low enrollment in clinical trials, most respondents cited a lack of trust—61% of African-Americans, 54% of non-Hispanic whites, 52% of Hispanics, and 51% of Asians.

The importance of physicians, institutions

Many of the individuals surveyed said they had learned of clinical trials via the Internet—56% of Asians, 52% of non-Hispanic whites, 50% of African-Americans, and 45% of Hispanics.

Far fewer said they had heard of trials during discussions with their doctors—22% of Hispanics, 22% of non-Hispanic whites, 20% of Asians, and 17% of African-Americans.

And most respondents said a doctor’s recommendation is a “very” or “somewhat” important factor in the decision to participate in a clinical trial—81% of Hispanics, 81% of non-Hispanic whites, 80% of Asians, and 78% of African-Americans.

Institutional reputation was also deemed an important factor by 74% of African-Americans, 72% of non-Hispanic whites, 66% of Hispanics, and 66% of Asians.

And many respondents said healthcare providers should play a major role in raising awareness of clinical trials. In fact, 42% of non-Hispanic whites, 38% of Hispanics, 36% of Asians, and 33% of African-Americans said providers have the greatest responsibility in educating the public about clinical trials.

“It’s imperative that healthcare providers and others help patients gain a deeper knowledge of clinical trials so all Americans can benefit from life-saving treatments,” Woolley said.

This survey was conducted by Zogby Analytics for Research!America, the Association of Clinical Research Organizations, the Clinical Research Forum, the Friends of the National Library of Medicine, and the Clinical Trials Transformation Initiative.

Photo by Rhoda Baer

Results of a nationwide poll indicate that many Americans believe participation in clinical trials is important.

And most of the individuals surveyed said they would participate in a trial if their doctor recommended it.

However, many respondents said they learned of clinical trials via the Internet, not from discussions with their physician. And most said a physician’s recommendation was an important factor in the decision to enroll in a clinical trial.

This poll was conducted online by Zogby Analytics. The results are available on the Research!America website.

The goal of the survey was to evaluate respondents’ perceptions about clinical trials and determine if perceptions differed according to racial groups. The survey included 684 non-Hispanic whites, 406 Hispanics, 403 African-Americans, and 300 Asians.

A willingness to participate

Most of the African-Americans (62%) and Hispanics (57%) polled said it’s very important to participate in a clinical trial to improve the health of others. Fifty percent of Asians agreed, as did 49% of non-Hispanic whites.

Furthermore, 75% of Hispanics, 72% of African-Americans, 71% of non-Hispanic whites, and 65% of Asians said they would likely participate in a clinical trial if it was recommended by a doctor.

And about three-quarters of all respondents said, assuming the correct privacy protections were in place, they would be willing to share personal health information to advance medical research.

“The poll reveals a willingness among minorities to participate in clinical trials to improve the quality of healthcare, but enrollment remains stubbornly low,” said Mary Woolley, president and CEO of Research!America.

Among those individuals surveyed, only 17% of Hispanics, 15% of African-Americans, 15% of non-Hispanic whites, and 11% of Asians said they or a family member had participated in a clinical trial.

When asked to give a reason for low enrollment in clinical trials, most respondents cited a lack of trust—61% of African-Americans, 54% of non-Hispanic whites, 52% of Hispanics, and 51% of Asians.

The importance of physicians, institutions

Many of the individuals surveyed said they had learned of clinical trials via the Internet—56% of Asians, 52% of non-Hispanic whites, 50% of African-Americans, and 45% of Hispanics.

Far fewer said they had heard of trials during discussions with their doctors—22% of Hispanics, 22% of non-Hispanic whites, 20% of Asians, and 17% of African-Americans.

And most respondents said a doctor’s recommendation is a “very” or “somewhat” important factor in the decision to participate in a clinical trial—81% of Hispanics, 81% of non-Hispanic whites, 80% of Asians, and 78% of African-Americans.

Institutional reputation was also deemed an important factor by 74% of African-Americans, 72% of non-Hispanic whites, 66% of Hispanics, and 66% of Asians.

And many respondents said healthcare providers should play a major role in raising awareness of clinical trials. In fact, 42% of non-Hispanic whites, 38% of Hispanics, 36% of Asians, and 33% of African-Americans said providers have the greatest responsibility in educating the public about clinical trials.

“It’s imperative that healthcare providers and others help patients gain a deeper knowledge of clinical trials so all Americans can benefit from life-saving treatments,” Woolley said.

This survey was conducted by Zogby Analytics for Research!America, the Association of Clinical Research Organizations, the Clinical Research Forum, the Friends of the National Library of Medicine, and the Clinical Trials Transformation Initiative.

Preparing pills for a clinical trial
Credit: Esther Dyson

Medication mistakes, reporting errors, and record changes are what led the US Food and Drug Administration (FDA) to delay approval of the anticoagulant apixaban (Eliquis), according to a report in Pharmaceutical Approvals Monthly.

The report reveals that a number of patients enrolled on the ARISTOTLE trial received the wrong medication or the wrong dose, some serious adverse events went unreported, and employees who worked at trial sites in China altered records to cover up noncompliance with “good clinical practice.”

Apixaban won FDA approval last December as prophylaxis for stroke and systemic embolism in patients with nonvalvular atrial fibrillation. And that approval was based on results of the ARISTOTLE trial.

Prior to the approval, the FDA twice rejected a new drug application filed by apixaban’s developers, Pfizer and Bristol-Myers Squibb. But the agency’s reasons were not immediately made public.

Now, the Pharmaceutical Approvals Monthly report and FDA documents show that “data irregularities” were behind the decision. 

In January 2012, Bristol-Myers Squibb notified the FDA of the cover-up attempt that occurred at (at least) 1 trial site in China. The company had learned that its senior manager at a site in Shanghai and an employee from a contract research organization had altered source records to conceal good clinical practice violations. (The employees were subsequently fired.)

According to FDA documents, the cover-up included failure to report 4 potential adverse events, late reports on 3 other events, and the omission of 3 patient outcomes. In addition, there were errors in patient names and dates, some Chinese and English records didn’t match up, and some patient records disappeared before a site visit by FDA inspectors.

Only 35 patients enrolled in the ARISTOTLE trial were treated at the Shanghai site, but the employees who perpetrated the fraud had also worked at 24 of the 36 trial sites in China.

So the FDA performed analyses excluding data from the Shanghai site alone, from the 24 sites where the employees worked, and from all 36 sites in China. And they found that apixaban’s efficacy still held up.

However, there was still the issue of ARISTOTLE participants receiving the wrong medication or the wrong dose. According to Bristol-Myers Squibb, the trial’s double-blind design allowed for dispensing errors.

Initially, the company said this meant that 7.3% of patients who were set to receive apixaban and 1.2% of patients who were set to receive warfarin may have received the wrong drug or dose at some point during the study. However, after additional review, the company said those percentages were likely much lower.

Regardless of the actual percentages, the FDA said this information suggests a pattern of inadequate oversight. And an independent review by FDA medical team leader Thomas Marciniak appears to support that statement. In addition to the aforementioned errors, his review revealed records of doctor visits taking place after patients’ deaths.

In spite of the errors and the fraud, the FDA said it remained convinced of apixaban’s efficacy. So the agency decided to approve the drug and leave out any mention of the data irregularities on the drug’s label.

Preparing pills for a clinical trial
Credit: Esther Dyson

Medication mistakes, reporting errors, and record changes are what led the US Food and Drug Administration (FDA) to delay approval of the anticoagulant apixaban (Eliquis), according to a report in Pharmaceutical Approvals Monthly.

The report reveals that a number of patients enrolled on the ARISTOTLE trial received the wrong medication or the wrong dose, some serious adverse events went unreported, and employees who worked at trial sites in China altered records to cover up noncompliance with “good clinical practice.”

Apixaban won FDA approval last December as prophylaxis for stroke and systemic embolism in patients with nonvalvular atrial fibrillation. And that approval was based on results of the ARISTOTLE trial.

Prior to the approval, the FDA twice rejected a new drug application filed by apixaban’s developers, Pfizer and Bristol-Myers Squibb. But the agency’s reasons were not immediately made public.

Now, the Pharmaceutical Approvals Monthly report and FDA documents show that “data irregularities” were behind the decision. 

In January 2012, Bristol-Myers Squibb notified the FDA of the cover-up attempt that occurred at (at least) 1 trial site in China. The company had learned that its senior manager at a site in Shanghai and an employee from a contract research organization had altered source records to conceal good clinical practice violations. (The employees were subsequently fired.)

According to FDA documents, the cover-up included failure to report 4 potential adverse events, late reports on 3 other events, and the omission of 3 patient outcomes. In addition, there were errors in patient names and dates, some Chinese and English records didn’t match up, and some patient records disappeared before a site visit by FDA inspectors.

Only 35 patients enrolled in the ARISTOTLE trial were treated at the Shanghai site, but the employees who perpetrated the fraud had also worked at 24 of the 36 trial sites in China.

So the FDA performed analyses excluding data from the Shanghai site alone, from the 24 sites where the employees worked, and from all 36 sites in China. And they found that apixaban’s efficacy still held up.

However, there was still the issue of ARISTOTLE participants receiving the wrong medication or the wrong dose. According to Bristol-Myers Squibb, the trial’s double-blind design allowed for dispensing errors.

Initially, the company said this meant that 7.3% of patients who were set to receive apixaban and 1.2% of patients who were set to receive warfarin may have received the wrong drug or dose at some point during the study. However, after additional review, the company said those percentages were likely much lower.

Regardless of the actual percentages, the FDA said this information suggests a pattern of inadequate oversight. And an independent review by FDA medical team leader Thomas Marciniak appears to support that statement. In addition to the aforementioned errors, his review revealed records of doctor visits taking place after patients’ deaths.

In spite of the errors and the fraud, the FDA said it remained convinced of apixaban’s efficacy. So the agency decided to approve the drug and leave out any mention of the data irregularities on the drug’s label.

Preparing pills for a clinical trial
Credit: Esther Dyson

Medication mistakes, reporting errors, and record changes are what led the US Food and Drug Administration (FDA) to delay approval of the anticoagulant apixaban (Eliquis), according to a report in Pharmaceutical Approvals Monthly.

The report reveals that a number of patients enrolled on the ARISTOTLE trial received the wrong medication or the wrong dose, some serious adverse events went unreported, and employees who worked at trial sites in China altered records to cover up noncompliance with “good clinical practice.”

Apixaban won FDA approval last December as prophylaxis for stroke and systemic embolism in patients with nonvalvular atrial fibrillation. And that approval was based on results of the ARISTOTLE trial.

Prior to the approval, the FDA twice rejected a new drug application filed by apixaban’s developers, Pfizer and Bristol-Myers Squibb. But the agency’s reasons were not immediately made public.

Now, the Pharmaceutical Approvals Monthly report and FDA documents show that “data irregularities” were behind the decision. 

In January 2012, Bristol-Myers Squibb notified the FDA of the cover-up attempt that occurred at (at least) 1 trial site in China. The company had learned that its senior manager at a site in Shanghai and an employee from a contract research organization had altered source records to conceal good clinical practice violations. (The employees were subsequently fired.)

According to FDA documents, the cover-up included failure to report 4 potential adverse events, late reports on 3 other events, and the omission of 3 patient outcomes. In addition, there were errors in patient names and dates, some Chinese and English records didn’t match up, and some patient records disappeared before a site visit by FDA inspectors.

Only 35 patients enrolled in the ARISTOTLE trial were treated at the Shanghai site, but the employees who perpetrated the fraud had also worked at 24 of the 36 trial sites in China.

So the FDA performed analyses excluding data from the Shanghai site alone, from the 24 sites where the employees worked, and from all 36 sites in China. And they found that apixaban’s efficacy still held up.

However, there was still the issue of ARISTOTLE participants receiving the wrong medication or the wrong dose. According to Bristol-Myers Squibb, the trial’s double-blind design allowed for dispensing errors.

Initially, the company said this meant that 7.3% of patients who were set to receive apixaban and 1.2% of patients who were set to receive warfarin may have received the wrong drug or dose at some point during the study. However, after additional review, the company said those percentages were likely much lower.

Regardless of the actual percentages, the FDA said this information suggests a pattern of inadequate oversight. And an independent review by FDA medical team leader Thomas Marciniak appears to support that statement. In addition to the aforementioned errors, his review revealed records of doctor visits taking place after patients’ deaths.

In spite of the errors and the fraud, the FDA said it remained convinced of apixaban’s efficacy. So the agency decided to approve the drug and leave out any mention of the data irregularities on the drug’s label.

Photo by Piotr Bodzek

AMSTERDAM—A recombinant factor IX Fc fusion protein (rFIXFc) can control bleeding among hemophilia B patients undergoing major surgery, according to data from the B-LONG study presented at ISTH 2013.

The goal of the phase 3 B-LONG study was to evaluate the safety, efficacy, and pharmacokinetics (PK) of rFIXFc among male patients with hemophilia B.

Previously released data from the study suggested rFIXFc can safely prevent bleeding in these patients, and the product stays in the body more than twice as long as the recombinant factor IX therapy BeneFIX.

At ISTH 2013, Jerry Powell, MD, of the University of California at Davis, presented an analysis of B-LONG data that demonstrated rFIXFc’s effects among hemophilia B patients who underwent major surgery (e-Poster PA 2.07-4).

The B-LONG study was sponsored by Biogen Idec and Sobi, the companies developing rFIXFc (also known as eftrenonacog alfa) as Alprolix.

The study included 123 male subjects with severe hemophilia B (≤2 IU/dL [2%] endogenous FIX). Patients were 12 years of age or older They had no current or previous FIX inhibitors and a history of 100 or more documented prior exposure days to FIX products.

Patients received rFIXFc in 1 of 4 treatment arms:

1. Weekly prophylaxis starting at 50 IU/kg, with PK-driven dose adjustments  (n=63)
2. Individualized interval prophylaxis starting at 100 IU/kg every 10 days, with PK-driven interval adjustments (n=29)
3. On-demand treatment at 20 IU/kg to 100 IU/kg (n=27)
4. Perioperative management (n=12, including 8 from arms 1-3).

The patients who required major surgery were placed in arm 4. Investigators and surgeons decided upon treatment for these patients based on considerations of their rFIXFc PK profile, the type of planned surgery, and the patients’ clinical status.

The 12 patients underwent a total of 14 major surgeries, including arthroscopic meniscectomy of knee (n=1), arthroscopic ankle fusion (n=1), knee replacements (n=5), and other (n=7).

The investigators/surgeons rated hemostasis as “excellent” in 13 of the surgeries and “good” for 1 procedure.

The median estimated blood loss was 65.5 mL (range, 0.0 to 300.0 mL) during surgery and 0.0 mL (range, 0.0 to 500 mL) after surgery. None of the patients required blood transfusions during surgery, but 2 patients received transfusions postoperatively.

In most of the surgeries—85.7%—patients required a single injection of rFIXFc to maintain hemostasis during the operation. The median dose was 90.9 IU/kg per injection.

Most patients required 1 to 2 injections of rFIXFc the day before and the day of surgery. And most patients required 2 to 3 injections from days 1 to 3 after surgery. So the median rFIXFc consumption was 146.1 IU/kg on the day of surgery, 164.6 IU/kg from days 1 to 3 after surgery, and 277.1 IU/kg for days 4 to 14 after surgery.

A majority of patients—83.3% (10/12)—experienced 1 or more adverse events related to treatment. Three patients experienced 6 adverse events, but these were resolved, and investigators said they were unrelated to rFIXFc treatment.

Additional analyses of B-LONG data were presented at ISTH 2013, including an analysis of rFIXFc in the treatment of bleeding episodes and a PK analysis of rFIXFc.

Photo by Piotr Bodzek

AMSTERDAM—A recombinant factor IX Fc fusion protein (rFIXFc) can control bleeding among hemophilia B patients undergoing major surgery, according to data from the B-LONG study presented at ISTH 2013.

The goal of the phase 3 B-LONG study was to evaluate the safety, efficacy, and pharmacokinetics (PK) of rFIXFc among male patients with hemophilia B.

Previously released data from the study suggested rFIXFc can safely prevent bleeding in these patients, and the product stays in the body more than twice as long as the recombinant factor IX therapy BeneFIX.

At ISTH 2013, Jerry Powell, MD, of the University of California at Davis, presented an analysis of B-LONG data that demonstrated rFIXFc’s effects among hemophilia B patients who underwent major surgery (e-Poster PA 2.07-4).

The B-LONG study was sponsored by Biogen Idec and Sobi, the companies developing rFIXFc (also known as eftrenonacog alfa) as Alprolix.

The study included 123 male subjects with severe hemophilia B (≤2 IU/dL [2%] endogenous FIX). Patients were 12 years of age or older They had no current or previous FIX inhibitors and a history of 100 or more documented prior exposure days to FIX products.

Patients received rFIXFc in 1 of 4 treatment arms:

1. Weekly prophylaxis starting at 50 IU/kg, with PK-driven dose adjustments  (n=63)
2. Individualized interval prophylaxis starting at 100 IU/kg every 10 days, with PK-driven interval adjustments (n=29)
3. On-demand treatment at 20 IU/kg to 100 IU/kg (n=27)
4. Perioperative management (n=12, including 8 from arms 1-3).

The patients who required major surgery were placed in arm 4. Investigators and surgeons decided upon treatment for these patients based on considerations of their rFIXFc PK profile, the type of planned surgery, and the patients’ clinical status.

The 12 patients underwent a total of 14 major surgeries, including arthroscopic meniscectomy of knee (n=1), arthroscopic ankle fusion (n=1), knee replacements (n=5), and other (n=7).

The investigators/surgeons rated hemostasis as “excellent” in 13 of the surgeries and “good” for 1 procedure.

The median estimated blood loss was 65.5 mL (range, 0.0 to 300.0 mL) during surgery and 0.0 mL (range, 0.0 to 500 mL) after surgery. None of the patients required blood transfusions during surgery, but 2 patients received transfusions postoperatively.

In most of the surgeries—85.7%—patients required a single injection of rFIXFc to maintain hemostasis during the operation. The median dose was 90.9 IU/kg per injection.

Most patients required 1 to 2 injections of rFIXFc the day before and the day of surgery. And most patients required 2 to 3 injections from days 1 to 3 after surgery. So the median rFIXFc consumption was 146.1 IU/kg on the day of surgery, 164.6 IU/kg from days 1 to 3 after surgery, and 277.1 IU/kg for days 4 to 14 after surgery.

A majority of patients—83.3% (10/12)—experienced 1 or more adverse events related to treatment. Three patients experienced 6 adverse events, but these were resolved, and investigators said they were unrelated to rFIXFc treatment.

Additional analyses of B-LONG data were presented at ISTH 2013, including an analysis of rFIXFc in the treatment of bleeding episodes and a PK analysis of rFIXFc.

Photo by Piotr Bodzek

AMSTERDAM—A recombinant factor IX Fc fusion protein (rFIXFc) can control bleeding among hemophilia B patients undergoing major surgery, according to data from the B-LONG study presented at ISTH 2013.

The goal of the phase 3 B-LONG study was to evaluate the safety, efficacy, and pharmacokinetics (PK) of rFIXFc among male patients with hemophilia B.

Previously released data from the study suggested rFIXFc can safely prevent bleeding in these patients, and the product stays in the body more than twice as long as the recombinant factor IX therapy BeneFIX.

At ISTH 2013, Jerry Powell, MD, of the University of California at Davis, presented an analysis of B-LONG data that demonstrated rFIXFc’s effects among hemophilia B patients who underwent major surgery (e-Poster PA 2.07-4).

The B-LONG study was sponsored by Biogen Idec and Sobi, the companies developing rFIXFc (also known as eftrenonacog alfa) as Alprolix.

The study included 123 male subjects with severe hemophilia B (≤2 IU/dL [2%] endogenous FIX). Patients were 12 years of age or older They had no current or previous FIX inhibitors and a history of 100 or more documented prior exposure days to FIX products.

Patients received rFIXFc in 1 of 4 treatment arms:

1. Weekly prophylaxis starting at 50 IU/kg, with PK-driven dose adjustments  (n=63)
2. Individualized interval prophylaxis starting at 100 IU/kg every 10 days, with PK-driven interval adjustments (n=29)
3. On-demand treatment at 20 IU/kg to 100 IU/kg (n=27)
4. Perioperative management (n=12, including 8 from arms 1-3).

The patients who required major surgery were placed in arm 4. Investigators and surgeons decided upon treatment for these patients based on considerations of their rFIXFc PK profile, the type of planned surgery, and the patients’ clinical status.

The 12 patients underwent a total of 14 major surgeries, including arthroscopic meniscectomy of knee (n=1), arthroscopic ankle fusion (n=1), knee replacements (n=5), and other (n=7).

The investigators/surgeons rated hemostasis as “excellent” in 13 of the surgeries and “good” for 1 procedure.

The median estimated blood loss was 65.5 mL (range, 0.0 to 300.0 mL) during surgery and 0.0 mL (range, 0.0 to 500 mL) after surgery. None of the patients required blood transfusions during surgery, but 2 patients received transfusions postoperatively.

In most of the surgeries—85.7%—patients required a single injection of rFIXFc to maintain hemostasis during the operation. The median dose was 90.9 IU/kg per injection.

Most patients required 1 to 2 injections of rFIXFc the day before and the day of surgery. And most patients required 2 to 3 injections from days 1 to 3 after surgery. So the median rFIXFc consumption was 146.1 IU/kg on the day of surgery, 164.6 IU/kg from days 1 to 3 after surgery, and 277.1 IU/kg for days 4 to 14 after surgery.

A majority of patients—83.3% (10/12)—experienced 1 or more adverse events related to treatment. Three patients experienced 6 adverse events, but these were resolved, and investigators said they were unrelated to rFIXFc treatment.

Additional analyses of B-LONG data were presented at ISTH 2013, including an analysis of rFIXFc in the treatment of bleeding episodes and a PK analysis of rFIXFc.

Blood for transfusion

Canada is lifting the lifetime ban on blood donations from men who have sex with men (MSM).

The country’s new policy will allow MSM to donate blood if they have remained celibate for 5 years. The policy is set to take effect July 22.

Health Canada approved this change based on a request from Canadian Blood Services and Héma-Québec submitted last December. 

The lifetime ban on MSM blood donation was insituted in the 1980s after thousands of Canadians were infected with HIV through blood transfusions.

In the US, the lifetime ban is still in place. But the UK, Australia, and other countries have adopted policies alowing MSM to donate if they have refrained from sexual activity for a certain period of time.

Supporters of the lifetime ban on MSM have said such a policy helps ensure a safe blood supply. But critics have said banning MSM is discriminatory, and the policy lacks scientific evidence to support it.

“We recognize that many people will feel that this change does not go far enough, but, given the history of the blood system in Canada, we see this as a first and prudent step forward on this policy,” said Dana Devine, Vice President of Medical, Scientific, and Research Affairs at Canadian Blood Services.

“It’s the right thing to do, and we are committed to regular review of this policy as additional data emerge and new technologies are implemented.”

Under the new policy, potential male blood donors will be asked whether they have had sex with a man in the past 5 years rather than “even once, since 1977,” which is how the policy has read until now.

Canadian Blood Services has been pursuing data to inform a policy change on MSM for several years. In September 2011, the organization’s board of directors passed a motion committing to re-examine this policy, with a view to reduce the lifetime exclusion to no less than 5 years and no longer than 10 years.

After conducting risk analyses and consulting with scientific experts, as well as patient and community groups, Canadian Blood Services and Héma-Québec submitted a policy request to Health Canada in December 2012.

Health Canada approved the policy change with the stipulation that blood operators must closely monitor and report the potential impacts of this change in terms of transmissible disease rates back to the regulator.

Blood for transfusion

Canada is lifting the lifetime ban on blood donations from men who have sex with men (MSM).

The country’s new policy will allow MSM to donate blood if they have remained celibate for 5 years. The policy is set to take effect July 22.

Health Canada approved this change based on a request from Canadian Blood Services and Héma-Québec submitted last December. 

The lifetime ban on MSM blood donation was insituted in the 1980s after thousands of Canadians were infected with HIV through blood transfusions.

In the US, the lifetime ban is still in place. But the UK, Australia, and other countries have adopted policies alowing MSM to donate if they have refrained from sexual activity for a certain period of time.

Supporters of the lifetime ban on MSM have said such a policy helps ensure a safe blood supply. But critics have said banning MSM is discriminatory, and the policy lacks scientific evidence to support it.

“We recognize that many people will feel that this change does not go far enough, but, given the history of the blood system in Canada, we see this as a first and prudent step forward on this policy,” said Dana Devine, Vice President of Medical, Scientific, and Research Affairs at Canadian Blood Services.

“It’s the right thing to do, and we are committed to regular review of this policy as additional data emerge and new technologies are implemented.”

Under the new policy, potential male blood donors will be asked whether they have had sex with a man in the past 5 years rather than “even once, since 1977,” which is how the policy has read until now.

Canadian Blood Services has been pursuing data to inform a policy change on MSM for several years. In September 2011, the organization’s board of directors passed a motion committing to re-examine this policy, with a view to reduce the lifetime exclusion to no less than 5 years and no longer than 10 years.

After conducting risk analyses and consulting with scientific experts, as well as patient and community groups, Canadian Blood Services and Héma-Québec submitted a policy request to Health Canada in December 2012.

Health Canada approved the policy change with the stipulation that blood operators must closely monitor and report the potential impacts of this change in terms of transmissible disease rates back to the regulator.

Blood for transfusion

Canada is lifting the lifetime ban on blood donations from men who have sex with men (MSM).

The country’s new policy will allow MSM to donate blood if they have remained celibate for 5 years. The policy is set to take effect July 22.

Health Canada approved this change based on a request from Canadian Blood Services and Héma-Québec submitted last December. 

The lifetime ban on MSM blood donation was insituted in the 1980s after thousands of Canadians were infected with HIV through blood transfusions.

In the US, the lifetime ban is still in place. But the UK, Australia, and other countries have adopted policies alowing MSM to donate if they have refrained from sexual activity for a certain period of time.

Supporters of the lifetime ban on MSM have said such a policy helps ensure a safe blood supply. But critics have said banning MSM is discriminatory, and the policy lacks scientific evidence to support it.

“We recognize that many people will feel that this change does not go far enough, but, given the history of the blood system in Canada, we see this as a first and prudent step forward on this policy,” said Dana Devine, Vice President of Medical, Scientific, and Research Affairs at Canadian Blood Services.

“It’s the right thing to do, and we are committed to regular review of this policy as additional data emerge and new technologies are implemented.”

Under the new policy, potential male blood donors will be asked whether they have had sex with a man in the past 5 years rather than “even once, since 1977,” which is how the policy has read until now.

Canadian Blood Services has been pursuing data to inform a policy change on MSM for several years. In September 2011, the organization’s board of directors passed a motion committing to re-examine this policy, with a view to reduce the lifetime exclusion to no less than 5 years and no longer than 10 years.

After conducting risk analyses and consulting with scientific experts, as well as patient and community groups, Canadian Blood Services and Héma-Québec submitted a policy request to Health Canada in December 2012.

Health Canada approved the policy change with the stipulation that blood operators must closely monitor and report the potential impacts of this change in terms of transmissible disease rates back to the regulator.

Thrombus
Credit: Andre E.X. Brown

SAN FRANCISCO—The novel antiplatelet agent cangrelor is more effective than clopidogrel as thromboprophylaxis for patients undergoing coronary stent procedures, results of the CHAMPION PHOENIX trial suggest.

Researchers found that intravenous cangrelor reduced the overall odds of complications from stenting procedures, including death, myocardial infarction, ischemia-driven revascularization, and stent thrombosis.

Treatment with cangrelor also resulted in significantly higher rates of major and minor bleeding as compared to clopidogrel. But the rates of severe bleeding were similar between the treatment arms.

These data were presented on March 10 at the 2013 American College of Cardiology Scientific Session and simultaneously published in NEJM. The study was sponsored by The Medicines Company, the makers of cangrelor.

“We are very excited about the potential for this new medication to reduce complications in patients receiving coronary stents for a wide variety of indications,” said investigator Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital in Boston.

“In addition to being much quicker to take effect and more potent than currently available treatment options, this intravenous drug is reversible and has a fast offset of action, which could be an advantage if emergency surgery is needed.”

In this randomized, double-blind trial, Dr Bhatt and his colleagues compared cangrelor to clopidogrel in 11,145 patients treated at 153 centers around the world.

The study included patients who were undergoing elective or urgent percutaneous coronary intervention. Patients with a high risk of bleeding or recent exposure to other anticoagulants were excluded.

The study’s primary efficacy endpoint was the incidence of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis.

At 48 hours, 4.7% of patients in the cangrelor arm had met this endpoint, compared to 5.9% of patients in the clopidogrel arm (P=0.005). At 30 days, the incidence was 6.0% in the cangrelor arm and 7.0% in the clopidogrel arm (P=0.03).

A secondary endpoint was the rate of stent thrombosis alone. At 48 hours, 0.8% of patients in the cangrelor arm had stent thrombosis, as did 1.4% of patients in the clopidogrel arm (P=0.01). At 30 days, the rate was 1.3% in the cangrelor arm and 1.9% in the clopidogrel arm (P=0.01).

The primary safety endpoint was severe bleeding according to GUSTO criteria. At 48 hours, it measured 0.16% in the cangrelor arm and 0.11% in the clopidogrel arm (P=0.44).

Secondary endpoints included major and minor bleeding (not related to coronary artery bypass grafting) according to ACUITY criteria. 

Major bleeding occurred in 4.3% of patients on cangrelor and 2.5% of patients on clopidogrel (P<0.001). And minor bleeding occurred in 11.8% of patients on cangrelor and 8.6% of patients on clopidogrel (P<0.001).

Other treatment-emergent adverse events included agitation, diarrhea, chest pain, dyspnea, and procedural pain. There were significantly more cases of transient dyspnea with cangrelor

than with clopidogrel, at 1.2% and 0.3%, respectively (P<0.001). But there were no statistically significant differences with regard to adverse events other than those mentioned here.

The overall rate of treatment-related adverse events was 20.2% in the cangrelor arm and 19.1% in the clopidogrel arm (P=0.13). And these events led to treatment discontinuation in 0.5% of patients in the cangrelor arm and 0.4% of patients in the clopidogrel arm. 

“The investigators feel the data are compelling,” Dr Bhatt concluded. “The data we’ve shown are clear and consistent across all relevant subgroups or patient populations. [Cangrelor] has several advantages, and nothing out there right now has quite the same biological properties.”

Thrombus
Credit: Andre E.X. Brown

SAN FRANCISCO—The novel antiplatelet agent cangrelor is more effective than clopidogrel as thromboprophylaxis for patients undergoing coronary stent procedures, results of the CHAMPION PHOENIX trial suggest.

Researchers found that intravenous cangrelor reduced the overall odds of complications from stenting procedures, including death, myocardial infarction, ischemia-driven revascularization, and stent thrombosis.

Treatment with cangrelor also resulted in significantly higher rates of major and minor bleeding as compared to clopidogrel. But the rates of severe bleeding were similar between the treatment arms.

These data were presented on March 10 at the 2013 American College of Cardiology Scientific Session and simultaneously published in NEJM. The study was sponsored by The Medicines Company, the makers of cangrelor.

“We are very excited about the potential for this new medication to reduce complications in patients receiving coronary stents for a wide variety of indications,” said investigator Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital in Boston.

“In addition to being much quicker to take effect and more potent than currently available treatment options, this intravenous drug is reversible and has a fast offset of action, which could be an advantage if emergency surgery is needed.”

In this randomized, double-blind trial, Dr Bhatt and his colleagues compared cangrelor to clopidogrel in 11,145 patients treated at 153 centers around the world.

The study included patients who were undergoing elective or urgent percutaneous coronary intervention. Patients with a high risk of bleeding or recent exposure to other anticoagulants were excluded.

The study’s primary efficacy endpoint was the incidence of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis.

At 48 hours, 4.7% of patients in the cangrelor arm had met this endpoint, compared to 5.9% of patients in the clopidogrel arm (P=0.005). At 30 days, the incidence was 6.0% in the cangrelor arm and 7.0% in the clopidogrel arm (P=0.03).

A secondary endpoint was the rate of stent thrombosis alone. At 48 hours, 0.8% of patients in the cangrelor arm had stent thrombosis, as did 1.4% of patients in the clopidogrel arm (P=0.01). At 30 days, the rate was 1.3% in the cangrelor arm and 1.9% in the clopidogrel arm (P=0.01).

The primary safety endpoint was severe bleeding according to GUSTO criteria. At 48 hours, it measured 0.16% in the cangrelor arm and 0.11% in the clopidogrel arm (P=0.44).

Secondary endpoints included major and minor bleeding (not related to coronary artery bypass grafting) according to ACUITY criteria. 

Major bleeding occurred in 4.3% of patients on cangrelor and 2.5% of patients on clopidogrel (P<0.001). And minor bleeding occurred in 11.8% of patients on cangrelor and 8.6% of patients on clopidogrel (P<0.001).

Other treatment-emergent adverse events included agitation, diarrhea, chest pain, dyspnea, and procedural pain. There were significantly more cases of transient dyspnea with cangrelor

than with clopidogrel, at 1.2% and 0.3%, respectively (P<0.001). But there were no statistically significant differences with regard to adverse events other than those mentioned here.

The overall rate of treatment-related adverse events was 20.2% in the cangrelor arm and 19.1% in the clopidogrel arm (P=0.13). And these events led to treatment discontinuation in 0.5% of patients in the cangrelor arm and 0.4% of patients in the clopidogrel arm. 

“The investigators feel the data are compelling,” Dr Bhatt concluded. “The data we’ve shown are clear and consistent across all relevant subgroups or patient populations. [Cangrelor] has several advantages, and nothing out there right now has quite the same biological properties.”

Thrombus
Credit: Andre E.X. Brown

SAN FRANCISCO—The novel antiplatelet agent cangrelor is more effective than clopidogrel as thromboprophylaxis for patients undergoing coronary stent procedures, results of the CHAMPION PHOENIX trial suggest.

Researchers found that intravenous cangrelor reduced the overall odds of complications from stenting procedures, including death, myocardial infarction, ischemia-driven revascularization, and stent thrombosis.

Treatment with cangrelor also resulted in significantly higher rates of major and minor bleeding as compared to clopidogrel. But the rates of severe bleeding were similar between the treatment arms.

These data were presented on March 10 at the 2013 American College of Cardiology Scientific Session and simultaneously published in NEJM. The study was sponsored by The Medicines Company, the makers of cangrelor.

“We are very excited about the potential for this new medication to reduce complications in patients receiving coronary stents for a wide variety of indications,” said investigator Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital in Boston.

“In addition to being much quicker to take effect and more potent than currently available treatment options, this intravenous drug is reversible and has a fast offset of action, which could be an advantage if emergency surgery is needed.”

In this randomized, double-blind trial, Dr Bhatt and his colleagues compared cangrelor to clopidogrel in 11,145 patients treated at 153 centers around the world.

The study included patients who were undergoing elective or urgent percutaneous coronary intervention. Patients with a high risk of bleeding or recent exposure to other anticoagulants were excluded.

The study’s primary efficacy endpoint was the incidence of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis.

At 48 hours, 4.7% of patients in the cangrelor arm had met this endpoint, compared to 5.9% of patients in the clopidogrel arm (P=0.005). At 30 days, the incidence was 6.0% in the cangrelor arm and 7.0% in the clopidogrel arm (P=0.03).

A secondary endpoint was the rate of stent thrombosis alone. At 48 hours, 0.8% of patients in the cangrelor arm had stent thrombosis, as did 1.4% of patients in the clopidogrel arm (P=0.01). At 30 days, the rate was 1.3% in the cangrelor arm and 1.9% in the clopidogrel arm (P=0.01).

The primary safety endpoint was severe bleeding according to GUSTO criteria. At 48 hours, it measured 0.16% in the cangrelor arm and 0.11% in the clopidogrel arm (P=0.44).

Secondary endpoints included major and minor bleeding (not related to coronary artery bypass grafting) according to ACUITY criteria. 

Major bleeding occurred in 4.3% of patients on cangrelor and 2.5% of patients on clopidogrel (P<0.001). And minor bleeding occurred in 11.8% of patients on cangrelor and 8.6% of patients on clopidogrel (P<0.001).

Other treatment-emergent adverse events included agitation, diarrhea, chest pain, dyspnea, and procedural pain. There were significantly more cases of transient dyspnea with cangrelor

than with clopidogrel, at 1.2% and 0.3%, respectively (P<0.001). But there were no statistically significant differences with regard to adverse events other than those mentioned here.

The overall rate of treatment-related adverse events was 20.2% in the cangrelor arm and 19.1% in the clopidogrel arm (P=0.13). And these events led to treatment discontinuation in 0.5% of patients in the cangrelor arm and 0.4% of patients in the clopidogrel arm. 

“The investigators feel the data are compelling,” Dr Bhatt concluded. “The data we’ve shown are clear and consistent across all relevant subgroups or patient populations. [Cangrelor] has several advantages, and nothing out there right now has quite the same biological properties.”

Prescription drugs
Credit: CDC

For a second time, the FDA has decided against approving rivaroxaban (Xarelto) to reduce the risk of cardiovascular events in patients with acute coronary syndrome (ACS).

The agency has issued a complete response letter to the drug’s makers, Janssen Pharmaceuticals.

The contents of the letter are not publicly known, but representatives at Janssen have said they “are evaluating the letter and will respond to the agency’s questions.”

This is not the first time the FDA has raised questions about the use of rivaroxaban in ACS. Last June, the agency issued a complete response letter requesting additional information on the drug.

A month before that, an FDA review committee had expressed concerns about missing follow-up data from the ATLAS ACS 2 TIMI 51 trial (JL Mega et al, NEJM, 2012).

So in September, Janssen supplied the FDA with data on the patients who had withdrawn from trial. The company was able to confirm the vital status information for 843 (63%) of the 1338 trial participants who previously had unknown vital status.

Of those 843 patients, 37 had died. The company said the deaths were equally distributed among the treatment groups—rivaroxaban at 2.5 mg, rivaroxaban at 5 mg, and placebo.

“We remain confident in the robustness and results of the ATLAS ACS 2 TIMI 51 trial, evidenced by a significant reduction in cardiovascular events, including a clinically important decrease in cardiovascular death . . . ,” said Christopher Nessel, Vice President at Janssen.

“While we saw an increase in major bleeding, there was no increase in fatal bleeding. We will continue to work with the FDA to address their questions.”

Rivaroxaban is already approved by the FDA to treat and prevent the recurrence of deep vein thrombosis and pulmonary embolism, as thromboprophylaxis in patients who have undergone knee or hip replacement surgery, as well as to reduce the risk of stroke in patients with non-valvular atrial fibrillation.

Prescription drugs
Credit: CDC

For a second time, the FDA has decided against approving rivaroxaban (Xarelto) to reduce the risk of cardiovascular events in patients with acute coronary syndrome (ACS).

The agency has issued a complete response letter to the drug’s makers, Janssen Pharmaceuticals.

The contents of the letter are not publicly known, but representatives at Janssen have said they “are evaluating the letter and will respond to the agency’s questions.”

This is not the first time the FDA has raised questions about the use of rivaroxaban in ACS. Last June, the agency issued a complete response letter requesting additional information on the drug.

A month before that, an FDA review committee had expressed concerns about missing follow-up data from the ATLAS ACS 2 TIMI 51 trial (JL Mega et al, NEJM, 2012).

So in September, Janssen supplied the FDA with data on the patients who had withdrawn from trial. The company was able to confirm the vital status information for 843 (63%) of the 1338 trial participants who previously had unknown vital status.

Of those 843 patients, 37 had died. The company said the deaths were equally distributed among the treatment groups—rivaroxaban at 2.5 mg, rivaroxaban at 5 mg, and placebo.

“We remain confident in the robustness and results of the ATLAS ACS 2 TIMI 51 trial, evidenced by a significant reduction in cardiovascular events, including a clinically important decrease in cardiovascular death . . . ,” said Christopher Nessel, Vice President at Janssen.

“While we saw an increase in major bleeding, there was no increase in fatal bleeding. We will continue to work with the FDA to address their questions.”

Rivaroxaban is already approved by the FDA to treat and prevent the recurrence of deep vein thrombosis and pulmonary embolism, as thromboprophylaxis in patients who have undergone knee or hip replacement surgery, as well as to reduce the risk of stroke in patients with non-valvular atrial fibrillation.

Prescription drugs
Credit: CDC

For a second time, the FDA has decided against approving rivaroxaban (Xarelto) to reduce the risk of cardiovascular events in patients with acute coronary syndrome (ACS).

The agency has issued a complete response letter to the drug’s makers, Janssen Pharmaceuticals.

The contents of the letter are not publicly known, but representatives at Janssen have said they “are evaluating the letter and will respond to the agency’s questions.”

This is not the first time the FDA has raised questions about the use of rivaroxaban in ACS. Last June, the agency issued a complete response letter requesting additional information on the drug.

A month before that, an FDA review committee had expressed concerns about missing follow-up data from the ATLAS ACS 2 TIMI 51 trial (JL Mega et al, NEJM, 2012).

So in September, Janssen supplied the FDA with data on the patients who had withdrawn from trial. The company was able to confirm the vital status information for 843 (63%) of the 1338 trial participants who previously had unknown vital status.

Of those 843 patients, 37 had died. The company said the deaths were equally distributed among the treatment groups—rivaroxaban at 2.5 mg, rivaroxaban at 5 mg, and placebo.

“We remain confident in the robustness and results of the ATLAS ACS 2 TIMI 51 trial, evidenced by a significant reduction in cardiovascular events, including a clinically important decrease in cardiovascular death . . . ,” said Christopher Nessel, Vice President at Janssen.

“While we saw an increase in major bleeding, there was no increase in fatal bleeding. We will continue to work with the FDA to address their questions.”

Rivaroxaban is already approved by the FDA to treat and prevent the recurrence of deep vein thrombosis and pulmonary embolism, as thromboprophylaxis in patients who have undergone knee or hip replacement surgery, as well as to reduce the risk of stroke in patients with non-valvular atrial fibrillation.

Thrombus
Credit: Andre E.X. Brown

New research suggests dabigatran is noninferior to warfarin as extended prophylaxis for recurrent venous thromboembolism (VTE), and warfarin presents a significantly higher risk of bleeding.

These results are from the RE-MEDY study, which compared the 2 drugs as long-term prophylaxis in patients who had received at least 3 months of VTE treatment.

The data appear in an NEJM article alongside results of the RE-SONATE study, which compared dabigatran and placebo in a similar patient population.

Both of these randomized, double-blind studies were sponsored by the makers of dabigatran, Boehringer Ingelheim.

In the RE-MEDY trial, 2856 patients were randomized in a 1:1 ratio to receive dabigatran or warfarin for up to 36 months. Patients either received active dabigatran at 150 mg twice daily and a warfarin-like placebo or active warfarin and a dabigatran-like placebo. The warfarin dose was adjusted to maintain an INR of 2.0 to 3.0.

In the RE-SONATE trial, 1343 patients were randomized to receive treatment for 6 months. They were assigned in a 1:1 ratio to receive dabigatran at 150 mg twice daily or a matching placebo.

Extended follow-up to evaluate the long-term risk of VTE recurrence took place 12 months after the completion of study treatment.

In RE-MEDY, recurrent VTE occurred in 1.8% of patients in the dabigatran arm and 1.3% of patients in the warfarin arm (P=0.01 for noninferiority).

In RE-SONATE, recurrent VTE occurred in 0.4% of patients in the dabigatran arm and 5.6% of patients in the placebo arm (P<0.001 for superiority).

The rate of clinically relevant or major bleeding was lower with dabigatran than with warfarin—at 5.6% and 10.2%, respectively (P<0.001).

But the rate of clinically relevant or major bleeding was higher with dabigatran than with placebo, at 5.3% and 1.8%, respectively (P=0.001).

“[These results] suggest dabigatran is a good option to prevent deep vein thrombosis and pulmonary embolism from happening again after an initial event,” said lead study author Sam Schulman, MD, PhD, of McMaster University in Hamilton, Ontario, Canada.

“They reinforce the efficacy and favorable safety profile of dabigatran seen in the RE-COVER trials, where dabigatran showed similar efficacy and a significant reduction in clinically relevant bleeding versus warfarin in the treatment of acute venous thromboembolism.”

Thrombus
Credit: Andre E.X. Brown

New research suggests dabigatran is noninferior to warfarin as extended prophylaxis for recurrent venous thromboembolism (VTE), and warfarin presents a significantly higher risk of bleeding.

These results are from the RE-MEDY study, which compared the 2 drugs as long-term prophylaxis in patients who had received at least 3 months of VTE treatment.

The data appear in an NEJM article alongside results of the RE-SONATE study, which compared dabigatran and placebo in a similar patient population.

Both of these randomized, double-blind studies were sponsored by the makers of dabigatran, Boehringer Ingelheim.

In the RE-MEDY trial, 2856 patients were randomized in a 1:1 ratio to receive dabigatran or warfarin for up to 36 months. Patients either received active dabigatran at 150 mg twice daily and a warfarin-like placebo or active warfarin and a dabigatran-like placebo. The warfarin dose was adjusted to maintain an INR of 2.0 to 3.0.

In the RE-SONATE trial, 1343 patients were randomized to receive treatment for 6 months. They were assigned in a 1:1 ratio to receive dabigatran at 150 mg twice daily or a matching placebo.

Extended follow-up to evaluate the long-term risk of VTE recurrence took place 12 months after the completion of study treatment.

In RE-MEDY, recurrent VTE occurred in 1.8% of patients in the dabigatran arm and 1.3% of patients in the warfarin arm (P=0.01 for noninferiority).

In RE-SONATE, recurrent VTE occurred in 0.4% of patients in the dabigatran arm and 5.6% of patients in the placebo arm (P<0.001 for superiority).

The rate of clinically relevant or major bleeding was lower with dabigatran than with warfarin—at 5.6% and 10.2%, respectively (P<0.001).

But the rate of clinically relevant or major bleeding was higher with dabigatran than with placebo, at 5.3% and 1.8%, respectively (P=0.001).

“[These results] suggest dabigatran is a good option to prevent deep vein thrombosis and pulmonary embolism from happening again after an initial event,” said lead study author Sam Schulman, MD, PhD, of McMaster University in Hamilton, Ontario, Canada.

“They reinforce the efficacy and favorable safety profile of dabigatran seen in the RE-COVER trials, where dabigatran showed similar efficacy and a significant reduction in clinically relevant bleeding versus warfarin in the treatment of acute venous thromboembolism.”

Thrombus
Credit: Andre E.X. Brown

New research suggests dabigatran is noninferior to warfarin as extended prophylaxis for recurrent venous thromboembolism (VTE), and warfarin presents a significantly higher risk of bleeding.

These results are from the RE-MEDY study, which compared the 2 drugs as long-term prophylaxis in patients who had received at least 3 months of VTE treatment.

The data appear in an NEJM article alongside results of the RE-SONATE study, which compared dabigatran and placebo in a similar patient population.

Both of these randomized, double-blind studies were sponsored by the makers of dabigatran, Boehringer Ingelheim.

In the RE-MEDY trial, 2856 patients were randomized in a 1:1 ratio to receive dabigatran or warfarin for up to 36 months. Patients either received active dabigatran at 150 mg twice daily and a warfarin-like placebo or active warfarin and a dabigatran-like placebo. The warfarin dose was adjusted to maintain an INR of 2.0 to 3.0.

In the RE-SONATE trial, 1343 patients were randomized to receive treatment for 6 months. They were assigned in a 1:1 ratio to receive dabigatran at 150 mg twice daily or a matching placebo.

Extended follow-up to evaluate the long-term risk of VTE recurrence took place 12 months after the completion of study treatment.

In RE-MEDY, recurrent VTE occurred in 1.8% of patients in the dabigatran arm and 1.3% of patients in the warfarin arm (P=0.01 for noninferiority).

In RE-SONATE, recurrent VTE occurred in 0.4% of patients in the dabigatran arm and 5.6% of patients in the placebo arm (P<0.001 for superiority).

The rate of clinically relevant or major bleeding was lower with dabigatran than with warfarin—at 5.6% and 10.2%, respectively (P<0.001).

But the rate of clinically relevant or major bleeding was higher with dabigatran than with placebo, at 5.3% and 1.8%, respectively (P=0.001).

“[These results] suggest dabigatran is a good option to prevent deep vein thrombosis and pulmonary embolism from happening again after an initial event,” said lead study author Sam Schulman, MD, PhD, of McMaster University in Hamilton, Ontario, Canada.

“They reinforce the efficacy and favorable safety profile of dabigatran seen in the RE-COVER trials, where dabigatran showed similar efficacy and a significant reduction in clinically relevant bleeding versus warfarin in the treatment of acute venous thromboembolism.”

Preparing drugs for a trial

Credit: Esther Dyson

After 2 deaths among patients receiving the BCL-2 inhibitor ABT-199, the company developing the drug has suspended enrollment in 5 trials and stopped dose-escalation of the drug.

The patients died of tumor lysis syndrome, a complication that likely stems from the drug’s potency, according to Tracy Sorrentino, a spokeswoman for the company, AbbVie.

Research has suggested the risk of tumor lysis syndrome might be eliminated by altering the dose of ABT-199, Sorrentino said.

But until that is confirmed, AbbVie has stopped dose-escalation in patients receiving ABT-199 and voluntarily suspended enrollment in phase 1 trials of the drug.

The trials are testing ABT-199, both alone and in combination, as a treatment for chronic lymphocytic leukemia, non-Hodgkin lymphoma, and small lymphocytic lymphoma.

Though enrollment has stopped for these trials, dosing of active patients in ABT-199 trials will continue. In addition, a study testing ABT-199 in women with systemic lupus erythematosus is still enrolling patients.

Sorrentino said AbbVie has “every expectation” the suspended enrollment is temporary, and refining the dose of ABT-199 may eliminate the problem. In fact, the company is still planning to begin phase 3 trials of the drug later this year.

Preparing drugs for a trial

Credit: Esther Dyson

After 2 deaths among patients receiving the BCL-2 inhibitor ABT-199, the company developing the drug has suspended enrollment in 5 trials and stopped dose-escalation of the drug.

The patients died of tumor lysis syndrome, a complication that likely stems from the drug’s potency, according to Tracy Sorrentino, a spokeswoman for the company, AbbVie.

Research has suggested the risk of tumor lysis syndrome might be eliminated by altering the dose of ABT-199, Sorrentino said.

But until that is confirmed, AbbVie has stopped dose-escalation in patients receiving ABT-199 and voluntarily suspended enrollment in phase 1 trials of the drug.

The trials are testing ABT-199, both alone and in combination, as a treatment for chronic lymphocytic leukemia, non-Hodgkin lymphoma, and small lymphocytic lymphoma.

Though enrollment has stopped for these trials, dosing of active patients in ABT-199 trials will continue. In addition, a study testing ABT-199 in women with systemic lupus erythematosus is still enrolling patients.

Sorrentino said AbbVie has “every expectation” the suspended enrollment is temporary, and refining the dose of ABT-199 may eliminate the problem. In fact, the company is still planning to begin phase 3 trials of the drug later this year.

Preparing drugs for a trial

Credit: Esther Dyson

After 2 deaths among patients receiving the BCL-2 inhibitor ABT-199, the company developing the drug has suspended enrollment in 5 trials and stopped dose-escalation of the drug.

The patients died of tumor lysis syndrome, a complication that likely stems from the drug’s potency, according to Tracy Sorrentino, a spokeswoman for the company, AbbVie.

Research has suggested the risk of tumor lysis syndrome might be eliminated by altering the dose of ABT-199, Sorrentino said.

But until that is confirmed, AbbVie has stopped dose-escalation in patients receiving ABT-199 and voluntarily suspended enrollment in phase 1 trials of the drug.

The trials are testing ABT-199, both alone and in combination, as a treatment for chronic lymphocytic leukemia, non-Hodgkin lymphoma, and small lymphocytic lymphoma.

Though enrollment has stopped for these trials, dosing of active patients in ABT-199 trials will continue. In addition, a study testing ABT-199 in women with systemic lupus erythematosus is still enrolling patients.

Sorrentino said AbbVie has “every expectation” the suspended enrollment is temporary, and refining the dose of ABT-199 may eliminate the problem. In fact, the company is still planning to begin phase 3 trials of the drug later this year.

Prescriptions
Credit: Steven Harbour

The US Food and Drug Administration (FDA) has granted accelerated approval for the immunomodulatory agent pomalidomide (Pomalyst) to treat patients with advanced multiple myeloma (MM).

Continued FDA approval for the drug may be contingent upon verification and description of clinical benefit in confirmatory trials.

Pomalidomide is intended for use in combination with dexamethasone to treat MM patients who have received at least 2 prior

therapies (including lenalidomide and a proteasome inhibitor) and who experienced progression within 60 days of their last treatment.

Pomalidomide has demonstrated some efficacy in this patient population in a number of studies.

In a study published in Blood last year (PG Richardson et al.), pomalidomide elicited responses in MM patients who were refractory to lenalidomide, bortezomib, or both drugs.

In a study presented at ASH 2011 (abstract 634), pomalidomide did not fare as well when given alone to patients with refractory MM. However, combining the drug with low-dose dexamethasone significantly improved responses.

A study presented at ASH 2012 (LBA-6) built upon those findings, showing that pomalidomide plus low-dose dexamethasone was superior to high-dose dexamethasone in MM patients who were refractory to lenalidomide and bortezomib.

Common side effects observed with pomalidomide include neutropenia, anemia, thrombocytopenia, fatigue, weakness, constipation, diarrhea, upper respiratory tract infections, back pain, and fever.

In addition, pomalidomide has been shown to cause venous thromboembolism, as well as severe, life-threatening birth defects in pregnant women. The drug carries a boxed warning alerting patients and healthcare professionals to both of these risks.

Because of the embryo-fetal risk, pomalidomide is available only through the Pomalyst Risk Evaluation and Mitigation Strategy (REMS) Program. Prescribers must be certified with the program by enrolling and complying with the REMS requirements.

Patients must sign a patient-physician agreement form and comply with the REMS requirements. In particular, female patients who are not pregnant but can become pregnant must comply with the pregnancy testing and contraception requirements, and males must comply with contraception requirements.

Pharmacies must be certified with the Pomalyst REMS Program, must only dispense the drug to patients who are authorized to receive it, and must comply with REMS requirements. Both lenalidomide and thalidomide have similar REMS.

Pomalidomide is marketed by Celgene, which is based in Summit, New Jersey.

Prescriptions
Credit: Steven Harbour

The US Food and Drug Administration (FDA) has granted accelerated approval for the immunomodulatory agent pomalidomide (Pomalyst) to treat patients with advanced multiple myeloma (MM).

Continued FDA approval for the drug may be contingent upon verification and description of clinical benefit in confirmatory trials.

Pomalidomide is intended for use in combination with dexamethasone to treat MM patients who have received at least 2 prior

therapies (including lenalidomide and a proteasome inhibitor) and who experienced progression within 60 days of their last treatment.

Pomalidomide has demonstrated some efficacy in this patient population in a number of studies.

In a study published in Blood last year (PG Richardson et al.), pomalidomide elicited responses in MM patients who were refractory to lenalidomide, bortezomib, or both drugs.

In a study presented at ASH 2011 (abstract 634), pomalidomide did not fare as well when given alone to patients with refractory MM. However, combining the drug with low-dose dexamethasone significantly improved responses.

A study presented at ASH 2012 (LBA-6) built upon those findings, showing that pomalidomide plus low-dose dexamethasone was superior to high-dose dexamethasone in MM patients who were refractory to lenalidomide and bortezomib.

Common side effects observed with pomalidomide include neutropenia, anemia, thrombocytopenia, fatigue, weakness, constipation, diarrhea, upper respiratory tract infections, back pain, and fever.

In addition, pomalidomide has been shown to cause venous thromboembolism, as well as severe, life-threatening birth defects in pregnant women. The drug carries a boxed warning alerting patients and healthcare professionals to both of these risks.

Because of the embryo-fetal risk, pomalidomide is available only through the Pomalyst Risk Evaluation and Mitigation Strategy (REMS) Program. Prescribers must be certified with the program by enrolling and complying with the REMS requirements.

Patients must sign a patient-physician agreement form and comply with the REMS requirements. In particular, female patients who are not pregnant but can become pregnant must comply with the pregnancy testing and contraception requirements, and males must comply with contraception requirements.

Pharmacies must be certified with the Pomalyst REMS Program, must only dispense the drug to patients who are authorized to receive it, and must comply with REMS requirements. Both lenalidomide and thalidomide have similar REMS.

Pomalidomide is marketed by Celgene, which is based in Summit, New Jersey.

Prescriptions
Credit: Steven Harbour

The US Food and Drug Administration (FDA) has granted accelerated approval for the immunomodulatory agent pomalidomide (Pomalyst) to treat patients with advanced multiple myeloma (MM).

Continued FDA approval for the drug may be contingent upon verification and description of clinical benefit in confirmatory trials.

Pomalidomide is intended for use in combination with dexamethasone to treat MM patients who have received at least 2 prior

therapies (including lenalidomide and a proteasome inhibitor) and who experienced progression within 60 days of their last treatment.

Pomalidomide has demonstrated some efficacy in this patient population in a number of studies.

In a study published in Blood last year (PG Richardson et al.), pomalidomide elicited responses in MM patients who were refractory to lenalidomide, bortezomib, or both drugs.

In a study presented at ASH 2011 (abstract 634), pomalidomide did not fare as well when given alone to patients with refractory MM. However, combining the drug with low-dose dexamethasone significantly improved responses.

A study presented at ASH 2012 (LBA-6) built upon those findings, showing that pomalidomide plus low-dose dexamethasone was superior to high-dose dexamethasone in MM patients who were refractory to lenalidomide and bortezomib.

Common side effects observed with pomalidomide include neutropenia, anemia, thrombocytopenia, fatigue, weakness, constipation, diarrhea, upper respiratory tract infections, back pain, and fever.

In addition, pomalidomide has been shown to cause venous thromboembolism, as well as severe, life-threatening birth defects in pregnant women. The drug carries a boxed warning alerting patients and healthcare professionals to both of these risks.

Because of the embryo-fetal risk, pomalidomide is available only through the Pomalyst Risk Evaluation and Mitigation Strategy (REMS) Program. Prescribers must be certified with the program by enrolling and complying with the REMS requirements.

Patients must sign a patient-physician agreement form and comply with the REMS requirements. In particular, female patients who are not pregnant but can become pregnant must comply with the pregnancy testing and contraception requirements, and males must comply with contraception requirements.

Pharmacies must be certified with the Pomalyst REMS Program, must only dispense the drug to patients who are authorized to receive it, and must comply with REMS requirements. Both lenalidomide and thalidomide have similar REMS.

Pomalidomide is marketed by Celgene, which is based in Summit, New Jersey.