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Adding bedaquiline to a five-drug background regimen for multidrug-resistant pulmonary tuberculosis significantly accelerated the time at which sputum cultures showed clearance of Mycobacterium tuberculosis in a phase IIb clinical trial, which was published online Aug. 21 in the New England Journal of Medicine.
The addition of 6 months of oral bedaquiline – a diarylquinoline that inhibits mycobacterial ATP synthase and depletes cellular energy stores – also significantly increased the number of patients who achieved such culture conversion (a surrogate for clinical cure), compared with adding placebo, in this industry-sponsored study. Bedaquiline "is the first antituberculosis drug with a new mechanism of action to be approved for use in multidrug-resistant TB in 40 years," said Dr. Andreas H. Diacon of the National Research Foundation Centre of Excellence for Biomedical Tuberculosis Research at Stellenbosch University in Cape Town, South Africa, and his associates.
Bedaquiline was approved in 2012 under the Food and Drug Administration’s accelerated-approval regulations for drugs that provide meaningful therapeutic benefit over existing therapies for serious or life-threatening conditions. The drug is approved only for patients for whom an effective treatment regimen cannot be constructed without it, a population in whom the benefits outweigh the risks.
In the trial, 160 adults with multidrug-resistant pulmonary TB were randomly assigned to receive either oral bedaquiline (79 patients) or matching placebo tablets (81 patients) for 24 weeks at medical centers in Brazil, India, Latvia, Peru, the Philippines, Russia, South Africa, and Thailand, in addition to the five-drug background regimen of antituberculosis drugs preferred at each location. They continued the background therapy for a further 96 weeks and had a final follow-up exam at the conclusion of that treatment. Sixty participants (38%) left the study prematurely, usually because of withdrawal of consent, adverse effects, nonadherence, loss to follow-up, and pregnancy. The number of and reasons for these discontinuations were similar between the two study groups.
The primary endpoint of the study was the median time to sputum conversion. This was significantly faster in the intervention group (83 days) than in the control group (125 days) in both the modified intention-to-treat analysis and the full intention-to-treat analysis. Moreover, more patients in the intervention group (79%) than in the placebo group (58%) showed culture conversion at 24 weeks, as well as at 120 weeks (62% vs 44%). And according to the World Health Organization definition of "cure," nearly twice as many patients in the bedaquiline group (58%) were cured as in the placebo group (32%) at 120 weeks, Dr. Diacon and his associates said (N. Engl. J. Med. 2014;371:723-32 [doi:10.1056/NEJMoa1313865]).
Fewer patients taking bedaquiline (2) than taking placebo (16) developed new resistance to at least one antituberculosis agent during the study. Rates, types, and severity of adverse events were comparable between the two study groups. However, mortality was significantly higher with bedaquiline (10 patients, 13% mortality) than with placebo (2 patients, 2% mortality), for reasons that are not yet understood but do not appear to be related to the study drug.
"A planned phase III study will enroll a larger number of patients, including HIV-positive patients receiving antiretroviral therapy," the investigators noted.
This study was funded by Janssen Pharmaceuticals. Dr. Diacon reported no financial conflicts of interest. His associates reported ties to Janssen; to its parent company, Johnson & Johnson; and to Quintiles.
The Food and Drug Administration approved the limited use of bedaquiline despite the unexpected finding of significantly increased mortality in the intervention group (13%) than in the control group (2%), because the length of time between the last receipt of bedaquiline and death – 329 days – makes it difficult to discern a mechanism by which the drug could be directly related to the deaths, even if bedaquiline’s long half-life is taken into consideration.
This imbalance in mortality is an important concern. However, 1 of the 10 deaths that occurred in patients who received bedaquiline was because of a motor vehicle accident, 5 were from disease progression (as were both deaths in the placebo group), and the remaining 4 had no apparent commonality. A confirmatory trial, a condition of the accelerated approval of the drug, should shed more light on this discrepancy in mortality.
Dr. Edward Cox and Dr. Katherine Laessig are in the Office of Antimicrobial Products and the Office of New Drugs, the Center for Drug Evaluation and Research, at the FDA. They made their remarks in a perspective piece accompanying Dr. Diacon’s report (N. Engl. J. Med. 2014;371:689-91 [doi:10.1056/NEJMp1314385]). They reported no financial conflicts of interest.
The Food and Drug Administration approved the limited use of bedaquiline despite the unexpected finding of significantly increased mortality in the intervention group (13%) than in the control group (2%), because the length of time between the last receipt of bedaquiline and death – 329 days – makes it difficult to discern a mechanism by which the drug could be directly related to the deaths, even if bedaquiline’s long half-life is taken into consideration.
This imbalance in mortality is an important concern. However, 1 of the 10 deaths that occurred in patients who received bedaquiline was because of a motor vehicle accident, 5 were from disease progression (as were both deaths in the placebo group), and the remaining 4 had no apparent commonality. A confirmatory trial, a condition of the accelerated approval of the drug, should shed more light on this discrepancy in mortality.
Dr. Edward Cox and Dr. Katherine Laessig are in the Office of Antimicrobial Products and the Office of New Drugs, the Center for Drug Evaluation and Research, at the FDA. They made their remarks in a perspective piece accompanying Dr. Diacon’s report (N. Engl. J. Med. 2014;371:689-91 [doi:10.1056/NEJMp1314385]). They reported no financial conflicts of interest.
The Food and Drug Administration approved the limited use of bedaquiline despite the unexpected finding of significantly increased mortality in the intervention group (13%) than in the control group (2%), because the length of time between the last receipt of bedaquiline and death – 329 days – makes it difficult to discern a mechanism by which the drug could be directly related to the deaths, even if bedaquiline’s long half-life is taken into consideration.
This imbalance in mortality is an important concern. However, 1 of the 10 deaths that occurred in patients who received bedaquiline was because of a motor vehicle accident, 5 were from disease progression (as were both deaths in the placebo group), and the remaining 4 had no apparent commonality. A confirmatory trial, a condition of the accelerated approval of the drug, should shed more light on this discrepancy in mortality.
Dr. Edward Cox and Dr. Katherine Laessig are in the Office of Antimicrobial Products and the Office of New Drugs, the Center for Drug Evaluation and Research, at the FDA. They made their remarks in a perspective piece accompanying Dr. Diacon’s report (N. Engl. J. Med. 2014;371:689-91 [doi:10.1056/NEJMp1314385]). They reported no financial conflicts of interest.
Adding bedaquiline to a five-drug background regimen for multidrug-resistant pulmonary tuberculosis significantly accelerated the time at which sputum cultures showed clearance of Mycobacterium tuberculosis in a phase IIb clinical trial, which was published online Aug. 21 in the New England Journal of Medicine.
The addition of 6 months of oral bedaquiline – a diarylquinoline that inhibits mycobacterial ATP synthase and depletes cellular energy stores – also significantly increased the number of patients who achieved such culture conversion (a surrogate for clinical cure), compared with adding placebo, in this industry-sponsored study. Bedaquiline "is the first antituberculosis drug with a new mechanism of action to be approved for use in multidrug-resistant TB in 40 years," said Dr. Andreas H. Diacon of the National Research Foundation Centre of Excellence for Biomedical Tuberculosis Research at Stellenbosch University in Cape Town, South Africa, and his associates.
Bedaquiline was approved in 2012 under the Food and Drug Administration’s accelerated-approval regulations for drugs that provide meaningful therapeutic benefit over existing therapies for serious or life-threatening conditions. The drug is approved only for patients for whom an effective treatment regimen cannot be constructed without it, a population in whom the benefits outweigh the risks.
In the trial, 160 adults with multidrug-resistant pulmonary TB were randomly assigned to receive either oral bedaquiline (79 patients) or matching placebo tablets (81 patients) for 24 weeks at medical centers in Brazil, India, Latvia, Peru, the Philippines, Russia, South Africa, and Thailand, in addition to the five-drug background regimen of antituberculosis drugs preferred at each location. They continued the background therapy for a further 96 weeks and had a final follow-up exam at the conclusion of that treatment. Sixty participants (38%) left the study prematurely, usually because of withdrawal of consent, adverse effects, nonadherence, loss to follow-up, and pregnancy. The number of and reasons for these discontinuations were similar between the two study groups.
The primary endpoint of the study was the median time to sputum conversion. This was significantly faster in the intervention group (83 days) than in the control group (125 days) in both the modified intention-to-treat analysis and the full intention-to-treat analysis. Moreover, more patients in the intervention group (79%) than in the placebo group (58%) showed culture conversion at 24 weeks, as well as at 120 weeks (62% vs 44%). And according to the World Health Organization definition of "cure," nearly twice as many patients in the bedaquiline group (58%) were cured as in the placebo group (32%) at 120 weeks, Dr. Diacon and his associates said (N. Engl. J. Med. 2014;371:723-32 [doi:10.1056/NEJMoa1313865]).
Fewer patients taking bedaquiline (2) than taking placebo (16) developed new resistance to at least one antituberculosis agent during the study. Rates, types, and severity of adverse events were comparable between the two study groups. However, mortality was significantly higher with bedaquiline (10 patients, 13% mortality) than with placebo (2 patients, 2% mortality), for reasons that are not yet understood but do not appear to be related to the study drug.
"A planned phase III study will enroll a larger number of patients, including HIV-positive patients receiving antiretroviral therapy," the investigators noted.
This study was funded by Janssen Pharmaceuticals. Dr. Diacon reported no financial conflicts of interest. His associates reported ties to Janssen; to its parent company, Johnson & Johnson; and to Quintiles.
Adding bedaquiline to a five-drug background regimen for multidrug-resistant pulmonary tuberculosis significantly accelerated the time at which sputum cultures showed clearance of Mycobacterium tuberculosis in a phase IIb clinical trial, which was published online Aug. 21 in the New England Journal of Medicine.
The addition of 6 months of oral bedaquiline – a diarylquinoline that inhibits mycobacterial ATP synthase and depletes cellular energy stores – also significantly increased the number of patients who achieved such culture conversion (a surrogate for clinical cure), compared with adding placebo, in this industry-sponsored study. Bedaquiline "is the first antituberculosis drug with a new mechanism of action to be approved for use in multidrug-resistant TB in 40 years," said Dr. Andreas H. Diacon of the National Research Foundation Centre of Excellence for Biomedical Tuberculosis Research at Stellenbosch University in Cape Town, South Africa, and his associates.
Bedaquiline was approved in 2012 under the Food and Drug Administration’s accelerated-approval regulations for drugs that provide meaningful therapeutic benefit over existing therapies for serious or life-threatening conditions. The drug is approved only for patients for whom an effective treatment regimen cannot be constructed without it, a population in whom the benefits outweigh the risks.
In the trial, 160 adults with multidrug-resistant pulmonary TB were randomly assigned to receive either oral bedaquiline (79 patients) or matching placebo tablets (81 patients) for 24 weeks at medical centers in Brazil, India, Latvia, Peru, the Philippines, Russia, South Africa, and Thailand, in addition to the five-drug background regimen of antituberculosis drugs preferred at each location. They continued the background therapy for a further 96 weeks and had a final follow-up exam at the conclusion of that treatment. Sixty participants (38%) left the study prematurely, usually because of withdrawal of consent, adverse effects, nonadherence, loss to follow-up, and pregnancy. The number of and reasons for these discontinuations were similar between the two study groups.
The primary endpoint of the study was the median time to sputum conversion. This was significantly faster in the intervention group (83 days) than in the control group (125 days) in both the modified intention-to-treat analysis and the full intention-to-treat analysis. Moreover, more patients in the intervention group (79%) than in the placebo group (58%) showed culture conversion at 24 weeks, as well as at 120 weeks (62% vs 44%). And according to the World Health Organization definition of "cure," nearly twice as many patients in the bedaquiline group (58%) were cured as in the placebo group (32%) at 120 weeks, Dr. Diacon and his associates said (N. Engl. J. Med. 2014;371:723-32 [doi:10.1056/NEJMoa1313865]).
Fewer patients taking bedaquiline (2) than taking placebo (16) developed new resistance to at least one antituberculosis agent during the study. Rates, types, and severity of adverse events were comparable between the two study groups. However, mortality was significantly higher with bedaquiline (10 patients, 13% mortality) than with placebo (2 patients, 2% mortality), for reasons that are not yet understood but do not appear to be related to the study drug.
"A planned phase III study will enroll a larger number of patients, including HIV-positive patients receiving antiretroviral therapy," the investigators noted.
This study was funded by Janssen Pharmaceuticals. Dr. Diacon reported no financial conflicts of interest. His associates reported ties to Janssen; to its parent company, Johnson & Johnson; and to Quintiles.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Bedaquiline may offer an alternative treatment for multidrug-resistant TB.
Major finding: The primary endpoint of the study – the median time to sputum conversion – was significantly faster in the intervention group (83 days) than in the control group (125 days), and more patients in the intervention group (79%) than in the placebo group (58%) showed culture conversion at 24 weeks, as well as at 120 weeks (62% vs 44%).
Data source: A randomized, double-blind, placebo-controlled, phase IIb clinical trial involving 160 adults with multidrug-resistant pulmonary TB treated for 24 weeks in eight countries.
Disclosures: This study was funded by Janssen Pharmaceuticals. Dr. Diacon reported no financial conflicts of interest. His associates reported ties to Janssen; to its parent company, Johnson & Johnson; and to Quintiles.
