Introduction
Methods
Mechanism of Action
Administration, Pharmacokinetics, and Pharmacodynamics
Dosing and Administration
Subject of study | References |
---|---|
Chemical synthesis | [20] |
Study of drug structure and mechanism | |
Anti-tuberculosis resistance to bedaquiline in vitro | |
Pharmacokinetics/pharmacodynamics in animal studies (such as mice studies) | |
Drug interaction studies in animals | |
Bactericidal efficacy studies against M. tuberculosis in animal studies | |
Bactericidal effect against M. tuberculosis in vitro | |
Bactericidal effect against other mycobacteria |
Clinical Evidence for the Efficacy of Bedaquiline in MDR-TB
The First Phase 2 Study of Bedaquiline
Study sites | Inclusion criteria | Exclusion criteria | Intervention: duration and regimens | Number of MDR patients (BDQ + OBR/OBR) | Findingsa
|
---|---|---|---|---|---|
6 sites in South Africa | Hospitalized patients | Past treatment for MDR-TB | 1. Initial 8 week phase, randomized to either: (a) BDQ + OBR (400 mg daily for 2 weeks then 200 mg 3 times per week for 6 weeks) OR (b) OBR alone | 47 (23/24) | Culture conversion up to 8 weeks [18] (a) Time to culture conversion using time point of 8 weeks: BDQ + OBR < OBR: HR 11.8 (2.3, 61.3), P = 0.0034** (b) Proportion culture conversion for BDQ + OBR (10/21, 47.6%) > OBR alone (2/23, 8.7%), P = 0.004**
|
Aged 18–65 years | XDR or pre-XDR (resistant to AG [other than streptomycin] or FQ) | Then, 2. Followed by OBR, for both groups, up to 2 years OBR in this study comprised kanamycin, ofloxacin, ethionamide, pyrazinamide, and cycloserine or terizidone | Overall Median age 33 years Median BMI 18.3 Cavitations on X-ray 85% Male 74% HIV prevalence 13% | Culture conversion up to 24 weeks [19] (a) Time to culture conversion using time point of 24 weeks: BDQ (78 days) + OBR < OBR (129 days) HR 2.3 (1.1, 4.7), P = 0.031 (b) Proportions culture conversion for BDQ + OBR (81.0%) > OBR alone (65.2%), P = 0.242**
| |
Sputum smear positive | Neurologic or severe extra-pulmonary manifestations of TB | Culture conversion up to 104 weeks [19] Proportion culture conversion in BDQ + OBR (11/21, 52.4%) > OBR alone (11/23, 47.8%), p = 0.76** | |||
DST: resistant to INH and RIF | HIV positive and CD4 <300 cells/μL | Mortality BDQ + OBR (2/23, 8.7%) vs OBR alone (2/24, 8.3%), P = 0.8. Onset of death: median 347 days [17] | |||
Received antiretroviral therapy or antifungal therapy within the last 90 days | |||||
History of significant cardiac arrhythmia | |||||
Drug hypersensitivity | |||||
Alcohol and drug abuse | |||||
Abnormal laboratory tests | |||||
Breast feeding or pregnancy |
The Second Phase 2 Study of Bedaquiline
Study sites | Inclusion criteria for patients | Exclusion criteria | Study design and intervention | Number of MDR patients (BDQ + OBR/OBR) | Findings |
---|---|---|---|---|---|
15 sites in Brazil, India, Latvia, Peru, Philippines, Russia, South Africa and Thailand | Newly diagnosed pulmonary MDR-TB | Same as for Table 3
| 1. Initial 24 week phase randomized to either: (a) BDQ + OBR (400 mg daily for 2 weeks then 200 mg 3 times per week for 22 weeks) OR (b) Placebo + OBR alone | 161a (80/81) | Culture conversion up to 24 weeksb [17] (a) Time to sputum culture conversion using time point of 24 weeks (primary end point): BDQ + OBR < OBR: HR 2.44 (95% CI 1.57, 3.80) P < 0.001c
(b) Proportion of sputum culture conversions at 24 weeks: BDQ + OBR (52/66, 78.8%) > OBR alone (38/66, 57.6%), P = 0.008 |
Drug susceptible TB or XDR-TB | Then, 2. Followed by 18–24 months of standard MDR-TB treatment | Culture conversion up to 72 weeksb [17] Proportion sputum cultures converted at 72 weeks: BDQ + OBR (47/66, 71.2%) > OBR alone (37/66, 56.1%), P = 0.069 | |||
Mortality BDQ + OBR (10/80, 12.5%) > OBR (2/81, 2.5%), P = 0.015**** Onset of death: median 313 days [17] |
Third Phase 2 Study of Bedaquiline
Study sites | Inclusion criteria for patients | Exclusion criteria | Study design and intervention | Number of MDR patients (BDQ + OBR) | Findings |
---|---|---|---|---|---|
33 sites in Asia, South Africa, Eastern Europe, South America | Newly and previously diagnosed smear positive patients with either: (a) MDR-TB (39.9%) (b) pre-XDR-TB (18.9%) (c) XDR (15.9%) . | As for Table 3, except patients with HIV with a CD4 count <250 cells/μL were excluded | Single arm study (a) 24 weeks of OBR and BDQ (400 mg daily for 2 weeks then 200 mg 3 times per week), Then, (b) Individualized 18-month to 24-month treatment for MDR-TB. | 233 (205a) | Culture conversion up to 24 weeks (a) Median time to culture conversion, using time-point of 24 weeks: 57 days (b) Culture conversion (mITTa): 79.5% |
Mortality BDQ + OBR (12/205, 5.6%), up to trial reporting cut-offb Onset of death: median 376 days since last intake of study drug [17] |
Clinical Evidence for Safety of Bedaquiline
Up to 24-week follow-up | All follow-ups | |||
---|---|---|---|---|
In patients taking BDQ for 24 weeksa
| In patients taking placebo for 24 weeksa
| In all patients taking BDQ | In all patients taking placebo | |
n = 79 |
n = 81 |
n = 102 |
n = 105 | |
n (%) |
n (%) |
n (%) |
n (%) | |
Any adverse event | 77 (97.5) | 77 (95.1) | 98 (96.1) | 100 (95.2) |
Gastrointestinal disorders | 50 (63.3) | 50 (61.7) | 59 (57.8) | 59 (56.2) |
Nausea | 30 (38.0) | 26 (32.1) | 36 (35.3) | 27 (25.7) |
Vomiting | 20 (25.3) | 21 (25.9) | 21 (20.6) | 24 (22.9) |
Upper abdominal pain | 9 (11.4) | 7 (8.6) | 10 (9.8) | 8 (7.6) |
Gastritis | 6 (7.6) | 13 (16.0) | 6 (5.9) | 13 (12.4) |
Diarrhea | 3 (3.8) | 11 (13.6) | 6 (5.9) | 12 (11.4) |
Nervous system disorders | 32 (40.5) | 21 (25.9) | 37 (36.3) | 24 (22.9) |
Headache | 22 (27.8) | 10 (12.3) | 24 (23.5) | 12 (11.4) |
Dizziness | 10 (12.7) | 10 (12.3) | 13 (12.7) | 12 (11.4) |
Musculoskeletal disorders | 35 (44.3) | 32 (39.5) | 41 (40.2) | 39 (37.1) |
Arthralgia | 26 (32.9) | 18 (22.2) | 30 (29.4) | 21 (20.0) |
Ear and labyrinth disorders | 24 (30.4) | 26 (32.1) | 32 (31.4) | 37 (35.2) |
Deafness | 9 (11.4) | 6 (7.4) | 12 (11.8) | 11 (10.5) |
Tinnitus | 2 (2.5) | 10 (12.3) | 2 (2.0) | 10 (9.5) |
Respiratory disorders | 25 (31.6) | 28 (34.6) | 28 (27.5) | 33 (31.4) |
Hemoptysis | 14 (17.7) | 9 (11.1) | 17 (16.7) | 13 (12.4) |
Infections and infestations | 25 (31.6) | 28 (34.6) | 28 (27.5) | 33 (31.4) |
Chest pain | 9 (11.4) | 6 (7.4) | 9 (8.8) | 8 (7.6) |
Skin and subcutaneous tissues | 19 (24.1) | 21 (25.9) | 25 (24.5) | 28 (26.7) |
Pruritis | 10 (12.7) | 11 (13.6) | 12 (11.8) | 13 (12.4) |
Psychiatric disorders | 15 (19.0) | 11 (13.6) | 16 (15.7) | 13 (12.4) |
Insomnia | 11 (13.9) | 9 (11.1) | 11 (10.8) | 10 (9.5) |
Eye disorders | 10 (12.7) | 14 (17.3) | 13 (12.7) | 15 (14.3) |
Blood and lymphatic disorders | 8 (10.1) | 4 (4.9) | 9 (8.8) | 4 (3.8) |
Reproductive system and breast disorders | 7 (8.9) | 10 (12.3) | 8 (7.8) | 13 (12.4) |
Deaths
Number | Days since last intake of BDQ | Phase 2 studya
| Treatment arm (bedaquiline + or placebo) | Premature discontinuation/exclusion from treatment | Last culture conversion status | Reported cause of death |
---|---|---|---|---|---|---|
1 | 2 | Second | BDQ | No | Converter | Alcohol poisoning |
2 | 12 | Third | BDQ | ns | Non-converter | Renal impairment |
3 | 27 | Third | BDQ | ns | Non-converter | Tuberculosis |
4 | 45 | Third | BDQ | ns | Non-converter | Tuberculosis |
5 | 71 | Third | BDQ | ns | Converter | Lung infection |
6 | 86 | Second | BDQ | No | Converter | Hepatitis/hepatic cirrhosis |
7 | 105 | Second | Placebo | No | Non-converter | Hemoptysis |
8 | 115 | First | BDQ | No | Non-converter | Acute myocardial infarction |
9 | 262 | Second | BDQ | Yes (non-compliance) | Relapse | Tuberculosis |
10 | 262 | Third | BDQ | ns | Converter | Congestive cardiac failure |
11 | 267 | First | Placebo | Yes (exclusion as XDR-TB) | Non-converter | Tuberculosis |
12 | 281 | Second | BDQ | No | Relapse | Tuberculosis |
13 | 288 | Third | BDQ | ns | Relapse | Tuberculosis |
14 | 314 | Second | BDQ | Yes (exclusion as XDR-TB) | Non-converter | Tuberculosis |
15 | 344 | Second | BDQ | No | Relapse | Tuberculosis |
16 | 427 | First | Placebo | Yes (exclusion as XDR-TB) | Non-converter | Tuberculosis |
17 | 463 | Third | BDQ | ns | Non-converter | Tuberculosis |
18 | 473 | Third | BDQ | ns | Non-converter | Hypertension |
19 | 476 | Third | BDQ | ns | Non-converter | Pyopneumothorax/respiratory failure |
20 | 479 | Third | BDQ | ns | Converter | Hemoptysis |
21 | 504 | First | BDQ | Yes (exclusion as XDR-TB) | Non-converter | Tuberculosis |
22 | 513 | Second | BDQ | No | Converter | Septic shock/peritonitis |
23 | 556 | Second | BDQ | No | Converter | Cerebrovascular accident |
24 | 632 | Third | BDQ | ns | Converter | Tuberculosis |
25 | 685 | Third | BDQ | ns | Non-converter | Cardiac arrest, pneumonia |
26 | 709 | Second | Placebo | Yes (non-compliance) | Non-converter | Tuberculosis |
27 | 787 | Second | BDQ | Yes (non-compliance) | Non-converter | Tuberculosis |
28 | 911 | Second | BDQ | Yes (increased transaminase) | Relapse | Motor vehicle accident |