A Phase 3 Study Assessing Safety and Efficacy of Bedaquiline Plus PA-824 Plus Linezolid in Subjects With Drug Resistant Pulmonary Tuberculosis
- Conditions
- Pulmonary Tuberculosis
- Interventions
- Registration Number
- NCT02333799
- Lead Sponsor
- Global Alliance for TB Drug Development
- Brief Summary
The purpose of this study is to evaluate the efficacy, safety, tolerability and pharmacokinetics of bedaquiline plus PA-824 plus linezolid after 6 months of treatment (option for 9 months for participants who remain culture positive at month 4) in participants with either pulmonary extensively drug resistant tuberculosis (XDR-TB), treatment intolerant or non-responsive multi-drug resistant tuberculosis (MDR-TB).
- Detailed Description
Up to 200 male and female participants aged 14 and over with confirmed sputum positive for M.tb. in culture pulmonary XDR-TB, or with pulmonary MDR-TB with a documented intolerability or non-response to the best treatment available for 6 months or more will be enrolled.
All participants will have up to a maximum of 9 days for screening, receive 6 months of treatment, and have followup visits performed 1 and 2 months after treatment completion and every 3 months after study treatment completion for 24 months. If a participant is culture positive or revert to being culture positive between Month 4 and Month 6 visits and their clinical condition suggests they may have ongoing TB infection, they may have treatment extended to 9 months (with 24 months of Follow Up) or be withdrawn from the study.
Participants who withdraw after \<14 days of IMP should attend an Early Withdrawal visit. Participants who withdraw after \>15 days of IMP should return for an Early Withdrawal visit and follow-up visits at 3, 6 and 24 months after their last dose of IMP to check for survival, SAEs and resolution of TB symptoms.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 109
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Bedaquiline + PA-824 + Linezolid PA-824 bedaquiline 400 mg once daily for 2 weeks then 200mg 3 times per week plus PA-824 200mg once daily plus linezolid 1200mg once daily. A reduction in the dose of linezolid (to either 600 mg qd or 300 mg qd), or temporary cessation of linezolid (due to a linezolid-specific toxicity), or of the full regimen per Investigator discretion was allowed for suspected drug related toxicity. Re-introduction of the regimen could be considered post a cessation not greater than 35 consecutive days. If participants had toxicity events related to linezolid prohibiting further treatment with that drug, they could remain on the bedaquiline and pretomanid study IMP if they received the initial total of 1200 mg daily dose of linezolid for at least the first 4 consecutive weeks of treatment and they were smear negative, or with trace/scanty results and judged to be clinically improving by the Investigator. Bedaquiline + PA-824 + Linezolid Bedaquiline bedaquiline 400 mg once daily for 2 weeks then 200mg 3 times per week plus PA-824 200mg once daily plus linezolid 1200mg once daily. A reduction in the dose of linezolid (to either 600 mg qd or 300 mg qd), or temporary cessation of linezolid (due to a linezolid-specific toxicity), or of the full regimen per Investigator discretion was allowed for suspected drug related toxicity. Re-introduction of the regimen could be considered post a cessation not greater than 35 consecutive days. If participants had toxicity events related to linezolid prohibiting further treatment with that drug, they could remain on the bedaquiline and pretomanid study IMP if they received the initial total of 1200 mg daily dose of linezolid for at least the first 4 consecutive weeks of treatment and they were smear negative, or with trace/scanty results and judged to be clinically improving by the Investigator. Bedaquiline + PA-824 + Linezolid Linezolid bedaquiline 400 mg once daily for 2 weeks then 200mg 3 times per week plus PA-824 200mg once daily plus linezolid 1200mg once daily. A reduction in the dose of linezolid (to either 600 mg qd or 300 mg qd), or temporary cessation of linezolid (due to a linezolid-specific toxicity), or of the full regimen per Investigator discretion was allowed for suspected drug related toxicity. Re-introduction of the regimen could be considered post a cessation not greater than 35 consecutive days. If participants had toxicity events related to linezolid prohibiting further treatment with that drug, they could remain on the bedaquiline and pretomanid study IMP if they received the initial total of 1200 mg daily dose of linezolid for at least the first 4 consecutive weeks of treatment and they were smear negative, or with trace/scanty results and judged to be clinically improving by the Investigator.
- Primary Outcome Measures
Name Time Method Proportion of Treatment Failure (Unfavorable Outcome), Defined as Bacteriologic Failure or Relapse or Clinical Failure (Derived) Through Follow-up Until 6 Months After the End of Treatment. 6 Months post End of Treatment Bacteriologic failure: During the treatment period, failure to attain culture conversion to negative.
Bacteriologic relapse: During the follow-up period, failure to maintain culture conversion to negative status in culture, with culture conversion to positive status with a Mycobacterium tuberculosis (M.tb.) strain that is genetically identical to the infecting strain at baseline.
Clinical failure: A change from protocol-specified tuberculosis (TB) treatment due to treatment failure, retreatment for TB during follow up, or TB-related death.
Note:
Culture conversion requires at least 2 consecutive culture negative/positive samples at least 7 days apart.
Participants who are documented at a visit as unable to produce sputum and who are clinically considered to be responding well to treatment will be considered to be culture negative at that visit.
- Secondary Outcome Measures
Name Time Method Proportion of Treatment Failure (Unfavorable Outcome), Defined as Bacteriologic Failure or Relapse or Clinical Failure (Derived) Through Follow-up Until 24 Months After the End of Treatment. 24 Months post End of Treatment Bacteriologic failure: During the treatment period, failure to attain culture conversion to negative.
Bacteriologic relapse: During the follow-up period, failure to maintain culture conversion to negative status in culture, with culture conversion to positive status with a Mycobacterium tuberculosis (M.tb.) strain that is genetically identical to the infecting strain at baseline.
Clinical failure: A change from protocol-specified TB treatment due to treatment failure, retreatment for TB during follow up, or TB-related death.
Note:
Culture conversion requires at least 2 consecutive culture negative/positive samples at least 7 days apart.
Participants who are documented at a visit as unable to produce sputum and who are clinically considered to be responding well to treatment will be considered to be culture negative at that visit.Time to Sputum Culture Conversion to Negative Status Through the Treatment Period Day 1 through End of Treatment, approximately 6 to 9 months of treatment Median time (in weeks) to culture negative status (first of 2 negative cultures without an intervening positive culture), MITT analysis.
Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped Day 1 to 14 days post-End of Treatment Treatment-emergent adverse events (TEAEs): Defined as adverse events which started or worsened on or after the first trial drug administration up to and including 14 days after the last trial drug administration.
#: Indicates TEAEs of special interest. TEAEs of special interest: Identified by pre-specified SMQ codes as confirmed by TB Alliance. Adverse events in System Organ Class "NERVOUS SYSTEM DISORDERS" are presented into the table. Preferred term "PERIPHERAL NEUROPATHY" was a grouping of terms "PERIPHERAL SENSORY NEUROPATHY", "NEUROPATHY PERIPHERAL", "PARAESTHESIA", "HYPOAESTHESIA", "PERIPHERAL MOTOR NEUROPATHY", "BURNING SENSATION", "HYPOREFLEXIA" and "PERIPHERAL SENSORIMOTOR NEUROPATHY".Proportion of Participants With Sputum Culture Conversion to Negative Status Week 4, 6, 8, 12, 16, 26, 39 Proportion of participants with sputum culture conversion to negative status for those positive at baseline at 4, 6, 8, 12, 16, and End of Treatment (26 or 39 weeks)
Number of Treatment Emergent Adverse Events (TEAEs) Day 1 to 14 days post-End of Treatment Treatment-emergent adverse events (TEAEs): adverse events which started or worsened on or after the first trial drug administration up to and including 14 days after the last trial drug administration. Grade I, II, III, IV TEAEs: DMID grade is indicated as Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe) and Grade 4 (potentially life-threatening). TEAEs of special interest based on Section 7.3 of the protocol. Liver-related adverse events: any adverse event with a High Level Group Term of HEPATIC AND BILIARY NEOPLASMS BENIGN, HEPATIC AND HEPATOBILIARY DISORDERS, HEPATOBILIARY DISORDERS CONGENITAL, HEPATOBILIARY NEOPLASMS MALIGNANT AND UNSPECIFIED, HEPATOBILIARY INVESTIGATIONS or HEPATOBILIARY THERAPEUTIC PROCEDURES.
Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest Day 1 to 14 days post-End of Treatment Treatment-emergent adverse events (TEAEs): Defined as adverse events which started or worsened on or after the first trial drug administration up to and including 14 days after the last trial drug administration. TEAEs of special interest: Identified by prespecified SMQ codes as confirmed by TB Alliance.
Section 7.3 of the protocol specified the "Monitoring and Safety for Specific Toxicities" and are presented here as TEAEs of special interest. These specific toxicities of interest were based on nonclinical toxicology findings of concern for any of the 3 trial drugs, or from identified toxicities based on the IBs for pretomanid and bedaquiline, on the product label for linezolid and literature reports of linezolid long-term toxicity.
Trial Locations
- Locations (3)
Task Applied Science - Brooklyn Chest Hospital
🇿🇦Ysterplaat, Cape Town, South Africa
King DinuZulu Hospital Complex
🇿🇦Sydenham, Durban, South Africa
Sizwe Tropical Disease Hospital
🇿🇦Sandringham, Johannesburg, South Africa