Evaluation of SQ109, High-dose Rifampicin, and Moxifloxacin in Adults With Smear-positive Pulmonary TB in a MAMS Design
- Conditions
- Tuberculosis, Pulmonary
- Interventions
- Dietary Supplement: pyridoxine
- Registration Number
- NCT01785186
- Lead Sponsor
- Michael Hoelscher
- Brief Summary
This study is a multiple-arm, multiple-stage (MAMS), phase 2, open label, randomized, controlled clinical trial that will compare the efficacy and safety of four experimental four drug regimens with a standard control regimen in patients with smear positive, pulmonary tuberculosis (TB). Patients will be randomly allocated to the control or one of the four experimental regimens in the ratio 2:1:1:1:1. Experimental regimens will be given for 12 weeks. Thereafter, participants in the experimental arms will receive continuation phase treatment for 14 weeks containing standard-dose rifampicin and isoniazid. All participants will receive 25 mg of vitamin B6 (pyridoxine) with every dose of INH to prevent INH-related neuropathy. Interim analyses will be conducted during the trial for efficacy, with the aim of identifying experimental arms that perform below a pre-specified efficacy threshold; these arms will then be stopped from further recruitment.
Following the first scheduled interim analysis on March 3rd, the Trial Steering Committee (TSC) followed a recommendation of the independent data monitoring committee (IDMC) and has stopped the enrolment into two of the arms in the MAMS-TB trial: HRZQ and HR20ZQ, based on these arms not meeting the pre-specified gain in efficacy over control. Importantly, there was no safety concern that prompted stopping recruitment to these arms. They recommended that recruitment to arm 2 (HRZQ) and 3 (HR20ZQ) be terminated as there was insufficient evidence that these regimens could shorten treatment. Importantly, there was no evidence that either arm was inferior to standard treatment (the control arm) with regards to efficacy. There was, however, sufficient evidence that the other intervention arms HR35ZE and HR20ZM could shorten treatment to continue enrolling patients.
- Detailed Description
This Phase II, multi-arm, multi-stage, open label, prospectively randomized, controlled clinical trial will compare the efficacy and safety of four experimental regimens with the control, standard treatment regimen in patients with smear positive, pulmonary tuberculosis (TB). There will be four experimental regimens. Participants will be randomly allocated to control or one of the four experimental intensive phase regimens in the ratio 2:1:1:1:1. The control and 4 experimental regimens are:
Control: HRZE isoniazid, rifampicin standard, pyrazinamide, ethambutol Arm 1: HRZQlow isoniazid, rifampicin standard, pyrazinamide, SQ109 150 mg Arm 2: HRZQhigh isoniazid, rifampicin standard, pyrazinamide, SQ109 300 mg Arm 3: HR20ZQhigh isoniazid, rifampicin 20 mg/kg, pyrazinamide, SQ109 300 mg Arm 4: HR20ZM isoniazid, rifampicin 20 mg/kg, pyrazinamide, moxifloxacin 400mg
Up to 372 participants will be randomized into this study, with 124 participants being randomized to the control arm and 62 participants to each experimental arm. With an expected loss to follow-up of 5%, the final power of the study to detect a hazard ratio of 1.8 for culture conversion to negative will be 90%, at the 5% significance level.
Participants will be randomised using a probabilistic minimisation algorithm based on site, baseline bacterial load as measured by GeneXpert MTB/RIF®, and HIV status. The allocated intensive phase of the four experimental arms will be administered daily for twelve weeks. During this time, participants will visit the study clinic on a weekly basis for sputum collection, safety monitoring and receipt of study medication. After the completion of the experimental treatment, participants in the experimental arms will receive daily standard continuation phase treatment for 14 weeks containing standard-dose RIF and INH to complete their TB treatment course. Participants in the control arm will receive eight weeks of intensive four-drug treatment (HRZE, followed by 18 weeks of the HR continuation phase treatment in line with the current WHO recommendations.
All participants will receive 25mg of Vitamin B6 (pyridoxine) with every dose of treatment in order to prevent INH-related neuropathy.
Interim analyses will be conducted during the trial for efficacy at predetermined times, with the aim of identifying experimental arms that perform below a pre-specified efficacy threshold. There will be no further recruitment to these arms.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 365
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Arm 1 (R35) pyridoxine Arm 1 (R35): HR35ZE isoniazid, rifampicin 35 mg/kg, pyrazinamide, ethambutol HRZQ SQ109 Arm 2 (Q): HRZQ isoniazid, rifampicin standard, pyrazinamide, SQ109 300 mg HRZQ Rifampicin Arm 2 (Q): HRZQ isoniazid, rifampicin standard, pyrazinamide, SQ109 300 mg HRZQ isoniazid Arm 2 (Q): HRZQ isoniazid, rifampicin standard, pyrazinamide, SQ109 300 mg HRZQ pyridoxine Arm 2 (Q): HRZQ isoniazid, rifampicin standard, pyrazinamide, SQ109 300 mg HR20ZQ SQ109 Arm 3 (R20Q): HR20ZQ isoniazid, rifampicin 20 mg/kg, pyrazinamide, SQ109 300 mg HR20ZQ pyridoxine Arm 3 (R20Q): HR20ZQ isoniazid, rifampicin 20 mg/kg, pyrazinamide, SQ109 300 mg HR20ZM pyridoxine Arm 4 (R20M): HR20ZM isoniazid, rifampicin 20 mg/kg, pyrazinamide, moxifloxacin 400 mg HRZE pyridoxine HRZE: Isoniazid, rifampicin standard, pyrazinamide, ethambutol Arm 1 (R35) isoniazid Arm 1 (R35): HR35ZE isoniazid, rifampicin 35 mg/kg, pyrazinamide, ethambutol Arm 1 (R35) Rifampicin Arm 1 (R35): HR35ZE isoniazid, rifampicin 35 mg/kg, pyrazinamide, ethambutol Arm 1 (R35) pyrazinamide Arm 1 (R35): HR35ZE isoniazid, rifampicin 35 mg/kg, pyrazinamide, ethambutol Arm 1 (R35) ethambutol Arm 1 (R35): HR35ZE isoniazid, rifampicin 35 mg/kg, pyrazinamide, ethambutol HRZQ pyrazinamide Arm 2 (Q): HRZQ isoniazid, rifampicin standard, pyrazinamide, SQ109 300 mg HR20ZQ Rifampicin Arm 3 (R20Q): HR20ZQ isoniazid, rifampicin 20 mg/kg, pyrazinamide, SQ109 300 mg HR20ZQ pyrazinamide Arm 3 (R20Q): HR20ZQ isoniazid, rifampicin 20 mg/kg, pyrazinamide, SQ109 300 mg HR20ZQ isoniazid Arm 3 (R20Q): HR20ZQ isoniazid, rifampicin 20 mg/kg, pyrazinamide, SQ109 300 mg HR20ZM pyrazinamide Arm 4 (R20M): HR20ZM isoniazid, rifampicin 20 mg/kg, pyrazinamide, moxifloxacin 400 mg HR20ZM Rifampicin Arm 4 (R20M): HR20ZM isoniazid, rifampicin 20 mg/kg, pyrazinamide, moxifloxacin 400 mg HR20ZM isoniazid Arm 4 (R20M): HR20ZM isoniazid, rifampicin 20 mg/kg, pyrazinamide, moxifloxacin 400 mg HRZE Rifampicin HRZE: Isoniazid, rifampicin standard, pyrazinamide, ethambutol HRZE Moxifloxacin HRZE: Isoniazid, rifampicin standard, pyrazinamide, ethambutol HRZE isoniazid HRZE: Isoniazid, rifampicin standard, pyrazinamide, ethambutol HRZE pyrazinamide HRZE: Isoniazid, rifampicin standard, pyrazinamide, ethambutol HRZE ethambutol HRZE: Isoniazid, rifampicin standard, pyrazinamide, ethambutol
- Primary Outcome Measures
Name Time Method Sputum Culture Conversion (2 Negative Cultures) Using Liquid Media 0 - 12 weeks From enrollment, the time to stable culture conversion (2 consecutive negative weekly cultures) in liquid media.
- Secondary Outcome Measures
Name Time Method Mycobacteriology Identification and Characterization by PCR and MIC 0 - 12 weeks Cultures grown from the screening period, and the last sputum sample with mycobacteriological growth will be assessed as follows:
* Identification of M. tuberculosis complex and RIF resistance by PCR (GeneXpert MTB/RIF®),
* First-line drug susceptibility testing of the M. tuberculosis isolates using the MGIT system for sensitivity to rifampicin; isoniazid, pyrazinamide, moxifloxacin or ethambutol.
* Minimum inhibitory concentrations (MIC) of SQ109, rifampicin and moxifloxacin.
* Typing of the infecting strain(s) by molecular methods.Pharmacokinetics Including AUC, Cl, t1/2, Vd, and Protein Binding 0 - 12 weeks Pharmacokinetic parameters will be assessed for rifampicin, moxifloxacin and SQ109:
* area under the plasma concentration curve from dosing to the end of the dosing interval (AUC 0-24) (in h\*ng/mL)
* the observed maximum concentration (Cmax( (in ng/mL)
* time to reach Cmax (Tmax)(in hours)
* the minimum observed plasma concentration 24 hours following the last dose (Cmin) (in hours),
* clearance (Cl) (in mL/minute),
* volume of distribution (Vd) (in L),
* elimination half-life (T1/2,) (in hours)
* free (protein-unbound) fraction (for rifampicin only) (in percent).Pharmacodynamics Including AUC0-24/MIC (h*ng/mL) and Cmax/MIC (ng/mL) 0 - 12 weeks By combining pharmacokinetic parameters and MIC values (see below), the pharmacodynamic indices AUC0-24/MIC (h\*ng/mL) and Cmax/MIC (ng/mL) will be calculated for individual patients for experimental drugs administered. Pharmacokinetic parameters and pharmacodynamic indices will be related to efficacy and safety/tolerability endpoints.
Time to First Negative Culture on Liquid and Solid Media 0 - 12 weeks Time to a convert to a single negative culture on liquid and solid media
Proportion of Negative Sputum Cultures 0 - 12 weeks Proportion of patients converting to negative sputum culture (2 consecutive weekly cultures) in liquid and solid media
Frequency of Adverse Events 0 - 12 weeks All Adverse Events (AE), and AEs considered to be drug-related will coded using standard AE dictionaries.
Rate of Change in Time to Positivity 0 - 12 weeks Rate of change in time to positivity in BD MGIT 960® liquid culture
Changes in Baseline Laboratory Safety Parameters During Treatment and Follow-up 0 - 12 weeks Frequency tables will be generated for visual acuity tests, 12 lead ECGs, clinical chemistry metrics, haematology, and urinalysis
Rate of Change in Quantitative PCR During Therapy 0 - 12 weeks GeneXpert MTB/RIF (Xpert) quantitative PCR results (counts per week
Occurence of Treatment Failure (Relapse or Emergence of Drug-resistance) 0 - 12 weeks Frequency of treatment failures (number of patients with relapse and/or development of drug resistance) will be recorded
Trial Locations
- Locations (7)
The Aurum Institute for Health Research
🇿🇦Johannesburg, South Africa
University of Cape Town, Centre for Tuberculosis Research Innovation
🇿🇦Cape Town, South Africa
NIMR - Mbeya Medical Research Programme
🇹🇿Mbeya, Tanzania
Wits Health Consortium
🇿🇦Johannesburg, South Africa
Ifakara Health Institute
🇹🇿Bagamoyo, Tanzania
TASK Applied Science
🇿🇦Bellville, South Africa
Kilimanjaro Christian Medical Centre (KCMC) / Kilimanjaro Clinical Research Institute (KCRI) (with affiliated field sites such as Kibong'oto National Tuberculosis Hospital Same, Mererani, Chekereni and Mawenzi Regional Hospital)
🇹🇿Moshi, Tanzania