Phase 2
N=365
Evaluation of SQ109, High-dose Rifampicin, and Moxifloxacin in Adults With Smear-positive Pulmonary TB in a MAMS Design
Tuberculosis, Pulmonary
Bottom Line
View on ClinicalTrials.gov: NCT01785186 ↗Enrolled (actual)
365
Serious AEs
6.3%
Results posted
Sep 2017
Primary outcome: Primary: Sputum Culture Conversion (2 Negative Cultures) Using Liquid Media — 48; 63; 66; 55 days
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 2
- Interventions
- SQ109 (Drug); Rifampicin (Drug); Moxifloxacin (Drug); isoniazid (Drug); pyrazinamide (Drug); ethambutol (Drug); pyridoxine (Dietary_supplement)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- Michael Hoelscher
- Primary completion
- Sep 2014
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Sputum Culture Conversion (2 Negative Cultures) Using Liquid Media |
48; 63; 66; 55; 62 | — |
| SECONDARY Frequency of Adverse Events |
53; 49; 42; 49; 92; 4 | — |
| SECONDARY Mycobacteriology Identification and Characterization by PCR and MIC |
— | — |
| SECONDARY Pharmacokinetics Including AUC, Cl, t1/2, Vd, and Protein Binding |
17.4; 170; 68.3; 57.8; 24.2 | — |
| SECONDARY Pharmacodynamics Including AUC0-24/MIC (h*ng/mL) and Cmax/MIC (ng/mL) |
— | — |
| SECONDARY Time to First Negative Culture on Liquid and Solid Media |
— | — |
| SECONDARY Proportion of Negative Sputum Cultures |
— | — |
| SECONDARY Rate of Change in Time to Positivity |
— | — |
| SECONDARY Rate of Change in Quantitative PCR During Therapy |
— | — |
| SECONDARY Occurence of Treatment Failure (Relapse or Emergence of Drug-resistance) |
— | — |
| SECONDARY Changes in Baseline Laboratory Safety Parameters During Treatment and Follow-up |
— | — |
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.
Eligibility Criteria
Inclusion Criteria
- The patient has given free, signed written or witnessed oral informed consent for study participation prior to all trial-related procedures, including HIV testing if HIV serostatus is not known or the last documented negative is more than four weeks ago.
- The patient has a diagnosis of pulmonary tuberculosis from a health clinic established by sputum smear and/or GeneXpert MTB/RIF® and/or chest X-ray.
- An adequate sputum bacterial load is confirmed by a Ziehl-Neelsen stained smear in the study laboratory, done from concentrated sputum found at least 1+ on the IUATLD/WHO scale.
- The patient has a valid rapid test result (GeneXpert MTB/RIF®) from the sputum positive for MTB complex, and indicating susceptibility to Rifampicin. This test must be done in the study laboratory.
- The patient is aged at least 18 years at the day of informed consent.
- The patient has a body weight in light clothing and without shoes of at least 35 kg, but not more than 90 kg.
- Female patients of childbearing potential must have a negative serum pregnancy test, and consent to practise an effective method of birth control until week 26. Effective birth control for female patients has to include two methods, including methods that the patient's sexual partner(s) use. At least one must be a barrier method. Female patients are considered not to be of childbearing potential if they are post-menopausal with no menses for the last 12 months, or surgically sterile (this condition is fulfilled by bilateral oophorectomy, hysterectomy, and by tubal ligation which is done at least 12 months prior to enrolment).
- Male patients must consent to use an effective contraceptive method, if their sexual partner(s) is/are of childbearing potential, and if they are not surgically sterile (see 6.). Contraception by male participants must be practised until at least week 24 to cover the period of spermatogenesis. Contraceptive methods used by male participants may include hormonal methods used by the partner(s).
- The patient has a firm home address that is readily accessible for visiting and willingness to inform the study team of any change of address during trial participation, or will be compliant to study schedule, in the discretion of the investigator.
Exclusion Criteria
- Circumstances that raise doubt about free, uncoerced consent to study participation (e.g. in a prisoner or mentally handicapped person)
- Poor General Condition where delay in treatment cannot be tolerated or death within three months is likely.
- The patient is pregnant or breast-feeding.
- The patient has an HIV infection and is receiving antiretroviral treatment (ART), and/or is likely to require ART during the twelve weeks of experimental study treatment as per local guidelines.
- The patient has a known intolerance to any of the study drugs, or concomitant disorders or conditions for which SQ109, rifampicin, moxifloxacin, or standard TB treatment are contraindicated.
- The patient has an history or evidence of clinically relevant metabolic, gastrointestinal, neurological, psychiatric or endocrine diseases, malignancy, or any other condition that will influence treatment response, study adherence or survival in the judgement of the investigator, especially:
clinically significant evidence of severe TB (e.g. miliary TB, TB meningitis. Limited lymph node involvement will not lead to exclusion); serious lung conditions other than TB or severe respiratory impairment in the discretion of the investigator; neuropathy, epilepsy or significant psychiatric disorder; uncontrolled and/or insulin-dependent diabetes; cardiovascular disease such as myocardial infarction, heart failure, coronary heart disease, uncontrolled hypertension (systolic blood pressure ≥160 mmHg and/or diastolic blood pressure of ≥100 mmHg on two occasions), arrhythmia, or tachyarrhythmia; long QT syndrome (see criterion 9.), or family history of long QT syndrome or sudden death of unknown or
Data sourced from ClinicalTrials.gov (NCT01785186). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.