Evaluation of SQ109, High-dose Rifampicin, and Moxifloxacin in Adults With Smear-positive Pulmonary TB in a MAMS Design

NCT01785186 | Completed Phase 2 Results DMC

• 1 other identifier: PanACEA-MAMS-TB-01
• Study Type: interventional
• Target: 365
• Locations: 2 countries
• Sites: 7

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.

Conditions

Tuberculosis, Pulmonary

Keywords

TB; Tuberculosis; MAMS - Multiple-arm, multiple-stage; Pulmonary; SQ109; High dose rifampicin; moxifloxacin

Outcome Measures

Primary Outcomes (1)

• Sputum Culture Conversion (2 Negative Cultures) Using Liquid Media

  From enrollment, the time to stable culture conversion (2 consecutive negative weekly cultures) in liquid media.

  0 - 12 weeks

Secondary Outcomes (10)

• Frequency of Adverse Events

  0 - 12 weeks

• Mycobacteriology Identification and Characterization by PCR and MIC

  0 - 12 weeks

• Pharmacokinetics Including AUC, Cl, t1/2, Vd, and Protein Binding

  0 - 12 weeks

• Pharmacodynamics Including AUC0-24/MIC (h*ng/mL) and Cmax/MIC (ng/mL)

  0 - 12 weeks

• Time to First Negative Culture on Liquid and Solid Media

  0 - 12 weeks

Study Arms (5)

Arm 1 (R35)

EXPERIMENTAL

Arm 1 (R35): HR35ZE isoniazid, rifampicin 35 mg/kg, pyrazinamide, ethambutol

Drug: Rifampicin; Drug: isoniazid; Drug: pyrazinamide; Drug: ethambutol; Dietary Supplement: pyridoxine

HRZQ

EXPERIMENTAL

Arm 2 (Q): HRZQ isoniazid, rifampicin standard, pyrazinamide, SQ109 300 mg

Drug: SQ109; Drug: Rifampicin; Drug: isoniazid; Drug: pyrazinamide; Dietary Supplement: pyridoxine

HR20ZQ

EXPERIMENTAL

Arm 3 (R20Q): HR20ZQ isoniazid, rifampicin 20 mg/kg, pyrazinamide, SQ109 300 mg

Drug: SQ109; Drug: Rifampicin; Drug: isoniazid; Drug: pyrazinamide; Dietary Supplement: pyridoxine

HR20ZM

EXPERIMENTAL

Arm 4 (R20M): HR20ZM isoniazid, rifampicin 20 mg/kg, pyrazinamide, moxifloxacin 400 mg

Drug: Rifampicin; Drug: isoniazid; Drug: pyrazinamide; Dietary Supplement: pyridoxine

HRZE

ACTIVE COMPARATOR

HRZE: Isoniazid, rifampicin standard, pyrazinamide, ethambutol

Drug: Rifampicin; Drug: Moxifloxacin; Drug: isoniazid; Drug: pyrazinamide; Drug: ethambutol; Dietary Supplement: pyridoxine

Interventions

SQ109 DRUG

SQ109 300 mg

HR20ZQ; HRZQ

Rifampicin DRUG

Rifampicin 10 to 35 mg/kg

Arm 1 (R35); HR20ZM; HR20ZQ; HRZE; HRZQ

Moxifloxacin DRUG

Moxifloxacin 400mg

HRZE

isoniazid DRUG

isoniazid 75 mg

Arm 1 (R35); HR20ZM; HR20ZQ; HRZE; HRZQ

pyrazinamide DRUG

pyrazinamide 400 mg

Arm 1 (R35); HR20ZM; HR20ZQ; HRZE; HRZQ

ethambutol DRUG

ethambutol 275 mg

Arm 1 (R35); HRZE

pyridoxine DIETARY_SUPPLEMENT

pyridoxine 25 mg

Arm 1 (R35); HR20ZM; HR20ZQ; HRZE; HRZQ

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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:
• History of previous TB within the last five years.
• Laboratory: at screening one or more of the following abnormalities were observed for the patient in screening laboratory: Serum amino aspartate transferase (AST) and/or serum alanine aminotransferase (ALT) activity \>3x the upper limit of normal; Serum total bilirubin level \>2.5 times the upper limit of normal; Creatinine clearance (CrCl) level lower than 30 mls/min; Complete blood count with hemoglobin level \<7.0 g/dL; Platelet count \<50,000/mm3; Serum potassium below the lower level of normal;
• ECG findings in the screening ECG: QTcB and/or QTcF of \>0.450 s; atrioventricular (AV) block with PR interval \> 0.20 s; prolongation of the QRS complex over 120 milliseconds; other changes in the ECG that are clinically relevant as per discretion of the investigator.
• The patient has had treatment with any other investigational drug within 1 month prior to enrolment, or enrolment into other clinical (intervention) trials is planned during week 1-26
• Previous anti-TB treatment: the patient has had previous treatment with drugs active against M. tuberculosis within the last 3 months, including but not limited to INH, EMB, RIF, PZA, amikacin, cycloserine, rifabutin, streptomycin, kanamycin, para-aminosalicylic acid, rifapentine, thioacetazone, capreomycin, fluoroquinolones, thioamides.
• QT prolonging medications: Administration within 30 days prior to study start, anticipated administration during the study period, or during the 12 weeks of experimental treatment, of any QT-prolonging agents such as, but not limited to, azithromycin, bepridil chloroquine, chlorpromazine, cisapride, cisapride, clarithromycin, disopyramide dofetilide, domperidone, droperidol, erythromycin, halofantrine, haloperidol, ibutilide, levomethadyl, lumefantrine, mefloquine, mesoridazine, methadone, moxifloxacin, pentamidine, pimozide, procainamide, quinidine, quinine, roxithromycin, sotalol, sparfloxacin, terfenadine, thioridazine. Exceptions may be made for participants who have received 3 days or less of one of these drugs or substances, if there has been a wash-out period equivalent to at least 5 half-lives of that drug or substance.
• Patients who have ever received amiodarone will be excluded from study participation.
• CYP 450 inducers/inhibitors: administration within 30 days prior to dosing, or planned administration until the end of week 12, of any drug(s) or substance(s) known to be strong inhibitors or inducers of cytochrome P450 enzymes, or specific inhibitors/inducers of SQ109-metabolizing enzymes as Exceptions may be made for subjects that have received 3 days or less of one of these drugs or substances, if a wash-out period equivalent to at least 5 half-lives of that drug or substance prior to study treatment is granted.

Sponsors & Collaborators

• Michael Hoelscher: lead
• Sequella, Inc.: collaborator
• European and Developing Countries Clinical Trials Partnership (EDCTP): collaborator
• German Federal Ministry of Education and Research: collaborator
• Medical Research Council: collaborator
• Radboud University Medical Center: collaborator

Study Sites (7)

TASK Applied Science

Bellville, 7530, South Africa

Location

University of Cape Town, Centre for Tuberculosis Research Innovation

Cape Town, 7700, South Africa

Location

Wits Health Consortium

Johannesburg, 2092, South Africa

Location

The Aurum Institute for Health Research

Johannesburg, 2193, South Africa

Location

Ifakara Health Institute

Bagamoyo, P.O.Box 74, Tanzania

Location

NIMR - Mbeya Medical Research Programme

Mbeya, P.O. Box 2410, Tanzania

Location

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, 2236, Tanzania

Location

Related Publications (2)

• Zhang N, Savic RM, Boeree MJ, Peloquin CA, Weiner M, Heinrich N, Bliven-Sizemore E, Phillips PPJ, Hoelscher M, Whitworth W, Morlock G, Posey J, Stout JE, Mac Kenzie W, Aarnoutse R, Dooley KE; Tuberculosis Trials Consortium (TBTC) and Pan African Consortium for the Evaluation of Antituberculosis Antibiotics (PanACEA) Networks. Optimising pyrazinamide for the treatment of tuberculosis. Eur Respir J. 2021 Jul 20;58(1):2002013. doi: 10.1183/13993003.02013-2020. Print 2021 Jul.

  PMID: 33542052 DERIVED

• Boeree MJ, Heinrich N, Aarnoutse R, Diacon AH, Dawson R, Rehal S, Kibiki GS, Churchyard G, Sanne I, Ntinginya NE, Minja LT, Hunt RD, Charalambous S, Hanekom M, Semvua HH, Mpagama SG, Manyama C, Mtafya B, Reither K, Wallis RS, Venter A, Narunsky K, Mekota A, Henne S, Colbers A, van Balen GP, Gillespie SH, Phillips PPJ, Hoelscher M; PanACEA consortium. High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial. Lancet Infect Dis. 2017 Jan;17(1):39-49. doi: 10.1016/S1473-3099(16)30274-2. Epub 2016 Oct 26.

  PMID: 28100438 DERIVED

MeSH Terms

Conditions

Tuberculosis, Pulmonary; Tuberculosis

Interventions

Rifampin; Moxifloxacin; Isoniazid; Pyrazinamide; Ethambutol; Pyridoxine

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Pyridines; Heterocyclic Compounds, 1-Ring; Pyrazines; Ethylenediamines; Diamines; Polyamines; Amines; Vitamin B 6; Picolines

Results Point of Contact

• Title: Dr. Norbert Heinrich
• Organization: Tropical Institute of the Ludwig-Maximilians University in Munich, Germany

heinrich@lrz.uni-muenchen.de

0049 89 2180 17605

Study Officials

• Michael Hoelscher, MD

  Klinikum of the University of Munich

  STUDY CHAIR

• Martin Boeree, MD

  Radboud University Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Prof.

Study Record Dates

• First Submitted: December 17, 2012
• First Posted: February 7, 2013
• Study Start: April 1, 2013
• Primary Completion: September 1, 2014
• Study Completion: March 1, 2015
• Last Updated: September 20, 2017
• Results First Posted: September 20, 2017

Record last verified: 2017-08

Locations

TA (3); ZA (4)