AzTrials
AzTrials

Tuberculosis, PulmonaryPhase 2NCT01785186

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

A Phase 2 study testing SQ109, Rifampicin and Moxifloxacin in people with Tuberculosis, Pulmonary, run by Michael Hoelscher at 7 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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). Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Tuberculosis, Pulmonary
What is being tested?
SQ109, Rifampicin and Moxifloxacin
Could I receive a placebo?
No, everyone receives an active treatment
How many people
365 participants
Where
7 sitesin 2 countries
Study dates
Apr 2013to Mar 2015
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
Show all 9Show fewer
  • 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.

Who cannot join

  • 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:
Show all 15Show fewer
  • 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 cardiac-related cause; Plasmodium spp. parasitemia as indicated by thick blood smear or a positive rapid test present at screening; Alcohol or other drug abuse that is sufficient to significantly compromise the safety or cooperation of the patient, includes substances prohibited by the protocol, or has led to significant organ damage at the discretion of the investigator.
  • 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.

Trial locations and contacts

7 sites in 2 countries.

7 sites in 2 countries

South Africa4 sites

  • TASK Applied Science

    Bellville, 7530

  • University of Cape Town, Centre for Tuberculosis Research Innovation

    Cape Town, 7700

  • Wits Health Consortium

    Johannesburg, 2092

  • The Aurum Institute for Health Research

    Johannesburg, 2193

Other trials in South Africa

Tanzania3 sites

  • Ifakara Health Institute

    Bagamoyo, P.O.Box 74

  • NIMR - Mbeya Medical Research Programme

    Mbeya, P.O. Box 2410

  • 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

Other trials in Tanzania

About this study

Official title: A Multiple Arm, Multiple Stage, Phase 2, OL, Randomized, Controlled Trial to Evaluate 4 Treatment Regimens of SQ109, Increased Doses of Rifampicin, and Moxifloxacin in Adults With Newly Diagnosed, Smear-positive Pulmonary Tuberculosis

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.

Read the 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.

Being tested
SQ109, Rifampicin, Moxifloxacin, isoniazid, pyrazinamide
Keywords
TB, Tuberculosis, MAMS - Multiple-arm, multiple-stage, Pulmonary, SQ109, High dose rifampicin, moxifloxacin
Medical subject headings
Tuberculosis, Pulmonary, Tuberculosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • SQ109Drug

    SQ109 300 mg

  • RifampicinDrug

    Rifampicin 10 to 35 mg/kg

  • MoxifloxacinDrug

    Moxifloxacin 400mg

  • isoniazidDrug

    isoniazid 75 mg

  • pyrazinamideDrug

    pyrazinamide 400 mg

  • ethambutolDrug

    ethambutol 275 mg

  • pyridoxineDietary supplement

    pyridoxine 25 mg

Study groups in NCT01785186
Study groupRoleWhat they receive
Arm 1 (R35)ExperimentalArm 1 (R35): HR35ZE isoniazid, rifampicin 35 mg/kg, pyrazinamide, ethambutol
Receives: Drug: Rifampicin; Drug: isoniazid; Drug: pyrazinamide; Drug: ethambutol; Dietary Supplement: pyridoxine
HRZQExperimentalArm 2 (Q): HRZQ isoniazid, rifampicin standard, pyrazinamide, SQ109 300 mg
Receives: Drug: SQ109; Drug: Rifampicin; Drug: isoniazid; Drug: pyrazinamide; Dietary Supplement: pyridoxine
HR20ZQExperimentalArm 3 (R20Q): HR20ZQ isoniazid, rifampicin 20 mg/kg, pyrazinamide, SQ109 300 mg
Receives: Drug: SQ109; Drug: Rifampicin; Drug: isoniazid; Drug: pyrazinamide; Dietary Supplement: pyridoxine
HR20ZMExperimentalArm 4 (R20M): HR20ZM isoniazid, rifampicin 20 mg/kg, pyrazinamide, moxifloxacin 400 mg
Receives: Drug: Rifampicin; Drug: isoniazid; Drug: pyrazinamide; Dietary Supplement: pyridoxine
HRZEActive comparatorHRZE: Isoniazid, rifampicin standard, pyrazinamide, ethambutol
Receives: Drug: Rifampicin; Drug: Moxifloxacin; Drug: isoniazid; Drug: pyrazinamide; Drug: ethambutol; Dietary Supplement: pyridoxine

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: 0 - 12 weeks

Secondary outcomes (10)

  1. Frequency of Adverse Events

    All Adverse Events (AE), and AEs considered to be drug-related will coded using standard AE dictionaries.

    Measured: 0 - 12 weeks

  2. Mycobacteriology Identification and Characterization by PCR and MIC

    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.

    Measured: 0 - 12 weeks

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

    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).

    Measured: 0 - 12 weeks

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

    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.

    Measured: 0 - 12 weeks

  5. Time to First Negative Culture on Liquid and Solid Media

    Time to a convert to a single negative culture on liquid and solid media

    Measured: 0 - 12 weeks

  6. Proportion of Negative Sputum Cultures

    Proportion of patients converting to negative sputum culture (2 consecutive weekly cultures) in liquid and solid media

    Measured: 0 - 12 weeks

  7. Rate of Change in Time to Positivity

    Rate of change in time to positivity in BD MGIT 960® liquid culture

    Measured: 0 - 12 weeks

  8. Rate of Change in Quantitative PCR During Therapy

    GeneXpert MTB/RIF (Xpert) quantitative PCR results (counts per week

    Measured: 0 - 12 weeks

  9. Occurence of Treatment Failure (Relapse or Emergence of Drug-resistance)

    Frequency of treatment failures (number of patients with relapse and/or development of drug resistance) will be recorded

    Measured: 0 - 12 weeks

  10. Changes in Baseline Laboratory Safety Parameters During Treatment and Follow-up

    Frequency tables will be generated for visual acuity tests, 12 lead ECGs, clinical chemistry metrics, haematology, and urinalysis

    Measured: 0 - 12 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted7 Feb 2013 (estimated)
  2. Study startApr 2013
  3. Primary completionSep 2014
  4. Study completionMar 2015

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
365 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01785186
Sponsor's protocol ID
PanACEA-MAMS-TB-01
Status last verified
Aug 2017
First submitted
17 Dec 2012
Last updated
20 Sep 2017
Data monitoring committee
Yes

Publications

  • 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.

    PubMed 33542052

  • 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.

    PubMed 28100438

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing SQ109, Rifampicin and Moxifloxacin in people with Tuberculosis, Pulmonary, run by Michael Hoelscher at 7 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 9 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 20 Sep 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 7 sites in South Africa, Tanzania. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 20 Sep 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Sputum Culture Conversion (2 Negative Cultures) Using Liquid Media (time frame: 0 - 12 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01785186, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Sep 2017.

AzTrials uses cookies for analytics and advertising. You can accept or reject them; the site works either way. Privacy Policy.

Free account

Log in to keep searching

You’ve used your 3 free searches. AzTrials is free: log in or create a free account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in