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TuberculosisPhase 2NC-005NCT02193776

A Phase 2 to Evaluate the Efficacy, Safety and Tolerability of Combinations of Bedaquiline, Moxifloxacin, PA-824 and Pyrazinamide in Adult Subjects With Drug-Sensitive or Multi Drug-Resistant Pulmonary Tuberculosis.

A Phase 2 study testing PA-824, bedaquiline and moxifloxacin in people with Tuberculosis, run by Global Alliance for TB Drug Development at 10 sites in 3 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

The purpose of this study is to determine the mycobactericidal activity of combinations of bedaquiline (J), moxifloxacin (M), PA-824 (Pa) and pyrazinamide (Z) regimens during 8 weeks of treatment. Read more about this study

Who is it for?
Ages 18 to 75 years
Conditions the study is for
Tuberculosis
What is being tested?
PA-824, bedaquiline and moxifloxacin
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
240 participants
Where
10 sitesin 3 countries
Study dates
23 Oct 2014to 7 Feb 2018
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 to 75 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Provide written, informed consent prior to all trial-related procedures. Male or female, aged between 18 and 75 years inclusive.
  • Body weight (in light clothing and with no shoes) between 35 and 100 kg, inclusive.
  • Tested at the trial appointed laboratory: M. Tb positive on molecular test (e.g. GeneXpert or Hain) and sputum smear-positive pulmonary TB on direct microscopy for acid-fast bacilli (at least 1+ on the IUATLD/WHO scale.
  • For DS-TB treatment arms (defined as sensitive to rifampicin based on molecular sensitivity testing), Subjects should be:
  • either newly diagnosed or untreated for at least 3 years after cure from a previous episode (Subject can give a history of cure and previous treatment); AND
  • Previous TB treatment must be discontinued as per exclusion criteria 16.
Show all 21Show fewer
  • For MDR-TB treatment arm (defined as resistant to rifampicin based on molecular sensitivity testing), Subjects should be:
  • sensitive to moxifloxacin by molecular sensitivity testing; AND
  • either newly diagnosed or could have previously been treated for DS-TB and/or MDR-TB (< 7 days of treatment). Previous MDR-TB treatment must be discontinued as per exclusion criteria 17.
  • A chest X-ray picture which in the opinion of the Investigator is compatible with TB.
  • Ability to produce an adequate volume of sputum as estimated from a screening Coached Spot Sputum Sample assessment (estimated 10 ml or more overnight production).
  • Be of non-childbearing potential or using effective methods of birth control, as defined below:
  • Non-childbearing potential:
  • Subject - not heterosexually active or practices sexual abstinence; or
  • Female Subject/sexual partner - bilateral oophorectomy, bilateral tubal ligation and/or hysterectomy or has been postmenopausal with a history of no menses for at least 12 consecutive months; or
  • Male Subject/sexual partner - vasectomised or has had a bilateral orchidectomy minimally three months prior to screening.
  • Effective birth control methods:
  • A double contraceptive method should be used as follows:
  • Double barrier method which can include any 2 of the following: a male condom, diaphragm, cervical cap, or female condom (male and female condoms should not be used together); or
  • Barrier method (one of the above) combined with hormone-based contraceptives or an intra-uterine device for the female Subject/partner; and are willing to continue practicing birth control methods throughout treatment and for 6 months (both male and female Subjects) after the last dose of study medication or discontinuation from study medication in case of premature discontinuation.
  • (Note: Hormone-based contraception alone may not be reliable when taking IMP; therefore, hormone-based contraceptives alone cannot be used by female Subjects or female partners of male Subjects to prevent pregnancy).

Who cannot join

  • Medical Criteria
  • Evidence of clinically significant (as judged by the Investigator), metabolic, gastrointestinal, cardiovascular, musculoskeletal, ophthalmological, pulmonary, neurological, psychiatric or endocrine diseases, malignancy, or other abnormalities (other than the indication being studied) including malaria. A rapid test for malaria may be carried out if indicated.
  • Karnofsky performance status score of < 60%.
  • Poor general condition where any delay in treatment cannot be tolerated per discretion of the Investigator.
  • Clinically significant evidence of extrathoracic TB (e.g. miliary TB, abdominal TB, urogenital TB, osteoarthritic TB, TB meningitis), as judged by the Investigator.
  • History of allergy or hypersensitivity to any of the study Investigational Medicinal Products or related substances.
Show all 47Show fewer
  • Known or suspected current alcohol and/or drug abuse (positive urine drug screen) or history thereof within the past 2 years that is, in the opinion of the Investigator, sufficient to compromise the safety and/or cooperation of the Subject.
  • For HIV infected Subjects:
  • having a CD4+ count <100 cells/µL;
  • with an AIDS-defining opportunistic infection or malignancies (except pulmonary TB);
  • currently treated with or will need to initiate antiretroviral therapy (ART) which is not compatible with the allowed ARTs and is not considered an appropriate candidate for switching to a regimen of ARVs which is allowed as follows:
  • Triple nucleoside reverse transcriptase inhibitor (NRTI) based regimen consisting of zidovudine, lamivudine, and abacavir;
  • Nevirapine based regimen consisting of nevirapine in combination with any NRTIs;
  • Lopinavir/ritonavir (Aluvia™) based regimen consisting of lopinavir/ritonavir (Aluvia™) in combination with any NRTIs;
  • Raltegravir in combination with nucleoside reverse transcriptase inhibitors (NRTIs);
  • cannot ensure a 2 week interval between commencing IMP and the start of ART.
  • Having participated in other clinical study/ies with investigational agent/s within 8 weeks prior to trial start.
  • Significant cardiac arrhythmia requiring medication.
  • Subjects with the following at screening (per measurements and reading done by Central ECG):
  • Marked prolongation of QT/QTc interval, e.g. confirmed demonstration of QTcF (Fridericia correction) or QTcB (Bazett correction) interval >450 ms at screening;
  • History of additional risk factors for Torsade de Pointes, e.g. heart failure, hypokalemia, family history of Long QT Syndrome;
  • Use of concomitant medications that are known to prolong the QT/QTc interval (see exclusion criteria 19);
  • Any clinically significant, in the opinion of the Investigator, ECG abnormality.
  • Females who are pregnant, breast-feeding, or planning to conceive a child during the study or within 6 months of cessation of treatment. Males planning to conceive a child during the study or within 6 months of cessation of treatment.
  • Diabetes Mellitus resulting in hospitalization in the past year.
  • Evidence of lens opacity on slit lamp ophthalmologic examination as defined by a grading of >1+ on the AREDS2 grading system.
  • For males, any history of a clinically significant abnormality in the reproductive system.
  • Specific Treatments
  • Previously received treatment with PA-824, bedaquiline or moxifloxacin as part of a clinical trial.
  • For the DS-TB treatment arms: treatment with any drug active against M. Tb within the 3 years prior to Day 1 (including but not limited to isoniazid, ethambutol, amikacin, bedaquiline, clofazimine, cycloserine, fluoroquinolones, rifabutin, rifampicin, streptomycin, kanamycin, para-aminosalicylic acid, rifapentine, pyrazinamide, thioacetazone, capreomycin, thioamides, metronidazole). Exceptions include the use of fluoroquinolones and metronidazole as short-term treatment (≤2 weeks) for Non-M.Tb infections. Treatment should have been discontinued at least 3 months prior to Day 1. Subjects who have previously received isoniazid prophylactically may be included in the trial as long as that treatment is/was discontinued at least 7 days prior to randomization into this trial.
  • MDR-TB Subjects may have previously been treated for DS-TB with first-line TB drugs (isoniazid, rifampicin, ethambutol, pyrazinamide and/or streptomycin) and/or received ≤7 days MDR-TB treatment, provided that treatment is/was discontinued at least 7 days prior to randomization. It should be confirmed that the MDR-TB treatment can be safely stopped and the screening period is long enough to allow for a washout period of 5 times the longest half-life of the drugs.
  • Any diseases or conditions in which the use of the standard TB drugs or any of their components is contra-indicated, including but not limited to acute gout, allergy to any TB drug, their component or to the IMP.
  • Use of any drug within 30 days prior to dosing known to prolong QTc interval (including but not limited to amiodarone, bepridil, chloroquine, chlorpromazine, cisapride, cyclobenzaprine, clarithromycin, disopyramide dofetilide, domperidone, droperidol, erythromycin, halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, methadone, pentamidine, pimozide, procainamide, quinidine, sotalol, sparfloxacin, thioridazine). Exceptions may be made for Subjects that have received 3 days or less of one of these drugs or substances, if there has been a wash-out period before administration of IMP equivalent to at least 5 half-lives of that drug or substance. Subjects who have taken drugs with long elimination half-lives such as amiodarone should be discussed with the Sponsor.
  • Use of any drugs or substances within 30 days prior to dosing known to be strong inhibitors or inducers of cytochrome P450 enzymes (including but not limited to quinidine, tyramine, ketoconazole, fluconazole, testosterone, quinine, gestodene, metyrapone, phenelzine, doxorubicin, troleandomycin, cyclobenzaprine, erythromycin, cocaine, furafylline, cimetidine, dextromethorphan). Exceptions may be made for Subjects that have received 3 days or less of one of these drugs or substances, if there has been a wash-out period before administration of IMP equivalent to at least 5 half-lives of that drug or substance.
  • Any ARVs other than allowable ARVs detailed in exclusion criteria no. 7 above.
  • Based on Laboratory Abnormalities:
  • Subjects with the following toxicities at screening as defined by the enhanced Division of Microbiology and Infectious Disease (DMID) adult toxicity table:
  • serum magnesium and calcium (corrected for albumin) levels outside of the laboratory's reference range
  • lipase grade 3 or greater (>2.0 x ULN);
  • creatinine grade 2 or greater (>1.5 x ULN);
  • hemoglobin grade 4 (<6.5 g/dL);
  • platelets > grade 2 (under 50x10(9) cells/L);
  • serum potassium less than the lower limit of normal for the laboratory;
  • aspartate aminotransferase (AST) grade 3 or greater (≥3.0 x ULN) to be excluded;
  • alanine aminotransferase (ALT) grade 3 or greater (≥3.0 x ULN) to be excluded;
  • alkaline phosphatase (ALP) grade 4 (>8.0 x ULN) to be excluded, grade 3 (≥3.0 - 8.0 x ULN) must be discussed with and approved by the Sponsor Medical Monitor;
  • total bilirubin grade 3 or greater (≥2.0 x ULN, or ≥1.50 x ULN when accompanied by any increase in other liver function test) to be excluded, grade 2 (≥1.50 x ULN, or ≥1.25 x ULN when accompanied by any increase in other liver function test) must be discussed with and approved by the Sponsor Medical Monitor

Trial locations and contacts

10 sites in 3 countries.

10 sites in 3 countries

South Africa7 sites

  • TASK Applied Science

    Cape Town, 7531

  • University of Cape Town Lung Institute (Pty) Ltd

    Cape Town, 7937

  • THINK: Tuberculosis & HIV Investigative Network of KwaZulu-Natal

    Durban

  • CHRU Themba Lethu Clinic

    Johannesburg

  • University of Witwatersrand, Clinical HIV Research Unit (CHRU), Helen Joseph Hospital

    Johannesburg

  • Klerksdorp Tshepong Hospital

    Jouberton, Klerksdorp, 2570

  • The Aurum Institute: Tembisa Hospital

    Tembisa, Gauteng, 1632

Other trials in South Africa

Tanzania2 sites

  • Ifakara Health Institute

    Bagamoyo

  • NIMR-Mbeya Medical Research Centre (MMRC)

    Mbeya

Other trials in Tanzania

Uganda1 site

  • Uganda Case Western Reserve University Research Collaboration

    Kampala

Other trials in Uganda

About this study

Official title: A Phase 2 Open-Label Partially Randomized Trial to Evaluate the Efficacy, Safety and Tolerability of Combinations of Bedaquiline, Moxifloxacin, PA-824 and Pyrazinamide During 8 Weeks of Treatment in Adult Subjects With Newly Diagnosed Drug-Sensitive or Multi Drug-Resistant, Smear-Positive Pulmonary Tuberculosis.

The purpose of this study is to determine the mycobactericidal activity of combinations of bedaquiline (J), moxifloxacin (M), PA-824 (Pa) and pyrazinamide (Z) regimens during 8 weeks of treatment.

Read the detailed description

The trial design is a phase 2, multi-center, open-label, partially randomized clinical trial in four parallel treatment groups. Subjects with drug-sensitive tuberculosis (DS-TB) will be randomized to receive either J(loading dose/three times a week)PaZ; or J(200mg)PaZ; or HRZE. Subjects with multi drug-resistant tuberculosis will receive J(200mg)MPaZ. The HRZE treatment arm is included as a control for the drug-sensitive treatments and as a control for the quantitative laboratory mycobacteriology testing.

A total of approximately 240 male and female, newly diagnosed subjects with drug-sensitive or multi drug-resistant, smear positive pulmonary tuberculosis aged 18 to 75 years (inclusive) will be included in the study. A total of 180 subjects with drug-sensitive tuberculosis (60 per treatment arm) will be randomized. Up to 60 subjects with multi-drug resistant tuberculosis will be assigned.

All subjects will have up to a maximum of 9 days screening, receive 8 weeks of treatment, and have follow-up visits at 2 and 12 weeks after study treatment completion or last dose of investigational medicinal product in the case of early withdrawal. Subjects who withdraw from the study after receiving < 14 days of investigational medicinal product, will only attend a follow-up visit at 2 weeks after last dose of investigational medicinal product.

Upon treatment completion, the subjects with drug-sensitive tuberculosis will be provided with sufficient doses of standard of care tuberculosis treatment, as appropriate, to cover the time period from attending their last visit at the study clinic until their scheduled visit at the TB clinic. All subjects with drug sensitive and multi-drug resistant tuberculosis will be referred to the local community tuberculosis clinics for standard anti-tuberculosis chemotherapy according to National Tuberculosis Guidelines.

Conditions
Tuberculosis
Being tested
PA-824, bedaquiline, moxifloxacin, pyrazinamide, isoniazid, rifampicin, pyrazinamide and ethambutol combination tablet
Keywords
Tuberculosis, Multi Drug-Resistant Tuberculosis, Drug-Sensitive Tuberculosis, PA-824, Bedaquiline, Moxifloxacin, Pyrazinamide, Quinolone, Pretomanid, NC-005
Medical subject headings
Tuberculosis, Tuberculosis, Multidrug-Resistant

What participants receive

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

  • PA-824Drug

    oral

  • bedaquilineDrug

    Also called TMC207, Sirturo

    oral

  • moxifloxacinDrug

    Also called BAY 12-8039, Avelox, Avalon, Avelon

    oral

  • pyrazinamideDrug

    oral

  • isoniazid, rifampicin, pyrazinamide and ethambutol combination tabletDrug

    oral

Study groups in NCT02193776
Study groupRoleWhat they receive
DS-TB: J(loading dose/t.i.w.)PaZExperimentalSubjects with DS-TB. J(loading dose/t.i.w.)PaZ: Bedaquiline 400mg once daily Days 1-14, 200mg three times per week Days 15-56; plus PA-824 200mg once daily Days 1-56; plus pyrazinamide 1500mg once daily Days 1-56.
Receives: Drug: PA-824; Drug: bedaquiline; Drug: pyrazinamide
DS-TB: J(200mg)PaZExperimentalSubjects with DS-TB. J(200mg)PaZ: Bedaquiline 200mg once daily Days 1-56; plus PA-824 200mg once daily Days 1-56; plus pyrazinamide 1500mg once daily Days 1-56.
Receives: Drug: PA-824; Drug: bedaquiline; Drug: pyrazinamide
MDR-TB: J(200mg)MPaZExperimentalSubjects with MDR-TB. J(200mg)MPaZ: Bedaquiline 200mg once daily Days 1-56; plus moxifloxacin 400mg once daily Days 1-56; plus PA-824 200mg once daily Days 1-56; plus pyrazinamide 1500mg once daily Days 1-56.
Receives: Drug: PA-824; Drug: bedaquiline; Drug: moxifloxacin; Drug: pyrazinamide
DS-TB: HRZEActive comparatorSubjects with DS-TB. HRZE tablets (Isoniazid 75mg plus rifampicin 150mg plus pyrazinamide 400mg plus ethambutol 275mg combination tablets) dosed once daily Days 1-56 per the Subject's weight as follows: 30-37kg: 2 tablets; 38-54kg: 3 tablets; 55-70kg: 4 tablets; 71kg and over: 5 tablets.
Receives: Drug: isoniazid, rifampicin, pyrazinamide and ethambutol combination tablet

What is being measured

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

  1. Rate of Change in Time to Sputum Culture Positivity (TTP) Over 8 Weeks in the Mycobacterial Growth Indicator Tube (MGIT) System

    The bactericidal activity (BA) was determined by the rate of change in TTP collected from overnight sputum samples over 8 weeks of treatment in the liquid culture media MGIT system, represented by the model-fitted log(TTP) results as calculated by the regression of the observed log(TTP) results over time. The bactericidal activity of log(TTP) over Day 0 to Day 56 (BATTP[0-56]) was presented and expressed as the daily percentage change in TTP from Day 0 to Day 56. The mean BATTP (0-56) was calculated from Bayesian non-linear mixed effects regression models fitted to log(TTP) collected from sputum samples (observed from Day 0 to Day 56).

    Measured: Day 0 to Day 56 (8 weeks)

Secondary outcomes (1)

  1. Number of Participants With Treatment Emergent Adverse Events (TEAEs)

    A TEAE was defined as any AE which started or worsened on or after first study drug administration up to and including the Day 70 follow-up visit (or up to and including 14 days after last study drug administration for participants not having Day 70 follow-up visit). Drug-related TEAEs were defined as TEAEs for which relationship to study drug was indicated as 'possible', 'probable', 'certain' or missing. TEAEs leading to death were defined as TEAEs resulted 'fatal' outcome. Serious TEAEs were defined as TEAEs for which serious was indicated as 'yes'. TEAEs leading to discontinuation of study drug were defined as TEAEs for which action taken with study drug was indicated as 'study drug stopped'. TEAEs leading to early withdrawal from study were defined as TEAEs resulted study discontinuation. Grade III and IV TEAEs were defined as TEAEs for which severity (DMID grade) was indicated as 'Grade 3 (severe)' and 'Grade 4 (potentially life-threatening)' or missing, respectively.

    Measured: First study drug administration (Day 1) up to and including the Day 70 follow-up visit (or up to and including 14 days after last study drug administration for participants not having the Day 70 follow-up visit) (70 days)

Timeline

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

  1. First posted18 Jul 2014 (estimated)
  2. Study start23 Oct 2014
  3. Primary completion8 Feb 2016
  4. Study completion7 Feb 2018

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
Parallel groups
Masking
None (open label)
Enrolment
240 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02193776
Sponsor's protocol ID
NC-005-(J-M-Pa-Z)
Acronym
NC-005
Status last verified
May 2019
First submitted
16 Jul 2014
Last updated
26 Jul 2019
Data monitoring committee
Yes

Publications

  • Tweed CD, Dawson R, Burger DA, Conradie A, Crook AM, Mendel CM, Conradie F, Diacon AH, Ntinginya NE, Everitt DE, Haraka F, Li M, van Niekerk CH, Okwera A, Rassool MS, Reither K, Sebe MA, Staples S, Variava E, Spigelman M. Bedaquiline, moxifloxacin, pretomanid, and pyrazinamide during the first 8 weeks of treatment of patients with drug-susceptible or drug-resistant pulmonary tuberculosis: a multicentre, open-label, partially randomised, phase 2b trial. Lancet Respir Med. 2019 Dec;7(12):1048-1058. doi: 10.1016/S2213-2600(19)30366-2. Epub 2019 Nov 12.

    PubMed 31732485

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing PA-824, bedaquiline and moxifloxacin in people with Tuberculosis, run by Global Alliance for TB Drug Development at 10 sites in 3 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 21 inclusion and 47 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 26 Jul 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 10 sites in South Africa, Tanzania, Uganda. 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 26 Jul 2019). 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?

Rate of Change in Time to Sputum Culture Positivity (TTP) Over 8 Weeks in the Mycobacterial Growth Indicator Tube (MGIT) System (time frame: Day 0 to Day 56 (8 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 NCT02193776, which also lists 1 linked publication.

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 26 Jul 2019.

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