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.

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT02193776
• Date of registration: 16/07/2014
• Prospective Registration: Yes
• Primary sponsor: Global Alliance for TB Drug Development
• Public title: 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. NC-005
• Scientific 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.
• Date of first enrolment: October 23, 2014
• Target sample size: 240
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT02193776
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 2

Countries of recruitment

South Africa, Tanzania, Uganda

Contacts

• Name: Rodney Dawson
• Affiliation: University of Cape Town Lung Institute

Key inclusion & exclusion criteria

Inclusion Criteria:

1. Provide written, informed consent prior to all trial-related procedures. Male or
female, aged between 18 and 75 years inclusive.

2. Body weight (in light clothing and with no shoes) between 35 and 100 kg, inclusive.

3. 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:

1. 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

2. Previous TB treatment must be discontinued as per exclusion criteria 16.

- For MDR-TB treatment arm (defined as resistant to rifampicin based on molecular
sensitivity testing), Subjects should be:

1. sensitive to moxifloxacin by molecular sensitivity testing; AND

2. 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.

4. A chest X-ray picture which in the opinion of the Investigator is compatible with TB.

5. 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).

6. Be of non-childbearing potential or using effective methods of birth control, as
defined below:

Non-childbearing potential:

1. Subject - not heterosexually active or practices sexual abstinence; or

2. 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

3. 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:

1. 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

2. 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).

Exclusion Criteria:

Medical Criteria

1. 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.

2. Karnofsky performance status score of < 60%.

3. Poor general condition where any delay in treatment cannot be tolerated per discretion
of the Investigator.

4. Clinically significant evidence of extrathoracic TB (e.g. miliary TB, abdominal TB,
urogenital TB, osteoarthritic TB, TB meningitis), as judged by the Investigator.

5. History of allergy or hypersensitivity to any of the study Investigational Medicinal
Products or related substances.

6. 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.

7. For HIV infected Subjects:

1. having a CD4+ count <100 cells/µL;

2. with an AIDS-defining opportunistic infection or malignancies (except pulmonary
TB);

3. 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);

4. cannot ensure a 2 week interval between commencing IMP and the start of ART.

8. Having participated in other clinical study/ies with investigational agent/s within 8
weeks prior to trial start.

9. Significant cardiac arrhythmia requiring medication.

10. Subjects with the following at screening (per measurements and reading done by Central
ECG):

1. Marked prolongation of QT/QTc interval, e.g. confirmed demonstration of QTcF
(Fridericia correction) or QTcB (Bazett correction) interval >450 ms at
screening;

2. History of additional risk factors for Torsade de Pointes, e.g. heart failure,
hypokalemia, family history of Long QT Syndrome;

3. Use of concomitant medications that are known to prolong the QT/QTc interval (see
exclusion criteria 19);

4. Any clinically significant, in the opinion of the Investigator, ECG abnormality.

11. 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.

12. Diabetes Mellitus resulting in hospitalization in the past year.

13. Evidence of lens opacity on slit lamp ophthalmologic examination as defined by a
grading of >1+ on the ARED


Age minimum: 18 Years
Age maximum: 75 Years
Gender: All

Health Condition(s) or Problem(s) studied

Tuberculosis

Intervention(s)

Drug: bedaquiline

Drug: isoniazid, rifampicin, pyrazinamide and ethambutol combination tablet

Drug: moxifloxacin

Drug: PA-824

Drug: pyrazinamide

Primary Outcome(s)

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)]

Secondary Outcome(s)

Number of Participants With Treatment Emergent Adverse Events (TEAEs) [Time Frame: 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)]

Secondary ID(s)

NC-005-(J-M-Pa-Z)

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Results

• Results available: Yes
• Date Posted: 26/07/2019
• URL: https://clinicaltrials.gov/ct2/show/results/NCT02193776