A Phase 3 Study Assessing the Safety and Efficacy of Bedaquiline Plus PA-824 Plus Linezolid in Subjects With Drug Resistant Pulmonary Tuberculosis

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT02333799
• Date of registration: 06/01/2015
• Prospective Registration: Yes
• Primary sponsor: Global Alliance for TB Drug Development
• Public title: A Phase 3 Study Assessing the Safety and Efficacy of Bedaquiline Plus PA-824 Plus Linezolid in Subjects With Drug Resistant Pulmonary Tuberculosis
• Scientific title: A Phase 3 Open-label Trial Assessing the Safety and Efficacy of Bedaquiline Plus PA-824 Plus Linezolid in Subjects With Pulmonary Infection of Either Extensively Drug-resistant Tuberculosis (XDR-TB) or Treatment Intolerant / Non-responsive Multi-drug Resistant Tuberculosis (MDR-TB).
• Date of first enrolment: March 2015
• Target sample size: 109
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT02333799
• Study type: Interventional
• Study design: Allocation: N/A. Intervention model: Single Group Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 3

Countries of recruitment

South Africa

Contacts

• Name: Francesca Conradie, MD
• Affiliation: CHRU Themba Lethu Clinic - Helen Joseph Hospital

• Name: Dan Everitt, MD
• Affiliation: Global Alliance for TB Drug Development

Key inclusion & exclusion criteria

Inclusion Criteria

1. Provide written, informed consent prior to all trial-related procedures (if under 18,
include consent of legal guardian).

2. Body weight of =35 kg (in light clothing and no shoes).

3. Willingness and ability to attend scheduled follow-up visits and undergo study
assessments

4. Provide consent to HIV testing (if an HIV test was performed within 1 month prior to
trial start, it should not be repeated as long as documentation can be provided [ELISA
and/or Western Blot]. If HIV status is a confirmed known positive, repeated HIV test
is not needed provided documentation is available.

5. Male or female, aged 14 years or above.

6. Subjects with one of the following pulmonary TB conditions:

a. XDR-TB with

i. documented culture positive (for M.tb.) results within 3 months prior to screening
or M.tb. confirmed in sputum based on molecular test within 3 months prior to or at
screening;

ii. documented resistance to isoniazid, rifamycins, a fluoroquinolone and an
injectable historically at any time or at screening;

b. MDR-TB documented by culture positive results (for M.tb.) within 3 months prior to
or at screening with documented non-response to treatment with the best available
regimen for 6 months or more prior to enrolment who in the opinion of the Investigator
have been adherent to treatment and will be adherent to study regimen;

c. MDR-TB documented by culture positive (for M.tb.) results within 3 months prior to
or at screening who are unable to continue second line drug regimen due to a
documented intolerance to:

i. PAS, ethionamide, aminoglycosides or fluoroquinolones;

ii. Current treatment not listed above that renders subject eligible for the study in
the Investigator's opinion.

7. Chest X-Ray picture (taken within a year prior to screening) consistent with pulmonary
TB in the opinion of the Investigator.

8. 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;

3. 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 investigational
medicinal products; therefore, hormone based contraceptives alone cannot be used by female
Subjects or female partners of male Subjects to prevent pregnancy.

Exclusion Criteria Medical History

1. Any condition in the Investigator's opinion (i.e., an unstable disease such as
uncontrolled diabetes or cardiomyopathy, extra-pulmonary TB requiring extended
treatment), where participation in the trial would compromise the well-being of
Subject or prevent, limit or confound protocol specified assessments.

2. Abuse of alcohol or illegal drugs, that in the opinion of the Investigator would
compromise the Subjects' safety or ability to follow through with all
protocol-specified visits and evaluations.

3. In the judgment of the Investigator, the patient is not expected to survive for more
than 12 weeks.

4. Karnofsky score < 50 within 30 days prior to entry.

5. Body Mass index (BMI) < 17 kg/m²

6. History of allergy or known hypersensitivity to any of the trial Investigational
Medicinal Products or related substances.

7. HIV infected Subjects having a CD4+ count = 50 cells/µL; For HIV infected Subjects
having a CD4+ count >50 cells/µL;

a. 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. Examples of allowed treatment
include but are not limited to the following. If there are any questions, discuss with
the Sponsor Medical Monitor for confirmation of appropriate ARV regimen.

i. Nevirapine based regimen consisting of nevirapine in combination with any NRTIs;

ii. Lopinavir/ritonavir (Aluvia™) based regimen consisting of lopinavir/ritonavir
(Aluvia™) in combination with any NRTIs;

iii. The combination of tenofovir/lamivudine/abacavir should be considered in patients
with normal renal function to address myelosuppression cross toxicity of idovudine and
linezolid;

iv. An alternate regimen that may be considered if the above are not appropriate is a
triple nucleosidase reverse transcriptase inhibitors (NRTI) based regimen consisting
of zidovudine, lamivudine and abacavir may be used with caution. Regimens including
zidovudine should be used with special caution as zivovudine and linezolid may both
cause peripheral nerve toxicity;

v. Raltegravir in combination with nucleoside reverse transcriptase inhibitors
(NRTIs). b. Cannot ensure a 2 week interval between commencing IMP and the start of
ART, if not already on ARTs.

8. Having participated in other clinical studies with dosing of investigational agents
within 8 weeks prior to trial start or currently enrolled in an investigational study
that includes treatment with medicinal agents. Subjects who are participating in
observational studies or who are in a follow up period of a trial that included drug
therapy may be considered for inclusion.

9. Significant cardiac arrhythmia requiring medication.

10. Subjects with the following at Screening:

1. QTcF interval on ECG >500 msec. Subjects with QTcF > 450 must be discussed with
the sponsor medical monitor before enrolment. <


Age minimum: 14 Years
Age maximum: N/A
Gender: All

Health Condition(s) or Problem(s) studied

Pulmonary Tuberculosis

Intervention(s)

Drug: Bedaquiline

Drug: PA-824

Drug: Linezolid

Primary Outcome(s)

Incidence of bacteriologic failure or relapse or clinical failure through follow up until 6 months after the end of treatment. [Time Frame: Treatment Period: Day 1, Week 1, 2, 4, 6, 8, 12, 16, 20, 26, 30, 34, 39 Follow Up: Month 1, 2, 3, 6, 9, 12, 15, 18, 21, 24]

Secondary Outcome(s)

Incidence of Treatment Emergent Adverse Events (TEAEs) presented by incidence, and seriousness, leading to TB related or non-TB related death. [Time Frame: Day 1, Week 1, 2, 4, 6, 8, 12, 16, 20, 26, 30, 34, 39, Follow-up Month 3, 6, 9, 12, 15, 18, 21, 24]

Time to sputum culture conversion to negative status through the treatment period. [Time Frame: Day 1, Week 1, 2, 4, 6, 8, 12, 16, 20, 26, Month 1, 2, 3, 6, 9, 12, 15, 18, 21, 24]

Proportion of subjects with sputum culture conversion to negative status at 4, 6, 8, 12, 16 and 26 or 39 weeks. [Time Frame: Week 4, 6, 8, 12, 16, 26, 39]

Time to sputum culture positivity [Time Frame: Treatment Period: Day 1, Week 1, 2, 4, 6, 8, 12, 16, 20, 26, 30, 34, 39 Follow Up: Month 1, 2, 3, 6, 9, 12, 15, 18, 21, 24]

All Subjects- Pre-dose sampling at weeks 2, 8 and 16 to measure Ctrough levels of bedaquiline, bedaquiline metabolite M2, Linezolid and PA-824. [Time Frame: Weeks 2, 8 and 16]

Secondary ID(s)

NiX-TB-(B-L-Pa)

Source(s) of Monetary Support

Please refer to primary and secondary sponsors