Shortening Treatment by Advancing Novel Drugs

NCT02342886 | Completed Phase 3 Results DMC

• 1 other identifier: NC-006-(M-PA-Z)
• Study Type: interventional
• Target: 284
• Locations: 7 countries
• Sites: 14

Brief Summary

The purpose of this study is to assess the efficacy, safety and tolerability of a combination of moxifloxacin, PA-824, and pyrazinamide treatments with varying doses and treatment lengths from 4 to 6 months in subjects with drug-sensitive (DS) pulmonary TB compared to standard HRZE treatment. This study will also assess the efficacy, safety and tolerability of a combination of moxifloxacin, PA-824, and pyrazinamide treatments after 6 months of treatment in subjects with multi drug-resistant (MDR) pulmonary TB compared to a combination of moxifloxacin, PA-824, and pyrazinamide treatments in DS-TB subjects.

Conditions

Tuberculosis, Pulmonary, Drug Sensitive; Tuberculosis, Pulmonary, Multi Drug-resistant

Keywords

Tuberculosis; Multi Drug-Resistant Tuberculosis; Drug-sensitive Tuberculosis; PA-824; Moxifloxacin; Pyrazinamide; Rifampicin; Isoniazid; Ethambutol; HRZE; HR; Pretomanid; NC-006; STAND

Outcome Measures

Primary Outcomes (2)

• Incidence of Combined Bacteriologic Failure or Relapse or Clinical Failure at Month 12 From Start of Therapy (Day 1) (Modified Intent to Treat [MITT] Population)

  Patients were classified as having a favorable, unfavorable or unassessable status at 12 months from the start of therapy. A favourable status was a negative culture status at 12 months from start of therapy in patients who had not already been classified as having an unfavorable outcome, and whose last positive culture result was followed by at least 2 negative culture results. Patients with an unfavorable status did not achieve/maintain culture negative status, or previously had culture negative status who following end of treatment (EOT), had 2 positive cultures, or had a positive culture not followed by 2 negative cultures, or were dying from any cause during treatment (except accidental cause not including suicide), or were dying from TB related causes during follow-up, or required an extension, restart or change of treatment except for reinfection/pregnancy, or failed to complete adequate treatment who were unassessable at 12 months or lost to follow-up/withdrawn before EOT.

  From Day 1 to Month 12.

• Incidence of Combined Bacteriologic Failure or Relapse or Clinical Failure at Month 12 From Start of Therapy (Day 1) (Per Protocol [PP] Population)

  Patients were classified as having a favorable, unfavorable or unassessable status at 12 months from the start of therapy. A favourable status was a negative culture status at 12 months from start of therapy in patients who had not already been classified as having an unfavorable outcome, and whose last positive culture result was followed by at least 2 negative culture results. Patients with an unfavorable status did not achieve/maintain culture negative status, or previously had culture negative status who following EOT, had 2 positive cultures, or had a positive culture not followed by 2 negative cultures, or died from any cause during treatment (except accidental cause not including suicide), or were dying from TB related causes during follow-up, or required a restart or change of treatment because of an unfavorable outcome with or without bacteriological confirmation, ie, on bacteriological, radiographic or clinical grounds.

  From Day 1 to Month 12.

Study Arms (5)

MDR-TB

EXPERIMENTAL

moxifloxacin 400 mg + PA-824 200 mg + pyrazinamide 1500 mg for 26 weeks.

Drug: Moxifloxacin; Drug: PA-824; Drug: Pyrazinamide

DS-TB (HRZE), HR

ACTIVE COMPARATOR

26 consecutive weeks to DS-TB subjects only, as follows: HRZE (Rifampicin, Isoniazid, Pyrazinamide, Ethambutol combination) Weeks 1-8 with daily dose per the subjects weight HR (Rifampicin plus isoniazid combination tablets) Weeks 9 - 26 with daily dose per the subjects weight Daily dose per the subjects weight as follows: 30-39kg: 2 tablets; 40-54kg: 3 tablets; 55 - 70kg: 4 tablets; 71kg and over: 5 tablets.

Drug: HRZE (Rifampicin, Isoniazid, Pyrazinamide, Ethambutol combination); Drug: HR (rifampicin plus isoniazid combination tablets)

DS-TB PA-824 200mg 26 weeks

EXPERIMENTAL

moxifloxacin 400 mg + PA-824 200 mg + pyrazinamide 1500 mg orally once daily for 26 weeks

Drug: Moxifloxacin; Drug: PA-824; Drug: Pyrazinamide

DS-TB PA-824 200mg 17 weeks

EXPERIMENTAL

moxifloxacin 400 mg + PA-824 200 mg + pyrazinamide 1500 mg orally once a day for 17 weeks

Drug: Moxifloxacin; Drug: PA-824; Drug: Pyrazinamide

DS-TB PA-824 100mg 17 weeks

EXPERIMENTAL

moxifloxacin 400 mg + PA-824 100 mg + pyrazinamide 1500 mg orally once daily for 17 weeks

Drug: Moxifloxacin; Drug: PA-824; Drug: Pyrazinamide

Interventions

Moxifloxacin DRUG

Oral

Also known as: BAY 12-8039, Avelox, Avalon, Avelon

DS-TB PA-824 100mg 17 weeks; DS-TB PA-824 200mg 17 weeks; DS-TB PA-824 200mg 26 weeks; MDR-TB

PA-824 DRUG

Oral

DS-TB PA-824 100mg 17 weeks; DS-TB PA-824 200mg 17 weeks; DS-TB PA-824 200mg 26 weeks; MDR-TB

Pyrazinamide DRUG

Oral

DS-TB PA-824 100mg 17 weeks; DS-TB PA-824 200mg 17 weeks; DS-TB PA-824 200mg 26 weeks; MDR-TB

HRZE (Rifampicin, Isoniazid, Pyrazinamide, Ethambutol combination) DRUG

Oral

Also known as: Rifafour e-275

DS-TB (HRZE), HR

HR (rifampicin plus isoniazid combination tablets) DRUG

Oral

DS-TB (HRZE), HR

Eligibility Criteria

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

You may qualify if:

• Signed written consent or witnessed oral consent in the case of illiteracy, prior to undertaking any trial-related procedures.
• Male or female, aged 18 years or over.
• Body weight (in light clothing and no shoes) ≥ 30 kg.
• Sputum positive for tubercule bacilli (at least 1+ on the International Union Against Tuberculosis and Lung Disease (IUATLD) and World Health Organization (WHO) scale on smear microscopy at the trial laboratory.
• Drug-Sensitive TB treatment arms subjects should be:
• sensitive to rifampicin by rapid sputum based test (may be sensitive or resistant to isoniazid) AND
• either newly diagnosed for TB or have a patient history of being untreated for at least 3 years after cure from a previous episode of TB. If they are entered into the trial due to being sensitive to rifampicin by rapid sputum based test, however on receipt of the rifampicin resistance testing using an indirect susceptibility test in liquid culture this shows they are rifampicin resistant, they will be:
• Possibly replaced as determined by the sponsor.
• MDR-TB treatment arm subjects should be resistant to rifampicin by rapid sputum based test (may be sensitive or resistant to isoniazid).
• A chest x-ray which in the opinion of the investigator is compatible with pulmonary TB.
• Be of non-childbearing potential or using effective methods of birth control, as defined below:
• Non-childbearing potential:
• Subject - not heterosexually active or practice sexual abstinence; or
• Female subject or male subjects female 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 or female subjects male sexual partner - vasectomised or has had a bilateral orchidectomy minimally three months prior to screening;

You may not qualify if:

• Any non TB related condition (including myasthenia gravis) where participation in the trial, as judged by the investigator, could compromise the well-being of the subject or prevent, limit or confound protocol specified assessments.
• Being or about to be treated for Malaria.
• Is critically ill and, in the judgment of the investigator, has a diagnosis likely to result in death during the trial or the follow-up period.
• TB meningitis or other forms of extrapulmonary tuberculosis with high risk of a poor outcome, or likely to require a longer course of therapy (such as TB of the bone or joint), as judged by the investigator.
• History of allergy or hypersensitivity to any of the trial IMP or related substances, including known allergy to any fluoroquinolone antibiotic, history of tendinopathy associated with quinolones or suspected hypersensitivity to any rifampicin antibiotics.
• For HIV infected subjects any of the following:
• CD4+ count \<100 cells/µL;
• Karnofsky score \<60%;
• Received intravenous antifungal medication within the last 90 days;
• WHO Clinical Stage 4 HIV disease.
• Resistant to fluoroquinolones (rapid, sputum - based molecular screening tests). If they are entered into the trial due to being sensitive to fluoroquinolones by rapid sputum based test, however on receipt of the fluoroquinolones resistance testing using an indirect susceptibility test in liquid culture this shows they are fluoroquinolones resistant, they will be:
• Possibly replaced as determined by the sponsor.
• Resistant to pyrazinamide (rapid, sputum - based molecular screening tests).
• Drug-Sensitive TB treatment arms subjects may be entered prior to receipt of the rapid, sputum - based molecular pyrazinamide resistance screening test result. On receipt of the result, if they are resistant, they will be:
• Possibly replaced as determined by the sponsor. MDR-TB treatment arm subjects may not be entered prior to receipt of the rapid, sputum - based molecular pyrazinamide resistance screening test result showing they are sensitive to pyrazinamide.

Sponsors & Collaborators

• Global Alliance for TB Drug Development: lead

Study Sites (26)

National Center for Tuberculosis and Lung Diseases

Tbilisi, 0101, Georgia

Location

Centre for Respiratory Disease Research (CRDR) Keny Medical Research Institute (KEMRI)

Nairobi, Kenya

Location

Centre for Respiratory Disease Research (CRDR) Kenya Medical Research Institute (KEMRI)

Nairobi, Kenya

Location

Pusat Perubatan Universiti Kebangsaan

Cheras, Kuala Lumpur, Malaysia

Location

Universiti Teknologi MARA

Batu Caves, Selangor, Malaysia

Location

Institute of Respiratory Medicine (IPR)

Kuala Lumpur, 53000, Malaysia

Location

Philippine General Hospital

Ermita, Manila, 1000, Philippines

Location

Vincent Balang

Pio del Pilar, Manila, 1230, Philippines

Location

Lung Center of Philippines

Manila, 1104, Philippines

Location

TASK

Bellville, Cape Town, 7531, South Africa

Location

University of Cape Town Lung Institute

Mowbray, Cape Town, 7700, South Africa

Location

Setshaba Research Centre

Pretoria, Gauteng, South Africa

Location

The Aurum Institute: Tembisa Hospital Cnr

Tembisa, Gauteng, 1632, South Africa

Location

CHRU Themba Lethu Clinic

Westdene, Johannesburg, South Africa

Location

Durban International Clinical Trials Unit (DbnlCTU)

Durban, KwaZulu-Natal, 4001, South Africa

Location

Klerksdorp Tshepong Hospital

Klerksdorp, North West, 2571, South Africa

Location

Synexus SA

Mamelodi East, Pretoria, South Africa

Location

Madibeng Centre for Research (MCR)

Brits, 0250, South Africa

Location

THINK: Tuberculosis & HIV Investigative Network of Kwazulu Natal

Durban, 4001, South Africa

Location

The Aurum Institute

Klerksdorp, South Africa

Location

The Aurum Institute: Rustenberg

Rustenburg, South Africa

Location

Ifakara Health Institute (IHI)

Dar es Salaam, Tanzania

Location

NIMR - Mbeya Medical Research Programme (MMRP)

Mbeya, Tanzania

Location

Kilimanjaro National Institute for Medical Research

Mwanza, Tanzania

Location

Uganda CWRU Research Collaboration

Kampala, Uganda

Location

Centre for Infectious Disease Research in Zambia (CIDRZ)

Lusaka, Zambia

Location

MeSH Terms

Conditions

Tuberculosis; Tuberculosis, Multidrug-Resistant

Interventions

Moxifloxacin; pretomanid; Pyrazinamide; Rifampin; Isoniazid

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Pyrazines; Heterocyclic Compounds, 1-Ring; Rifamycins; Heterocyclic Compounds, 4 or More Rings; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Pyridines

Limitations and Caveats

Following 3 deaths associated with hepatotoxicity, recruitment was suspended, followed by a partial clinical hold by the United States Food and Drug Association. The hold was removed but the Sponsor permanently stopped recruitment in December 2016.

Results Point of Contact

• Title: Leandra Lombard, Director, Clinical Operations
• Organization: TB Alliance

Leandra.Lombard@tballiance.org

+27 87 700 3900

Study Officials

• Stephen H Gillespie, MD

  University of St Andrews

  PRINCIPAL INVESTIGATOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 14, 2014
• First Posted: January 21, 2015
• Study Start: February 1, 2015
• Primary Completion: January 1, 2018
• Study Completion: May 1, 2018
• Last Updated: March 26, 2019
• Results First Posted: March 26, 2019

Record last verified: 2019-03

Locations

ZA (1); PH (3); MY (3); GE (1); UG (1); KE (2); TA (3)