Essentiality of INH in TB Therapy

NCT01589497 | Completed Phase 2 Results DMC

• 2 other identifiers: ACTG A53071U01AI068636
• Study Type: interventional
• Target: 69
• Locations: 1 country
• Sites: 2

Brief Summary

Tuberculosis (TB) disease is caused by bacteria that have infected the lung. TB bacteria are very small living agents that are spread by coughing and can be killed by taking TB drugs. To kill these TB bacteria TB patients have to take a combination of four drugs for 2 months and then two drugs for a further 4 months. During the first 2 months patients take rifampicin, isoniazid, ethambutol, and pyrazinamide. After that patients take only isoniazid and rifampicin for a further 4 months, making a total of 6 months therapy. In A5307 the investigators wanted to test a new combination of drugs to see if the investigators could treat TB faster in the future. Studies in animals have suggested that one of the four drugs, isoniazid, only works for a few days and may not be needed after the first two doses of TB treatment to kill the TB bacteria. After that its effects wear off to the point that it may even interfere with the other drugs. The investigators wanted to see if stopping isoniazid early, or using moxifloxacin, a different drug, instead could treat TB faster. This study was the first time that this type of regimen without isoniazid had been tested in humans. If the investigators could show that isoniazid stops working after a few days, the investigators could then try to see if they could possibly make a better tuberculosis treatment in the future.

Conditions

Tuberculosis

Outcome Measures

Primary Outcomes (1)

• Daily Decrease in log10 Transformed Colony-forming Unit (CFU) Counts Per ml Sputum From Baseline (Study Treatment Initiation) to Day 14

  The daily decrease was calculated as follows: EBA0-14(CFU)= \[baseline log10 CFU/mL sputum (mean of log10 CFU/mL at pre-entry and day 0) - log10 CFU/mL at day 14\]/14. For a CFU/ml count of 0, the log10 CFU/mL was set to 0. No formal statistical testing was conducted to compare the arms. Please refer to the explanation in the Protocol Section.

  Pre-entry, Day 0 and Day 14

Secondary Outcomes (31)

• Daily Change in Time to Positivity (TTP) From Baseline (Study Treatment Initiation) to Day 14

  Pre-entry, Day 0 and Day 14

• Daily Change in log10 Transformed Colony-forming Unit (CFU) Counts Per mL Sputum From Baseline (Study Treatment Initiation) to Day 2

  Pre-entry, Day 0 and Day 2

• Daily Change in log10 Colony-forming Unit (CFU) Counts Per mL Sputum From Day 2 to Day 14

  Day 2 and day 14

• Daily Change in Time to Positivity (TTP) From Baseline (Study Treatment Initiation) to Day 2

  Pre-entry, Day 0 and Day 2

• Daily Change in Time to Positivity (TTP) From Day 2 to Day 14

  Day 2 and Day 14

Study Arms (4)

RHZE-RHZE

ACTIVE COMPARATOR

Participants were administered rifampin-isoniazid-pyrazinamide-ethambutol (RHZE) from Day 1 to Day 14.

Drug: Rifampicin; Drug: Isoniazid; Drug: Pyrazinamide; Drug: Ethambutol

RHZE-RZE

ACTIVE COMPARATOR

Participants were administered RHZE from Day 1 to Day 2, then rifampin-pyrazinamide-ethambutol (RZE) from Day 3 to Day 14.

Drug: Rifampicin; Drug: Isoniazid; Drug: Pyrazinamide; Drug: Ethambutol

RHZE-RMZE

ACTIVE COMPARATOR

Participants were administered RHZE Day 1 to Day 2 and rifampin-moxifloxacin-pyrazinamide-ethambutol (RMZE) from Day 3 to Day 14.

Drug: Rifampicin; Drug: Isoniazid; Drug: Pyrazinamide; Drug: Ethambutol; Drug: Moxifloxacin

RZE-RZE

ACTIVE COMPARATOR

Participants were administered only RZE from Day 1 through Day 14.

Drug: Rifampicin; Drug: Pyrazinamide; Drug: Ethambutol

Interventions

Rifampicin DRUG

Participants with body weight \</= 50kg were administered one 450 mg tablet orally once daily. Participants with body weight \>50kg were administered one 600 mg tablet orally once daily.

RHZE-RHZE; RHZE-RMZE; RHZE-RZE; RZE-RZE

Isoniazid DRUG

Participants were administered three 100 mg tablets or one 300 mg tablet once daily.

RHZE-RHZE; RHZE-RMZE; RHZE-RZE

Pyrazinamide DRUG

Participants with a body weight of 40-55 kg were administered two 500 mg tablets orally once daily. Participants with a body weight of 56-75 kg were administered three 500 mg tablets orally once daily. Participants with a body weight of 76-90 kg were administered four 500 mg tablets orally once daily.

RHZE-RHZE; RHZE-RMZE; RHZE-RZE; RZE-RZE

Ethambutol DRUG

Participants with a body weight of 40-55 kg were administered two 400 mg tablets orally once daily. Participants with a body weight of 56-75 kg were administered three 400 mg tablets orally once daily. Participants with a body weight of 76-90 kg were administered four 400 mg tablets orally once daily.

RHZE-RHZE; RHZE-RMZE; RHZE-RZE; RZE-RZE

Moxifloxacin DRUG

Participants were administered one 400 mg tablet orally once a day.

Also known as: Avelon

RHZE-RMZE

Eligibility Criteria

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

You may qualify if:

• Absence of HIV-1 infection within 30 days prior to study entry OR
• HIV-1 infection
• Sputum positive for acid fast bacilli (AFB) by smear-microscopy ≥1+ on the WHO/IUALTD scale within 1 day prior to study entry.
• Isoniazid and rifampin sensitivity, based on Hain GenoType MTBDR Plus assay performed within 7 days prior to study entry.
• Body weight: 40 kg to 90 kg, inclusive
• Age ≥ 18 years at study entry.
• Certain laboratory values, as defined in the protocol, obtained within 30 days prior to entry
• For HIV-positive candidates only: CD4+ cell count of \> 200 cells/mm\^3, determined within 7 days prior to study entry at a DAIDS approved laboratory.
• For females of reproductive potential, negative serum or urine pregnancy test within 7 days prior to entry.
• Female participants who are participating in sexual activity that could lead to pregnancy must agree to use one reliable non-hormonal form of contraceptive (ie, condoms, with a spermicidal agent; a diaphragm, or cervical cap with spermicide; or an IUD) while receiving study medications.
• Radiographic findings consistent with pulmonary TB from a chest x-ray performed within 14 days prior to entry.
• Ability and willingness of study candidate or legal guardian/representative to provide informed consent.
• Willingness to be hospitalized for approximately 3 weeks.
• Ability to provide at least 10mL of sputum during an overnight collection prior to study entry.
• NOTE: Candidates who do not produce an overnight sputum sample of sufficient quality and quantity will be considered screen failures. However, if a candidate's failure to produce sufficient sputum appears to be due to poor technique rather than low volume of sputum production, this evaluation may be repeated.

You may not qualify if:

• Receipt of INH prophylaxis or any tuberculosis therapy within 7 days prior to study entry or for more than 7 cumulative days in the last 6 months, or receipt of any fluoroquinolone in the 1 month prior to entry.
• Currently on anti-retroviral treatment (ART), has been on ART within 30 days, or is expected to initiate ART within 2 weeks after study entry.
• Breastfeeding.
• Known intolerance to any of the study drugs.
• Resistance to rifampicin determined by GeneXpert within 7 days prior to study entry.
• Known history of resistance to isoniazid or rifampin or known close exposure (i.e., household exposure) to someone with MDR TB or known study candidate default on previous TB treatment (ie, the study candidate was diagnosed with TB, started TB treatment but did not complete that treatment).
• Known allergy to any fluoroquinolone antibiotic.
• History of prolonged QT syndrome or a QTc of \> 450 ms (using Fridericia's correction)..
• Current or planned therapy with quinidine, procainamide, amiodarone, sotalol, or ziprasidone during the 2 weeks of on-study tuberculosis treatment.
• Current or prior diagnosis of pulmonary silicosis.
• Advanced disease as defined by Karnofsky score ≤ 70 at screening.
• Any of the following current comorbidities, complications, or underlying medical conditions:
• poorly controlled diabetes, as determined by the site investigator
• currently uncontrolled hypertension (ie, requiring acute medical treatment or immediate hospitalization)
• miliary TB

Sponsors & Collaborators

• Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator

Study Sites (2)

University of Cape Town Lung Institute (UCTLI) CRS (31792)

Cape Town, Western Cape, 7705, South Africa

Location

TASK Applied Science CRS (31718)

Bellville, 7531, South Africa

Location

Related Publications (2)

• The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004 (Clarification, August 2009).

  BACKGROUND

• Diacon A, Miyahara S, Dawson R, Sun X, Hogg E, Donahue K, Urbanowski M, De Jager V, Fletcher CV, Hafner R, Swindells S, Bishai W. Assessing whether isoniazid is essential during the first 14 days of tuberculosis therapy: a phase 2a, open-label, randomised controlled trial. Lancet Microbe. 2020 Jun;1(2):e84-e92. doi: 10.1016/s2666-5247(20)30011-2. Epub 2020 Jun 8.

  PMID: 33834177 DERIVED

MeSH Terms

Conditions

Tuberculosis

Interventions

Rifampin; Isoniazid; Pyrazinamide; Ethambutol; Moxifloxacin

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

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

Results Point of Contact

• Title: ACTG Clinicaltrials.gov Coordinator
• Organization: ACTG Network Coordinating Center, Social & Scientific Systems, Inc.

ACTGCT.Gov@s-3.com

(301) 628-3313

Study Officials

• William Bishai, MD, PhD

  Johns Hopkins Center for TB Research

  STUDY CHAIR

• Andreas Diacon, MD, PhD

  TASK Applied Science CRS

  STUDY CHAIR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 30, 2012
• First Posted: May 2, 2012
• Study Start: June 30, 2015
• Primary Completion: January 28, 2016
• Study Completion: February 10, 2016
• Last Updated: April 6, 2018
• Results First Posted: April 4, 2017

Record last verified: 2018-03

Locations

ZA (2)