Essentiality of INH in TB Therapy

NCT ID: NCT01589497

Last Updated: 2018-04-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 69 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-06-30
• Study Completion Date: 2016-02-10

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.

Detailed Description

This was a Phase IIa open label, randomized clinical trial comparing the early bactericidal activity (EBA) of four anti-tuberculosis regimens. Participants with acid fast bacilli (AFB) smear-positive pulmonary tuberculosis were hospitalized from screening through Day 15 of the study, during which time, sputum, blood, and urine were collected. Participants returned to the clinic on Day 28 for the final visit. The study duration was 29 days.

The purpose of the study was to estimate the primary outcome within each study arm and the study was not designed for between arm comparisons.

Conditions

Tuberculosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

RHZE-RHZE

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

Group Type: ACTIVE_COMPARATOR

Rifampicin

Intervention Type: 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.

Isoniazid

Intervention Type: DRUG

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

Pyrazinamide

Intervention Type: 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.

Ethambutol

Intervention Type: 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-RZE

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

Group Type: ACTIVE_COMPARATOR

Rifampicin

Intervention Type: 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.

Isoniazid

Intervention Type: DRUG

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

Pyrazinamide

Intervention Type: 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.

Ethambutol

Intervention Type: 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-RMZE

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

Group Type: ACTIVE_COMPARATOR

Rifampicin

Intervention Type: 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.

Isoniazid

Intervention Type: DRUG

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

Pyrazinamide

Intervention Type: 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.

Ethambutol

Intervention Type: 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.

Moxifloxacin

Intervention Type: DRUG

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

RZE-RZE

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

Group Type: ACTIVE_COMPARATOR

Rifampicin

Intervention Type: 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.

Pyrazinamide

Intervention Type: 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.

Ethambutol

Intervention Type: 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.

Interventions

Rifampicin

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.

Intervention Type: DRUG

Isoniazid

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

Intervention Type: DRUG

Pyrazinamide

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.

Intervention Type: DRUG

Ethambutol

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.

Intervention Type: DRUG

Moxifloxacin

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

Intervention Type: DRUG

Other Intervention Names

Avelon

Eligibility Criteria

Inclusion Criteria

• 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.

Exclusion Criteria

• 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
• neurological TB (including TB of the spine, TB meningitis)
• peripheral neuropathy ≥ Grade 2 according to the December 2004 (Clarification, August 2009) Division of AIDS (DAIDS) Toxicity Table, within 90 days prior to study entry
• Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
• Estimated overnight sputum production of < 10 mL.
• Requirement for concomitant medications that may potentially interact with study drugs.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: collaborator

Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

William Bishai, MD, PhD

Role: STUDY_CHAIR

Johns Hopkins Center for TB Research

Andreas Diacon, MD, PhD

Role: STUDY_CHAIR

TASK Applied Science CRS

Locations

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

Cape Town, Western Cape, South Africa

TASK Applied Science CRS (31718)

Bellville, , South Africa

Countries

South Africa

References

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).

Reference Type: 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.

Reference Type: DERIVED

PMID: 33834177 (View on PubMed)

Other Identifiers

1U01AI068636

Identifier Type: NIH

Identifier Source: secondary_id

View Link

ACTG A5307

Identifier Type: -

Identifier Source: org_study_id