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TuberculosisPhase 2NCT01589497

Essentiality of INH in TB Therapy

A Phase 2 study testing Rifampicin, Isoniazid and Pyrazinamide in people with Tuberculosis, run by Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections at 2 sites in South Africa.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Tuberculosis
What is being tested?
Rifampicin, Isoniazid and Pyrazinamide
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
69 participants
Where
2 sitesSouth Africa
Study dates
30 Jun 2015to 10 Feb 2016
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • 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.

Who cannot join

  • 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).
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  • 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.

Trial locations and contacts

2 sites in 1 country.

South Africa2 sites

  • TASK Applied Science CRS (31718)

    Bellville, 7531

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

    Cape Town, Western Cape, 7705

Other trials in South Africa

About this study

Official title: Essentiality of Isoniazid in Tuberculosis Therapy

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.

Read the 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
Being tested
Rifampicin, Isoniazid, Pyrazinamide, Ethambutol, Moxifloxacin
Medical subject headings
Tuberculosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • RifampicinDrug

    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.

  • IsoniazidDrug

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

  • PyrazinamideDrug

    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.

  • EthambutolDrug

    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.

  • MoxifloxacinDrug

    Also called Avelon

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

Study groups in NCT01589497
Study groupRoleWhat they receive
RHZE-RHZEActive comparatorParticipants were administered rifampin-isoniazid-pyrazinamide-ethambutol (RHZE) from Day 1 to Day 14.
Receives: Drug: Rifampicin; Drug: Isoniazid; Drug: Pyrazinamide; Drug: Ethambutol
RHZE-RZEActive comparatorParticipants were administered RHZE from Day 1 to Day 2, then rifampin-pyrazinamide-ethambutol (RZE) from Day 3 to Day 14.
Receives: Drug: Rifampicin; Drug: Isoniazid; Drug: Pyrazinamide; Drug: Ethambutol
RHZE-RMZEActive comparatorParticipants were administered RHZE Day 1 to Day 2 and rifampin-moxifloxacin-pyrazinamide-ethambutol (RMZE) from Day 3 to Day 14.
Receives: Drug: Rifampicin; Drug: Isoniazid; Drug: Pyrazinamide; Drug: Ethambutol; Drug: Moxifloxacin
RZE-RZEActive comparatorParticipants were administered only RZE from Day 1 through Day 14.
Receives: Drug: Rifampicin; Drug: Pyrazinamide; Drug: Ethambutol

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: Pre-entry, Day 0 and Day 14

Secondary outcomes (31)

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

    The daily change in TTP was calculated as follows:

    EBA0-14(TTP) = [baseline TTP (mean of TTP at pre-entry and day 0) - TTP at day 14]/14.

    Measured: Pre-entry, Day 0 and Day 14

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

    The daily change in log10 CFU/mL sputum was calculated as follows:

    EBA0-2(CFU) = (baseline log10 CFU/mL sputum (mean of log10 CFU/mL at pre-entry and day 0) - log10 CFU/mL at day 2)/2.

    For a CFU/mL count of 0, the log10 CFU/mL was set to 0.

    Measured: Pre-entry, Day 0 and Day 2

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

    The daily change in log10 CFU/mL sputum was calculated as follows:

    EBA2-14(CFU) = (log10 CFU/mL at day 2 - log10 CFU/mL at day 14)/12.

    For a CFU/mL count of 0, the log10 CFU/mL was set to 0.

    Measured: Day 2 and day 14

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

    The daily change in TTP was calculated as follows:

    EBA0-2(TTP) = (baseline TTP (mean of TTP at pre-entry and day 0) - TTP at day 2)/2.

    Measured: Pre-entry, Day 0 and Day 2

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

    The daily change in TTP was calculated as follows:

    EBA2-14(TTP) = (TTP at day 2 - TTP at day 14)/12.

    Measured: Day 2 and Day 14

  6. Log10 Transformed Colony-forming Unit (CFU) Count Per mL From Sputum Samples at Baseline and Day 14

    The log10 CFU count per mL from sputum samples processed by standard method or decontaminated method.

    Measured: Pre-entry, Day 0 and Day 14

  7. Correlation Between Time to Positivity (TTP) and log10 Transformed Colony-forming Unit (CFU) Counts Per mL

    Pearson correlation coefficient was used to examine the correlation between TTP and log10 CFU among all qualified samples obtained on study

    Measured: Pre-entry, Day 0, Day 1, Day 2, Day 3, Day 5, Day 7, Day 9, Day 11 and Day 14

  8. Pharmacokinetic Parameter (PK) Area Under the Concentration-time Curve (AUC0-24hour) for Rifampicin (RIF)

    Pharmacokinetic Parameter Area Under the Concentration-time Curve (AUCs) of Rifampicin from 0 to 24 hours obtained at Day 1 and Day 14

    Measured: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Rifampicin dosing at Day 1 and Day 14

  9. Rifampicin PK Parameter Clearance (CL/F)

    Rifampicin PK parameter Clearance (CL/F) obtained Day 1 and Day 14

    Measured: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Rifampicin dosing at Day 1 and Day 14

  10. Rifampicin PK Parameter Maximum Plasma Concentration (Cmax)

    Rifampicin PK parameter Parameter Maximum Plasma Concentration (Cmax) obtained Day 1 and Day 14

    Measured: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Rifampicin dosing at Day 1 and Day 14

  11. Rifampicin PK Parameter Last Concentration (CLast)

    Rifampicin (RIF) PK parameter Last Concentration (CLast) obtained Day 1 and Day 14. The lower limit of quantification of the assay (LLOQ) for RIF was 40 ng/mL. The results below the lower limit of quantification were assigned as one-half the value of the LLOQ, which was 20 ng/mL.

    Measured: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Rifampicin dosing at Day 1 and Day 14

  12. AUC0-24hour for Isoniazid (INH) at Day 1

    PK AUCs of Isoniazid (INH) from 0 to 24 hours obtained at Day 1

    Measured: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 1

  13. Isoniazid PK Parameter CL/F at Day 1

    Isoniazid PK parameter CL/F obtained Day 1

    Measured: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 1

  14. Isoniazid PK Parameter Cmax at Day 1

    Isoniazid PK parameter Cmax obtained Day 1

    Measured: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 1

  15. Isoniazid PK Parameter CLast at Day 1

    Isoniazid (INH) PK parameter CLast obtained Day 1. The lower limit of quantification of the assay (LLOQ) for INH was 100 ng/mL. The results below the lower limit of quantification were assigned as one-half the value of the LLOQ, which was 50 ng/mL.

    Measured: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 1

  16. AUC0-24hour for Isoniazid at Day 14

    PK AUCs of Isoniazid from 0 to 24 hours obtained at Day 14

    Measured: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 14

  17. Isoniazid PK Parameter CL/F at Day 14

    Isoniazid PK parameter CL/F obtained Day 14

    Measured: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 14

  18. Isoniazid PK Parameter Cmax at Day 14

    Isoniazid PK parameter Cmax obtained Day 14

    Measured: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 14

  19. Isoniazid PK Parameter CLast at Day 14

    Isoniazid (INH) PK parameter CLast obtained Day 14. The lower limit of quantification of the assay (LLOQ) for INH was 100 ng/mL. The results below the lower limit of quantification were assigned as one-half the value of the LLOQ, which was 50 ng/mL.

    Measured: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 14

  20. AUC0-24hour for Pyrazinamide (PZA)

    PK AUCs of Pyrazinamide (PZA) from 0 to 24 hours obtained at Day 1 and Day 14

    Measured: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Pyrazinamide dosing at Day 1 and Day 14

  21. Pyrazinamide PK Parameter CL/F

    Pyrazinamide PK parameter CL/F obtained Day 1 and Day 14

    Measured: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Pyrazinamide dosing at Day 1 and Day 14

  22. Pyrazinamide PK Parameter Cmax

    Pyrazinamide PK parameter Cmax obtained Day 1 and Day 14

    Measured: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Pyrazinamide dosing at Day 1 and Day 14

  23. Pyrazinamide PK Parameter CLast

    Pyrazinamide PK parameter CLast obtained Day 1 and Day 14

    Measured: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Pyrazinamide dosing at Day 1 and Day 14

  24. AUC0-24hour for Ethambutol (EMB)

    PK AUCs of Ethambutol (EMB) from 0 to 24 hours obtained at Day 1 and Day 14

    Measured: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Ethambutol dosing at Day 1 and Day 14

  25. Ethambutol PK Parameter CL/F

    Ethambutol PK parameter CL/F obtained Day 1 and Day 14

    Measured: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Ethambutol dosing at Day 1 and Day 14

  26. Ethambutol PK Parameter Cmax

    Ethambutol PK parameter Cmax obtained Day 1 and Day 14

    Measured: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Ethambutol dosing at Day 1 and Day 14

  27. Ethambutol PK Parameter CLast

    Ethambutol PK parameter CLast obtained Day 1 and Day 14

    Measured: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Ethambutol dosing at Day 1 and Day 14

  28. AUC0-24hour for Moxifloxacin (Mox) at Day 14

    PK AUCs of Moxiflozacin (Mox) from 0 to 24 hours obtained at Day 14

    Measured: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Moxifloxacin dosing at Day 14

  29. Moxifloxacin PK Parameter CL/F at Day 14

    Moxifloxacin PK parameter CL/F obtained Day 14

    Measured: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Moxifloxacin dosing at Day 14

  30. Moxifloxacin PK Parameter Cmax at Day 14

    Moxifloxacin PK parameter Cmax obtained Day 14

    Measured: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Moxifloxacin dosing at Day 14

  31. Moxifloxacin PK Parameter CLast at Day 14

    Moxifloxacin PK parameter CLast obtained Day 14

    Measured: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Moxifloxacin dosing at Day 14

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted2 May 2012 (estimated)
  2. Study start30 Jun 2015
  3. Primary completion28 Jan 2016
  4. Study completion10 Feb 2016

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
69 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01589497
Sponsor's protocol ID
ACTG A5307
Other IDs
1U01AI068636
Status last verified
Mar 2018
First submitted
30 Apr 2012
Last updated
6 Apr 2018
Data monitoring committee
Yes

Publications

  • 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).

  • 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.

    PubMed 33834177

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Rifampicin, Isoniazid and Pyrazinamide in people with Tuberculosis, run by Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections at 2 sites in South Africa.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 15 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 6 Apr 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in South Africa. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 4 Apr 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Daily Decrease in log10 Transformed Colony-forming Unit (CFU) Counts Per ml Sputum From Baseline (Study Treatment Initiation) to Day 14 (time frame: Pre-entry, Day 0 and Day 14). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01589497, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Apr 2018.

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