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HIV InfectionPhase 2/3NCT00080119

Daily Isoniazid to Prevent Tuberculosis in Infants Born to Mothers With HIV

A Phase 2/3 study testing Isoniazid (INH) and Trimethoprim/Sulfamethoxazole (TMP/SMX) in people with HIV Infection and Tuberculosis, run by International Maternal Pediatric Adolescent AIDS Clinical Trials Group at 6 sites in 2 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

Tuberculosis (TB) is highly endemic in sub-Saharan Africa. The increased burden of TB in settings with high prevalence of the Human Immunodeficiency Virus (HIV) is associated with high rates of transmission of Mycobacterium tuberculosis (M.tb) to both adults and children. Read more about this study

Who is it for?
Ages 91 to 120 daysHealthy volunteers can take part
What is being tested?
Isoniazid (INH) and Trimethoprim/Sulfamethoxazole (TMP/SMX)
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
1,354 participants
Where
6 sitesin 2 countries
Study dates
Feb 2004to May 2009
Phase
Phase 2/3
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 91 to 120 days
  • All sexes
  • Healthy volunteers accepted
  • Child

Who may be able to join

  • Mother is HIV-infected. Hard copy documentation of the mother's HIV infection is unnecessary if a positive DNA PCR from her infant is available.
  • Received Bacille Calmette-Guerin (BCG) vaccine up to and including the 30th day of life and at least 90 days prior to study entry
  • Able to complete all study requirements
  • Physician assessment of age-appropriate neurodevelopment in which the chronological age is corrected for gestational age for prematurely born infants
  • Parent or legal guardian able and willing to provide signed informed consent
  • Plan to live in the study area for at least 4 years
  • For inclusion in HIV-infected stratum, infant must have a positive HIV-1 DNA PCR; for inclusion in HIV-uninfected stratum, infant must have a negative HIV-1 DNA PCR performed at >= 4 weeks of age

Who cannot join

  • Previous diagnosis of TB infection, TB disease or current treatment for TB infection or TB disease
  • Previous receipt of INH
  • Contact with a known acid fast bacilli (AFB) sputum smear or culture-positive case of TB before study entry
  • Current acute or recurrent (3 or more prior episodes) lower respiratory tract disease
  • Chronic persistent diarrhea
  • Failure to thrive
Show all 15Show fewer
  • Contraindications for use of INH or TMP/SMX
  • Require certain medications
  • Known or suspected immune system diseases other than HIV
  • Current or previous diagnosis of or treatment for cancer
  • Current immunosuppressive therapy greater than 1 mg/kg/day of prednisone or equivalent
  • Anticipated long-term oral or intravenous corticosteroid therapy (greater than 3 weeks). Those receiving nonsteroidal anti-inflammatory agents and inhaled corticosteroids are not excluded.
  • Grade 3 or greater AST/SGOT, ALT/SGPT, ANC, hemoglobin, platelet count, rash, neuropathy, or myopathy at screening
  • Any Grade 4 clinical or laboratory toxicity within 14 days prior to study entry
  • Other acute or chronic conditions that, in the opinion of the investigator, may interfere with the study

Trial locations and contacts

6 sites in 2 countries.

6 sites in 2 countries

South Africa5 sites

  • University of Cape Town, Red Cross Children's Hospital

    Cape Town

  • University of Stellenbosch, Tygerberg Hospital

    Cape Town

  • Nelson R. Mandela School of Medicine, University of KwaZulu Natal, Durban

    Durban, 4001

  • Perinatal HIV Research Unit at Chris Hani Baragwanath Hospital

    Johannesburg, 2013

  • Chris Hani Baragwanath Hospital, Harriet Shezi Clinic

    Johannesburg

Other trials in South Africa

Botswana1 site

  • Princess Marina Hospital

    Gaborone

Other trials in Botswana

About this study

Official title: A Randomized, Double Blind, Placebo Controlled Trial to Determine the Efficacy of Isoniazid (INH) in Preventing Tuberculosis Disease and Latent Tuberculosis Infection Among Infants With Perinatal Exposure to HIV

Tuberculosis (TB) is highly endemic in sub-Saharan Africa. The increased burden of TB in settings with high prevalence of the Human Immunodeficiency Virus (HIV) is associated with high rates of transmission of Mycobacterium tuberculosis (M.tb) to both adults and children. Children infected with TB have a higher risk of developing severe disease than adults with TB. The purpose of this study was to determine if the antibiotic isoniazid (INH) prevented TB infection in infants born to HIV-infected mothers.

Read the detailed description

Tuberculosis (TB) and the Human Immunodeficiency Virus (HIV) are major public health problems in southern Africa, and the incidence of TB in South Africa is among the highest in the world. TB is caused by the highly contagious bacterium Mycobacterium tuberculosis. The use of Isoniazid (INH) prophylaxis in adults has been associated with reduced risk of TB disease in high-risk populations. Delay in initiating INH prophylaxis in children has resulted in more cases of childhood TB infection. This study evaluated the effectiveness of INH prophylaxis in preventing TB infection in infants born to HIV-infected mothers in southern Africa.

Infants were randomly assigned to receive either INH or placebo by mouth daily, beginning between the 91st and 120th day of life, and at least 90 days after Bacille Calmette-Guerin (BCG) vaccination. At sites in South Africa, HIV-infected infants received daily trimethoprim/sulfamethoxazole (TMP/SMX) as Pneumocystis jiroveci pneumonia (PCP) prophylaxis until at least 1 year of age; HIV-uninfected infants received TMP/SMX until at least 6 months of age.

The study was to follow participants for 192 weeks. Study visits occurred at study entry and every 12 weeks until week 192. A physical exam and blood collection occurred at each study visit. Infants were assessed for peripheral neuropathy every 12 weeks until week 96 and for TB at weeks 96, 144, and 192. The study also assessed medication adherence.

As of November 12, 2008, follow-up was revised. All participants were permanently discontinued from study follow-up by February 28, 2009 and no later than May 31, 2009. Only clinical evaluations were performed for all participants. For HIV-infected participants, the study drug was stopped at the next scheduled visit. For HIV-uninfected subjects, the study drug was discontinued immediately.

Being tested
Isoniazid (INH), Trimethoprim/Sulfamethoxazole (TMP/SMX), Isoniazid Placebo (PL)
Keywords
Treatment Naive, INH Prophylaxis, HIV Seronegativity
Medical subject headings
HIV Infections, Tuberculosis, Pneumonia, Pneumocystis

What participants receive

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

  • Isoniazid (INH)Drug

    Antibiotic for the prevention and treatment of TB

  • Trimethoprim/Sulfamethoxazole (TMP/SMX)Drug

    Antibiotic for the prevention and treatment of pneumocystis pneumonia (PCP)

  • Isoniazid Placebo (PL)Drug

    Isoniazid placebo and TMP/SMX

Study groups in NCT00080119
Study groupRoleWhat they receive
HIVneg/INHExperimentalPerinatally exposed, HIV-uninfected (HIVneg) children receiving Isoniazid (INH)10-20 mg/kg orally once a day for 96 weeks + Trimethoprim/Sulfamethoxazole (TMP/SMX) 5 mg/kg of TMP component orally once a day until HIV status is confirmed and child is no longer at risk of acquiring HIV through breastfeeding
Receives: Drug: Isoniazid (INH); Drug: Trimethoprim/Sulfamethoxazole (TMP/SMX)
HIVneg/PLPlacebo comparatorPerinatally exposed, HIV-uninfected (HIVneg) children receiving Isoniazid placebo (PL) orally once a day for 96 weeks + TMP/SMX 5 mg/kg of TMP component orally once a day until HIV status is confirmed and child is no longer at risk of acquiring HIV through breastfeeding
Receives: Drug: Isoniazid Placebo (PL)
HIVpos/INHExperimentalHIV-infected (HIVpos) children receiving Isoniazid (INH) 10-20 mg/kg orally once a day for 96 weeks + TMP/SMX 5 mg/kg of TMP component orally once a day until one year of age. TMP/SMX may have been continued after one year of age according to WHO guidelines.
Receives: Drug: Isoniazid (INH); Drug: Trimethoprim/Sulfamethoxazole (TMP/SMX)
HIVpos/PLPlacebo comparatorHIV-infected (HIVpos) children receiving Isoniazid placebo (PL) orally once a day for 96 weeks + TMP/SMX 5 mg/kg of TMP component orally once a day until one year of age. TMP/SMX may have been continued after one year of age according to WHO guidelines.
Receives: Drug: Isoniazid Placebo (PL)

What is being measured

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

  1. Time to Development of Tuberculosis (TB) Disease or Death Among HIV-infected Children

    Criteria for diagnosis with TB disease: Definite-isolation of Mycobacterium TB (M.tb) or +ve stain on cerebrospinal fluid (CSF); Probable- +ve acid fast bacilli (AFB) stain on fluids/tissues other than CSF and sufficient clinical criteria/radiographic evidence suggestive of TB; Possible-abnormal chest radiograph suggestive of pulmonary TB (PTB) and either a +ve tuberculin skin test (TST) or minimum score on algorithm for clinical TB. Records reviewed by Endpoint Review Group. Results report percent of participants reaching TB disease/death by week 96 calculated using the Kaplan-Meier method.

    Measured: Through to week 96

  2. Time From Randomization to Development of TB Infection or Death Among Perinatally Exposed, HIV-uninfected Children

    Criteria for diagnosis with TB infection were outlined in the protocol. TB infection included TB disease (see primary outcome measure 1 for definition) and latent TB infection. Latent TB infection was diagnosed by a positive tuberculin skin test (TST) based on a purified protein derivative (PPD) performed at week 96. Participant records were reviewed by an Endpoint Review Group to verify that participants had met the criteria for TB infection. Results report percent of participants reaching TB infection or death by week 96 calculated using the Kaplan-Meier method.

    Measured: Through to week 96

Secondary outcomes (7)

  1. Time From Randomization to Development of TB Infection or Death Among HIV-infected Children

    Criteria for diagnosis with TB infection were outlined in the protocol. TB infection included TB disease (see primary outcome measure 1 for definition) and latent TB infection. Latent TB infection was diagnosed by a positive TST based on a PPD performed at week 96. Participant records were reviewed by an Endpoint Review Group to verify that participants had met the criteria for TB infection. Results report percent of participants reaching TB infection or death by week 96 calculated using the Kaplan-Meier method.

    Measured: Through to week 96

  2. Time From Randomization to HIV Disease Progression or Death Among HIV-infected Children

    HIV disease progression was defined as any advancement in Centers for Disease Control (CDC) disease category from entry or death. If a participant was CDC disease category C at entry progression was defined as death. Results report percent of participants with HIV progression or death by week 96 calculated using the Kaplan-Meier method.

    Measured: Through to week 96

  3. Time From Randomization to Development of TB Disease or Death Among Perinatally Exposed, HIV-uninfected Children

    Criteria for diagnosis with TB disease were: Definite-isolation of M.tb or positive stain on CSF; Probable-positive AFB stain on fluids/tissues other than CSF and sufficient clinical criteria/radiographic evidence suggestive of TB; Possible-abnormal chest radiograph suggestive of PTB and either a +ve TST or minimum score on algorithm to diagnose clinical TB. All records were reviewed by an Endpoint Review Group to verify that participants had met the criteria for TB disease. Results report percent of participants reaching TB disease/death by week 96 calculated using the Kaplan-Meier method.

    Measured: Through to week 96

  4. Time From Randomization to Development of TB Disease Among HIV Infected and Perinatally Exposed, HIV-uninfected Children

    Criteria for diagnosis with TB disease were: Definite-isolation of M.tb or positive stain on CSF; Probable-positive AFB stain on fluids/tissues other than CSF and sufficient clinical criteria/radiographic evidence suggestive of TB; Possible-abnormal chest radiograph suggestive of PTB and either a +ve TST or minimum score on algorithm to diagnose clinical TB. All records were reviewed by an Endpoint Review Group to verify that participants had met the criteria for TB disease. Results report percent of participants reaching TB disease/death by week 96 calculated using the Kaplan-Meier method.

    Measured: Through to week 96

  5. Time From Randomization to Development of TB Infection Among HIV-infected and Perinatally Exposed, HIV-uninfected Children

    Criteria for diagnosis with TB infection were outlined in the protocol. TB infection included TB disease (see primary outcome measure 1 for definition) and latent TB infection. Latent TB infection was diagnosed by a positive TST based on a PPD performed at week 96. Participant records were reviewed by an Endpoint Review Group to verify that participants had met the criteria for TB infection. Results report percent of participants reaching TB infection by week 96 calculated using the Kaplan-Meier method.

    Measured: Through to week 96

  6. Time From Randomization to Death Among HIV-infected and Perinatally Exposed, HIV-uninfected Children

    Deaths from any cause were included. Results report percent of participants dying by week 96 calculated using the Kaplan-Meier method.

    Measured: Through to week 96

  7. Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children

    Signs, symptoms and laboratory values were graded according to the Division of AIDS Adverse Event Grading System. Any event of grade 3 or higher not present at entry that occurred after randomization was classified as a new event. Results report percent of participants with a new event by week 96 calculated using the Kaplan-Meier method.

    Measured: Through to week 96

Timeline

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

  1. First posted25 Mar 2004 (estimated)
  2. Study startFeb 2004
  3. Primary completionMay 2009
  4. Study completionMay 2009

Why it stopped: Data Safety Monitoring Board (DSMB) recommended stopping study due to futility

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 2/3
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
Masking
Triple blind
Who is masked
Participant, Care provider, Investigator
Enrolment
1,354 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00080119
Sponsor's protocol ID
PACTG P1041
Other IDs
U01AI068632
Status last verified
Jan 2019
First submitted
23 Mar 2004
Last updated
5 Feb 2019
Data monitoring committee
Yes

Publications

  • Chintu C, Mwaba P. Tuberculosis in children with human immunodeficiency virus infection. Int J Tuberc Lung Dis. 2005 May;9(5):477-84.

    PubMed 15875917

  • Corbett EL, Watt CJ, Walker N, Maher D, Williams BG, Raviglione MC, Dye C. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med. 2003 May 12;163(9):1009-21. doi: 10.1001/archinte.163.9.1009.

    PubMed 12742798

  • de Jong BC, Israelski DM, Corbett EL, Small PM. Clinical management of tuberculosis in the context of HIV infection. Annu Rev Med. 2004;55:283-301. doi: 10.1146/annurev.med.55.091902.103753.

    PubMed 14746522

  • Toossi Z. Virological and immunological impact of tuberculosis on human immunodeficiency virus type 1 disease. J Infect Dis. 2003 Oct 15;188(8):1146-55. doi: 10.1086/378676. Epub 2003 Sep 30.

    PubMed 14551885

  • Cotton MF, Schaaf HS, Lottering G, Weber HL, Coetzee J, Nachman S; PACTG 1041 Team. Tuberculosis exposure in HIV-exposed infants in a high-prevalence setting. Int J Tuberc Lung Dis. 2008 Feb;12(2):225-7.

    PubMed 18230259

  • Cotton M, Kim S, Rabie H, Coetzee J, Nachman S. A window into a public program for prevention of mother to child transmission of HIV: evidence from a prospective clinical trial. South Afr J HIV Med. 2009 Jan 1;10(4):16-19. doi: 10.4102/sajhivmed.v10i4.257.

    PubMed 20607114

  • Gupta A, Montepiedra G, Gupte A, Zeldow B, Jubulis J, Detrick B, Violari A, Madhi S, Bobat R, Cotton M, Mitchell C, Spector S; IMPAACT NWCS113 and P1041 Study Team. Low Vitamin-D Levels Combined with PKP3-SIGIRR-TMEM16J Host Variants Is Associated with Tuberculosis and Death in HIV-Infected and -Exposed Infants. PLoS One. 2016 Feb 12;11(2):e0148649. doi: 10.1371/journal.pone.0148649. eCollection 2016.

    PubMed 26872154

  • Madhi SA, Nachman S, Violari A, Kim S, Cotton MF, Bobat R, Jean-Philippe P, McSherry G, Mitchell C; P1041 Study Team. Primary isoniazid prophylaxis against tuberculosis in HIV-exposed children. N Engl J Med. 2011 Jul 7;365(1):21-31. doi: 10.1056/NEJMoa1011214.

    PubMed 21732834

Questions about this trial

What is this clinical trial studying?

A Phase 2/3 study testing Isoniazid (INH) and Trimethoprim/Sulfamethoxazole (TMP/SMX) in people with HIV Infection and Tuberculosis, run by International Maternal Pediatric Adolescent AIDS Clinical Trials Group at 6 sites in 2 countries.

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 7 inclusion and 15 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: stopped early, as of the sponsor's last update on 5 Feb 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 6 sites in South Africa, Botswana. 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. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined 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.

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

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 19 Oct 2010). 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?

Time to Development of Tuberculosis (TB) Disease or Death Among HIV-infected Children (time frame: Through to week 96). The study lists 2 primary outcomes in all. 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 NCT00080119, which also lists 8 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 5 Feb 2019.

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