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

NCT00080119 | Terminated Phase 2 Results DMC

• 2 other identifiers: PACTG P1041U01AI068632
• Study Type: interventional
• Target: 1,354
• Locations: 2 countries
• Sites: 6

Brief 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. 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.

Conditions

HIV Infection; Tuberculosis; Pneumocystis Jiroveci Pneumonia

Keywords

Treatment Naive; INH Prophylaxis; HIV Seronegativity

Outcome Measures

Primary Outcomes (2)

• 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.

  Through to week 96

• 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.

  Through to week 96

Secondary Outcomes (7)

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

  Through to week 96

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

  Through to week 96

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

  Through to week 96

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

  Through to week 96

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

  Through to week 96

Study Arms (4)

HIVneg/INH

EXPERIMENTAL

Perinatally 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

Drug: Isoniazid (INH); Drug: Trimethoprim/Sulfamethoxazole (TMP/SMX)

HIVneg/PL

PLACEBO COMPARATOR

Perinatally 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

Drug: Isoniazid Placebo (PL)

HIVpos/INH

EXPERIMENTAL

HIV-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.

Drug: Isoniazid (INH); Drug: Trimethoprim/Sulfamethoxazole (TMP/SMX)

HIVpos/PL

PLACEBO COMPARATOR

HIV-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.

Drug: Isoniazid Placebo (PL)

Interventions

Isoniazid (INH) DRUG

Antibiotic for the prevention and treatment of TB

HIVneg/INH; HIVpos/INH

Trimethoprim/Sulfamethoxazole (TMP/SMX) DRUG

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

HIVneg/INH; HIVpos/INH

Isoniazid Placebo (PL) DRUG

Isoniazid placebo and TMP/SMX

HIVneg/PL; HIVpos/PL

Eligibility Criteria

• Age: 91 Days - 120 Days
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• International Maternal Pediatric Adolescent AIDS Clinical Trials Group: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator
• Comprehensive International Program of Research on AIDS: collaborator
• Secure the Future Foundation: collaborator

Study Sites (6)

Princess Marina Hospital

Gaborone, Botswana

Location

University of Cape Town, Red Cross Children's Hospital

Cape Town, South Africa

Location

University of Stellenbosch, Tygerberg Hospital

Cape Town, South Africa

Location

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

Durban, 4001, South Africa

Location

Perinatal HIV Research Unit at Chris Hani Baragwanath Hospital

Johannesburg, 2013, South Africa

Location

Chris Hani Baragwanath Hospital, Harriet Shezi Clinic

Johannesburg, South Africa

Location

Related Publications (8)

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

  PMID: 15875917 BACKGROUND

• 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.

  PMID: 12742798 BACKGROUND

• 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.

  PMID: 14746522 BACKGROUND

• 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.

  PMID: 14551885 BACKGROUND

• 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.

  PMID: 18230259 RESULT

• 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.

  PMID: 20607114 RESULT

• 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.

  PMID: 26872154 DERIVED

• 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.

  PMID: 21732834 DERIVED

MeSH Terms

Conditions

HIV Infections; Tuberculosis; Pneumonia, Pneumocystis

Interventions

Isoniazid; Trimethoprim; Sulfamethoxazole; Trimethoprim, Sulfamethoxazole Drug Combination

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Lung Diseases, Fungal; Mycoses; Pneumocystis Infections; Respiratory Tract Infections; Pneumonia; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Pyrimidines; Benzenesulfonamides; Sulfonamides; Amides; Sulfanilamides; Aniline Compounds; Amines; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Sulfur Compounds; Drug Combinations; Pharmaceutical Preparations

Limitations and Caveats

DSMB recommended stopping study due to futility: "no compelling reason to enroll additional infants" or "to continue to treat participants with the blinded study medication". Week 192 analyses not done as \<4% (26%) of HIVpos (HIVneg) reached wk 192

Results Point of Contact

• Title: Melissa Allen, Director, IMPAACT Operations Center
• Organization: Family Health International (FHI 360)

mallen@fhi360.org

(919) 405-1429

Study Officials

• Shabir Madhi, MD

  University of Witwatersrand, South Africa

  STUDY CHAIR

• George McSherry, MD

  UMDNJ - New Jersey Medical School

  STUDY CHAIR

• Charles D. Mitchell, MD

  University of Miami

  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: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK

Study Record Dates

• First Submitted: March 23, 2004
• First Posted: March 25, 2004
• Study Start: February 1, 2004
• Primary Completion: May 1, 2009
• Study Completion: May 1, 2009
• Last Updated: February 5, 2019
• Results First Posted: October 19, 2010

Record last verified: 2019-01

Locations

BO (1); ZA (5)