Evaluating the Safety of Immediate Versus Deferred Isoniazid Preventive Therapy Among HIV-Infected Pregnant Women

NCT01494038 | Completed Phase 4 Results DMC

• 3 other identifiers: P107810732IMPAACT P1078
• Study Type: interventional
• Target: 956
• Locations: 8 countries
• Sites: 13

Brief Summary

Tuberculosis (TB) is a leading cause of death among HIV-infected persons in low-income settings and can be a serious complication for HIV-infected pregnant women and their infants. Isoniazid (INH) preventive therapy (IPT) is effective in preventing TB infection in HIV-infected adults, but the safety of IPT in pregnant women is unknown. This study evaluated the safety of IPT among HIV-infected pregnant women.

Conditions

HIV Infections; Tuberculosis

Outcome Measures

Primary Outcomes (1)

• Incidence Rate of Combined Endpoint: Grade 3 or Higher Adverse Events (AEs) Related to Treatment, or AE Causing Discontinuation of Treatment

  Incidence rate, calculated by Mantel-Haenszel (MH), weighted by gestational age strata 1) gestational age at entry less than 24 weeks or 2) gestational age at entry greater than or equal to 24 weeks. AE's include laboratory results, signs/symptoms, or diagnoses; graded as per Division of AIDS (DAIDS) or by protocol-defined hepatotoxicity measures. Related to treatment indicates possibly, probably, or definitely related to INH or Placebo for INH as judged by Independent Endpoint Review Committee. Discontinuation refers to permanent discontinuation of study treatment.

  Measured from study entry through Week 48 after birth

Secondary Outcomes (38)

• Number of Mothers With a Fetal Death

  Measured from study entry through end of pregnancy

• Number of Mothers With a Fetus Small for Gestational Age

  Measured at delivery

• Number of Mothers With an Infant Born Prematurely

  Measured at delivery

• Number of Mothers With a Low Birth-weight Infant

  Measured on day of birth

• Number of Mothers With an Infant With a Congenital Anomaly

  Measured from study entry through Week 48 after birth

Study Arms (2)

Arm A (Immediate INH Treatment)

EXPERIMENTAL

Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum.

Drug: Isoniazid (INH); Drug: Placebo for isoniazid (INH)

Arm B (Deferred INH Treatment)

EXPERIMENTAL

Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum.

Drug: Isoniazid (INH); Drug: Placebo for isoniazid (INH)

Interventions

Isoniazid (INH) DRUG

300-mg tablet once daily by mouth, either from entry through Week 28 antepartum (Arm A) or from Week 12 postpartum through Week 40 postpartum (Arm B)

Arm A (Immediate INH Treatment); Arm B (Deferred INH Treatment)

Placebo for isoniazid (INH) DRUG

Placebo tablet once daily by mouth, either from Week 28 visit through Week 40 postpartum (Arm A) or from entry until Week 12 postpartum visit (Arm B)

Arm A (Immediate INH Treatment); Arm B (Deferred INH Treatment)

Eligibility Criteria

• Age: 13 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Documented HIV-1 infection, defined as positive results from two samples collected at different time points. All samples tested must be whole blood, serum, or plasma. More information on this criterion can be found in the protocol.
• Documented HIV treatment, according to World Health Organization (WHO) guidelines, for prevention of mother-to-child transmission (PMTCT) and standard of care for HIV infection
• Pregnant females age 18 years or older
• Pregnant females between greater than or equal to 13 and less than 18 who are able and willing to provide signed informed consent under local law or pregnant females unable to consent under local law whose parents/legal guardians provide consent or "minimum age of consent according to locally applicable laws or regulations"
• Pregnancy gestational age confirmed by best available method at site to be greater than or equal to 14 weeks through less than or equal to 34 weeks (34 weeks, 6 days)
• Weight greater than or equal to 35 kg at screening
• The following laboratory values obtained within 30 days prior to study entry:
• Absolute neutrophil count (ANC) greater than or equal to 750 cells/mm\^3
• Hemoglobin greater than or equal to 7.5 g/dL
• Platelet count greater than or equal to 50,000/mm\^3
• Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT), alkaline phosphatase (ALT)/serum glutamic pyruvic transaminase (SGPT), and total bilirubin less than or equal to 1.25 times the upper limit of normal (ULN). (Note: If participant is taking atazanavir, direct bilirubin may be used to determine eligibility.)
• Intent to remain in current geographical area of residence for the duration of the study

You may not qualify if:

• Any woman with a positive TB symptom screen per WHO guidelines, including any one or more of the following: any cough, fever, self-reported weight loss, or night sweats. Note: If a potential participant is found to be negative for TB upon further testing, the participant may be rescreened for the study.
• Any positive acid-fast bacillus (AFB) smear, Xpert, or any other rapid TB screening test or culture from any site within the past 12 weeks, or chest radiograph (x-ray) with findings suggestive of active TB, or clinician suspects active TB
• Known exposure to AFB smear-positive active TB case within past 12 weeks prior to study entry
• Reported INH exposure (more than 30 days) in the past year prior to study entry
• Receipt of any TB or atypical mycobacteria therapy for more than 30 days in the past year
• Evidence of acute hepatitis, such as jaundice, dark urine (not concentrated urine), and/or acholic stools sustained for more than 3 days within 90 days prior to entry. More information on this criterion can be found in the protocol.
• Grade 1 or higher peripheral neuropathy. More information on this criterion can be found in the protocol.
• History of acute systemic adverse reaction or allergy to INH
• Known current heavy alcohol use (more than 2 drinks per week) or alcohol exposure that, in the investigator's opinion, would compromise participation and the outcome of this study
• Presence of new AIDS-defining opportunistic infection that has been treated less than 30 days prior to study entry
• Receipt of an investigational agent or chemotherapy for active malignancy within 30 days prior to study entry
• Any clinically significant diseases (other than HIV infection) or clinically significant findings during the screening medical history or physical examination that, in the investigator's opinion, would compromise participation and the outcome of this study

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (13)

Gaborone CRS

Gaborone, Botswana

Location

Molepolole CRS

Gaborone, Botswana

Location

Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS

Port-au-Prince, HT-6110, Haiti

Location

Byramjee Jeejeebhoy Medical College (BJMC) CRS

Pune, Maharashtra, 411001, India

Location

Soweto IMPAACT CRS

Johannesburg, Gauteng, 1862, South Africa

Location

Desmond Tutu TB Centre - Stellenbosch University (DTTC-SU) CRS

Cape Town, Western Cape, 7505, South Africa

Location

Fam-Cru Crs

Cape Town, Western Cape, 7505, South Africa

Location

Kilimanjaro Christian Medical Centre (KCMC)

Moshi, Tanzania

Location

Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS

Chiang Mai, 50200, Thailand

Location

MU-JHU Research Collaboration (MUJHU CARE LTD) CRS

Kampala, Uganda

Location

Seke North CRS

Chitungwiza, Zimbabwe

Location

St Mary's CRS

Chitungwiza, Zimbabwe

Location

Harare Family Care CRS

Harare, Zimbabwe

Location

Related Publications (6)

• Akolo C, Adetifa I, Shepperd S, Volmink J. Treatment of latent tuberculosis infection in HIV infected persons. Cochrane Database Syst Rev. 2010 Jan 20;2010(1):CD000171. doi: 10.1002/14651858.CD000171.pub3.

  PMID: 20091503 BACKGROUND

• Zar HJ, Cotton MF, Strauss S, Karpakis J, Hussey G, Schaaf HS, Rabie H, Lombard CJ. Effect of isoniazid prophylaxis on mortality and incidence of tuberculosis in children with HIV: randomised controlled trial. BMJ. 2007 Jan 20;334(7585):136. doi: 10.1136/bmj.39000.486400.55. Epub 2006 Nov 3.

  PMID: 17085459 BACKGROUND

• Cantwell MF, Snider DE Jr, Cauthen GM, Onorato IM. Epidemiology of tuberculosis in the United States, 1985 through 1992. JAMA. 1994 Aug 17;272(7):535-9.

  PMID: 8046808 BACKGROUND

• Gupta A, Singh P, Aaron L, Montepiedra G, Chipato T, Stranix-Chibanda L, Chanaiwa V, Vhembo T, Mutambanengwe M, Masheto G, Raesi M, Bradford S, Golner A, Costello D, Kulkarni V, Shayo A, Kabugho E, Jean-Phillippe P, Chakhtoura N, Sterling TR, Theron G, Weinberg A; IMPAACT P1078 TB APPRISE Study Team. Timing of maternal isoniazid preventive therapy on tuberculosis infection among infants exposed to HIV in low-income and middle-income settings: a secondary analysis of the TB APPRISE trial. Lancet Child Adolesc Health. 2023 Oct;7(10):708-717. doi: 10.1016/S2352-4642(23)00174-8. Epub 2023 Aug 24.

  PMID: 37634517 DERIVED

• Montepiedra G, Kim S, Weinberg A, Theron G, Sterling TR, LaCourse SM, Bradford S, Chakhtoura N, Jean-Philippe P, Evans S, Gupta A. Using a Composite Maternal-Infant Outcome Measure in Tuberculosis-Prevention Studies Among Pregnant Women. Clin Infect Dis. 2021 Aug 2;73(3):e587-e593. doi: 10.1093/cid/ciaa1674.

  PMID: 33146706 DERIVED

• Gupta A, Montepiedra G, Aaron L, Theron G, McCarthy K, Bradford S, Chipato T, Vhembo T, Stranix-Chibanda L, Onyango-Makumbi C, Masheto GR, Violari A, Mmbaga BT, Aurpibul L, Bhosale R, Mave V, Rouzier V, Hesseling A, Shin K, Zimmer B, Costello D, Sterling TR, Chakhtoura N, Jean-Philippe P, Weinberg A; IMPAACT P1078 TB APPRISE Study Team. Isoniazid Preventive Therapy in HIV-Infected Pregnant and Postpartum Women. N Engl J Med. 2019 Oct 3;381(14):1333-1346. doi: 10.1056/NEJMoa1813060.

  PMID: 31577875 DERIVED

Related Links

• Manual for Expedited Reporting of Adverse Events to Division of AIDS (DAIDS), Version 2.0, January 2010
• Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004 (Clarification, August 2009)

MeSH Terms

Conditions

HIV Infections; Tuberculosis

Interventions

Isoniazid

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

Intervention Hierarchy (Ancestors)

Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring

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

• Amita Gupta, MD, MHS

  Johns Hopkins University

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 14, 2011
• First Posted: December 16, 2011
• Study Start: August 19, 2014
• Primary Completion: September 6, 2017
• Study Completion: September 6, 2017
• Last Updated: November 5, 2021
• Results First Posted: November 20, 2018

Record last verified: 2018-10

Locations

TA (1); ZI (3); HA (1); ZA (3); IN (1); UG (1); BO (2); TH (1)