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

Tracking Information
First Submitted Date ICMJE	December 14, 2011
First Posted Date ICMJE	December 16, 2011
Last Update Posted Date	September 20, 2017
Actual Study Start Date ICMJE	April 2014
Actual Primary Completion Date	September 6, 2017 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: December 22, 2011)	Grade 3 or higher adverse events (AEs) [ Time Frame: Measured through Week 48 postpartum ]; Grade 3 or higher AEs possibly, probably, or definitely associated with INH/placebo for INH or permanent discontinuation of INH/placebo for INH due to an adverse reaction in women after randomization
Original Primary Outcome Measures ICMJE; (submitted: December 14, 2011)	Grade 3 or higher adverse events (AEs) [ Time Frame: Measured through Week 48 postpartum ]; Grade 3 or higher AEs possibly, probably or definitely associated with INH/Placebo for INH or permanent discontinuation of INH/Placebo for INH due to an adverse reaction in women after randomization
Change History	Complete list of historical versions of study NCT01494038 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: December 14, 2011)	Fetal death [ Time Frame: Measured through Week 48 after birth ]; Fetus small for gestational age [ Time Frame: Measured through Week 48 after birth ]; Premature birth of infant (less than 37 weeks gestation) [ Time Frame: Measured through Week 48 after birth ]; Low birth weight of infant [ Time Frame: Measured through Week 48 after birth ]; Congenital anomalies of infant [ Time Frame: Measured through Week 48 after birth ]; Grade 3 or higher clinical or laboratory AEs for fetus/infant [ Time Frame: Measured through Week 48 after birth ]; HIV infection of infant [ Time Frame: Measured through Week 48 after birth ]; Maternal TB [ Time Frame: Measured through Week 48 postpartum ]; Infant TB [ Time Frame: Measured through Week 48 after birth ]; Death of infant [ Time Frame: Measured through Week 48 after birth ]; Death of mother [ Time Frame: Measured through Week 48 postpartum ]; Resistance to INH in isolates of Mycobacterium tuberculosis from mothers who develop culture-confirmed TB [ Time Frame: Measured through Week 48 postpartum ]; Resistance to INH in isolates of Mycobacterium tuberculosis from infants who develop culture-confirmed TB [ Time Frame: Measured through Week 48 after birth ]; Intensive pharmacokinetic (PK) outcomes [ Time Frame: Measured through Week 16 postpartum ]; Interferon-gamma release assay (IGRA) result in women [ Time Frame: Measured through Week 44 postpartum ]; IGRA result in infants [ Time Frame: Measured through Week 44 after birth ]; Tuberculin skin test (TST) in women [ Time Frame: Measured through Week 44 postpartum ]; TST for infants [ Time Frame: Measured through Week 44 after birth ]; Adherence to INH/placebo for INH among women as assessed by self-report and pill count [ Time Frame: Measured throughout Week 48 postpartum ]; Occurrence of hepatotoxicity [ Time Frame: Measured throughout Week 48 postpartum ]
Original Secondary Outcome Measures ICMJE	Same as current
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Evaluating the Safety of Immediate Versus Deferred Isoniazid Preventive Therapy Among HIV-Infected Pregnant Women
Official Title ICMJE	A Phase IV Randomized Double-Blind Placebo-Controlled Trial to Evaluate the Safety of Immediate (Antepartum-Initiated) Versus Deferred (Postpartum-Initiated) Isoniazid Preventive Therapy Among HIV-Infected Women in High Tuberculosis (TB) Incidence Settings
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 for HIV-infected adults, but the safety of IPT in pregnant women is unknown. This study will evaluate the safety of IPT among HIV-infected pregnant women.
Detailed Description	TB disease is the most common HIV-related opportunistic infection and is a leading cause of death among HIV-infected persons in low-income settings. When TB occurs during or soon after pregnancy, it can cause complications for the mother as well as infant TB or death. Infant TB is very difficult to diagnose, and up to half of infant TB cases are caused by maternal TB. It has been shown that treatment for active TB is safe and effective during pregnancy and that IPT is safe and effective in preventing TB infection in HIV-infected adults. However, the safety of IPT in HIV-infected pregnant women is not known, especially in regard to its combination with highly active retroviral therapy (HAART). This study will evaluate the safety of immediate (antepartum, or before delivery) versus deferred (postpartum, or after delivery) IPT among HIV-infected pregnant women in high TB incidence settings. HIV-infected pregnant women will be randomly assigned to one of two arms. Arm A (immediate/antepartum INH) will receive oral INH once daily from study entry through Week 28 antepartum. At Week 28 antepartum, Arm A will receive oral placebo once daily until Week 40 postpartum. Arm B (deferred/postpartum INH group) will receive oral placebo once daily from study entry to Week 12 postpartum. At Week 12 postpartum, Arm B will receive oral INH once daily through Week 40 postpartum. Women in both arms will receive oral prenatal multivitamins and pyridoxine (vitamin B6) once daily from study entry through Week 40 postpartum. Study visits for women will occur at screening, entry, every 4 weeks until labor and delivery, at labor and delivery, and every 4 weeks after delivery until 48 weeks postpartum. Visits will consist of giving a medical history and undergoing a physical exam and blood collection; all visits through the delivery visit will also include an obstetrical exam. Presence of HIV infection will be documented at screening and a tuberculin skin test (TST) will be administered at the delivery visit and at the Week 44 postpartum visit. Some postpartum visits will include a urine pregnancy test. Study visits for infants will occur at birth and at several time points through Week 48. These visits will include a medical history, physical exam, and blood collection. Plasma collected from women and infants during this study will be stored for future studies. Some women and infants may have hair samples collected during the study, but this is optional.
Study Type ICMJE	Interventional
Study Phase	Phase 4
Study Design ICMJE	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Care Provider); Primary Purpose: Prevention
Condition ICMJE	HIV Infections; Tuberculosis
Intervention ICMJE	Drug: Isoniazid (INH) 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); Drug: Placebo for isoniazid (INH) 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)
Study Arms	Experimental: Arm A (Immediate INH Treatment) Women in Arm A will receive immediate, or antepartum-initiated, INH treatment. Women will receive INH at study entry through Week 28, then will switch to placebo for INH treatment through Week 40 postpartum. Interventions: Drug: Isoniazid (INH) Drug: Placebo for isoniazid (INH); Experimental: Arm B (Deferred INH Treatment) Women in Arm B will receive deferred, or postpartum-initiated, INH treatment. Women will receive placebo for INH at study entry through Week 12 postpartum, then will switch to INH through Week 40 postpartum. Interventions: Drug: Isoniazid (INH) Drug: Placebo for isoniazid (INH)
Publications *	Akolo C, Adetifa I, Shepperd S, Volmink J. Treatment of latent tuberculosis infection in HIV infected persons. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD000171. doi: 10.1002/14651858.CD000171.pub3. Review.; 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. Epub 2006 Nov 3.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Completed
Actual Enrollment ICMJE; (submitted: September 19, 2017)	956
Original Estimated Enrollment ICMJE; (submitted: December 14, 2011)	950
Actual Study Completion Date	September 6, 2017
Actual Primary Completion Date	September 6, 2017 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	Inclusion Criteria: 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 Exclusion Criteria: 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
Sex/Gender	Sexes Eligible for Study: Female
Ages	13 Years and older (Child, Adult, Older Adult)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	Botswana, Haiti, India, South Africa, Tanzania, Thailand, Uganda, Zimbabwe
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT01494038
Other Study ID Numbers ICMJE	P1078; 10732 ( Registry Identifier: DAIDS ES ); IMPAACT P1078
Has Data Monitoring Committee	Yes
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	National Institute of Allergy and Infectious Diseases (NIAID)
Study Sponsor ICMJE	National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators ICMJE	Not Provided
Investigators ICMJE	Study Chair: Amita Gupta, MD, MHS Johns Hopkins University
PRS Account	National Institute of Allergy and Infectious Diseases (NIAID)
Verification Date	September 2017
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP