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
Results First Submitted Date	September 6, 2018
Results First Posted Date	November 20, 2018
Last Update Posted Date	November 20, 2018
Actual Study Start Date ICMJE	August 19, 2014
Actual Primary Completion Date	September 6, 2017 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: October 22, 2018)	Incidence Rate of Combined Endpoint: Grade 3 or Higher Adverse Events (AEs) Related to Treatment, or AE Causing Discontinuation of Treatment [ Time Frame: Measured from study entry through Week 48 after birth ]; 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.
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: October 22, 2018)	Number of Mothers With a Fetal Death [ Time Frame: Measured from study entry through end of pregnancy ]Fetal deaths include both stillbirths and spontaneous abortions; in case of a multiple birth, mothers who had at least one fetal death; Number of Mothers With a Fetus Small for Gestational Age [ Time Frame: Measured at delivery ]Small for gestational age was determined by physician at site; Number of Mothers With an Infant Born Prematurely [ Time Frame: Measured at delivery ]Premature birth is defined as gestational age of < 37 weeks at delivery.; Number of Mothers With a Low Birth-weight Infant [ Time Frame: Measured on day of birth ]Low birth weight is defined as weight < 2500 mg; Number of Mothers With an Infant With a Congenital Anomaly [ Time Frame: Measured from study entry through Week 48 after birth ]Includes congenital anomalies meeting the Metropolitan Atlanta Congenital Defects Program criteria.; Number of Mothers With an Adverse Pregnancy Outcome: Spontaneous Abortion, Stillbirth, Premature Birth, Low Birth Weight, or Congenital Anomaly [ Time Frame: Measured from study entry through Week 48 after birth ]In case of a multiple birth, mothers who had at least one adverse pregnancy outcome. Spontaneous abortion is intra-uterine fetal death prior to 20 weeks of gestational age; stillbirth, the same, >= 20 weeks; preterm delivery, < 37 weeks of gestational age; low birth weight, < 2,500 grams, and congenital anomalies meeting the Metropolitan Atlanta Congenital Defects Program criteria.; Number of Infants With Grade 3 or Higher Clinical or Laboratory AE [ Time Frame: Measured from study entry through Week 48 after birth ]Laboratory, sign/symptom, or diagnoses graded as 3 or higher by DAIDS criteria.; Number of Infants With Grade 3 or Higher Clinical or Laboratory AE Related to Treatment [ Time Frame: Measured from study entry through Week 48 after birth ]As before, but AE is judged to be possibly, probably, or definitely related to INH or Placebo for INH, by clinic medical staff; Number of Infants Which Are HIV-infected [ Time Frame: Measured from study entry through study Week 44 ]HIV infection determined during follow-up period. Infection at birth or during breastfeeding; Number of Infants Hospitalized [ Time Frame: Measured from study entry through Week 48 after birth ]Hospitalization due to reasons other than birth; Incidence Rate of TB Infection Among Mothers [ Time Frame: Measured from study entry to Week 48 after birth ]Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata. Probable or confirmed TB infection, as judged by Secondary Endpoint Review Committee; Incidence Rate of Tuberculosis (TB) Among Infants [ Time Frame: Measured from study entry through Week 48 after birth ]Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata. Probable or confirmed TB, or congenital TB as defined using the Cantwell criteria (see reference), judged by the Secondary Endpoint Review Committee. Includes an infant death due to unknown cause.; Incidence Rate of Infant Death [ Time Frame: Measured from study entry through Week 48 after birth ]Incidence rate was calculated by Mantel-Haenszel, weighted by gestational age strata.; Incidence Rate of Maternal Deaths [ Time Frame: Measured from study entry through Week 48 postpartum ]Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata.; Incidence Rate of Combined Endpoints: Maternal TB or Maternal Death [ Time Frame: Measured from study entry through Week 48 after birth ]Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata.; Incidence Rate of Combined Endpoints: Infant TB or Infant Death [ Time Frame: Measured from study entry through Week 48 after birth ]Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata.; Incidence Rate of Combined Endpoints: Maternal TB, Maternal Death, Infant TB, or Infant Death [ Time Frame: Measured from study entry through Week 48 after birth ]Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata.; Incidence Rate of Combined Endpoint, Antepartum: Grade 3 or Higher AE Related to Treatment, or Discontinuation of Treatment Due to AE [ Time Frame: Measured from study entry through end of pregnancy ]Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata; Incidence Rate of Combined Endpoint, up to 12 Weeks Postpartum: Grade 3 or Higher AE Related to Treatment, or Discontinuation of Treatment Due to AE [ Time Frame: Measured from study entry through 12 weeks after birth ]Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata.; Incidence Rate, Antepartum, of Grade 3 or Higher AE [ Time Frame: Measured from study entry through end of pregnancy ]Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata.; Incidence Rate, up to 12 Weeks Postpartum, of Grade 3 or Higher AE [ Time Frame: Measured from study entry through 12 weeks postpartum ]Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata.; Incidence Rate, Antepartum, of Hepatotoxicity, Defined by Protocol-specific Definition of Hepatotoxicity, Related to Treatment [ Time Frame: Measured from study entry through delivery ]Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata. Protocol-specific definition of hepatotoxicity: Any one of the following: 1) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 5 times the upper limit of normal (ULN), where ULN is specified by the clinic physician; 2) Total bilirubin > 3 X ULN; 3) ALT greater than 3 X ULN and total bilirubin greater than 2 X ULN; or 4) ALT > 3 X ULN and persistent symptomatic clinical hepatitis; Incidence Rate, to 12 Weeks Postpartum, of Hepatotoxicity, Protocol-specific Definition, Related to Treatment [ Time Frame: Measured from study entry through 12 weeks postpartum ]Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata; Incidence Rate, Antepartum, of Hepatotoxicity, Protocol-specific Definition, Any Cause [ Time Frame: Measured from study entry through delivery ]Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata.; Incidence Rate, to 12 Weeks Postpartum, of Hepatotoxicity, Protocol-specific Definition, Any Cause [ Time Frame: Measured from study entry through 12 weeks postpartum ]Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata.; Incidence Rate, Antepartum, of Hepatotoxicity, Defined by DAIDS, Related to Treatment [ Time Frame: Measured from study entry through delivery ]Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata. Hepatotoxicity definition as defined by DAIDS AE grading criteria 1.0.; Incidence Rate, up to 12 Weeks Postpartum, of Hepatotoxicity, Defined by DAIDS, Related to Treatment [ Time Frame: Measured from study start through 12 weeks postpartum ]Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata; Incidence Rate, Antepartum, of Hepatotoxicity, Defined by DAIDS, Any Cause [ Time Frame: Measured from study entry through delivery ]Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata.; Incidence Rate, up to 12 Weeks Postpartum, of Hepatotoxicity, Defined by DAIDS, Any Cause [ Time Frame: Measured from study start through 12 weeks postpartum ]Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata.; Number of Mothers With Tuberculosis Resistant to INH [ Time Frame: Measured from study entry through Week 48 postpartum ]Resistance to INH from isolates of Mycobacterium tuberculosis, as a percentage of mothers who develop culture-confirmed TB; Number of Infants With Tuberculosis Resistant to INH [ Time Frame: Measured from study entry through Week 48 after birth ]Resistance to INH from isolates of Mycobacterium tuberculosis, as a percentage of infants who develop culture-confirmed TB; Pharmacokinetic (PK) Parameter: Adjusted Mean of Area Under the Curve of Plasma Concentration Versus Time (AUC24h), for INH [ Time Frame: Measured at antepartum (third trimester and >= 2 weeks after starting study drug) and week 16 postpartum (+/-) 4 weeks) while on active INH; blood samples were drawn pre-dose and at 1, 2, 4, 6, 8, and 12 hours post-dosing. ]Pharmacokinetic parameter was estimated from population PK modeling fitted to the intensive PK data. AUC0-24h was predicted using population pharmacokinetic model using the NONMEM software program. A 2-compartment model with first-order absorption with transit compartment and first-order elimination with well-stirred liver model to capture hepatic clearance and first-pass extraction with 1 parameter (hepatic intrinsic clearance) was used,; Pharmacokinetic (PK) Parameter: Adjusted Mean of Area Under the Curve (AUC24h), for EFV [ Time Frame: Measured at antepartum (third trimester and >= 2 weeks after starting study drug) and week 16 postpartum (+/-) 4 weeks) while on active INH; blood samples were drawn pre-dose and at 1, 2, 4, 6, 8, and 12 hours post-dosing. ]Pharmacokinetic parameter was estimated from population PK modeling fitted to the intensive PK data. AUC0-24h was predicted using population pharmacokinetic model using the NONMEM software program. A 2-compartment model with first-order absorption with transit compartment and first-order elimination with well-stirred liver model to capture hepatic clearance and first-pass extraction with 1 parameter (hepatic intrinsic clearance) was used,; Agreement Between Interferon-gamma Release Assay (IGRA) TB Test and Tuberculin Skin Test (TST) Results, Women at Delivery [ Time Frame: Measured at delivery ]IGRA done by Quantiferon Gold Test (QGIT). For women, TST is considered positive if greater than or equal to 5 mm; Agreement Between IGRA and TST TB Test Results, Infant [ Time Frame: Measured at week 44 after birth ]The TST result was positive if greater than or equal to 10 mm in HIV-negative infants, or greater than or equal to 5 mm in HIV-positive infants.; Agreement Between IGRA and TST TB Tests, Women at 44 Weeks Postpartum [ Time Frame: Measured at Week 44 postpartum ]IGRA done by Quantiferon Gold Test (QGIT). For women, TST is considered positive if greater than or equal to 5 mm; Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Self-report [ Time Frame: Adherence reported every 4 weeks during active treatment; study entry through week 28 for Arm A, week 12 postpartum through week 40 postpartum for Arm B ]Adherence is the percentage of expected doses taken during the 28 week active treatment period, categorized as poor (<60%), reasonable (>= 60%, <80%), good (>=80%, <90%), or excellent (>= 90%). Measured by participant's self-report of doses taken within the last 3 days.; Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Pill Count [ Time Frame: Adherence reported every 4 weeks during active treatment; study entry through week 28 for Arm A, week 12 postpartum through week 40 postpartum for Arm B ]Adherence is the percentage of expected doses taken during the 28 week active treatment period. Pill count: participants returned their prescription pill containers, and the remaining (unused) pills were counted.
Original 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 ]
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 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.
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 evaluated 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 were randomly assigned (1:1) to one of two arms: Arm A (immediate/antepartum INH) and Arm B (deferred/postpartum INH group). Women in both arms received oral prenatal multivitamins and pyridoxine (vitamin B6) once daily from study entry through Week 40 postpartum. Study visits for women occurred 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 consisted of giving a medical history and undergoing a physical exam and blood collection; all visits through the delivery visit also included an obstetrical exam. Presence of HIV infection was documented at screening and a tuberculin skin test (TST) was administered at the delivery visit and at the Week 44 postpartum visit. Study visits for infants occurred at birth and at several time points through Week 48. These visits included a medical history, physical exam, and blood collection. Intensive pharmacokinetic (PK) samples, that is, samples taken at many different time points within a 24-hour test period, were collected from a small subset of women, one test period at antepartum and one at postpartum. Sparse PK samples, that is, samples taken at fewer time points within the test period, were collected on all women, once each at antepartum and postpartum.
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 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. Interventions: Drug: Isoniazid (INH) Drug: Placebo for isoniazid (INH); Experimental: Arm B (Deferred INH Treatment) 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. 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.; 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.
* 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	October 2018
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP