Clinical trial NCT01494038: Evaluating the Safety of Immediate Versus Deferred Isoniazid Preventive Therapy Among HIV-Infected Pregnant Women
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: HIV Infections
Tuberculosis
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2011-12-16
Enrollment: 956
Sex: FEMALE
Minimum age (years): 13
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

Eligibility criteria: 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

Primary outcomes:
measure: Incidence Rate of Combined Endpoint: Grade 3 or Higher Adverse Events (AEs) Related to Treatment, or AE Causing Discontinuation of Treatment
timeFrame: Measured from study entry through Week 48 after birth
Secondary outcomes:
measure: Number of Mothers With a Fetal Death
timeFrame: Measured from study entry through end of pregnancy
measure: Number of Mothers With a Fetus Small for Gestational Age
timeFrame: Measured at delivery
measure: Number of Mothers With an Infant Born Prematurely
timeFrame: Measured at delivery
measure: Number of Mothers With a Low Birth-weight Infant
timeFrame: Measured on day of birth
measure: Number of Mothers With an Infant With a Congenital Anomaly
timeFrame: Measured from study entry through Week 48 after birth
measure: Number of Mothers With an Adverse Pregnancy Outcome: Spontaneous Abortion, Stillbirth, Premature Birth, Low Birth Weight, or Congenital Anomaly
timeFrame: Measured from study entry through Week 48 after birth
measure: Number of Infants With Grade 3 or Higher Clinical or Laboratory AE
timeFrame: Measured from study entry through Week 48 after birth
measure: Number of Infants With Grade 3 or Higher Clinical or Laboratory AE Related to Treatment
timeFrame: Measured from study entry through Week 48 after birth
measure: Number of Infants Which Are HIV-infected
timeFrame: Measured from study entry through study Week 44
measure: Number of Infants Hospitalized
timeFrame: Measured from study entry through Week 48 after birth
measure: Incidence Rate of TB Infection Among Mothers
timeFrame: Measured from study entry to Week 48 after birth
measure: Incidence Rate of Tuberculosis (TB) Among Infants
timeFrame: Measured from study entry through Week 48 after birth
measure: Incidence Rate of Infant Death
timeFrame: Measured from study entry through Week 48 after birth
measure: Incidence Rate of Maternal Deaths
timeFrame: Measured from study entry through Week 48 postpartum
measure: Incidence Rate of Combined Endpoints: Maternal TB or Maternal Death
timeFrame: Measured from study entry through Week 48 after birth
measure: Incidence Rate of Combined Endpoints: Infant TB or Infant Death
timeFrame: Measured from study entry through Week 48 after birth
measure: Incidence Rate of Combined Endpoints: Maternal TB, Maternal Death, Infant TB, or Infant Death
timeFrame: Measured from study entry through Week 48 after birth
measure: Incidence Rate of Combined Endpoint, Antepartum: Grade 3 or Higher AE Related to Treatment, or Discontinuation of Treatment Due to AE
timeFrame: Measured from study entry through end of pregnancy
measure: 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
timeFrame: Measured from study entry through 12 weeks after birth
measure: Incidence Rate, Antepartum, of Grade 3 or Higher AE
timeFrame: Measured from study entry through end of pregnancy
measure: Incidence Rate, up to 12 Weeks Postpartum, of Grade 3 or Higher AE
timeFrame: Measured from study entry through 12 weeks postpartum
measure: Incidence Rate, Antepartum, of Hepatotoxicity, Defined by Protocol-specific Definition of Hepatotoxicity, Related to Treatment
timeFrame: Measured from study entry through delivery
measure: Incidence Rate, to 12 Weeks Postpartum, of Hepatotoxicity, Protocol-specific Definition, Related to Treatment
timeFrame: Measured from study entry through 12 weeks postpartum
measure: Incidence Rate, Antepartum, of Hepatotoxicity, Protocol-specific Definition, Any Cause
timeFrame: Measured from study entry through delivery
measure: Incidence Rate, to 12 Weeks Postpartum, of Hepatotoxicity, Protocol-specific Definition, Any Cause
timeFrame: Measured from study entry through 12 weeks postpartum
measure: Incidence Rate, Antepartum, of Hepatotoxicity, Defined by DAIDS, Related to Treatment
timeFrame: Measured from study entry through delivery
measure: Incidence Rate, up to 12 Weeks Postpartum, of Hepatotoxicity, Defined by DAIDS, Related to Treatment
timeFrame: Measured from study start through 12 weeks postpartum
measure: Incidence Rate, Antepartum, of Hepatotoxicity, Defined by DAIDS, Any Cause
timeFrame: Measured from study entry through delivery
measure: Incidence Rate, up to 12 Weeks Postpartum, of Hepatotoxicity, Defined by DAIDS, Any Cause
timeFrame: Measured from study start through 12 weeks postpartum
measure: Number of Mothers With Tuberculosis Resistant to INH
timeFrame: Measured from study entry through Week 48 postpartum
measure: Number of Infants With Tuberculosis Resistant to INH
timeFrame: Measured from study entry through Week 48 after birth
measure: Pharmacokinetic (PK) Parameter: Adjusted Mean of Area Under the Curve of Plasma Concentration Versus Time (AUC24h), for INH
timeFrame: 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.
measure: Pharmacokinetic (PK) Parameter: Adjusted Mean of Area Under the Curve (AUC24h), for EFV
timeFrame: 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.
measure: Agreement Between Interferon-gamma Release Assay (IGRA) TB Test and Tuberculin Skin Test (TST) Results, Women at Delivery
timeFrame: Measured at delivery
measure: Agreement Between IGRA and TST TB Test Results, Infant
timeFrame: Measured at week 44 after birth
measure: Agreement Between IGRA and TST TB Tests, Women at 44 Weeks Postpartum
timeFrame: Measured at Week 44 postpartum
measure: Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Self-report
timeFrame: 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
measure: Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Pill Count
timeFrame: 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
Other outcomes:
Locations:
city: Gaborone
country: Botswana
facility: Gaborone CRS
city: Gaborone
country: Botswana
facility: Molepolole CRS
city: Port-au-Prince
country: Haiti
facility: Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS
city: Pune
country: India
facility: Byramjee Jeejeebhoy Medical College (BJMC) CRS
state: Maharashtra
city: Johannesburg
country: South Africa
facility: Soweto IMPAACT CRS
state: Gauteng
city: Cape Town
country: South Africa
facility: Desmond Tutu TB Centre - Stellenbosch University (DTTC-SU) CRS
state: Western Cape Province
city: Cape Town
country: South Africa
facility: Fam-Cru Crs
state: Western Cape Province
city: Moshi
country: Tanzania
facility: Kilimanjaro Christian Medical Centre (KCMC)
city: Chiang Mai
country: Thailand
facility: Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS
city: Kampala
country: Uganda
facility: MU-JHU Research Collaboration (MUJHU CARE LTD) CRS
city: Chitungwiza
country: Zimbabwe
facility: Seke North CRS
city: Chitungwiza
country: Zimbabwe
facility: St Mary's CRS
city: Harare
country: Zimbabwe
facility: Harare Family Care CRS
Study officials:
affiliation: Johns Hopkins University
name: Amita Gupta, MD, MHS
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.