HIV InfectionsPhase 4NCT01494038
Evaluating the Safety of Immediate Versus Deferred Isoniazid Preventive Therapy Among HIV-Infected Pregnant Women
A Phase 4 study testing Isoniazid (INH) in people with HIV Infections and Tuberculosis, run by National Institute of Allergy and Infectious Diseases (NIAID) at 13 sites in 8 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 13 years and older, women only
- Conditions the study is for
- HIV Infections, Tuberculosis
- What is being tested?
- Isoniazid (INH)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 956 participants
- Where
- 13 sitesin 8 countries
- Study dates
- 19 Aug 2014to 6 Sep 2017
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 13 years and older
- Women only
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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.
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- 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
Trial locations and contacts
13 sites in 8 countries.
13 sites in 8 countries
South Africa3 sites
Desmond Tutu TB Centre - Stellenbosch University (DTTC-SU) CRS
Cape Town, Western Cape, 7505
Fam-Cru Crs
Cape Town, Western Cape, 7505
Soweto IMPAACT CRS
Johannesburg, Gauteng, 1862
Zimbabwe3 sites
Seke North CRS
Chitungwiza
St Mary's CRS
Chitungwiza
Harare Family Care CRS
Harare
Haiti1 site
Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS
Port-au-Prince, HT-6110
India1 site
Byramjee Jeejeebhoy Medical College (BJMC) CRS
Pune, Maharashtra, 411001
Thailand1 site
Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS
Chiang Mai, 50200
About this study
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
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.
Read the 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.
- Conditions
- HIV Infections, Tuberculosis
- Being tested
- Isoniazid (INH), Placebo for isoniazid (INH)
- Medical subject headings
- HIV Infections, Tuberculosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
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)
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)
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: Isoniazid (INH); Drug: Placebo for isoniazid (INH) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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: Measured from study entry through Week 48 after birth
Secondary outcomes (38)
Number of Mothers With a Fetal Death
Fetal deaths include both stillbirths and spontaneous abortions; in case of a multiple birth, mothers who had at least one fetal death
Measured: Measured from study entry through end of pregnancy
Number of Mothers With a Fetus Small for Gestational Age
Small for gestational age was determined by physician at site
Measured: Measured at delivery
Number of Mothers With an Infant Born Prematurely
Premature birth is defined as gestational age of < 37 weeks at delivery.
Measured: Measured at delivery
Number of Mothers With a Low Birth-weight Infant
Low birth weight is defined as weight < 2500 mg
Measured: Measured on day of birth
Number of Mothers With an Infant With a Congenital Anomaly
Includes congenital anomalies meeting the Metropolitan Atlanta Congenital Defects Program criteria.
Measured: Measured from study entry through Week 48 after birth
Number of Mothers With an Adverse Pregnancy Outcome: Spontaneous Abortion, Stillbirth, Premature Birth, Low Birth Weight, or Congenital Anomaly
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.
Measured: Measured from study entry through Week 48 after birth
Number of Infants With Grade 3 or Higher Clinical or Laboratory AE
Laboratory, sign/symptom, or diagnoses graded as 3 or higher by DAIDS criteria.
Measured: Measured from study entry through Week 48 after birth
Number of Infants With Grade 3 or Higher Clinical or Laboratory AE Related to Treatment
As before, but AE is judged to be possibly, probably, or definitely related to INH or Placebo for INH, by clinic medical staff
Measured: Measured from study entry through Week 48 after birth
Number of Infants Which Are HIV-infected
HIV infection determined during follow-up period. Infection at birth or during breastfeeding
Measured: Measured from study entry through study Week 44
Number of Infants Hospitalized
Hospitalization due to reasons other than birth
Measured: Measured from study entry through Week 48 after birth
Incidence Rate of TB Infection Among Mothers
Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata. Probable or confirmed TB infection, as judged by Secondary Endpoint Review Committee
Measured: Measured from study entry to Week 48 after birth
Incidence Rate of Tuberculosis (TB) Among Infants
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.
Measured: Measured from study entry through Week 48 after birth
Incidence Rate of Infant Death
Incidence rate was calculated by Mantel-Haenszel, weighted by gestational age strata.
Measured: Measured from study entry through Week 48 after birth
Incidence Rate of Maternal Deaths
Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata.
Measured: Measured from study entry through Week 48 postpartum
Incidence Rate of Combined Endpoints: Maternal TB or Maternal Death
Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata.
Measured: Measured from study entry through Week 48 after birth
Incidence Rate of Combined Endpoints: Infant TB or Infant Death
Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata.
Measured: Measured from study entry through Week 48 after birth
Incidence Rate of Combined Endpoints: Maternal TB, Maternal Death, Infant TB, or Infant Death
Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata.
Measured: Measured from study entry through Week 48 after birth
Incidence Rate of Combined Endpoint, Antepartum: Grade 3 or Higher AE Related to Treatment, or Discontinuation of Treatment Due to AE
Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata
Measured: Measured from study entry through end of pregnancy
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
Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata.
Measured: Measured from study entry through 12 weeks after birth
Incidence Rate, Antepartum, of Grade 3 or Higher AE
Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata.
Measured: Measured from study entry through end of pregnancy
Incidence Rate, up to 12 Weeks Postpartum, of Grade 3 or Higher AE
Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata.
Measured: Measured from study entry through 12 weeks postpartum
Incidence Rate, Antepartum, of Hepatotoxicity, Defined by Protocol-specific Definition of Hepatotoxicity, Related to Treatment
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
Measured: Measured from study entry through delivery
Incidence Rate, to 12 Weeks Postpartum, of Hepatotoxicity, Protocol-specific Definition, Related to Treatment
Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata
Measured: Measured from study entry through 12 weeks postpartum
Incidence Rate, Antepartum, of Hepatotoxicity, Protocol-specific Definition, Any Cause
Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata.
Measured: Measured from study entry through delivery
Incidence Rate, to 12 Weeks Postpartum, of Hepatotoxicity, Protocol-specific Definition, Any Cause
Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata.
Measured: Measured from study entry through 12 weeks postpartum
Incidence Rate, Antepartum, of Hepatotoxicity, Defined by DAIDS, Related to Treatment
Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata. Hepatotoxicity definition as defined by DAIDS AE grading criteria 1.0.
Measured: Measured from study entry through delivery
Incidence Rate, up to 12 Weeks Postpartum, of Hepatotoxicity, Defined by DAIDS, Related to Treatment
Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata
Measured: Measured from study start through 12 weeks postpartum
Incidence Rate, Antepartum, of Hepatotoxicity, Defined by DAIDS, Any Cause
Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata.
Measured: Measured from study entry through delivery
Incidence Rate, up to 12 Weeks Postpartum, of Hepatotoxicity, Defined by DAIDS, Any Cause
Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata.
Measured: Measured from study start through 12 weeks postpartum
Number of Mothers With Tuberculosis Resistant to INH
Resistance to INH from isolates of Mycobacterium tuberculosis, as a percentage of mothers who develop culture-confirmed TB
Measured: Measured from study entry through Week 48 postpartum
Number of Infants With Tuberculosis Resistant to INH
Resistance to INH from isolates of Mycobacterium tuberculosis, as a percentage of infants who develop culture-confirmed TB
Measured: Measured from study entry through Week 48 after birth
Pharmacokinetic (PK) Parameter: Adjusted Mean of Area Under the Curve of Plasma Concentration Versus Time (AUC24h), for INH
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,
Measured: 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 (PK) Parameter: Adjusted Mean of Area Under the Curve (AUC24h), for EFV
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,
Measured: 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.
Agreement Between Interferon-gamma Release Assay (IGRA) TB Test and Tuberculin Skin Test (TST) Results, Women at Delivery
IGRA done by Quantiferon Gold Test (QGIT). For women, TST is considered positive if greater than or equal to 5 mm
Measured: Measured at delivery
Agreement Between IGRA and TST TB Test Results, Infant
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.
Measured: Measured at week 44 after birth
Agreement Between IGRA and TST TB Tests, Women at 44 Weeks Postpartum
IGRA done by Quantiferon Gold Test (QGIT). For women, TST is considered positive if greater than or equal to 5 mm
Measured: Measured at Week 44 postpartum
Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Self-report
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.
Measured: 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
Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Pill Count
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.
Measured: 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
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Dec 2011 (estimated)
- Study start19 Aug 2014
- Primary completion6 Sep 2017
- Study completion6 Sep 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for HIV InfectionsStudies of the same condition, open and under way.
- More trials run by National Institute of Allergy and Infectious Diseases (NIAID)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Care provider
- Enrolment
- 956 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Amita Gupta, MD, MHS, Study chair, Johns Hopkins University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01494038
- Sponsor's protocol ID
- P1078
- Other IDs
- 10732, IMPAACT P1078
- Status last verified
- Oct 2018
- First submitted
- 14 Dec 2011
- Last updated
- 5 Nov 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
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;2010(1):CD000171. doi: 10.1002/14651858.CD000171.pub3.
PubMed 20091503Zar 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.
PubMed 17085459Cantwell 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.
PubMed 8046808Gupta 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.
PubMed 37634517Montepiedra 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.
PubMed 33146706Gupta 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.
PubMed 31577875
Study at a glance
From the registry record, last updated by the sponsor on 5 Nov 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01494038
- Acronym / sponsor ID
- P1078
- Conditions
- HIV Infections, Tuberculosis
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 956 participants (actual)
- Lead sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)US National Institutes of Health
- Study start
- 19 Aug 2014 (actual)
- Primary completion
- 6 Sep 2017 (actual)
- Study completion
- 6 Sep 2017 (actual)
- First posted
- 16 Dec 2011 (estimated)
- Results
- Posted 20 Nov 2018
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, care provider)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Arm A (Immediate INH Treatment) | Experimental | Drug: Isoniazid (INH), Drug: Placebo for isoniazid (INH)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. |
| Arm B (Deferred INH Treatment) | Experimental | Drug: Isoniazid (INH), Drug: Placebo for isoniazid (INH)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. |
Who may qualify
- Ages
- 13 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (12 listed)
- 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)
Key exclusion criteria (12 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| 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 | Arm A (Immediate INH Treatment), Arm B (Deferred INH Treatment) |
| 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) | Drug | Arm A (Immediate INH Treatment), Arm B (Deferred INH Treatment) |
Primary outcome
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.
38 secondary outcomes
Number of Mothers With a Fetal Death
Time frame: Measured from study entry through end of pregnancy
Number of Mothers With a Fetus Small for Gestational Age
Time frame: Measured at delivery
Number of Mothers With an Infant Born Prematurely
Time frame: Measured at delivery
Number of Mothers With a Low Birth-weight Infant
Time frame: Measured on day of birth
Number of Mothers With an Infant With a Congenital Anomaly
Time frame: Measured from study entry through Week 48 after birth
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
Number of Infants With Grade 3 or Higher Clinical or Laboratory AE
Time frame: Measured from study entry through Week 48 after birth
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
Number of Infants Which Are HIV-infected
Time frame: Measured from study entry through study Week 44
Number of Infants Hospitalized
Time frame: Measured from study entry through Week 48 after birth
Incidence Rate of TB Infection Among Mothers
Time frame: Measured from study entry to Week 48 after birth
Incidence Rate of Tuberculosis (TB) Among Infants
Time frame: Measured from study entry through Week 48 after birth
Incidence Rate of Infant Death
Time frame: Measured from study entry through Week 48 after birth
Incidence Rate of Maternal Deaths
Time frame: Measured from study entry through Week 48 postpartum
Incidence Rate of Combined Endpoints: Maternal TB or Maternal Death
Time frame: Measured from study entry through Week 48 after birth
Incidence Rate of Combined Endpoints: Infant TB or Infant Death
Time frame: Measured from study entry through Week 48 after birth
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 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 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, Antepartum, of Grade 3 or Higher AE
Time frame: Measured from study entry through end of pregnancy
Incidence Rate, up to 12 Weeks Postpartum, of Grade 3 or Higher AE
Time frame: Measured from study entry through 12 weeks postpartum
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, to 12 Weeks Postpartum, of Hepatotoxicity, Protocol-specific Definition, Related to Treatment
Time frame: Measured from study entry through 12 weeks postpartum
Incidence Rate, Antepartum, of Hepatotoxicity, Protocol-specific Definition, Any Cause
Time frame: Measured from study entry through delivery
Incidence Rate, to 12 Weeks Postpartum, of Hepatotoxicity, Protocol-specific Definition, Any Cause
Time frame: Measured from study entry through 12 weeks postpartum
Incidence Rate, Antepartum, of Hepatotoxicity, Defined by DAIDS, Related to Treatment
Time frame: Measured from study entry through delivery
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 Rate, Antepartum, of Hepatotoxicity, Defined by DAIDS, Any Cause
Time frame: Measured from study entry through delivery
Incidence Rate, up to 12 Weeks Postpartum, of Hepatotoxicity, Defined by DAIDS, Any Cause
Time frame: Measured from study start through 12 weeks postpartum
Number of Mothers With Tuberculosis Resistant to INH
Time frame: Measured from study entry through Week 48 postpartum
Number of Infants With Tuberculosis Resistant to INH
Time frame: Measured from study entry through Week 48 after birth
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 (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.
Agreement Between Interferon-gamma Release Assay (IGRA) TB Test and Tuberculin Skin Test (TST) Results, Women at Delivery
Time frame: Measured at delivery
Agreement Between IGRA and TST TB Test Results, Infant
Time frame: Measured at week 44 after birth
Agreement Between IGRA and TST TB Tests, Women at 44 Weeks Postpartum
Time frame: Measured at Week 44 postpartum
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
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
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Nov 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 20091503Akolo 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.
- Background: PubMed 17085459Zar 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.
- Background: PubMed 8046808Cantwell 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.
- Derived from this study: PubMed 37634517Gupta 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.
- Derived from this study: PubMed 33146706Montepiedra 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.
- Derived from this study: PubMed 31577875Gupta 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.
- Manual for Expedited Reporting of Adverse Events to Division of AIDS (DAIDS), Version 2.0, January 2010Link provided by the sponsor.
- 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)Link provided by the sponsor.
- Metropolitan Atlanta Congenital Defects Program (MACDP)Link provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Amita Gupta, MD, MHS study chair
Johns Hopkins University
13 sites in 8 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Isoniazid (INH) in people with HIV Infections and Tuberculosis, run by National Institute of Allergy and Infectious Diseases (NIAID) at 13 sites in 8 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 5 Nov 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 13 sites in South Africa, Zimbabwe, Botswana, Haiti, India and 3 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 20 Nov 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01494038, which also lists 6 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Nov 2021.