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
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 956
- 试验地点
- 13
- 主要终点
- Incidence Rate of Combined Endpoint: Grade 3 or Higher Adverse Events (AEs) Related to Treatment, or AE Causing Discontinuation of Treatment
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Double (Participant, Care Provider)
入排标准
- 年龄范围
- 13 Years 至 —（Child, Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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.
干预措施: Isoniazid (INH) (Drug)
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.
干预措施: Placebo for isoniazid (INH) (Drug)
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.
干预措施: Isoniazid (INH) (Drug)
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.
干预措施: Placebo for isoniazid (INH) (Drug)
结局指标
主要结局
Incidence Rate of Combined Endpoint: Grade 3 or Higher Adverse Events (AEs) Related to Treatment, or AE Causing Discontinuation of Treatment
时间窗: 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.
次要结局
- Number of Mothers With a Fetal Death(Measured from study entry through end of pregnancy)
- Number of Infants With Grade 3 or Higher Clinical or Laboratory AE(Measured from study entry through Week 48 after birth)
- Number of Infants Which Are HIV-infected(Measured from study entry through study Week 44)
- Number of Mothers With a Fetus Small for Gestational Age(Measured at delivery)
- Number of Infants Hospitalized(Measured from study entry through Week 48 after birth)
- 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(Measured from study entry through 12 weeks after birth)
- Incidence Rate, Antepartum, of Hepatotoxicity, Protocol-specific Definition, Any Cause(Measured from study entry through delivery)
- Incidence Rate, up to 12 Weeks Postpartum, of Hepatotoxicity, Defined by DAIDS, Any Cause(Measured from study start through 12 weeks postpartum)
- Number of Mothers With an Infant Born Prematurely(Measured at delivery)
- Number of Mothers With a Low Birth-weight Infant(Measured on day of birth)
- Number of Mothers With an Infant With a Congenital Anomaly(Measured from study entry through Week 48 after birth)
- Number of Mothers With an Adverse Pregnancy Outcome: Spontaneous Abortion, Stillbirth, Premature Birth, Low Birth Weight, or Congenital Anomaly(Measured from study entry through Week 48 after birth)
- Incidence Rate of TB Infection Among Mothers(Measured from study entry to Week 48 after birth)
- Incidence Rate of Combined Endpoints: Infant TB or Infant Death(Measured from study entry through Week 48 after birth)
- Incidence Rate, up to 12 Weeks Postpartum, of Hepatotoxicity, Defined by DAIDS, Related to Treatment(Measured from study start through 12 weeks postpartum)
- Number of Infants With Grade 3 or Higher Clinical or Laboratory AE Related to Treatment(Measured from study entry through Week 48 after birth)
- Incidence Rate of Infant Death(Measured from study entry through Week 48 after birth)
- Incidence Rate of Maternal Deaths(Measured from study entry through Week 48 postpartum)
- Incidence Rate of Combined Endpoints: Maternal TB or Maternal Death(Measured from study entry through Week 48 after birth)
- Incidence Rate, Antepartum, of Grade 3 or Higher AE(Measured from study entry through end of pregnancy)
- Incidence Rate, up to 12 Weeks Postpartum, of Grade 3 or Higher AE(Measured from study entry through 12 weeks postpartum)
- Incidence Rate, Antepartum, of Hepatotoxicity, Defined by DAIDS, Related to Treatment(Measured from study entry through delivery)
- Incidence Rate of Tuberculosis (TB) Among Infants(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(Measured from study entry through end of pregnancy)
- Number of Infants With Tuberculosis Resistant to INH(Measured from study entry through Week 48 after birth)
- Agreement Between IGRA and TST TB Test Results, Infant(Measured at week 44 after birth)
- Agreement Between IGRA and TST TB Tests, Women at 44 Weeks Postpartum(Measured at Week 44 postpartum)
- Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Pill Count(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)
- Incidence Rate of Combined Endpoints: Maternal TB, Maternal Death, Infant TB, or Infant Death(Measured from study entry through Week 48 after birth)
- Incidence Rate, to 12 Weeks Postpartum, of Hepatotoxicity, Protocol-specific Definition, Related to Treatment(Measured from study entry through 12 weeks postpartum)
- Incidence Rate, to 12 Weeks Postpartum, of Hepatotoxicity, Protocol-specific Definition, Any Cause(Measured from study entry through 12 weeks postpartum)
- Number of Mothers With Tuberculosis Resistant to INH(Measured from study entry through Week 48 postpartum)
- Incidence Rate, Antepartum, of Hepatotoxicity, Defined by Protocol-specific Definition of Hepatotoxicity, Related to Treatment(Measured from study entry through delivery)
- Incidence Rate, Antepartum, of Hepatotoxicity, Defined by DAIDS, Any Cause(Measured from study entry through delivery)
- Pharmacokinetic (PK) Parameter: Adjusted Mean of Area Under the Curve of Plasma Concentration Versus Time (AUC24h), for INH(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(Measured at delivery)
- Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Self-report(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)
- Pharmacokinetic (PK) Parameter: Adjusted Mean of Area Under the Curve (AUC24h), for EFV(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.)