Clinical trial NCT04518228: Pharmacokinetic Properties of Antiretroviral and Anti-Tuberculosis Drugs During Pregnancy and Postpartum
Official title: Pharmacokinetic Properties of Antiretroviral and Anti-Tuberculosis Drugs During Pregnancy and Postpartum
Study type: OBSERVATIONAL
Overall status: ACTIVE_NOT_RECRUITING
Conditions: HIV Infections
Tuberculosis
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: International Maternal Pediatric Adolescent AIDS Clinical Trials Group
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: National Institute of Mental Health (NIMH)
name: Gilead Sciences
name: ViiV Healthcare
name: Merck Sharp & Dohme LLC
First posted: 2020-08-19
Enrollment: 205
Sex: FEMALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Pregnant and postpartum women living with and without HIV (WLHIV and HIV-uninfected women) receiving ARV and/or TB drugs under study, and their infants.

Brief summary: The purpose of this study is to evaluate the pharmacokinetic (PK) properties of antiretroviral (ARV) and anti-tuberculosis (TB) drugs administered during pregnancy and postpartum.

Detailed description: This study will evaluate the pharmacokinetic (PK) properties of antiretroviral (ARV) and anti-tuberculosis (TB) drugs administered during pregnancy and postpartum.

IMPAACT 2026 is a Phase IV observational clinical study. Participants are not assigned to the drugs under study, but are already receiving the drugs for clinical care by prescription of their clinical care providers. They are enrolled into study arms according to the drugs they are receiving through clinical care, and if on multiple drugs of interest, are able to enroll into multiple arms simultaneously. No ARVs or TB treatment drugs are supplied as part of this study. All drugs under study are provided by non-study sources. The study sponsor added this observational study to an existing investigational new drug (IND) number for off-label use in case the participant's clinical care provider decides to prescribe a higher dose than the approved dose if the PK results for the approved dose indicate that drug exposure may be inadequate.

This study is comprised of five components which in turn are comprised of arms specific to each drug or drug combination being evaluated:

* Component 1 (Arms 1.1, 1.2. 1.3. 1.4. and 1.5): Pregnant women living with HIV (WLHIV) receiving oral ARVs and no TB drugs, and their infants.
* Component 2 (Arm 2.1): Pregnant WLHIV and HIV-uninfected women who received long-acting/extended release ARVs during pregnancy, and their infants.
* Component 3 (Arms 3.1, 3.2, and 3.3): Pregnant WLHIV receiving ARVs and first-line TB treatment, and their infants.
* Component 4 (Arm 4.1): Pregnant WLHIV and HIV-uninfected women receiving second-line TB treatment, and their infants.
* Component 5 (Arms 5.1, 5.2. and 5.3): Postpartum WLHIV breastfeeding while receiving oral ARVs, and their infants.

Each arm will open to accrual independently and will accrue independently over approximately 36 months from the first enrollment in each arm.

Participants in Component 1 will be followed up to 12 weeks after delivery for mothers and up to 24 weeks after birth for infants. Participants in Component 2 will be followed up to 5 weeks after delivery for mothers and infants. Participants in Components 3, 4, and 5 will be followed up to 24 weeks after delivery for mothers and infants.

Study visits may include:

* Component 1: Maternal clinical and laboratory evaluations and PK sampling at second trimester (2T), third trimester (3T), delivery, and 6-12 weeks post-partum (PP). Infant clinical evaluations and washout PK sampling at birth and 5-9 days after birth.
* Component 2: Maternal clinical and laboratory evaluations and PK sampling at delivery. Infant clinical evaluations and washout PK sampling at birth, 5-9 days, and 12-16 days after birth. Maternal and infant breast milk transfer PK sampling at 5-9 days, 12-16 days, and 3-5 weeks after delivery.
* Component 3: Maternal clinical and laboratory evaluations and PK sampling at second trimester (2T), third trimester (3T), delivery, and 2-8 weeks post-partum (PP). Infant clinical evaluations and washout PK sampling at birth and 5-9 days after birth. Maternal and infant breast milk transfer PK sampling at 5-9 days, 2-8 weeks, and 16-24 weeks after delivery.
* Component 4: Maternal clinical and laboratory evaluations and PK sampling at second trimester (2T), third trimester (3T), delivery, and 2-8 weeks post-partum (PP). Infant clinical evaluations and washout PK sampling at birth and 5-9 days after birth. Maternal and infant breast milk transfer PK sampling at 5-9 days, 2-8 weeks, and 16-24 weeks after delivery.
* Component 5: Maternal and infant clinical evaluations and breast milk transfer PK sampling at 5-9 days, 2-12 weeks, and 16-24 weeks after delivery.

Eligibility criteria: Inclusion Criteria:

Component 1: Pregnant WLHIV receiving oral ARVs and no TB drugs, and their infants

* Mother is of legal age or otherwise able to provide independent informed consent as determined by site standard operating procedures (SOPs) and consistent with site institutional review board (IRB)/ethics committee (EC) policies and procedures, and is willing and able to provide written informed consent for her own and her infant's participation in this study.
* Prior to study entry, HIV status confirmed as HIV infected per study protocol.
* At study entry, pregnant and in one of the following two enrollment windows based on best available obstetrical estimate of gestational age:

  * Second trimester: gestational age of 20 0/7 to 26 6/7 weeks
  * Third trimester: gestational age of 30 0/7 to 37 6/7 weeks
* At study entry, receiving at least one of the following oral ARV drugs or drug combinations, based on maternal report and available medical records:

  * Arm 1.1: Bictegravir (BIC) 50 mg q.d.
  * Arm 1.2: Doravirine (DOR) 100 mg q.d.
  * Arm 1.3: Tenofovir alafenamide (TAF) - 10 mg q.d. boosted with cobicistat
  * Arm 1.4: TAF 25 mg q.d. without boosting
  * Arm 1.5: TAF 25 mg q.d. boosted with cobicistat or ritonavir
* At study entry, planning to continue the current ARV regimen through at least 12 weeks post-delivery, based on maternal report and available medical records.
* At study entry, has been receiving the drug or drug combination under study at the required dose for at least two weeks, based on maternal report and available medical records.
* At study entry, assessed by study staff as having no identified barriers to completing initial PK sampling within 20 0/7 - 26 6/7 weeks gestation (second trimester) or 30 0/7 to 37 6/7 weeks gestation (third trimester) and within 14 days of enrollment.
* At study entry, if receiving a generic formulation of the drug or drug combination under study, approval of the formulation per study protocol.
* At study entry, not receiving any TB drugs (for either prophylaxis or treatment), based on maternal report and available medical records.

Component 2: Pregnant WLHIV and HIV-uninfected women who received long-acting/extended release ARVs during pregnancy, and their infants

* If of legal age or otherwise able to provide independent informed consent as determined by site SOPs and consistent with site IRB/EC policies and procedures: Willing and able to provide written informed consent for her own and her infant's participation in this study.
* If not of legal age or otherwise unable to provide independent informed consent as determined by site SOPs and consistent with site IRB/EC policies and procedures: Parent/guardian or other legally authorized representative of the mother and her infant is willing and able to provide written informed consent for the mother and her infant's study participation; in addition, when applicable, the mother is willing and able to provide written assent for her own and her infant's study participation.
* At study entry, intends to deliver at the study-affiliated clinic or hospital, based on maternal report.
* At study entry, gestational age of at least 24 0/7 weeks based on best available obstetrical estimate of gestational age, and not yet delivered.
* At study entry, has received at least one administration of the following, based on available medical records, during the current pregnancy:

  * Arm 2.1: Long-acting injectable formulation of cabotegravir (CAB LA) (any dose)

Component 3: Pregnant WLHIV receiving ARVs with first-line TB treatment, and their infants

* Mother is of legal age or otherwise able to provide independent informed consent as determined by site SOPs and consistent with site IRB/EC policies and procedures, and is willing and able to provide written informed consent for her own and her infant's participation in this study.
* Prior to study entry, HIV status confirmed as HIV infected per study protocol.
* At study entry, pregnant and in one of the following two enrollment windows, based on best available obstetrical estimate of gestational age:

  * Second trimester: gestational age of 20 0/7 to 26 6/7 weeks
  * Third trimester: gestational age of 30 0/7 to 37 6/7 weeks
* At study entry, receiving at least two of the following first-line TB treatment drugs under study AND at least one of the following ARV drugs or drug combinations under study, based on maternal report and available medical records:

  * First-line TB treatment drugs:
  * Isoniazid (INH) 4-6 mg/kg (max 300 mg) q.d.
  * Rifampin (RIF) 8-12 mg/kg (max 600 mg) q.d.
  * Rifabutin (RFB) 150-300 mg q.d.
  * Ethambutol (EMB) 15-20 mg/kg q.d.
  * Pyrazinamide (PZA) 20-30 mg/kg q.d.
  * Moxifloxacin (MFX) 400 mg or 800mg q.d
  * ARVs:
  * Arm 3.1: Dolutegravir (DTG) 50 mg b.i.d. when combined with RIF or 50 mg q.d. if RIF is not part of the TB regimen
  * Arm 3.2: Atazanavir/ritonavir (ATV/r) ≥300/100 mg q.d. or Darunavir/ritonavir (DRV/r) ≥ 600/100 mg b.i.d.
  * Arm 3.3: Lopinavir/ritonavir (LPV/r) 800/200 mg b.i.d.
* At study entry, has been receiving the drug combination under study at the required dose for at least two weeks based on maternal report and available medical records.
* At study entry, assessed by study staff as having no identified barriers to completing initial PK sampling within 20 0/7 - 26 6/7 weeks gestation (second trimester) or 30 0/7 to 37 6/7 weeks gestation (third trimester) and within 14 days of enrollment.
* At study entry, if receiving a generic ARV or TB formulation of the drug or drug combination under study, approval of the formulation per study protocol.
* At study entry, planning to continue the current ARV regimen through at least 8 weeks post-delivery, based on maternal report and available medical records.

Component 4 Inclusion Criteria: Pregnant WLHIV and HIV-uninfected women receiving second-line TB treatment, and their infants

* Mother is of legal age or otherwise able to provide independent informed consent as determined by site SOPs and consistent with site IRB/EC policies and procedures, and is willing and able to provide written informed consent for her own and her infant's participation in this study.
* Prior to study entry, HIV status confirmed as HIV-infected or HIV-uninfected, per study protocol.
* At study entry, pregnant and in one of the following two enrollment windows based on best available obstetrical estimate of gestational age:

  * Second trimester: gestational age of 20 0/7 to 26 6/7 weeks
  * Third trimester: gestational age of 30 0/7 to 37 6/7 weeks
* At study entry, receiving at least one of the following second-line TB treatment drugs under study, based on maternal report and available medical records:

  * Arm 4.1: Second-line TB treatment drugs:
  * Levofloxacin (LFX) 750mg - 1000mg q.d.
  * Clofazimine (CFZ) 100mg q.d.
  * Linezolid (LZD) 300mg - 600mg q.d.
  * Bedaquiline (BDQ) 200mg t.i.w.
  * Delamanid (DLM) 100mg b.i.d.
  * Moxifloxacin (MFX) 400mg or 800mg q.d and at least one other second-line TB treatment drug under study
* At study entry, has been receiving the drugs under study at the required dose for at least two weeks, based on maternal report and available medical records.
* At study entry, assessed by study staff as having no identified barriers to completing initial PK sampling within 20 0/7 - 26 6/7 weeks gestation (second trimester) or 30 0/7 to 37 6/7 weeks gestation (third trimester) and within 14 days of enrollment.
* At study entry, if receiving a generic formulation of the drug(s) under study, approval of the formulation per study protocol.

Component 5: Postpartum WLHIV breastfeeding while receiving oral ARVs, and their infants

* Mother is of legal age or otherwise able to provide independent informed consent as determined by site SOPs and consistent with site IRB/EC policies and procedures, and is willing and able to provide written informed consent for her own and her infant's participation in this study.
* Prior to study entry, HIV status confirmed as HIV infected, per study protocol.
* At study entry, within 5-9 days post-delivery (inclusive).
* At study entry, breastfeeding mother-infant pair intends to continue exclusive breastfeeding through at least 16 weeks post-delivery.
* At study entry, mother is receiving any of the following oral ARV drugs or drug combinations:

  * Arm 5.1: Atazanavir/ritonavir (ATV/r)
  * Arm 5.2: Darunavir/ritonavir (DRV/r)
  * Arm 5.3: Lopinavir/ritonavir (LPV/r)
* At study entry, mother has been receiving the drug(s) or drug combination(s) under study at the required dose for at least two weeks, based on maternal report and available medical records.
* At study entry, assessed by study staff as having no identified barriers to completing initial PK sampling within the 5-9 days post-delivery PK sampling window.
* At study entry, mother is planning to continue the current ARV regimen through at least 16 weeks post-delivery, based on maternal report and available medical records.
* At study entry, if receiving a generic ARV formulation of the drug or drug combination under study, approval of the formulation per study protocol.
* At study entry, infant weighs at least 1000 grams, based on available medical records.
* At study entry, infant does not have any severe congenital malformation or other medical condition not compatible with life or that would interfere with study participation or interpretation, as judged by the site investigator.

Components 1-4 Exclusion Criteria:

* At study entry, mother has received within the past 14 days medicines known to interfere with absorption, metabolism, or clearance of the drug or drug combination under study (see study protocol) based on maternal report and available medical records.

  * Note: RIF is permitted for mothers in Components 3 and 4 being evaluated for TB and ARV drug interactions.
* At study entry, has a clinical or laboratory finding or condition that, in the opinion of the site investigator, is likely to require a change of the ARV or TB drug under study during the period of study follow-up.
* Arms 1.3, 1.4 and 1.5 only: At study entry, mother has received TDF-based therapy within the past 6 months.

Component 5 Exclusion Criteria

* Mother is currently enrolled in Components 1, 2, 3, or 4.
* At study entry, the mother or infant has received within the past 14 days medicines known to interfere with absorption, metabolism, or clearance of the drug or drug combination under study based on maternal report and available medical records (see study protocol).
* At study entry, mother or infant has a clinical or laboratory finding or condition that, in the opinion of the site investigator, is likely to require a change of the drug under study during study follow-up.

Primary outcomes:
measure: Number of women who meet area under the curve (AUC) target in second trimester (2T)
timeFrame: Measured at 2T (20 0/7 weeks to 26 6/7 weeks of pregnancy)
measure: Number of women who meet area under the curve (AUC) target in third trimester (3T)
timeFrame: Measured at 3T (30 0/7 weeks to 37 6/7 weeks of pregnancy)
measure: Number of women who meet area under the curve (AUC) in postpartum (PP)
timeFrame: Measured at PP (6 to 12 weeks after delivery)
measure: Area under the curve (AUC) in second trimester (2T)
timeFrame: Measured at 2T (20 0/7 weeks to 26 6/7 weeks of pregnancy)
measure: Area under the curve (AUC) in third trimester (3T)
timeFrame: Measured at 3T (30 0/7 weeks to 37 6/7 weeks of pregnancy)
measure: Area under the curve (AUC) postpartum (PP)
timeFrame: Measured at PP (6 to 12 weeks after delivery)
measure: Tenofovir-diphosphate (TFV-DP) concentrations in peripheral blood mononuclear cells (PBMCs) and dried blood spots (DBS) in second trimester (2T)
timeFrame: Measured at 2T (20 0/7 weeks to 26 6/7 weeks of pregnancy)
measure: Tenofovir-diphosphate (TFV-DP) concentrations in peripheral blood mononuclear cells (PBMCs) and dried blood spots (DBS) in third trimester (3T)
timeFrame: Measured at 3T (30 0/7 weeks to 37 6/7 weeks of pregnancy)
measure: Tenofovir-diphosphate (TFV-DP) concentrations in peripheral blood mononuclear cells (PBMCs) and dried blood spots (DBS) postpartum (PP)
timeFrame: Measured at PP (6 to 12 weeks after delivery)
measure: Cord blood/maternal plasma concentration ratio at delivery
timeFrame: Measured on Day 0
measure: Infant washout half-life after delivery (if not breastfeeding)
timeFrame: Measured on Day 0
measure: Maternal breast milk/maternal plasma concentration ratio (if breast feeding)
timeFrame: Measured at Day 0
measure: Infant plasma concentration at breast milk PK visit (if breast feeding)
timeFrame: Measured through Week 5
measure: Area under the curve (AUC) at second trimester (2T)
timeFrame: Measured at 2T (20 0/7 weeks to 26 6/7 weeks of pregnancy)
measure: Area under the curve (AUC) at third trimester (3T)
timeFrame: Measured at 3T (30 0/7 weeks to 37 6/7 weeks of pregnancy)
measure: Area under the curve (AUC) postpartum (PP)
timeFrame: Measured at PP (6 to 12 weeks after delivery)
measure: Area under the curve (AUC) at second trimester (2T)
timeFrame: Measured at 2T (20 0/7 weeks to 26 6/7 weeks of pregnancy)
measure: Area under the curve (AUC) at third trimester (3T)
timeFrame: Measured at 3T (30 0/7 weeks to 37 6/7 weeks of pregnancy)
measure: Area under the curve (AUC) postpartum (PP)
timeFrame: Measured at PP (6 to 12 weeks after delivery)
measure: Maternal breast milk/maternal plasma concentration ratio
timeFrame: Measured through Week 24
measure: Infant plasma concentration
timeFrame: Measured through Week 24
Secondary outcomes:
measure: Ratio of cord blood concentration to maternal blood concentration
timeFrame: Measured at Day 0
measure: Infant washout half-life of drug after birth (if the infant is not breastfeeding, and if the half-life is estimable)
timeFrame: Measured through Day 9
measure: Maternal breast milk/maternal plasma concentration ratio
timeFrame: Measured through Week 24
measure: Infant plasma concentration
timeFrame: Measured through Week 24
measure: Efavirenz, lopinavir, atazanavir, darunavir, dolutegravir, and/or raltegravir: AUC at second trimester (2T), third trimester (3T), and postpartum (PP)
timeFrame: Measured at Measured at 2T (20 0/7 to 26 6/7 weeks of pregnancy), 3T (30 0/7 to 37 6/7 weeks or pregnancy, and PP (2-8 weeks after delivery)
measure: Frequency of grade 3 or higher maternal adverse events
timeFrame: Measured through Week 24
measure: Frequency of grade 2 or higher infant adverse events
timeFrame: Measured through Week 24
measure: Frequency of maternal and infant serious adverse events
timeFrame: Measured through Week 24
measure: Frequency of grade 3 or higher maternal adverse events assessed as related to the drug under study
timeFrame: Measured through Week 24
measure: Frequency of grade 2 or higher infant adverse events assessed as related to the drug under study
timeFrame: Measured through Week 24
measure: Pregnancy outcome: occurrence of live birth versus fetal loss/stillbirth.
timeFrame: Measured on Day 0
measure: Gestational age at birth
timeFrame: Measured on Day 0
measure: Birth weight
timeFrame: Measured on Day 0
measure: Occurrence of congenital anomaly
timeFrame: Measured from Day 0 through Week 24 for Components 1, 3, 4 and 5; measured from Day 0 through Week 5 for Component 2
measure: Occurrence of mitochondrial disorder
timeFrame: Measured from Day 0 through Week 24 for Components 1, 3, 4 and 5; measured from Day 0 through Week 5 for Component 2
measure: Number of infants with confirmed positive HIV nucleic acid test result
timeFrame: Measured from Day 0 through Week 24
measure: Maternal HIV-1 RNA
timeFrame: Measured at 2T (20 0/7 to 26 6/7 weeks of pregnancy), 3T (30 0/7 to 37 6/7 weeks or pregnancy, and PP (2-12 weeks after delivery)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Usc La Nichd Crs
state: California
city: Los Angeles
country: United States
facility: David Geffen School of Medicine at UCLA NICHD CRS
state: California
city: San Diego
country: United States
facility: University of California, UC San Diego CRS- Mother-Child-Adolescent HIV Program
state: California
city: Aurora
country: United States
facility: Univ. of Colorado Denver NICHD CRS
state: Colorado
city: Fort Lauderdale
country: United States
facility: South Florida CDTC Ft Lauderdale NICHD CRS
state: Florida
city: Jacksonville
country: United States
facility: University of Florida Jacksonville NICHD CRS
state: Florida
city: Miami
country: United States
facility: Pediatric Perinatal HIV NICHD CRS
state: Florida
city: Atlanta
country: United States
facility: Emory University School of Medicine NICHD CRS
state: Georgia
city: Chicago
country: United States
facility: Rush University Cook County Hospital Chicago NICHD CRS
state: Illinois
city: Chicago
country: United States
facility: Lurie Children's Hospital of Chicago (LCH) CRS (Site ID: 4001)
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins Univ. Baltimore NICHD CRS
state: Maryland
city: Bronx
country: United States
facility: Bronx-Lebanon Hospital Center NICHD CRS
state: New York
city: Bronx
country: United States
facility: Jacobi Med. Ctr. Bronx NICHD CRS
state: New York
city: Molepolole
country: Botswana
facility: Molepolole CRS (Site ID: 12702)
state: Kweneng District
city: Gaborone
country: Botswana
facility: Gaborone CRS (Site ID: 12701)
state: South-East District
city: Ribeirão Preto
country: Brazil
facility: Univ. of Sao Paulo Brazil NICHD CRS (Site ID: 5074)
state: São Paulo
city: Rio De Janeiro
country: Brazil
facility: Hospital Federal dos Servidores do Estado NICHD CRS
city: Rio De Janeiro
country: Brazil
facility: Hosp. Geral De Nova Igaucu Brazil NICHD CRS
city: Pune
country: India
facility: Byramjee Jeejeebhoy Medical College (BJMC) CRS
state: Maharashtra
city: Kericho
country: Kenya
facility: Kenya Medical Research Institute / Walter Reed Project Clinical Research Center, Kericho CRS
city: Lilongwe
country: Malawi
facility: Malawi CRS
city: San Juan
country: Puerto Rico
facility: IMPAACT/ Gamma Project/ UPR Pediatric HIV/AIDS Research CRS
city: Johannesburg
country: South Africa
facility: Wits RHI Shandukani Research
state: Gauteng
city: Cape Town
country: South Africa
facility: Desmond Tutu TB Centre - Stellenbosch University (DTTC-SU) CRS
city: Johannesburg
country: South Africa
facility: Sizwe CRS
city: Tygerberg Hills
country: South Africa
facility: Famcru Crs
city: Moshi
country: Tanzania
facility: Kilimanjaro Christian Medical Centre (KCMC) (Site ID: 5118)
city: Bangkok
country: Thailand
facility: Siriraj Hospital, Mahidol University NICHD CRS
state: Bangkoknoi
city: Kampala
country: Uganda
facility: Baylor-Uganda CRS
Study officials:
affiliation: Boston University
name: Mark Mirochnick, MD
role: STUDY_CHAIR
References: