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Pharmacokinetic Properties of Antiretroviral and Anti-Tuberculosis Drugs During Pregnancy and Postpartum

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ClinicalTrials.gov Identifier: NCT04518228
Recruitment Status : Recruiting
First Posted : August 19, 2020
Last Update Posted : September 14, 2021
Sponsor:
Collaborators:
International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Institute of Mental Health (NIMH)
Gilead Sciences
ViiV Healthcare
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

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.

Condition or disease Intervention/treatment Phase
HIV Infections Tuberculosis Drug: Bictegravir (BIC) Drug: Tenofovir alafenamide (TAF) Drug: Cabotegravir (CAB) Drug: Dolutegravir (DTG) Drug: Atazanavir/ritonavir (ATV/r) Drug: Darunavir/ritonavir (DRV/r) Drug: Lopinavir/ritonavir (LPV/r) Drug: Cobicistat Drug: Ritonavir Drug: First-Line TB Treatment Drug: Second-Line TB Treatment Drug: Doravirine (DOR) Phase 4

Detailed Description:

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

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.

No ARVs or TB treatment drugs are supplied as part of this study. All drugs under study are provided by non-study sources.

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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 325 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pharmacokinetic Properties of Antiretroviral and Anti-Tuberculosis Drugs During Pregnancy and Postpartum
Actual Study Start Date : June 8, 2021
Estimated Primary Completion Date : October 15, 2025
Estimated Study Completion Date : October 15, 2025

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Component 1: Arm 1.1: Bictegravir (BIC) 50 mg q.d.
Women ≥ 20 weeks gestation not receiving TB drugs and receiving bictegravir (BIC) 50 mg once daily (q.d.), and their infants
Drug: Bictegravir (BIC)
Administered consistent with the package inserts and/or instructions provided by the non-study sources who prescribe or supply the drugs to participants

Experimental: Component 1: Arm 1.2: Doravirine (DOR) 100 mg q.d.
Women ≥ 20 weeks gestation not receiving TB drugs and receiving doravirine (DOR) 100 mg q.d., and their infants
Drug: Doravirine (DOR)
Administered consistent with the package inserts and/or instructions provided by the non-study sources who prescribe or supply the drugs to participants

Experimental: Component 1: Arm 1.3: Tenofovir alafenamide (TAF) 10 mg q.d.
Women ≥ 20 weeks gestation not receiving TB drugs and receiving tenofovir alafenamide (TAF) 10 mg q.d. boosted with cobicistat, and their infants
Drug: Tenofovir alafenamide (TAF)
Administered consistent with the package inserts and/or instructions provided by the non-study sources who prescribe or supply the drugs to participants

Drug: Cobicistat
Administered consistent with the package inserts and/or instructions provided by the non-study sources who prescribe or supply the drugs to participants

Experimental: Component 1: Arm 1.4: TAF 25 mg q.d. without boosting
Women ≥ 20 weeks gestation not receiving TB drugs and receiving TAF 25 mg q.d. without boosting, and their infants
Drug: Tenofovir alafenamide (TAF)
Administered consistent with the package inserts and/or instructions provided by the non-study sources who prescribe or supply the drugs to participants

Experimental: Component 1: Arm 1.5: TAF 25 mg q.d. with boosting
Women ≥ 20 weeks gestation not receiving TB drugs and receiving TAF 25 mg q.d. boosted with cobicistat or ritonavir, and their infants
Drug: Tenofovir alafenamide (TAF)
Administered consistent with the package inserts and/or instructions provided by the non-study sources who prescribe or supply the drugs to participants

Drug: Cobicistat
Administered consistent with the package inserts and/or instructions provided by the non-study sources who prescribe or supply the drugs to participants

Drug: Ritonavir
Administered consistent with the package inserts and/or instructions provided by the non-study sources who prescribe or supply the drugs to participants

Experimental: Component 2: Arm 2.1: CAB LA
Women ≥ 24 weeks gestation who received at least one dose of long-acting injectable formulation of cabotegravir (CAB LA) any dose during pregnancy, and their infants
Drug: Cabotegravir (CAB)
Administered consistent with the package inserts and/or instructions provided by the non-study sources who prescribe or supply the drugs to participants

Experimental: Component 3: Arm 3.1: Dolutegravir (DTG) 50 mg
Women ≥ 20 weeks gestation receiving first-line TB treatment with at least two of the following TB treatment drugs: isoniazid (INH), rifampin (RIF), rifabutin (RFB), ethambutol (EMB), pyrazinamide (PZA), moxifloxacin (MFX), and receiving dolutegravir (DTG) 50 mg twice daily (b.i.d.) when combined with RIF or 50 mg q.d. if RIF is not part of the TB regimen, and their infants
Drug: Dolutegravir (DTG)
Administered consistent with the package inserts and/or instructions provided by the non-study sources who prescribe or supply the drugs to participants

Drug: First-Line TB Treatment

Participants will be receiving first-line TB treatment with at least two of the following TB treatment drugs: isoniazid (INH), rifampin (RIF), rifabutin (RFB), ethambutol (EMB), pyrazinamide (PZA), or moxifloxacin (MFX).

Drugs will be administered consistent with the package inserts and/or instructions provided by the non-study sources who prescribe or supply the drugs to participants.


Experimental: Component 3: Arm 3.2: ATV/r or DRV/r
Women ≥ 20 weeks gestation receiving first-line TB treatment with at least two of the following TB treatment drugs: isoniazid (INH), rifampin (RIF), rifabutin (RFB), ethambutol (EMB), pyrazinamide (PZA), moxifloxacin (MFX), and receiving atazanavir/ritonavir (ATV/r) ≥ 300/100 mg q.d. or darunavir/ritonavir (DRV/r) ≥ 600/100 mg b.i.d., and their infants
Drug: Atazanavir/ritonavir (ATV/r)
Administered consistent with the package inserts and/or instructions provided by the non-study sources who prescribe or supply the drugs to participants

Drug: Darunavir/ritonavir (DRV/r)
Administered consistent with the package inserts and/or instructions provided by the non-study sources who prescribe or supply the drugs to participants

Drug: First-Line TB Treatment

Participants will be receiving first-line TB treatment with at least two of the following TB treatment drugs: isoniazid (INH), rifampin (RIF), rifabutin (RFB), ethambutol (EMB), pyrazinamide (PZA), or moxifloxacin (MFX).

Drugs will be administered consistent with the package inserts and/or instructions provided by the non-study sources who prescribe or supply the drugs to participants.


Experimental: Component 3: Arm 3.3: Lopinavir/ritonavir (LPV/r) 800/200 mg
Women ≥ 20 weeks gestation receiving first-line TB treatment with at least two of the following TB treatment drugs: isoniazid (INH), rifampin (RIF), rifabutin (RFB), ethambutol (EMB), pyrazinamide (PZA), moxifloxacin (MFX), and receiving lopinavir/ritonavir (LPV/r) 800/200 mg b.i.d., and their infants
Drug: Lopinavir/ritonavir (LPV/r)
Administered consistent with the package inserts and/or instructions provided by the non-study sources who prescribe or supply the drugs to participants

Drug: First-Line TB Treatment

Participants will be receiving first-line TB treatment with at least two of the following TB treatment drugs: isoniazid (INH), rifampin (RIF), rifabutin (RFB), ethambutol (EMB), pyrazinamide (PZA), or moxifloxacin (MFX).

Drugs will be administered consistent with the package inserts and/or instructions provided by the non-study sources who prescribe or supply the drugs to participants.


Experimental: Component 4: Arm 4.1: Second-line TB treatment drugs

Women ≥ 20 weeks gestation receiving at least one of the following second-line TB treatment drugs, and their infants:

  • Levofloxacin (LFX) 750mg - 1000mg q.d.
  • Clofazimine (CFZ) 100mg q.d.
  • Linezolid (LZD) 300mg - 600mg q.d.
  • Bedaquiline (BDQ) 200mg three times per week (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
Drug: Second-Line TB Treatment

Participants will be receiving second-line TB treatment with at least one of the following 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 three times per week (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

Drugs will be administered consistent with the package inserts and/or instructions provided by the non-study sources who prescribe or supply the drugs to participants.


Experimental: Component 5: Arm 5.1: ATV/r
Women post-delivery receiving ATV/r, and their infants
Drug: Atazanavir/ritonavir (ATV/r)
Administered consistent with the package inserts and/or instructions provided by the non-study sources who prescribe or supply the drugs to participants

Experimental: Component 5: Arm 5.2: DRV/r
Women post-delivery receiving DRV/r, and their infants
Drug: Darunavir/ritonavir (DRV/r)
Administered consistent with the package inserts and/or instructions provided by the non-study sources who prescribe or supply the drugs to participants

Experimental: Component 5: Arm 5.3: LPV/r
Women post-delivery receiving LPV/r, and their infants
Drug: Lopinavir/ritonavir (LPV/r)
Administered consistent with the package inserts and/or instructions provided by the non-study sources who prescribe or supply the drugs to participants




Primary Outcome Measures :
  1. Number of women who meet area under the curve (AUC) target in second trimester (2T) [ Time Frame: Measured at 2T (20 0/7 weeks to 26 6/7 weeks of pregnancy) ]
    For Arms 1.1, and 1.2: BIC, DOR only

  2. Number of women who meet area under the curve (AUC) target in third trimester (3T) [ Time Frame: Measured at 3T (30 0/7 weeks to 37 6/7 weeks of pregnancy) ]
    For Arms 1.1, and 1.2: BIC, DOR only

  3. Number of women who meet area under the curve (AUC) in postpartum (PP) [ Time Frame: Measured at PP (6 to 12 weeks after delivery) ]
    For Arms 1.1, and 1.2: BIC, DOR only

  4. Area under the curve (AUC) in second trimester (2T) [ Time Frame: Measured at 2T (20 0/7 weeks to 26 6/7 weeks of pregnancy) ]
    For Arms 1.1, and 1.2: BIC, DOR only

  5. Area under the curve (AUC) in third trimester (3T) [ Time Frame: Measured at 3T (30 0/7 weeks to 37 6/7 weeks of pregnancy) ]
    For Arms 1.1, and 1.2: BIC, DOR only

  6. Area under the curve (AUC) postpartum (PP) [ Time Frame: Measured at PP (6 to 12 weeks after delivery) ]
    For Arms 1.1, and 1.2: BIC, DOR only

  7. Tenofovir-diphosphate (TFV-DP) concentrations in peripheral blood mononuclear cells (PBMCs) and dried blood spots (DBS) in second trimester (2T) [ Time Frame: Measured at 2T (20 0/7 weeks to 26 6/7 weeks of pregnancy) ]
    For Arms 1.3, 1.4, and 1.5 only

  8. Tenofovir-diphosphate (TFV-DP) concentrations in peripheral blood mononuclear cells (PBMCs) and dried blood spots (DBS) in third trimester (3T) [ Time Frame: Measured at 3T (30 0/7 weeks to 37 6/7 weeks of pregnancy) ]
    For Arms 1.3, 1.4, and 1.5 only

  9. Tenofovir-diphosphate (TFV-DP) concentrations in peripheral blood mononuclear cells (PBMCs) and dried blood spots (DBS) postpartum (PP) [ Time Frame: Measured at PP (6 to 12 weeks after delivery) ]
    For Arms 1.3, 1.4, and 1.5 only

  10. Cord blood/maternal plasma concentration ratio at delivery [ Time Frame: Measured on Day 0 ]
    For Arm 2.1.: CAB only

  11. Infant washout half-life after delivery (if not breastfeeding) [ Time Frame: Measured on Day 0 ]
    For Arm 2.1: CAB only

  12. Maternal breast milk/maternal plasma concentration ratio (if breast feeding) [ Time Frame: Measured at Day 0 ]
    For Arm 2.1: CAB only

  13. Infant plasma concentration at breast milk PK visit (if breast feeding) [ Time Frame: Measured through Week 5 ]
    For Arm 2.1: CAB only

  14. Area under the curve (AUC) at second trimester (2T) [ Time Frame: Measured at 2T (20 0/7 weeks to 26 6/7 weeks of pregnancy) ]
    For Arms 3.1, 3.2 and 3.3 only

  15. Area under the curve (AUC) at third trimester (3T) [ Time Frame: Measured at 3T (30 0/7 weeks to 37 6/7 weeks of pregnancy) ]
    For Arms 3.1, 3.2 and 3.3 only

  16. Area under the curve (AUC) postpartum (PP) [ Time Frame: Measured at PP (6 to 12 weeks after delivery) ]
    For Arms 3.1, 3.2 and 3.3 only

  17. Area under the curve (AUC) at second trimester (2T) [ Time Frame: Measured at 2T (20 0/7 weeks to 26 6/7 weeks of pregnancy) ]
    For Arm 4.1 only

  18. Area under the curve (AUC) at third trimester (3T) [ Time Frame: Measured at 3T (30 0/7 weeks to 37 6/7 weeks of pregnancy) ]
    For Arm 4.1 only

  19. Area under the curve (AUC) postpartum (PP) [ Time Frame: Measured at PP (6 to 12 weeks after delivery) ]
    For Arm 4.1 only

  20. Maternal breast milk/maternal plasma concentration ratio [ Time Frame: Measured through Week 24 ]
    For Arms 5.1, 5.2, and 5.3 only

  21. Infant plasma concentration [ Time Frame: Measured through Week 24 ]
    For Arms 5.1, 5.2, and 5.3 only


Secondary Outcome Measures :
  1. Ratio of cord blood concentration to maternal blood concentration [ Time Frame: Measured at Day 0 ]
    For Components 1, 3 and 4, all Arms

  2. Infant washout half-life of drug after birth (if the infant is not breastfeeding, and if the half-life is estimable) [ Time Frame: Measured through Day 9 ]
    For Components 1, 3 and 4, all Arms

  3. Maternal breast milk/maternal plasma concentration ratio [ Time Frame: Measured through Week 24 ]
    For Components 3 and 4, if assessed

  4. Infant plasma concentration [ Time Frame: Measured through Week 24 ]
    For Components 3 and 4, if assessed

  5. Efavirenz, lopinavir, atazanavir, darunavir, dolutegravir, and/or raltegravir: AUC at second trimester (2T), third trimester (3T), and postpartum (PP) [ Time Frame: 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) ]
    For Component 4 only

  6. Frequency of grade 3 or higher maternal adverse events [ Time Frame: Measured through Week 24 ]
    Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017

  7. Frequency of grade 2 or higher infant adverse events [ Time Frame: Measured through Week 24 ]
    Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017

  8. Frequency of maternal and infant serious adverse events [ Time Frame: Measured through Week 24 ]
    Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017

  9. Frequency of grade 3 or higher maternal adverse events assessed as related to the drug under study [ Time Frame: Measured through Week 24 ]
    Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017

  10. Frequency of grade 2 or higher infant adverse events assessed as related to the drug under study [ Time Frame: Measured through Week 24 ]
    Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017

  11. Pregnancy outcome: occurrence of live birth versus fetal loss/stillbirth. [ Time Frame: Measured on Day 0 ]
  12. Gestational age at birth [ Time Frame: Measured on Day 0 ]
  13. Birth weight [ Time Frame: Measured on Day 0 ]
  14. Occurrence of congenital anomaly [ Time Frame: Measured from Day 0 through Week 24 for Components 1, 3, 4 and 5; measured from Day 0 through Week 5 for Component 2 ]
  15. Occurrence of mitochondrial disorder [ Time Frame: Measured from Day 0 through Week 24 for Components 1, 3, 4 and 5; measured from Day 0 through Week 5 for Component 2 ]
  16. Number of infants with confirmed positive HIV nucleic acid test result [ Time Frame: Measured from Day 0 through Week 24 ]
    Determined according to diagnosis per local standard of care

  17. Maternal HIV-1 RNA [ Time Frame: 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) ]


Information from the National Library of Medicine

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Layout table for eligibility information
Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04518228


Locations
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United States, Florida
University of Florida Jacksonville NICHD CRS Recruiting
Jacksonville, Florida, United States, 32209
Contact: Saniyyah Mahmoudi, A.R.N.P.    904-244-2896    saniyyah.mahmoudi@jax.ufl.edu   
Pediatric Perinatal HIV NICHD CRS Not yet recruiting
Miami, Florida, United States, 33136
Contact: Grace Alvarez, M.P.H., CCRP    305-243-4447    galvarez2@miami.edu   
United States, Illinois
Lurie Children's Hospital of Chicago (LCH) CRS (Site ID: 4001) Not yet recruiting
Chicago, Illinois, United States, 60614
Contact: Margaret A Sanders, M.P.H.    312-227-8275    msanders@luriechildrens.org   
South Africa
Wits RHI Shandukani Research Recruiting
Johannesburg, Gauteng, South Africa, 2001
Contact: Hermien Gous, Pharm. D.    27-11-3585500 ext 5502    hgous@wrhi.ac.za   
Sizwe CRS Not yet recruiting
Johannesburg, South Africa, 2131
Contact: Linah Baloyi    27-11-8823912    lbaloyi@witshealth.co.za   
Zimbabwe
Seke North CRS (Site ID: 30306) Not yet recruiting
Seke North, Chitungwiza, Zimbabwe
Contact: Teacler G Nematadzira, MBChB    263-772288155    tnematadzira@uz-ctrc.org   
St Mary's CRS (Site ID: 30303) Not yet recruiting
St. Mary's, Chitungwiza, Zimbabwe
Contact: Suzen Maonera, M.Sc., B.Sc., R.N.    263-772-288160    smaonera@uz-ctrc.org   
Harare Family Care CRS (Site ID: 31890) Not yet recruiting
Harare, Zimbabwe
Contact: Sukunena J Maturure, RGN    263-712437682    smaturure@uzchs-ctrc.org   
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Institute of Mental Health (NIMH)
Gilead Sciences
ViiV Healthcare
Merck Sharp & Dohme Corp.
Investigators
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Study Chair: Mark Mirochnick, MD Boston University
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Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT04518228    
Other Study ID Numbers: IMPAACT 2026
38609 ( Registry Identifier: DAIDS-ES Registry Number )
First Posted: August 19, 2020    Key Record Dates
Last Update Posted: September 14, 2021
Last Verified: September 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individual participant data that underlie results in the publication, after deidentification.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame: Beginning 3 months following publication and available throughout period of funding of the International Maternal Pediatric Adolescent AIDS Clinical Trial (IMPAACT) Network by NIH.
Access Criteria:
  • With whom?

    • Researchers who provide a methodologically sound proposal for use of the data that is approved by the IMPAACT Network.
  • For what types of analyses?

    • To achieve aims in the proposal approved by the IMPAACT Network.
  • By what mechanism will data be made available?

    • Researchers may submit a request for access to data using the IMPAACT "Data Request" form at: https://www.impaactnetwork.org/resources/study-proposals.htm. Researchers of approved proposals will need to sign an IMPAACT Data Use Agreement before receiving the data

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Tuberculosis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Ritonavir
Lopinavir
Atazanavir Sulfate
Darunavir
Tenofovir
Dolutegravir
Cobicistat
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
HIV Integrase Inhibitors
Integrase Inhibitors