Doravirine Dose Optimisation in Pregnancy

Study Overview
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Brief Summary
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A randomised, open label, controlled PK standard of care vs doravirine plus 2 nucleoside reverse transcriptase inhibitors backbone in pregnant women initiating combination antiretroviral therapy in the second trimester of pregnancy.

Detailed Description
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Women diagnosed HIV positive in the second trimester of pregnancy in South Africa will be enrolled and randomised 1:1 to receive standard of care or doravirine plus 2 NRTI backbone. Participants will receive study treatment until delivery and up to 28 weeks postpartum, with a maximum total of 14 months of study treatment. Given the high prevalence of NNRTI resistance, alternative ARV treatment options are essential. Doravirine is licenced for the treatment of HIV-1 in adults in North America and Europe. Whilst the efficacy and safety of doravirine has been established in non-pregnant adults, there are no adequate human data available to establish whether DOR poses a risk to pregnancy outcomes. It is important to have data on the safety and pharmacokinetics of the drug during pregnancy and in particularly the third trimester of pregnancy in order to support its use. The hypothesis for this study is that pregnancy influences the pharmacokinetics of doravirine when initiated in the second trimester.

Official Title
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Doravirine Dose Optimisation in Pregnancy

Conditions
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HIV

Intervention / Treatment
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* Drug: Doravirine
* Drug: Dolutegravir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women ≥ 18 years old Ability to give informed consent prior to participation Willing and able to comply with all study requirements HIV positive Pregnant (initiating cART ≥ 12 weeks and < 26 weeks gestation) Intention to breastfeed postpartum Exclusion Criteria: Received any cART in preceding 6 months Chronic hepatitis B (HBV) infection with clinical evidence of transaminitis Elevations in serum levels of alanine aminotransferase (ALT) > 5 times the upper limit of normal (ULN) or ALT > 3xULN and bilirubin >2xULN (with > 35 % direct bilirubin) Previous documented failure of an NNRTI-containing cART regimen Previous history of hypersensitivity to any ARV Concomitant medication which are inducers of SoC and DOR metabolism (e.g. rifampicin, anti-epileptic agents, rifabutin, St John's Wort, mitotane, enzalutamide, lumacaftor). Contraindicated medications can be found on Liverpool Drug Interactions website (hiv-druginteractions.org) Participants with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption cannot take DOR as the tablet contains lactose monohydrate Clinical depression or clinical judgment suggests increased risk of suicidality

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Delstrigo<br>doravirine/lamivudine/tenofovir disoproxil 100 mg/ 300 mg/ 245 mg film coated tablets, dosed 1 tablet once daily for the duration of the study | Drug: Doravirine<br>* Fixed dose combination of doravirine, lamivudine and tenofovir disoproxil<br>* Other names: Delstrigo;|
| Active Comparator: Standard of care<br>dolutegravir/lamivudine/tenofovir disoproxil 50 mg/300 mg/245 mg film coated tablets, dosed 1 tablet once daily for the duration of the study | Drug: Dolutegravir<br>* Fixed dose combination of dolutegravir, lamivudine and tenofovir disoproxil<br>* Other names: TLD;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC of doravirine in pregnant women | Pharmacokinetic parameters of doravirine in pregnancy - AUC | 24 to 28 weeks gestation, 32 to 36 weeks gestation, 6 weeks postpartum | 
| Cmax of doravirine in pregnant women | Pharmacokinetic parameters of doravirine in pregnancy - Cmax | 24 to 28 weeks gestation, 32 to 36 weeks gestation, 6 weeks postpartum | 
| Cmin of doravirine in pregnant women | Pharmacokinetic parameters of doravirine in pregnancy - Cmin | 24 to 28 weeks gestation, 32 to 36 weeks gestation, 6 weeks postpartum | 
| CL/F of doravirine in pregnant women | Pharmacokinetic parameters of doravirine in pregnancy - CL/F | 24 to 28 weeks gestation, 32 to 36 weeks gestation, 6 weeks postpartum | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the number of treatment related adverse events by DAIDS v2.1 | Safety and tolerability of doravirine in mothers and neonates | Until study completion, a maximum of 13 months | 
| To determine the concentration of doravirine in breastmilk, in breastfed infants, in genital tract, cord blood | Pharmacokinetics of doravirine in various compartments | 24 to 28 weeks gestation, 32 to 36 weeks gestation, 6 weeks postpartum | 
| To assess maternal viral load responses | Viral load assessment | Delivery and 6 months postpartum | 
| To determine infant transmissions in the first 6 months of life using HIV viral load | Assessment of perinatal transmission using HIV viral load | Delivery until 6 months postpartum | 
| To assess the prevalence or emergence of HIV drug resistance by determining HIV mutations | Assessment of drug resistance tests | Until study completion, a maximum of 13 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pregnancy