DoraDO: Doravirine Dose Optimisation in Pregnancy
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 4 |
Detailed Description
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Delstrigo 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
Fixed dose combination of doravirine, lamivudine and tenofovir disoproxil
Other Names:
|
| Active Comparator: Standard of care 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
Fixed dose combination of dolutegravir, lamivudine and tenofovir disoproxil
Other Names:
|
Outcome Measures
Primary Outcome Measures
- AUC of doravirine in pregnant women [24 to 28 weeks gestation, 32 to 36 weeks gestation, 6 weeks postpartum]
Pharmacokinetic parameters of doravirine in pregnancy - AUC
- Cmax of doravirine in pregnant women [24 to 28 weeks gestation, 32 to 36 weeks gestation, 6 weeks postpartum]
Pharmacokinetic parameters of doravirine in pregnancy - Cmax
- Cmin of doravirine in pregnant women [24 to 28 weeks gestation, 32 to 36 weeks gestation, 6 weeks postpartum]
Pharmacokinetic parameters of doravirine in pregnancy - Cmin
- CL/F of doravirine in pregnant women [24 to 28 weeks gestation, 32 to 36 weeks gestation, 6 weeks postpartum]
Pharmacokinetic parameters of doravirine in pregnancy - CL/F
Secondary Outcome Measures
- To assess the number of treatment related adverse events by DAIDS v2.1 [Until study completion, a maximum of 13 months]
Safety and tolerability of doravirine in mothers and neonates
- To determine the concentration of doravirine in breastmilk, in breastfed infants, in genital tract, cord blood [24 to 28 weeks gestation, 32 to 36 weeks gestation, 6 weeks postpartum]
Pharmacokinetics of doravirine in various compartments
- To assess maternal viral load responses [Delivery and 6 months postpartum]
Viral load assessment
- To determine infant transmissions in the first 6 months of life using HIV viral load [Delivery until 6 months postpartum]
Assessment of perinatal transmission using HIV viral load
- To assess the prevalence or emergence of HIV drug resistance by determining HIV mutations [Until study completion, a maximum of 13 months]
Assessment of drug resistance tests
Other Outcome Measures
- Viral dynamics in the genital tract of mothers [Baseline and 32 to 36 weeks gestation]
Assessment of viral load in the genital tract
- PK in the genital tract of mothers [Baseline and 32 to 36 weeks gestation]
Assessment of drug concentrations in the genital tract
- PK of DOR in breastmilk, breastfed infants and in the genital tract [Delivery, 6 weeks postpartum and 24 weeks postpartum]
Assessment of drug concentrations in non-plasma compartments
- Prevalence or emergence of HIV drug resistance by determining HIV mutations [Baseline to 24 weeks postpartum]
Assessment of drug resistance tests
Eligibility Criteria
Criteria
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Desmond Tutu Health Foundation | Cape Town | South Africa |
Sponsors and Collaborators
- University of Liverpool
- Liverpool School of Tropical Medicine
- Desmond Tutu Health Foundation
Investigators
- Principal Investigator: Saye Khoo, University of Liverpool
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- UoL001707