Clinical trial NCT05630638: Doravirine Dose Optimisation in Pregnancy
Official title: Doravirine Dose Optimisation in Pregnancy
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: HIV
Keywords: Pregnancy
Lead sponsor: University of Liverpool
Sponsor class: OTHER
Collaborators: name: Liverpool School of Tropical Medicine
name: Desmond Tutu Health Foundation
First posted: 2022-11-29
Enrollment: 76
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: AUC of doravirine in pregnant women
timeFrame: 24 to 28 weeks gestation, 32 to 36 weeks gestation, 6 weeks postpartum
measure: Cmax of doravirine in pregnant women
timeFrame: 24 to 28 weeks gestation, 32 to 36 weeks gestation, 6 weeks postpartum
measure: Cmin of doravirine in pregnant women
timeFrame: 24 to 28 weeks gestation, 32 to 36 weeks gestation, 6 weeks postpartum
measure: CL/F of doravirine in pregnant women
timeFrame: 24 to 28 weeks gestation, 32 to 36 weeks gestation, 6 weeks postpartum
Secondary outcomes:
measure: To assess the number of treatment related adverse events by DAIDS v2.1
timeFrame: Until study completion, a maximum of 13 months
measure: To determine the concentration of doravirine in breastmilk, in breastfed infants, in genital tract, cord blood
timeFrame: 24 to 28 weeks gestation, 32 to 36 weeks gestation, 6 weeks postpartum
measure: To assess maternal viral load responses
timeFrame: Delivery and 6 months postpartum
measure: To determine infant transmissions in the first 6 months of life using HIV viral load
timeFrame: Delivery until 6 months postpartum
measure: To assess the prevalence or emergence of HIV drug resistance by determining HIV mutations
timeFrame: Until study completion, a maximum of 13 months
Other outcomes:
measure: Viral dynamics in the genital tract of mothers
timeFrame: Baseline and 32 to 36 weeks gestation
measure: PK in the genital tract of mothers
timeFrame: Baseline and 32 to 36 weeks gestation
measure: PK of DOR in breastmilk, breastfed infants and in the genital tract
timeFrame: Delivery, 6 weeks postpartum and 24 weeks postpartum
measure: Prevalence or emergence of HIV drug resistance by determining HIV mutations
timeFrame: Baseline to 24 weeks postpartum
Locations:
city: Cape Town
country: South Africa
facility: Desmond Tutu Health Foundation
Study officials:
affiliation: University of Liverpool
name: Saye Khoo
role: PRINCIPAL_INVESTIGATOR
References: