Clinical trial NCT03249181: Dolutegravir in Pregnant HIV Mothers and Their Neonates
Official title: Dolutegravir in Pregnant HIV Mothers and Their Neonates
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV-1-infection
Pregnancy Related
Keywords: MTCT
Antiretroviral
Pregnancy
Africa
Lead sponsor: University of Liverpool
Sponsor class: OTHER
Collaborators: name: UNITAID
name: University of Cape Town
name: Liverpool School of Tropical Medicine
name: Infectious Diseases Institute, Uganda
name: Radboud University Medical Center
First posted: 2017-08-15
Enrollment: 268
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: An open-label, multi-centre randomised controlled trial
Primary purpose: TREATMENT

Brief summary: To evaluate dolutegravir (DTG) efficacy in women who present with untreated HIV in late pregnancy.

An open-label, multi-centre randomised controlled trial of DTG vs efavirenz-based regimens for women commencing cART in late pregnancy. HIV positive pregnant women presenting with untreated HIV infection in late (≥28 weeks gestation) pregnancy will be randomised 1:1 to receive DTG (50mg once daily) + 2 nucleoside reverse transcriptase inhibitors (NRTIs) or EFV + 2 NRTIs (SoC)

Detailed description: This is an open-label, randomised controlled trial of DTG versus EFV -based regimens for 250 women commencing cART in late pregnancy, randomised 1:1 to DTG vs EFV-based cART. The purpose of this study is to inform treatment guidelines and for the first time specifically address the treatment needs of this group of women- hence the trial is powered for superiority over EFV. The primary endpoints is maternal VL at delivery, with secondary endpoints including safety and tolerability of DTG in both mother and infant, VL decline in breast milk, development of drug resistance, pharmacokinetics of DTG in mother-infant pairs, pharmacogenomics factors relating to efficacy or toxicity of DTG, and MTCT of HIV up to 72 weeks postpartum. Two sites have been selected - Infectious Diseases Institute, Makerere University, Kampala, Uganda and the University of Cape Town, South Africa - both have a strong track record of successfully delivering collaborative multidisciplinary research in PMTCT. Furthermore, health economics analysis to examine costs and cost-effectiveness of DTG in late-presenting pregnant women will be conducted

The desired outcome of this project is to establish high quality evidence and operational guidance for use of DTG in late pregnancy. Late-presenting HIV-infected pregnant women are an important, but neglected group of vulnerable individuals in whom a randomised controlled intervention of HIV treatment has never previously been undertaken. This work will be done in relationship with WHO and the Clinton Health Access Initiative to ensure successful delivery of the project objectives.

Eligibility criteria: Inclusion Criteria:

1. Evidence of a personally signed and dated informed consent document indicating that the participant has been informed of all pertinent aspects of the study.
2. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
3. Women aged 18 years or older
4. Pregnant ( ≥28 weeks gestation by best available gestation estimation)
5. Untreated HIV infection in late pregnancy

Exclusion Criteria:

1. Received any antiretroviral drugs in previous 12 months
2. Ever received integrase inhibitors
3. Previous documented failure of an NNRTI-containing ART regimen, previous EFV-associated toxicity or other history of ARV use that would preclude randomisation based on investigator judgement
4. Serum haemoglobin \<8.0 g/dl
5. eGFR\<50 ml/min\*
6. 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).
7. History or clinical suspicion of unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hyperbilirubinaemia, oesophageal or gastric varices or persistent jaundice).
8. Severe pre-eclampsia (e.g. HELLP), or other pregnancy related events such as renal or liver abnormalities (e.g. grade 2 or above proteinuria,, total bilirubin, ALT or AST)\* at the time of enrolment
9. Paternal objection for infant participation in DTG arm (where disclosure has taken - applies to Uganda site only
10. Medical, psychiatric or obstetric condition that might affect participation in the study based on investigator judgement
11. Receiving any of the following medications (current or within past 2 weeks): anti-epileptic drugs, TB therapy, or other drugs known to significantly interact with either DTG or EFV

Primary outcomes:
measure: HIV Viral Load at Delivery
timeFrame: by delivery
Secondary outcomes:
measure: Plasma viral load
timeFrame: By delivery
measure: Maternal viral load to 48 weeks
timeFrame: 48 weeks postpartum
measure: Maternal viral load to 72 weeks
timeFrame: 72 weeks postpartum
measure: Occurrence of MTCT
timeFrame: 48 weeks postpartum
measure: Occurrence of MTCT
timeFrame: 72 weeks postpartum
Other outcomes:
measure: Drug toxicities as defined by DAIDS criteria
timeFrame: Each study visit up to 72 weeks postpartum
measure: Drug toxicities as defined by DAIDS criteria
timeFrame: Each study visit up to 72 weeks postpartum
measure: Drug toxicities as defined by DAIDS criteria
timeFrame: Each study visit up to 72 weeks postpartum
measure: Drug toxicities as defined by DAIDS criteria
timeFrame: Each study visit up to 72 weeks postpartum
measure: Drug toxicities as defined by DAIDS criteria
timeFrame: Each study visit up to 72 weeks postpartum
measure: Drug toxicities as defined by DAIDS criteria
timeFrame: Each study visit up to 72 weeks postpartum
measure: Safety endpoint: Maternal mental health (Edinburgh Postnatal Depression Scale)
timeFrame: Enrolment, 4 weeks after ART initiation, every postnatal visit up to 72 weeks postpartum
measure: Safety endpoint: Maternal mental health (Hospital Anxiety and Depression Scale)
timeFrame: Enrolment, 4 weeks after ART initiation, every postnatal visit up to 72 weeks postpartum
measure: Safety of DTG in infant: Birth outcomes (Surface examination for anomalies)
timeFrame: At birth
measure: Safety of DTG in infant: Birth outcomes (Ballard Score for Maturity)
timeFrame: At birth
measure: Safety of DTG in infant: Birth outcomes (Weight)
timeFrame: At birth
measure: Safety of DTG in infant: Birth outcomes (Length)
timeFrame: At birth
measure: Safety of DTG in infant: Growth and development (Infant gross motor screening tool)
timeFrame: 24, 48 and 72 weeks postpartum
measure: Safety and tolerability of DTG exposure to infant: Maternal report (Safety questionnaire)
timeFrame: Delivery and all postnatal follow-up to 72 weeks
measure: Safety of DTG exposure to infant (Blood glucose)
timeFrame: Delivery and 6 weeks postpartum
measure: Safety of DTG exposure to infant
timeFrame: 6 weeks postpartum
measure: Safety of DTG exposure to infant
timeFrame: 6 weeks postpartum
measure: Safety of DTG exposure to infant
timeFrame: 6 weeks postpartum
Locations:
city: Cape Town
country: South Africa
facility: University of Cape Town
state: Western Cape
city: Kampala
country: Uganda
facility: Infectious Diseases Institute
Study officials:
affiliation: University of Liverpool
name: Saye H Khoo
role: STUDY_CHAIR
References:
citation: Malaba TR, Nakatudde I, Kintu K, Colbers A, Chen T, Reynolds H, Read L, Read J, Stemmet LA, Mrubata M, Byrne K, Seden K, Twimukye A, Theunissen H, Hodel EM, Chiong J, Hu NC, Burger D, Wang D, Byamugisha J, Alhassan Y, Bokako S, Waitt C, Taegtmeyer M, Orrell C, Lamorde M, Myer L, Khoo S; DolPHIN-2 Study Group. 72 weeks post-partum follow-up of dolutegravir versus efavirenz initiated in late pregnancy (DolPHIN-2): an open-label, randomised controlled study. Lancet HIV. 2022 Aug;9(8):e534-e543. doi: 10.1016/S2352-3018(22)00173-4.
citation: Ochanda PN, Lamorde M, Kintu K, Wang D, Chen T, Malaba T, Myer L, Waitt C, Reynolds H, Khoo S. A randomized comparison of health-related quality of life outcomes of dolutegravir versus efavirenz-based antiretroviral treatment initiated in the third trimester of pregnancy. AIDS Res Ther. 2022 Jun 7;19(1):24. doi: 10.1186/s12981-022-00446-3.
citation: Kintu K, Malaba TR, Nakibuka J, Papamichael C, Colbers A, Byrne K, Seden K, Hodel EM, Chen T, Twimukye A, Byamugisha J, Reynolds H, Watson V, Burger D, Wang D, Waitt C, Taegtmeyer M, Orrell C, Lamorde M, Myer L, Khoo S; DolPHIN-2 Study Group. Dolutegravir versus efavirenz in women starting HIV therapy in late pregnancy (DolPHIN-2): an open-label, randomised controlled trial. Lancet HIV. 2020 May;7(5):e332-e339. doi: 10.1016/S2352-3018(20)30050-3.