Dolutegravir in Pregnant HIV Mothers and Their Neonates (DolPHIN-2)

Study Description

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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)

Condition or disease	Intervention/treatment	Phase
HIV-1-infection; Pregnancy Related	Drug: Dolutegravir; Drug: Standard of Care (EFV + 2 NRTI backbone)	Phase 3

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	250 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Intervention Model Description:	An open-label, multi-centre randomised controlled trial
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Dolutegravir in Pregnant HIV Mothers and Their Neonates
Actual Study Start Date :	January 22, 2018
Estimated Primary Completion Date :	September 2020
Estimated Study Completion Date :	March 2021

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Dolutegravir; Dolutegravir group (DTG+2 NRTIs) - to make best comparison with standard of care, these NRTIs should be those recommended by national policy. Participants randomized to the study drug will be commenced on an antiretroviral regimen comprising DTG 50mg once daily in combination with 2 NRTIs	Drug: Dolutegravir; Patients randomized to the study drug will be commenced on an antiretroviral regimen comprising DTG 50mg once daily in combination with 2 NRTIs
Active Comparator: Standard of Care (EFV + 2 NRTI backbone); Participants randomized to receive standard of care will receive the currently used antiretroviral regimens in keeping with national policy (EFV + 2NRTIs at both study sites).	Drug: Standard of Care (EFV + 2 NRTI backbone); Patients randomized to receive standard of care will receive the currently used antiretroviral regimens in keeping with national policy.

Outcome Measures

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Primary Outcome Measures :

1. HIV Viral Load at Delivery [ Time Frame: by delivery ]
   <50 copies/ mL

Secondary Outcome Measures :

1. Plasma viral load [ Time Frame: By delivery ]
   <1000 copies/ mL
2. Maternal viral load to 48 weeks [ Time Frame: 48 weeks postpartum ]
   Proportion <50 and <1000 copies/ mL
3. Maternal viral load to 72 weeks [ Time Frame: 72 weeks postpartum ]
   Proportion <50 and <1000 copies/ mL
4. Occurrence of MTCT [ Time Frame: 48 weeks postpartum ]
   Proportion of infants with HIV infection
5. Occurrence of MTCT [ Time Frame: 72 weeks postpartum ]
   Proportion of infants with HIV infection

Other Outcome Measures:

1. Drug toxicities as defined by DAIDS criteria [ Time Frame: Each study visit up to 72 weeks postpartum ]
   Safety questionnaire
2. Drug toxicities as defined by DAIDS criteria [ Time Frame: Each study visit up to 72 weeks postpartum ]
   CBC
3. Drug toxicities as defined by DAIDS criteria [ Time Frame: Each study visit up to 72 weeks postpartum ]
   Serum creatinine (mg/dL)
4. Drug toxicities as defined by DAIDS criteria [ Time Frame: Each study visit up to 72 weeks postpartum ]
   ALT (U/mL)
5. Drug toxicities as defined by DAIDS criteria [ Time Frame: Each study visit up to 72 weeks postpartum ]
   Blood urea nitrogen (mg/dL)
6. Drug toxicities as defined by DAIDS criteria [ Time Frame: Each study visit up to 72 weeks postpartum ]
   Creatine phosphokinase (U/mL)
7. Safety endpoint: Maternal mental health (Edinburgh Postnatal Depression Scale) [ Time Frame: Enrolment, 4 weeks after ART initiation, every postnatal visit up to 72 weeks postpartum ]
   Edinburgh Postnatal Depression Scale
8. Safety endpoint: Maternal mental health (Hospital Anxiety and Depression Scale) [ Time Frame: Enrolment, 4 weeks after ART initiation, every postnatal visit up to 72 weeks postpartum ]
   Hospital Anxiety and Depression Scale
9. Safety of DTG in infant: Birth outcomes (Surface examination for anomalies) [ Time Frame: At birth ]
   Surface examination for anomalies
10. Safety of DTG in infant: Birth outcomes (Ballard Score for Maturity) [ Time Frame: At birth ]
    Ballard Score for Maturity
11. Safety of DTG in infant: Birth outcomes (Weight) [ Time Frame: At birth ]
    Weight
12. Safety of DTG in infant: Birth outcomes (Length) [ Time Frame: At birth ]
    Length
13. Safety of DTG in infant: Growth and development (Infant gross motor screening tool) [ Time Frame: 24, 48 and 72 weeks postpartum ]
    Infant gross motor screening tool
14. Safety and tolerability of DTG exposure to infant: Maternal report (Safety questionnaire) [ Time Frame: Delivery and all postnatal follow-up to 72 weeks ]
    Safety questionnaire
15. Safety of DTG exposure to infant (Blood glucose) [ Time Frame: Delivery and 6 weeks postpartum ]
    Blood glucose
16. Safety of DTG exposure to infant [ Time Frame: 6 weeks postpartum ]
    ALT (U/mL)
17. Safety of DTG exposure to infant [ Time Frame: 6 weeks postpartum ]
    Blood urea nitrogen (mg/dL)
18. Safety of DTG exposure to infant [ Time Frame: 6 weeks postpartum ]
    Serum creatinine (mg/dL)

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	Female
Accepts Healthy Volunteers:	No

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

Contacts and Locations

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Locations

South Africa
University of Cape Town
Cape Town, Western Cape, South Africa
Uganda
Infectious Diseases Institute
Kampala, Uganda

Sponsors and Collaborators

University of Liverpool

UNITAID

University of Cape Town

Liverpool School of Tropical Medicine

Infectious Diseases Institute, Uganda

Radboud University

Investigators

Study Chair:	Saye H Khoo	University of Liverpool

More Information

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Responsible Party:	Catriona Waitt, Senior Lecturer in Pharmacology, University of Liverpool
ClinicalTrials.gov Identifier:	NCT03249181 History of Changes
Other Study ID Numbers:	DolPHIN-2
First Posted:	August 15, 2017
Last Update Posted:	September 26, 2018
Last Verified:	September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Studies a U.S. FDA-regulated Drug Product:		No
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by Catriona Waitt, University of Liverpool:

MTCT; Antiretroviral; Pregnancy; Africa

Additional relevant MeSH terms:

Dolutegravir; HIV Integrase Inhibitors; Integrase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action	Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Anti-Infective Agents