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Safety and Pharmacokinetics of Dolutegravir in Pregnant HIV Mothers and Their Neonates: A Pilot Study (DolPHIN1)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02245022
Recruitment Status : Active, not recruiting
First Posted : September 19, 2014
Last Update Posted : October 10, 2018
Sponsor:
Collaborators:
ViiV Healthcare
Makerere University
Information provided by (Responsible Party):
Catriona Waitt, University of Liverpool

Brief Summary:

Aim: To evaluate dolutegravir (DTG) pharmacokinetics in pregnant HIV-infected women

Rationale: In developing countries many women present with a new HIV diagnosis in late pregnancy, and are at high risk of transmitting infection during delivery. Moreover, women may acquire NNRTI resistance from primary transmission, or use of nevirapine (NVP) in previous pregnancies. In these circumstances, DTG is likely to be more effective in reducing mother to child transmission of HIV than NNRTI-based regimens.

Study design: HIV positive pregnant women presenting with untreated HIV infection in late (≥28 -36 weeks gestation) pregnancy will be randomised 1:1 to receive DTG (50mg once daily) or standard of care (nevirapine or efavirenz) + 2 NRTIs. PK (0-24h) profile will be sampled in third trimester and post-partum.

Although this is primarily a PK study (and has been powered as such) randomisation is included to allow comparison of plasma HIV VL responses against standard of care (NVP or EFV) and is essential for evaluation of secondary endpoints of safety and efficacy of DTG in pregnancy.

Number recruited N=30 per group


Condition or disease Intervention/treatment Phase
HIV Pregnancy Drug: Dolutegravir 50mg od Drug: Standard of Care Phase 2 Phase 3

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Safety and Pharmacokinetics of Dolutegravir in Pregnant HIV Mothers and Their Neonates: A Pilot Study
Actual Study Start Date : March 14, 2017
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : December 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
Experimental: Dolutegravir 50mg od
30 patients who will receive dolutegravir 50mg once daily plus the same NRTI backbone as the active comparator group (lamivudine and tenofovir)
Drug: Dolutegravir 50mg od
Patients randomised to receive either Dolutegravir 50mg od or standard of care (Efavirenz 600mg od) plus Lamivudine 300mg od/ Tenofovir 300mg od
Other Names:
  • Tivicay (ViiV Healthcare)
  • GSK1349572

Active Comparator: Standard of Care
Patients randomised to receive antiretroviral therapy as per Uganda national guidelines (Efavirenz 600mg od based plus Tenofovir 300mg od and Lamivudine 300mg od)
Drug: Standard of Care
Patients are randomised 1:1 to receive either Dolutegravir 50mg once daily in combination with Lamivudine 300mg od and tenofovir 300mg od or standard of care (Efavirenz 600mg plus Lamivudine 300mg od and tenofovir 300mg od)
Other Names:
  • Efavirenz 600mg od
  • Lamivudine 300mg od
  • Tenofovir 300mg od




Primary Outcome Measures :
  1. AUC0-24 of DTG in pregnant women in third trimester and 2 weeks postpartum [ Time Frame: In 3rd trimester and 2 weeks postpartum ]
    Rich PK with sampling at t0, 1, 2, 4, 6, 8 and 24 hours relative to drug dose


Secondary Outcome Measures :
  1. Safety and tolerability of DTG [ Time Frame: Up to 6 months postpartum ]
    Safety questionnaires at every scheduled and unscheduled study visit Infant safety questionnaires at all post-partum visits Self-reporting

  2. Proportion of women in each arm with VL < 50 copies/mL, and <400 copies/mL at delivery [ Time Frame: At delivery ]
    HIV viral load will be measured at enrollment into the study and at delivery

  3. Change in viral load over the first 4 weeks of therapy [ Time Frame: 4 weeks after treatment started ]
    HIV viral load will be measured at enrollment and after 4 weeks of antiretroviral therapy

  4. Cord:maternal plasma DTG ratio [ Time Frame: At delivery ]
    A maternal blood sample and a cord blood sample will be taken at delivery to calculate the transplacental transfer of Dolutegravir

  5. Maternal plasma: breastmilk DTG ratio [ Time Frame: At 2 weeks postpartum, and after 1, 2 and 3 days after transfer back to standard of care medications ]
    At the timepoints indicated, a single maternal blood sample and a sample of breast milk will be taken to measure Dolutegravir levels in both matrices and allow estimation of transmammary drug exposure

  6. Infant DTG levels [ Time Frame: At maternal steady state (2 weeks postpartum) and at 1, 2 and 3 days after transfer to standard of care ]
    Infants from the Dolutegravir arm (N=30) will be randomised 1:1:1 to return for PK sampling 1, 2 or 3 days after the mother has discontinued Dolutegravir and changed to Standard of Care treatment. All infants will have a single capillary blood sample (heel prick) taken at 2 weeks postpartum, and then at the time point they have been randomised to.

  7. Incidence and severity of adverse events and laboratory abnormalities [ Time Frame: Up to 3 days after change to standard of care ]
    Laboratory test measured routinely up until 3 days after change to standard of care. In addition, patients will remain under follow-up until 6 months postpartum, and laboratory tests will be performed if clinically indicated at any point. The routinely measured 'safety bloods' in this study are Full Blood Count, Urea and Electrolytes including eGFR, Liver Function Tests including Alanine Aminotransferase and Bilirubin

  8. Absolute values and changes over time in laboratory parameters [ Time Frame: Until 3 days after change back to standard of care ]
    Laboratory tests will be performed routinely until 3 days after change to standard of care regime, but the study will continue to follow the women until 6 months postpartum. Lab tests will be performed if clinically indicated at any time point

  9. Proportion of subjects who discontinue treatment due to adverse events [ Time Frame: Until 2 weeks postpartum ]
    Mothers will be switched to standard of care at 2 weeks postpartum

  10. Proportion of mother to child transmission of HIV [ Time Frame: 6 months postpartum ]
    Infant HIV testing by PCR will be undertaken at six weeks and six months of age, as per Uganda National Policy

  11. Pharmacogenomic factors affecting DTG PK in pregnancy and transfer to infant via placenta or breastmilk [ Time Frame: Single 5ml sample at rich PK visit ]
    Blood sample for genomic testing will be taken at the same time as the rich PK sampling, either in the third trimester or at 2 weeks postpartum. A panel of known SNPs for the major drug metabolising enzymes known to alter the pharmacokinetics of efavirenz, lamivudine and tenofovir will be analysed (primarily SNPs affecting CYP2B6)



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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:

  • Able to provide informed consent
  • Willing to participate,
  • Women age 18 years and above
  • Pregnant
  • Untreated HIV infection in late pregnancy at ≥28 - 36 weeks gestation

Exclusion Criteria:

  • Received antiretroviral drugs in previous 6 months
  • Ever received integrase inhibitors
  • Serum haemoglobin < 8.0 g/dl
  • 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)
  • eGFR < 50ml/min
  • Active Hepatitis B infection, history or clinical suspicion of unstable liver disease, or subjects with severe liver disease (Class C by Childs-Hugh criteria)
  • Severe pre-eclampsia (e.g. HELLP), or other pregnancy related events such as renal or liver abnormalities (e.g. grade 2 or above proteinuria, elevation in serum creatinine (above 2.5 x ULN), total bilirubin ALT or AST)
  • Paternal non-consent (where disclosure to male partner has been made)
  • Clinical depression or clinical judgement suggests increased risk of suicidality

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02245022


Locations
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South Africa
Desmond Tutu HIV Foundation
Cape Town, Western Cape, South Africa
Uganda
Infectious Diseases Institute
Kampala, Uganda
Sponsors and Collaborators
University of Liverpool
ViiV Healthcare
Makerere University
Investigators
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Principal Investigator: Saye H Khoo, PhD, MBChB University of Liverpool
Principal Investigator: Mohammed Lamorde, PhD, MBChB Infectious Diseases Institute, Makerere University

Additional Information:
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Responsible Party: Catriona Waitt, Site sub-investigator, University of Liverpool
ClinicalTrials.gov Identifier: NCT02245022     History of Changes
Other Study ID Numbers: PK12
First Posted: September 19, 2014    Key Record Dates
Last Update Posted: October 10, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
HIV
Prevention of mother to child transmission
Africa
Uganda
Pharmacokinetics
Pregnancy
Breastfeeding

Additional relevant MeSH terms:
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Tenofovir
Lamivudine
Efavirenz
Dolutegravir
Antiviral Agents
Anti-Infective Agents
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Retroviral Agents
Anti-HIV Agents
Cytochrome P-450 CYP2C9 Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Cytochrome P-450 CYP2C19 Inhibitors
Cytochrome P-450 CYP2B6 Inducers
Cytochrome P-450 Enzyme Inducers
Cytochrome P-450 CYP3A Inducers
HIV Integrase Inhibitors
Integrase Inhibitors