Pan African Clinical Trials Registry
South African Medical Research Council, South African Cochrane Centre
PO Box 19070, Tygerberg, 7505, South Africa
Telephone: +27 21 938 0506 / +27 21 938 0834 Fax: +27 21 938 0836
Email: pactradmin@mrc.ac.za Website: pactr.samrc.ac.za
Trial no.: PACTR201909810587438 Date of Approval: 27/09/2019
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title Safety and efficacy of Dolutegravir and EFV400 for pregnant and breastfeeding women: a randomized non-inferiority clinical trial
Official scientific title Safety and efficacy of Dolutegravir and EFV400 for pregnant and breastfeeding women: a randomized non-inferiority clinical trial
Brief summary describing the background and objectives of the trial Elimination of mother to child transmission of HIV is considered as one of the priorities for World Health Organization (WHO) and national programs. Safe and effective antiretroviral drugs during pregnancy and breastfeeding are the key to achieving the elimination strategy in 2020. Dolutegravir (DTG), a second-generation integrase strand transfer inhibitor-based antiretroviral therapy(ART) regimen demonstrated minimum drug interaction, lower risk of treatment discontinuation and superior virological suppression against other first-line agents, including efavirenz and boosted protease inhibitors. DTG and low dose EFV 400mg/day (EFV400) are recommended by WHO as an alternative first-line regimen for adults. Safety and efficacy data on the use of DTG and EFV400 in pregnant and breastfeeding women are scare. Both DTG and EFV are metabolized by genetically polymorphic enzymes UGT1A1 and CYP2B6 respectively. Investigating the pharmacokinetics (PK), pharmacodynamics (PD) and pharmacogenetics (PGx) of DTG in resource-limited genetically diverse African populations is an important step towards optimizing antiretroviral therapy during pregnancy and breastfeeding. We propose a multi-national, clinical trial to identify the optimal ART regimen for pregnant and breast feeding women by comparing two ART regimens: the specific objectives are: 1) To show that [TDF, 3TC, EFV400] is non-inferior to [TDF, 3TC, DTG]; 2) To show that DTG and EFV400 based regimens are safe for pregnant and breast feeding women.
Type of trial RCT
Acronym (If the trial has an acronym then please provide) PREGART
Disease(s) or condition(s) being studied Infections and Infestations
Sub-Disease(s) or condition(s) being studied HIV/AIDS
Purpose of the trial Treatment: Drugs
Anticipated trial start date 01/06/2019
Actual trial start date 01/06/2019
Anticipated date of last follow up 31/12/2025
Actual Last follow-up date 31/12/2025
Anticipated target sample size (number of participants) 1156
Actual target sample size (number of participants)
Recruitment status Recruiting
Publication URL
Secondary Ids Issuing authority/Trial register
STUDY DESIGN
Intervention assignment Allocation to intervention If randomised, describe how the allocation sequence was generated Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms Masking If masking / blinding was used
Parallel: different groups receive different interventions at same time during study Randomised Stratified allocation where factors such as age, gender, center, or previous treatment are used in the stratification Sealed opaque envelopes Open-label(Masking Not Used)
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Control Group Dolutegravir or DTG A fixed-dose combination of TDF 300 mg, 3TC 300 mg, and DTG 50 mg per day During pregnancy and at least one year after delivery Active-Treatment of Control Group 578 Active-Treatment of Control Group
Experimental Group EFV400 A fixed-dose combination of TDF 300 mg + 3TC 300 mg EFV 400mg per day During pregnancy and at least one year after delivery The intervention arm (Arm 2) 578
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
- HIV infected pregnant women who are in their 2nd trimester of pregnancy in Ethiopian and Ugandan recruitment sites. - HIV infected pregnant women who are older than 18 years of age - ART naïve HIV infected pregnant women or women who are on first-line ART during 2nd trimester of pregnancy irrespective of the duration on ART and are willing to be switched to the regimen they are assigned to. - Ability to stay in regular follow up during the duration of pregnancy, delivery and during breast feeding; and, - Consenting to exclusively breastfeed, continue participating in the study during breastfeeding, and to allow their infants to participate in the study. - Consenting to use mandatory long-acting contraception for 48 months post-partum for women assigned to the DTG arm. - Being on second-line ART during the first trimester of pregnancy - Presence of co-infection (such as TB) and chronic illnesses including diabetes mellitus (DM), hypertension and cardiac diseases, and bad obstetric history including miscarriage or early neonatal death - Not consenting to participate or to be on long-acting contraception for 48 months post-partum if assigned to the DTG arm. Adult: 19 Year-44 Year 18 Year(s) 45 Year(s) Female
ETHICS APPROVAL
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
No 30/05/2019 National Research and Ethics Review Commettee
Ethics Committee Address
Street address City Postal code Country
NA Addis Ababa 1120 Ethiopia
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome • Virological suppression at delivery: Virological suppression will be defined as an undetectable HIV-RNA level (which is < 200 copies/mL) [28]. HIV-1 RNA will be quantified with ANRS generic real-time PCR test. Primary efficacy endpoint will be a comparison of the proportion of participants in each randomly assigned treatment group with a plasma HIV-1 viral < 200 copies per mL at delivery. • Mother to child transmission of HIV: Primary efficacy endpoint for infants born to HIV infected women will be the proportion of infants with no MTCT. Babies will be tested for MTCT of HIV using dried blood spot (DBS) DNA PCR at delivery, 6 weeks and 6 months; and at the age of 12 months using HIV antibody testing. Infant HIV infection will be diagnosed based on available infant diagnosis guidelines in Ethiopia and Uganda. At delivery
Secondary Outcome • Proportion of participants in each randomly assigned treatment group with plasma HIV-1 viral load less than 200 and 400 copies per mL at delivery, comparisons between treatment groups, time to loss of virological response (plasma HIV-1 viral load ≥200 copies per mL); mean change from baseline in log10 plasma HIV-1 viral load; mean change in CD4 cell counts; • Type, frequency and severity of adverse events including gestational and drug induced CNS and psychiatric disorder, hepatotoxicity, rash as per EFV and DTG product information that occur during trial and to their potential relations with the drug. CNS includes abnormal dreaming, anxiety, cerebellar disorder and ataxia, dizziness, headache and migraine, vivid dream, insomnia, hallucination, and somnolence. Psychiatric includes depression, fatal suicide, manic reactions, and severe depression. • Mean or median change from baseline in biochemical, haematological, and fasting lipid and glycaemic parameters; rates, rates of opportunistic infections, serious non-AIDS-defining illnesses, and deaths. • Between-group comparisons of change from baseline in health-related quality-of-life scores; depression, anxiety, and stress scores; and self-reported adherence to treatment. • HIV Drug Resistance: Drug resistance testing will be done to determine the proportion of mothers who developed drug resistance in each arm. Genotypic resistance tests will be performed in plasma samples with HIV-1 RNA ≥ 1,000 copies/ml using the consensus technique of AC11 ANRS 2007 v16; possibleresistance will also be considered as resistance (www.hivfrenchresistance.org/). • Maternal and neonatal drug side effects: drug adverse effect monitoring will be done regularly for both mother and fetus/infant including severity assessment using clinical evaluation, obstetric ultrasound and according to DAIDS table [23]. Birth outcomes will be recorded including gestation, birth weight, any congenital anomalies, hospitalization, morbidity, and mortality. At each follow up and at delivery
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Hawassa University Referral Hospital NA Hawassa 1560 Ethiopia
JCRC NA Kampala Uganda
FUNDING SOURCES
Name of source Street address City Postal code Country
European and Developing Countries Clinical Trials Partnership 2509 AA The Hague, The Netherlands The Hague 93015 Netherlands
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor Hawassa University NA Hawassa Ethiopia University
COLLABORATORS
Name Street address City Postal code Country
Makerere University University Rd Kampala Uganda
Karolinska Intitutet Alfred Nobels alle 8, 141 52 Huddinge, Sweden Stockholm Sweden
Istituto Superiore di Sanita Viale Regina Elena 299 - Roma Rome Italy
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Birkneh Tadesse birknehtilahun@gmail.com +251911551807 Referral st
City Postal code Country Position/Affiliation
Hawassa Ethiopia Associate Professor
Role Name Email Phone Street address
Public Enquiries Dejene Hailu dejenkassa@yahoo.com +251916829271 NA
City Postal code Country Position/Affiliation
Hawassa Ethiopia Associate Professor
Role Name Email Phone Street address
Scientific Enquiries Abel Gedefaw abel.gedefaw@yahoo.com +251916580632 NA
City Postal code Country Position/Affiliation
Hawassa Ethiopia Assistant Professor
Role Name Email Phone Street address
Scientific Enquiries Siraj Hussein sirajhu123@gmail.com +251911077435 Hawassa Referral St
City Postal code Country Position/Affiliation
Hawassa Ethiopia Assistant Professor of Microbiology
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes Deidentified individual participant data will be shared upon request to the principal investigator of the trial. Data on HIV infection and treatment-associated infections among pregnant women will be shared on a case by case review basis. Clinical Study Report,Informed Consent Form,Statistical Analysis Plan,Study Protocol IPD will be shared once the study is completed. Access permission will be decided based on predefined criteria. The main parameters will include noncommercial use and signing a confidentiality agreement.
URL Results Available Results Summary Result Posting Date First Journal Publication Date
No
Result Upload 1: Result Upload 2: Result Upload 3: Result Upload 4: Result Upload 5:
Result URL Hyperlinks Link To Protocol
Result URL Hyperlinks
Changes to trial information