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 0835 or +27 21 938 0967
Email: pactradmin@mrc.ac.za Website: pactr.samrc.ac.za
Trial no.: PACTR202112758618724 Date of Registration: 20/12/2021
Trial Status: Retrospective registration - This trial was registered after enrolment of the first participant
TRIAL DESCRIPTION
Public title D3-Penta 21- A randomised non-inferiority trial with nested PK to assess DTG/3TC fixed dose formulations for the maintenance of virological suppression in children with HIV infection aged 2 to <15 years old
Official scientific title D3-Penta 21- A randomised non-inferiority trial with nested PK to assess DTG/3TC fixed dose formulations for the maintenance of virological suppression in children with HIV infection aged 2 to <15 years old
Brief summary describing the background and objectives of the trial HIV has shifted from a deadly disease to a chronic infection with improved survival dependent upon life-long ART. Current HIV treatment guidelines recommend first-line ART regimens consisting of three antiretroviral drugs: two nucleoside/nucleotide analogue reverse-transcriptase inhibitors (NRTIs) as a backbone combined with a nonnucleoside reverse-transcriptase inhibitor (NNRTI), a boosted protease inhibitor (PI), or an integrase strand transfer inhibitor (INSTI) as the third agent or ‘anchor’ drug. Life-long ART presents new challenges of treatment fatigue and long-term toxicities, and the growing population in need of ART pose critical public health questions over the long-term financial sustainability of continued ART scale-up. In response to this, research interest has shifted beyond survival and viral suppression to optimising treatment safety and health-related quality of life[1] with focus on regimens that are easier to take, offer less risk of toxicity and are more affordable, while remaining highly effective. Dual therapy, using two antiretrovirals instead of three with at least one anchor drug, is one of these approaches for initial and maintenance therapy.[2-6]
Type of trial RCT
Acronym (If the trial has an acronym then please provide) D3
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 01/06/2021
Actual trial start date
Anticipated date of last follow up 30/06/2024
Actual Last follow-up date
Anticipated target sample size (number of participants) 370
Actual target sample size (number of participants)
Recruitment status Active, not recruiting
Publication URL Open Access via UK PubMed Central (PMC)
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
Factorial: participants randomly allocated to either no, one, some or all interventions simultaneously Randomised Permuted block randomization Allocation was determined by the holder of the sequence who is situated off site Open-label(Masking Not Used)
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Experimental Group DTG and 3TC Dolutegravir (DTG) and lamivudine (3TC) (known as DTG/3TC) vs. standard-of-care(SOC) consisting of 2 nucleos(t)ide reverse transcriptase inhibitor (NRTI) and a third (anchor) drug (either an integrase strand transfer inhibitor (INSTI), a protease inhibitor (PI) or a non- nucleoside reverse transcriptase inhibitor (NNRTI Dosing according to weightband groups 6 to <10kg, 10 to <14kg, 14 to <20kg, 20 to <25kg ( DT), 25 to <40kg using WHO weightband 96 Weeks Dolutegravir (DTG) and lamivudine (3TC) (known as DTG/3TC) vs. standard-of care (SOC) consisting of 2 nucleos(t)ide reverse transcriptase inhibitor (NRTI) and a third (anchor) drug (either an integrase strand transfer inhibitor (INSTI), a protease inhibitor (PI) or a non- nucleoside reverse transcriptase inhibitor (NNRTI) 185
Control Group Standard of care Standard of care three-drug ART regimen _ as per South African DOH Guidelines 96 weeks Standard of care three-drug ART regimen _ as per South African DOH Guidelines 185 Active-Treatment of Control Group
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
1. HIV-1 infected children who are virologically suppressed for at least the last 6 months prior to enrolmenta,b 2. Aged 2 to <15 years old 3. Weight 6 kg or higher 4. Children on the same triple-drug PI/r, NNRTI or INSTI containing ART regimen for at least 3 months 5. Girls who have reached menarche must have a negative pregnancy test at screening and randomisation 6. Girls who are sexually active must be willing to adhere to highly effective methods of contraceptionc 7. A parent or legal guardian is willing and able to give informed consent on behalf of the child as per national legislation and willing to adhere to the protocol 8. Participant is willing to give informed assent if the trial site clinician deems them old enough and able to understand the age-appropriate information about participation in the study 1. Any previous switch in ART regimen for virological, immunological or clinical treatment failure 2. Any changes in ART in the last 6 months for reasons other than due to child’s growth, drug stock-outs, changes in country guidelines and treatment simplification 3. Evidence of previous resistance to 3TC or INSTIa 4. Any prior use of regimens consisting of single or dual NRTIs with the exception of a course of zidovudine for PMTCT 5. Known allergy or contraindications to dolutegravir or lamivudine 6. Diagnosis of tuberculosis and on anti-tuberculosis treatment; children can be enrolled after successful tuberculosis treatmentb 7. Treatment of co-morbidities with drugs which have significant interactions with antiretroviral treatment, requiring dose adjustment of the study drugs (children can be enrolled after the illness resolves) 8. Randomisation visit more than 12 weeks after the most recent screening visit 9. Evidence of hepatitis B infection with no protective immunity against hepatitis B: participants positive for HBsAg or HBcAb and negative for HBsAb 10. Anticipated need for hepatitis C virus therapy with interferon-based regimen prior to the primary endpoint. 11. Screening ALT equal to 3 or more times the upper limit of normal AND bilirubin equal to 2 or more times the upper limit of normal (ALT ≥3xULN AND bilirubin ≥2xULN) 12. Screening ALT equal to 5 or more times the upper limit of normal ALT (≥5xULN) 13. Patients with severe hepatic impairment or unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent jaundice), or known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) 14. Screening creatinine clearance <50 mL/min/1.73m2 d 15. Patients aged ≥6 years at moderate or high risk of suicide as determined by Columbia-Suicide Severity Rating Scale (C-SSRS) e 16. Girls who are pregnant or breastfeeding 17. Children who are in the legal custody of the State and do not have a parent or guardian able to provide informed consent on their behalf. Adolescent: 13 Year(s)-17 Year(s),Child: 6 Year-12 Year,Preschool Child: 2 Year-5 Year 2 Year(s) 15 Year(s) Both
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
Yes 15/10/2020 University of the Witwatersrand Human Research Ethics Committee Medical
Ethics Committee Address
Street address City Postal code Country
1 jan Smuts Avenue Braamfontein Johannesburg 2000 South Africa
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 22/09/2020 SAHPRA South Africa Health Products Authority
Ethics Committee Address
Street address City Postal code Country
Building A Loftus Park 402 Kirkness Street Arcadia Pretoria Pretoria 0001 South Africa
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome Proportion of children with confirmed viral rebound (defined as the first of two consecutive HIV-1 RNA =50c/mL) by week 96 12 weekly
Secondary Outcome Proportion of children with confirmed viral rebound (defined as the first of two consecutive HIV-1 RNA =50c/mL) by week 48 Proportion of children with confirmed HIV-1 RNA =50c/mL at weeks 48 and 96 (modified FDA snapshot) Proportion of children with HIV-1 RNA =50c/mL at weeks 24, 48 and 96 (including blips and confirmed measures =50c/mL) New resistance-associated mutations in those with confirmed HIV-1 RNA =50c/mL Time to any new or recurrent WHO 3 or WHO 4 event or death Change in CD4 (absolute and percentage) from baseline to weeks 24, 48 and 96 12 weekly
Secondary Outcome Secondary Safety Outcome Measures- Incidence of serious adverse events, grade 3 and 4 clinical and laboratory adverse events Incidence of adverse events leading to discontinuation or modification of the treatment regimen Proportion of children with a change in ART for toxicity or switch to second-line Change in blood lipids from baseline to weeks 48 and 96 Change in creatinine clearance estimated using bedside-Schwartz to weeks 48 and 96 12 weekly
Secondary Outcome Patient-reported outcome measures - Adherence as assessed by participant/care-giver questionnaires Acceptability, sleep and mood, suicidal ideation and health-related quality of life as assessed by participant/care-giver completed questionnaires 12 weekly
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Perinatal HIV Research Unit PHRU Soweto New Nurses Home Chris Hani Baragwanath Academic Hospital Chris Hani Road Soweto Johannesburg Gauteng Johannesburg 1862 South Africa
Perinatal HIV Research Unit PHRU Matlosana Klerksdorp Tshepong Hospital Complex Benji Olifant Road Jouberton Klerksdorp Klerksdorp 2571 South Africa
Durban International Clinical Research Site Enhancing Care Foundation Parkhome Gate 1 King Edward VIII Hospital Umbilo Road, Congella Durban Durban 4013 South Africa
FUNDING SOURCES
Name of source Street address City Postal code Country
ViiV Healthcare 980 Great West Road Brentford Middlesex TW8 9GS UK Brentford Middlesex TW8 9GS United Kingdom
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor Fondazione Penta Onlus Penta Fondazione Penta Onlus, Torre della Ricerca Pediatrica Corso Stati Uniti 4, Padova, 35127 Padova 35127 Italy Commercial Sector/Industry
COLLABORATORS
Name Street address City Postal code Country
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Avy Violari violari@mweb.co.za 0027119899700 Perinatal HIV Research Unit New Nurses Home Chris Hani Baragwanath Academic Hospital Chris Hani Road Soweto, 1862 Gauteng
City Postal code Country Position/Affiliation
Johannesburg 1862 South Africa National Principal Investigator
Role Name Email Phone Street address
Public Enquiries Fatima Mayat mayatf@phru.co.za 0027119899700 Perinatal HIV Research Unit New Nurses Home Chris Hani Baragwanath Academic Hospital Chris Hani Road Soweto, 1862 Gauteng
City Postal code Country Position/Affiliation
Johannesburg 1862 South Africa Director Phru
Role Name Email Phone Street address
Scientific Enquiries Avy Violari violari@mweb.co.za 0027119899700 Perinatal HIV Research Unit New Nurses Home Chris Hani Baragwanath Academic Hospital Chris Hani Road Soweto, 1862 Gauteng
City Postal code Country Position/Affiliation
Johannesburg 1862 South Africa National Principal Investigator
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes It is anticipated that a number of opportunities will arise for publication during the course of and following completion of the D3 trial. Publications include papers (including abstracts) for presentation at national and international meetings, as well as the preparation of manuscripts for peer-reviewed publication. Informed Consent Form,Study Protocol 6 months Can be requested from Trial Steering Committee
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