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.: PACTR202301600757432 Date of Approval: 24/01/2023
Trial Status: Retrospective registration - This trial was registered after enrolment of the first participant
TRIAL DESCRIPTION
Public title Improving HIV-1 Control in Africa With Long Acting Antiretrovirals (IMPALA)
Official scientific title Efficacy, Safety and Effectiveness of Injectable Cabotegravir / Rilpivirine in Improving HIV-1 Control in Sub-Saharan Africa : A Pragmatic Phase 3b Open- Label Randomized Controlled Trial.
Brief summary describing the background and objectives of the trial Detailed Description: IMPALA is a randomized, open-label, multicenter, interventional study of 540 virologically suppressed (<200 c/mL) HIV-1 infected adults (18 years or older) who have a history of sub-optimal adherence to daily oral ART and/or engagement in HIV care. IMPALA seeks to demonstrate the non-inferior antiviral effectiveness of switching to long acting injectable rilpivirine (RPV LA) plus long acting injectable cabotegravir (CAB LA) given every 2 months (Q2M CAB LA + RPV LA) by IM compared to the continuation of first-line daily oral ART containing 2 nucleoside reverse transcriptase inhibitor (NRTIs) plus an integrase strand transfer inhibitor (INSTI; dolutegravir [DTG]). After providing written informed consent, participants will be evaluated for eligibility during the screening period. Participants who are viremic (HIV VL >200 c/mL) at the time of screening will be virologically suppressed (for >3 months) on a regimen of 2 NRTIs plus DTG prior to randomization. On Day 1 virologically suppressed (<200 c/mL for at least 3 months) individuals will be randomized 1:1 to either continue daily oral ART (2 NRTI + DTG, control arm), or switch to Q2M CAB LA + RPV LA IM, the intervention arm. Those randomized to the intervention arm will be offered either optional oral lead-in (OLI) of 1 month daily oral CAB and RPV or a direct to injection (DTI) approach. This decision to dose with or without an OLI Phase will be determined by the study participant following the informed consent discussion with the investigator. The total duration of the study will be 24 months. Any participant who has received at least a single dose of CAB LA + RPV LA and discontinues the regimen for any reason before Month 24 must start suppressive daily oral ART within 2 months of the last injection. There will be an optional real-world extension phase, provided the regimen is deemed to be non-inferior at Month 12 and 24.
Type of trial RCT
Acronym (If the trial has an acronym then please provide) b
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 01/11/2022
Actual trial start date 08/12/2022
Anticipated date of last follow up 01/11/2024
Actual Last follow-up date
Anticipated target sample size (number of participants) 540
Actual target sample size (number of participants)
Recruitment status Recruiting
Publication URL
Secondary Ids Issuing authority/Trial register
NCT05546242 Clinical Trials.gov
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 Simple randomization using a randomization table created by a computer software program 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 Injectable Long Acting Cabotegravir and Long Acting Rilpivirine Injectable long-acting cabotegravir 600mg + long-acting rilpivirine 900mg administered every 2 months Other Name: Vocabria /Rekambys 24 Months The first 4 weeks of the treatment differ depending on whether participant opts for direct to injection (DTI) or Oral lead-in (OLI). DTI: participants will remain on daily oral ART for 4weeks after randomization and will receive the 1st injection of IM CAB LA 600mg+RPV LA 900mg at the Month 1 visit. 2nd injections administered at Month 2, followed by maintenance injections every 2 months (Q2M) OLI: participants will receive the study intervention in 2 phases: Participants will receive CAB 30mg+RPV 25mg OD for 4weeks to be taken daily with food. The purpose of the optional OLI Phase is to allow an opportunity for participants to assess tolerability of the combination prior to administration of the injectables. There is no proven benefit to this approach After 4weeks participants return for the Month 1 visit to receive the 1st IM CAB LA 600mg+RPV LA 900mg injections. The 2nd injections administered at Month 2 and then continuation injections will be administered Q2M 270
Control Group Antiretroviral Oral antiretroviral therapy in the form of 2NRTIs + dolutegravir 50mg administered daily 24 Months ART group Participants will take a daily oral combination of 2 NRTIs plus DTG 50mg. Ideally, the single tablet fixed-dose combination regimen of (tenofovir disoproxil fumarate [TDF] 300 mg + lamivudine [3TC] 300 mg (or emtricitabine [FTC] 200 mg) + DTG 50 mg) will be used as per local country guidelines up to Month 24. If there are preexisting reasons why TDF or 3TC cannot be used as the NRTI backbone then alternative NRTIs are acceptable. Participants will be permitted to switch daily oral ART drugs in case of toxicity, after discussion with the coordinating center. 270 Active-Treatment of Control Group
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
18 years of age and above HIV-1 infection confirmed in clinic records or by study team. Two consecutive HIV-1 VL <200 copies/mL ≥3 months apart prior to randomization. On an oral regimen of 2NRTI + DTG as part of first line ART Is identified as a participant with a history of, sub-optimal ART adherence or engagement in care based on one or more of the following criteria: Documented detectable HIV-1 VL (>1000 c/mL) on all-oral ART (EFV/NVP or DTG-based) in the prior 2 years despite being ART-experienced for ≥3 months. History of being lost to follow-up from care (>4 weeks elapsed since a missed scheduled clinic appointment or refill in the prior 2 years). Failed to link to HIV care despite ≥3 months elapsed since HIV diagnosis. Females: human chorionic gonadotrophin (HCG) negative and willing to use one highly effective form of contraception if woman of reproductive potential Must sign informed consent form (ICF) indicating that the participant understands the purpose of, and procedures required for, the study and is willing to participate in the study. Willing and able to attend all clinic appointments. Not virologically suppressed (VL<200 c/mL) for ≥3 months at the end of the screening process. Previous use, or intention to use, protease inhibitor-based ART at any time. Evidence of prior HIV-1 resistance test with NNRTI drug resistance mutations (other than K103N) and/or INSTI drug resistance mutations. Unwillingness to receive 2 injections on a 2 monthly basis. Unwilling to use a form of contraception. Pregnant, breastfeeding or planning to become pregnant during the study period. Requires tuberculosis therapy or other drug with clinically relevant drug interaction High risk of seizures, including participants with an unstable or poorly controlled seizure disorder. Has active TB or other mycobacterial disease and requires treatment. Advanced liver disease, known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) or history of cirrhosis. Chronic Hepatitis C with planned or anticipated use of Hep C therapy Evidence of hepatitis B virus (HBV) infection based on the results of testing at Screening for Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody (HBcAb), Hepatitis B surface antibody (HBsAb) as follows: Participants positive for HBsAg are excluded Participants negative for HBsAg but positive for HBcAb, with no evidence of HBsAb are excluded NOTE: Participants positive for HBcAb due to prior infection (negative HBsAg status) and with evidence of HBsAb have some immunity to HBV and have low risk of reactivation so are not excluded. Current or anticipated need for chronic anticoagulation therapy. Previous use of oral or injectable CAB or RPV. Any Grade 4 laboratory abnormality at the conclusion of screening process. Creatinine clearance (CrCl) <50 mL/min/1.732 by Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) equation. Alanine aminotransferase (ALT) > 3×upper limit of normal (ULN). Has a tattoo or other dermatological condition overlying the gluteus region that could interfere with ISR interpretation 80 and over: 80+ Year,Adolescent: 13 Year-18 Year,Adult: 19 Year-44 Year,Aged: 65+ Year(s),Middle Aged: 45 Year(s)-64 Year(s) 18 Year(s) 80 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 27/10/2022 Uganda Virus Research Institute
Ethics Committee Address
Street address City Postal code Country
Plot 51-59 Nakiwogo Road Entebbe 256 Uganda
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome HIV-1 viral load at 12 months [ Time Frame: 12 months ] Proportion with plasma HIV-1 viral load (VL) <50 c/mL at 12 months (by Food and Drug Administration [FDA] snapshot algorithm) 12 Months
Secondary Outcome Confirmed virologic failure on 2 consecutive occasions [ Time Frame: 12 months ] Proportion with confirmed virologic failure (CVF) [plasma HIV-1 VL ≥200 c/mL on 2 consecutive occasions] Confirmed virologic failure on 2 consecutive occasions [ Time Frame: 24 months ] Proportion with confirmed virologic failure (CVF) [plasma HIV-1 VL ≥200 c/mL on 2 consecutive occasions] Lost to follow up [ Time Frame: 12 months ] Proportion with LTFU [>4 weeks elapsed since their last missed appointment] Lost to follow up [ Time Frame: 24 months ] Proportion with LTFU [>4 weeks elapsed since their last missed appointment] HIV-1 viral load <200c/mL [ Time Frame: 12 months ] Proportion with plasma HIV-1 VL <200 c/mL Change in CD4+ T cell count [ Time Frame: 12 months ] Change in CD4+ T cell count from baseline Change in CD4+ T cell count [ Time Frame: 24 months ] Change in CD4+ T cell count from baseline HIV disease progression [ Time Frame: 24 months ] Incidence of HIV disease progression (HIV/AIDS related hospitalizations, illness or deaths) Adverse Events [ Time Frame: 12 months ] Incidence of adverse events (AEs) Adverse Events [ Time Frame: 24 months ] Incidence of adverse events (AEs) Grade 3 and 4 Adverse Events [ Time Frame: 12 months ] Incidence of AEs, Grade 3 and 4 excluding injection site reactions Grade 3 and 4 Adverse Events [ Time Frame: 24 months ] Incidence of AEs, Grade 3 and 4 excluding injection site reactions Injection Site Reactions [ Time Frame: 24 months ] Frequency of injection site reactions of any grade 24 months
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
MRC UVRI LSHTM Uganda Research Unit Plot 51-59 Nakiwogo Road Entebbe 256 Uganda
Infectious Diseases Institute Kampala Mulago Hospital Kampala 256 Uganda
Joint Clinical Research Center Fortportal Fortportal regional referral Hospital Fortportal 256 Uganda
Joint clinical Research Center Lubowa Lubowa Kampala 256 Uganda
Kenyatta National Hospital Nairobi Hospital Road Nairobi 254 Kenya
Jaramogi Oginga Odinga Teaching and Referral Hospital Kisumu-Kakamega Kisumu 254 Kenya
CAPRISA 3 University Avenue Durban 27 South Africa
Desmond TuTu Health Foundation 3 woodlands road Cape Town 27 South Africa
FUNDING SOURCES
Name of source Street address City Postal code Country
Janssen Pharmaceutica NV Turnhoutseweg 30,2340 Beerse 32 Belgium
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor MRC UVRI LSHTM Uganda Research Unit Plot 51-59 Nakiwogo Road Entebbe 256 Uganda Clinical Trials Unit
COLLABORATORS
Name Street address City Postal code Country
University of Nairobi University way Nairobi 254 Kenya
MRC UVR LSHTM Uganda Research Unit Entebbe Hospital Grade A Entebbe 256 Uganda
Joint Clinical Research center Lubowa Kampala 256 Uganda
Infectious Diseases institute Mulago Kampala 256 Uganda
Center for the AIDS programmed of Research in South Africa University of Kwazulu Natal Durban 27 South Africa
Desmond Tutu Health Foundation University of Cape Town ,Anzio Road Cape Town 27 South Africa
Joint Clinical research center Fort portal Fort portal Hospital Fort Portal 256 Uganda
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Eugene Ruzagira Eugene.Ruzagira@mrcuganda.org 256417704000 Plot 51-59 Nakiwogo Road
City Postal code Country Position/Affiliation
Entebbe 256 Uganda Head of HEI MRC UVR LSHTM
Role Name Email Phone Street address
Scientific Enquiries Fiona Cresswell Fiona.Cresswell@lshtm.ac.uk 256414704000 Entebbe
City Postal code Country Position/Affiliation
Entebbe 256 Uganda Chief Investigator
Role Name Email Phone Street address
Public Enquiries Victoria Babirye Tumusiime Victoria.Tumusiime@mrcuganda.org 256417704000 Plot 51-59 Nakiwogo road
City Postal code Country Position/Affiliation
Entebbe 256 Uganda Clinical Trial Manager MRC UVRI LSHTM Uganda Research Unit
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes Data shall be available to researchers after the end of the study and main publication has been made. Researchers wishing to access data should contact the Trial Management Group in the email: impala@lists.lshtm.ac.uk . All data exchange must comply with information governance and Data protection policies in all countries relevant to the disclosure. Analytic Code,Clinical Study Report,Informed Consent Form,Statistical Analysis Plan,Study Protocol 12 months of study completion Contact the Trial management Group at: impala@lists.lshtm.ack.uk
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