| Protocol No: | ECCT/23/05/07 | Date of Protocol: | 01-12-2021 |
| Study Title: | Long-Acting Treatment in Adolescents (LATA) A randomised open-label 2-arm 96 week trial in virologically suppressed HIV-1-positive adolescents aged 12-19 years of age in Sub-Saharan Africa |
| Study Objectives: |
1.2.2 PRIMARY OUTCOME
The proportion of participants with confirmed virological rebound, defined as 2 consecutive plasma HIV-RNA ≥50 copies/mL at any time up to the 96-week assessment.
1.2.3 SECONDARY OUTCOMES
1.2.3.A EFFICACY
(i) Proportion of participants with HIV-RNA ≥50 copies/mL at 48 and 96 weeks using a modified FDA snapshot algorithm
(ii) The proportion of participants with HIV-RNA ≥1000 copies/mL (confirmed) by week 96
(iii) The proportion of participants with HIV-RNA ≥200 copies/mL (confirmed) by week 96
(iv) The number and type of HIV mutations (reverse transcriptase and integrase) in participants with confirmed virological rebound
(v) HIV-RNA <50 copies/mL at 24, 48 and 96 weeks
avirological rebound is defined as two consecutive HIV-RNA ≥50 copies/mL. As obtaining resistance data is challenging when viral loads are very low, resistance testing may need to be restricted to samples with a higher VL where the chances of being able to sequence are greater; this will also be dependent on available technologies for testing.
1.2.3.B SAFETY
(i) Change in toxicity profile including change in metabolic parameters (lipids, HbA1c, phosphate),
liver function tests (ALT), renal function (eGFR) from baseline to 96 weeks; change in anthropometric measures, including weight, from baseline to 48 and 96 weeks
(ii) Time to any new or recurrent WHO grade 3 or WHO grade 4 event or death
(iii) Incidence of serious, grade 3, 4 and 5, and treatment-modifying (of any grade) adverse events
(iv) The proportion of participants with any change from baseline ART regimen
(v) Change in CD4+ and CD8+ T-cell count from baseline to 48 and 96 weeks
(vi) LA group only: incidence of injection site reactions of any grade
1.2.3.C PATIENT-REPORTED OUTCOMES
(i) Adherence (days missed of oral medication and/or missed scheduled injection visits), acceptability, wellbeing and neuropsychiatric problems (e.g. depression, anxiety and sleep disturbance)
(ii) LA group only: perception of injection
(iii) Healthcare resource utilisation (as a sub-study outcome)
(iv) Health-related quality-of-life (as a sub-study outcome)
(v) Perception of body shape using Stunkard figure rating scales (as a sub-study outcome)
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| Laymans Summary: |
In LATA we will compare two different ways of taking HIV medicines. In the trial you are randomised, with an equal chance that you will either go into the long-acting injectable group or get a daily tablet by mouth. This is what happens depending on which group you are randomised to:
• Long-Acting Injectable Group: In this group, there are 2 options. The first is to stay on your current HIV medicines by mouth and then to start the injections around 4 weeks after randomisation. If this is the choice, then at week 4, the first 2 injections will be given, the second t o ill be given 4 ee s later, and then it’s every 8 ee s from then on. The second option is to switch to taking one tablet of cabotegravir and one tablet of rilpivirine for approximately 4-5 weeks before starting the injections. The reason that some people might choose to have the tablet forms first, is to make sure they tolerate them. This is called an oral lead-in (OLI). For the OLI group, and as long as liver test results at 4 weeks are within normal levels, the first two injections will be given at around 5 weeks (about a week after the week 4 visit), the second two are given 4 weeks later, and then it’s every 8 ee s from then on.
• Continuous Oral Treatment Group: this group will continue to take all their HIV medicines every day by mouth. However, to join the trial, some participants will have to change some of their oral medications as the combination being used is dolutegravir with tenofovir plus either lamivudine or emtricitabine as a single tablet taken once a day, called TLD.
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| 1 | Section 1.1.2 Addition of information regarding registration of Cabenuva by the FDA following MOCHA data Inclusion of females who have recently returned to oral ART (<1 year prior to pregnancy) in PK analysis. Section 1.1.4 Clarification of minimising risk of pregnancy in trial participants. Section 1.1.7 Update as BREATHER Plus was fully enrolled in May 2022. Section 1.2.3.B Clarification of safety secondary outcomes. Section 2.1.1 Clarification of site PI qualification requirements, in line with MRC CTU Protocol template v9.0. Section 2.1.2 Clarification of adequate resources, in line with MRC CTU Protocol template v9.0. Section 2.2 Clarification of approval and activation, in line with MRC CTU Protocol template v9.0. Section 3.2 Confirmation of eligibility criteria footnotes for HIV VL, HIV-2 testing, Hepatitis B SAg testing and major resistance to NNRTI/INSTIs. Section 3.5.2 Clarification of re-screening criteria. Section 4.2 Clarification of randomisation procedures, including the removal of option for MRC CTU to perform manual randomisation when database/internet outages. Guidance for week 4a and week 4b visits performed on the same day. Section 5.1.5 Addition of guidance on needle length for administration of LA injectables. Section 5.1.5.A Guidance for week 4a and week 4b visits performed on the same day. Section 5.2.3 Clarification for participants on TAF during TB treatment. Section 5.5.2 Confirmation that inventory logs will be reviewed on a monthly basis. Section 5.5.3 Clarification on timing of administering LA injectables Guidance regarding participants taking oral bridging for >60 days added. Section 5.7.1.A Addition of fatty liver AR associated with TLD in table 3 in line with updated IB. Section 5.7.1.B Updated reference safety information on Cabotegravir and Rilpivirine added in line with updated IB Addition of week 96 and 124 safety profiles from the FLAIR study. Section 5.8 Additional guidance added for protocol treatment discontinuation. Section 6 Addition of visit schedule tool for planning trial visits. Section 6.1.1 Re-formatted for clarity. Section 6.1.2 Formatting updated for clarity and consistency Correction of visit procedures at week 4a for LA group Addition of health economics questionnaire at weeks 16 and 64 Addition of perception of injection questionnaire at every visit where an injection was given at the previous visit Clarification for SAE and NE follow up at the end of the trial. Section 6.2.1 Clarification of guidance for recalling participants with raised VL results. Section 6.3 Correction of LATA reportable events for reporting suicidal ideation or behaviours. Section 6.6.1 Addition of health economics questionnaire at weeks 16and 64 Update to guidance for real-time viral load testing for all pregnant participants. Section 6.7.1.B Details of pregnancy PK sample collection removed as participants will follow individual PK schedule based on their level of consent and when the pregnancy is identified Inclusion of participants who have recently returned to oral ART (<1 year prior to pregnancy) in pregnancy PK sub study. Section 6.7.2 Addition of guidance regarding standard-of-care syphilis testing during pregnancy. Section 6.7.3.B Rilpivirine safety profile in pregnancy amended in line with updated IB. Section 6.11.1.A Clarification of post-trial LAI access in a subsequent protocol. Section 6.11.1.B Clarification on post-trial safety reporting duration in control group Section 7.2 Clarification of requirements for reporting suicidal ideation or behaviours (moved from Section 7.2.1.C to Section 7.2). Section 7.2.1.D Clarification of procedures for reporting pregnancy notable events, including that spontaneous abortions/miscarriages, congenital abnormality or birth defect are SAEs.Clarification of guidance for reporting other notable events and product quality complaints. Section 7.2.1.E Clarification of procedures for assessing expectedness. Section 7.2.1.F Clarification of procedures for reporting events. Section 7.2.1.G Clarification of procedures for reporting events. Section 7.3 Clarification of procedures for MRC CTU assessment of expectedness. Section 8.3.2 Addition of guidance provided on definition and documentation for source data. Section 9.3 Pre-specification of non-inferiority margin dependent on control event rate. Section 9.4 Addition of Estimand for the primary outcome. Section 9.6 Clarification of analysis to be used for clinical events Clarification of ‘failure rate’ as ‘rate of confirmed viral rebound’. Section 10.2 Addition of reference to the Neuropsychiatric Manual of Operations. Section 10.2.1 Clarification on Neuropsychiatric questionnaires for the sub-study. Section 10.3.2.B Inclusion of participants who have recently returned to oral ART (<1 year prior to pregnancy) in pregnancy PK substudy Updated guidance for pregnancy PK sample collection. Section 11.2.1 Clarification from ‘virological failure’ to ‘virological rebound’ Clarification that all participants in the LA group must provide written informed consent to document their decision to continue on LA injectables or return back to oral ART. Section 13 Funding updated to include the grant code for the MRCCTU at UCL between 2021-2026 (MC_UU_00004/03). Section 17 Addition of LATA group email. Section 18 Inclusion of protocol v2.0 amendments summary. Section 19 Update to references. |
| 2 | This amendment introduces the LATA Extension Phase (LEP) to provide continued access to long-acting injectable cabotegravir and rilpivirine (CAB/RPV LAI) for eligible adolescents previously enrolled in the LATA trial, following completion of their 96-week participation. At our site we will be enrolling 37 participants into this phase of the trial. The LEP will allow ongoing treatment and safety monitoring for up to two years post-trial, or until participants no longer derive clinical benefit or trial-defined discontinuation criteria are met. The amendment also outlines follow-up procedures for participants discontinuing LAI, including 12 months of safety reporting for serious adverse events (SAEs) and notable events. Detailed provisions for pregnancy management, viral load monitoring, and safety reporting are included. No additional efficacy data will be collected, and data management will be paper-based with oversight by the Sponsor (UCL). |
| Abstract of Study: |
SUMMARY INFORMATION
LATA (Long-Acting Treatment in Adolescents)
Long-Acting Treatment in Adolescents (LATA) - A randomised open-label 2-arm 96 week trial in virologically suppressed HIV-1-positive adolescents aged 12-19 years of age in Sub-Saharan Africa
Study Design
Open-label, randomised (1:1), 2-arm, multicentre, 96 weeks, non-inferiority trial
Participant population
Adolescents aged 12 to 19 years of age living with HIV-1 who are not pregnant or breastfeeding, and are virologically-suppressed (HIV-1 RNA <50 copies/mL) for at least one year, without any known history of treatment failure, on a 3-drug combination ART consisting of an anchor drug with a 2-drug nucleos(t)ide reverse transcriptase inhibitor (NRTI) backbone
Setting
Kenya, South Africa, Uganda and Zimbabwe
Interventions to be Compared
Continuous Therapy (CT) control group: Control group is continuous daily oral combination ART consisting of dolutegravir (DTG), with a tenofovir (TFV) and lamivudine(3TC)/emtricitabine(FTC) backbone
Long Acting (LA) injectable group: Intervention group is long-acting injectable, cabotegravir (CAB) LA and rilpivirine (RPV) LA given every 8-weeks after an optional 4-week oral lead-in period with oral cabotegravir and rilpivirine, and two loading doses separated by 4 weeks.
Study Hypothesis
CAB LA + RPV LA therapy will provide non-inferior sustained virological suppression compared to continuous treatment with DTG + TFV and 3TC or FTC
Primary Outcome Measure(s)
The proportion of participants with confirmed virological rebound, defined as 2 consecutive plasma HIV-RNA ≥50 copies/mL at any time up to the 96-week assessment
Secondary Outcome Measure(s)
Efficacy
(i) Proportions of participants with HIV-RNA ≥50 copies/mL at 48 and 96 weeks using a modified FDA snapshot algorithm
(ii) The proportion of participants with HIV-RNA ≥1000 copies/mL (confirmed) by week 96
(iii) The proportion of participants with HIV-RNA ≥200 copies/mL (confirmed) by week 96
(iv) The number and type of HIV mutations (reverse transcriptase and integrase) in participants with confirmed virological rebound
(v) HIV-RNA <50 copies/mL at 24, 48 and 96 weeks
Safety
(i) Change in metabolic parameters (lipids, HbA1c, phosphate), liver function tests (ALT), renal function (eGFR) from baseline to 96 weeks; change in anthropometric measures, including weight, from baseline to 48 and 96 weeks
(ii) Time to any new or recurrent WHO grade 3 or WHO grade 4 event or death
(iii) Incidence of serious, grade 3, 4 and 5, and treatment-modifying (of any grade) adverse events
(iv) The proportion of participants with any change from baseline ART regimen
(v) Change in CD4+ and CD8+ T-cell count from baseline to 48 and 96 weeks
(vi) LA group only: incidence of injection-site reactions of any grade
Patient-reported outcomes
(i) Adherence, acceptability, wellbeing and neuropsychiatric problems (e.g. depression, anxiety and sleep disturbance)
(ii) LA group only: perception of injection
(iii) Healthcare resource utilisation (as a sub-study outcome)
(iv) Health-related quality-of-life (as a sub-study outcome)
(v) Perception of body shape using Stunkard figure rating scales (as a sub-study outcome)
Randomisation
Participants will be randomised 1:1 to one of the two treatment groups
Number of Participants to be Studied
N=460, with 230 in each group
Duration of follow-up in the trial
A minimum of 96 weeks per participant – individual follow-up will continue until the last participant reaches 96 weeks follow-up.a
a Participants on LA injectables will be followed for safety (Serious Adverse Events and Notable Adverse Events, and Notable Events) for 12 months after their last injections received whilst participating in LATA; this means follow-up of patients in the LA group will continue for up to one year after end of randomised follow-up). For participants who continue to receive LA injectables after this 12 month post-LATA period, safety reporting requirements will be described in a separate protocol. See section 6.11
Ancillary Studies/Substudies
Nested substudies:
â–ª Social science
â–ª Neuropsychiatric toxicity
â–ª Metabolic
â–ª Health economics
â–ª Pharmacology
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| 2 | Purpose of the LEP
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