| Protocol No: | ECCT/22/05/02 | Date of Protocol: | 18-03-2020 |
| Study Title: |
A randomised open-label 2-arm, 96-week trial evaluating the efficacy, safety and acceptability of short cycle (five days on, two days off) dolutegravir/tenofovir-based triple antiretroviral therapy (ART) compared to daily dolutegravir/tenofovir-based triple ART in virologically suppressed HIV-infected adolescents aged 12 to 19 years of age in sub-Saharan Africa
|
||||||||||
| A randomised open-label 2-arm, 96-week trial evaluating the efficacy, safety and acceptability of short cycle (five days on, two days off) dolutegravir/tenofovir-based triple antiretroviral therapy (ART) compared to daily dolutegravir/tenofovir-based triple ART in virologically suppressed HIV-infected adolescents aged 12 to 19 years of age in sub-Saharan Africa Final Version 2.0 | |||||||||||
| _ A randomised open-label 2-arm, 96-week trial evaluating the efficacy, safety and acceptability of short cycle (five days on, two days off) dolutegravir/tenofovir-based triple antiretroviral therapy (ART) compared to daily dolutegravir/tenofovir-based triple ART in virologically suppressed HIV-infected adolescents aged 12 to 19 years of age in sub-Saharan Africa v 3.0 dated 24 March 2023 | |||||||||||
| Study Objectives: | The BREATHER PLUS trial will evaluate the virological efficacy, safety, acceptability and Quality of Life of DTG-based Short-cycle Therapy with weekends off compared with Continuous Therapy with a DTG-based ART regimen, to optimise treatment for HIV-infected adolescents in sub-Saharan Africa. The backbone drugs will consist of tenofovir either as the TAF or TDF formulations partnered with either 3TC or FTC. Importantly for generalisability to low- and middle-income settings, the trial will be conducted using standard-of-care real-time viral load monitoring as recommended by the World Health Organization (currently annual in sub-Saharan Africa); with additional plasma samples taken for safety monitoring by the Independent Data Monitoring Committee (IDMC) but not returned to doctors/patients. |
||||||||||
| Laymans Summary: |
BREATHER Plus is a study organised by an international group of researchers from Europe and Africa.
Background: The goal of HIV treatment is to make sure the HIV virus in the blood remains very low. This is called having an undetectable viral load (virological suppression). If this goal is achieved and sustained life-long, then people living with HIV can live a healthy life, with a normal life expectancy. However, it is challenging to take medication every single day for life. This may be an even bigger challenge for teenagers living with HIV. In an earlier study, called BREATHER, having weekends off HIV medicines using a combination that included an HIV treatment called efavirenz, was found to be safe and effective in HIV-infected young people. The young people taking part in the study also liked having weekends off their treatment.
What is the BREATHER Plus trial?
BREATHER Plus builds on what we found in the BREATHER study. But, instead of looking at weekends off efavirenz-based HIV treatment, we are looking at weekends off a different HIV treatment called dolutegravir.
In BREATHER Plus we will compare two different ways of taking HIV medicines that include the HIV medicine dolutegravir:
Short Cycle Therapy: where people taking part will take all their HIV medicines during the week but stop taking them at weekends (either Friday and Saturday or Saturday and Sunday)
Continuous Treatment: where people taking part will take all their HIV medicines every day without any interruptions
People joining BREATHER Plus will have an equal chance of being randomised to one of the two groups.
Who will be invited to join the BREATHER Plus trial?
We want 460 young people living with HIV from Kenya, South Africa, Uganda and Zimbabwe to be part of this trial. People taking part need to be 12 to 19 years old, HIV-1-infected, have undetectable HIV viral load for at least the last year, on combination antiretroviral therapy, and never have switched HIV medication in the past because of treatment failure. The combination antiretroviral therapy needs to include tenofovir, lamivudine (or emtricitabine) as the ‘backbone’ and dolutegravir. The participant needs to have been this 3-drug combination for at least a month before they can join. Also, participants can’t join the trial if they are pregnant or breastfeeding. In order to join, adolescents who are at least 18 years old will need to sign a consent form. This describes what the trial is about and what is required of participants. Adolescents aged 12 to 17 years old will have to sign an assent form – this assent form describes what the trial is about and what is required of participants. The parent/guardian/carer of adolescents aged 12 to 17 years old will also need to sign a consent form. Each person taking part will stay in the trial for at least 96 weeks (about 2 years) although it may be longer, up to 4 years.
What will the trial involve?
Among the first people to enter the trial, 30 will be asked to come back every week for the first 4 weeks. There will be a blood test at each of these visits to measure the amount of HIV virus (viral load) in the blood. In general, people taking part in the trial will be asked to visit the clinic every 8 weeks until the last participant has been in the trial for 96 weeks. We will ask questions about health, wellbeing and mood at some of the visits. For girls who have started their periods, we will do a pregnancy test at each visit. At most visits, we will take a blood sample, some of which will be stored and looked at later to measure the amount of HIV virus in the blood. We will also take an additional blood and urine sample once a year, these stored samples will be used to look at the health of people’s kidneys, heart and other organ systems. Everyone will get their viral load result once a year, like people not in the study. In a small group of people we will check how well their pills are being taken using a special pill bottle that triggers every time the bottle is opened and the pills are taken. These special bottles are called MEMSCAPS. The MEMSCAPS will be used in one small group of participants in the first year of the study for 6 months, and a different group in year 2 for 6 months. This is to closely monitor how well people are manage to stick to taking their pills as they should in this trial. In addition to the main trial, there are two sub-studies (smaller studies within the main trial), which people taking part will be invited to take part in. Participants in BREATHER Plus will be invited to take part in a social science sub-study where there are interviews and focus groups to find out how people feel about HIV and their medication. In another sub-study, the mood (neuropsychiatric) sub-study, there are additional surveys to find out if you people are having problems with feeling down or worried or having sleep problems. These sub-studies require additional consent, so people can decide if they do or don’t want to take part in these sub-studies, and whether someone chooses to join or not won’t affect being in the BREATHER Plus trial.
What will the trial show us?
The trial will hopefully be able to show whether having weekends off dolutegravir-based HIV medicine with a ‘backbone’ that includes tenofovir and lamivudine/emtricitabine works as well as taking HIV medicines every day in HIV-infected young people. If the weekends off strategy works for dolutegravir-based HIV medicine partnered with the tenofovir and lamivudine/emtricitabine ‘backbone’, then we hope HIV guidelines will change to recommend this as an option for how people take this combination for their HIV treatment.
|
||||||||||
| 1 | Initially we had requested for approval to enroll adolescents between 12 to 19 years who are the main study population in the Breather Plus study. We however realized that there is a considerable population of children who are living with HIV who are under the care of institutions such as children’s/foster homes. These children, may not have the same level of attention as children being raised by parents, and are sometimes prone to poor adherence and may greatly benefit from a breather in taking their medication. We feel that this particular population may benefit from the findings of this study and we therefore feel it is prudent to include them in the study. Please note that we therefore intend to enroll children in traditional family setups as well as those in children’s homes. | ||||||||||
| 2 | The amendments Includes the following: 1. Minor corrections throughout the protocol for spelling, punctuation, grammar and document link/location corrections 2. Visit schedule updated to reflect 12-weekly visits from year two onwards 3. Addition of UK to list of researchers 4. Addition of general information | ||||||||||
| Abstract of Study: |
SUMMARY INFORMATION
BREATHER Plus
Long Title of Trial
A randomised open-label 2-arm, 96-week trial evaluating the efficacy, safety and acceptability of short cycle (5 days on, 2 days off) dolutegravir/tenofovir-based triple antiretroviral therapy (ART) compared to daily dolutegravir/tenofovir-based triple ART in virologically suppressed HIV-infected adolescents aged 12 to 19 years in sub-Saharan Africa
Version
2.0
Date
18-Mar-2020
Study Design
Open-label, randomised (1:1), multicentre, non-inferiority trial
Type of Participants to be Studied
HIV-infected, non-pregnant, non-breastfeeding adolescents aged 12 to 19 years of age, virologically-suppressed for at least one year, without any history of treatment failure, on 3-drug combination antiretroviral (ART) consisting of dolutegravir with a 2-drug NRTI backbone consisting of tenofovir and lamivudine/emtricitabine for at least 1 month. All participants will be recruited in sub-Saharan Africa
Setting
Kenya, South Africa, Uganda and Zimbabwe
Interventions to be Compared
CT group: Control group is continuous combination ART consisting of dolutegravir, with a tenofovir and lamivudine/emtricitabine backbone
SCT group: Intervention group is short-cycle
combination ART, consisting of dolutegravir, with a tenofovir and lamivudine/emtricitabine backbone. The SCT group will follow a cycle of 5 consecutive days on ART (Monday to Friday inclusive or Sunday to Thursday inclusive) and the same 2 consecutive days off every week (i.e. Saturday and Sunday, or Friday and Saturday)
Study Hypotheses
Dolutegravir-based SCT with a tenofovir and lamivudine/emtricitabine backbone will provide non-inferior sustained virological suppression compared to continuous dolutegravir-based ART with a tenofovir and lamivudine/emtricitabine backbone
Primary Outcome Measure(s)
The proportion of participants with confirmed virological rebound, defined as the first of 2 consecutive plasma HIV-RNA ≥50 copies/mL at any time up to the 96-week assessment
Secondary Outcome Measure(s)
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 number and type of HIV mutations at confirmed virological rebound
(iv) HIV-RNA <50 copies/mL and no switch to second-line ART for treatment failure at 24, 48, 64 and 96 weeks
Safety
(i) Change in toxicity profile including change in metabolic parameters (lipids, HbA1c, phosphate), renal function (eGFR) from baseline to 96 weeks; change in anthropometric measures 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 and 4, and treatment-modifying grade 1-2 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
Patient-reported outcomes
(i) Adherence, acceptability, wellbeing and neuropsychiatric problems (e.g. depression, anxiety and sleep disturbance)
(ii) Healthcare resource utilisation (as a sub-study outcome)
(iii) Health-related quality-of-life (as a sub-study outcome)
Randomisation
Participants will be allocated 1:1 to one of the two 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
Ancillary Studies/Substudies
Nested substudies:
SCT pilot
Adherence using the Medication Event Monitoring Systems (MEMSTM 6 TrackCap)
Social science
Neuropsychiatric toxicity
Health economics
Sponsor
UCL
Funder
EDCTP; Medical Research Council programme number MC_UU_12023/26.
MRC CTU at UCL Project Leader
Professor Sarah L. Pett
|
||||||||||
| 1 |
Initially we had requested for approval to enroll adolescents between 12 to 19 years who are the main study population in the Breather Plus study. We however realized that there is a considerable population of children who are living with HIV who are under the care of institutions such as children’s/foster homes. These children, may not have the same level of attention as children being raised by parents, and are sometimes prone to poor adherence and may greatly benefit from a breather in taking their medication. We feel that this particular population may benefit from the findings of this study and we therefore feel it is prudent to include them in the study. Please note that we therefore intend to enroll children in traditional family setups as well as those in children’s homes.
| ||||||||||
| 2 |
|