Condition category
Infections and Infestations
Date applied
03/02/2020
Date assigned
17/02/2020
Last edited
14/10/2020
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Not yet recruiting

Plain English Summary

Background and study aims
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 including 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.

BREATHER Plus builds on what the researchers found in the BREATHER study. But, instead of looking at weekends off efavirenz-based HIV treatment, the researchers are looking at weekends off a different HIV treatment called dolutegravir.

In BREATHER Plus the researchers 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.

Who can participate?
Patients aged 12 – 19 years who are HIV infected and have been on anti-retroviral therapy for over one year.

What does the study involve?
People joining BREATHER Plus will have an equal chance of being randomised to one of the two groups. The first 30 people who enter the trial, will be asked to come back every week for the first 4 weeks. There will be a blood test at these visits. The test will be 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 and wellbeing and your mood at each visit. 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 for routine tests. Some of the blood sample 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 samples 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 manage to stick to taking their pills as they should in this trial. In addition to the main trial, there are several 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 substudy where there are interviews to find out how people feel about HIV and their medication, and a mood substudy, to find out if people are having problems with feeling down or worried about HIV, their medication and other things going on in their lives. These two substudies require additional consent, so people can decide if they do or don’t want to take part in these, and it won’t affect being in the BREATHER Plus trial.

What are the possible benefits and risks of participating?
Benefits: Making treatment better and easier to take for all young people living with HIV, a reduced dose of medicine and fewer side effects.
RIsks: The weekends off may not control the virus as well as taking medicines every day. This could mean viral load goes up, and participants have to change to different medicines to bring it down to undetectable.

Where is the study run from?
1. Baylor College of Medicine Children’s Foundation (Uganda)
2. Joint Clinical Research Centre (JCRC) (Uganda)
3. University of Zimbabwe Clinical Research Centre (UZCRC)
4. Moi University, AMPATH Centre (Kenya)
5. Department of Paediatrics and Child Health, King Edward VIII Hospital (South Africa)

When is the study starting and how long is it expected to run for?
October 2020 to December 2024.

Who is funding the study?
1. European and Developing Countries Clinical Trials Partnership
2. Medical Research Council (UK)

Who is the main contact?
Prof. Sarah Pett, s.pett@ucl.ac.uk

Trial website

Contact information

Type

Scientific

Primary contact

Prof Sarah Pett

ORCID ID

http://orcid.org/0000-0002-4851-4727

Contact details

MRC Clinical Trials Unit at UCL
Institute of Clinical Trials & Methodology
90 High Holborn 2nd Floor
London
WC1V 6LJ
United Kingdom
+44 (0)207 670 4785
s.pett@ucl.ac.uk

Additional identifiers

EudraCT number

Nil known

ClinicalTrials.gov number

Nil known

Protocol/serial number

129629

Study information

Scientific title

Breather Plus: 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

Acronym

Study hypothesis

Current study hypothesis as of 07/04/2020:
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
_____
Previous study hypothesis:
Dolutegravir (DTG)-based SCT will provide non-inferior sustained virological suppression compared to continuous DTG-based ART.

Ethics approval

Conditionally approved 06/04/2020, UCL Research Ethics Committee (Office of the Vice Provost Research, 2 Taviton Street, University College London, London, UK; +44 (0)20 7679 8717; ethics@ucl.ac.uk), ref: 16929.001, pending local country approvals.

Study design

Open-label randomized (1:1) multicentre non-inferiority trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Other

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

HIV

Intervention

Current interventions as of 07/04/2020:

Control group: Control group is continuous combination ART consisting of dolutegravir, with a tenofovir and lamivudine/emtricitabine backbone
Experimental 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)

Treatment will continue for the duration of the trial/follow-up. The total duration of treatment/follow up for all study arms is for a minimum of 96 weeks, until the last participant has reached 96 weeks visit (so for participants entering the trial early, this could mean 4 years on the trial). The randomisation will be 1:1, using permuted blocks with variable sizes, developed by the trial statistician. Randomisation will take place using an eDC platform.

______
Previous interventions:

Control group: Continuous dolutegravir-based combination ART
Experimental group: Short-Cycle Therapy (SCT) dolutegravir-based combination ART. 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).

Treatment will continue for the duration of the trial/follow-up. The total duration of treatment/follow up for all study arms is for a minimum of 96 weeks, until the last participant has reached 96 weeks visit (so for participants entering the trial early, this could mean 4 years on the trial). The randomisation will be 1:1, using permuted blocks with variable sizes, developed by the trial statistician. Randomisation will take place using an eDC platform.

Intervention type

Drug

Phase

Phase III

Drug names

Dolutegravir 50mg oral with tenofovir disproxil (245mg) fumarate co-formulated with emtricitabine (200mg) or lamivudine (300mg) (TRU) oral in a fixed dose combination or separately

Dolutegravir 50mg oral with tenofovir alafenamide fumarate (25mg) co-formulated with emtricitabine (200mg) or lamivudine (300mg) (f/lTAF) oral in a fixed dose combination or separately

Primary outcome measure

Current primary outcome measure as of 07/04/2020:

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

_____

Previous primary outcome measure:

Incidence of confirmed virological rebound, defined as 2 consecutive plasma HIV-RNA ≥50 copies/mL at any time up to the 96-week assessment

Secondary outcome measures

Current secondary outcome measures as of 07/04/2020:

1. Efficacy:
1.1. Proportion of participants with HIV-RNA ≥50 copies/mL at 48 and 96 weeks using the FDA snapshot algorithm
1.2. Proportion of participants with HIV-RNA ≥1000 copies/mL (confirmed) by week 96
1.3. The number and type of HIV mutations at confirmed virological rebound
1.4 HIV-RNA <50 copies/mL and no switch to second-line ART for treatment failure at 24, 48, 64 and 96 weeks
2. Safety:
2.1. 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
2.2. Time to any new or recurrent WHO grade 3 or WHO grade 4 event or death
2.3. Incidence of serious, grade 3 and 4, and treatment-modifying grade 1-2 adverse events
2.4. The proportion of participants with any change from baseline ART regimen
2.5. Change in CD4+ and CD8+ T-cell count from baseline to 48 and 96 weeks
3. Patient-reported outcomes:
3.1. Adherence, acceptability, well-being, and neuropsychiatric problems (e.g. depression, anxiety and sleep disturbance)
3.2. Healthcare resource utilisation (as a sub-study outcome)
3.3. Health-related quality-of-life (as a sub-study outcome)

_____

Previous secondary outcome measures:

1. Efficacy
1.1. Proportion of participants with HIV-RNA ≥50 copies/mL at 48 and 96 weeks using the FDA snapshot algorithm
1.2. Proportion of participants with HIV-RNA ≥1000 copies/mL (confirmed) by week 96
1.3. The number and type of HIV mutations at confirmed virological rebound
1.4 HIV-RNA <50 copies/mL and no switch to second-line ART for treatment failure at 24, 48, 64 and 96 weeks

2. Safety
2.1. 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
2.2. Incidence of clinical events (WHO 3 and 4 events; death)
2.3. Incidence of serious, grade 3 and 4, and treatment-modifying grade 1-2 adverse events over 96 weeks
2.4. The proportion of participants with any change from baseline ART regimen by week 96
2.5. Change in CD4+ and CD8+ T-cell count from baseline to 48 and 96 weeks

3. Patient-reported outcomes
3.1. Adherence, acceptability, well-being, and neuropsychiatric toxicities
3.2. Healthcare resource utilisation (as a sub-study outcome)
3.3. Health-related quality-of-life (as a sub-study outcome)

Overall trial start date

01/01/2020

Overall trial end date

31/12/2024

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

Current inclusion criteria as of 07/04/2020:
1. HIV-1-infected
2. Aged 12-19 years
3. Aware of HIV status
4. On ART for ≥1 year, with no previous regimen change for treatment failure
5. On ART consisting of DTG, tenofovir and lamivudine/emtricitabine for ≥1 month prior to screening
6. Virologically suppressed with all HIV-1 RNA viral loads < 50copies/ml* in the last 12 months up to and including screening. Additionally there must be one result < 50copies/ml* at least 12 months prior to screening and the viral load at trial screening must be < 50 copies/ml*
7. Girls who are sexually active must be willing to adhere to highly effective methods of contraception**
8. Written informed consent/assent provided by participant (if aged 18 to 19 years) and/or carer/legal guardian (if participate aged 12 to 17 years) as appropriate
9. Written informed assent in participates aged 12 to 17 years

*VL <100 copies/ml is allowed for diluted samples with maximum dilution 1:5, except for the screening sample where the VL must be < 50 copies/ml in an undiluted sample
**Highly effective contraception are injectable, implantable, oral and intrauterine contraceptives which have an expected failure rate <1% per year

______

Previous inclusion criteria:

1. HIV-1-infected
2. Aged 12-19 years
3. Aware of HIV status
4. On ART consisting of 2NRTI and a third agent (with no previous regimen change for treatment failure)
5. On ART for ≥1 year
6. On DTG-based ART for ≥1 month prior to screening
7. Virologically suppressed with all HIV-1 RNA viral loads <50copies/mL* in the last 12 months up to and including screening. Additionally there must be one result <50copies/ml* at least 12 months prior to screening and the viral load at trial screening must be <50 copies/mL
9. Written informed consent/assent provided by participant and/or carer/legal guardian as appropriate

*VL <100 copies/ml is allowed for diluted samples with maximum dilution 1:5, except for the screening sample where the VL must be <50 copies/ml in an undiluted sample

Participant type

Patient

Age group

Mixed

Gender

Both

Target number of participants

460 participants with 230 in each arm

Participant exclusion criteria

Current exclusion criteria as of 07/04/2020:

1. Females who are pregnant or breastfeeding
2. Females who plan to become pregnant during the trial follow-up or are unwilling to use a highly effective method of contraception** for the duration of the trial if sexually active
3. Moderate or High risk score on the Columbia-Suicide Severity Rating Scale
4. On treatment for any active TB
5. Contraindication to continued receipt of dolutegravir or any formulation of tenofovir, emtricitabine/lamivudine
6. Underlying medical condition that in the opinion of the Investigator precludes participation
7. Previous randomisation in the LATA trial

**Highly effective contraception are injectable, implantable, oral and intrauterine contraceptives which have an expected failure rate <1% per year

_____

Previous exclusion criteria:

1. Females who are pregnant or breastfeeding
2. Females who plan to become pregnant during the trial follow-up or are unwilling to avoid pregnancy* for 96 weeks
3. Moderate or High risk score on the Columbia-Suicide Severity Rating Scale **
4. On treatment for any active TB
5. Contraindication to receipt of dolutegravir, any formulation of tenofovir, emtricitabine/lamivudine
6. Previous randomisation in the LATA trial
*methods of avoiding pregnancy include the following: use depot or implant hormonal contraception, oral contraception or intrauterine device.
**Participants initially ineligible on the basis of a moderate or high risk score on the Columbia-Suicide Severity Rating Scale if in the opinion of the Investigator it is safe for them to be rescreened

Recruitment start date

01/07/2021

Recruitment end date

01/04/2022

Locations

Countries of recruitment

Kenya, South Africa, Uganda, Zimbabwe

Trial participating centre

Baylor College of Medicine Children’s Foundation
Block 5 Mulago Hospital P.O Box 72052
Kampala
N/A
Uganda

Trial participating centre

Joint Clinical Research Centre (JCRC)
Plot 101 Lubowa Estates, off Entebbe road, P.O. Box 10005 Wakiso District,
Kampala
N/A
Uganda

Trial participating centre

University of Zimbabwe Clinical Research Centre (UZCRC)
1578 Avondale
Harare
N/A
Zimbabwe

Trial participating centre

Moi University, AMPATH Centre
Nandi Road
Eldoret
4606-30100
Kenya

Trial participating centre

Department of Paediatrics and Child Health, King Edward VIII Hospital
Nelson R Mandela School of Medicine University of KwaZulu-Natal Sydney Rd Umbilo
Durban
4013
South Africa

Sponsor information

Organisation

University College London

Sponsor details

Gower St
Bloomsbury
London
WC1E 6BT
United Kingdom
+44 (0)20 7679 2000
mrcctu.bplata@ucl.ac.uk

Sponsor type

University/education

Website

http://www.ucl.ac.uk/

Funders

Funder type

Government

Funder name

European and Developing Countries Clinical Trials Partnership

Alternative name(s)

A Parceria entre a Europa e os Países em Desenvolvimento para a Realização de Ensaios Clínicos, The European & Developing Countries Clinical Trials Partnership, Le partenariat Europe-Pays en développement pour les essais cliniques, EDCTP

Funding Body Type

private sector organisation

Funding Body Subtype

International organizations

Location

Netherlands

Funder name

Medical Research Council

Alternative name(s)

MRC

Funding Body Type

government organisation

Funding Body Subtype

National government

Location

United Kingdom

Results and Publications

Publication and dissemination plan

Open access publication(s) in a high impact peer-reviewed journal.

IPD sharing statement:
The datasets generated during and/or analysed during the current study will be stored in a publically available repository. The EDCTP2 programme is funded under the Horizon 2020 programme (H2020) and is committed to open
access. Open access refers to the practice of providing online access to scientific information that is free of
charge to the end-user and reusable. This encompasses:
- Peer-reviewed scientific research articles (published in scholarly journals)
- Research data (data underlying publications, curated data and/or raw data).

Intention to publish date

31/12/2025

Participant level data

Stored in repository

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

14/10/2020: The recruitment start date was changed from 01/10/2020 to 01/07/2021. 07/04/2020: The following changes were made to the trial record: 1. The ethics approval was added. 2. The scientific title was changed from "Breather Plus: A randomised open-label 2-arm, 96-week trial evaluating the efficacy, safety and acceptability of short cycle therapy (5 days on, 2 days off) dolutegravir-based combination antiretroviral therapy (ART) compared to daily dolutegravir-based ART in virologically suppressed HIV-infected adolescents aged 12 to 19 years in sub-Saharan Africa" to "Breather Plus: 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" 3. The hypothesis was changed. 4. The interventions were changed. 5. The primary outcome measure was changed. 6. The secondary outcome measures were changed. 7. The inclusion criteria were changed. 8. The exclusion criteria were changed. 12/02/2020: Trial’s existence confirmed by European and Developing Countries Clinical Trials Partnership.