SMILE: Strategy for Maintenance of HIV suppression with dolutegravir + darunavir/ritonavir in children (PENTA 17)
| ISRCTN | ISRCTN11193709 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN11193709 |
| EudraCT/CTIS number | 2013-001476-37 |
| Secondary identifying numbers | PENTA 17 |
- Submission date
- 19/02/2015
- Registration date
- 06/03/2015
- Last edited
- 12/06/2023
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Infections and Infestations
Plain English Summary
Background and study aims
The human immunodeficiency virus (HIV) is a virus that attacks the immune system, making an affected person less able to fight infection and disease. It can be caught though unprotected sex, sharing drug needles, via transfusions of contaminated blood and blood products and from the mother to her baby during pregnancy, birth and breastfeeding. There is no cure for the condition, but there are a number of drug treatments that enable HIV+ people to live a long and healthy life. Acquired immune deficiency syndrome (AIDS) is the last stage of HIV infection, at which point the immune system is unable to fight life-threatening infections. With early diagnosis and effective treatment, most people with HIV do not go on to develop AIDS. SMILE is a study that will compare two different HIV (antiretroviral) medicine combinations. Taking antiretroviral medicines every day without missing a dose is important. This is to stop the virus becoming resistant which can happen if the virus levels in the blood are not low enough. However, some young people experience difficulty in taking several medications every day, particularly if this is more than once a day, and so doctors and scientists are now working towards easier ways for people to take the medicines. Newer antiretrovirals which are taken once daily include Prezista (darunavir) which is taken with a small dose of Norvir (ritonavir) and dolutegravir. In SMILE we will examine whether it is safe and effective to take Prezista + Norvir + dolutegravir compared to continuing to take current antiretroviral medications. Also, NRTIs are a particularly prone to cause adverse side effects. Therefore it may be important to reduce cumulative NRTI exposure in children.
Who can participate?
HIV+ children aged between 6-18 years
What does the study involve?
Children participating in the study are randomized by age (6 to <12 years, 12 to <18 years) and region (Africa vs non Africa). In each randomised arm, at least 70 children by age group are included. Those in group 1 receive the NRTI-sparing regimen - dolutegravir + darunavir/ritonavir (DRV/r) (DUAL). Those in group 2 receive the usual standard of care (triple anti-retroviral therapy including 2 NRTIs + boosted PI/NNRTI) (TRIPLE). All participants are followed until the last patient recruited reaches week 48. The period of recruitment is 72 weeks.
What are the possible benefits and risks of participating?
As the study medicines only need to be taken once a day, it is expected that participants will find it easier to remember to take their medicines and suffer fewer long term side-effects. Possible disadvantages include the participants having to take more trips to the clinic, and, for patients in group 1, taking Prezista and dolutegravir together with the low dose of Norvir will not be as effective as their usual medicine at keeping the level of virus low. Side effects not previously experienced could also occur such as headache, tummy pain, nausea, rash, cough or insomnia.
Where is the study run from?
A total of 96 hospitals internationally are taking part in the study.
When is the study starting and how long is it expected to run for?
January 2013 to July 2018
Who is funding the study?
PENTA Foundation (Italy)
Who is the main contact?
Mr Luigi Comacchio
luigi.comacchio@pentafoundation.org
Contact information
Public
Torre di Ricerca Pediatrica
Corso Stati Uniti 4
Padova
35124
Italy
| Phone | +390498215448 |
|---|---|
| luigi.comacchio@pentafoundation.org |
Study information
| Study design | A two arm parallel group, non-inferiority, open-label, multi-centre, randomised controlled trial. |
|---|---|
| Primary study design | Interventional |
| Secondary study design | |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Scientific title | A two-arm, Phase 2/3 multicentre, open-label, randomised study evaluating safety and antiviral effect of current standard antiretroviral therapy compared to once daily integrase inhibitor administered with darunavir/ritonavir (DRV/r) in HIV-1 infected, virologically suppressed paediatric participants. |
| Study acronym | SMILE |
| Study hypothesis | Current hypothesis as of 06/08/2019: Children with chronic HIV infection on ART with suppressed viral load will maintain similar levels of suppression with once daily integrase inhibitor (INSTI) + darunavir/r compared to continued standard of care triple ART. Previous hypothesis: Children with chronic HIV infection on ART with suppressed viral load will maintain similar levels of suppression with elvitegravir + darunavir/r compared to continued standard of care triple ART. |
| Ethics approval(s) | French Ethics Committee - submitted |
| Condition | HIV infection |
| Intervention | Current intervention as of 06/08/2019: Eligible participants will be randomised in a 1:1 ratio to switch to once daily INSTI + DRV/r or continue triple therapy. Randomisation will be stratified by age (6 to <12 years, 12 to <18 years) and region (African sites vs non-African sites) using permuted blocks of randomly varying sizes.The once-daily INSTI to be used is dolutegravir. Children weighing 40 kg or more will receive 800 mg darunavir, 100 mg ritonavir and 50 mg dolutegravir. Previous intervention: Arm 1: NRTI-sparing regimen - elvitegravir (EVG) + darunavir/ritonavir (DRV/r) Arm 2: Standard of care (triple anti-retroviral therapy including 2 NRTIs + boosted PI/NNRTI) |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase II/III |
| Drug / device / biological / vaccine name(s) | Current drug names as of 06/08/2019: 1. Dolutegravir 2. Darunavir 3. Ritonavir Previous drug names: 1. Elvitegravir 2. Darunavir 3. Ritonavir |
| Primary outcome measure | Percentage of patients with HIV-1 RNA ever ≥50 copies/ml (confirmed within 4 weeks) at any time up to week 48 |
| Secondary outcome measures | Percentage of patients with HIV-1 RNA ever ≥ 50 c/mL (confirmed within 4 weeks) at any time up to week 48 1. Percentage of patients with HIV-1 RNA < 50 c/mL at week 48 2. Percentage of patients with HIV-1 RNA ≥ 50 c/mL at week 24 3. Percentage of patients withHIV-1 RNA ≥ 400c/mL at week 24 and week 48 4. All grade 3 or 4 clinical adverse events (particularly lipodystrophy) 5. All grade 3 or 4 laboratory adverse events 6. Any adverse event at least possibly related to study drugs or leading to treatment modifications 7. Occurrence of new resistance mutations 8. Changes in CD4 (absolute and percentage) from baseline to weeks 24 and 48 9. Change in ART (defined as any change from the ART regimen at randomisation) 10. New or recurrent CDC/WHO stage C or severe stage B event or death 11. Blood lipids 12. Adherence as measured by questionnaire and visual analogue scale 13. Acceptability and quality of life over 48 weeks as assessed by patient completed questionnaires 14. Height and weight 15. Tanner scales (in participants aged over 8 years) 16. Date of first menses |
| Overall study start date | 01/01/2013 |
| Overall study end date | 30/09/2020 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Child |
| Lower age limit | 6 Years |
| Upper age limit | 18 Years |
| Sex | Both |
| Target number of participants | 300 |
| Total final enrolment | 318 |
| Participant inclusion criteria | 1. HIV-1 infected children weighing ≥ 17 kg at the screening visit 2. Aged 6 to < 18 years old 3. Parents or guardians, and children where appropriate, willing and able to give informed consent and to adhere to the protocol 4. Children must have all HIV-1 RNA viral load <50c/mL for at least 12 months with a minimum of two separate results before screening. 5. Children on a 3-drug PI/r or NNRTI containing regimen for at least 6 months. 6. Children/parents/guardians prepared to switch if randomised to elvitegravir + darunavir/ritonavir arm 7. Children and parents prepared to restart the current ART regimen after simplification if viral load restart criteria are met (see Section 5.5) 8. For children aged 6-12 either: 8.1. Children and caregivers are willing to participate in the lead-in PK study if the child is aged 6-12 and the PK study is still enrolling children in their weight band* OR 8.2. Data from the lead-in PK study have been analysed and children aged 6-12 can be enrolled directly into the main study * only children randomised to Arm 1 will take part |
| Participant exclusion criteria | 1. Receiving or requiring agents with interactions with darunavir, RTV, or EVG 2. Evidence of resistance to DRV or integrase inhibitors (for participants in clinical sites where resistance testing is standard of care) 3. Previous exposure to integrase inhibitors for more than 2 weeks 4. History of previous encephalopathy 5. Intercurrent illness (randomisation can take place after the illness resolves) 6. Creatinine, AST or ALT of grade 3 or above at screening. 7. Diagnosis of tuberculosis and on anti-tuberculosis treatment (children can be enrolled after successful tuberculosis treatment) 8. Hepatitis B or Hepatitis C co-infection 9. Pregnancy or risk of pregnancy in girls of child-bearing potential unless committed to taking effective contraception |
| Recruitment start date | 01/09/2015 |
| Recruitment end date | 31/07/2018 |
Locations
Countries of recruitment
- Argentina
- Belgium
- Brazil
- Denmark
- England
- France
- Germany
- Greece
- Ireland
- Italy
- Mexico
- Netherlands
- Poland
- Portugal
- Romania
- South Africa
- Spain
- Sweden
- Switzerland
- Thailand
- Uganda
- United Kingdom
Study participating centres
Paris
75019
France
Birmingham
B9 5SS
United Kingdom
London
SE5 9RS
United Kingdom
Westminster Bridge Road
London
SE1 7EH
United Kingdom
Sponsor information
Research organisation
Torre di Ricerca Pediatrica
Corso Stati Uniti 4
Padova
35127
Italy
| Phone | +390498215448 |
|---|---|
| luigi.comacchio@pentafoundation.org | |
| Website | www.penta-id.org |
"ROR" |
https://ror.org/00d7mpc92 |
Funders
Funder type
Research organisation
No information available
Results and Publications
| Intention to publish date | |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Not expected to be made available |
| Publication and dissemination plan | Regarding publications: we intend to publish the study results at the end of the trial and will present the trial at several conferences throughout its duration |
| IPD sharing plan | Not provided at time of registration |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Basic results | 22/12/2021 | 20/05/2022 | No | No | |
| Results article | 02/06/2023 | 12/06/2023 | Yes | No |
Editorial Notes
12/06/2023: Publication reference and total final enrolment added.
20/05/2022: EU Clinical Trials Register results added.
06/08/2019: The following changes have been made to reflect the change of integrase inhibitor used from elvitegravir to dolutegravir:
1. The scientific title has been changed from "A phase 2/3 multicentre, open-label, randomised study evaluating safety and antiviral effect of elvitegravir (EVG) administered with darunavir/ritonavir (DRV/r) compared to current standard antiretroviral therapy in HIV-1 infected, virologically suppressed paediatric participants." to "A two-arm, Phase 2/3 multicentre, open-label, randomised study evaluating safety and antiviral effect of current standard antiretroviral therapy compared to once daily integrase inhibitor administered with darunavir/ritonavir (DRV/r) in HIV-1 infected, virologically suppressed paediatric participants."
2. The public title has been changed from "SMILE: Strategy for Maintenance of HIV suppression with elvitegravir + darunavir/ritonavir in children (PENTA 17)" to "SMILE: Strategy for Maintenance of HIV suppression with dolutegravir + darunavir/ritonavir in children (PENTA 17)".
3. The study hypothesis has been changed.
4. The overall trial end date has been changed from 31/07/2018 to 30/09/2020.
5. The intervention has been changed.
6. The drug names have been changed.
7. Heartlands Hospital, King's College Hospital and Evelina London Children's Hospital have been added as trial participating centres.
8. The plain English summary has been changed to replace "elvitegravir" with "dolutegravir" throughout.
