Strategy for Maintenance of HIV Suppression With Once Daily Integrate Inhibitor+Darunavir/Ritonavir in Children (SMILE)

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.

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 Overview

• Status: Completed
• Conditions: HIV Infection
• Intervention / Treatment: Drug: SOC; Drug: DTG +DRV/r

Detailed Description

A two arm parallel group, non-inferiority, open-label, multi-centre, randomised controlled trial.

• Study Type: Interventional
• Enrollment (Actual): 318
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
    • Hospital Garrahan
• France
  • Cannes, France
    • Centre Hospitalier Andrée Rosemon
  • Nantes, France
    • CHU Hôtel Dieu - Nantes
• Mexico
  • Mexico City, Mexico
    • Hospital General Mexico
• Portugal
  • Lisbon, Portugal
    • Hospital de Dona Estefânia - CHLC
  • Porto, Portugal
    • Centro Materno-Infantil de Norte
• South Africa
  • Cape Town, South Africa
    • FAM-CRU
  • Soweto, South Africa
    • PHRU
• Spain
  • Barcelona, Spain
    • Hospital San Joan de Deu
  • Madrid, Spain
    • Hospital La Paz
  • Madrid, Spain
    • Hospital Universitario 12 de Octubre
  • Madrid, Spain
    • Hospital Clinico San Carlos
  • Madrid, Spain
    • Hospital General Gregorio Marañón
  • Madrid, Spain
    • Hospital Universitario de Getafe
• Switzerland
  • Bern, Switzerland
    • Inselpital Bern
  • Saint Gallen, Switzerland
    • Kantonsspital St Gallen
  • Zürich, Switzerland
    • Kinderspital Zürich
• Thailand
  • Chanthaburi, Thailand
    • Prapokklao Hospital
  • Chiang Mai, Thailand
    • Nakornping Hospital
  • Chiang Rai, Thailand
    • Chiangrai Prachanukroh Hospital
  • Kalasin, Thailand
    • Kalasin Hospital
  • Khon Kaen, Thailand
    • Khonkaen Hospital
  • Phayao, Thailand
    • Phayao Hospital
• Uganda
  • Kampala, Uganda
    • Baylor
  • Mbarara, Uganda
    • JCRC
• Ukraine
  • Kiev, Ukraine
    • Kiev
  • Kryvyi Rih, Ukraine
    • Kryvyi Rih
• United Kingdom
  • Birmingham, United Kingdom
    • Birmingham Heartlands Hospital
  • Bristol, United Kingdom
    • Bristol Hospital
  • London, United Kingdom
    • Evelina Children Hospital, St Thomas's Hospital
  • London, United Kingdom
    • King's College Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. HIV-1 infected children aged ≥ 12 years old and weighing ≥40kg* at the screening visit
2. Aged 12 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 loads <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 24 weeks
6. Children/parents/guardians prepared to switch if randomised to once daily integrase inhibitor + DRV/RTV 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. Be affiliated or beneficiary to Health Social security scheme (in countries where this is mandatory)

   • Initially enrolment will be of participants ≥ 12 years old and ≥40kg only. DTG 50 mg will be supplied by ViiV Healthcare.

     • As more data become available on younger children, a protocol amendment is planned to include younger children and/or lower weight bands.

Exclusion Criteria:

1. Receiving or requiring agents with interactions with DRV, RTV, or any once daily integrase inhibitor (Appendix 14)
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. Intercurrent illness (randomisation can take place after the illness resolves)
5. Creatinine ≥ 1.8ULN or ALT ≥ 5ULN or ALT ≥ 3ULN and bilirubin ≥2ULN at screening.
6. Patients with severe hepatic impairment or unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent jaundice), known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
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
10. History or presence of known allergy or some other contraindication to the study drugs or their components as described in the SmPC

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard of Care group (SOC); triple anti-retroviral therapy including 2 NRTIs + boosted PI/NNRTI	Drug: SOC; Standard of care (continuing triple anti-retroviral therapy including 2 NRTIs + boosted PI/NNRTI)
Experimental: DTG+DRV/r; NRTI-sparing regimen: Once daily integrase inhibitor (INSTI) + darunavir/ritonavir (DRV/r)	Drug: DTG +DRV/r; NRTI-sparing regimen: Once daily integrase inhibitor (INSTI) + darunavir/ritonavir (DRV/r)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percentage of patients with HIV-1 RNA ever ≥ 50 c/mL (confirmed within 4 weeks)	at any time up to week 48

Secondary Outcome Measures

Outcome Measure	Time Frame
Percentage of patients with HIV-1 RNA < 50 c/mL	at week 48
Percentage of patients with HIV-1 RNA ≥ 50 c/mL	at week 24
Percentage of patients withHIV-1 RNA ≥ 400c/mL	at week 24 and week 48
Percentage of patients with any grade 3 or 4 clinical adverse events (particularly lipodystrophy); any grade 3 or 4 laboratory adverse events	over 48 weeks
All grade 3 or 4 laboratory adverse events	over 48 weeks
Any adverse event at least possibly related to study drugs or leading to treatment modifications	over 48 weeks
Occurrence of new resistance mutations	over 48 weeks
Changes in CD4 (absolute and percentage)	from baseline to weeks 24 and 48
Change in ART (defined as any change from the ART regimen at randomisation)	at week 0
New or recurrent CDC/WHO stage C or severe stage B event or death	over 48 weeks
Blood lipids	over 48 weeks
Adherence as measured by questionnaire and visual analogue scale	over 48 weeks
Acceptability and quality of life over 48 weeks as assessed by patient completed questionnaires	over 48 weeks
Tanner scales (in participants aged over 8 years)	over 48 weeks
Date of first menses	over 48 weeks
Height	Over 48 weeks
Weight	over 48 weeks

Collaborators and Investigators

• Sponsor: PENTA Foundation
• Collaborators: Institut National de la Santé Et de la Recherche Médicale, France; MRC CTU at UCL; PHPT

Study record dates

Study Major Dates

• Study Start: June 1, 2016
• Primary Completion (Actual): August 1, 2020
• Study Completion (Actual): October 1, 2020

Study Registration Dates

• First Submitted: February 19, 2015
• First Submitted That Met QC Criteria: March 3, 2015
• First Posted (Estimate): March 9, 2015

Study Record Updates

• Last Update Posted (Actual): March 30, 2021
• Last Update Submitted That Met QC Criteria: March 25, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections
• Other Study ID Numbers: SMILE (PENTA 17); ANRS1 52 (Other Identifier: France Agency for research on AIDS and viral hepatitis)