ODYSSEY (PENTA 20)

Phase 2

Completed

Conditions: HIV Infection

Interventions: Drug: Standard of Care
Drug: Dolutegravir

Registration Number: NCT02259127

Lead Sponsor: PENTA Foundation

Brief Summary: A new anti-HIV medicine (Dolutegravir) combined with 2 currently used anti-HIV medicines is non-inferior to the standard combination of medicines used in terms of efficacy and better in terms of toxicity.

Detailed Description: The ODYSSEY study was an international randomised trial evaluating dolutegravir based antiretroviral therapy (ART) versus standard of care in HIV-infected children aged less than 18 years who were starting first line treatment (ODYSSEY A) or switching to second line treatment (ODYSSEY B). Participants had visits 4 weeks and 12 weeks after randomisation and every 12 weeks subsequent of that. They were followed up for a minimum of 96 weeks. The primary objective of the study was to assess the difference in virological or clinical failure by 96 weeks between children receiving a DTG-based regimen and those on standard of care.

At the end of study visit for the randomised phase, children and carers were invited to consent to extended follow-up. Children's visit schedules and care were as per local clinic guidelines. Participants were followed up until July 2023 in this phase of the trial. The objectives of the extended follow-up were two-fold: 1. to provide safety data for ViiV Healthcare for participants who, in the opinion of the treating physician, continue to derive benefit from dolutegravir and receive dolutegravir from ViiV Healthcare where it was not available through their country's national HIV treatment programme; 2. to monitor long-term safety and effectiveness of dolutegravir versus standard of care.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 792

Inclusion Criteria

ALL PATIENTS:

Children ≥28 days and <18 years weighing ≥3kg with confirmed HIV-1 infection
Parents/carers and children, where applicable, give informed written consent
Girls aged 12 years or older who have reached menses must have a negative pregnancy test at screening and be willing to adhere to effective methods of contraception if sexually active
Children with co-infections who need to start ART can be enrolled into ODYSSEY according to local/national guidelines
Parents/carers and children, where applicable, willing to adhere to a minimum of 96 weeks' follow-up
- Children weighing 3 to <14kg must be eligible and willing to participate in the Weight band (WB)-Pharmacokinetics (PK)1 substudy unless direct enrolment for the child's weight band has opened following the WB-PK1 substudy and/or dosing information has become available from the IMPAACT P1093 DTG dose-finding study.

ADDITIONAL CRITERIA FOR ODYSSEY A:

• Planning to start first-line ART

ADDITIONAL CRITERIA FOR ODYSSEY B:

Planning to start second-line ART defined as either: (i) switch of at least 2 ART drugs due to treatment failure; or (ii) switch of only the third agent due to treatment failure where drug sensitivity tests show no mutations conferring Nucleoside Reverse Transcriptase Inhibitor (NRTI) resistance
Treated with only one previous ART regimen. Single drug substitutions for toxicity, simplification, changes in national guidelines or drug availability are allowed
At least one NRTI with predicted preserved activity available for a background regimen
In settings where resistance tests are routinely available, at least one new active NRTI from tenofovir disoproxil fumarate, abacavir or zidovudine should have preserved activity based on cumulative results of resistance tests
In settings where resistance tests are not routinely available, children who are due to switch according to national guidelines should have at least one new NRTI predicted to be available from tenofovir disoproxil fumarate, abacavir or zidovudine
Viral load ≥ 500 c/ml at screening visit

Exclusion Criteria

History or presence of known allergy or contraindications to dolutegravir
History or presence of known allergy or contraindications to proposed available NRTI backbone or proposed available SOC third agent.
Alanine aminotransferase (ALT) ≥ 5 times the upper limit of normal, OR ALT ≥3x upper limit of normal and bilirubin ≥2x upper limit of normal
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)
Anticipated need for Hepatitis C virus (HCV) therapy during the study
Pregnancy or breastfeeding
Evidence of lack of susceptibility to integrase inhibitors or more than a 2-week exposure to antiretrovirals of this class

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
SOC arm	Standard of Care	Standard of Care (SOC) for ODYSSEY A is defined as a PI or non nucleoside transcriptase inhibitors + 2 or 3 nucleoside transcriptase inhibitor SOC for ODYSSEY B is defined as a PI or non nucleoside transcriptase inhibitor+ 2 nucleoside transcriptase inhibitors
DTG arm	Dolutegravir	DTG + 2 nucleoside transcriptase inhibitors

Primary Outcome Measures

Name	Time	Method
Difference in Proportion With Failure (Clinical or Virological)	96 weeks post randomisation	Treatment failure by 96 weeks. Estimated using time to the first occurrence of any of the following components: * Insufficient virological response defined as \< 1 log10 drop at week 24 and switch to second/third line ART for treatment failure * Viral Load (VL)\>400 c/ml at or after 36 weeks confirmed by next visit * Death due to any cause * Any new or recurrent AIDS defining event (WHO 4) or severe WHO 3 events, adjudicated by the Endpoint Review Committee

Secondary Outcome Measures

Name	Time	Method
HIV-1 RNA <50c/ml at 96 Weeks	96 weeks post randomisation	Proportion of children with viral load suppression \<50 c/ml at 96 weeks.
Mean Change in Total Cholesterol From Baseline to Week 96	96 weeks post randomisation	Reporting mean change from global baseline value across both arms.
Grade 3 or Above Clinical and Laboratory Adverse Events	Randomised phase: follow-up was censored when the last participant reached 96 weeks of follow-up (142 weeks (IQR:124 to 159) in ≥14kg cohort and 124 weeks (112 to 137) in <14kg cohort).	Incidence of new clinical and laboratory grade 3 and 4 adverse events
HIV-1 RNA <400c/mL at 96 Weeks	96 weeks post randomisation	Proportion of children with viral load suppression \<400 c/ml at 96 weeks
Serious Adverse Events	Randomised phase: follow-up was censored when the last participant reached 96 weeks of follow-up (142 weeks (IQR:124 to 159) in ≥14kg cohort and 124 weeks (112 to 137) in <14kg cohort).	Incidence of serious adverse events
Treatment Failure by 48 Weeks	48 weeks post randomisation	Treatment failure by 48 weeks. Difference in proportion with clinical or virological failure (as defined above)
Mean Change in CD4 Count From Baseline to Week 96	96 weeks post randomisation	Reporting mean change from the global baseline value across both arms.
Adverse Events Leading to ART Modification Any Grade	Randomised Phase	Incidence of adverse events (of any grade) leading to treatment modification
Treatment Failure by 144 Weeks	144 weeks post randomisation	Treatment failure by 144 weeks. Difference in proportion with clinical or virological failure (as defined above)
WHO 4, Severe WHO 3 Events and Death	Randomised phase: follow-up was censored when the last participant reached 96 weeks of follow-up (142 weeks (IQR:124 to 159) in ≥14kg cohort and 124 weeks (112 to 137) in <14kg cohort).	Rate of clinical events : WHO 4, severe WHO 3 events and death
Per Protocol: Treatment Failure by 96 Weeks	96 weeks post randomisation	Per protocol: treatment failure by 96 weeks post randomisation
NRTI Resistance After Virologic Failure	96 weeks post randomisation	NRTI resistance after virologic failure 96 weeks post randomisation. Major International AIDS Society (IAS) drug-resistance mutations were defined according to the 2019 update of the IAS drug-resistance mutations.
PI Resistance After Virologic Failure	96 weeks post randomisation	PI resistance after virologic failure 96 weeks post randomisation. Major International AIDS Society (IAS) drug-resistance mutations were defined according to the 2019 update of the IAS drug-resistance mutations.
Any Drug Class Resistance After Virologic Failure	96 weeks post randomisation	Any drug class resistance after virologic failure 96 weeks post randomisation Major International AIDS Society (IAS) drug-resistance mutations were defined according to the 2019 update of the IAS drug-resistance mutations.
NNRTI Resistance After Virologic Failure	96 weeks post randomisation	NNRTI resistance after virologic failure 96 weeks post randomisation. Major International AIDS Society (IAS) drug-resistance mutations were defined according to the 2019 update of the IAS drug-resistance mutations.
NRTI Emerging Resistance After Virologic Failure	96 weeks post randomisation	NRTI emerging resistance after virologic failure 96 weeks post randomisation Major International AIDS Society (IAS) drug-resistance mutations were defined according to the 2019 update of the IAS drug-resistance mutations. \>=14kg cohort: among participants with virologic failure and exposure to the drug class, percentage of participants with emerging resistance was estimated under an assumption of the same proportion of new resistance in participants with an available baseline resistance test and those without. \<14kg cohort: percentage reported for participants with whom a resistance test was available post-failure and at baseline, and exposed to drug-class during trial.
NNRTI Emerging Resistance After Virologic Failure	96 weeks post randomisation	NNRTI emerging resistance after virologic failure 96 weeks post randomisation Major International AIDS Society (IAS) drug-resistance mutations were defined according to the 2019 update of the IAS drug-resistance mutations. \>=14kg cohort: among participants with virologic failure and exposure to the drug class, percentage of participants with emerging resistance was estimated under an assumption of the same proportion of new resistance in participants with an available baseline resistance test and those without. \<14kg cohort: percentage reported for participants with whom a resistance test was available post-failure and at baseline, and exposed to drug-class during trial.
INSTI Resistance After Virologic Failure	96 weeks post randomisation	INSTI resistance after virologic failure 96 weeks post randomisation Major International AIDS Society (IAS) drug-resistance mutations were defined according to the 2019 update of the IAS drug-resistance mutations.
Emerging Resistance to Any Drug Class After Virologic Failure	96 weeks post randomisation	Emerging resistance to any drug class after virologic failure 96 weeks post randomisation Major International AIDS Society (IAS) drug-resistance mutations were defined according to the 2019 update of the IAS drug-resistance mutations. \>=14kg cohort: among participants with virologic failure and exposure to the drug class, percentage of participants with emerging resistance was estimated under an assumption of the same proportion of new resistance in participants with an available baseline resistance test and those without. \<14kg cohort: percentage reported for participants with whom resistance test was available post-failure and at baseline, and exposed to drug-class during trial.
Health-related Quality of Life Questionnaire	Randomised phase: follow-up was censored when the last participant reached 96 weeks of follow-up (142 weeks (IQR:124 to 159) in ≥14kg cohort and 124 weeks (112 to 137) in <14kg cohort).	Adapted from the Euro Quality of Life Questionnaire (Qol)-5D questionnaire The EQ5D-3L (3-level version of EQ-5D) questionnaire contains five questions about the participants' quality of life: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each question has three dimensions: no problems, some problems, and extreme problems. This analysis reports whether the participant reports any problems (some or extreme). Percentages are of participants completing at least one EQ5D-3L questionnaire during follow-up. Reported in \>=14kg cohort paper (https://www.nejm.org/doi/full/10.1056/NEJMoa2108793)
PI Emerging Resistance After Virologic Failure	96 weeks post randomisation	PI emerging resistance after virologic failure 96 weeks post randomisation Major International AIDS Society (IAS) drug-resistance mutations were defined according to the 2019 update of the IAS drug-resistance mutations. \>=14kg cohort: among participants with virologic failure and exposure to the drug class, percentage of participants with emerging resistance was estimated under an assumption of the same proportion of new resistance in participants with an available baseline resistance test and those without. \<14kg cohort: percentage reported for participants with whom a resistance test was available post-failure and at baseline, and exposed to drug-class during trial.
INSTI Emerging Resistance After Virologic Failure	96 weeks post randomisation	INSTI emerging resistance after virologic failure 96 weeks post randomisation Major International AIDS Society (IAS) drug-resistance mutations were defined according to the 2019 update of the IAS drug-resistance mutations. \>=14kg cohort: among participants with virologic failure and exposure to the drug class, percentage of participants with emerging resistance was estimated under an assumption of the same proportion of new resistance in participants with an available baseline resistance test and those without. \<14kg cohort: percentage reported for participants with whom a resistance test was available post-failure and at baseline, and exposed to drug-class during trial. The integrase gene was not sequenced for the standard of care arm.
Time to Any New or Recurrent AIDS Defining Event (WHO 4) or Severe WHO 3 Events	Randomised phase: follow-up was censored when the last participant reached 96 weeks of follow-up (142 weeks (IQR:124 to 159) in ≥14kg cohort and 124 weeks (112 to 137) in <14kg cohort).	Time to any new or recurrent AIDS defining event (WHO 4) or severe WHO 3 events adjudicated by the Endpoint Review Committee. Reported in \>=14kg and \<14kg papers. \>=14kg cohort paper (https://www.nejm.org/doi/full/10.1056/NEJMoa2108793) \<14kg cohort paper (https://www.thelancet.com/journals/lanhiv/article/PIIS2352-3018(22)00163-1/fulltext)
Adherence Questionnaire	Randomised phase: follow-up was censored when the last participant reached 96 weeks of follow-up (142 weeks (IQR:124 to 159) in ≥14kg cohort and 124 weeks (112 to 137) in <14kg cohort).	The proportion of adherence questionnaires where the participant/carer reports missing a dose within the last week will be compared between randomised groups. Reported in \>=14kg and \<14kg papers. \>=14kg cohort paper (https://www.nejm.org/doi/full/10.1056/NEJMoa2108793) \<14kg cohort paper (https://www.thelancet.com/journals/lanhiv/article/PIIS2352-3018(22)00163-1/fulltext)
Acceptability Questionnaire	Randomised phase: follow-up was censored when the last participant reached 96 weeks of follow-up (142 weeks (IQR:124 to 159) in ≥14kg cohort and 124 weeks (112 to 137) in <14kg cohort).	Number of participants reported to have problems with size, taste or swallowing of the medicines as assessed by Acceptability questionnaire Reported in \>=14kg and \<14kg papers. \>=14kg cohort paper (https://www.nejm.org/doi/full/10.1056/NEJMoa2108793) \<14kg cohort paper (https://www.thelancet.com/journals/lanhiv/article/PIIS2352-3018(22)00163-1/fulltext)

Trial Locations

Locations (27): Universitata Frankfurt
🇩🇪
Frankfurt, Germany
UkE Eppendorf Hamburg
🇩🇪
Hamburg, Germany
Centro Materno-Infantil de Norte
🇵🇹
Porto, Portugal
King Edward VIII Hospital
🇿🇦
Durban, South Africa
Africa Health Research Institute (AHRI)
🇿🇦
Hlabisa, South Africa
PHRU Klerksdorp
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Klerksdorp, South Africa
Kid-Cru
🇿🇦
Parow, South Africa
PHRU
🇿🇦
Soweto, South Africa
Hospital San Joan de Defu
🇪🇸
Barcelona, Spain
Hospital 12 de Octubre
🇪🇸
Madrid, Spain
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Universitata Frankfurt
🇩🇪Frankfurt, Germany