ODYSSEY (PENTA 20)

PENTA Foundation792 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

792

Conditions

HIV Infection

Interventions

DolutegravirDRUG

Standard of CareDRUG

PI or non nucleoside transcriptase inhibitors

Eligibility

Sex: ALLMin age: 28 DaysMax age: 18 Years

Medical Language ↔ Plain English

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

Locations (28)

Universitata Frankfurt

Frankfurt, Germany

Outcomes

Primary Outcomes

Difference in Proportion With Failure (Clinical or Virological)

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

Time frame: 96 weeks post randomisation

Secondary Outcomes

HIV-1 RNA <50c/ml at 96 Weeks

Proportion of children with viral load suppression \<50 c/ml at 96 weeks.

Time frame: 96 weeks post randomisation

HIV-1 RNA <400c/mL at 96 Weeks

Proportion of children with viral load suppression \<400 c/ml at 96 weeks

Time frame: 96 weeks post randomisation

Mean Change in CD4 Count From Baseline to Week 96

Reporting mean change from the global baseline value across both arms.

Time frame: 96 weeks post randomisation

Mean Change in Total Cholesterol From Baseline to Week 96

Reporting mean change from global baseline value across both arms.

Time frame: 96 weeks post randomisation

Serious Adverse Events

Incidence of serious adverse events

Time frame: 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).

Data from ClinicalTrials.gov

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UkE Eppendorf Hamburg

Centro Materno-Infantil de Norte

Porto, Portugal

King Edward VIII Hospital

Durban, South Africa

Africa Health Research Institute (AHRI)

Hlabisa, South Africa

PHRU Klerksdorp

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

...and 18 more locations

Grade 3 or Above Clinical and Laboratory Adverse Events

Incidence of new clinical and laboratory grade 3 and 4 adverse events

Time frame: 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).

Adverse Events Leading to ART Modification Any Grade

Incidence of adverse events (of any grade) leading to treatment modification

Time frame: Randomised Phase

Treatment Failure by 48 Weeks

Treatment failure by 48 weeks. Difference in proportion with clinical or virological failure (as defined above)

Time frame: 48 weeks post randomisation

Treatment Failure by 144 Weeks

Treatment failure by 144 weeks. Difference in proportion with clinical or virological failure (as defined above)

Time frame: 144 weeks post randomisation

WHO 4, Severe WHO 3 Events and Death

Rate of clinical events : WHO 4, severe WHO 3 events and death

Time frame: 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).

Per Protocol: Treatment Failure by 96 Weeks

Per protocol: treatment failure by 96 weeks post randomisation

Time frame: 96 weeks post randomisation

Any Drug Class Resistance After Virologic Failure

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.

Time frame: 96 weeks post randomisation

NRTI Resistance After Virologic Failure

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.

Time frame: 96 weeks post randomisation

NNRTI Resistance After Virologic Failure

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.

Time frame: 96 weeks post randomisation

PI Resistance After Virologic Failure

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.

Time frame: 96 weeks post randomisation

INSTI Resistance After Virologic Failure

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.

Time frame: 96 weeks post randomisation

Emerging Resistance to Any Drug Class After Virologic Failure

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.

Time frame: 96 weeks post randomisation

NRTI Emerging Resistance After Virologic Failure

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.

Time frame: 96 weeks post randomisation

NNRTI Emerging Resistance After Virologic Failure

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.

Time frame: 96 weeks post randomisation

PI Emerging Resistance After Virologic Failure

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.

Time frame: 96 weeks post randomisation

INSTI Emerging Resistance After Virologic Failure

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 frame: 96 weeks post randomisation

Time to Any New or Recurrent AIDS Defining Event (WHO 4) or Severe WHO 3 Events

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)

Time frame: 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).

Adherence Questionnaire

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)

Time frame: 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).

Health-related Quality of Life Questionnaire

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)

Time frame: 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).

Acceptability Questionnaire

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)

Time frame: 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).