Safety and pharmacokinetics of oral and long-acting injectable cabotegravir or long-acting injectable rilpivirine in virologically suppressed adolescents with HIV (IMPAACT 2017/MOCHA) : a phase 1/2, multicentre, open-label, non-comparative, dose-finding study
Copyright © 2024 Elsevier Ltd. All rights reserved..
BACKGROUND: Combined intramuscular long-acting cabotegravir and long-acting rilpivirine constitute the first long-acting combination antiretroviral therapy (ART) regimen approved for adults with HIV. The goal of the IMPAACT 2017 study (MOCHA [More Options for Children and Adolescents]) was to assess the safety and pharmacokinetics of these drugs in adolescents.
METHODS: In this phase 1/2, multicentre, open-label, non-comparative, dose-finding study, virologically suppressed adolescents (aged 12-17 years; weight ≥35 kg; BMI ≤31·5 kg/m2) with HIV-1 on daily oral ART were enrolled at 15 centres in four countries (Botswana, South Africa, Thailand, and the USA). After 4-6 weeks of oral cabotegravir (cohort 1C) or rilpivirine (cohort 1R), participants received intramuscular long-acting cabotegravir or long-acting rilpivirine every 4 weeks or 8 weeks per the adult dosing regimens, while continuing pre-study ART. The primary outcomes were assessments of safety measures, including all adverse events, until week 4 for oral cabotegravir and until week 16 for long-acting cabotegravir and long-acting rilpivirine, and pharmacokinetic measures, including the area under the plasma concentration versus time curve during the dosing interval (AUC0-tau) and drug concentrations, at week 2 for oral dosing of cabotegravir and at week 16 for intramuscular dosing of cabotegravir and rilpivirine. Enrolment into cohort 1C or cohort 1R was based on the participant's pre-study ART, meaning that masking was not done. For pharmacokinetic analyses, blood samples were drawn at weeks 2-4 after oral dosing and weeks 4-16 after intramuscular dosing. Safety outcome measures were summarised using frequencies, percentages, and exact 95% CIs; pharmacokinetic parameters were summarised using descriptive statistics. This trial is registered at ClinicalTrials.gov, NCT03497676, and is closed to enrolment.
FINDINGS: Between March 19, 2019, and Nov 25, 2021, 55 participants were enrolled: 30 in cohort 1C and 25 in cohort 1R. At week 16, 28 (97%, 95% CI 82-100) of the 29 dose-evaluable participants in cohort 1C and 21 (91%; 72-99) of the 23 dose-evaluable participants in cohort 1R had reported at least one adverse event, with the most common being injection-site pain (nine [31%] in cohort 1C; nine [39%] in cohort 1R; none were severe). One (4%, 95% CI 0-22) participant in cohort 1R had an adverse event of grade 3 or higher, leading to treatment discontinuation, which was defined as acute rilpivirine-related allergic reaction (self-limiting generalised urticaria) after the first oral dose. No deaths or life-threatening events occurred. In cohort 1C, the week 2 median cabotegravir AUC0-tau was 148·5 (range 37·2-433·1) μg·h/mL. The week 16 median concentrations for the every-4-weeks and every-8-weeks dosing was 3·11 μg/mL (range 1·22-6·19) and 1·15 μg/mL (<0·025-5·29) for cabotegravir and 52·9 ng/mL (31·9-148·0) and 39·1 ng/mL (27·2-81·3) for rilpivirine, respectively. These concentrations were similar to those in adults.
INTERPRETATION: Study data support using long-acting cabotegravir or long-acting rilpivirine, given every 4 weeks or 8 weeks, per the adult dosing regimens, in virologically suppressed adolescents aged 12 years and older and weighing at least 35 kg.
FUNDING: The National Institutes of Health and ViiV Healthcare.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:11 |
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| Enthalten in: |
The lancet. HIV - 11(2024), 4 vom: 16. Apr., Seite e211-e221 |
| Sprache: |
Englisch |
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| Links: |
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| Themen: |
Anti-HIV Agents |
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| Anmerkungen: |
Date Completed 29.03.2024 Date Revised 16.04.2024 published: Print ClinicalTrials.gov: NCT03497676 Citation Status MEDLINE |
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| doi: |
10.1016/S2352-3018(23)00300-4 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Safety and pharmacokinetics of oral and long-acting injectable cabotegravir or long-acting injectable rilpivirine in virologically suppressed adolescents with HIV (IMPAACT 2017/MOCHA) |b a phase 1/2, multicentre, open-label, non-comparative, dose-finding study |
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| 500 | |a Date Revised 16.04.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a ClinicalTrials.gov: NCT03497676 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2024 Elsevier Ltd. All rights reserved. | ||
| 520 | |a BACKGROUND: Combined intramuscular long-acting cabotegravir and long-acting rilpivirine constitute the first long-acting combination antiretroviral therapy (ART) regimen approved for adults with HIV. The goal of the IMPAACT 2017 study (MOCHA [More Options for Children and Adolescents]) was to assess the safety and pharmacokinetics of these drugs in adolescents | ||
| 520 | |a METHODS: In this phase 1/2, multicentre, open-label, non-comparative, dose-finding study, virologically suppressed adolescents (aged 12-17 years; weight ≥35 kg; BMI ≤31·5 kg/m2) with HIV-1 on daily oral ART were enrolled at 15 centres in four countries (Botswana, South Africa, Thailand, and the USA). After 4-6 weeks of oral cabotegravir (cohort 1C) or rilpivirine (cohort 1R), participants received intramuscular long-acting cabotegravir or long-acting rilpivirine every 4 weeks or 8 weeks per the adult dosing regimens, while continuing pre-study ART. The primary outcomes were assessments of safety measures, including all adverse events, until week 4 for oral cabotegravir and until week 16 for long-acting cabotegravir and long-acting rilpivirine, and pharmacokinetic measures, including the area under the plasma concentration versus time curve during the dosing interval (AUC0-tau) and drug concentrations, at week 2 for oral dosing of cabotegravir and at week 16 for intramuscular dosing of cabotegravir and rilpivirine. Enrolment into cohort 1C or cohort 1R was based on the participant's pre-study ART, meaning that masking was not done. For pharmacokinetic analyses, blood samples were drawn at weeks 2-4 after oral dosing and weeks 4-16 after intramuscular dosing. Safety outcome measures were summarised using frequencies, percentages, and exact 95% CIs; pharmacokinetic parameters were summarised using descriptive statistics. This trial is registered at ClinicalTrials.gov, NCT03497676, and is closed to enrolment | ||
| 520 | |a FINDINGS: Between March 19, 2019, and Nov 25, 2021, 55 participants were enrolled: 30 in cohort 1C and 25 in cohort 1R. At week 16, 28 (97%, 95% CI 82-100) of the 29 dose-evaluable participants in cohort 1C and 21 (91%; 72-99) of the 23 dose-evaluable participants in cohort 1R had reported at least one adverse event, with the most common being injection-site pain (nine [31%] in cohort 1C; nine [39%] in cohort 1R; none were severe). One (4%, 95% CI 0-22) participant in cohort 1R had an adverse event of grade 3 or higher, leading to treatment discontinuation, which was defined as acute rilpivirine-related allergic reaction (self-limiting generalised urticaria) after the first oral dose. No deaths or life-threatening events occurred. In cohort 1C, the week 2 median cabotegravir AUC0-tau was 148·5 (range 37·2-433·1) μg·h/mL. The week 16 median concentrations for the every-4-weeks and every-8-weeks dosing was 3·11 μg/mL (range 1·22-6·19) and 1·15 μg/mL (<0·025-5·29) for cabotegravir and 52·9 ng/mL (31·9-148·0) and 39·1 ng/mL (27·2-81·3) for rilpivirine, respectively. These concentrations were similar to those in adults | ||
| 520 | |a INTERPRETATION: Study data support using long-acting cabotegravir or long-acting rilpivirine, given every 4 weeks or 8 weeks, per the adult dosing regimens, in virologically suppressed adolescents aged 12 years and older and weighing at least 35 kg | ||
| 520 | |a FUNDING: The National Institutes of Health and ViiV Healthcare | ||
| 650 | 4 | |a Multicenter Study | |
| 650 | 4 | |a Clinical Trial, Phase II | |
| 650 | 4 | |a Clinical Trial, Phase I | |
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a Anti-HIV Agents |2 NLM | |
| 650 | 7 | |a cabotegravir |2 NLM | |
| 650 | 7 | |a HMH0132Z1Q |2 NLM | |
| 650 | 7 | |a Diketopiperazines |2 NLM | |
| 650 | 7 | |a Pyridones |2 NLM | |
| 650 | 7 | |a Rilpivirine |2 NLM | |
| 650 | 7 | |a FI96A8X663 |2 NLM | |
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| 700 | 1 | |a Marzinke, Mark A |e verfasserin |4 aut | |
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| 700 | 1 | |a Moye, John H |e verfasserin |4 aut | |
| 700 | 1 | |a Heckman, Barbara |e verfasserin |4 aut | |
| 700 | 1 | |a Lowenthal, Elizabeth D |e verfasserin |4 aut | |
| 700 | 1 | |a Ward, Shawn |e verfasserin |4 aut | |
| 700 | 1 | |a Milligan, Ryan |e verfasserin |4 aut | |
| 700 | 1 | |a Samson, Pearl |e verfasserin |4 aut | |
| 700 | 1 | |a Best, Brookie M |e verfasserin |4 aut | |
| 700 | 1 | |a Harrington, Conn M |e verfasserin |4 aut | |
| 700 | 1 | |a Ford, Susan L |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Jenny |e verfasserin |4 aut | |
| 700 | 1 | |a Crauwels, Herta |e verfasserin |4 aut | |
| 700 | 1 | |a Vandermeulen, Kati |e verfasserin |4 aut | |
| 700 | 1 | |a Agwu, Allison L |e verfasserin |4 aut | |
| 700 | 1 | |a Smith-Anderson, Christiana |e verfasserin |4 aut | |
| 700 | 1 | |a Camacho-Gonzalez, Andres |e verfasserin |4 aut | |
| 700 | 1 | |a Ounchanum, Pradthana |e verfasserin |4 aut | |
| 700 | 1 | |a Kneebone, Jared L |e verfasserin |4 aut | |
| 700 | 1 | |a Townley, Ellen |e verfasserin |4 aut | |
| 700 | 1 | |a Bolton Moore, Carolyn |e verfasserin |4 aut | |
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| 700 | 1 | |a Cheung, S Y Amy |e investigator |4 oth | |
| 700 | 1 | |a Chounta, Vasiliki |e investigator |4 oth | |
| 700 | 1 | |a Deprez, Isabelle |e investigator |4 oth | |
| 700 | 1 | |a Desmond, Alicia Catherine |e investigator |4 oth | |
| 700 | 1 | |a Han, Kelong |e investigator |4 oth | |
| 700 | 1 | |a Hanley, Sherika |e investigator |4 oth | |
| 700 | 1 | |a Lin, Yu-Wei |e investigator |4 oth | |
| 700 | 1 | |a Patel, Faeezah |e investigator |4 oth | |
| 700 | 1 | |a Paul, Mary E |e investigator |4 oth | |
| 700 | 1 | |a Roberts, Gilly |e investigator |4 oth | |
| 700 | 1 | |a Whitson, Kyle |e investigator |4 oth | |
| 700 | 1 | |a Zabih, Sara |e investigator |4 oth | |
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