Superiority and cost-effectiveness of monthly extended-release buprenorphine versus daily standard of care medication: a pragmatic, parallel-group, open-label, multicentre, randomised, controlled, phase 3 trialResearch in context
Summary: Background: Daily methadone maintenance or buprenorphine treatment is the standard-of-care (SoC) medication for opioid use disorder (OUD). Subcutaneously injected, extended-release buprenorphine (BUP-XR) may be more effective—but there has been no superiority evaluation. Methods: This prag...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-12-01
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| Series: | EClinicalMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589537023004881 |
| _version_ | 1797598019363799040 |
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| author | John Marsden Mike Kelleher Eilish Gilvarry Luke Mitcheson Jatinder Bisla Angela Cape Fiona Cowden Edward Day Jonathan Dewhurst Rachel Evans Will Hardy Andrea Hearn Joanna Kelly Natalie Lowry Martin McCusker Caroline Murphy Robert Murray Tracey Myton Sophie Quarshie Rob Vanderwaal April Wareham Dyfrig Hughes Zoë Hoare |
| author_facet | John Marsden Mike Kelleher Eilish Gilvarry Luke Mitcheson Jatinder Bisla Angela Cape Fiona Cowden Edward Day Jonathan Dewhurst Rachel Evans Will Hardy Andrea Hearn Joanna Kelly Natalie Lowry Martin McCusker Caroline Murphy Robert Murray Tracey Myton Sophie Quarshie Rob Vanderwaal April Wareham Dyfrig Hughes Zoë Hoare |
| author_sort | John Marsden |
| collection | DOAJ |
| description | Summary: Background: Daily methadone maintenance or buprenorphine treatment is the standard-of-care (SoC) medication for opioid use disorder (OUD). Subcutaneously injected, extended-release buprenorphine (BUP-XR) may be more effective—but there has been no superiority evaluation. Methods: This pragmatic, parallel-group, open-label, multi-centre, effectiveness superiority randomised, controlled, phase 3 trial was conducted at five National Health Service community-based treatment clinics in England and Scotland. Participants (adults aged ≥ 18 years; all meeting DSM-5 diagnostic criteria for moderate or severe OUD at admission to their current maintenance treatment episode) were randomly assigned (1:1) to receive continued daily SoC (liquid methadone (usual dose range: 60–120 mg) or sublingual/transmucosal buprenorphine (usual dose range: 8–24 mg) for 24 weeks; or monthly BUP-XR (Sublocade;® two injections of 300 mg, then four maintenance injections of 100 mg or 300 mg, with maintenance dose selected by response and preference) for 24 weeks. In the intent-to-treat population (senior statistician blinded to blinded to treatment group allocation), and with a seven-day grace period after randomisation, the primary endpoint was the count of days abstinent from non-medical opioids between days 8–168 (i.e., weeks 2–24; range: 0–161 days). Safety was reported for the intention-to- treat population. Adopting a broad societal perspective inclusive of criminal justice, NHS and personal social service costs, a trial-based cost-utility analysis estimated the Incremental Cost-effectiveness Ratio (ICER) per quality-adjusted life year (QALY) of BUP-XR versus SoC at the National Institute for Health and Care Excellence threshold. The study was registered EudraCT (2018-004460-63) and ClinicalTrials.gov (NCT05164549), and is completed. Findings: Between Aug 9, 2019 and Nov 2, 2021, 314 participants were randomly allocated to receive SoC (n = 156) or BUP-XR (n = 158). Participants were abstinent from opioids for an adjusted mean of 104.37 days (standard error [SE] 9.89; range: 0–161 days) in the SoC group and an adjusted mean of 123.43 days (SE 4.76; range: 24–161 days) in the BUP-XR group (adjusted incident rate ratio [IRR] 1.18, 95% confidence interval [CI] 1.05–1.33; p-value 0.004). The incidence of any adverse event was higher in the BUP-XR group than the SoC group (128 [81.0%] of 158 participants versus 67 [42.9%] of 156 participants, respectively—most commonly rapidly-resolving (mild–moderate range) pain from drug administration in the BUP-XR group (121 [26.9%] of 450 adverse events). There were 11 serious adverse events (7.0%) in the 158 participants in the BUP-XR group, and 18 serious adverse events (11.5%) in the 156 participants in the SoC group—none judged to be related to study treatment. The BUP-XR treatment group had a mean incremental cost of £1033 (95% central range [CR] −1189 to 3225) and was associated with a mean incremental QALY of 0.02 (95% CR 0.00–0.05), and an ICER of £47,540 (0.37 probability of being cost-effective at the £30,000/QALY gained willingness-to-pay threshold). However, BUP-XR dominated the SoC among participants who were rated more severe at study baseline, and among participants in maintenance treatment for more that 28 days at study enrolment. Interpretation: Evaluated against the daily oral SoC, monthly BUP-XR is clinically superior, delivering greater abstinence from opioids, and with a comparable safety profile. BUP-XR was not cost-effective in a base case cost-utility analysis using the societal perspective, but it was more effective and less costly (dominant) among participants with more severe OUD, or those whose current treatment episode was longer than 28 days. Further trials are needed to evaluate if BUP-XR is associated with better clinical and health economic outcomes over the longer term. Funding: Indivior. |
| first_indexed | 2024-03-11T03:13:29Z |
| format | Article |
| id | doaj.art-74984ad835324f68b7da701787e3a009 |
| institution | Directory Open Access Journal |
| issn | 2589-5370 |
| language | English |
| last_indexed | 2024-03-11T03:13:29Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EClinicalMedicine |
| spelling | doaj.art-74984ad835324f68b7da701787e3a0092023-11-18T04:29:32ZengElsevierEClinicalMedicine2589-53702023-12-0166102311Superiority and cost-effectiveness of monthly extended-release buprenorphine versus daily standard of care medication: a pragmatic, parallel-group, open-label, multicentre, randomised, controlled, phase 3 trialResearch in contextJohn Marsden0Mike Kelleher1Eilish Gilvarry2Luke Mitcheson3Jatinder Bisla4Angela Cape5Fiona Cowden6Edward Day7Jonathan Dewhurst8Rachel Evans9Will Hardy10Andrea Hearn11Joanna Kelly12Natalie Lowry13Martin McCusker14Caroline Murphy15Robert Murray16Tracey Myton17Sophie Quarshie18Rob Vanderwaal19April Wareham20Dyfrig Hughes21Zoë Hoare22Addictions Department, School of Academic Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, United Kingdom; South London and Maudsley NHS Foundation Trust, United Kingdom; Corresponding author. Addictions Department, School of Academic Psychiatry, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, Addiction Sciences Building, 4 Windsor Walk, Denmark Hill SE5 8AF, United Kingdom.Addictions Department, School of Academic Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, United Kingdom; South London and Maudsley NHS Foundation Trust, United KingdomCumbria, Northumberland, Tyne and Wear NHS Foundation Trust, Newcastle Addictions Service, Newcastle Upon Tyne, United KingdomAddictions Department, School of Academic Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, United Kingdom; South London and Maudsley NHS Foundation Trust, United KingdomKing’s Clinical Trials Unit, Research Management and Innovation Directorate, King’s College London, United KingdomKing’s Clinical Trials Unit, Research Management and Innovation Directorate, King’s College London, United KingdomNHS Tayside and Dundee Health and Social Care Partnership, Scotland, United KingdomBirmingham and Solihull Mental Health, NHS Foundation Trust, Birmingham, United KingdomAddictions Division, Greater Manchester Mental Health NHS Foundation Trust, Manchester, United KingdomSchool of Health Sciences, Bangor University, Wales, United KingdomClinic for Health Economics and Medicines Evaluation, Bangor University, Wales, United KingdomCumbria, Northumberland, Tyne and Wear NHS Foundation Trust, Newcastle Addictions Service, Newcastle Upon Tyne, United KingdomKing’s Clinical Trials Unit, Research Management and Innovation Directorate, King’s College London, United KingdomAddictions Department, School of Academic Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, United Kingdom; South London and Maudsley NHS Foundation Trust, United KingdomLambeth Service User Council, South London and Maudsley NHS Foundation Trust, United KingdomKing’s Clinical Trials Unit, Research Management and Innovation Directorate, King’s College London, United KingdomCumbria, Northumberland, Tyne and Wear NHS Foundation Trust, Newcastle Addictions Service, Newcastle Upon Tyne, United KingdomAddictions Division, Greater Manchester Mental Health NHS Foundation Trust, Manchester, United KingdomCumbria, Northumberland, Tyne and Wear NHS Foundation Trust, Newcastle Addictions Service, Newcastle Upon Tyne, United KingdomSouth London and Maudsley NHS Foundation Trust, United KingdomPatient and Public Involvement and Engagement Representative, United KingdomClinic for Health Economics and Medicines Evaluation, Bangor University, Wales, United KingdomSchool of Health Sciences, Bangor University, Wales, United KingdomSummary: Background: Daily methadone maintenance or buprenorphine treatment is the standard-of-care (SoC) medication for opioid use disorder (OUD). Subcutaneously injected, extended-release buprenorphine (BUP-XR) may be more effective—but there has been no superiority evaluation. Methods: This pragmatic, parallel-group, open-label, multi-centre, effectiveness superiority randomised, controlled, phase 3 trial was conducted at five National Health Service community-based treatment clinics in England and Scotland. Participants (adults aged ≥ 18 years; all meeting DSM-5 diagnostic criteria for moderate or severe OUD at admission to their current maintenance treatment episode) were randomly assigned (1:1) to receive continued daily SoC (liquid methadone (usual dose range: 60–120 mg) or sublingual/transmucosal buprenorphine (usual dose range: 8–24 mg) for 24 weeks; or monthly BUP-XR (Sublocade;® two injections of 300 mg, then four maintenance injections of 100 mg or 300 mg, with maintenance dose selected by response and preference) for 24 weeks. In the intent-to-treat population (senior statistician blinded to blinded to treatment group allocation), and with a seven-day grace period after randomisation, the primary endpoint was the count of days abstinent from non-medical opioids between days 8–168 (i.e., weeks 2–24; range: 0–161 days). Safety was reported for the intention-to- treat population. Adopting a broad societal perspective inclusive of criminal justice, NHS and personal social service costs, a trial-based cost-utility analysis estimated the Incremental Cost-effectiveness Ratio (ICER) per quality-adjusted life year (QALY) of BUP-XR versus SoC at the National Institute for Health and Care Excellence threshold. The study was registered EudraCT (2018-004460-63) and ClinicalTrials.gov (NCT05164549), and is completed. Findings: Between Aug 9, 2019 and Nov 2, 2021, 314 participants were randomly allocated to receive SoC (n = 156) or BUP-XR (n = 158). Participants were abstinent from opioids for an adjusted mean of 104.37 days (standard error [SE] 9.89; range: 0–161 days) in the SoC group and an adjusted mean of 123.43 days (SE 4.76; range: 24–161 days) in the BUP-XR group (adjusted incident rate ratio [IRR] 1.18, 95% confidence interval [CI] 1.05–1.33; p-value 0.004). The incidence of any adverse event was higher in the BUP-XR group than the SoC group (128 [81.0%] of 158 participants versus 67 [42.9%] of 156 participants, respectively—most commonly rapidly-resolving (mild–moderate range) pain from drug administration in the BUP-XR group (121 [26.9%] of 450 adverse events). There were 11 serious adverse events (7.0%) in the 158 participants in the BUP-XR group, and 18 serious adverse events (11.5%) in the 156 participants in the SoC group—none judged to be related to study treatment. The BUP-XR treatment group had a mean incremental cost of £1033 (95% central range [CR] −1189 to 3225) and was associated with a mean incremental QALY of 0.02 (95% CR 0.00–0.05), and an ICER of £47,540 (0.37 probability of being cost-effective at the £30,000/QALY gained willingness-to-pay threshold). However, BUP-XR dominated the SoC among participants who were rated more severe at study baseline, and among participants in maintenance treatment for more that 28 days at study enrolment. Interpretation: Evaluated against the daily oral SoC, monthly BUP-XR is clinically superior, delivering greater abstinence from opioids, and with a comparable safety profile. BUP-XR was not cost-effective in a base case cost-utility analysis using the societal perspective, but it was more effective and less costly (dominant) among participants with more severe OUD, or those whose current treatment episode was longer than 28 days. Further trials are needed to evaluate if BUP-XR is associated with better clinical and health economic outcomes over the longer term. Funding: Indivior.http://www.sciencedirect.com/science/article/pii/S2589537023004881Opioid use disorderStandard of careExtended-release buprenorphineEffectivenessCost-effectiveness |
| spellingShingle | John Marsden Mike Kelleher Eilish Gilvarry Luke Mitcheson Jatinder Bisla Angela Cape Fiona Cowden Edward Day Jonathan Dewhurst Rachel Evans Will Hardy Andrea Hearn Joanna Kelly Natalie Lowry Martin McCusker Caroline Murphy Robert Murray Tracey Myton Sophie Quarshie Rob Vanderwaal April Wareham Dyfrig Hughes Zoë Hoare Superiority and cost-effectiveness of monthly extended-release buprenorphine versus daily standard of care medication: a pragmatic, parallel-group, open-label, multicentre, randomised, controlled, phase 3 trialResearch in context EClinicalMedicine Opioid use disorder Standard of care Extended-release buprenorphine Effectiveness Cost-effectiveness |
| title | Superiority and cost-effectiveness of monthly extended-release buprenorphine versus daily standard of care medication: a pragmatic, parallel-group, open-label, multicentre, randomised, controlled, phase 3 trialResearch in context |
| title_full | Superiority and cost-effectiveness of monthly extended-release buprenorphine versus daily standard of care medication: a pragmatic, parallel-group, open-label, multicentre, randomised, controlled, phase 3 trialResearch in context |
| title_fullStr | Superiority and cost-effectiveness of monthly extended-release buprenorphine versus daily standard of care medication: a pragmatic, parallel-group, open-label, multicentre, randomised, controlled, phase 3 trialResearch in context |
| title_full_unstemmed | Superiority and cost-effectiveness of monthly extended-release buprenorphine versus daily standard of care medication: a pragmatic, parallel-group, open-label, multicentre, randomised, controlled, phase 3 trialResearch in context |
| title_short | Superiority and cost-effectiveness of monthly extended-release buprenorphine versus daily standard of care medication: a pragmatic, parallel-group, open-label, multicentre, randomised, controlled, phase 3 trialResearch in context |
| title_sort | superiority and cost effectiveness of monthly extended release buprenorphine versus daily standard of care medication a pragmatic parallel group open label multicentre randomised controlled phase 3 trialresearch in context |
| topic | Opioid use disorder Standard of care Extended-release buprenorphine Effectiveness Cost-effectiveness |
| url | http://www.sciencedirect.com/science/article/pii/S2589537023004881 |
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