Summary Background Extended-release naltrexone (XR-NTX), an opioid antagonist, and sublingual buprenorphine-naloxone (BUP-NX), a partial opioid agonist, are pharmacologically and conceptually distinct interventions to prevent opioid relapse. We aimed to estimate the difference in opioid relapse-free survival between XR-NTX and BUP-NX. Methods We initiated this 24 week, open-label, randomised controlled, comparative effectiveness trial at eight US community-based inpatient services and followed up participants as outpatients. Participants were 18 years or older, had Diagnostic and Statistical Manual of Mental Disorders-5 opioid use disorder, and had used non-prescribed opioids in the past 30 days. We stratified participants by treatment site and opioid use severity and used a web-based permuted block design with random equally weighted block sizes of four and six for randomisation (1:1) to receive XR-NTX or BUP-NX. XR-NTX was monthly intramuscular injections (Vivitrol; Alkermes) and BUP-NX was daily self-administered buprenorphine-naloxone sublingual film (Suboxone; Indivior). The primary outcome was opioid relapse-free survival during 24 weeks of outpatient treatment. Relapse was 4 consecutive weeks of any non-study opioid use by urine toxicology or self-report, or 7 consecutive days of self-reported use. This trial is registered with ClinicalTrials.gov, NCT02032433. Findings Between Jan 30, 2014, and May 25, 2016, we randomly assigned 570 participants to receive XR-NTX (n=283) or BUP-NX (n=287). The last follow-up visit was Jan 31, 2017. As expected, XR-NTX had a substantial induction hurdle: fewer participants successfully initiated XR-NTX (204 [72%] of 283) than BUP-NX (270 [94%] of 287; p<0·0001). Among all participants who were randomly assigned (intention-to-treat population, n=570) 24 week relapse events were greater for XR-NTX (185 [65%] of 283) than for BUP-NX (163 [57%] of 287; hazard ratio [HR] 1·36, 95% CI 1·10–1·68), most or all of this difference accounted for by early relapse in nearly all (70 [89%] of 79) XR-NTX induction failures. Among participants successfully inducted (per-protocol population, n=474), 24 week relapse events were similar across study groups (p=0·44). Opioid-negative urine samples (p<0·0001) and opioid-abstinent days (p<0·0001) favoured BUP-NX compared with XR-NTX among the intention-to-treat population, but were similar across study groups among the per-protocol population. Self-reported opioid craving was initially less with XR-NTX than with BUP-NX (p=0·0012), then converged by week 24 (p=0·20). With the exception of mild-to-moderate XR-NTX injection site reactions, treatment-emergent adverse events including overdose did not differ between treatment groups. Five fatal overdoses occurred (two in the XR-NTX group and three in the BUP-NX group). Interpretation In this population it is more difficult to initiate patients to XR-NTX than BUP-NX, and this negatively affected overall relapse. However, once initiated, both medications were equally safe and effective. Future wo...

for the Study of Comparative Treatments for Retinal Vein Occlusion 2 (SCORE2) Investigator Group IMPORTANCE Intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections are used to treat a variety of posterior segment conditions, including some associated with glaucoma, such as macular edema due to central retinal vein occlusion (CRVO). Therefore, information regarding intraocular pressure (IOP)-related events associated with anti-VEGF therapies is important to help balance the risks and benefits over the course of therapy.OBJECTIVE To investigate IOP-related events among participants in the Study of Comparative Treatments for Retinal Vein Occlusion 2 (SCORE2).DESIGN, SETTING, AND PARTICIPANTS Secondary analysis of a randomized clinical trial that included 312 participants with macular edema secondary to CRVO or hemiretinal vein occlusion (HRVO) who were not taking IOP-lowering medications at baseline. First randomization occurred on September 14, 2014, and contained data through data freeze on April 1, 2020. Analysis took place from April 2020 through December 2020.INTERVENTIONS Study participants were initially randomized to 6 monthly intravitreal injections of aflibercept or bevacizumab. At month 6, protocol-defined good responders were rerandomized to continued monthly or treat-and-extend dosing of their originally assigned study drug, and protocol-defined poor or marginal responders were switched to alternative treatment. After month 12, participants were treated as per investigator discretion.MAIN OUTCOMES AND MEASURES Three different outcomes: (1) IOP elevation more than 10 mm Hg from baseline, (2) IOP to a level higher than 35 mm Hg, and (3) IOP-lowering incisional or laser surgery. RESULTSOf the 312 participants meeting inclusion criteria (138 [44.2%] were female; mean [SD] age, 67.8 [12.1] years), 25 (8.0%) had IOP elevation more than 10 mm Hg over baseline through month 60, and 5 (1.6%) had IOP higher than 35 mm Hg. The 60-month Kaplan-Meier cumulative incidence of IOP elevation more than 10 mm Hg over baseline was 0.13 (95% CI, 0.08-0.19), and the 60-month Kaplan-Meier cumulative incidence of IOP higher than 35 mm Hg was 0.02 (95% CI, 0.01-0.06), and did not differ among participants initially randomly assigned to receive aflibercept or bevacizumab. Three participants (1.0%) underwent IOP-lowering incisional surgery, and 3 participants (1.0%) underwent IOP-lowering glaucoma laser surgery.CONCLUSIONS AND RELEVANCE Intravitreal anti-VEGF injections are used to treat some conditions associated with glaucoma, such as macular edema due to CRVO, and the rates of IOP-related events in this trial support monitoring IOP in eyes treated with anti-VEGF therapy for macular edema associated with CRVO or HRVO for up to 60 months.

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ImportanceRetinal vein occlusion is the second most common retinal vascular disease. Bevacizumab was demonstrated in the Study of Comparative Treatments for Retinal Vein Occlusion 2 (SCORE2) to be noninferior to aflibercept with respect to visual acuity in study participants with macular edema due to central retinal vein occlusion (CRVO) or hemiretinal vein occlusion (HRVO) following 6 months of therapy. In this study, the cost-utility of bevacizumab vs aflibercept for treatment of CRVO is evaluated.ObjectiveTo investigate the relative cost-effectiveness of bevacizumab vs aflibercept for treatment of macular edema associated with CRVO or HRVO.Design, Setting, and ParticipantsThis economic evaluation study used a microsimulation cohort of patients with clinical and demographic characteristics similar to those of SCORE2 participants and a Markov process. Parameters were estimated and validated using a split-sample approach of the SCORE2 population. The simulated cohort included 5000 patients who were evaluated 100 times, each with a different set of characteristics randomly selected based on the SCORE2 trial. SCORE2 data were collected from September 2014 October 2019, and data were analyzed from October 2019 to July 2021.InterventionsBevacizumab (followed by aflibercept among patients with a protocol-defined poor or marginal response to bevacizumab at month 6) vs aflibercept (followed by a dexamethasone implant among patients with a protocol-defined poor or marginal response to aflibercept at month 6).Main Outcomes and MeasuresIncremental cost-utility ratio.ResultsThe simulation demonstrated that patients treated with aflibercept will have an expected cost $18 127 greater than those treated with bevacizumab in the year following initiation. When coupled with the lack of clinical superiority over bevacizumab (ie, patients treated with bevacizumab had a gain over aflibercept in visual acuity letter score of 4 in the treated eye and 2 in the fellow eye), these results demonstrate that first-line treatment with bevacizumab dominated aflibercept in the simulated cohort of SCORE2 participants. At current price levels, aflibercept would be considered the preferred cost-effective option only if treatment restored the patient to nearly perfect health.Conclusions and RelevanceWhile there will be some patients with CRVO-associated or HRVO-associated macular edema who will benefit from first-line treatment with aflibercept rather than bevacizumab, given the minimal differences in visual acuity outcomes and large cost differences for bevacizumab vs aflibercept, first-line treatment with bevacizumab is cost-effective for this condition.

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