Perspectives on Extended-Release Naltrexone Induction among Patients Living with HIV and Opioid Use Disorder: A Qualitative Analysis

BACKGROUND: The CHOICES study randomized participants with HIV and opioid use disorder (OUD) to HIV clinic-based extended-release naltrexone (XR-NTX), which requires complete cessation of opioid use, versus treatment-as-usual (i.e., buprenorphine, methadone). Study participants randomized to XR-NTX were interviewed to assess their experiences with successful and unsuccessful XR-NTX induction. METHODS: Semi-structured qualitative interviews were completed with a convenience sample of study participants with HIV and OUD (n = 37) randomized to XR-NTX in five HIV clinics between 2018 and 2019. All participants approached agreed to be interviewed. Interviews were digitally recorded, professionally transcribed, and analyzed using thematic analysis. RESULTS: Participants included women (43%), African Americans (62%) and Hispanics (16%), between 27 to 69 years of age. Individuals who completed XR-NTX induction (n = 20) reported experiencing (1) readiness for change, (2) a supportive environment during withdrawal including comfort medications, and (3) caring interactions with staff. Four contrasting themes emerged among participants (n = 17) who did not complete induction: (1) concern and anxiety about withdrawal including past negative experiences, (2) ambivalence about or reluctance to stop opioids, (3) concerns about XR-NTX effects, and (4) preferences for other medications. CONCLUSIONS: The results highlight opportunities to improve initiation of XR-NTX in high-need groups. Addressing expectations regarding induction may enhance XR-NTX initiation rates. Trial Registration ClinicalTrials.gov: NCT03275350. Registered September 7, 2017. https://clinicaltrials.gov/ct2/show/NCT03275350?term=extended+release+naltrexone&cond=Opioid+Use

Use of Single IRBs for Multi-Site Studies: A Case Report and Commentary from a National Drug Abuse Treatment Clinical Trials Network Study

Recent NIH policy stipulates that multi-site studies must use a single or IRB (Institutional Review Board) in order to streamline the review process while maintaining standards for human subjects protection. The Western States Node of the Clinical Trials Network (CTN) used a single IRB for protocol CTN-0067, a clinical trial testing the use of an opioid antagonist (extended-release naltrexone) versus opioid agonists (buprenorphine or methadone) for opioid use disorders among individuals living with HIV. This case study discusses the processes and challenges associated with use of a single IRB. These lessons are also informed by other single IRB experiences within the CTN. The intention of the NIH single IRB policy is to facilitate efficient IRB processes. Advanced planning and transparent communication, however, are critical to avoid stalling IRB approval and protocol implementation. Research teams need to account for local IRB willingness to cede to a single IRB and understand the variations in interpretations of abbreviated reviews. In order to facilitate the effective use of single IRBs, recommendations include assigning staff at each study site for IRB submission coordination and interaction with the lead site IRB staff, training investigators and key regulatory staff on expectations for working with single IRBs, dedicating a regulatory specialist at the lead site to manage the process, developing a communication plan, and supporting the development of strong working relationships with local regulatory staff and the single IRB. The CTN experiences with single IRBs may provide insights for other investigators

Use of single IRBs for multi-site studies: A case report and commentary from a National Drug Abuse Treatment Clinical Trials Network study

Recent NIH policy stipulates that multi-site studies must use a single or IRB (Institutional Review Board) in order to streamline the review process while maintaining standards for human subjects protection. The Western States Node of the Clinical Trials Network (CTN) used a single IRB for protocol CTN-0067, a clinical trial testing the use of an opioid antagonist (extended-release naltrexone) versus opioid agonists (buprenorphine or methadone) for opioid use disorders among individuals living with HIV. This case study discusses the processes and challenges associated with use of a single IRB. These lessons are also informed by other single IRB experiences within the CTN. The intention of the NIH single IRB policy is to facilitate efficient IRB processes. Advanced planning and transparent communication, however, are critical to avoid stalling IRB approval and protocol implementation. Research teams need to account for local IRB willingness to cede to a single IRB and understand the variations in interpretations of abbreviated reviews. In order to facilitate the effective use of single IRBs, recommendations include assigning staff at each study site for IRB submission coordination and interaction with the lead site IRB staff, training investigators and key regulatory staff on expectations for working with single IRBs, dedicating a regulatory specialist at the lead site to manage the process, developing a communication plan, and supporting the development of strong working relationships with local regulatory staff and the single IRB. The CTN experiences with single IRBs may provide insights for other investigators. Keywords: Institutional Review Boards, Single IRB, Clinical trial regulations, NIH IRB regulation

Exercise- and strategy-based physiotherapy-delivered intervention for preventing repeat falls in people with Parkinson's: the PDSAFE RCT

BACKGROUND: People with Parkinson's disease are twice as likely to experience a fall as a healthy older person, often leading to debilitating effects on confidence, activity levels and quality of life. OBJECTIVE: To estimate the effect of a physiotherapy programme for fall prevention among people with Parkinson's disease. DESIGN: A multicentre, pragmatic, investigator-masked, individually randomised controlled trial (RCT) with prespecified subgroup analyses. SETTING: Recruitment from NHS hospitals and clinics and community and social services in eight English regions with home-based interventions. PARTICIPANTS: A total of 474 people with Parkinson's disease (i.e. Hoehn and Yahr scale stages 1-4) were recruited: 238 were assigned to a physiotherapy programme and 236 were assigned to usual care. Random allocation was 50 : 50. INTERVENTIONS: All participants received routine care; the usual-care group received an information digital versatile disc (DVD) and a single advice session at trial completion. The intervention group had an individually tailored, progressive, home-based fall avoidance strategy training programme with balance and strengthening exercises: PDSAFE. MAIN OUTCOME MEASURES: The primary outcome was the risk of repeat falling, collected by self-report monthly diaries between 0 and 6 months after randomisation. Secondary outcomes included near-falls, falls efficacy, freezing of gait (FoG), health-related quality of life, and measurements taken using the Mini-Balance Evaluation Systems Test (Mini-BESTest), the Chair Stand Test (CST), the Geriatric Depression Scale, the Physical Activity Scale for the Elderly and the Parkinson's Disease Questionnaire. RESULTS: PDSAFE is the largest RCT of falls management among people with Parkinson's disease: 541 patients were screened for eligibility. The average age was 72 years, and 266 out of 474 (56%) participants were men. Of the 474 randomised participants, 238 were randomised to the intervention group and 236 were randomised to the control group. No difference in repeat falling within 6 months of randomisation was found [PDSAFE group to control group odds ratio (OR) 1.21, 95% confidence interval (CI) 0.74 to 1.98; p = 0.447]. An analysis of secondary outcomes demonstrated better balance (Mini-BESTest: mean difference 0.95, 95% CI 0.24 to 1.67; p = 0.009), functional strength (CST: p = 0.041) and falls efficacy (Falls Efficacy Scale - International: mean difference 1.6, 95% CI -3.0 to -0.19; p = 0.026) with near-falling significantly reduced with PDSAFE (OR 0.67, 95% CI 0.53 to 0.86; p = 0.001) at 6 months. Prespecified subgroup analysis (i.e. disease severity and FoG) revealed a PDSAFE differing effect; the intervention may be of benefit for people with moderate disease but may increase falling for those in the more severe category, especially those with FoG. LIMITATIONS: All participants were assessed at primary outcome; only 73% were assessed at 12 months owing to restricted funding. CONCLUSIONS: PDSAFE was not effective in reducing repeat falling across the range of people with Parkinson's disease in the trial. Secondary analysis demonstrated that other functional tasks and self-efficacy improved and demonstrated differential patterns of intervention impact in accordance with disease severity and FoG, which supports previous secondary research findings and merits further primary evaluation. FUTURE WORK: Further trials of falls prevention on targeted groups of people with Parkinson's disease are recommended. TRIAL REGISTRATION: Current Controlled Trials ISRCTN48152791. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 36. See the NIHR Journals Library website for further project information. Sarah E Lamb is funded by the NIHR Collaboration for Leadership in Applied Health Research and Care (CLAHRC) at Oxford Health NHS Foundation Trust, the NIHR Oxford Biomedical Research Centre at the Oxford University Hospitals NHS Foundation Trust and CLAHRC Oxford. Victoria A Goodwin is supported by the NIHR Collaborations for Leadership in Applied Health Research and Care in the South West Peninsula (PenCLAHRC). Lynn Rochester is supported by the NIHR Newcastle Biomedical Research Centre based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University. The research was also supported by the NIHR Newcastle Clinical Research Facility Infrastructure funding. Helen C Roberts is supported by CLAHRC Wessex and the NIHR Southampton Biomedical Research Centre.status: publishe

Workplaces of the Future – How are they Studied? A Literature Study of Foresight and Delphi Methods

Background: People with Parkinson’s disease are twice as likely to experience a fall as a healthy older person, often leading to debilitating effects on confidence, activity levels and quality of life. Objective: To estimate the effect of a physiotherapy programme for fall prevention among people with Parkinson’s disease. Design: A multicentre, pragmatic, investigator-masked, individually randomised controlled trial (RCT) with prespecified subgroup analyses. Setting: Recruitment from NHS hospitals and clinics and community and social services in eight English regions with home-based interventions. Participants: A total of 474 people with Parkinson’s disease (i.e. Hoehn and Yahr scale stages 1–4) were recruited: 238 were assigned to a physiotherapy programme and 236 were assigned to usual care. Random allocation was 50: 50. Interventions: All participants received routine care; the usual-care group received an information digital versatile disc (DVD) and a single advice session at trial completion. The intervention group had an individually tailored, progressive, home-based fall avoidance strategy training programme with balance and strengthening exercises: PDSAFE. Main outcome measures: The primary outcome was the risk of repeat falling, collected by self-report monthly diaries between 0 and 6 months after randomisation. Secondary outcomes included near-falls, falls efficacy, freezing of gait (FoG), health-related quality of life, and measurements taken using the Mini-Balance Evaluation Systems Test (Mini-BESTest), the Chair Stand Test (CST), the Geriatric Depression Scale, the Physical Activity Scale for the Elderly and the Parkinson’s Disease Questionnaire. Results: PDSAFE is the largest RCT of falls management among people with Parkinson’s disease: 541 patients were screened for eligibility. The average age was 72 years, and 266 out of 474 (56%) participants were men. Of the 474 randomised participants, 238 were randomised to the intervention group and 236 were randomised to the control group. No difference in repeat falling within 6 months of randomisation was found [PDSAFE group to control group odds ratio (OR) 1.21, 95% confidence interval (CI) 0.74 to 1.98; p = 0.447]. An analysis of secondary outcomes demonstrated better balance (Mini-BESTest: mean difference 0.95, 95% CI 0.24 to 1.67; p = 0.009), functional strength (CST: p = 0.041) and falls efficacy (Falls Efficacy Scale – International: mean difference 1.6, 95% CI –3.0 to –0.19; p = 0.026) with near-falling significantly reduced with PDSAFE (OR 0.67, 95% CI 0.53 to 0.86; p = 0.001) at 6 months. Prespecified subgroup analysis (i.e. disease severity and FoG) revealed a PDSAFE differing effect; the intervention may be of benefit for people with moderate disease but may increase falling for those in the more severe category, especially those with FoG. Limitations: All participants were assessed at primary outcome; only 73% were assessed at 12 months owing to restricted funding. Conclusions: PDSAFE was not effective in reducing repeat falling across the range of people with Parkinson’s disease in the trial. Secondary analysis demonstrated that other functional tasks and self-efficacy improved and demonstrated differential patterns of intervention impact in accordance with disease severity and FoG, which supports previous secondary research findings and merits further primary evaluation. Future work: Further trials of falls prevention on targeted groups of people with Parkinson’s disease are recommended. Trial registration: Current Controlled Trials ISRCTN48152791.</p

Multicentre, randomised controlled trial of PDSAFE, a physiotherapist-delivered fall prevention programme for people with Parkinson's

OBJECTIVE: To estimate the effect of a physiotherapist-delivered fall prevention programme for people with Parkinson's (PwP). METHODS: People at risk of falls with confirmed Parkinson's were recruited to this multicentre, pragmatic, investigator blind, individually randomised controlled trial with prespecified subgroup analyses. 474 PwP (Hoehn and Yahr 1-4) were randomised: 238 allocated to a physiotherapy programme and 236 to control. All participants had routine care; the control group received a DVD about Parkinson's and single advice session at trial completion. The intervention group (PDSAFE) had an individually tailored, progressive home-based fall avoidance strategy training programme with balance and strengthening exercises. The primary outcome was risk of repeat falling, collected by self-report monthly diaries, 0-6 months after randomisation. Secondary outcomes included Mini-BESTest for balance, chair stand test, falls efficacy, freezing of gait, health-related quality of life (EuroQol EQ-5D), Geriatric Depression Scale, Physical Activity Scale for the Elderly and Parkinson's Disease Questionnaire, fractures and rate of near falling. RESULTS: Average age is 72 years and 266 (56%) were men. By 6 months, 116 (55%) of the control group and 125 (61.5%) of the intervention group reported repeat falls (controlled OR 1.21, 95% CI 0.74 to 1.98, p=0.447). Secondary subgroup analyses suggested a different response to the intervention between moderate and severe disease severity groups. Balance, falls efficacy and chair stand time improved with near falls reduced in the intervention arm. CONCLUSION: PDSAFE did not reduce falling in this pragmatic trial of PwP. Other functional tasks improved and reduced fall rates were apparent among those with moderate disease. TRIAL REGISTRATION NUMBER: ISRCTN48152791.status: publishe

Cost-effectiveness of the PDSAFE personalised physiotherapy intervention for fall prevention in Parkinson’s: an economic evaluation alongside a randomised controlled trial

Background: PDSAFE is an individually-tailored, physiotherapist-delivered, balance, strength and strategy training programme aimed at preventing falls among people with Parkinson's. We evaluated the cost-effectiveness of PDSAFE compared with usual care for people with Parkinson's at higher risk of falling, from a UK National Health Service and Personal Social Service perspective. Methods: Resource use and quality of life data (EQ-5D-3L) were collected from 238 participants randomised to the PDSAFE intervention and 236 participants randomised to control, at baseline, 3 months, 6 months (primary outcome), and 12 months. Adjusted cost and quality-adjusted life-years (QALYs) were estimated using generalised linear models and uncertainty estimated using a non-parametric bootstrap. Results: Over 6 months, the PDSAFE intervention was associated with an incremental cost of £925 (95% CI £428 to £1422) and a very small and statistically insignificant QALY gain of 0.008 (95% CI - 0.006 to 0.021). The resulting incremental cost-effectiveness ratio (ICER) was £120,659 per QALY and the probability of the intervention being cost-effective at a UK threshold of £30,000/QALY was less than 1%. The ICER varied substantially across subgroups although no subgroup had an ICER lower than the £30,000 threshold. The result was sensitive to the time horizon with the ICER reducing to £55,176 per QALY when adopting a 12-month time horizon and assuming a sustained treatment effect on QoL, nevertheless, the intervention was still not cost-effective according to the current UK threshold. Conclusions: Evidence from this trial suggests that the PDSAFE intervention is unlikely to be cost-effective at 6 months. The 12-month analysis suggested that the intervention became closer to being cost-effective if quality of life effects were sustained beyond the intervention period, however this would require confirmation. Further research, including qualitative studies, should be conducted to better understand the treatment effect of physiotherapy and its impact on quality of life in people with Parkinson's given existing mixed evidence on this topic. Trial registration: ISRCTN48152791. Registered 17 April 2014. http://www.isrctn.com/ISRCTN48152791.</p

Feasibility and safety of extended-release naltrexone treatment of opioid and alcohol use disorder in HIV clinics: a pilot/feasibility randomized trial.

Background and aimsHIV-infected people with substance use disorders are least likely to benefit from advances in HIV treatment. Integration of extended-release naltrexone (XR-NTX) into HIV clinics may increase engagement in the HIV care continuum by decreasing substance use. We aimed to compare (1) XR-NTX treatment initiation, (2) retention and (3) safety of XR-NTX versus treatment as usual (TAU) for treating opioid use disorder (OUD) and/or alcohol use disorder (AUD) in HIV clinics.DesignNon-blinded randomized trial of XR-NTX versus pharmacotherapy TAU.SettingHIV primary care clinics in Vancouver, BC, Canada and Chicago, IL, USA.ParticipantsFifty-one HIV-infected patients seeking treatment for OUD (n = 16), AUD (n = 27) or both OUD and AUD (n = 8).MeasurementsPrimary outcomes were XR-NTX initiation (receipt of first injection within 4 weeks of randomization) and retention at 16 weeks. Secondary outcomes generated point estimates for change in substance use, HIV viral suppression [HIV RNA polymerase chain reaction (pcr) &lt; 200 copies/ml] and safety.FindingsTwo-thirds (68%) of participants assigned to XR-NTX initiated treatment, and 88% of these were retained on XR-NTX at 16 weeks. In comparison, 96% of TAU participants initiated treatment, but only 50% were retained on medication at 16 weeks. Mean days of opioid use in past 30 days decreased from 17.3 to 4.1 for TAU and from 20.3 to 7.7 for XR-NTX. Mean heavy drinking days decreased from 15.6 to 5.7 for TAU and 12.5 to 2.8 for XR-NTX. Among those with OUD, HIV suppression improved from 67 to 80% for XR-NTX and 58 to 75% for TAU. XR-NTX was well tolerated, with no precipitated withdrawals and one serious injection-site reaction.ConclusionsExtended-release naltrexone (XR-NTX) is feasible and safe for treatment of opioid use disorder and alcohol use disorder in HIV clinics. Treatment initiation appears to be lower and retention greater for XR-NTX compared with treatment as usual (clinicaltrials.gov NCT01908062)