Subcutaneous Injection of Adalimumab Trial compared with Control (SCIATiC): a randomised controlled trial of adalimumab injection compared with placebo for patients receiving physiotherapy treatment for sciatica

Abstract

Background Biological treatments such as adalimumab (Humira®; AbbVie Ltd, Maidenhead, UK) are antibodies targeting tumour necrosis factor alpha, released from ruptured intervertebral discs, which might be useful in sciatica. Recent systematic reviews concluded that they might be effective, but that a definitive randomised controlled trial was needed. Usual care in the NHS typically includes a physiotherapy intervention. Objectives To test whether or not injections of adalimumab plus physiotherapy are more clinically effective and cost-effective than injections of saline plus physiotherapy for patients with sciatica. Design Pragmatic, parallel-group, randomised controlled trial with blinded participants and clinicians, and an outcome assessment and statistical analysis with concurrent economic evaluation and internal pilot. Setting Participants were referred from primary care and musculoskeletal services to outpatient physiotherapy clinics. Participants Adults with persistent symptoms of sciatica of 1–6 months’ duration and with moderate to high levels of disability. Eligibility was assessed by research physiotherapists according to clinical criteria for diagnosing sciatica. Interventions After a second eligibility check, trial participants were randomised to receive two doses of adalimumab (80 mg and then 40 mg 2 weeks later) or saline injections. Both groups were referred for a course of physiotherapy. Main outcome measures Outcomes were measured at the start, and after 6 weeks’ and 6 months’ follow-up. The main outcome measure was the Oswestry Disability Index (ODI). Other outcomes: leg pain version of the Roland–Morris Disability Questionnaire, Sciatica Bothersomeness Index, EuroQol-5 Dimensions, 5-level version, Hospital Anxiety and Depression Scale, resource use, risk of persistent disabling pain, pain trajectory based on a single question, Pain Self-Efficacy Questionnaire, Tampa Scale of Kinesiophobia and adverse effects. Sample size To detect an effect size of 0.4 with 90% power, a 5% significance level for a two-tailed t-test and 80% retention rate, 332 participants would have needed to be recruited. Analysis plan The primary effectiveness analysis would have been linear mixed models for repeated measures to measure the effects of time and group allocation. An internal pilot study would have involved the first 50 participants recruited across all centres. The primary economic analysis would have been a cost–utility analysis. Results The internal pilot study was discontinued as a result of low recruitment after eight participants were recruited from two out of six sites. One site withdrew from the study before recruitment started, one site did not complete contract negotiations and two sites signed contracts shortly before trial closure. In the two sites that did recruit participants, recruitment was slow. This was partly because of operational issues, but also because of a low rate of uptake from potential participants. Limitations Although large numbers of invitations were sent to potential participants, identified by retrospective searches of general practitioner (GP) records, there was a low rate of uptake. Two sites planned to recruit participants during GP consultations but opened too late to recruit any participants. Conclusion The main failure was attributable to problems with contracts. Because of this we were not able to complete the internal pilot or to test all of the different methods for primary care recruitment we had planned. A trial of biological therapy in patients with sciatica still needs to be done, but would require a clearer contracting process, qualitative research to ensure that patients would be willing to participate, and simpler recruitment methods. Trial registration Current Controlled Trials ISRCTN14569274. 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. 21, No. 60. See the NIHR Journals Library website for further project information.

Recruitment, consent and retention of participants in randomised controlled trials: a review of trials published in the National Institute for Health Research (NIHR) Journals Library (1997–2020)

“…The RCT with the highest final recruitment target and highest number recruited was an obstetrics trial investigating computerised interpretation of fetal heart rate during labour 24. There were four trials that recruited less than 10 participants, two were discontinued at the end of an internal pilot phase due to low recruitment25 26 and the remaining two had no pilot phase 27 28. Overall, 63% (245/388) of trials recruited to their final recruitment target but 32% (79/245) of these trials required an extension to their recruitment period to meet the target.…”

“…The median retention rate (per cent of randomised participants retained and assessed in the analysis of the primary outcome) was found to be 88% (IQR: 80%–97%). There were four trials25 26 28 39 with a retention rate of 0%, these trials were all stopped early due to problems with recruitment and the planned statistical analysis for the primary outcome was not performed. Retention rates do not differ greatly between the five NIHR journals (p=0.118) (table 4).…”

Comprehensive review of statistical methods for analysing patient-reported outcomes (PROs) used as primary outcomes in randomised controlled trials (RCTs) published by the UK’sHealth Technology Assessment(HTA) journal (1997–2020)

“…Two trials with PROs as primary outcomes were excluded as they were closed without conducting a statistical analysis of the data using the statistical methods that were proposed in the report. 16 17 It should be noted that the first RCT with a PRO as a clinical outcome was published in the HTA journal in 1999, 18 and the earlier reports published in the HTA journal were mainly systematic reviews.…”