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Background The primary endpoint in diabetes-related foot ulcer (DFU) trials is often time to healing, defined as complete re-epithelialisation with absence of drainage, requiring clinical expert assessment as the gold standard. Central blinded photograph review for confirmation of healing is increasingly being undertaken for internal validity. The Diabetic Foot Ulcer Photography study aims to determine the agreement between blinded independent review panel members for assessing ulcer healing status in patients with DFUs.Methods and analysis Photographs of ulcers clinically assessed as healed or not healed across 300 participants recruited to one of two randomised controlled trials (MIDFUT and CODIFI2), will be independently reviewed by a central blinded panel consisting of four clinicians with expertise in ulcer healing assessment. Staff at recruiting sites will take photographs using a standardised camera and protocol. Photographs will be reviewed at three levels of magnification: raw image, image standardised to a measurement scale included in the photograph and standardised image with magnification permitted. Reviewers will assess the healing status and their confidence level in making a healing judgement, with reasons reported for a low confidence rating. Analysis at each level of magnification will estimate inter- and intra-rater reliability on the assessments of healing of photographs with the clinical assessment (primary) and confidence rating using multivariable logistic mixed models. Analysis of the learning curve for the assessment of healing and confidence rating will use exponential and two-phase models.Ethics and dissemination Ethics approval has been granted by the National Research Ethics Service Committees (MIDFUT 17/YH/0055; CODIFI2 18-WS-0235). All participants will provide a written informed consent for photography before recruited onto the respective study. Photographs will be transferred to the trials’ coordinating centre via a secure file transfer service and saved in a restricted access folder on a secure server. Results will be disseminated via publications in scientific journals and conference presentations.Trial registration number MIDFUT (ISRCTN64926597) and CODIFI2 (ISRCTN74929588).

Background Hand eczema is common and a cause of morbidity and occupational disability. When education, irritant/contact allergen avoidance, moisturisation and topical corticosteroids are insufficient to control chronic hand eczema, ultraviolet therapy or systemic immune-modifying drugs are used. There is no treatment pathway generally accepted by UK dermatologists. Primary objective Compare alitretinoin and ultraviolet therapy as first-line therapy in terms of disease activity at 12 weeks post planned start of treatment. Design Prospective, multicentre, open-label, two-arm parallel group, adaptive randomised controlled trial with one planned interim analysis, and an economic evaluation. Setting UK secondary care dermatology outpatient clinics. Participants Patients with severe chronic hand eczema unresponsive to at least 4 weeks of treatment with potent topical corticosteroids. Primary end point Natural logarithm of the Hand Eczema Severity Index + 1, 12 weeks post planned start of treatment. Randomisation Participants randomised 1 : 1 by minimisation to alitretinoin or ultraviolet therapy for 12 to 24 weeks. Blinding Blinded primary end-point assessor. Results Intention-to-treat population: 441 (100.0%) participants; 220 (49.9%) alitretinoin and 221 (50.1%) ultraviolet therapy. At least one dose was received by 212 (96.4%) alitretinoin and 196 (88.7%) ultraviolet therapy participants. Primary outcome The unadjusted median (interquartile range) relative change in hand eczema severity index at 12 weeks was 30% (10–70%) of that at baseline for alitretinoin compared with 50% (20–100%) for ultraviolet therapy. There was a statistically significant benefit of alitretinoin compared with ultraviolet therapy at 12 weeks, with an estimated fold change or relative difference (95% confidence interval) = 0.66 (0.52 to 0.82), p = 0.0003 at 12 weeks. There was no evidence of a difference at 24 or 52 weeks, with the estimated fold change (95% confidence interval) equal to 0.92 (0.798 to 1.08) and 1.27 (0.97 to 1.67), respectively. Primary analysis results were consistent for secondary end points Fifty-nine per cent allocated to alitretinoin and 61% allocated to ultraviolet therapy achieved a clear/almost clear assessment during the trial period. Differential treatment compliance observed: 145 (65.9%) alitretinoin and 53 (24.0%) ultraviolet therapy participants confirmed compliance (≥ 80% received, no treatment breaks > 7 days during first 12 weeks). High levels of missing data were observed. Safety One hundred and thirty-five reportable adverse events across 79 participants, 55 (25.0%) alitretinoin and 24 (10.9%) ultraviolet therapy. Four serious adverse events (two alitretinoin, two ultraviolet therapy). Four pregnancies reported (three alitretinoin, one ultraviolet therapy). No new safety signals were detected. Conclusion As a first-line therapy, alitretinoin showed more rapid improvement and superiority to ultraviolet therapy at week 12. This difference was not observed at later time points. Alitretinoin is cost-effective at weeks 12 and 52. Ultraviolet therapy is cost-effective after 10 years, with a high degree of uncertainty. Hand eczema severity index may be a useful primary outcome measure for hand eczema trials; ALPHA results will inform future trials. Limitations Treatment compliance was poor for ultraviolet therapy. Regular twice weekly treatment was not received by most patients. Assessment of long-term effects of randomised treatments was complicated by use of second-line treatments post treatment phase. Further work Further analysis of substudies and pilot data will provide valuable information for future studies. A clear need for better therapeutic approaches for severe chronic hand eczema remains. Future studies will need to further address long-term benefits of treatments given. Trial registration This trial is registered as ISRCTN80206075. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 12/186/01) and is published in full in Health Technology Assessment; Vol. 28, No. 59. See the NIHR Funding and Awards website for further award information. Plain language summary What was the question? The main question was which treatment was better at easing symptoms of severe hand eczema after 12 weeks. The two treatments compared were ones used most often by UK dermatologists. The first is a tablet called alitretinoin, which is taken once a day. The second is called ultraviolet therapy, where hands are soaked in a special liquid and placed under ultraviolet light twice a week at a hospital. What did we do? We treated 220 patients with alitretinoin and 221 patients with ultraviolet therapy. Patients received treatment for 12 to 24 weeks depending on how well their hand eczema responded. Patients could have different treatments afterwards, and we collected information on their hand eczema symptoms for up to 1 year. What did we find? After 12 weeks, severe hand eczema symptoms improved for both groups of patients but improved most for patients who took alitretinoin. However, 1 year after joining the trial, there was no evidence of a difference between alitretinoin and ultraviolet therapy as a first-line treatment. More patients stopped ultraviolet therapy early compared with patients who received alitretinoin. Different treatments may have been prescribed after the first treatment. What does this mean? Alitretinoin provides a convenient, instant relief or a ‘quick fix’ for patients with severe hand eczema. Alitretinoin is more convenient for lots of people, but it is important to have other options available for people who would prefer not to, or are unable to, take alitretinoin. For example, people who take alitretinoin can experience unwanted side effects, and people who are able to become pregnant must also use contraception. Long-term control of severe hand eczema is important. Individual discussions on the pros and cons of each treatment for hand eczema symptoms is needed. Providing flexible options to attend ultraviolet therapy appointments could be helpful (e.g. weekend/evenings). Scientific summary Background Hand eczema (HE) is common and an important cause of morbidity and occupational disability. One-year prevalence of HE is up to 10% in the general population, with 5–7% developing chronic hand eczema (CHE). Current evidence is not compelling enough to guide clinical practice. When patient education, irritant/contact allergen avoidance, moisturisation and topical corticosteroids are insufficient to control CHE, ultraviolet therapy (PUVA) or systemic immune-modifying drugs are used. There is no treatment pathway generally accepted among UK dermatologists. Most UK dermatology centres use phototherapy (mostly Immersion PUVA) or alitretinoin as first-line treatment for uncontrolled CHE. ALPHA is the first trial comparing alitretinoin with Immersion PUVA as a first-line therapy for patients with uncontrolled severe CHE. Objectives Primary objective Compare alitretinoin and Immersion PUVA as first-line therapy in terms of disease activity at 12 weeks post planned start of treatment. Secondary objectives Compare alitretinoin and Immersion PUVA in terms of disease activity over time (focusing on 24 and 52 weeks post planned start of treatment). Compare alitretinoin and Immersion PUVA in terms of time to relapse. Compare alitretinoin and Immersion PUVA in terms of quality of life (QoL) and patient benefit over 52 weeks post planned start of treatment. Determine cost-effectiveness of alitretinoin compared with Immersion PUVA over the short and longer term. Determine the educational need for patients. Compare alitretinoin and Immersion PUVA in terms of safety. Exploratory objectives included subgroup analyses to assess whether treatment response is affected by pre-specified baseline characteristics. Methods Design Prospective, multicentre, open-label, two-arm parallel group, adaptive randomised controlled trial with one planned interim analysis and an economic evaluation. Participants Patients with severe CHE unresponsive to at least 4 weeks of treatment with potent topical corticosteroids. Primary end point Natural logarithm of the Hand Eczema Severity Index (HECSI) + 1 at 12 weeks post planned start of treatment. Secondary end points Disease activity, measured by HECSI, modified Total Lesion Scoring System (mTLSS) and Physician’s Global Assessment (PGA) at 12, 24, 52 weeks post planned start of treatment. Time to relapse, defined as time between achieving clear/almost clear overall on the blinded assessor PGA and scoring 75% of their baseline HECSI, with sensitivity assessed by redefining relapse as 50% of their baseline HECSI. Dermatology Life Quality Index (DLQI) and Patient Benefit Index for Hand Eczema (PBI-HE) at 12, 24 and 52 weeks post planned start of treatment. Person-Centred Dermatology Self-Care Index (PeDeSi) at 12 and 52 (or 24) weeks post planned start of treatment. Reported adverse events (AEs) and serious adverse events (SAEs) over 52 weeks post planned start of treatment. Cost-effectiveness of alitretinoin compared with Immersion PUVA at week 12, 52 (short term) and over 10 years (long term). Randomisation Participants were randomised using minimisation 1 : 1 to alitretinoin 30 mg/day or Immersion PUVA for 12 weeks to 24 weeks. Randomisation factors were: randomising site, disease duration, clinical phenotype, atopy status, DLQI and skin type. Analysis Linear mixed models accounting for the longitudinal data structure were fitted to primary (HECSI) and secondary end points (mTLSS, DLQI) on the intention-to-treat (ITT) population, with adjustment for: smoking history, body mass index (BMI), foot involvement, baseline score, time since planned start of treatment and treatment group. Participant and participant–time interaction were fitted as random effects. An ordinal logistic mixed model was fitted to the PGA, and an ordinal logistic model without random effects was fitted to the PeDeSI at 12 weeks. Exploratory analyses explored differential treatment effects in pre-planned subgroups, correlation of scoring systems and second-line therapies, and safety data were summarised. Total cost and quality-adjusted life-years (QALYs) were estimated at weeks 12, 52, and 10 years after treatment initiation. The latter were combined to estimate short- and long-term cost-effectiveness. Short-term cost-effectiveness was estimated via a within-trial analysis at weeks 12 and 52 and via Markov model to estimate 10-year cost-effectiveness of both interventions. A resource use questionnaire was used to estimate short- and long-term cost of interventions and standard care, while EuroQol-5 Dimensions, three-level version (EQ-5D-3L) responses were used to estimate utility values and generate QALYs. This analysis followed the NHS and personal and social perspective (PSS). Cost-effectiveness was determined using National Institute for Health and Care Excellence (NICE) guidelines. Secondary analysis included societal perspective and QALYs determined by the DLQI. Data collection Data were collected at baseline, 4-weekly to week 36 and 8-weekly to week 52. Sample size A minimum of 500 and maximum of 780 participants were required to detect a relative difference, or fold change, of 1.3 in HECSI score between treatment arms at 12 weeks post planned start of treatment (80% power; two-sided 5% significance level) assuming a coefficient of variation (CV) between 1.175 and 1.7 and 20% attrition. Note that a fold change of 1.3 is equivalent to a fold change of 0.77 if there was a benefit in the opposite direction. A sample size review was planned after 364 participants reached 12 weeks post planned start of treatment but was conducted early in August 2017. Following Data Monitoring and Ethics Committee (DMEC) review, a sample size of 514 participants was recommended based on a CV of 1.2. Results Screening and recruitment Thirty-one NHS hospitals in England, Scotland and Wales assessed 1557 patients for eligibility, registered 582 (37.4%) and randomised 441 (75.8%) participants between October 2015 and June 2021. Of 1557 patients screened, 642 (41.2%) were ineligible, with 347 (54.0%) not having a severe CHE diagnosis. Of 915 eligible patients, 582 (63.6%) were consented and registered. Of 333 patients who did not consent, 74 (22.2%) thought the Immersion PUVA schedule or travel was inconvenient, and 28 (8.4%) did not want alitretinoin. Of 141 patients not randomised, the main reasons were not meeting the eligibility criteria [n = 69 (48.9%)] or patient choice [n = 29 (20.6%)]. Of patients randomised, 220 (49.9%) were allocated to alitretinoin and 221 (50.1%) to Immersion PUVA. Of those allocated to alitretinoin, 201 (91.4%) started treatment within 7 days post randomisation compared with 165 (74.7%) of those allocated to Immersion PUVA. In total, 132 (29.9%) participants withdrew from, or were lost to, follow-up. The ITT population included 441 (100.0%) participants. Primary outcome Hand eczema severity index at 12 weeks In terms of relative change, the median [interquartile range (IQR)] score at 12 weeks was equal to 30% (10–70%) of that at baseline for the alitretinoin group compared with 50% (20–100%) in the Immersion PUVA group. There was a statistically significant benefit of alitretinoin compared with Immersion PUVA at 12 weeks, with an estimated fold change of 0.66 (0.52, 0.82), p = 0.0003 at 12 weeks. Secondary end points Hand eczema severity index over 52 weeks There was no evidence of a difference between alitretinoin and Immersion PUVA at 24 weeks or 52 weeks, with the estimated fold change [95% confidence interval (CI)] equal to 0.92 (0.798 to 1.08) and 1.27 (0.97 to 1.67), respectively. Modified total lesion symptom score over 52 weeks There was no evidence of a difference between treatment groups over 52 weeks, with the estimated difference (95% CI) equal to −0.37 (−1.23 to 0.48) at 12 weeks, −0.14 (−0.84 to 0.56) at 24 weeks and 0.41 (−0.59 to 1.40) at 52 weeks. Physician’s Global Assessment over 52 weeks At 12 weeks, the proportion of participants with available data achieving clear or almost clear (via blinded assessment) was 27.6% (47/170) for alitretinoin and 23.6% (35/148) for Immersion PUVA. Over 52 weeks, 59.4% (123/207) of alitretinoin participants with available data achieved at least one clear/almost clear assessment compared with 61.5% (118/192) of Immersion PUVA participants. There was no evidence of a difference between treatment groups over 52 weeks, with the estimated odds ratios (alitretinoin vs. Immersion PUVA) for achieving lower PGA scores and 95% CI equal to 1.22 (0.90 to 1.64) at 12 weeks, 1.18 (0.89 to 1.56) at 24 weeks and 1.10 (0.64 to 1.89) at 52 weeks. Dermatology quality of life index over 52 weeks There was a statistically significant benefit of alitretinoin compared with Immersion PUVA, with mean scores (95% CI) estimated to be 0.95 (0.09 to 1.82) lower at 12 weeks for the alitretinoin group compared with Immersion PUVA. There was no statistically significant treatment effect at 24 weeks [estimated difference in mean scores = −0.18 (−0.92 to 0.56)], but at 52 weeks, there was a statistically significant treatment effect with increased scores in the alitretinoin group compared with the Immersion PUVA group [estimated difference in mean scores = −1.62 (−2.62 to −0.62)]. The differences observed in the DLQI were not clinically significant. Person-Centred Dermatology Self-Care Index at 12 weeks At baseline, 16.1% (n = 71) were assessed as having sufficient knowledge, ability and confidence to self-manage their condition, with a similar distribution of education needs across treatment groups. At 12 weeks, the proportion of participants with available data who had sufficient knowledge and education was 26.2% (117/324), 28.0% (49/175) in the alitretinoin group and 24.2% (36/149) in the Immersion PUVA group. There was no evidence of a difference in terms of educational need between treatment groups, with an estimated odds ratio (alitretinoin vs. Immersion PUVA) of 0.65 (0.39 to 1.08). Patient Benefit Index – hand eczema over 52 weeks At 12 weeks, the median (IQR) score was equal to 2.3 (1.4–3.2) in the alitretinoin group and 1.9 (0.9–2.8) in the Immersion PUVA group. At 24 weeks, the median (IQR) score was unchanged at 2.3 (1.2–3.5) in the alitretinoin group but had increased to 2.8 (1.4–3.5) in the Immersion PUVA group. At 52 weeks, the median (IQR) score was 2.6 (1.6–3.3) in the alitretinoin group and 3.0 (1.7–3.6) in the Immersion PUVA group. Time to relapse At treatment phase completion, 34.1% (N = 75) of participants allocated to alitretinoin achieved a clear or almost clear response, compared with 25.8% (N = 57) allocated to Immersion PUVA. When relapse was defined as 75% of the baseline HECSI score, 20% (n = 15) of alitretinoin responders relapsed compared with 15.8% (n = 9) of Immersion PUVA responders. When relapse was defined as 50% of the baseline HECSI score, 37.3% (n = 28) of alitretinoin responders and 36.8% (n = 21) of Immersion PUVA responders relapsed. Health economic analysis Within-trial estimated costs indicate that Immersion PUVA is more costly than alitretinoin at weeks 12 and 52 (week 12: £3236 vs. £1904; week 52: £4424 vs. £3336, respectively). Treatment costs are the main drivers of Immersion PUVA costs (including therapy cost, medication and follow-up). Out-of-pocket expenditures are also higher for patients assigned to Immersion PUVA. These increase the cost difference at weeks 12 and 52 (from £1333 to £1650 at week 12 and from £1081 to £1841 at week 52). Immersion PUVA’s QALYs are higher at both time points (week 12: 0.165 vs. 0.159 and week 52: 0.798 vs. 0.761). When using DLQI, the estimated QALYs were slightly higher for alitretinoin compared with Immersion PUVA (week 12: 0.158 vs. 0.154; week 52: 0.784 vs. 0.782, respectively). When combined, the incremental cost-effectiveness ratios (ICERs) indicate alitretinoin is cost-effective at weeks 12 and 52 in all scenarios (primary analysis, societal perspective, and QALYs derived from DLQI). These results are robust, as the probability of cost-effectiveness is between 96% and 100%. Long-term cost-effectiveness The 10-year cost estimates indicate that patients allocated to alitretinoin are slightly more costly than Immersion PUVA (£5432 vs. £5361, respectively). In terms of QALYs, Immersion PUVA is slightly more effective (6.535 vs. 6.530, respectively). The latter suggests Immersion PUVA is the cost-effective strategy; however, results are uncertain, as only 50% of the probabilistic analysis iterations indicate this is the case. Safety data Seventy-nine participants had 135 reportable AEs, 25.0% (n = 55) participants allocated to alitretinoin and 10.9% (n = 24) participants allocated to Immersion PUVA. There were four serious AEs (SAEs; two alitretinoin, two Immersion PUVA); one suspected/expected to be related to treatment, and three related to underlying CHE. There were four pregnancies (three alitretinoin, one Immersion PUVA), including one alitretinoin patient in active treatment, who stopped treatment immediately. Treatment compliance In total, 212 (96.4%) participants randomised to alitretinoin and 196 (88.7%) randomised to Immersion PUVA received treatment. Full ‘trial’ compliance (≥ 80% received and no treatment breaks > 7 days during the first 12 weeks) was observed in 65.9% (N = 145) participants allocated to alitretinoin and 24.0% (N = 53) allocated to Immersion PUVA. Subgroup analysis No differential treatment effects were observed within subgroups defined by disease duration, clinical phenotype, disease severity, presence of atopy, filaggrin loss of function mutation, smoking history, BMI, foot involvement or biomarkers identified through tape stripping. Conclusion Alitretinoin and Immersion PUVA both led to reductions in symptoms. As a first-line therapy, alitretinoin showed a more rapid improvement and was superior to Immersion PUVA in terms of primary end point at 12 weeks. This difference was not observed at later time points. Alitretinoin was more cost-effective over the short term (12 and 52 weeks) with robust results. Long-term analysis indicates that Immersion PUVA is cost-effective in the long term; these results, however, are uncertain. These findings will inform clinical management of patients with severe CHE. Alitretinoin may be considered as the recommended first-line therapy; however, Immersion PUVA may also be considered for longer-term outcomes, particularly in patients where alitretinoin is not an appropriate treatment. Recruitment was difficult, with perceived treatment pathway challenges. The trial implemented a self-referral service, through which 13.8% of randomised participants were recruited. The Immersion PUVA schedule was problematic, with more than 20% of participants declining participation citing this as their main reason. Immersion PUVA treatment compliance was poor, and regular twice-weekly treatment was not achieved by most patients. Hand eczema severity index (HECSI) was the chosen primary outcome measure because it incorporated more details about the condition compared with PGA, which had been used previously. Furthermore, HECSI is continuous rather than discrete, which meant a smaller sample size was required for a desired level of power. The results from ALPHA will help inform future CHE trial designs. Most participants had some educational need for how to manage their condition, and overall, there remains a need for better therapeutic approaches for severe CHE. Just 59% and 61% of patients allocated to alitretinoin and Immersion PUVA, respectively, were known to achieve a clear/almost clear assessment at any time point during the trial period. Further work includes deeper analysis of substudies and pilot data to inform future research, which is needed to understand the long-term effects of treatments. Trial registration This trial is registered as ISRCTN80206075. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 12/186/01) and is published in full in Health Technology Assessment; Vol. 28, No. 59. See the NIHR Funding and Awards website for further award information.

Background Posterior cervical foraminotomy and anterior cervical discectomy are routinely used operations to treat cervical brachialgia, although definitive evidence supporting superiority of either is lacking. Objective The primary objective was to investigate whether or not posterior cervical foraminotomy is superior to anterior cervical discectomy in improving clinical outcome. Design This was a Phase III, unblinded, prospective, United Kingdom multicentre, parallel-group, individually randomised controlled superiority trial comparing posterior cervical foraminotomy with anterior cervical discectomy. A rapid qualitative study was conducted during the close-down phase, involving remote semistructured interviews with trial participants and health-care professionals. Setting National Health Service trusts. Participants Patients with symptomatic unilateral cervical brachialgia for at least 6 weeks. Interventions Participants were randomised to receive posterior cervical foraminotomy or anterior cervical discectomy. Allocation was not blinded to participants, medical staff or trial staff. Health-care use from providing the initial surgical intervention to hospital discharge was measured and valued using national cost data. Main outcome measures The primary outcome measure was clinical outcome, as measured by patient-reported Neck Disability Index score 52 weeks post operation. Secondary outcome measures included complications, reoperations and restricted American Spinal Injury Association score over 6 weeks post operation, and patient-reported Eating Assessment Tool-10 items, Glasgow–Edinburgh Throat Scale, Voice Handicap Index-10 items, PainDETECT and Numerical Rating Scales for neck and upper-limb pain over 52 weeks post operation. Results The target recruitment was 252 participants. Owing to slow accrual, the trial closed after randomising 23 participants from 11 hospitals. The qualitative substudy found that there was support and enthusiasm for the posterior cervical FORaminotomy Versus Anterior cervical Discectomy in the treatment of cervical brachialgia trial and randomised clinical trials in this area. However, clinical equipoise appears to have been an issue for sites and individual surgeons. Randomisation on the day of surgery and processes for screening and approaching participants were also crucial factors in some centres. The median Neck Disability Index scores at baseline (pre surgery) and at 52 weeks was 44.0 (interquartile range 36.0–62.0 weeks) and 25.3 weeks (interquartile range 20.0–42.0 weeks), respectively, in the posterior cervical foraminotomy group (n = 14), and 35.6 weeks (interquartile range 34.0–44.0 weeks) and 45.0 weeks (interquartile range 20.0–57.0 weeks), respectively, in the anterior cervical discectomy group (n = 9). Scores appeared to reduce (i.e. improve) in the posterior cervical foraminotomy group, but not in the anterior cervical discectomy group. The median Eating Assessment Tool-10 items score for swallowing was higher (worse) after anterior cervical discectomy (13.5) than after posterior cervical foraminotomy (0) on day 1, but not at other time points, whereas the median Glasgow–Edinburgh Throat Scale score for globus was higher (worse) after anterior cervical discectomy (15, 7, 6, 6, 2, 2.5) than after posterior cervical foraminotomy (3, 0, 0, 0.5, 0, 0) at all postoperative time points. Five postoperative complications occurred within 6 weeks of surgery, all after anterior cervical discectomy. Neck pain was more severe on day 1 following posterior cervical foraminotomy (Numerical Rating Scale – Neck Pain score 8.5) than at the same time point after anterior cervical discectomy (Numerical Rating Scale – Neck Pain score 7.0). The median health-care costs of providing initial surgical intervention were £2610 for posterior cervical foraminotomy and £4411 for anterior cervical discectomy. Conclusions The data suggest that posterior cervical foraminotomy is associated with better outcomes, fewer complications and lower costs, but the trial recruited slowly and closed early. Consequently, the trial is underpowered and definitive conclusions cannot be drawn. Recruitment was impaired by lack of individual equipoise and by concern about randomising on the day of surgery. A large prospective multicentre trial comparing anterior cervical discectomy and posterior cervical foraminotomy in the treatment of cervical brachialgia is still required. Trial registration This trial is registered as ISRCTN10133661. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 21. See the NIHR Journals Library website for further project information. Plain language summary Cervical brachialgia is pain that starts in the neck and passes down into the arm. Although most people with cervical brachialgia recover quickly, in some patients pain persists, and in 15% of patients pain is so severe that they are unable to work. In the posterior cervical FORaminotomy Versus Anterior cervical Discectomy in the treatment of cervical brachialgia trial, we investigated two neck surgeries used to treat this problem: posterior cervical foraminotomy (surgery from the back of the neck) and anterior cervical discectomy (surgery from the front of the neck). This trial aimed to find out if one of them is better than the other at relieving pain and more cost-effective for the National Health Service. We assessed patients’ quality of life 1 year after their surgery and how their pain changed over the course of the year. We also measured the number of complications patients had in the first 6 weeks after their operation. Recruitment was slow and so the trial was stopped early, after only 23 patients from 11 hospitals had been randomly allocated to the two surgery groups. We had planned to recruit 252 participants to the trial; the number of participants we were able to recruit in practice was too small to enable us to determine which surgery is better at relieving pain. To find out why the trial had struggled to recruit, we asked hospital staff and participants about their experiences. We found that hospital staff sometimes struggled to organise everything needed to randomise patients on the day of surgery. Some staff also found it difficult to randomise patients as they had an opinion on which surgery they thought the patient should receive. The data collected in the trial will still be useful to help design future research. Finding out which surgery is better at relieving pain remains important, and the data we have collected will support answering this question in future. Scientific summary Background As people age, degenerative disease affects the intervertebral discs, facet joints and ligamentum flavum in the cervical spine. Consequently, the nerve root foramina may change shape and the nerve roots become compressed, causing a syndrome called cervical radiculopathy. Cervical radiculopathy is characterised by neck pain and cervical brachialgia, with the symptom of pain originating in the neck and radiating down into the upper arm. The reported incidence of cervical brachialgia is 1.79 cases per 1000 per year, with > 110,000 cases of brachialgia annually in the UK. Cervical brachialgia typically affects people aged 40–60 years, with up to 15% of patients unable to work because of the pain. In most patients, brachialgia is self-resolving with conservative management strategies. However, if symptoms persist 6 weeks to 3 months after onset, two of the available surgical techniques used (in the UK) to treat cervical brachialgia are posterior cervical foraminotomy (PCF) and anterior cervical discectomy (ACD). The most common and current standard operation is ACD, approaching from the front of the neck. The procedure is effective, but there is a high incidence of significant, potentially permanent, complications, including dysphagia and hoarse voice, which can be devastating to a patient’s quality of life. Alternatively, PCF can be undertaken from the back of the neck. Unlike ACD, PCF avoids risk to the structures in front of the spine including the carotid artery, sympathetic trunk, recurrent laryngeal nerve, larynx and pharynx, but may result in higher levels of postoperative neck pain and a greater need for revision surgery. Controversy therefore exists over which procedure is superior for the treatment of cervical brachialgia, and the decision on which procedure to use is frequently left to surgeon preference. The posterior cervical FORaminotomy Versus Anterior cervical Discectomy in the treatment of cervical brachialgia (FORVAD) trial aimed to robustly compare the two procedures, with the ambition of providing definitive evidence that would guide surgical decision-making for patients with cervical brachialgia symptoms requiring surgical intervention. Objectives The primary objective of the trial was to determine whether PCF is superior to ACD in terms of improving clinical outcome, as measured by the Neck Disability Index (NDI) at 52 weeks post operation, among patients with persistent cervical brachialgia for whom conservative management has failed. The secondary objectives were comparison of the two surgeries in terms of NDI score, patient-reported neck and upper-limb pain, dysphagia and globus, hoarse voice symptoms, incidence of revision surgery, cost effectiveness over 52 weeks post operation, the extent and severity of a patient’s spinal cord functional impairment, and incidence of surgical complications up to 6 weeks post operation. The exploratory objectives were to explore the impact of variations in the optional surgical components of PCF (open or minimal-access surgery) and ACD (surgery with or without a plate) on NDI and EuroQol-5 Dimensions, three-level version (EQ-5D-3L) scores. Design The FORVAD trial was a UK multicentre, Phase III, parallel-group, superiority, individually randomised controlled trial comparing the clinical effectiveness and cost effectiveness of PCF with those of ACD among patients experiencing symptomatic unilateral cervical brachialgia for at least 6 weeks, with confirmed nerve root compression on magnetic resonance imaging or computerised tomography myelography. Neither participants nor medical or clinical trial staff in the FORVAD trial were blinded to the treatment allocated. The trial incorporated an internal pilot phase to assess the feasibility of trial delivery against prespecified recruitment criteria. Participants were randomised (1 : 1) to receive PCF or ACD via minimisation incorporating a random element, with minimisation factors of centre, duration of upper-limb symptoms and smoking status. Participants were followed up in clinic at day 1 and 6 weeks post operation, and by post at 12, 26, 39 and 52 weeks post operation. The target sample size was 252 participants (126 per trial arm). This number was required to have 90% power to detect the minimum clinically important difference of 10% (5 points) in the change in NDI score at 52 weeks post operation, assuming a between-patient standard deviation of 23 units, two-sided 5% significance level and 10% loss to follow-up. For the analysis of the primary outcome measure, it was intended to use a multilevel linear regression model incorporating random effects with respect to centre, and adjusting for baseline (day 0) NDI score and minimisation factors (duration of upper limb symptoms and smoking status). The statistical analysis plan was amended prior to final analysis of the data to account for the restricted sample size owing to the early closure of the trial and was limited to descriptive summaries. Setting The trial aimed to recruit from 15 NHS hospitals throughout the UK. Participating surgeons were expected to perform both trial procedures and were required to have performed a minimum of 10 of each surgical procedure and to have completed a bespoke training package on the e-brain platform [www.ebrain.net (accessed 25 April 2022)]. Participants Patients were eligible to participate if they had been diagnosed with unilateral cervical brachialgia that had persisted for at least 6 weeks, resultant from single-level nerve entrapment, and conservative management had previously failed. Patients with cervical myelopathy, spinal cord compression or who had previously had cervical spine surgery were excluded. Eligibility waivers were not granted in this trial. Interventions Pre-operative investigations and preparation were as per individual site protocol. Participants received either PCF or ACD. Minimal- and open-access techniques were permitted for PCF. For ACD, the choice of fusion material and the decision to use a plate were left to surgeon discretion. Postoperative care was also as per individual site protocol. Main outcome measures The primary outcome measure was the patient-reported percentage NDI score at 52 weeks post operation. Secondary patient-reported outcomes (collected at baseline; at days 1 and 6; and at 12, 26, 39 and 52 weeks post operation) were collected using the Numerical Rating Scale–Neck Pain (NRS-NP), the Numerical Rating Scale–Arm Pain (NRS-AP), the validated PainDETECT, the Eating Assessment Tool-10 items (EAT-10), the Glasgow–Edinburgh Throat Scale (GETS) and the Voice Handicap Index-10 items (VHI-10) tools. Secondary clinical outcomes included a restricted version of the American Spinal Injury Association (ASIA) assessment scale, intraoperative and postoperative complications, incidence of reoperations within 52 weeks of operation and assessment of hoarse voice from additional voice recordings collected from randomly selected participants using the grade, roughness, breathiness, asthenia and strain scoring system. Exploratory outcomes included whether participants receiving PCF received minimal- or open-access surgery, and whether participants receiving ACD received surgery with or without a plate. Patient-reported outcomes were recorded using the EQ-5D-3L, which, alongside collected health resource use data, informed cost-effectiveness analysis. Results Owing to slower than expected accrual, the trial closed to recruitment after randomising 23 participants, 14 to PCF and 9 to ACD, from 11 sites. Therefore, results from the trial should be interpreted with caution because of the small sample size. The median NDI scores at baseline and 52 weeks were 44.0 [interquartile range (IQR) 36.0–62.0] and 25.3 (IQR 20.0–42.0) in the PCF group, respectively, indicating a reduction (improvement) from baseline. In the ACD group, the median scores at baseline and 52 weeks were 35.6 (IQR 34.0–44.0) and 45.0 (IQR 20.0–57.0), respectively. Unlike the PCF group, NDI scores did not appear to improve from baseline in the ACD group. For the NRS-NP and NRS-AP, there was an initial increase from baseline in neck pain score on day 1 post operation in both groups [median 5.5 (IQR 4.0–8.0) at baseline to 8.5 (IQR 6.0–10.0) at 1 day post operation in the PCF group; median 5.0 (IQR 4.0–7.0) at baseline to 7.0 (IQR 4.0–9.0) at 1 day post operation in the ACD group]. Neck pain decreased after day 1 in both treatment groups; at 52 weeks, the median scores were 4.0 (IQR 2.0–5.0) in the PCF group and 5.0 (IQR 3.0–7.0) in the ACD group. In both groups, arm pain improved on day 1 [median 3.0 (IQR 2.0–8.0) in the PCF group; median 4.0 (IQR 0.5–5.0) in the ACD group] and reached its lowest level 12 weeks post operation [median 3.0 (IQR 2.0–8.0) in the PCF group; median 2.5 (IQR 0.0–5.0) in the ACD group]. Thereafter, arm pain deteriorated (increased), but remained below baseline [median 5.0 (IQR 2.0–7.0) in the PCF group and median 5.0 (IQR 3.0–6.0) in the ACD group at 52 weeks]. PainDETECT category scores fluctuated over the postoperative period in the PCF group, but reduced over time in the ACD group, suggesting that in the ACD group a higher proportion of the participants had developed nociceptive, rather than neuropathic, pain. The ASIA score remained unchanged in both treatment groups over the 6-week assessment period. For the EAT-10 and the VHI-10 outcomes, the ACD group had worse outcomes at day 1 [median EAT-10 scores of 0.0 (IQR 0.0–4.0) in the PCF group and 13.5 (IQR 3.5–16.0) in the ACD group, and median VHI-10 scores of 0.0 (IQR 0.0–2.0) in the PCF group and 2.0 (IQR 0.5–8.5) in the ACD group], after which the two groups are comparable. However, the median GETS score was worse in the ACD group postoperatively, although the IQRs in each treatment group overlap at all time points except day 1. Five postoperative complications were reported in five participants throughout the trial, all occurring in the ACD group. Reported complications included two instances of dysphagia and three ‘other’ complications: ‘wound infection’, ‘urinary retention’ and ‘wound redness stitches overnight’. No serious or unexpected serious complications, deaths or reoperations were reported. The health economics and qualitative study The revised aims of the cost-effectiveness analysis were to describe the costs of the surgical interventions, health-care service use and participant out-of-pocket expenditures, and the productivity costs of losses associated with the surgery and its consequences. Responses to the EQ-5D-3L questionnaire of generic health-related quality of life and the rate of data completion are summarised. All costs are based on 2019/20 prices and are presented without discounting, as the time horizon of the analysis is 52 weeks. The costs of the intervention were heavily influenced by outliers in the PCF group, resulting in mean health-care costs of initial surgery, including devices, operation and hospital stay, of £2745 [95% confidence interval (CI) £2344 to £3147] for the PCF group (n = 12) and £4295 (95% CI £3436 to £5154) for the ACD group (n = 8). The corresponding median costs were £2622 (IQR £2402–2824) for participants undergoing PCF and £4423 (IQR £3849–4821) for participants undergoing ACD. These costs were driven by the time in theatre, which was a mean of 30 minutes (median 45 minutes) shorter for PCF (mean 61 minutes, median 52 minutes, IQR 49–60 minutes) than for ACD (mean 91 minutes, median 100 minutes, IQR 75–109 minutes). Results aggregated up to week 6 are presented owing to high attrition thereafter. The mean costs from the NHS and Personal Social Services perspective were £2716 (95% CI £2345 to £3087) for the PCF group and £4133 (95% CI £3099 to £5167) for the ACD group; the median costs were £2634 (IQR £2444–2741) and £4214 (IQR £3602–4994) for the PCF and ACD groups, respectively. The mean per-patient costs to society were £4608 (95% CI £2514 to £6703) for the PCF group and £5015 (95% CI £2286 to £7743) for the ACD group; the median costs were £4097 (IQR £2448–6591) and £4143 (IQR £4126–4284) for the PCF and ACD groups, respectively. At baseline, severe problems with anxiety and depression were more common, and pain and discomfort according to the EQ-5D-3L classification system was more severe in the PCF group than in the ACD group, resulting in mean utility scores of 0.291 (95% CI 0.07 to 0.51) and 0.595 (95% CI 0.40 to 0.78) for PCF and ACD, respectively. The corresponding median scores were 0.210 (IQR –0.01 to 0.60) and 0.689 (IQR 0.66–0.69). This is likely to have played a role in the larger observed gains from baseline in postoperative EuroQol-5 Dimensions (EQ-5D) scores for participants in the PCF group than in the ACD group [median change at 6 weeks of 0.10 (IQR 0.00–0.13) and 0.02 (IQR –0.03 to 0.06), respectively]. A rapid qualitative study was conducted during trial close-down to understand the experiences of health-care professionals and participants who participated in the FORVAD trial and why recruitment had been challenging, with the aim of informing future research in this area. Semistructured interviews were conducted with 18 health-care professionals (research nurses and surgeons) and two participants who had participated in the FORVAD trial. Interviews explored participants’ experiences of the FORVAD trial and their reasons for taking part, and staff experiences of recruiting to the FORVAD trial and neurosurgery trials in general. Interviews were audio-recorded and transcribed verbatim. Transcripts were analysed using rapid qualitative analysis. There was no single key factor that limited recruitment, and several themes were identified as common to all sites. Surgeons at participating sites supported the trial, and recognised collective clinical equipoise; however, many had preferences for one or the other procedure, linked to their usual practice. Organisation of the trial recruitment pathway varied, with some sites choosing to direct potentially eligible patients to dedicated clinics and other sites taking a more ad hoc approach. In the FORVAD trial, the dedicated clinic approach appeared to contribute to more eligible patients being identified and recruited, although staff at other sites explained that dedicated clinics did not fit easily with their clinical pathways. Randomisation on the day of surgery presented ethical and organisational challenges, and, where possible, should be avoided in future surgical trials. Organisation and implementation of a surgical trial in neurosurgery are complex and present many challenges. Future trials in neurosurgery should identify aspects of the protocol where it is possible to offer flexibility and ensure early multidisciplinary involvement at sites to maximise the effective integration of trial and clinical pathways. Conclusions The data suggest that PCF may be associated with better outcomes, fewer complications and lower cost, but the trial recruited slowly and was closed early. As a consequence, the trial is underpowered and definitive conclusions cannot be drawn. Trial recruitment was impaired by the lack of individual equipoise and concern about randomising on the day of surgery. A large prospective multicentre trial comparing ACD and PCF in the treatment of cervical brachialgia is still required. Trial registration This trial is registered as ISRCTN10133661. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 21. See the NIHR Journals Library website for further project information.