Multimodal Intervention for Painful Diabetic Neuropathy: NeuOst Feasibility Trial

This is the feasibility study of a single-site parallel three-armed participant-blinded controlled randomised efficacy trial of a 5-week course of the 'NeuOst treatment', compared to a designated control intervention, and to usual care only, for adults with pDPN.

Eligible participants are adults diagnosed with diabetes and pDPN, as evaluated with clinical questionnaires during an initial telephone screening. Participants with foot ulcerations, amputations, and advanced organ failure are excluded. Twelve participants per arm (36 in total) will be recruited via social media, local print media, and a poster and leaflet campaign in relevant clinics.

Blocked randomisation will allocate participants in a 1:1:1 ratio, using permuted block sizes. The test intervention consists of five weekly 1-hour sessions of semi-standardised augmented manual therapy with a specifically trained provider (NeuOst), in addition to participants' continued usual care. The control intervention will be specifically matched following current guidance, replicating the NeuOst intervention in all aspects except selected components which the study aims to investigate. Providers will be UK-registered osteopaths. Both test and control intervention were developed with extensive involvement of people with pDPN and practitioners. The third study arm will be a Usual Care (UC) group, consisting of baseline and follow-up assessments only. All trial participants can continue their usual care outside the trial, although participants will be asked to not alter their medication regimens or nonpharmacological management if possible.

An independent combined steering \& data-monitoring committee (TSC/DMC) will monitor the trial throughout and include a stakeholder representative. Participants will be reimbursed for their travel expenses but not time. Screening and follow-up data collection will be conducted electronically or via the phone to minimise trial burden. The timepoints of follow-up are immediately after treatment completion, and at 8 and 16 weeks from randomisation.

Key methodological and reporting guidance for feasibility trials will be followed, and a protocol pre-registered. Ethical approval was obtained from the institutional Research Ethics Committee.

Feasibility of a definite trial will be judged according to pre-specified criteria regarding the primary feasibility outcomes following pre-specified progression rules: Recruitment, consent rates, treatment completion, retention rates, interventionist fidelity in treatment delivery, data completeness, treatment acceptability, blinding success, and adverse events. Secondary outcomes include measures of pain intensity, interference, and quality, sleep, quality of life, and fear of falling.

The sample size of 36 was a pragmatic decision based on available funding and the trial is not powered to detect meaningful differences in clinical outcomes. Analysis of feasibility outcomes will be largely descriptive. For clinical outcomes, a pre-specified blinded analysis will provide estimates of changes in clinical outcome measures and their variance, modelling differently sized confidence intervals and presenting them as forest plot with the MCID indicated. This information can then be used for sample size calculations for a potential full-scale trial. Qualitative data from interviews with volunteering participants and trial interventionists will provide further nuance for progression decisions or intervention refinement.

Eligibility Criteria:
Inclusion Criteria:

* Medical diagnosis of diabetes mellitus (type 1 or type 2) as per patient self-report.
* Distal symmetrical peripheral neuropathy (defined as a score of ≥4 on the Michigan Neuropathy Screening Instrument (questionnaire part) (Herman et al., 2012)).
* Neuropathic pain as assessed by DN4 questionnaire (defined as a score of ≥3 of 7 self-reported items) (Spallone et al., 2012).
* Stable analgesic medication regimen for at least 3 weeks prior to anticipated study enrolment and no revision of regimen planned within the next 3 months.
* Stable attendance of out-of-study nonpharmacological therapies for neuropathic pain or professional exercise programmes (including gym classes and manual therapy) for at least 3 weeks prior to anticipated study enrolment and no revision of routine planned within the next 3 months.
* Participants capable of giving informed consent themselves.
* Participants able to speak, understand, and read English at conversational levels.
* Age: 18 and older.

Exclusion Criteria:

* Contraindications to manual therapy and conservative pain management (as determined by recruiting staff during screening calls or the trial provider at the initial or any other appointment; May include medical emergencies and suspected severe pathology, advanced osteoporosis, and active foot ulcerations)
* Past or scheduled amputations
* Advanced renal failure
* Recent physical trauma and suspected fracture
* Currently experiencing severe depressive or other current and severe psychopathology such as bipolar/psychosis, and/or presenting with active suicidal risk
* Carpal Tunnel Syndrome diagnosis or symptoms as the only source of neuropathic pain
* Unable or unwilling to provide consent for study participation
* Unable to attend in-person appointments at treatment site (for health reasons)
* Unable to attend in-person appointments at treatment site (for organisational reasons)
* Knowing other participants signed up to the study (to avoid group contamination)
* Concomitant participation in another clinical intervention study
* Changes in medication or physical activity programmes in the past 1 month or planned for the next 3 months.