Exercise therapy and patient education versus intra-articular saline injections in the treatment of knee osteoarthritis: an evidence-based protocol for an open-label randomised controlled trial (the DISCO trial)

Background Knee osteoarthritis (OA) is a highly prevalent musculoskeletal condition causing pain, physical disability, and reduced quality of life. Exercise and patient education are non-pharmacological interventions for knee OA unanimously recommended as first-line treatments based on extensive research evidence. However, none of the numerous randomised controlled trials of exercise and education for knee OA has used adequate sham/placebo comparison groups because the ‘active’ ingredients are unknown. Designing and executing an adequate and ‘blindable placebo’ version of an exercise and education intervention is impossible. Therefore, using an open-label study design, this trial compares the efficacy of a widely used ‘state-of-art’ exercise and education intervention (Good Life with osteoarthritis in Denmark; GLAD) with presumably inert intra-articular saline injections on improvement in knee pain in patients with knee OA. Methods In this open-label randomised trial, we will include 200 patients with radiographically verified OA of the knee and randomly allocate them to one of two interventions: (i) 8 weeks of exercise and education (GLAD) or (ii) Intra-articular injections of 5 ml isotonic saline every second week for a total of 4 injections. Outcomes are taken at baseline, after 8 weeks of treatment (week 9; primary endpoint) and after an additional 4 weeks of follow-up (week 12). The primary outcome is change from baseline in the Knee Injury and Osteoarthritis Outcome Score questionnaire (KOOS) pain subscale score. Secondary outcomes include the Physical function in Activities of Daily Living, Symptoms, and Knee-related Quality of Life subscales of the KOOS, the patients’ global assessment of disease impact, physical performance tests, and presence of knee joint swelling. Discussion This current trial compares a presumably active treatment (GLAD) with a presumably inert treatment (IA saline injections). Both study interventions have well-established and anticipated similar effects on knee OA symptoms, but the underlying mechanisms are unknown. The interpretation of the results of this trial will likely be difficult and controversial but will contribute to a better understanding of the bias introduced in the effect estimation of classically unblindable exercise and education interventions for knee OA. Trial registration www.ClinicalTrials.govNCT03843931. Prospectively registered on 18 February 2019.


Protocol version 3
Date and version identifier 27 Funding 4 Sources and types of financial, material, and other support 31 Roles and responsibilities 5a Names, affiliations, and roles of protocol contributors 31 5b Name and contact information for the trial sponsor 1 5c Role of study sponsor and funders, if any, in study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication, including whether they will have ultimate authority over any of these activities 31 5d Composition, roles, and responsibilities of the coordinating centre, steering committee, endpoint adjudication committee, data management team, and other individuals or groups overseeing the trial, if applicable (see Item 21a for data monitoring committee)

Methods: Assignment of interventions (for controlled trials)
Allocation: Sequence generation 16a Method of generating the allocation sequence (eg, computergenerated random numbers), and list of any factors for stratification. To reduce predictability of a random sequence, details of any planned restriction (eg, blocking) should be provided in a separate document that is unavailable to those who enrol participants or assign interventions 9-10 Allocation concealmen t mechanism 16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered, opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned 9-10 Implementa tion 16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to interventions 9-10 Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome assessors, data analysts), and how

BRIEF NAME 1.
Provide the name or a phrase that describes the intervention. ____12___ ___________

2.
Describe any rationale, theory, or goal of the elements essential to the intervention. ____3-5____ ___________

3.
Materials: Describe any physical or informational materials used in the intervention, including those provided to participants or used in intervention delivery or in training of intervention providers.
Provide information on where the materials can be accessed (e.g. online appendix, URL).

4.
Procedures: Describe each of the procedures, activities, and/or processes used in the intervention, including any enabling or support activities.

5.
For each category of intervention provider (e.g. psychologist, nursing assistant), describe their expertise, background and any specific training given.

6.
Describe the modes of delivery (e.g. face-to-face or by some other mechanism, such as internet or telephone) of the intervention and whether it was provided individually or in a group.

7.
Describe the type(s) of location(s) where the intervention occurred, including any necessary infrastructure or relevant features.

11.
Planned: If intervention adherence or fidelity was assessed, describe how and by whom, and if any strategies were used to maintain or improve fidelity, describe them.

12.
Actual: If intervention adherence or fidelity was assessed, describe the extent to which the intervention was delivered as planned.

BRIEF NAME 1.
Provide the name or a phrase that describes the intervention. ____10___ _supplement 2_

2.
Describe any rationale, theory, or goal of the elements essential to the intervention. ___3-5___ _supplement 2_

3.
Materials: Describe any physical or informational materials used in the intervention, including those provided to participants or used in intervention delivery or in training of intervention providers.
Provide information on where the materials can be accessed (e.g. online appendix, URL).

4.
Procedures: Describe each of the procedures, activities, and/or processes used in the intervention, including any enabling or support activities.

5.
For each category of intervention provider (e.g. psychologist, nursing assistant), describe their expertise, background and any specific training given.

6.
Describe the modes of delivery (e.g. face-to-face or by some other mechanism, such as internet or telephone) of the intervention and whether it was provided individually or in a group.