The Anti-Freaze-F Study- Anti-TNF for Treatment of Frozen Shoulder - a Feasibility Study

Study Overview
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Brief Summary
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Frozen shoulder is a common condition affecting approximately 9% of people aged 25-64 years. During the early phase the pain is usually unbearable and the later restriction in movement is severely limiting. It occurs when the flexible tissue (capsule) that surrounds the shoulder joint becomes inflamed, thickened and tight. The pain can be very severe and lasts 3-9 months, followed by a 4-12 month period of increasing stiffness, after which the condition usually improves. Frozen shoulder often affects a person's ability to sleep, carry out everyday activities, and work. Current treatments include rest, painkillers, anti-inflammatories, physiotherapy and steroid injections. If stiffness persists, surgery is sometimes recommended. However, there is no evidence that any of these treatments lead to significant benefit in the long term, with many being ineffective. The aim of this study is to find out if it is possible to run a larger trial to test whether an injection of adalimumab can reduce pain and prevent the disease from getting worse, if given during the early painful phase of frozen shoulder. The investigators need to conduct this smaller study first to be sure it's possible to identify and treat people with early stage frozen shoulder, before they conduct a much larger trial to find out if this treatment works. In this study the investigators will include 84 adults from 5 sites with painful early stage frozen shoulder who have not yet received treatment. People will be randomised to receive either an injection of the drug adalimumab or a dummy injection of saline (placebo) directly into the shoulder joint, both guided by ultrasound. All participants will also receive standardized advice on how to manage their shoulder pain. The investigators will assess participants before treatment and three months later. Adalimumab has been used very successfully to treat other inflammatory diseases such as rheumatoid arthritis. This study has been funded by the NIHR RfPB programme and 180 Life Sciences.

Official Title
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Anti-TNF (Adalimumab) Injection for the Treatment of Adults With Frozen Shoulder During the Pain-predominant Phase: a Multi-centre, Randomised, Double Blind, Parallel Group, Feasibility Study

Conditions
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Frozen Shoulder

Intervention / Treatment
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* Drug: Adalimumab Injection
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women aged 18 years and above. With a new episode of shoulder pain attributable to pain-predominant stage of frozen shoulder (i.e. within approximately 3 months of onset of symptoms) diagnosed using criteria set out in the BESS guidelines (33) (Appendix 1); Who are not being considered for surgery; Able to understand spoken and written English; Willing and able to give informed consent for trial participation and comply with all study requirements and time line; Willing to allow his or her General Practitioner be notified of participation in the trial. If female and of child-bearing potential OR if male and their partner is of child-bearing potential - willing to use effective contraception throughout the treatment period and for 5 months after the last injection.- Exclusion Criteria: Those with frozen shoulder secondary to significant shoulder trauma (e.g., dislocation, fracture or full thickness tear requiring surgery) or other causes (e.g. recent breast cancer surgery or radiotherapy); Those with a neurological disease affecting the shoulder; Those with bilateral concurrent frozen shoulder; Those with other shoulder disorders (e.g., inflammatory arthritis, rotator cuff disorders, glenohumeral joint instability) or with red flags consistent with the criteria set out in the BESS guidelines (33); Those who have received corticosteroid injection for shoulder pain in the last 12 weeks to either shoulder; Those currently taking any anti-TNF drug; Those being treated with coumarin anticoagulants, such as warfarin; Those who have participated in another research study involving an investigational medicinal product in the past 12 weeks; Those with significant renal or hepatic impairment; Those with contra-indications to anti-TNF injection: 10.1 Known allergy to any anti-TNF agent or any of the excipients; 10.2 Known Active tuberculosis (TB) or history of TB. 10.3 Known Active infection (chronic or localised) or known history of recurring infections or condition which may predispose patients to infection, including the use of concomitant immunosuppressive medications; 10.4 Known Moderate to severe heart failure (NYHA class III/IV); 10.5 Those known to have HIV, Hepatitis B or C; 10.6 Those at risk of Hepatitis B infection; 10.7 Those diagnosed with Multiple Sclerosis (MS) or other central or peripheral nervous system demyelinating disorders; 10.8 Those who have ever been diagnosed with cancer, except basal cell carcinoma (BCC); 10.9 Those requiring live vaccination prior towithin 12 weeks after of the last trial injection or within the 4 weeks prior to randomisation; 10.10 Those taking biologic DMARDS; 10.11 Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the study, or may influence the result of the study, or the participant's ability to participate in the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Participants will be randomised to either receive Adalimumab or Placebo.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A<br>Participants will receive 2 injections of adalimumab. First injection: 160mg in 3.2ml Second injection approximately 2-3 weeks later 80mg in 1.6ml | Drug: Adalimumab Injection<br>* 40mg in 0.8ml preparation in vials from Fresenius Kabi Ltd<br>|
| Placebo Comparator: Arm B<br>Participants will receive 2 injections of placebo First injection: 3.2ml Second injection approximately 2-3 weeks later 1.6ml | Drug: Placebo<br>* Saline [0.9% NaCl]<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of recruitment of participants with pain predominant frozen shoulder | Ability to screen and identify potential participants with pain-predominant early stage frozen shoulder (i.e. within approximately 3 months of onset of symptoms). | At 12 Months | 
| Number of participants consenting to be included in the trial . | Willingness of eligible participants to consent and be randomised to intervention. | At 12 Months | 
| Days between baseline assessment and time to first injection. | Practicalities of delivering the intervention, including time to first injection (within 2 weeks of randomisation). | at 2 weeks | 
| Days Between first injection and second injection. | Practicalities of delivering the intervention, including time between first injection and second injection (within 4-6 weeks of randomisation). | At 6 weeks | 
| Standard deviation of the Shoulder Pain and Disability Index (SPADI) score and attrition rate at 3 months from baseline in order to estimate the sample size for a definitive trial. | SPADI score range from 0 to 100, lower scores indicate better outcome | 3 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain (Shoulder Pain And Disability Index, 5-item subscale) | score range from 0 to 100, lower scores indicate better outcome | These will be recorded at baseline and 3 months | 
| Function (Shoulder Pain And Disability Index, 8-item subscale) | score range from 0 to 100, lower scores indicate better outcome | These will be recorded at baseline and 3 months | 
| Fear Avoidance Belief Questionnaire | score range from 0 to 24, higher scores indicate better outcomes | This will be measured at baseline and 3 months | 
| Pain Self Efficacy Questionnaire | score range from 0 to 12, higher scores indicate better outcomes | These will be recorded at baseline and 3 months | 
| Insomnia Severity Index | Sleep disturbance will be measured using the Insomnia Severity Index, score range from 0 to 28, higher scores indicate worse outcomes | These will be recorded at baseline and 3 months | 
| Return to desired activities (RDA) | Return to desired activities will be measured using an adapted version of the Disabilities of the Arm, Shoulder and Hand (QUICKDASH) questionnaire | These will be recorded at baseline and 3 months | 
| Global impression of change | this will be measured using the Likert scale, score range from -5 to +5, higher scores indicate better outcomes | These will be recorded at baseline and 3 months | 
| Number of visits to Healthcare Professionals |  | These will be recorded at baseline and 3 months | 
| Adverse events graded 3 or above (clinician assessed) related to intra-articular injection of adalimumab in the shoulder |  | These will be recorded after the first injection and at 3 months | 
| Shoulder range of motion in degrees using a goniometer |  | These will be recorded at baseline and 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adhesive capsulitis