Conditions: Frozen Shoulder
Keywords: Adhesive capsulitis
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 9
Healthy volunteers: no

Brief summary:
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.

Detailed description:

Arms:
arm 1: Participants will receive 2 injections of adalimumab. First injection: 160mg in 3.2ml Second injection approximately 2-3 weeks later 80mg in 1.6ml arm 2: Participants will receive 2 injections of placebo First injection: 3.2ml Second injection approximately 2-3 weeks later 1.6ml

Interventions: intervention 1: Adalimumab Injection intervention 2: Placebo
Intervention descriptions: intervention 1: 40mg in 0.8ml preparation in vials from Fresenius Kabi Ltd intervention 2: Saline \[0.9% NaCl\]

Protocol document:
Prot_SAP_000.pdf: 
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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 
Short Title: The Anti-Freaze-F Study- “Anti-TNF for Treatment of Frozen Shoulder – a Feasibility 
Study” 
 
 
Date and Version Number: v3.0_22Nov2022 
 
ISRCTN:   27075727   
EudraCT Number:  2021-003509-23 
    
IRAS ID: 1004069      
 
Chief Investigator 
Professor Jagdeep Nanchahal, University of Oxford 
 (Chief Investigator) 
Sponsor 
University of Oxford 
Co-investigators 
Associate Professor Sally Hopewell, University of Oxford 
Professor Sallie Lamb, University of Exeter 
Professor Sir Mark Feldmann, University of Oxford 
Professor Amar Rangan, South Tees Hospitals NHS Foundation Trust  
Associate Professor Susan Dutton, University of Oxford  
Ms Jane Preece (Patient and Public Involvement Contributor) 
Funder 
National Institute of Health Research - Research for Patient Benefit 
(Project reference: 201031); 
180 Life Sciences 
Statistician  Signature: 
 
 
Chief 
Investigator 
Signature: 
 
 
 
Conflict of interest declaration 
Professor Sir Marc Feldman and Professor Jagdeep Nanchahal are co-founders and hold equity in 180 
Life Sciences, the company funding the purchase of adalimumab, the investigational medicinal 
product to be used in this trial. 
 
 
 


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Confidentiality Statement 
This document contains confidential information that must not be disclosed to anyone other than the 
Sponsor, the Investigator Team, HRA, host organisation, and members of the Research Ethics 
Committee and Regulatory Authorities unless authorised to do so. 
Acknowledgements 
The writing of this protocol was supported by the National Institute for Health Research (NIHR) 
Collaboration for Leadership in Applied Health Research and Care Oxford at Oxford Health NHS 
Foundation Trust.  
This study will be coordinated by the UKCRC registered Oxford Clinical Trials Research Unit (OCTRU) 
at the University of Oxford. 
 


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ABBREVIATIONS 
Anti-Freaze 
Anti-TNF for Treatment of Frozen Shoulder 
BESS 
British Elbow and Shoulder Society 
DSMC 
Data Safety Monitoring Committee 
GCP 
Good Clinical Practice 
GP 
General Practitioner 
MHRA 
Medicines and Health care products Regulatory Agency 
NHS 
National Health Service 
NICE 
National Institute for Health and Care Excellence 
nIMP 
Non-Investigational Medicinal Product 
NIHR 
National Institute for Health Research 
OCTRU 
Oxford Clinical Trials Research Unit 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOP 
Standard Operating Procedure 
SPADI 
Shoulder Pain and Disability Index 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 
UKCRC 
United Kingdom Clinical Research Collaboration 
 
 
 
 
 


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Table of Contents  
1. TRIAL SUMMARY .................................................................................................................... 7 
2. LAY SUMMARY ..................................................................................................................... 10 
3. INTRODUCTION .................................................................................................................... 11 
3.1. BACKGROUND AND RATIONALE ................................................................................................ 11 
3.1.1. Problem being addressed ................................................................................................... 11 
3.1.2. Why is this research important ........................................................................................... 11 
3.1.3 Review of existing evidence ................................................................................................. 13 
3.1.3. Choice of comparators ........................................................................................................ 13 
3.2. AIM AND OBJECTIVES ................................................................................................................ 15 
3.3. DESIGN ....................................................................................................................................... 16 
4. METHODS - PARTICIPANTS, INTERVENTIONS AND OUTCOMES .......................................... 18 
4.1. STUDY SETTING .......................................................................................................................... 18 
4.2. ELIGIBILITY CRITERIA .................................................................................................................. 18 
4.2.1. Inclusion criteria .................................................................................................................. 18 
4.2.2. Exclusion criteria ................................................................................................................. 19 
4.3. INTERVENTIONS ......................................................................................................................... 20 
4.3.1. Adalimumab/Placebo Injection........................................................................................... 20 
4.3.1.1 IMP Description ................................................................................................................. 21 
4.3.1.2 Supply and Storage of IMPs .............................................................................................. 22 
4.3.1.3 Preparation and labelling of IMPs ..................................................................................... 22 
4.3.3. Physiotherapy advice leaflet ............................................................................................... 23 
4.3.4. Concomitant care ................................................................................................................ 23 
4.3.5 Contraindicated medications ............................................................................................... 23 
4.3.6 Post-trial treatment ............................................................................................................. 24 
4.3.7 Compliance with treatment ................................................................................................. 24 
4.4. OUTCOMES ................................................................................................................................ 24 
4.4.1. Feasibility objectives ........................................................................................................... 24 
4.4.2. Outcomes ............................................................................................................................ 25 
4.5. PARTICIPANT TIMELINE .............................................................................................................. 27 
4.6. RECRUITMENT ............................................................................................................................ 28 
4.6.1. Recruitment of sites ............................................................................................................ 28 
4.6.2. Recruitment of participants ................................................................................................ 28 


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4.6.3. Screening and eligibility assessment................................................................................... 29 
4.6.4. Informed consent ................................................................................................................ 29 
5. METHODS - ASSIGNMENT OF INTERVENTIONS ................................................................... 30 
5.1. ALLOCATION ............................................................................................................................... 30 
5.2. BLINDING.................................................................................................................................... 30 
5.3 TRIAL-SPECIFIC SCREENING TESTS .............................................................................................. 31 
5.4 CODE BREAK ................................................................................................................................ 32 
5.5. SAMPLE SIZE ............................................................................................................................... 32 
6. METHODS - DATA COLLECTION, MANAGEMENT AND ANALYSIS ........................................ 32 
6.1. DATA COLLECTION METHODS .................................................................................................... 33 
6.1.1. Baseline data collection ...................................................................................................... 33 
6.1.2. Follow-up data collection .................................................................................................... 33 
6.1.3. Discontinuation / withdrawal of participants ..................................................................... 34 
6.2. DATA MANAGEMENT ................................................................................................................. 35 
6.2.1 Source Data .......................................................................................................................... 36 
6.3. STATISTICAL METHODS .............................................................................................................. 36 
6.4. EMBEDDED QUALITATIVE STUDY ............................................................................................... 37 
6.5. PROGRESSION CRITERIA ............................................................................................................. 38 
7. MONITORING METHODS ..................................................................................................... 39 
7.1. DATA MONITORING ................................................................................................................... 39 
7.1.1. Data Monitoring .................................................................................................................. 39 
7.2. SAFETY REPORTING .................................................................................................................... 39 
7.2.1. Definitions ........................................................................................................................... 39 
7.2.2. Causality .............................................................................................................................. 40 
7.2.3 Procedures for recording adverse events ............................................................................ 40 
7.2.4. Reporting procedure for serious adverse events ............................................................... 41 
7.2.5. Reporting procedure for Suspected Unexpected Serious Adverse Events ......................... 42 
7.2.6. Development Safety Update Reports ................................................................................. 42 
7.3. Pregnancy ................................................................................................................................... 43 
7.3.1 Contraception ...................................................................................................................... 43 
7.4. QUALITY ASSURANCE PROCEDURES .......................................................................................... 44 
7.5. SERIOUS BREACHES .................................................................................................................... 44 
8. APPROVAL AND DISSEMINATION ........................................................................................ 45 
8.1. APPROVALS ................................................................................................................................ 45 


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8.2. PROTOCOL AMENDMENTS ........................................................................................................ 45 
8.3. CONFIDENTIALITY....................................................................................................................... 45 
8.4. ACCESS TO DATA ........................................................................................................................ 46 
8.5. DISSEMINATION POLICY ............................................................................................................. 46 
9. STUDY ADMINISTRATION ..................................................................................................... 47 
9.1. Key contacts ............................................................................................................................... 47 
9.2. Roles and responsibilities ........................................................................................................... 47 
9.2.1. Protocol contributors .......................................................................................................... 47 
9.2.2. Sponsor and funder ............................................................................................................. 47 
9.2.3. Committees ......................................................................................................................... 47 
9.2.4. Projected study timelines and milestones .......................................................................... 48 
9.2.5 Definition of end of trial ....................................................................................................... 48 
10.1. APPENDIX 1: BRITISH ELBOW AND SHOULDER SOCIETY DIAGNOSTIC ALORITHM .................. 49 
10.2. APPENDIX 2: SCHEDULE OF PROCEDURES ............................................................................... 50 
10.3: APPENDIX 3: AMENDMENT HISTORY ....................................................................................... 51 
11. REFERENCES ....................................................................................................................... 53 
 
 
 


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1. TRIAL SUMMARY 
World Health Organization Registration Data Set 
Title 
Anti-TNF (adalimumab) injection for the treatment of shoulder 
pain in adults with frozen shoulder: a feasibility study 
Trial register and number 
EUDRA-CT: 2021-003509-23 
Date of registration 
21 June 2021 
Secondary Trial ID Number/s REC Reference: 21/NE/0214 
Chief Investigator 
Professor Jagdeep Nanchahal 
Kennedy Institute of Rheumatology 
University of Oxford 
jagdeep.nanchahal@kennedy.ox.ac.uk  
Funder 
National Institute for Health Research - Research for Patient Benefit 
(Project reference 201031); 
180 Life Sciences 
Sponsor 
University of Oxford 
University of Oxford/ RGEA – Research Governance, Ethics and 
Assurance Team 
ctrg@admin.ox.ac.uk  
Clinical Trials Unit 
Oxford Clinical trials Research Unit (OCTRU) 
Nuffield Department of Orthopaedics, Rheumatology & 
Musculoskeletal Sciences 
octrutrialshub@ndorms.ox.ac.uk 
Central contact 
Anti-Freaze-F Trial Manager 
Kennedy Institute of Rheumatology 
University of Oxford. 
aff@kennedy.ox.ac.uk  
 
Scientific Contact 
Professor Jagdeep Nanchahal 
Kennedy Institute of Rheumatology 
University of Oxford 
jagdeep.nanchahal@kennedy.ox.ac.uk 
Statistician 
Associate Professor Susan Dutton 
OCTRU, Centre for Statistics in Medicine  
Nuffield Department of Orthopaedics, Rheumatology & 
Musculoskeletal Sciences 
susan.dutton@csm.ox.ac.uk 
Committees 
Trial Oversight Committee 
Ben Fisher – Chair (rheumatologist) -B.Fisher@bham.ac.uk 
 
Trial Management Committee 
Jagdeep Nanchahal – jagdeep.nanachahal@kennedy.ox.ac.uk 


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Brief title (acronym) 
Anti-Freaze-F - Anti-TNF for Treatment of Frozen Shoulder – a 
Feasibility Study 
Countries of recruitment 
 England 
Health condition  
Frozen Shoulder (adhesive capsulitis) 
Focus of study 
To assess the feasibility of conducting a large randomised 
controlled trial to assess whether an intra-articular injection of 
adalimumab can reduce pain and improve function in people with 
pain predominant early stage frozen shoulder. 
Interventions 
 
i) Anti-TNF injection  
 
 
 
 
 
 
ii) Placebo injection 
 
 
 
 
 
 
Physiotherapy advice leaflet 
 
 
Intra-articular injection of anti-TNF (adalimumab 160mg; 3.2ml), 
under guided ultrasound. A second injection of 80mg in 1.6ml will 
be administered 2-3 weeks after the first injection  
 
 
 
Placebo injection (saline [0.9% sodium chloride] 3.2ml), under 
guided ultrasound. A second injection of 1.6ml saline will be 
administered 2-3 weeks after the first injection  
 
 
 
All participants will receive a physiotherapy advice leaflet about the 
management of frozen shoulder.  
Key eligibility criteria 
Men and women ≥18 years with a new episode of shoulder pain 
attributable to early stage frozen shoulder who have not received 
injection or physiotherapy for shoulder pain in the last 3 months, 
nor being considered for surgery. 
Study design 
Study type: A feasibility study 
Allocation: Randomised 1:1         
Intervention model: Parallel 
Primary purpose: Treatment 
Phase: Pilot  
Blinding: Participant and outcome assessor blind 
Target sample size 
84 (1:1 randomisation) 
Duration of follow up 
3 months  
Planned trial period 
24 months 
Primary objectives 
The main objectives of the feasibility study are to assess the: 
• 
Ability to screen and identify potential participants with pain-
predominant early stage frozen shoulder (i.e. within 
approximately 3 to 9 months of onset of symptoms). 


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• 
Willingness of eligible participants to consent and be 
randomised to intervention. 
• 
Practicalities of delivering the intervention, including time to 
first injection (within 2 weeks of randomisation) and 
number of participants receiving second injection. 
• 
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. 
Secondary objectives 
To assess the follow up rates and viability of patient reported 
outcome measures and range of shoulder motion at 3 months 
follow up for a definitive trial: 
Patient reported: 
• 
Pain and function (Shoulder Pain And Disability Index) 
• 
Pain (Shoulder Pain And Disability Index, 5-item subscale) 
• 
Function (Shoulder Pain And Disability Index, 8-item subscale) 
• 
Psychological factors (Fear Avoidance Belief Questionnaire) 
• 
Pain Self Efficacy Questionnaire 
• 
Sleep disturbance (Insomnia Severity Index) 
• 
Return to desired activities (Patient-reported) 
• 
Global impression of change (Likert scale) 
• 
Participant Range of Movement Questionnaire 
• 
Healthcare resource use 
• 
Adverse events graded 3 or above (clinician assessed) related 
to intra-articular injection of adalimumab in the shoulder 
 
Clinician assessed: 
• 
Shoulder range of movement  
 
Embedded qualitative sub-study (optional participation): 
• 
To explore the patients’ experiences of being recruited to a 
randomised trial of anti-TNF injection for frozen shoulder. 
• 
To understand what helps or hinders participant recruitment 
to the trial intervention. 
Data Sharing statement 
Summary results data will be available on the trial registration 
database within 12 months of the end of the trial. Requests for 
data (anonymised trial participant level data) will only be 
provided at the end of the trial to external researchers who 
provide a methodologically sound proposal to the trial team 
(and who will be required to sign a data sharing access 
agreement with the Sponsor) and in accordance with the NIHR 
guidance. After the end of the study a anonymised study 
dataset will be created and stored for as long as it is useful, 
and may be shared with other researcher upon request (as 
defined above).  Participant consent for this is included in the 
informed consent form for the study. 
 
 


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2. LAY SUMMARY 
Anti-Freaze-F - Anti-TNF for Treatment of Frozen Shoulder – a Feasibility Study 
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. It's not fully understood why this happens but it is more 
common in people with diabetes or Dupuytren's disease, which causes the fingers to curl into the 
palm. It can also occur following shoulder injury or surgery. 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. Steroid injections only help in the short term. 
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. We need to conduct this smaller study first to be sure it’s possible 
to identify and treat people with early stage frozen shoulder within the current NHS system, before 
we conduct a much larger trial to find out if this treatment works.  
In this study we will include 84 adults 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. We 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 drug has been chosen as the biological processes underlying frozen shoulder are similar to 
those in Dupuytren’s disease, where we found it helps to stop the cells causing the disease. 
The views of patients with frozen shoulder are important to us and have been incorporated into 
this study. We have worked with a group of patients who have experienced frozen shoulder. All 
were supportive of our study aims and design. They provided useful feedback that has been 
incorporated into the study. A patient representative is part of the team for this application. Patient 
representatives will also be part of the committee that oversees the study.  


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3. INTRODUCTION 
3.1. BACKGROUND AND RATIONALE 
3.1.1. Problem being addressed 
Frozen shoulder (adhesive capsulitis) is an extremely painful and debilitating condition and affected 
individuals struggle with activities of daily living and significant sleep disturbance as a result of pain (1). 
The condition is very common, affecting about 9% of people in the UK aged 25-64 years (2), and 20% 
develop the same problem in the other shoulder (3). Frozen shoulder may develop as a primary 
condition or secondarily following surgery or trauma. Up to 30% of patients with diabetes develop 
frozen shoulder and the symptoms are more persistent and recalcitrant in this group (1). 
 
The classic description of the development of frozen shoulder is of three overlapping phases (4, 5). The 
initial pain predominant inflammatory phase is characterised by constant pain and difficulty sleeping, 
and lasts between 3 and 9 months. This progresses to a stiffness predominant fibrotic stage with 
progressive restriction of motion, particularly external rotation and elevation of the shoulder, and 
impairment of function, and lasts between 4 and 12 months. The pain changes from being constant to 
being manifest at the end of range of motion and of reduced intensity. There is a gradual improvement 
in range of motion and stiffness over a 12-48 month period, although end of range pain may persist.  
The average duration of the condition is 30 months (range 1 to 3.5 years) (6). Full resolution of 
symptoms does not always occur, but persistent symptoms are usually mild. At the mean follow-up of 
52 months, 59% have a near normal shoulder, 35% have mild/moderate symptoms, and 6% have 
severe symptoms (3). 
 
3.1.2. Why is this research important? 
Problems associated with frozen shoulder can have a major impact on patient health. They are a 
significant cause of morbidity and disability with substantial socioeconomic burden, affecting an 
individual’s capacity to work and perform daily activities. The NHS currently invests vast amounts of 
money on unproven therapies and steroid injections (7, 8). Shoulder problems have a major impact on 
primary care services, accounting for 2.4% of all GP consultations in the UK (9). The average spend per 
patient in the NHS for a musculoskeletal condition is £461.13 per person each year, costing the UK 
economy £7.4 billion per year (10). 
 
The aetiology of frozen shoulder is poorly understood and consequently there is no consensus on the 
optimal treatment. The majority of patients with early stage frozen shoulder are managed in primary 


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care or at primary care interface musculoskeletal services by physiotherapists and GPs. During the pain 
predominant phase, standard treatment consists of rest, advice, analgesics, physiotherapy and 
corticosteroid injections to address the symptoms. A corticosteroid injection typically costs £147-£332, 
depending on the mode of delivery. A set of six physiotherapy sessions costs around £321 and an 
assessment and advice session costs £53 (11). Evidence of their effectiveness remains poor, usual care 
can be highly variable, and there are currently no recommended National Institute for Health and Care 
Excellence (NICE) approved clinical guidelines (4). Patients with persistent stiffness may be referred to 
secondary care for capsular release by manipulation under anaesthesia, hydrodilatation or 
arthroscopic capsular release (4). From NHS Reference Costs (11) the average cost for MUA 
manipulation under anaesthesia is £424, and with rehabilitation and surgical review this increases to 
£1446. The cost of arthroscopic capsular release is £1182 and with similar follow-up is £2204. 
 
Due to the lack of evidence, a NIHR funded trial (UK FroST ISRCTN48804508) compared physiotherapy 
plus corticosteroid injection, manipulation under anaesthesia with a steroid injection, and arthroscopic 
capsular release supplemented with a steroid injection in patients with unilateral frozen shoulder 
characterised by ≥50% restriction in external rotation of the shoulder (12). None of the treatments 
were found to be clinically superior and the mean differences in the assessment of shoulder pain and 
function were less than the target difference for all three treatments. This trial recruited patients from 
secondary care and so it is very unlikely that it will include many people with early stage frozen 
shoulder in the initial pain-predominant inflammatory phase. Anti-Freaze-F is specifically targeting 
people with early stage pain-predominant frozen shoulder. If successful, this research could provide 
evidence for a new treatment for a very common debilitating condition, avoiding the need for surgery 
and prolonged physiotherapy, thereby reducing NHS costs. 
 
Our study is specifically designed to address an unmet medical need for a common disabling condition. 
It will address shortcomings of previous research by targeting the diseased tissue directly at the early 
pain- predominant inflammatory stage to prevent the progression to fibrosis and the need for more 
invasive treatments and prolonged recovery. Our aim is to assess the feasibility of conducting a large 
randomised controlled trial to assess whether an intra-articular injection of adalimumab (a drug 
targeting the inflammatory mediator tumour necrosis factor [TNF]) can reduce pain and prevent the 
disease from getting worse if given during the early pain- predominant phase (i.e. within approximately 
3 to 9 months of onset of symptoms). Our proposed research is the first stage in the development of 
a new treatment for frozen shoulder that is based on the pathology of the disease and delivered during 
the early inflammatory stage. If successful, this research could provide evidence for a new treatment 


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for a very common debilitating condition and thereby reduce NHS costs. 
 
3.1.3 Review of existing evidence 
There is limited efficacy for the treatment currently offered to patients with frozen shoulder. Two 
Cochrane reviews have concluded that whilst oral steroid or local steroid injections lead to short term 
benefit in pain and range of motion, the effects are not maintained beyond 6 weeks (8, 12, 13). A more 
recent systematic review (based on data from 5 RCTs) also found some short-term benefit of 
corticosteroid injection compared to placebo but this pain relief was not sustained in the long term 
(14). Other Cochrane reviews concluded that there is no evidence that physiotherapy or ultrasound 
therapy are beneficial (15), and that manual therapy with exercise is less effective than corticosteroid 
injection in the short term (16). These findings are supported by an HTA report which found that, of all 
treatment options available, the only short-term benefit (based on data from 2 RCTs) was from steroid 
injection in addition to home exercise in patients with symptoms of less than 6 months (17). In 
addition, manipulation under anaesthesia was found to be no better than home exercise programme 
(17), and the use of arthrographic joint distention with glucocorticoid and saline was no better than 
sham procedure (18). None of the treatment modalities assessed in the UK FROST trial (manipulation 
under anaesthesia, arthroscopic capsular release or early structured physiotherapy, all supplemented 
with steroid injection) achieved the target improvement in the score of shoulder pain and function 
(19). 
 
3.1.3. Choice of comparators 
Anti-TNF (adalimumab) injection 
Whilst the pathogenesis of frozen shoulder remains largely unknown, a recent systematic review 
confirmed the presence of fibrosis and the role of inflammation (6). The affected tissues are infiltrated 
by immune cells, including macrophages, mast cells, T cells, and there are elevated levels of pro-
inflammatory cytokines, including TNF, IL-6 and IL-1ß (20, 21), with myofibroblasts contributing to 
matrix deposition and fibrosis (22). More than 50% of patients with frozen shoulder also have 
Dupuytren’s disease (23) and the underlying pathology of frozen shoulder is similar to Dupuytren’s 
disease (22, 24) where we have shown that the myofibroblast phenotype is critically dependent on the 
local production of low levels of the pro-inflammatory cytokine TNF (25). In a dose-ranging proof of 
concept phase 2a clinical trial (RIDD trial) we found that local injection of 40mg of adalimumab in 0.4ml 
directly into Dupuytren’s nodules resulted in downregulation of the myofibroblast phenotype (26). The 
only previous study to examine the effects of anti-TNF in frozen shoulder administered 40mg of 
adalimumab subcutaneously systemically in 8 patients or intra-articular steroid (40mg prednisolone) 


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in 10 patients every 2 weeks on up to 3 occasions (27). The authors found no improvement in the 
adalimumab group although there was improvement in the steroid cohort. However, the patients were 
not selected from those at the early pain-predominant inflammatory phase of disease. Importantly, 
the anti-TNF was administered systemically and, based on analysis of tissue obtained from patients 
participating in our trial of adalimumab for Dupuytren’s disease (26), we believe that a trial of 
intralesional administration is more likely to target the involved tissues since cytokines like TNF are 
primarily local mediators, leading to local inflammation.  
 
The palmar nodules in patients with Dupuytren’s disease are readily identifiable clinically. However, 
the only means of accurately delivering adalimumab to the involved areas in patients with frozen 
shoulder is by ultrasound guidance. Furthermore, due to the larger area involved, we will use 160mg 
of adalimumab in 3.2ml. It is possible that some patients may fail to gain significant improvement in 
symptoms following administration of 160mg of adalimumab. The half-life of adalimumab is 2 weeks 
and up to 160mg can be administered as a loading dose in patients with inflammatory disorders such 
as Crohn’s disease (https://bnf.nice.org.uk/drug/adalimumab.html#indicationsAndDoses . Patients 
will receive a second injection of adalimumab (80mg in 1.6ml) at 2-3 weeks after the initial injection.  
We are not aware of any other trials for frozen shoulder investigating the efficacy of using a drug 
targeting a defined inflammatory cytokine. The anti-TNF drugs have a very strong safety profile, having 
been used in over 10 million people, adalimumab in over 5 million, and more than 25,000 patients 
have been recruited to trials of adalimumab, which is approved for 9 different disorders. In these, only 
0.2% of patients with chronic inflammatory disorders discontinued long-term use of the drug, which is 
administered every 2 weeks, due to adverse effects. Anti-TNF drugs not routinely administered as an 
intra-articular injection, although there are a few reports of outcomes in patients with inflammatory 
or osteoarthritis (28-31). We are not aware of any trials where intra-articular injection of adalimumab 
has been used in people with frozen shoulder. Adalimumab is not currently licenced for use as an intra-
articular injection for pain-predominant early-stage frozen shoulder and therefore will be used off 
license for the purposes of this trial. Therefore, as part of this feasibility trial we will also assess the 
safety of anti-TNF injection when given as an intra-articular injection, by recording any clinician 
reported grade 3 or above adverse events.  
 
Administration of adalimumab should not pose any risks in relation to COVID-19 vaccinations or to 
patients who may have contracted COVID-19. None of the approved vaccines involve live viruses. 
Adalimumab was being trialled in UK care home residents for the treatment of COVID-19, although 
this trial has been closed because of the lack of eligible participants due to the success of the 


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vaccination programme. Adalimumab is also being trialled by the US military for this indication.  
 
Placebo injection 
Given that the available evidence  suggests that at best steroid injection only leads to short-term pain 
relief (14), we will use a placebo injection of saline (0.9% sodium chloride) as the comparator. We 
believe that the use of a placebo injection is ethical in the context of this trial given that lack of existing 
treatment options specifically targeting people with early stage frozen shoulder in the initial pain-
predominant inflammatory phase (17). Unlike steroid (triamcinolone), which is a white suspension, 
saline has the same appearance and viscosity as adalimumab which means we will be able to blind 
participants as to their treatment allocation. This is especially important given the subjective nature 
of some of the outcomes we plan to assess in the trial which are patient-reported, including one of 
our primary objectives, which will be utilised as outcomes in the definitive trial. 
 
3.2. AIM AND OBJECTIVES 
Our overall aim is to assess the feasibility of conducting a large randomised controlled trial to assess 
whether an intra-articular injection of adalimumab can reduce pain and improve function in people 
with early stage frozen shoulder. 
 
Primary objectives 
The main objectives of this feasibility study are to assess the: 
• 
Ability to screen and identify potential participants with pain-predominant early stage frozen 
shoulder (i.e. within approximately 3 to 9 months of onset of symptoms). 
• 
Willingness of eligible participants to consent and be randomised to intervention. 
• 
Practicalities of delivering the intervention, including time to first injection (ideally within 2 weeks 
of randomisation) and number of participants receiving a second injection. 
• 
Standard deviation of the Shoulder Pain and Disability Index (SPADI) score and attrition rate at 3 
months from baseline in order to inform an estimation of the sample size for a definitive trial. 
 
To be certain that we inject participants while they are still in the early pain-predominant 
inflammatory stage, which can be within as little as 3 months of onset of symptoms.,. Our experience 
of the NIHR HTA funded GRASP trial (ISRCTN16539266) (32) for people with shoulder pain due to a 
rotator cuff disorder suggests that this will be challenging within the current NHS treatment 
pathways; hence the need to conduct a study to assess feasibility prior to a definitive trial. 


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Secondary outcomes 
To assess the follow up rates and viability of patient reported outcome measures and range of 
shoulder motion at the 3 month follow up stage for a definitive randomised controlled trial to assess 
the effectiveness of local injection of adalimumab. Three-month follow up has been chosen to reflect 
the primary outcome of the future definitive trial, which is improvement in shoulder pain and function, 
reflecting the need to treat participants while in the early pain-predominant inflammatory stage. 
 
Patient reporting outcomes will comprise Pain and function (Shoulder Pain And Disability Index 
(SPADI)); Pain (Shoulder Pain and Disability Index, 5-item subscale); Function (Shoulder Pain and 
Disability Index, 8-item subscale); Psychological factors (Fear Avoidance Belief Questionnaire); Pain 
Self Efficacy Questionnaire; Sleep disturbance (Insomnia Severity Index); Return to desired activities; 
Global impression of change (Likert scale); Health resource use. 
 
Adalimumab is not currently licenced for use as an intra-articular injection for people with pain-
predominant early-stage frozen shoulder and will be used off license for the purposes of this trial. 
Therefore, as part of this feasibility trial we will also assess the safety of anti-TNF injection and record 
Adverse Events assessed by a clinician to be grade 3 or above as a result of the IMP injection. 
 
Clinician assessed outcome: 
• 
Shoulder range of movement. 
 
Embedded qualitative sub-study (optional participation): 
• 
To explore the patients’ experiences of being recruited to a randomised trial of anti-TNF injection 
for frozen shoulder. 
• 
To understand what helps or hinders participant recruitment to the trial intervention. 
 
3.3. DESIGN 
Multi-centre, randomised, double blind, parallel group, feasibility study, with an embedded qualitative 
sub-study. Participants will be allocated to receive either: 1) intra-articular injection of anti-TNF 
(adalimumab 160mg) or 2) placebo injection (saline), both under ultrasound guidance. A second 
injection of the allocated treatment (adalimumab 80mg) or equivalent volume of placebo will be 
administered at 2-3 weeks. All participants will receive a physiotherapy advice leaflet providing 
education and advice about frozen shoulder and pain management. 


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Figure 1: Study flow diagram 
 
 
 
 
 
 
 
Consent for Anti-Freaze-F trial 
Patient screened and assessed for 
eligibility 
Baseline assessment (questionnaire 
and range of shoulder motion) 
Randomisation (n=84) 
Placebo (3.2ml saline) injection 
under ultrasound (n=42) plus 
Physiotherapy advice leaflet 
Adalimumab (160mg in 3.2ml) 
injection under ultrasound (n=42) 
plus Physiotherapy advice leaflet 
Second injection of saline (1.6ml)  
Excluded: 
Did not meet eligibility 
criteria 
Declined to participate 
Usual care 
Patient with frozen shoulder 
approached and provided with 
patient information leaflet 
Second injection of Adalimumab 
(80mg in 1.6ml) 
Follow up: 3 months   
Follow up: 3 months   


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4. METHODS - PARTICIPANTS, INTERVENTIONS AND OUTCOMES 
4.1. STUDY SETTING 
Participants will be recruited from at least five NHS primary-care-based musculoskeletal services and 
their related physiotherapy services, with treatment delivered within these services or the local 
secondary care site dependant on the local service provision. Participants may also be recruited from 
directly from NHS secondary-care-based musculoskeletal services, dependant on local service 
provision at sites. Musculoskeletal services treat people with a range of musculoskeletal conditions. 
They provide a screening, assessment and treatment service and are usually run by specialist 
practitioners including extended-scope physiotherapists, GPs with a specialist interest in 
musculoskeletal conditions, rheumatologists and orthopaedic surgeons, dependent on local service 
provision at site. 
 
4.2. ELIGIBILITY CRITERIA 
Adults 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 to 9 months of onset of symptoms) diagnosed 
using British Elbow and Shoulder Society (BESS) guidelines and part of the NICE-accredited standards 
(33), who are not being considered for surgery and able to understand spoken and written English will 
be assessed for eligibility. Imaging, including plain radiographs, may be used to confirm a diagnosis of 
frozen shoulder and  rule out other pathology such as glenohumeral arthritis (34) as per standard NHS 
care (i.e. not as part of trial procedures).  
 
Following a diagnosis of frozen shoulder, eligibility for Anti-Freaze-F will be assessed. 
 
4.2.1. Inclusion criteria 
We will include:  
• 
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 to 9 months of onset of symptoms) diagnosed using criteria set 
out in the BESS guidelines (35) (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; 


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• 
Willing to allow his or her General Practitioner be notified of participation in the trial. 
• 
If female, and of child-bearing potential, willing to use effective contraception throughout the 
treatment period and for 5 months after the last injection. See section 7.3 and 7.3.1 for 
definitions.  
 
4.2.2. Exclusion criteria 
We will exclude:  
• 
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 early stage  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 (35);  
• 
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:  
• 
Known allergy to any anti-TNF agent or any of the excipients; 
• 
Known Active tuberculosis (TB) or history of TB or at risk of developing TB e.g. through 
the use of immunosuppressants (see below (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; 
• 
Known Moderate to severe heart failure (NYHA class III/IV); 
• 
Those known to have HIV, Hepatitis B or C; 
• 
Those at risk of Hepatitis B infection; 


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• 
Those diagnosed with Multiple Sclerosis (MS) or other central or peripheral nervous 
system demyelinating disorders; 
• 
Those who have ever been diagnosed with cancer, except basal cell carcinoma (BCC); 
• 
Those requiring live vaccination within 5 months  of the last trial injection or within 
the 4 weeks prior to randomisation; 
• 
Those taking biologic DMARDS; 
• 
Females who are currently breastfeeding.  
• 
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. 
 
4.3. INTERVENTIONS 
4.3.1. Adalimumab/Placebo Injection 
Eligible participants will be allocated to receive either an intra-articular injection of adalimumab 
(160mg in 3.2ml for the first injection, 80mg in 1.6ml for second injection) or placebo (normal saline 
[0.9% NaCl] 3.2ml for the first injection and 1.6ml for the second injection). The dose of 160mg 
followed by 80mg two weeks later was selected as this is the approved loading dose in patients with 
inflammatory bowel disease. The shoulder joint capsule is vascular and we anticipate that absorption 
into the blood stream will follow similar kinetics as when the adalimumab is administered 
subcutaneously. The injection will be given into the anterior shoulder joint space in the rotator cuff 
interval where there is maximal inflammation of the capsule and synovium, under guided ultrasound. 
The injection treatment is to be given within ideally 2 weeks after randomisation by an appropriately 
qualified practitioner, with experience of treating frozen shoulder by ultrasound guided injection who 
is appropriately delegated to do so. The practitioner will be either a GP with a specialist interest in 
musculoskeletal conditions, rheumatologist, extended scope physiotherapist, orthopaedic surgeon, 
sonographer or radiologist, dependant on the local service provision at site. The practitioner will need 
to confirm that the participant is still in the pain predominant phase before administering the first 
injection. If the practitioner deems that the participant is no longer in the pain predominant phase, 
the participant will not receive the injection and the reason will be recorded on the trial specific 
injection treatment log; the participant will still be included in the 3-month follow up assessment.  
 
If a participant has symptoms of COVID-19, tests positive for COVID-19 or is self-isolating due to 
government guidelines and is unable to attend for either injection, the visit will be delayed until they 


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receive confirmation of a negative test result or have recovered as long as they remain in the pain 
predominant stage. If a participant is no longer considered to be in the pain predominant stage and is 
unable to have the injections this will be recorded on the injection CRF and will be recorded as a 
withdrawn from treatment but they will continue to be followed up at 3 months.   
 
The only means of accurately delivering the drug to the involved areas in patients with frozen shoulder 
is by ultrasound guidance. The skin at the site of injection of adalimumab/placebo will be infiltrated 
with the local anaesthetics to reduce the pain of the injection in accordance with local practice for an 
injection into the shoulder joint. Following administration of the local anaesthetic, there will be 
minimal discomfort associated with the intra-articular injection. Once adalimumab has been drawn 
up, it tends to lose it potency and this precludes preparation of the syringes before the patient 
presents for treatment. For this trial, no more than 30 minutes will elapse from when the injection is 
drawn up to when the injection is given.  
 
The adalimumab/placebo will typically be delivered using a syringe fitted with typically a 21 gauge 
needle or greater. All participants irrespective of whether they are still in the pain predominant phase, 
will receive a second injection (adalimumab/placebo) administered 2-3 weeks after the first injection, 
unless the participant declines the second injection. The reason will be recorded on the trial specific 
injection treatment log and the participant will still be included in the 3-month follow up assessment. 
Participants will be advised to continue with their physiotherapy and resume normal activities 
immediately after the injection. Participants will be provided with a written information leaflet 
advising them that there will be no restriction on their activities after the injection and what to do if 
they experience any side effects.  Each patient will receive a maximum of two injections, either 
adalimumab or placebo. Injection details, including time from randomisation to injection delivery, will 
be recorded on a trial specific injection treatment log. A second injection will not be administered if 
any related grade 3 or above Adverse Event as per the Common Terminology Criteria for Adverse 
Events (CTCAE) v5.0 occur following the first injection, or if the patient tests positive for TB or hepatitis 
B surface antigen.  
 
4.3.1.1 IMP Description 
Adalimumab is a human monoclonal antibody with Marketing Authorisation but will be used off-label 
for this trial.  
Normal saline (0.9% NaCl) will be used as the placebo. 
 


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4.3.1.2 Supply and Storage of IMPs 
Participating sites are to procure adalimumab (Idacio from Fresenius Kabi) (40mg / 0.8 ml vials) and 
normal saline (0.9% NaCl). The adalimumab must be stored in a refrigerator (2°C – 8°C) and must not 
be frozen. The vial should be kept in the outer carton in order to protect from light, it may be stored 
at temperatures up to a maximum of 25°C for a period of up to 14 days. Sites need to ensure that they 
procure the adalimumab from Fresenius Kabi in vials rather than a pre-filled syringe or pen. The 
needles fitted to the pre-filled syringes is too short for shoulder joint injection. Fresnius Kabi is the 
only company that supplies the adalimumab in vials. Use of this product will avoid the necessity to 
transfer the IMP from the pre-filled syringe to another syringe before injection. The cost of IMP 
purchase for the trial will be reimbursed by the Sponsor. Funding for purchase of the adalimumab and 
placebo will be provided by 180 Life Sciences. The IMP will be dispensed upon receipt of a trial-specific 
prescription. Where the IMP is collected from pharmacy/handled by staff who are blinded to 
treatment the IMP packaging will be obscured, in a sealed opaque plastic bag. Specific instructions 
that will cover the importance of keeping the IMP blinded will be provided at the Site Initiation Visit 
as it is not always possible for unblinded staff to collect the IMP from pharmacy.  Trial-specific 
dispensing logs are required to be maintained. Trial-specific accountability for bulk receipt and 
returns/destruction will be required. There will be no provision of the IMP after the trial period. 
 
4.3.1.3 Preparation and labelling of IMPs 
A trial-specific annex 13 compliant label will be applied to the IMP prior to dispensing under the 
Regulation 37 exemption. Preparation of the IMP needs to occur in a clinic room/area separate from 
the participant to ensure the participant remains blinded to their treatment allocation immediately 
prior to injection. 
 
Adalimumab: 
The adalimumab, 160mg in 3.2ml or 80mg in 1.6ml, will be drawn up from the vials. 
  
Normal saline: 
3.2ml or 1.6 ml of saline (0.9% NaCl) will be drawn up.  
 
Both the IMP and placebo have a similar viscosity and appearance so that the two treatments, 
adalimumab or saline, will be indistinguishable. The same type of syringe and needle will be used for 
injection of both adalimumab and saline thus maintaining the blinding of the participant and staff not 
involved in preparation or administering the IMP. 


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4.3.3. Physiotherapy advice leaflet 
All participants will receive a physiotherapy advice leaflet providing education and advice about 
frozen shoulder and pain management, which is especially important during the early pain-
predominant stage of frozen shoulder (4). Physiotherapy during the early pain-predominate stage of 
frozen shoulder is primarily directed at pain relief (e.g. heat, cold and other pain relieving modalities) 
as forcing the joint to move can make it more painful and is best not pursued. Participants will be 
advised to take over-the-counter analgesia (e.g. paracetamol with or without codeine, oral or topical 
nonsteroidal anti-inflammatory drug) as required, in accordance with the BESS guidelines (35). In 
addition, all of the participants will be provided with advice on modifying activities that exacerbate 
symptoms and on sleeping positions, drawing on materials used in the GRASP trial (32) and UK FROST 
trial (12). In addition, the advice leaflet will include a simple set of self-guided physiotherapy 
exercises, which participants can use once the early pain-predominant stage reduces and to increase 
shoulder joint mobilisation. Exercises will include passive mobilisation of the shoulder and capsular 
stretching, drawing on materials used in the UK FroST trial where appropriate (12). Joint mobilisation 
combined with stretching exercises has been found to be more effective than stretching exercises 
alone (36, 37). As low health literacy levels are a major consideration when developing materials, 
plain English and patient representative involvement will be used to optimise material accessibility.  
 
4.3.4. Concomitant care 
Participants may seek other forms of treatment during the follow-up period of the trial but will be 
informed that they should use usual routes (e.g. through GP referral) to do so. Additional treatments 
(including consultation with primary and secondary care, additional physiotherapy, injection use, or 
alternative therapies) will be recorded as a treatment outcome as part of the 3 month follow up 
questionnaire. 
 
4.3.5 Contraindicated medications 
Concomitant administration of biologic DMARDS is contraindicated during the treatment period and 
until 4 months after the last injection. The use of live vaccines must also be avoided until 12 weeks 
after the last injection. 
 
 
 


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4.3.6 Post-trial treatment 
Participants will transfer to normal care at the end of the trial.  There will be no provision of the IMP 
beyond the trial period. 
 
4.3.7 Compliance with treatment 
Adherence to treatment will be defined as receiving an injection within 2 weeks of randomisation. The 
number of participants receiving a second injection will also be recorded. 
 
4.4. OUTCOMES 
4.4.1. Feasibility objectives 
The main aim of this feasibility study is to determine whether a future definitive trial would be feasible 
and to determine the sample size for the definitive trial to assess the effectiveness of adalimumab. We 
will focus on the main areas of uncertainty relating to the acceptability to be randomised to intra-
articular injection of the anti-TNF (adalimumab) and the ability to identify and recruit and treat 
participants who have pain-predominant early stage frozen shoulder within the current NHS patient 
pathway for musculoskeletal conditions. In addition, we will collect outcome measures at 3 months, 
including SPADI and range of shoulder motion. 
 
We have confidence from screening data from the GRASP trial (32) (where frozen shoulder is an 
exclusion criteria) that there are sufficient potential participants to investigate the feasibility criteria. 
To determine the feasibility of a definitive randomised controlled trial, the success criteria will be: 
 
• 
Ability to screen and identify potential participants with pain-predominant stage frozen shoulder. 
• 
Willingness of eligible participants to consent and be randomised to intervention. 
• 
Practicalities of delivering the intervention, including time to first injection and number of 
participants receiving a second injection. 
 
Data to assess our feasibility objectives will be collected at each site via a trial specific screening log; 
reasons for ineligibility and / or participants declining to participate in the trial will be recorded where 
available. The screening log will not contain any patient identifiers and will use screening numbers. 
Injection details, including time from randomisation to injection delivery, will be monitored based on 
the information recorded on the trial specific injection treatment logs.   


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4.4.2. Outcomes 
Outcomes (Table 2) will be collected at baseline and at 3-months to assess the feasibility of collecting 
these in a future definitive trial and to obtain the variability estimates required for estimation of the 
sample size of the definitive trial. Patient reported outcomes will include shoulder pain and function 
measured using the SPADI scale (primary outcome for definitive trial) (38, 39); sub-domains of pain 
(SPADI 5-item pain subscale), function (SPADI 8-item disability subscale) (38, 39); shoulder range of 
motion (Participant Shoulder Movement Questionnaire); psychological factors (Fear Avoidance Belief 
Questionnaire) (40); pain self-efficacy questionnaire (41); sleep disturbance (Insomnia Severity Index) 
(42); patient global impression of change (43); return to desired activities; additional health resource 
use for index shoulder (e.g. consultation with primary and secondary care, additional physiotherapy, 
injection use, or alternative therapies).  
 
The choice of outcome measures is based on OMERACT 2016 core outcome set for shoulder disorders 
(44) and a systematic review of core outcomes used in studies of frozen shoulder (45).  
 
At the 3-month follow up, a blinded outcome assessor will collect an objective measure of shoulder 
function and performance: 
• 
Participants will undergo measurement  of range of motion of the shoulder, including active  
flexion, extension, abduction internal and external rotation, limitation of which has been 
shown to be pathognomonic of frozen shoulder in the absence of glenohumeral arthritis (46). 
 
Table 2: Summary of patient outcomes assessed 
 
Outcome 
Measurement 
Pain and function 
Shoulder Pain and Disability Index (SPADI) (38, 39) 13-item total scale 
Pain 
Shoulder Pain and Disability Index (SPADI) (38, 39) 5-item subscale 
Function 
Shoulder Pain and Disability Index (SPADI) (38, 39) 8-item subscale 
Shoulder range of 
motion 
Participant Shoulder Movement Questionnaire 
Psychological factors 
Fear Avoidance Belief Questionnaire – physical activity 5-item 
subscale (40) 
Pain Self-efficacy questionnaire (short form) (41) 
Sleep disturbance 
Insomnia Severity Index (42) 
Global impression of 
treatment 
Patient-rated Likert scale (43) 
Return to desired 
activities  
Patient-reported return to desired activities, including work, social 
life and sport activities 
Health resource use 
Patient-reported  


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Adverse Events 
Any Grade 3 or above AEs that have occurred from Consent up until 
the 3 month Follow up. 
 
See section 7.2. SAFETY REPORTING for safety data collection 
 


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4.5. PARTICIPANT TIMELINE 
TIMEPOINT 
(post 
randomisation 
unless stated 
otherwise) 
 
Screening 
0-2 
weeks 
4-5 weeks  
3 month 
follow up 
ENROLLMENT: 
 
 
 
 
Screening log  
✓ 
 
 
 
Informed consent  
✓ 
 
 
 
Eligibility confirmed 
✓ 
 
 
 
Randomisation  
✓ 
 
 
 
INTERVENTIONS: 
 
 
 
 
1st Anti-TNF/placebo 
injection  
 
✓ 
 
 
Physiotherapy 
advice leaflet 
provision 
✓ 
 
 
 
2nd Anti-
TNF/placebo 
injection  
 
 
✓1 
 
ASSESSMENTS: 
 
 
 
 
Serological 
testing 
e.g. 
TB 
ELISpot, 
Hepatitis B surface 
antigen 
 
✓ 
 
 
Pregnancy testing (if 
needed) 
✓ 
 
 
 
Baseline 
questionnaire 
✓ 
 
 
 
ROM Assessment 
✓ 
 
 
✓ 
Follow-up 
questionnaire 
 
 
 
✓ 
Follow-up clinic visit 
 
 
 
✓ 
Qualitative interview 
(optional) 
 
 
 
✓* within 4 
weeks of 
intervention 
delivery 
AE Reporting (grade 
3 or above) 
✓ 
✓ 
✓ 
✓ 
1. 
The second injection must be 2-3 weeks after the 1st injection.  
 


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4.6. RECRUITMENT 
4.6.1. Recruitment of sites 
The feasibility study will be conducted across at least five primary care-based musculoskeletal services 
and their related physiotherapy services, and as appropriate to local service provision/facilities their 
local secondary care site in the UK. Participants may also be recruited from directly from NHS 
secondary-care-based musculoskeletal services, dependant on local service provision at sites. We will 
utilise our existing network of collaborators from the GRASP trial which recruited from 20 sites in 
England (32). Sites will be chosen so they reflect a range of settings (urban and rural) and are able to 
deliver the trial interventions. The local Principal Investigator will be responsible for the conduct of 
the research at their site. The Principal Investigator will identify the staff responsible for the conduct 
of the trial and ensure that the trial roles and responsibilities are assigned in writing using the trial 
delegation log. They will also help with local queries and study promotion. All potential sites will be 
screened with a site feasibility questionnaire to ensure they have sufficient potential participants and 
the clinical expertise and capacity to provide the treatments and manage the patients. Participants 
may also be recruited directly from NHS secondary-care-based musculoskeletal services, dependant 
on local service provision at sites. 
 
4.6.2. Recruitment of participants 
Participants will be recruited from the musculoskeletal services if referred by their GP, physiotherapy 
service, or self-referred for investigation/treatment of a new episode of shoulder pain. GPs and 
primary-care-based physiotherapy services within the local area surrounding each study site will be 
informed about the trial. Posters advertising the Anti-Freaze-F trial will be displayed in local GP 
surgeries, physiotherapy departments and musculoskeletal clinics to raise awareness of the trial with 
patients and clinicians. The trial will also have a presence on social media to further raise awareness 
of the trial amongst the public and professionals as well as being used to provide an update on trial 
progress.  The trial will have a dedicated website hosted by Oxford Clinical Trials Research Unit. We 
will also contact patient organisations such as the Dupuytren’s Society and Diabetes UK which 
represent patient groups with a high prevalence of frozen shoulder. These methods of recruitment 
have proved very useful in our trial of anti-TNF injections for people with early stage Dupuytren’s 
disease (47). Participants will be able to claim for reasonable reimbursement for travel to and from 
their study appointments using the University of Oxford expense form which will be provided in the 
investigator Site File.   
 


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4.6.3. Screening and eligibility assessment 
Potential participants will attend their musculoskeletal service clinic appointment in accordance with 
standard NHS procedures at each site. The treating practitioner will undertake a clinical assessment 
according to their usual practice. If a patient fulfils the criteria for pain-predominant stage of frozen 
shoulder, the option to participate in the trial will be discussed and they will be assessed by an 
appropriately qualified  practitioner (i.e. a member of the participant’s direct care team) to determine 
whether they meet the Anti-Freaze-F trial eligibility criteria based on their medical history and where 
available medical records (as described in Section 4.2) (i.e. no trial specific tests would be undertaken 
until informed consent is given). Patients will be provided with a copy of the participant information 
sheet, and asked if they wish to participate in the trial. Patients who meet the eligibility criteria and 
who would like to participate in the trial will be approached for informed consent and only then will 
the trial-specific screening tests be undertaken.  
 
4.6.4. Informed consent 
Informed consent for participation in the trial will be sought. As part of the process of obtaining 
informed consent, the exact nature of the study will be explained, what it will involve for the 
participant including expectations that the participant will be willing and able to attend sessions to 
receive the study intervention, and any risks involved in taking part. The potential participant will have 
the opportunity to discuss issues and ask questions. The process of obtaining informed consent may 
take place during the initial musculoskeletal clinic appointment or may require a second research 
appointment. This second research appointment may be either face-to-face or virtual depending on 
local facilities at each site. All participants will be informed that they can decline to participate and 
can withdraw from the study at any time for any reason without prejudice to future care, and with no 
obligation to give the reason for withdrawal. We will record anonymised information on the age, 
ethnicity and sex of those who decline to participate so that we can assess the generalisability of those 
recruited. Participants may request a follow-up phone call if they require more time to consider the 
study or wish to speak to their GP or other independent parties before deciding whether they will 
participate in the study.  
 
A clinical member of the site staff for example A Research Nurse or Clinician Responsible for the 
patient or another member of the research team who has been trained in Good Clinical Practice (GCP), 
authorised to do so by the Principal Investigator, will obtain informed consent. A medically qualified 
doctor will be available during or following the consent process in case of queries relating to their 
medical care.  The process for seeking, confirming and documenting informed consent will be either 


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paper based (written consent) or digital (eConsent) depending on local facilities at each site. Where 
consent is taken in person at site, for written consent, the consent form will be signed and dated by 
the participant and the researcher; a copy of the signed consent form will be given to the participant. 
The original consent form will be retained at the study site in the Investigator Site File. For consent 
that is taken digitally within REDCap (handwritten signature using a finger or a stylus or biometric 
eSignatures), a copy of the participants consent form will be emailed to the participant to an email 
address provided by them. The eConsent form will be downloaded from SIMS (an Oxford Clinical Trials 
Research Unit programme that transfers data securely from REDCap so that sites are able to download 
completed CRFs and consent forms) by the site research team and retained in the Investigator Site 
File. Electronic tablets will be provided to each site to log onto the REDCap Data Management system 
to enter the data directly into the trial database.  
Where consent is taken remotely, as part of a virtual consultation, eConsent will be used with 
participants asked to provide a handwritten signature using a finger or a stylus or biometric eSignature 
on their tablet, mobile phone or other electronic device.  
 
 
5. METHODS - ASSIGNMENT OF INTERVENTIONS  
5.1. ALLOCATION 
Consented participants will be randomised to intervention groups (1:1) using a validated web-based 
centralised randomisation service provided by the Oxford Clinical Trials Research Unit . This will either 
be undertaken directly by the research team at the site or by contacting the Trial Office over the 
phone, which will access the system on their behalf, depending on the facilities available at the study 
sites. If the telephone option is used, site staff will need access to the Screening and Randomisation 
CRF to provide screening and eligibility details to the Trial Office member of staff so that they can 
enter these details into the randomisation system and provide site staff with a Trial ID. Randomisation 
will be computer-generated and stratified by centre, using a variable block size to ensure the 
participants from each study site have an equal chance of receiving either intervention. Participants 
will only be randomised following eligibility assessment and after informed consent has been 
obtained.  
 
5.2. BLINDING 


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Study participants will be blinded to their treatment allocation. The clinician delivering the treatment 
injection will not be blinded to the treatment allocation as they will be required to prepare and 
administer the IMP.  They will not be involved with any further trial-specific assessment of the 
participant. They will be educated on the importance of maintaining the blind of both study 
participants and the rest of the site staff.  All other site staff, except pharmacy staff, will be blinded. 
The clinician assessed outcomes at the 3 month follow-up clinic visit will be undertaken by a blinded 
member of the clinical team at site. The trial statistician, Trial Office staff member undertaking checks 
of dispensed medication, and data entry personnel will not be blinded to the treatment allocation. 
The remaining members of the trial management team, including the staff conducting the qualitative 
interviews will be blinded to treatment allocation until after the data analysis is complete.  
 
5.3 TRIAL-SPECIFIC SCREENING TESTS 
Participants will undergo serological testing (e.g. TB ELISpot) to check for latent TB, as detailed in the 
adalimumab SmPC. Participants will also undergo serological testing for hepatitis B surface antigen as 
detailed in the adalimumab SmPC. Approximately 10ml of blood will be taken from each participant 
for these tests. These tests are to be carried out locally therefore the samples will be processed within 
72 hours at the local site lab and any remaining should be destroyed in compliance with HTA and local 
procedures.  
These tests will be performed at the time the patient attends for their first injection appointment. The 
risks of reactivation of TB are well-documented only in patients who receive anti-TNF therapy on a 
regular basis e.g. every 2 weeks for adalimumab, in the long term. Discussions with Prof Chris Conlon, 
former head of the Oxford TB service, indicated that the risk of TB reactivation following a single 
injection are low and any participant for whom the serology test result shows them to be TB positive 
will be referred for a chest X-ray and to the local TB service and will not receive any further trial 
treatment; they will still be included in the 3 month follow up assessment as specified in the protocol. 
Similarly, the risk of reactivation of latent hepatitis B after a single injection of adalimumab is very low 
and any participant that test positive for hepatitis B surface antigen will be referred to their local 
infectious disease service. They will be recorded as withdrawn from treatment but will continue to be 
followed up at the 3 month time point.  
 
Participants who do not meet the eligibility criteria or who do not wish to participate will receive the 
standard NHS treatment. We will record anonymised information on the age and sex of those who 


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decline to participate so that we can assess the generalisability of those screened. The reasons for 
declining will be asked and any answers given will be recorded.  
 
5.4 CODE BREAK 
Based on the well-known safety profile of the IMP, it is not anticipated that there will be any suspected 
unexpected serious adverse reactions. In the event that the participant has a serious adverse reaction 
within 3 months of the last injection and there is a need to unblind for emergency purposes the PI at 
site will have 24/7 access to the randomisation database (RRAMP) and can access the treatment 
allocation for that one participant without delay.  The CTU will be notified immediately that an 
unblinding has occurred. 
All participants will be provided with a laminated card to present to any treating physicians with 
outline details of the trial treatment as well as contact details of the site in the event of unblinding.   
 
5.5. SAMPLE SIZE 
The main feasibility objective and therefore the basis of the sample size estimate is participant 
recruitment at least 5 centres with a staggered start. The target sample size is 84 participants, 
equivalent of 1 to 2 participants per month per site over 12 months, allowing for staggered opening 
of sites. Seventy is the recommended minimum target sample size when including an estimate of the 
SD in an external pilot trial (48). The sample size has been increased from 70 to a total of 84 
participants in order to increase precision of the estimate of the standard deviation of SPADI at 3 
months, the proposed primary outcome for the definitive trial, and to take into account possible 
attrition (based on an attrition rate of 15%). This attrition rate is a conservative estimate based on 
attrition rates for the GRASP trial (14% at 6 months) (32) and UK FroST (11% at 3 months) (12) which 
represent similar populations to those anticipated in Anti-FREAZE. This sample size will enable an 
estimate of a participation rate of 30% with a precision of +/- 5% based on 280 eligible participants 
being identified. We have selected a conservative recruitment rate given the uncertainty around the 
ability to identify, recruit and inject participants with early stage frozen shoulder. We anticipate that 
we will be able to recruit the required number of participants over a 12 month period. See Section 6.4 
for details related to the sample size for the embedded qualitative sub-study. 
 
6. METHODS - DATA COLLECTION, MANAGEMENT AND ANALYSIS 


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6.1. DATA COLLECTION METHODS 
6.1.1. Baseline data collection 
After the participants have been assessed for eligibility and informed consent has been obtained, 
participants will be asked to complete a baseline assessment questionnaire that will record simple 
demographic information and baseline measurements for the primary and secondary outcomes, 
shown in Table 3. The questionnaires will be available in both an online and paper format as, due to 
their frozen shoulder, participants may find one format much easier to complete than the other.   
 
Table 3: Outcomes and time points of assessment  
 
Outcome 
Measurement 
 
Time point 
Demographic 
Age, Sex, Height, Weight, Ethnicity, Smoking, Date 
of frozen shoulder diagnosis, Duration of 
symptoms, Hand dominance, Affected shoulder. 
Diabetes and type, Dupuytren’s Disease 
0 
Shoulder range of 
movement 
Clinician assessed (goniometry measured) active 
shoulder flexion, extension, abduction, internal 
and external rotation.  
Patient Reported ROM Questionnaire  
0, 3 months 
Pain and function 
Shoulder Pain and Disability Index (SPADI) (38, 39) 
13-item total scale 
0, 3 months 
Pain 
Shoulder Pain and Disability Index (SPADI) (38, 39) 
5-item subscale 
0, 3 months 
 
Function 
Shoulder Pain and Disability Index (SPADI) (38, 39) 
8-item subscale 
0, 3 months 
Psychological 
factors 
Fear Avoidance Belief Questionnaire physical 
activity 5-item subscale (40) 
Pain Self-efficacy questionnaire (short form) (41) 
0, 3 months 
Sleep disturbance 
Insomnia Severity Index (42) 
 
0, 3 months 
Global impression of 
treatment 
Patient-rated Likert scale (43) 
3 months 
Return to desired 
activities  
Patient-reported return to desired activities, 
including work, social life and sport activities (49) 
0, 3 months 
Health resource use 
Consultation with primary and secondary care, 
additional physiotherapy, injection use, or 
alternative therapies for index shoulder 
3 months 
 
Adverse Events 
Any Grade 3 or above AEs that have occurred 
from Consent up until the 3 month Follow up.  
3 months 
 
6.1.2. Follow-up data collection 


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Follow up will be conducted via face to face clinic assessment and patient reported questionnaire at 
3 months after randomisation. Detail of the outcomes to be assessed, how they will be measured and 
at which time points are shown in Table 3.  
 
Participants who are unable to attend the face to face appointment will be asked to complete the 3 
month follow up questionnaire and return it to the Anti-Freaze-F Trial Office in a prepaid envelope 
(the ROM participant Questionnaire can only be completed on paper, these will be supplied to the site 
to send out to participants if needed) or online (web-based version of the questionnaire) as 
appropriate. The reason why a participant is unable to attend the face to face clinic appointment will 
be recorded and whether this was due to potential COVID-19 restrictions or due to other reasons.  For 
those who do not respond to the initial 3 month follow up questionnaire a reminder questionnaire 
will be sent 2 weeks later. Telephone and email follow-up will be used (2 weeks later) to contact those 
who do not respond to either the initial or reminder questionnaire. For those participants who have 
requested for digital communication, the ROM will need to be sent to them via the post in paper 
format. These participants will be send digital reminders if we do not receive the ROM questionnaire 
back at the trial office. Telephone and email follow-up will also be used to collect a core set of 
questionnaire items for the Shoulder Pain and Disability Index (SPADI) (primary outcome) if these have 
not been fully completed on the returned questionnaire.  
 
6.1.3. Discontinuation / withdrawal of participants 
Participants will be informed that they have the right to withdraw from the Anti-Freaze-F trial at any 
time without having to provide a reason and with no impact on their future health care. A participant 
may wish to discontinue their treatment and/or withdraw from follow-up data collection. If a 
participant wishes to discontinue their treatment, the study team will contact the participant and ask 
if they are still willing to participate in the collection of follow-up data. Participants that continue to 
participate in follow-up data collection will not be considered a withdrawal in accordance with the 
principles of the intention to treat (ITT) analysis. If a participant wishes to withdraw from follow-up 
data collection, data collected up to the point of withdrawal will still be used, as detailed in the PIL. 
Results from the blood samples taken will still be used. These will have been destroyed by the local 
laboratory once the samples have been tested for Hepatitis B/TB. If a participant decides to withdraw 
before they are given the injection but after the blood sample has been taken, the sample will be 
destroyed within 72 hours in accordance with HTA and local procedures.   
 


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In addition to participant self-withdrawal, an investigator may decide to withdraw a participant from 
Anti-Freaze-F if considered necessary for any reason including ineligibility arising subsequent to their 
initial enrolment in the trial or for clinical reasons based on safety grounds (i.e. any relate grade 3 or 
above Adverse Event as per the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 (see 
Section 7.2) or tests positive for TB or hepatitis B surface antigen). Participants will still be included in 
the 3-month follow up assessment. The reason for withdrawal (if given) will be recorded on the study 
CRFs.  
 
6.2. DATA MANAGEMENT 
All data will be processed according to the UK General Data Protection Regulations (GDPR) and the 
Data Protection Act 2018. All documents will be stored safely in confidential conditions. A data 
management and sharing plan will be produced for the trial and will include reference to 
confidentiality, access and security arrangements. All trial-specific documents, except for the signed 
consent form and follow-up contact details, will refer to the participant with a unique study participant 
number/code and not by name.  
 
Trial data will be collected and managed using REDCap electronic data capture tools hosted at OCTRU, 
University of Oxford. REDCap (Research Electronic Data Capture) is a secure, web-based application 
designed to support data capture for research studies, providing 1) an intuitive interface for validated 
data entry; 2) audit trails for tracking data manipulation and export procedures; 3) automated export 
procedures for seamless data downloads to common statistical packages; and 4) procedures for 
importing data from external sources. 
 
Wherever possible, trial data will be entered directly into the trial database by site staff or participants 
using an electronic tablet provided by the trial, with the questionnaire already opened to complete. 
Participants and staff should wash their hands or use anti-bacterial gel before handling the tablets to 
ensure infection control. Data on paper forms or captured during phone calls to participants will be 
entered into the trial database by suitably trained Trial office staff.  Full details will be recorded in the 
DMP. The participants will be identified by a unique trial specific number in any data extract. 
Identifiable data will only be accessible by members of the study team with a demonstrated need 
(managed via access controls within the application) and any additional processing of this will only be 
for the purposes of  communication  with the participant (e.g., sending follow-up reminders for online 
form completion or telephone follow-up). 
 


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Data will be collected from participants via eCRFs at screening, baseline and 3 month follow up. Sites 
will be provided will an electronic tablet to use for data collection and the ROM assessment will be 
provided in paper format. If the site or participant are not able to complete the CRFs electronically 
(due to poor internet connection), paper-based CRFs will be available in the Investigator Site File, these 
will be returned to the central Trial Office in Oxford via post using a pre-addressed stamped envelope, 
email as appropriate, or via Trial Office staff at site visits. Sites will send copies of consent forms (if 
completed paper-based) to the Trial Office via secure NHS email, or via recorded delivery. Participant 
data will be stored and transported in accordance with OCTRU SOPs. Participants who claim 
reasonable travel expenses will have their financial information held in accordance with the University 
of Oxford financial policy for 7 Years. 
 
Upon completion of the trial, and with appropriate participant consent, anonymised research data 
may be shared with other organisations on request to the Chief Investigator and in accordance with 
the data sharing policies of OCTRU, the Sponsor and funder(s); as detailed in section 8.4 of the protocol 
(Access to Data). Participant electronic files will be filed in numerical order and stored in a secure and 
accessible manner on the ANTI-FREAZE F secure eTMF. Trial documentation including data will be 
archived for a maximum of 5 years. The Investigator Site File and associated documents should be 
archived in line with local site R&D policies.  
 
6.2.1 Source Data 
Source documents are where data are first recorded, and from which participants’ CRF data are 
obtained. These include, but are not limited to, hospital records (from which medical history and 
previous and concurrent medication may be summarised into the CRF), clinical and office charts, 
laboratory and pharmacy records, diaries, microfiches, radiographs, and correspondence. CRF entries 
will be considered source data if the CRF is the site of the original recording (e.g. there is no other 
written or electronic record of data).  All documents will be stored safely in confidential conditions. 
On all trial-specific documents, other than the signed consent, the participant will be referred to by 
the trial participant number/code, not by name. 
 
The following data are expected to be recorded directly on the CRFs hence are to be considered source 
documents: 
• 
All participant completed questionnaires. 
 
6.3. STATISTICAL METHODS 


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Feasibility outcomes will be reported, including the number of participants approached, those eligible, 
consenting to randomisation and follow-up, the delivery of intervention (including time to first 
injection), withdrawal rate, the number receiving a second injection (per group and overall) and data 
completeness. Baseline characteristics (including possible stratification factors for the definitive trial) 
will be reported using descriptive statistics, separately per group and overall using the mean and 
standard deviation (or median and inter-quartile range if non-normally distributed) for continuous 
variables and the number and percentage of participants in each group for categorical variables. 
Measures of central location and dispersion of clinical and patient reported outcome measures, 
including health resource use, at 3 months will be reported and differences between treatments for 
the intention-to-treat population (i.e. the population of participants as randomised) will be reported 
with 95% confidence intervals. The standard deviation of the proposed primary outcome for the larger, 
main trial, SPADI at 3 months, will be used to inform an estimation of the sample size required for the 
definitive trial. An estimate of treatment effectiveness will be reported together with its 95% 
confidence interval. This along with change from baseline in range of shoulder motion at 3 months will 
provide an indication of potential efficacy of the intervention but will not be powered to provide a 
definitive result, which will only follow the fully powered definitive main trial. Even small increases in 
range of shoulder motion are important to people with frozen shoulder, where pain and restricted 
shoulder movement can be very debilitating. As such, we will use a 10-degree improvement in active 
flexion with any associated improvement in active external rotation of the shoulder to mean a 
potentially important difference (50). If we observe this difference between groups in our feasibility 
study with short follow up and a small sample this would indicate potential efficacy, which should then 
be formally, tested in the full trial. Adverse events and serious adverse events (S/AEs) will be 
summarised per group and overall in all patients. 
 
6.4. EMBEDDED QUALITATIVE STUDY 
Participants will be invited by the research team to receive further information about the qualitative 
sub-study at the time of consent to the main trial. Those who have agreed to be receive more 
information will then be contacted by a member of the qualitative research team within 2 weeks to 
ask if they would like to participate in the sub study. The aims of the qualitative study are to explore 
the patients’ experiences of being recruited to a randomised trial of anti-TNF injection for frozen 
shoulder, of the treatment received and follow-up schedule, and to understand what helps participant 
recruitment to the trial intervention.  
 


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After obtaining signed consent individual telephone interviews will be conducted within 4 weeks of 
either intervention delivery by a qualitative researcher using a semi-structured interview guide with 
open-ended questions. All participants will be asked to reaffirm their consent before the start of the 
interview. We aim to interview a purposive sample of up to 15 participants (or until we reach data 
saturation, the qualitative researcher will also be blinded) to provide variability for age, gender, 
ethnicity and geographical representation. Interviews will be audio recorded using a password 
protected digital recorder and field notes will be taken). Immediately after each interview, the audio 
files will be saved under unique non-identifiable study IDs on the Anti-Freaze F secure eTMF. The audio 
files will be transcribed verbatim by an external transcription service approved by the University of 
Oxford. The audio files and transcripts will be sent and returned using a password protected folder via 
a suitably secure method. Once returned the transcribing company will not retain any files.  The 
transcripts will be checked against the audio-files and all identifiable information such as names of 
people or places will be removed. The de-identified transcripts will be stored using the study IDs. The 
transcripts will be uploaded into QSR NVivo analysis software version 12.  As these are considered 
source data copies of the anonymised typed transcripts and original audio recordings will be kept in a 
secure place within the University of Oxford for a maximum of 5 years and then destroyed. An 
inductive thematic analysis will be undertaken to develop categories and themes (51). The study 
findings will be reported following the Standards for Reporting Qualitative Research (SRQR) guidelines 
(52). 
 
6.5. PROGRESSION CRITERIA 
Progression criteria for the future definitive trial will be judged using a traffic light system whereby 
‘Green’ indicates it is feasible to proceed to a definitive trial with the current procedures, ‘Amber’ 
indicates modification to one or more aspect of the study is required before proceeding to the future 
definitive trial, and ‘Red’ indicates it is not feasible (53). The decision to progress to a future definitive 
trial will be made by the Trial Management Group in conjunction with the Trial Steering Committee, 
based on the criteria in Table 4. It will also be informed by findings from the embedded qualitative 
study and any potential signal of efficacy due to improvement in range of shoulder motion as a result 
of anti-TNF injection. 
 
Table 4: Progression criteria 
 
Green 
Amber 
Red 
Feasibility to recruit: % of potentially eligible 
patients with frozen shoulder screened across 5 
≥33% 
≥20% to 32% 
<20% 


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sites in 12 months eligible for recruitment 
Success of consent process: % of eligible 
participants consented 
≥33% 
≥20% to 32% 
<20% 
Intervention delivery: % of participants receive 
1st injection as randomised within specified 
timeframe 
≥75% 
≥50% to 74% 
<50% 
 
7. MONITORING METHODS  
7.1. DATA MONITORING 
7.1.1. Data Monitoring  
A monitoring plan, including risk assessment, will be developed according to OCTRU SOPs. The 
monitoring activities will be based on the outcome of the risk assessment and may involve central 
monitoring or site monitoring visits.  
 
7.2. SAFETY REPORTING 
7.2.1. Definitions 
Adverse Event (AE) 
Any untoward medical occurrence in a clinical trial participant 
administered a medicinal product and which does not necessarily have 
a causal relationship with this treatment. 
Adverse Reaction (AR) 
 
An untoward and unintended response in a participant to an 
investigational medicinal product that is related to any dose 
administered to that participant. 
The phrase “response to an investigational medicinal product” means 
that a causal relationship between a trial medication and an adverse 
event is at least a reasonable possibility, i.e., the relationship cannot 
be ruled out. 
All cases judged by either the reporting medically qualified 
professional or the sponsor as having a reasonable suspected causal 
relationship to the trial medication qualify as adverse reactions. 
Serious 
Adverse 
Event 
(SAE) 
An SAE is any untoward medical occurrence that: 
1. results in death, 
2. is life-threatening, 


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3. requires inpatient hospitalisation or prolongation of existing 
hospitalisation, 
4. results in persistent or significant disability/incapacity, or 
5. consists of a congenital anomaly or birth defect. 
Other “important medical events” may also be considered serious if 
they jeopardise the participant or require an intervention to prevent 
one of the above consequences. 
The term “life-threatening” in the definition of “serious” refers to an 
event in which the participant was at risk of death at the time of the 
event; it does not refer to an event which hypothetically might have 
caused death if it were more severe. 
Serious Adverse Reaction 
(SAR) 
An adverse event that is both serious and, in the opinion of the 
reporting investigator, is believed with reasonable probability to be 
due to one of the trial treatments, based on the information provided. 
Suspected 
Unexpected 
Serious Adverse Reaction 
(SUSAR) 
A serious adverse reaction, the nature and severity of which is not 
consistent with the information about the medicinal product in 
question set out in the summary of product characteristics (SmPC) for 
that product. 
 
7.2.2. Causality 
The relationship of each adverse event to the trial medication must be determined by a medically 
qualified individual according to the following definitions: 
 
Relationship to intervention 
Attribution 
(causality) 
Description 
Unrelated 
Unrelated 
The AE is clearly NOT related to the intervention 
Unlikely 
The AE is doubtfully related to the intervention 
Related 
Possible 
The AE may be related to the intervention 
Probable 
The AE is likely related to the intervention 
Definite 
The AE is clearly related to the intervention 
 
7.2.3 Procedures for recording adverse events 
The safety profile of adalimumab is well known, with the most common adverse reactions being mild 
injection site reactions. The Common Terminology Criteria for Adverse Events (CTCAE) v5.0 (will be 
used to guide recording Adverse Events including grading of the event. Only clinician assessed AEs, 
graded 3 and above, occurring during the trial for each participant, from their consent until  the 3 


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month follow up and that are considered related to the IMP will be recorded on the CRF. Participants 
will be asked by the treating clinician at their 2nd injection visit if they have experienced any AEs as a 
result of their 1st injection. Similarly, participants will be asked if they have experienced any AEs as a 
result of their 2nd injection at the 3 month follow up appointment. Based on the information provided 
by the participant the treating clinician will then make an assessment as to whether it should be 
recorded as an AE grade 3 or above.  The capture of all AEs in the trial CRFs is not deemed necessary 
due to the period of time for which the IMP has had a marketing authorisation and it’s well established 
safety profile.  
 
The following information will be recorded: adverse event term and grade, date of onset and end date, 
severity, assessment of relatedness to IMP/injection procedure, other suspect drug or device, action 
taken and outcome. Follow-up information should be provided as necessary. AEs considered related 
to the trial medication injection as judged by a medically qualified investigator will be followed either 
until resolution, or the event is considered stable. It will be left to the Investigator’s clinical judgment 
to decide whether or not an AE is of sufficient severity to require the participant’s removal from 
treatment. A participant may also voluntarily withdraw from treatment due to what he or she 
perceives as an intolerable AE. If either of these occurs, the participant must be given appropriate care 
under medical supervision until symptoms cease, or the condition becomes stable. Adverse events 
occurring as a result of the physiotherapy leaflet issued in the trial will not be recorded as part of the 
trial. The trial risk assessment identified no safety concerns, as advice and exercises given will be 
routine exercises that are used in standard care for this population. (16). 
 
7.2.4. Reporting procedure for serious adverse events 
SAEs occurring to a participant, from the time of their consent up to 28 days after their last injection 
of trial treatment, must be reported to the Trial Office.  Only SAEs that are related to trial medication 
(adalimumab/placebo) or the injection of the trial medication are required to be reported to the trial 
office. The reporting to the trial team of SAEs not related to the IMP/injection is deemed not 
necessary. Causality (relatedness) must be assessed by a medically qualified doctor.  
 
SAEs must be recorded on the trial specific SAE form electronically via REDCap. The SAE must be 
reported immediately (within a very short period of time and under no circumstances should this 
exceed 24 hours following knowledge of the SAE) following the Site Study Team becoming aware of 
the event. Alternatively, a paper SAE form can be completed and must be submitted to the Trial Office 
via email: 


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Trial Office contact:  aff@kennedy.ox.ac.uk 
 
The Trial Office will review the information on the SAE and raise immediate queries for any key data 
which is missing. In the event where the reporting site does not provide an assessment of causality 
the Trial Office will assume that the event is related to the IMP. The SAE form will also be reviewed by 
a Nominated Person, as per OCTRU SOPs for safety reporting, who will provide an assessment of 
expectedness in line with the reference safety information for the IMP(s). The SAE form will also be 
reviewed by the Chief Investigator. In the event where any representative of the Sponsor (CI/Trial 
team/Nominated Person) disagrees with the assessment of the site PI, a discussion will be encouraged 
between the two to re-assess the event. If either the PI or the representative of the Sponsor continue 
to assess the event as related, both assessments will be recorded, and the event will be considered as 
related. If the event is both related and unexpected this will be reported as a SUSAR by the Trial Office 
or delegate to the relevant Competent Authorities, UK Ethics, Sponsor and other bodies in which the 
national and local regulations of participating sites require, as per 7.2.5 below. All related SAEs will be 
followed till resolved or no further information is expected. SAEs will only be considered closed when 
signed off by the local PI. For this study, adverse events and serious adverse events are likely to be 
rare. If they occur, they will be reviewed by the Trial Management Group.  
 
The reference safety information (RSI) will be section 4.8 of the Summary of Product Characteristics 
(SmPC) for both Adalimumab and placebo.  The RSI used will be the current Sponsor and MHRA 
approved version at the time of the event occurrence. The SmPC to be used as the RSI will be specified 
in the MHRA applications.  
 
7.2.5. Reporting procedure for Suspected Unexpected Serious Adverse Events 
Any SAEs that fulfil the definition of a SUSAR will be reported to the Competent Authority, - the 
Medicines and Health care products Regulatory Agency (MHRA) (if the SUSAR is related to the 
IMP/plaecbo), Research Ethics Committee (REC) and sponsor within 7 calendar days of the trial 
management team in the Trial Office becoming aware of the event if it resulted in death or was life 
threatening, or 15 calendar days for any other event. Treatment allocation will be unblinded prior to 
SUSAR reporting. 
 
7.2.6. Development Safety Update Reports 


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The CI will submit (in addition to the expedited reporting above) DSURs once a year throughout the 
clinical trial, or on request, to the Competent Authority (MHRA in the UK), Ethics Committee, HRA 
(where required), and Sponsor. 
 
7.3. Pregnancy 
The manufacturer advises women of child-bearing potential to follow adequate contraceptive 
precautions for 5 months after the last injection. A woman of child bearing potential is defined as a 
premenopausal female capable of becoming pregnant. The SmPC states that a large number (approx. 
1500) of pregnancies exposed to adalimumab in the first trimester does not indicate an increase in 
the rate of malformation in the newborn, however all females of child bearing potential will be asked 
if there is a possibility that they could be pregnant as part of the eligibility assessment before being 
randomised to the study. If there is a possibility they could be pregnant they will be offered a 
pregnancy test to confirm that they are not pregnant. If they refuse to take a pregnancy test they 
would be deemed ineligible. If pregnancy does occur in study participants treated with adalimumab – 
there is a potential for these infants to be at an increased risk of infection as adalimumab may cross 
the placenta into the serum of infants born to women treated with adalimumab during pregnancy. 
Administration of live vaccines (e.g. BCG vaccine) to infants exposed to adalimumab in utero is not 
recommended for 5 months following the mother’s last adalimumab injection during pregnancy.  
 
In the occurrence of pregnancy in a trial participant, no further doses of adalimumab are to be given, 
and the pregnancy must be reported as soon as the trial team are made aware to the Anti Freaze-F 
Trial team via completion of the Anti-Freaze-F Pregnancy Notification Form which must be emailed to 
AFF@Kennedy.ox.ac.uk. Alternatively, site can complete the electronic Pregnancy Notification Form 
via REDCap. The pregnancy must be followed up by the investigator until delivery for congenital 
abnormality or birth defect, at which point it would fall within the definition of a serious adverse event. 
 
7.3.1 Contraception 
The following are considered adequate contraception for the purpose of this trial: 
• 
combined (oestrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation : oral, intravaginal, transdermal  
• 
progestogen-only hormonal contraception associated with inhibition of ovulation : oral, 
injectable, implantable 
• 
intrauterine device (IUD)  


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• 
intrauterine hormone-releasing system ( IUS)  
• 
bilateral tubal occlusion  
• 
vasectomised partner 1  
• 
sexual abstinence 2  
1 Vasectomised partner is a highly effective birth control method provided that partner is the 
sole sexual partner of the WOCBP trial participant and that the vasectomised partner has 
received medical assessment of the surgical success. 
2 In the context of this guidance sexual abstinence is considered a highly effective method 
only if defined as refraining from heterosexual intercourse during the entire period of risk 
associated with the study treatments, in this trial – this is a 120 day period from the last 
dose of IMP.   
 
7.4. QUALITY ASSURANCE PROCEDURES 
This study will be part of the Oxford Clinical Trials Research Unit (OCTRU) trial portfolio, with personnel 
working according to OCTRU SOPs. The OCTRU SOPs and related quality assurance and control 
procedures will be used by the trial team to ensure that the study procedures are assessed and carried 
out as defined in this protocol. The study may be monitored or audited in accordance with the current 
approved protocol, principles of GCP, relevant regulations and SOPs.  
 
Quality assurance checks will be carried out by the trial team to ensure that all participants receive 
the drug treatment to which they are allocated at randomisation. This will be carried out via periodic 
review of the participating site injection treatment logs by an unblinded member of the trial team. 
The sites will receive feedback from quality control checks to maintain and improve fidelity. Any issues 
identified will be addressed by engaging the site staff in more training and by increasing the intensity 
of monitoring by the central trial team. If issues persist, they will be escalated to the trial oversight 
committees. 
 
7.5. SERIOUS BREACHES 
The Medicines for Human Use (Clinical Trials) Regulations contain a requirement for the notification 
of “serious breaches” to the MHRA within 7 days of the sponsor becoming aware of the breach. 
A serious breach is defined as “A breach of GCP or the trial protocol which is likely to affect to a 
significant degree:  
(a) the safety or physical or mental integrity of the subjects of the trial; or 


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(b) the scientific value of the trial”. 
In the event that a serious breach is suspected, the sponsor (University of Oxford - RGEA – Research 
Governance, Ethics and Assurance Team) will be contacted within 1 working day. In collaboration with 
the Chief Investigator, the serious breach will be reviewed by the sponsor and, if appropriate, the 
sponsor will report it to the REC, MHRA and the NHS host organisation within 7 calendar days. 
 
8. APPROVAL AND DISSEMINATION 
8.1. APPROVALS 
The trial protocol and all related documentation (e.g., informed consent forms, participant 
information leaflets, patient questionnaires and any proposed advertising material) will be approved 
by the appropriate Health Research Authority Research Ethics Committee (REC). The trial will be given 
the identification number REC Ref, Integrated Research Application System (IRAS) ID and EudraCT 
number. The trial will be approved by the UK Competent Authority, the Medicines and Healthcare 
Regulatory Agency (MHRA), as it is classified as a clinical trial of an investigational medicinal product 
(CTIMP). The trial will be conducted in compliance with the approved protocol and standard operating 
procedures (SOPs), the Declaration of Helsinki, the principles of Good Clinical Practice (GCP), the UK 
Data Protection Act and all other applicable regulatory and governance frameworks including the UK 
policy framework for health and social care research. 
 
8.2. PROTOCOL AMENDMENTS 
Modifications to the protocol that may affect the conduct of the study, the potential benefit to the 
patient or patient safety, including significant changes in the study objectives, study design, patient 
population, sample sizes, study procedures or significant administrative aspects, will require a formal 
amendment to the protocol. Substantial amendments will be agreed by the Trial Management Group 
(TMG) and Sponsor office (University of Oxford) and submitted for HRA, REC and/or MHRA approval 
prior to implementation. All substantial amendments will be transparently described in resulting trial 
reports. Non-substantial amendments to the protocol will be agreed by the TMG and Sponsor office 
(University of Oxford). The REC will be notified of any non-substantial amendments. 
 
8.3. CONFIDENTIALITY 
The trial staff will ensure that the participants’ anonymity is maintained. The participants will be 
identified by a unique participant study number / code on case report forms, audio recordings and 


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transcripts, and any electronic databases holding study data. All paper documents will be stored 
securely in locked filing cabinets at the Oxford Clinical Trials Research Unit offices and will only be 
accessible to trial staff and authorised personnel. The trial will comply with OCTRU SOPs and any 
personal details (e.g., addresses for posting follow-up questionnaires) held by the central trial team in 
or in an electronic database will be clearly marked as Personal Contact Data so that it will not be 
included in any extracts used for analysis. All trial data will only be accessed by authorised personnel. 
The consent form includes consent for these data to be held. If a participant does not wish to receive 
a summary of the results of the trial (as indicated on the consent form) their contact details will be 
destroyed when all of their study visits have been completed.  
 
8.4. ACCESS TO DATA 
Direct access to source and/or research data will be granted to authorised representatives of the 
Sponsor, regulatory authorities or the host institution for monitoring and/or auditing of the study to 
ensure compliance with regulations. Summary results data will be included on the trial registration 
database within 12 months of the end of the trial. Requests for data (anonymised trial participant level 
data) will only be provided to external researchers who provide a methodologically sound proposal to 
the trial team (and who will be required to sign a data sharing access agreement with the Sponsor) 
and/or in accordance with the NIHR’s guidance. 4.6.3 (as defined above). Participant consent for this 
is included in the informed consent form for the study. 
 
8.5. DISSEMINATION POLICY 
The trial will be prospectively registered, prior to ethics approval, on the International Standard 
Randomised Controlled Trial Number register and a EudraCT number obtained. The trial protocol will 
be published in an open-access peer-reviewed journal in accordance with the Standard Protocol Items: 
Recommendations for Interventional Trials statement (SPIRIT, www.spirit-statement.org/). The trial 
results will be published in an open-access journal, in accordance with funder policy on open-access 
research. The trial results will be reported following the Consolidated Standards of Reporting Trials 
guideline (CONSORT, www.consort-statement.org). Shortly after formal publication, we will inform 
the participants of the trial results in the form of a Trial Newsletter which will be sent to them in the 
post. The participants will be asked if they would like to be informed of the trial results as part of their 
original consent process.  
 


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9. STUDY ADMINISTRATION 
9.1. Key contacts 
Central Trial Office contact 
Anti-Freaze-F Trial Manager 
Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 
7FY 
Email: aff@kennedy.ox.ac.uk  
 
Sponsor contact 
Research Governance, Ethics and Assurance Team (RGEA) , University of Oxford, Joint Research Office, 
1st floor,  Boundary Brook House, Churchill Drive, Headington, Oxford, OX3 7GB 
Email: ctrg@admin.ox.ac.uk 
 
9.2. Roles and responsibilities 
9.2.1. Protocol contributors 
The Anti-Freaze-F study is a collaboration between NHS clinical sites from across the UK and several 
academic and NHS institutions with significant experience in clinical trials and management of 
musculoskeletal conditions. The study will be part of the portfolio of the United Kingdom Clinical 
Research Collaboration (UKCRC) fully registered CTU – Oxford Clinical Trials Research Unit at the 
University of Oxford.  
 
9.2.2. Sponsor and funder 
This research is primarily funded by the National Institute for Health Research – Research for Patient 
Benefit, with additional funding from 180 Life Sciences via their UK subsidiary Cannbiorex.  
 
The sponsor is the University of Oxford. The sponsor has a specialist insurance policy in place – Newline 
Underwriting Management Ltd at Lloyd’s of London – that will operate in the event of any participant 
suffering harm as a result of their involvement in the research. NHS indemnity operates in respect of 
the clinical treatment that is provided. 
 
9.2.3. Committees 
Trial Management Group 


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A Trial Management Group (TMG) consisting of the core study team, Chief Investigators and co-
applicants will be responsible for the day-to-day running of the study and will meet monthly to report 
on progress and ensure milestones are met. A trial manager will oversee all aspects of the day-to-day 
trial management. The trial will be managed by a team at the Oxford Clinical Trials Research Unit. 
 
Combined Trial Oversight Committee 
A Combined Trial Oversight Committee consisting of a clinician(s), physiotherapist, trial statistician 
and participant representative, independent of the TMG and co-applicant team, will be appointed to 
monitor the trial’s progress, provide independent advice and monitor data arising from the trial and 
recommend whether there are any ethical or safety reasons why the trial should not continue. 
 
9.2.4. Projected study timelines and milestones 
Project months 
Tasks 
1-5 months 
Finalise protocol, regulatory approvals sought and gained, intervention 
manualisation, initial site set-up 
6-17 months 
Study recruitment period 
9-20 months 
3 month follow-up of participants 
21-24 months 
Analysis and write up of feasibility study 
 
9.2.5 Definition of end of trial  
The end of the trial is defined as when all data have been received and all queries resolved. 
 
 
 


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10.1. APPENDIX 1: BRITISH ELBOW AND SHOULDER SOCIETY DIAGNOSTIC 
ALORITHM  
 
British Elbow and Shoulder Society, diagnosis of shoulder problems in primary care (35) 
 


 
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10.2. APPENDIX 2: SCHEDULE OF PROCEDURES 
Activity 
Screening 
Visit 1 
(injection 1) 
Visit 2 
(2nd injection) 
3 month 
Follow Up 
Qualitative sub-
study – optional 
participation 
Diagnosis of pain-predominant 
frozen shoulder 
✓ 
 
 
 
 
Assessment of eligibility for trial 
✓ 
 
 
 
 
pregnancy test (if applicable) 
✓ 
 
 
 
 
Informed consent 
✓ 
 
 
 
 
Blood sample for serological 
testing for latent TB and Hepatitis 
B surface antigen 
 
✓ 
 
 
 
Completion of questionnaires 
✓ 
 
 
✓ 
 
Shoulder range of movement 
✓ 
 
 
✓ 
 
Randomisation 
✓ 
 
 
 
 
Physiotherapy advice leaflet 
✓ 
 
 
 
 
Injection of local anaesthetic 
 
✓ 
✓ 
 
 
Injection of adalimumab/placebo 
under guided ultrasound 
 
✓ 
✓ 
 
 
Assessment of AEs (grade 3 or 
above) 
✓ 
✓ 
✓ 
✓ 
 
Qualitative sub-study: telephone 
interview (optional) 
 
 
 
 
✓✓* within 4 weeks 
of 1st intervention 
delivery 


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10.3: APPENDIX 3: AMENDMENT HISTORY 
Amendment 
no. 
Protocol 
version no. 
Date issued 
Author(s) of 
changes 
Details of changes made 
6 
V3.0 
DDMMMYYYY 
Alison Evans 
Amended the time frame of 
inclusion criteria to more 
accurately reflect the period 
of pain predominant early 
stage frozen shoulder of 3 to 
9 months. 
 
Added the Participant Range 
of Movement CRF 
 
Amended the description of 
the needle gauge from 18 to 
21 
 
Added sentences to reflect 
the trial presence on social 
media and its aim of being 
present on publicly available 
web-platforms. 
 
Added that sites will use 
SIMS to download 
completed eConsent Forms 
for filing. 
 
Added that sites can 
complete an electronic 
Pregnancy Notification Form 
via REDCap. 
 


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Added that SAEs should be 
reported by sites via the 
electronic form on REDCap 
and that a paper form is 
available if necessary and 
should be emailed to the 
trial office. 
 
Typographical errors and 
omissions corrected. 
 
Protocol amendments will be submitted to the sponsor for approval prior to submission to the HRA, 
REC and MHRA. 
 
 
 


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