Frozen Shoulder
Conditions
Keywords
Adhesive capsulitis
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.
Interventions
40mg in 0.8ml preparation in vials from Fresenius Kabi Ltd
DRUGPlacebo
Saline \[0.9% NaCl\]
Sponsors
National Institute for Health Research, United Kingdom
180 Life Sciences
University of Oxford
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
The participant will be blinded along with the assessor and other site staff. The injector and pharmacy will not be blinded.
Intervention model description
Participants will be randomised to either receive Adalimumab or Placebo.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Men and women aged 18 years and above. 2. With a new episode of shoulder pain attributable to pain-predominant stage of frozen shoulder (i.e. within approximately 3 months of onset of symptoms) diagnosed using criteria set out in the BESS guidelines (33) (Appendix 1); 3. Who are not being considered for surgery; 4. Able to understand spoken and written English; 5. Willing and able to give informed consent for trial participation and comply with all study requirements and time line; 6. Willing to allow his or her General Practitioner be notified of participation in the trial. 7. If female and of child-bearing potential OR if male and their partner is of child-bearing potential - willing to use effective contraception throughout the treatment period and for 5 months after the last injection.-
Exclusion criteria
1. 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); 2. Those with a neurological disease affecting the shoulder; 3. Those with bilateral concurrent frozen shoulder; 4. Those with other shoulder disorders (e.g., inflammatory arthritis, rotator cuff disorders, glenohumeral joint instability) or with red flags consistent with the criteria set out in the BESS guidelines (33); 5. Those who have received corticosteroid injection for shoulder pain in the last 12 weeks to either shoulder; 6. Those currently taking any anti-TNF drug; 7. Those being treated with coumarin anticoagulants, such as warfarin; 8. Those who have participated in another research study involving an investigational medicinal product in the past 12 weeks; 9. Those with significant renal or hepatic impairment; 10. Those with contra-indications to anti-TNF injection: 10.1 Known allergy to any anti-TNF agent or any of the excipients; 10.2 Known Active tuberculosis (TB) or history of TB. 10.3 Known Active infection (chronic or localised) or known history of recurring infections or condition which may predispose patients to infection, including the use of concomitant immunosuppressive medications; 10.4 Known Moderate to severe heart failure (NYHA class III/IV); 10.5 Those known to have HIV, Hepatitis B or C; 10.6 Those at risk of Hepatitis B infection; 10.7 Those diagnosed with Multiple Sclerosis (MS) or other central or peripheral nervous system demyelinating disorders; 10.8 Those who have ever been diagnosed with cancer, except basal cell carcinoma (BCC); 10.9 Those requiring live vaccination prior to within 12 weeks after of the last trial injection or within the 4 weeks prior to randomisation; 10.10 Those taking biologic DMARDS; 10.11 Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the study, or may influence the result of the study, or the participant's ability to participate in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Eligible With Pain Predominant Frozen Shoulder | 3 Months | Ability to screen and identify potential participants with pain-predominant early stage frozen shoulder (i.e. within approximately 3 months of onset of symptoms). |
| Number of Participants Consenting to be Included in the Trial | 3 Months | Willingness of eligible participants to consent and be randomised to intervention. |
| Time From Randomisation to First Injection | 2 weeks | Practicalities of delivering the intervention, including time to first injection (within 2 weeks of randomisation). |
| Time From First Injection to Second Injection | 6 weeks | Practicalities of delivering the intervention, including time between first injection and second injection (within 4-6 weeks of randomisation). |
| Shoulder Pain and Disability Index (SPADI) Score | Baseline and 3 months | Score ranges from 0 to 100, lower scores indicate better outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Return to Desired Activities (RDA) | Baseline and 3 months | Return to desired activities measured using an adapted version of the Disabilities of the Arm, Shoulder and Hand (QUICKDASH) questionnaire. Score ranges from 3 to 15, lower scores indicate better outcomes. |
| Global Impression of Change | 3 months | This was measured using the Likert scale. Score ranges from -5 (very much worse) to +5 (completely recovered) with a value of 0 suggesting no change. Higher scores indicate better outcomes. |
| Pain (Shoulder Pain And Disability Index, 5-item Subscale) | Baseline and 3 months | Score ranges from 0 to 100, lower scores indicate better outcome. |
| Adverse Events Graded 3 or Above | Consent to 3 months follow-up | Any adverse event (graded 3 or above) that has resulted from the trial. The Common Terminology Criteria for Adverse Events (CTCAE) v5.0 was used to guide recording adverse events including grading of the event. Grade 3: Severe symptoms or medically significant but not life-threatening but may be disabling or limit self care in Activities of Daily Living. Grade 4: Life threatening consequences; urgent or emergent intervention needed. Grade 5: Death related to or due to adverse event. |
| Shoulder Range of Movement | Baseline and 3 months | Clinician assessed (goniometry measured) active shoulder flexion, extension, abduction, internal and external rotation. Range of flexion and abduction: 0-180 degrees. Range of extension, internal rotation and external rotation: 0-90 degrees. |
| Health Resource Use | 3 months | Consultation with primary and secondary care, additional physiotherapy, injection use, or alternative therapies for index shoulder |
| Function (Shoulder Pain And Disability Index, 8-item Subscale) | Baseline and 3 months | Score ranges from 0 to 100, lower scores indicate better outcome. |
| Fear Avoidance Belief Questionnaire | Baseline and 3 months | Score ranges from 0 to 24, higher scores indicate better outcomes. |
| Pain Self Efficacy Questionnaire | Baseline and 3 months | Score ranges from 0 to 12, higher scores indicate better outcomes. |
| Insomnia Severity Index | Baseline and 3 months | Sleep disturbance measured using the Insomnia Severity Index, score ranges from 0 to 28, higher scores indicate worse outcomes. |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Adalimumab Participants received 2 injections of adalimumab. First injection: 160mg in 3.2ml. Second injection approximately 2-3 weeks later: 80mg in 1.6ml.
Adalimumab Injection: 40mg in 0.8ml preparation in vials from Fresenius Kabi Ltd. | 4 |
| Placebo Participants received 2 injections of placebo. First injection: 3.2ml. Second injection approximately 2-3 weeks later: 1.6ml.
Placebo: Saline \[0.9% NaCl\] | 5 |
| Total | 9 |
Baseline characteristics
| Characteristic | Adalimumab | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 57.5 years STANDARD_DEVIATION 5.9 | 52.8 years STANDARD_DEVIATION 5 | 54.9 years STANDARD_DEVIATION 5.6 |
| Diabetes No | 3 Participants | 2 Participants | 5 Participants |
| Diabetes Type 1 | 0 Participants | 1 Participants | 1 Participants |
| Diabetes Type 2 | 1 Participants | 2 Participants | 3 Participants |
| Dupuytren's disease No | 4 Participants | 4 Participants | 8 Participants |
| Dupuytren's disease Yes | 0 Participants | 1 Participants | 1 Participants |
| Duration of symptoms | 19.5 weeks STANDARD_DEVIATION 13.1 | 12.2 weeks STANDARD_DEVIATION 2.3 | 15.4 weeks STANDARD_DEVIATION 9 |
| Handedness Left | 2 Participants | 1 Participants | 3 Participants |
| Handedness Right | 2 Participants | 4 Participants | 6 Participants |
| If ever smoked, number of cigarettes/day | — | 12 cigarettes per day STANDARD_DEVIATION 11.3 | 12 cigarettes per day STANDARD_DEVIATION 11.3 |
| Race/Ethnicity, Customized White British | 4 Participants | 5 Participants | 9 Participants |
| Region of Enrollment United Kingdom | 4 Participants | 5 Participants | 9 Participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 6 Participants |
| Smoking status Former smoker | 0 Participants | 2 Participants | 2 Participants |
| Smoking status Never smoked | 4 Participants | 3 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 5 |
| other Total, other adverse events | 0 / 4 | 0 / 5 |
| serious Total, serious adverse events | 0 / 4 | 0 / 5 |
Outcome results
Primary
Number of Participants Consenting to be Included in the Trial
Willingness of eligible participants to consent and be randomised to intervention.
Time frame: 3 Months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Screened Participants | Number of Participants Consenting to be Included in the Trial | 9 Participants |
Primary
Number of Participants Eligible With Pain Predominant Frozen Shoulder
Ability to screen and identify potential participants with pain-predominant early stage frozen shoulder (i.e. within approximately 3 months of onset of symptoms).
Time frame: 3 Months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Screened Participants | Number of Participants Eligible With Pain Predominant Frozen Shoulder | 39 Participants |
Primary
Shoulder Pain and Disability Index (SPADI) Score
Score ranges from 0 to 100, lower scores indicate better outcome.
Time frame: Baseline and 3 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Screened Participants | Shoulder Pain and Disability Index (SPADI) Score | Baseline | 70.8 score on a scale | Standard Deviation 16.6 |
| All Screened Participants | Shoulder Pain and Disability Index (SPADI) Score | 3 months | 40.1 score on a scale | Standard Deviation 30 |
| Placebo | Shoulder Pain and Disability Index (SPADI) Score | Baseline | 55.4 score on a scale | Standard Deviation 21.5 |
| Placebo | Shoulder Pain and Disability Index (SPADI) Score | 3 months | 45.8 score on a scale | Standard Deviation 25.3 |
Primary
Time From First Injection to Second Injection
Practicalities of delivering the intervention, including time between first injection and second injection (within 4-6 weeks of randomisation).
Time frame: 6 weeks
Population: All participants received their treatment as allocated and in line with the trial protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All Screened Participants | Time From First Injection to Second Injection | 18.5 days | Standard Deviation 3.3 |
| Placebo | Time From First Injection to Second Injection | 20.8 days | Standard Deviation 5.9 |
Primary
Time From Randomisation to First Injection
Practicalities of delivering the intervention, including time to first injection (within 2 weeks of randomisation).
Time frame: 2 weeks
Population: All participants received their treatment as allocated and in line with the trial protocol. One participant in the adalimumab group received their injection 18 days post- randomisation as they were not available until then.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All Screened Participants | Time From Randomisation to First Injection | 12.3 days | Standard Deviation 4.8 |
| Placebo | Time From Randomisation to First Injection | 7.2 days | Standard Deviation 4.1 |
Secondary
Adverse Events Graded 3 or Above
Any adverse event (graded 3 or above) that has resulted from the trial. The Common Terminology Criteria for Adverse Events (CTCAE) v5.0 was used to guide recording adverse events including grading of the event. Grade 3: Severe symptoms or medically significant but not life-threatening but may be disabling or limit self care in Activities of Daily Living. Grade 4: Life threatening consequences; urgent or emergent intervention needed. Grade 5: Death related to or due to adverse event.
Time frame: Consent to 3 months follow-up
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Screened Participants | Adverse Events Graded 3 or Above | 0 Adverse events graded 3 or above |
| Placebo | Adverse Events Graded 3 or Above | 0 Adverse events graded 3 or above |
Secondary
Fear Avoidance Belief Questionnaire
Score ranges from 0 to 24, higher scores indicate better outcomes.
Time frame: Baseline and 3 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Screened Participants | Fear Avoidance Belief Questionnaire | Baseline | 17.3 score on a scale | Standard Deviation 3.3 |
| All Screened Participants | Fear Avoidance Belief Questionnaire | 3 months | 9.3 score on a scale | Standard Deviation 6.2 |
| Placebo | Fear Avoidance Belief Questionnaire | Baseline | 17.4 score on a scale | Standard Deviation 3.6 |
| Placebo | Fear Avoidance Belief Questionnaire | 3 months | 12.8 score on a scale | Standard Deviation 5.9 |
Secondary
Function (Shoulder Pain And Disability Index, 8-item Subscale)
Score ranges from 0 to 100, lower scores indicate better outcome.
Time frame: Baseline and 3 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Screened Participants | Function (Shoulder Pain And Disability Index, 8-item Subscale) | Baseline | 63.1 score on a scale | Standard Deviation 15.6 |
| All Screened Participants | Function (Shoulder Pain And Disability Index, 8-item Subscale) | 3 months | 38.8 score on a scale | Standard Deviation 30.3 |
| Placebo | Function (Shoulder Pain And Disability Index, 8-item Subscale) | Baseline | 47.5 score on a scale | Standard Deviation 25.7 |
| Placebo | Function (Shoulder Pain And Disability Index, 8-item Subscale) | 3 months | 42.0 score on a scale | Standard Deviation 24.7 |
Secondary
Global Impression of Change
This was measured using the Likert scale. Score ranges from -5 (very much worse) to +5 (completely recovered) with a value of 0 suggesting no change. Higher scores indicate better outcomes.
Time frame: 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All Screened Participants | Global Impression of Change | 2.3 score on a scale | Standard Deviation 2.2 |
| Placebo | Global Impression of Change | 0.0 score on a scale | Standard Deviation 3 |
Secondary
Health Resource Use
Consultation with primary and secondary care, additional physiotherapy, injection use, or alternative therapies for index shoulder
Time frame: 3 months
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| All Screened Participants | Health Resource Use | Steroid injection (injection outside of the trial) | Yes | 1 Participants |
| All Screened Participants | Health Resource Use | Steroid injection (injection outside of the trial) | No | 3 Participants |
| All Screened Participants | Health Resource Use | NHS community-based services (physiotherapist) | Yes | 1 Participants |
| All Screened Participants | Health Resource Use | NHS community-based services (physiotherapist) | No | 3 Participants |
| All Screened Participants | Health Resource Use | Hospital as NHS outpatient (physiotheraphy department) | Yes | 2 Participants |
| All Screened Participants | Health Resource Use | Hospital as NHS outpatient (physiotheraphy department) | No | 2 Participants |
| All Screened Participants | Health Resource Use | Admitted as an inpatient | Yes | 0 Participants |
| All Screened Participants | Health Resource Use | Admitted as an inpatient | No | 4 Participants |
| All Screened Participants | Health Resource Use | Had surgery | Yes | 0 Participants |
| All Screened Participants | Health Resource Use | Had surgery | No | 4 Participants |
| Placebo | Health Resource Use | Admitted as an inpatient | No | 5 Participants |
| Placebo | Health Resource Use | Steroid injection (injection outside of the trial) | Yes | 0 Participants |
| Placebo | Health Resource Use | Hospital as NHS outpatient (physiotheraphy department) | No | 5 Participants |
| Placebo | Health Resource Use | Steroid injection (injection outside of the trial) | No | 5 Participants |
| Placebo | Health Resource Use | Had surgery | No | 5 Participants |
| Placebo | Health Resource Use | NHS community-based services (physiotherapist) | Yes | 0 Participants |
| Placebo | Health Resource Use | Admitted as an inpatient | Yes | 0 Participants |
| Placebo | Health Resource Use | NHS community-based services (physiotherapist) | No | 5 Participants |
| Placebo | Health Resource Use | Had surgery | Yes | 0 Participants |
| Placebo | Health Resource Use | Hospital as NHS outpatient (physiotheraphy department) | Yes | 0 Participants |
Secondary
Insomnia Severity Index
Sleep disturbance measured using the Insomnia Severity Index, score ranges from 0 to 28, higher scores indicate worse outcomes.
Time frame: Baseline and 3 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Screened Participants | Insomnia Severity Index | Baseline | 17.8 score on a scale | Standard Deviation 5 |
| All Screened Participants | Insomnia Severity Index | 3 months | 9.8 score on a scale | Standard Deviation 6.7 |
| Placebo | Insomnia Severity Index | Baseline | 17.6 score on a scale | Standard Deviation 4 |
| Placebo | Insomnia Severity Index | 3 months | 13.2 score on a scale | Standard Deviation 7.6 |
Secondary
Pain Self Efficacy Questionnaire
Score ranges from 0 to 12, higher scores indicate better outcomes.
Time frame: Baseline and 3 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Screened Participants | Pain Self Efficacy Questionnaire | Baseline | 9 score on a scale | Standard Deviation 3.6 |
| All Screened Participants | Pain Self Efficacy Questionnaire | 3 months | 10.5 score on a scale | Standard Deviation 1.3 |
| Placebo | Pain Self Efficacy Questionnaire | Baseline | 9.2 score on a scale | Standard Deviation 1.9 |
| Placebo | Pain Self Efficacy Questionnaire | 3 months | 8.2 score on a scale | Standard Deviation 2.8 |
Secondary
Pain (Shoulder Pain And Disability Index, 5-item Subscale)
Score ranges from 0 to 100, lower scores indicate better outcome.
Time frame: Baseline and 3 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Screened Participants | Pain (Shoulder Pain And Disability Index, 5-item Subscale) | Baseline | 78.5 score on a scale | Standard Deviation 18.4 |
| All Screened Participants | Pain (Shoulder Pain And Disability Index, 5-item Subscale) | 3 months | 41.5 score on a scale | Standard Deviation 32.7 |
| Placebo | Pain (Shoulder Pain And Disability Index, 5-item Subscale) | Baseline | 63.2 score on a scale | Standard Deviation 19.5 |
| Placebo | Pain (Shoulder Pain And Disability Index, 5-item Subscale) | 3 months | 49.6 score on a scale | Standard Deviation 27.3 |
Secondary
Return to Desired Activities (RDA)
Return to desired activities measured using an adapted version of the Disabilities of the Arm, Shoulder and Hand (QUICKDASH) questionnaire. Score ranges from 3 to 15, lower scores indicate better outcomes.
Time frame: Baseline and 3 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Screened Participants | Return to Desired Activities (RDA) | Baseline | 9.0 score on a scale | Standard Deviation 4.5 |
| All Screened Participants | Return to Desired Activities (RDA) | 3 month | 5.5 score on a scale | Standard Deviation 3.8 |
| Placebo | Return to Desired Activities (RDA) | Baseline | 9.4 score on a scale | Standard Deviation 2.7 |
| Placebo | Return to Desired Activities (RDA) | 3 month | 8.4 score on a scale | Standard Deviation 3.6 |
Secondary
Shoulder Range of Movement
Clinician assessed (goniometry measured) active shoulder flexion, extension, abduction, internal and external rotation. Range of flexion and abduction: 0-180 degrees. Range of extension, internal rotation and external rotation: 0-90 degrees.
Time frame: Baseline and 3 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Screened Participants | Shoulder Range of Movement | 3-month external rotation | 28.8 degrees | Standard Deviation 6.3 |
| All Screened Participants | Shoulder Range of Movement | 3-month abduction | 105.0 degrees | Standard Deviation 56.1 |
| All Screened Participants | Shoulder Range of Movement | Baseline flexion | 71.3 degrees | Standard Deviation 26.3 |
| All Screened Participants | Shoulder Range of Movement | Baseline internal rotation | 23.8 degrees | Standard Deviation 18.9 |
| All Screened Participants | Shoulder Range of Movement | Baseline extension | 26.3 degrees | Standard Deviation 18 |
| All Screened Participants | Shoulder Range of Movement | 3-month internal rotation | 21.3 degrees | Standard Deviation 17 |
| All Screened Participants | Shoulder Range of Movement | 3-month extension | 30.0 degrees | Standard Deviation 8.2 |
| All Screened Participants | Shoulder Range of Movement | Baseline external rotation | 22.5 degrees | Standard Deviation 8.7 |
| All Screened Participants | Shoulder Range of Movement | Baseline abduction | 50.0 degrees | Standard Deviation 30.3 |
| All Screened Participants | Shoulder Range of Movement | 3-month flexion | 112.5 degrees | Standard Deviation 54.8 |
| Placebo | Shoulder Range of Movement | 3-month external rotation | 55.0 degrees | Standard Deviation 16.2 |
| Placebo | Shoulder Range of Movement | 3-month flexion | 140.0 degrees | Standard Deviation 25.7 |
| Placebo | Shoulder Range of Movement | Baseline extension | 27.6 degrees | Standard Deviation 9.5 |
| Placebo | Shoulder Range of Movement | Baseline flexion | 101.6 degrees | Standard Deviation 24.7 |
| Placebo | Shoulder Range of Movement | 3-month extension | 40.6 degrees | Standard Deviation 9.8 |
| Placebo | Shoulder Range of Movement | Baseline abduction | 69.0 degrees | Standard Deviation 26.6 |
| Placebo | Shoulder Range of Movement | 3-month abduction | 115.0 degrees | Standard Deviation 42.7 |
| Placebo | Shoulder Range of Movement | Baseline internal rotation | 40.2 degrees | Standard Deviation 40.8 |
| Placebo | Shoulder Range of Movement | 3-month internal rotation | 41.0 degrees | Standard Deviation 37.8 |
| Placebo | Shoulder Range of Movement | Baseline external rotation | 15.0 degrees | Standard Deviation 16.9 |