Dupuytren's Disease
Conditions
Keywords
Dupuytren, adalimumab, anti TNF, phase II clinical trial, randomized controlled trial, double-blind method, Dupuytren's, Dupuytren's contracture
Brief summary
Dupuytren's disease is a very common condition, affecting 4% of the general UK and US population. It causes the fingers to curl irreversibly into the palm and can be extremely disabling. The disease usually starts as a small firm lump (nodule) in the palm, and in about 40% of patients advances to form cords that pull the fingers into the palm. There is no approved treatment for the early stage of disease. Once patients have established deformities, the diseased tissue can removed by surgery or cut using less invasive techniques such as a needle or an enzyme. However, recovery following surgery usually takes several months and recurrence rates with the less invasive techniques are high. The investigators have unravelled the cellular process that initiates and maintains the disease progress and identified tumour necrosis factor (TNF) as a new target for treatment. Based on these findings the investigators plan to test the effects of adalimumab, an anti-TNF drug which currently approved for use in patients with rheumatoid arthritis and other inflammatory conditions. The aim of the study is to find out whether treatment by injection with adalimumab directly into the diseased tissue will control the advance of early Dupuytren's disease better than a placebo injection with normal saline. The investigators will first carry out a small trial in up to 40 patients with established disease to determine the best dose that reduces the activity of the cells responsible for the disorder (Dose Response study). In this part patients who will be having surgery to remove their diseased tissue will receive a single injection of adalimumab into the nodule in their hand about 2 weeks before surgery. The tissue that is then removed during surgery will be analysed in the investigator's laboratories to determine the effect of the drug on the tissue. Patients will be followed for 12 weeks after surgery. In the second part of the study the investigators will assess whether the optimal dose of the drug prevents early disease advancing in 138 patients (Early Disease study). Patients who take part in the second part of the study will receive a total of 4 injections of adalimumab into the nodule in their hand at three monthly intervals. They will then be checked at 3 & 9 months after the last injection. In additional to assessing the effect of the injections on the nodule and hand function, information will also be collected to assess the cost effectiveness of the treatment.
Interventions
DRUGAdalimumab
DRUGSaline
Sponsors
Department of Health, United Kingdom
Wellcome Trust
180 Therapeutics LP
University of Oxford
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
During Dose Response part of the trial the Investigator will be blinded. During the Early Disease part of the trial the Investigator will not be blinded but will not carry out any outcome assessments.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participant is willing and able to give informed consent for participation in the study. * Male or Female, aged 18 years or above. * For Part 1: Diagnosed with DD affecting the fingers resulting in flexion deformities of ≥30° at the metacarpophalangeal joint and or the proximal interphalangeal joint with impaired hand function and awaiting surgery. Or for Part 2: Participants with early disease nodules who have shown or reported progression of the disease in the previous 6 months with flexion deformities of their fingers of ≤30° at the metacarpophalangeal and/or at the proximal interphalangeal joint, i.e. total flexion deformity of up to 60°. * The DD nodule to be treated must be distinct and identifiable. * Female participants of child bearing potential, and male participants whose partner is of child bearing potential, must be willing to ensure that they or their partner use effective contraception throughout the treatment period and for 5 months following the last research injection. Acceptable methods of contraception include: a combination of male condom with either cap, diaphragm or sponge with spermicide (double barrier methods), injectables, the combined oral contraceptive pill (at a stable dose for at least 3 months before entering the study), an intrauterine device, vasectomised partner, or true sexual abstinence (when this is in line with the preferred and usual lifestyle of the participant). * Participant results from safety screening tests within normal ranges within 12 weeks of enrolment, with the exception that an earlier clear chest x-ray result may be used where this is in accordance with the time frames of local standard procedures for anti-TNF screening. * Able (in the Investigators opinion) and willing to comply with all study requirements. * Willing to allow his or her general practitioner to be notified of participation in the study. * Sufficient language fluency to ensure informed consent is obtained and to complete the questionnaires pertaining to hand function.
Exclusion criteria
* For Part 1: Participant has previously had fasciectomy, dermofasciectomy, needle fasciotomy, collagenase injection, steroid injection or radiotherapy to treat Dupuytren's disease in the digit concerned. Or for Part 2: Participant has previously had fasciectomy, dermofasciectomy, needle fasciotomy, collagenase injection, steroid injection to the digit to be treated or radiotherapy to treat Dupuytren's disease in the hand concerned. * Female participant who is pregnant, lactating or planning pregnancy during the course of the study and for 5 months following last injection. * Male participant who is planning a pregnancy during the course of the study and for 5 months following last injection. * Significant renal or hepatic impairment. * For Part 1: Scheduled elective surgery or other procedures requiring general anaesthesia during the study other than the scheduled Dupuytren's surgery. Or for Part 2: Scheduled elective surgery or other procedures requiring general anaesthesia during the study * Participant who has ever been diagnosed with cancer, is terminally ill or is inappropriate for placebo medication * Systemic inflammatory disorder such as rheumatoid arthritis (RA) or inflammatory bowel disease. * 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. * Participated in another research study involving an investigational medicinal product in the past 12 weeks. * Known allergy to any anti-TNF agent. * Have HIV or hepatitis B or C. * Known to have an infection or history of repeated infections. * History of Tuberculosis (TB). * Have Multiple Sclerosis (MS) or other demyelinating disease. * History of local injection site reactions. * Needle phobia. * Have moderate or severe heart failure. * Part 1: Being treated with coumarin anticoagulants, such as warfarin. * Have known lung fibrosis (thickening of lung tissue). * Being treated with concomitant biologic DMARDS. * Have received a live vaccine within the previous 4 weeks. Participants may receive concurrent vaccinations but must avoid the use of live vaccines for 12 weeks after their last injection. * Part1: Have received parenteral steroid within the previous 6 weeks. * Part 2: Participants at risk of Hepatitis B infection.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Early Disease: Nodule Hardness at 12 Months | 12 months | Tonometry - A hardness score in arbitrary units with 0 being the lowest hardness and 100 being the greatest hardness units on a scale. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Early Disease: Nodule Size | 12 months | Measured in mm\^2 where 0 is the smallest and 50 is the largest unit on a scale |
| Early Disease: Grip Strength | 12 months | Jamar meter |
| Early Disease: Extension Deficit of Affected Joint | 12 months | Overall passive extension deficit of joint affected by treated nodule (degrees) |
| Early Disease: Patient Reported Outcomes | 12 months | Michigan Hand Questionnaire - overall hand function with 0 as the lowest ability and 100 best possible ability units on a scale. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Early Disease: Analysis of Resource Use Data | 18 months | Patient completed questionnaire about health & social care and financial costs of Dupuytren's disease |
Countries
Netherlands, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Anti-TNF Adalimumab
Adalimumab | 70 |
| Placebo Saline
Saline | 70 |
| Total | 140 |
Baseline characteristics
| Characteristic | Total | Anti-TNF | Placebo |
|---|---|---|---|
| Affected joint metacarpophalangeal | 114 Participants | 54 Participants | 60 Participants |
| Affected joint proximal interphalangeal | 26 Participants | 16 Participants | 10 Participants |
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 46 Participants | 23 Participants | 23 Participants |
| Age, Categorical Between 18 and 65 years | 94 Participants | 47 Participants | 47 Participants |
| alcohol consumption (Units/week) 14-35 | 43 Participants | 23 Participants | 20 Participants |
| alcohol consumption (Units/week) Non Drinker | 16 Participants | 9 Participants | 7 Participants |
| alcohol consumption (Units/week) over 35 | 4 Participants | 2 Participants | 2 Participants |
| alcohol consumption (Units/week) up to 13 | 77 Participants | 36 Participants | 41 Participants |
| Associated medical conditions Missing | 1 Participants | 0 Participants | 1 Participants |
| Associated medical conditions No | 72 Participants | 39 Participants | 33 Participants |
| Associated medical conditions Yes | 67 Participants | 31 Participants | 36 Participants |
| Bilateral Dupytrens's disease no | 65 Participants | 31 Participants | 34 Participants |
| Bilateral Dupytrens's disease yes | 75 Participants | 39 Participants | 36 Participants |
| Current smoker no | 133 Participants | 66 Participants | 67 Participants |
| Current smoker Yes | 7 Participants | 4 Participants | 3 Participants |
| Diabetes no | 131 Participants | 67 Participants | 64 Participants |
| Diabetes Type 1 | 1 Participants | 0 Participants | 1 Participants |
| Diabetes Type 2 | 8 Participants | 3 Participants | 5 Participants |
| Epilepsy no | 137 Participants | 69 Participants | 68 Participants |
| Epilepsy yes | 3 Participants | 1 Participants | 2 Participants |
| Family History (1st Degree Relatives) No | 85 Participants | 45 Participants | 40 Participants |
| Family History (1st Degree Relatives) Yes | 55 Participants | 25 Participants | 30 Participants |
| Frozen Shoulder Both Sides | 10 Participants | 3 Participants | 7 Participants |
| Frozen Shoulder Left | 15 Participants | 10 Participants | 5 Participants |
| Frozen Shoulder None | 103 Participants | 51 Participants | 52 Participants |
| Frozen Shoulder Right | 12 Participants | 6 Participants | 6 Participants |
| Garrod's Knuckle pads No | 109 Participants | 58 Participants | 51 Participants |
| Garrod's Knuckle pads Yes | 31 Participants | 12 Participants | 19 Participants |
| Hand Dominance left | 15 Participants | 5 Participants | 10 Participants |
| Hand Dominance missing | 1 Participants | 0 Participants | 1 Participants |
| Hand Dominance right | 124 Participants | 65 Participants | 59 Participants |
| Liver disease no | 140 Participants | 70 Participants | 70 Participants |
| Liver disease yes | 0 Participants | 0 Participants | 0 Participants |
| Peyronie's disease No | 134 Participants | 67 Participants | 67 Participants |
| Peyronie's disease Yes | 6 Participants | 3 Participants | 3 Participants |
| Plantar Disease Missing | 1 Participants | 0 Participants | 1 Participants |
| Plantar Disease No | 117 Participants | 58 Participants | 59 Participants |
| Plantar Disease Yes | 22 Participants | 12 Participants | 10 Participants |
| Previous significant trauma to affected hand no | 113 Participants | 57 Participants | 56 Participants |
| Previous significant trauma to affected hand yes | 27 Participants | 13 Participants | 14 Participants |
| Race and Ethnicity Not Collected | 0 Participants | — | — |
| Ray affected by study nodule Index | 2 Participants | 0 Participants | 2 Participants |
| Ray affected by study nodule Little | 39 Participants | 16 Participants | 23 Participants |
| Ray affected by study nodule Middle | 21 Participants | 15 Participants | 6 Participants |
| Ray affected by study nodule Ring | 78 Participants | 39 Participants | 39 Participants |
| Region of Enrollment United Kingdom | 140 participants | 70 participants | 70 participants |
| Sex: Female, Male Female | 47 Participants | 27 Participants | 20 Participants |
| Sex: Female, Male Male | 93 Participants | 43 Participants | 50 Participants |
| Significant exposure to occupational vibration no | 130 Participants | 66 Participants | 64 Participants |
| Significant exposure to occupational vibration yes | 10 Participants | 4 Participants | 6 Participants |
| Treatment for Dupytren's disease in other hand No | 109 Participants | 53 Participants | 56 Participants |
| Treatment for Dupytren's disease in other hand Yes | 31 Participants | 17 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 70 | 0 / 70 |
| other Total, other adverse events | 9 / 70 | 9 / 70 |
| serious Total, serious adverse events | 0 / 70 | 1 / 70 |
Outcome results
Primary
Early Disease: Nodule Hardness at 12 Months
Tonometry - A hardness score in arbitrary units with 0 being the lowest hardness and 100 being the greatest hardness units on a scale.
Time frame: 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Anti-TNF | Early Disease: Nodule Hardness at 12 Months | 58.1 Durometer Arbitrary Units (AU) | Standard Deviation 11.8 |
| Placebo | Early Disease: Nodule Hardness at 12 Months | 61.2 Durometer Arbitrary Units (AU) | Standard Deviation 9.8 |
Secondary
Early Disease: Extension Deficit of Affected Joint
Overall passive extension deficit of joint affected by treated nodule (degrees)
Time frame: 12 months
Population: baseline were mean imputed. 12 Months: Adalimumab n=63, Saline n=65
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Anti-TNF | Early Disease: Extension Deficit of Affected Joint | Overall passive extension deficit of joint affected by treatment nodule | 3.3 degrees | Standard Deviation 10.2 |
| Anti-TNF | Early Disease: Extension Deficit of Affected Joint | MCP:passive extension deficit of joint affected by treated nodule | 0.0 degrees | Standard Deviation 0 |
| Anti-TNF | Early Disease: Extension Deficit of Affected Joint | PIP: passive extension deficit of joint affected by treated nodule | 14.7 degrees | Standard Deviation 17.7 |
| Placebo | Early Disease: Extension Deficit of Affected Joint | Overall passive extension deficit of joint affected by treatment nodule | 5.0 degrees | Standard Deviation 12.8 |
| Placebo | Early Disease: Extension Deficit of Affected Joint | MCP:passive extension deficit of joint affected by treated nodule | 1.4 degrees | Standard Deviation 5.7 |
| Placebo | Early Disease: Extension Deficit of Affected Joint | PIP: passive extension deficit of joint affected by treated nodule | 30.0 degrees | Standard Deviation 20.4 |
Secondary
Early Disease: Grip Strength
Jamar meter
Time frame: 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Anti-TNF | Early Disease: Grip Strength | 34.5 kg | Standard Deviation 10.7 |
| Placebo | Early Disease: Grip Strength | 38.3 kg | Standard Deviation 11.9 |
Secondary
Early Disease: Nodule Size
Measured in mm\^2 where 0 is the smallest and 50 is the largest unit on a scale
Time frame: 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Anti-TNF | Early Disease: Nodule Size | 21.8 mm^2 | Standard Deviation 18.7 |
| Placebo | Early Disease: Nodule Size | 35.9 mm^2 | Standard Deviation 28.9 |
Secondary
Early Disease: Patient Reported Outcomes
Michigan Hand Questionnaire - overall hand function with 0 as the lowest ability and 100 best possible ability units on a scale.
Time frame: 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Anti-TNF | Early Disease: Patient Reported Outcomes | 83.5 score on a scale | Standard Deviation 16.1 |
| Placebo | Early Disease: Patient Reported Outcomes | 78.8 score on a scale | Standard Deviation 16 |
Other Pre-specified
Early Disease: Analysis of Resource Use Data
Patient completed questionnaire about health & social care and financial costs of Dupuytren's disease
Time frame: 18 months