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Repurposing Anti-TNF for Treating Dupuytren's Disease (RIDD)

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ClinicalTrials.gov Identifier: NCT03180957
Recruitment Status : Completed
First Posted : June 8, 2017
Last Update Posted : April 20, 2021
Sponsor:
Collaborators:
Department of Health, United Kingdom
Wellcome Trust
180 Therapeutics LP
Information provided by (Responsible Party):
University of Oxford

Tracking Information
First Submitted Date  ICMJE May 23, 2017
First Posted Date  ICMJE June 8, 2017
Last Update Posted Date April 20, 2021
Actual Study Start Date  ICMJE March 2, 2016
Actual Primary Completion Date November 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 30, 2018)
  • Dose Response: expression of mRNA for α-SMA [ Time Frame: Analysis of tissue removed at 12-18 days post-treatment ]
  • Early Disease: change in nodule hardness between baseline at 12 months [ Time Frame: 12 months ]
    Tonometry
Original Primary Outcome Measures  ICMJE
 (submitted: June 7, 2017)
  • Dose Response: expression of mRNA for α-SMA [ Time Frame: Analysis of tissue removed at 12-18 days post-treatment ]
  • Early Disease: change in nodule hardness from baseline at 12 weeks [ Time Frame: 12 weeks ]
    Tonometry
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 30, 2018)
  • Dose Response: expression of mRNA for COL-1A1, COL-3A1, cadherin 11 [ Time Frame: Analysis of tissue removed at 12-18 days post-treatment ]
  • Dose Response: Levels of α-SMA and collegen protein [ Time Frame: Analysis of tissue removed at 12-18 days post-treatment ]
  • Dose Response: Nodule hardness [ Time Frame: 2 weeks post treatment ]
    Tonometry
  • Dose Response: Visual comparison of surgical wounds using hand photographs [ Time Frame: 2 weeks post surgery ]
  • Dose Response & Early Disease: Change in nodule size and vascularity from baseline [ Time Frame: 2 weeks post treatment (dose response) / 18 months (early disease) ]
    Pixel analysis of ultrasound imaging
  • Dose Response and Early Disease: participant injection experience [ Time Frame: Baseline (Dose response) / 12 months (early disease) ]
    Numeric rating scale of pain
  • Dose Response & Early Disease: Adverse event assessment [ Time Frame: 2 weeks (dose response) / 12 months (early disease) ]
    Assessment of the injection site for pre-specified Adverse Events; surgery site assessment (Dose response only): wound assessment criteria, Centres for Disease Control and Prevention.
  • Early Disease: Nodule hardness [ Time Frame: 18 months post treatment ]
    Tonometry
  • Early Disease: range of motion of the affected digit [ Time Frame: 18 months ]
    Goniometer reading
  • Early Disease: Grip strength [ Time Frame: 18 months ]
    Jamar meter
  • Early Disease: patient reported outcomes [ Time Frame: 18 months ]
    Michigan Hand Outcomes Questionnaire
  • Early Disease: patient reported outcomes [ Time Frame: 18 months ]
    Participant identified activity most restricted by DD scored on a scale of 1-10
  • Early Disease: progression to surgery of the digit being assessed [ Time Frame: 18 months ]
Original Secondary Outcome Measures  ICMJE
 (submitted: June 7, 2017)
  • Dose Response: expression of mRNA for COL-1A1 and COL-3A1 [ Time Frame: Analysis of tissue removed at 12-18 days post-treatment ]
  • Dose Response: Levels of α-SMA protein [ Time Frame: Analysis of tissue removed at 12-18 days post-treatment ]
  • Dose Response: Nodule hardness [ Time Frame: 2 weeks post treatment ]
    Tonometry
  • Dose Response & Early Disease: Change in nodule size and vascularity from baseline [ Time Frame: 2 weeks post treatment (dose response) / 18 months (early disease) ]
    Pixel analysis of ultrasound imaging
  • Dose Response and Early Disease: participant injection experience [ Time Frame: Baseline (Dose response) / 12 months (early disease) ]
    Numeric rating scale of pain
  • Dose Response & Early Disease: Adverse event assessment [ Time Frame: 2 weeks (dose response) / 12 months (early disease) ]
    Assessment of the injection site for pre-specified Adverse Events; surgery site assessment (Dose response only): wound assessment criteria, Centres for Disease Control and Prevention.
  • Early Disease: range of motion of the affected digit [ Time Frame: 18 months ]
    Goniometer reading
  • Early Disease: Grip strength [ Time Frame: 18 months ]
    Jamar meter
  • Early Disease: patient reported outcomes [ Time Frame: 18 months ]
    Michigan hand Outcomes Questionnaire
  • Early Disease: patient reported outcomes [ Time Frame: 18 months ]
    Participant identified activity most restricted by DD scored on a scale of 1-10
  • Early Disease: progression to surgery of the digit being assessed [ Time Frame: 18 months ]
Current Other Pre-specified Outcome Measures
 (submitted: February 5, 2018)
  • Dose Response & Early Disease: Circulating levels of adalimumab in the blood [ Time Frame: 2 weeks (dose response) / 12 months (early disease) ]
  • Dose Response & Early Disease: Circulating levels of antibodies to adalimumab in the blood [ Time Frame: 2 weeks (dose response) / 12 months (early disease) ]
  • Dose Response: Acceptability of the injection and return to paid work [ Time Frame: 12 weeks post-surgery ]
    Patient-completed questionnaire: numeric rating scale
  • Early Disease: Cost effectiveness [ Time Frame: 18 months ]
    EQ-5D-5L data
  • Early disease: Analysis of resource use data [ Time Frame: 18 months ]
    Patient completed questionnaire about health & social care and financial costs of Dupuytren's disease
  • Dose Response & Early Disease: Exploratory Objective: Investigation of newly identified relevant molecular markers [ Time Frame: Dose Response: 12-18 days post treatment (tissue)/ 2 weeks post treatment (blood). Early Disease: 3 & 12 months post 1st treatment (blood) ]
Original Other Pre-specified Outcome Measures
 (submitted: June 7, 2017)
  • Dose Response & Early Disease: Circulating levels of adalimumab in the blood [ Time Frame: 2 weeks (dose response) / 12 months (early disease) ]
  • Dose Response & Early Disease: Circulating levels of antibodies to adalimumab in the blood [ Time Frame: 2 weeks (dose response) / 12 months (early disease) ]
  • Dose Response: Acceptability of the injection and return to paid work [ Time Frame: 12 weeks post-surgery ]
    Patient-completed questionnaire: numeric rating scale
  • Early Disease: Cost effectiveness [ Time Frame: 18 months ]
    EQ-5D-5L data
 
Descriptive Information
Brief Title  ICMJE Repurposing Anti-TNF for Treating Dupuytren's Disease
Official Title  ICMJE A Multi-centre, Double Blind, Randomised, Placebo-controlled, Parallel Group, Phase II Trial to Determine the Efficacy of Intra-nodular Injection of Anti-TNF to Control Disease Progression in Early Dupuytren's Disease, With a Dose Response.
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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, 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.
Primary Purpose: Treatment
Condition  ICMJE Dupuytren's Disease
Intervention  ICMJE
  • Drug: Adalimumab
    Other Name: Humira
  • Drug: Saline
Study Arms  ICMJE
  • Experimental: Anti-TNF
    adalimumab
    Intervention: Drug: Adalimumab
  • Placebo Comparator: Placebo
    saline
    Intervention: Drug: Saline
Publications * Nanchahal J, Ball C, Davidson D, Williams L, Sones W, McCann FE, Cabrita M, Swettenham J, Cahoon NJ, Copsey B, Anne Francis E, Taylor PC, Black J, Barber VS, Dutton S, Feldmann M, Lamb SE. Anti-Tumour Necrosis Factor Therapy for Dupuytren's Disease: A Randomised Dose Response Proof of Concept Phase 2a Clinical Trial. EBioMedicine. 2018 Jul;33:282-288. doi: 10.1016/j.ebiom.2018.06.022. Epub 2018 Jul 6.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: October 18, 2019)
209
Original Estimated Enrollment  ICMJE
 (submitted: June 7, 2017)
178
Actual Study Completion Date  ICMJE December 2020
Actual Primary Completion Date November 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Netherlands,   United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03180957
Other Study ID Numbers  ICMJE 11069
HICF-R8-433 ( Other Grant/Funding Number: Health Innovation Challenge Fund )
2015-001780-40 ( EudraCT Number )
ISRCTN27786905 ( Registry Identifier: ISRCTN )
15/SC/0259 ( Other Identifier: UK Health Research Authority )
CTU0028 ( Other Identifier: OCTRU )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Current Responsible Party University of Oxford
Original Responsible Party Same as current
Current Study Sponsor  ICMJE University of Oxford
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE
  • Department of Health, United Kingdom
  • Wellcome Trust
  • 180 Therapeutics LP
Investigators  ICMJE
Principal Investigator: Jagdeep Nanchahal, PhD FRCS University of Oxford
PRS Account University of Oxford
Verification Date October 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP