Condition category
Skin and Connective Tissue Diseases
Date applied
15/10/2015
Date assigned
18/11/2015
Last edited
09/11/2016
Prospective/Retrospective
Retrospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
Dupuytren's disease (DD) is a common condition which causes the fingers to gradually curl into the palm so that they can no longer be straightened. It is caused by a thickening of the thin layer of tissue which lies under the skin of the palm (connective tissue). This thickening often starts in a small area, causing a small, hard lump (nodule) to form under the skin. Although these nodules are effectively harmless, over time they grow into cords of shortened (contracted) tissue which pull the fingers towards the palm. There is large variation in how quickly the disease progresses, and there are currently no effective treatments for early stage disease to slow or prevent progression. Once the disease is advanced, the main way of treating the hand deformity is by surgically removing the contracted tissue. This operation can take a long time to recover from and patients often require a long period of physiotherapy. New theories are emerging that DD may be caused by a protein called tumour necrosis factor (TNF), which causes inflammation . Adalimumab is a drug which blocks the action of TNF and is normally used to treat arthritis. The current study consists of two parts. In part one, the study aims to find out the effectiveness of treatment with adalimumab at different doses in patients with advanced DD. In part two, the study aims of find out whether injections of adalimumab can help treat patients with early stage DD.

Who can participate?
Adults with late stage Dupuytren's disease (part one) who are having surgery to remove the Dupuytren’s tissue, and adults with early stage Dupuytren's disease (part two) which is getting worse.

What does the study involve?
Before starting either part of the study, all potential participants are seen by a doctor to check they are able to take part. Other visits include physical tests to see how well the hand functions, questionnaires about health and hand function, blood tests, and ultrasound imaging and digital photographs of the hand. In part one, participants are asked to attend a clinic at the hospital to receive an injection of either adalimumab or a placebo (dummy injection) two weeks before their surgery. Some participants receive bigger doses than others so that the best dose can be found. They are also asked to donate their surgically removed Dupuytren’s tissue so it can be examined in the laboratory. They are also seen by researchers over three months when they attend the clinic as part of their usual surgery care. In part two, participants are asked to attend a clinic seven times over eighteen months. On four of these visits, participants are given injections of either adalimumab or a placebo. Participants are equally likely to receive adalimumab as the dummy. In both parts of the study, none of the researchers working with the participants, and none of the participants, know who receives which.

What are the possible benefits and risks of participating?
In part one, there are no direct benefits to participants, as they will be receiving the surgery whether they take part or not. In part two, participants may benefit from the possibility of adalimumab slowing the development of the disease, but there will be no direct medical benefit to participants who receive the dummy injection. For all participants there is a risk of experiencing unwanted side effects from the adalimumab, such as redness, swelling or pain at the injection site, or sore throat or sinus infections.

Where is the study run from?
1. St John's Hospital, Livingston (UK)
2. Nuffield Orthopaedic Centre, Oxford (UK)
3. Queen Victoria Hospital, East Grinstead (UK)

When is the study starting and how long is it expected to run for?
October 2015 to October 2018

Who is funding the study?
1. Wellcome Trust (UK) Grant Code: 102538 (HICF)
2. Department of Health (UK)
3. 180 Therapeutics (UK)

Who is the main contact?
1. Dr Jennifer Swettenham (Public)
ridd@kennedy.ox.ac.uk
2. Professor Jagdeep Nanchahal (Scientific)

Trial website

http://ridd.octru.ox.ac.uk/

Contact information

Type

Public

Primary contact

Dr Jennifer Swettenham

ORCID ID

http://orcid.org/0000-0001-7527-4602

Contact details

Kennedy Institute of Rheumatology
Roosevelt Drive
Headington
NDORMS
University of Oxford
Oxford
OX3 7LD
United Kingdom
+44 1865 612610
ridd@kennedy.ox.ac.uk

Type

Scientific

Additional contact

Prof Jagdeep Nanchahal

ORCID ID

http://orcid.org/0000-0002-9579-9411

Contact details

Kennedy Institute of Rheumatology
Roosevelt Drive
Headington
NDORMS
University of Oxford
Oxford
OX3 7FY
United Kingdom

Additional identifiers

EudraCT number

2015-001780-40

ClinicalTrials.gov number

Protocol/serial number

8.0

Study information

Scientific title

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

Acronym

RIDD

Study hypothesis

Part 1: To establish an effective dose of the research drug for treating Dupuytren's disease by analysing patient’s tissue in the laboratory.

Part 2: To determine whether dose of the research drug controls disease progression better than the placebo in patients with early Dupuytren's disease.

Ethics approval

NRES Committee South Central - Oxford B, 23/06/2015, ref: 15/SC/0259

Study design

Multi-centre double-blind randomised placebo-controlled phase II trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a participant information sheet.

Condition

Dupuytren's disease of the hand

Intervention

Interventions as of 09/11/2016:
Part 1: Dose response. Participants will have advanced Dupuytren's and will be scheduled for surgery to treat the contracture. Up to 40 participants will be recruited and the ratio of participants receiving adalimumab to saline placebo will be 3:1. All participants will be injected on one occasion, two weeks before their planned surgery, into their Dupuytren’s nodule. The maximum dose that may be used is 80 mg adalimumab.

Part 2: Randomised controlled trial. Participants with early stage Dupuytren's will be randomised 1:1 to receive injections of either adalimumab or saline (placebo control). The dose will be 40 mg adalimumab or the equivalent volume of saline. Participants will receive 4 treatments, 3 months apart over a year.


Original interventions:
Part 1: Dose response run-in. Participants will have advanced Dupuytren's and will be scheduled for surgery to treat the contracture. There will be 5 dose cohorts with progression to the next, higher, dose group only if no more than 1 patient from the cohort of 8 has an unplanned admission to hospital or unplanned surgery related to the surgery for Dupuytren’s disease of the affected finger. Within each dose cohort, 6 participants will be injected on one occasion with adalimumab, and 2 participants will be injected on one occasion with the same volume of saline (placebo control).
The doses will be:
1. 0.3 ml into the Dupuytren's nodule (15 mg adalimumab)
2. 0.5 ml into the Dupuytren's nodule (25 mg adalimumab)
3. 0.7 ml into the Dupuytren's nodule (35 mg adalimumab)
4. 0.7 ml into the Dupuytren's nodule (35 mg adalimumab) AND 0.8 ml subcutaneously into the abdomen (40 mg adalimumab)
5. 0.7 ml into the Dupuytren's nodule (35 mg adalimumab) AND 2 x 0.8 ml subcutaneously into the abdomen (80 mg adalimumab)

Part 2: Randomised controlled trial. Participants with early stage Dupuytren's will be randomised 1:1 to receive injections of either adalimumab or saline (placebo control). The dose will have been determined from the results of Part 1. Participants will receive 4 treatments, 3 months apart over a year.

Intervention type

Drug

Phase

Phase II

Drug names

Adalimumab (humira)

Primary outcome measures

Part 1:
Expression of mRNA for α-SMA in the nodule tissue removed as part of planned surgery 12-18 days after treatment.

Part 2:
The hardness of the hand overlying the treated nodule measured using tonometry before, and at 3, 6, 9, 12 and 18 months after treatment.

Secondary outcome measures

Secondary outcome measures as of 08/11/2016:
Part 1:
1. Expression of mRNA for COL-1A1 and COL-3A1 in the nodule tissue removed as part of planned surgery 12-18 days after treatment
2. Levels of α-SMA protein in the removed nodule tissue
3. The hardness of the hand overlying the treated nodule measured using tonometry at baseline and 2 weeks after treatment
4. Nodule size and vascularity measured with ultrasound imaging at baseline and 2 weeks after treatment
5. The experience of the injection rated by the participant immediately after treatment
6. Assessment of the injection site for adverse events by observation at each research visit

Part 2:
1. Nodule size measured with ultrasound imaging at baseline, and at 3, 6, 9, 12 and 18 months after first treatment
2. Grip strength measured with a dynamometer at baseline, and at 3, 6, 9, 12 and 18 months after first treatment
3. Range of motion of the affected digit measured with a goniometer at baseline, and at 3, 6, 9, 12 and 18 months after first treatment
4. Patient reported outcomes are measured using the Michigan Hand Outcomes Questionnaire (MHQ) and the rating of the activity most restricted by Dupuytren’s disease at baseline and at 3, 6, 9, 12 and 18 months after first treatment
5. Clinical assessment of the hand at baseline and at 3, 6, 9, 12 and 18 months after first treatment
6. The experience of the injection rated by the participant immediately after each treatment
7. Progression to surgery of the finger being assessed during the 18 month follow-up
8. Assessment of the injection site for adverse events by observation at each research visit

Secondary outcome measures (part 1) as of 07/03/2016:
1. Expression of mRNA for COL-1A1 and COL-3A1 in the nodule tissue removed as part of planned surgery 12-18 days after treatment
2. The hardness of the hand overlying the treated nodule measured using tonometry at baseline and 2 weeks after treatment
3. Nodule size and vascularity measured with ultrasound imaging at baseline and 2 weeks after treatment
4. Assessment of the injection site for adverse events by observation at each research visit

Original secondary outcome measures:
Part 1:
1. Expression of mRNA for COL-1 in the nodule tissue removed as part of planned surgery 12-18 days after treatment
2. The hardness of the hand overlying the treated nodule measured using tonometry at baseline, 2 weeks after treatment
3. Nodule size and vascularity measured with ultrasound imaging at baseline, 1 and 2 weeks after treatment
4. Grip strength measured with a dynamometer bat baseline, 2 weeks after treatment and at 12 weeks after surgery
5. Range of motion of the affected digit measured with a goniometer at baseline, 2 weeks after treatment and at 12 weeks after surgery
6. Patient reported outcomes are measured using the Michigan Hand Outcomes Questionnaire (MHQ) and the rating of the activity most restricted by Dupuytren’s disease at baseline, 2 weeks after treatment and at 12 weeks after surgery
7. The experience of the injection rated by the participant immediately after treatment
8. Assessment of the injection site for adverse events by observation at each research visit

Part 2:
1. Nodule size and vascularity and cord extent measured with ultrasound imaging at baseline, and at 3, 6, 9, 12 and 18 months after first treatment
2. Grip strength measured with a dynamometer at baseline, and at 3, 6, 9, 12 and 18 months after first treatment
3. Range of motion of the affected digit measured with a goniometer at baseline, and at 3, 6, 9, 12 and 18 months after first treatment
4. Patient reported outcomes are measured using the Michigan Hand Outcomes Questionnaire (MHQ) and the rating of the activity most restricted by Dupuytren’s disease at baseline and at 3, 6, 9, 12 and 18 months after first treatment
5. Clinical assessment of the hand at baseline and at 3, 6, 9, 12 and 18 months after first treatment
6. The experience of the injection rated by the participant immediately after each treatment
7. Progression to surgery of the finger being assessed during the 18 month follow-up
8. Assessment of the injection site for adverse events by observation at each research visit

Overall trial start date

12/10/2015

Overall trial end date

11/10/2018

Reason abandoned

Eligibility

Participant inclusion criteria

Part 1:
1. Aged 18 years or above
2. Participant is willing and able to give informed consent for participation in the study
3. Diagnosed with Dupuytren’s disease affecting the fingers resulting in flexion deformities of greater than 30° at the metacarpophalangeal joint and or the proximal interphalangeal joint with impaired hand function and awaiting surgery
4. The Dupuytren’s disease nodule to be treated must be distinct and identifiable
5. 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).
6. Participant results from safety screening tests within normal ranges within 8 weeks of enrolment, with the exception that an earlier clear CXR result may be used where this is in accordance with the time frames of local standard procedures for anti-TNF screening.
7. Able (in the Investigators opinion) and willing to comply with all study requirement
8. Willing to allow his or her general practitioner to be notified of participation in the study
9. Sufficient language fluency to ensure informed consent is obtained and to complete the questionnaires pertaining to hand function

Part 2:
1. Aged 18 years or above
2. Participant is willing and able to give informed consent for participation in the study
3. Patients with early Dupuytren’s disease nodules who also show progression of the disease in the previous 6 months with flexion deformities of less than 30° at the metacarpophalangeal and/or at the proximal interphalangeal joint, i.e. total flexion deformity of up to 60°
4. The Dupuytren’s disease nodule to be treated must be distinct and identifiable.
5. 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).
6. Participant results from safety screening tests within normal ranges within 8 weeks of enrolment, with the exception that an earlier clear CXR result may be used where this is in accordance with the time frames of local standard procedures for anti-TNF screening.
7. Able (in the Investigators opinion) and willing to comply with all study requirement
8. Willing to allow his or her general practitioner to be notified of participation in the study
9. Sufficient language fluency to ensure informed consent is obtained and to complete the questionnaires pertaining to hand function

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Part 1: 40; Part 2: 138

Participant exclusion criteria

Part 1:
1. Participant has previously had fasciectomy, dermofasciectomy, needle fasciotomy, collagenase injection, steroid injection or radiotherapy to treat Dupuytren’s disease in the digit concerned
2. Female participant who is pregnant, lactating or planning pregnancy during the course of the study and for 5 months following last injection
3. Male participant who is planning a pregnancy during the course of the study and for 5 months following last injection
4. Significant renal or hepatic impairment
6. Scheduled elective surgery or other procedures requiring general anaesthesia during the study other than the scheduled Dupuytren’s surgery
7. Participant who has ever been diagnosed with cancer, is terminally ill or is inappropriate for placebo medication
8. Systemic inflammatory disorder such as rheumatoid arthritis or inflammatory bowel disease
9. 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
10. Participated in another research study involving an investigational medicinal product in the past 12 weeks
11. Known allergy to any anti-TNF agent
12. Have HIV or hepatitis B or C
13. Known to have an infection or history of repeated infections
14. History of Tuberculosis (TB)
15. Have Multiple Sclerosis (MS) or other demyelinating disease
16. History of local injection site reactions
17. Needle phobia
18. Have moderate or severe heart failure
19. Being treated with coumarin anticoagulants, such as warfarin
20. Have known lung fibrosis (thickening of lung tissue)
21. Being treated with concomitant biologic DMARDS
22. 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.
23. Have received parenteral steroid within the previous 6 weeks
24. Participants with epilepsy or a known allergy to tetracaine may take part in the study but will not receive Ametop gel as a local anaesthetic. Participants with a known allergy to lidocaine or prilocaine will not receive lidocaine/prilocaine cream/EMLA cream as a local anaesthetic.

Part 2:
1. Participant has previously had fasciectomy, dermofasciectomy, needle fasciotomy, collagenase injection or steroid injection to treat Dupuytren’s disease in the hand concerned
2. Female participant who is pregnant, lactating or planning pregnancy during the course of the study and for 5 months following last injection
3. Male participant who is planning a pregnancy during the course of the study and for 5 months following last injection
4. Significant renal or hepatic impairment
5. Scheduled elective surgery or other procedures requiring general anaesthesia during the study
6. Participant who has ever been diagnosed with cancer, is terminally ill or is inappropriate for placebo medication
7. Systemic inflammatory disorder such as RA or inflammatory bowel disease
8. 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
9. Participated in another research study involving an investigational medicinal product in the past 12 weeks
10. Known allergy to any anti-TNF agent
11. Have HIV or hepatitis B or C
12. Known to have an infection or history of repeated infections
13. History of Tuberculosis (TB)
14. Have Multiple Sclerosis (MS) or other demyelinating disease
15. History of local injection site reactions
16. Needle phobia
17. Have moderate or severe heart failure
19. Have known lung fibrosis (thickening of lung tissue)
20. Being treated with concomitant biologic DMARDS
21.Have received a live vaccine within the previous 4 weeks. Patients Participants may receive concurrent vaccinations but must avoid the use of live vaccines for 12 weeks after their last injection
22. Participants with epilepsy or a known allergy to tetracaine may take part in the study but will not receive Ametop gel as a local anaesthetic. Participants with a known allergy to lidocaine or prilocaine will not receive lidocaine/prilocaine cream/EMLA cream as a local anaesthetic.
23. Patients at risk of Hepatitis B infection
24. Have received parenteral steroid within the previous 6 weeks

Recruitment start date

20/10/2015

Recruitment end date

11/04/2018

Locations

Countries of recruitment

United Kingdom

Trial participating centre

St John's Hospital
Howden Road West Howden
Livingston
EH54 6PP
United Kingdom

Trial participating centre

Queen Victoria Hospital
Holtye Road
East Grinstead
RH19 3DZ
United Kingdom

Trial participating centre

Nuffield Orthopaedic Centre
Oxford University Hospitals NHS Foundation Trust Windmill Road Headington
Oxford
OX3 7HE
United Kingdom

Sponsor information

Organisation

University of Oxford

Sponsor details

Clinical Trials and Research Governance
Joint Research Office
Block 60
Churchill Hospital
Headington
Oxford
OX3 7LE
United Kingdom

Sponsor type

University/education

Website

https://www.admin.ox.ac.uk/researchsupport/contacts/rs/ctrg/

Funders

Funder type

Not defined

Funder name

Wellcome Trust

Alternative name(s)

Funding Body Type

private sector organisation

Funding Body Subtype

international

Location

United Kingdom

Funder name

Department of Health (United Kingdom)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

180 Therapeutics

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Intention to publish in peer reviewed scientific journals, present at national and international conferences, submit to regulatory authorities.
The results of part one of the study will be published in the the second quarter of 2017.
The results of part two of the study will be published in the the third quarter of 2018.

Intention to publish date

01/06/2017

Participant level data

To be made available at a later date

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes

09/11/2016: The following changes have been made to the record following an extensive protocol review: 1. The interventions and secondary outcome measures have been updated 2. The inclusion criteria "Stable dose of current regular medication for at least 4 weeks prior to study entry" has been removed from the inclusion criteria for both part one and two and having previously had radiotherapy and "Have received parenteral steroid within the previous 6 weeks" have been added to the exclusion criteria. 3. Two additional trial participating centres have been added 07/03/2016: The secondary outcome measures for part one of the study have been updated.