Study protocol: A multi-centre, double blind, randomised, placebo-controlled, parallel group, phase II trial (RIDD) to determine the efficacy of intra-nodular injection of anti-TNF to control disease progression in early Dupuytren’s disease, with an embedded dose response study.

Abstract

Dupuytren’s disease is a common fibrotic condition of the hand affecting 4% of the population and causes the fingers to curl irreversibly into the palm. It has a strong familial tendency, there is no approved treatment for early stage disease, and patients with established digital contractures are most commonly treated by surgery. This is associated with prolonged recovery, and less invasive techniques have high recurrence rates. The myofibroblasts, the cells responsible for the excessive matrix deposition and contraction, are aggregated in nodules. Using excised diseased and control human tissue, we found that immune cells interspersed amongst the myofibroblasts secrete cytokines. Of these, only tumour necrosis factor (TNF) promoted the development of myofibroblasts. The clinically approved anti-TNF agents led to inhibition of the myofibroblast phenotype in vitro. This clinical trial is designed to assess the efficacy of the anti-TNF agent adalimumab on participants with early disease. The first part is a dose-ranging study where nodules of participants already scheduled for surgery will be injected with either placebo (saline) or varying doses of adalimumab. The excised tissue will then be analysed for markers of myofibroblast activity. The second part of the study will recruit participants with early stage disease. They will be randomised 1: 1 to receive either adalimumab or placebo at 3 month intervals over 1 year and will then be followed for a further 6 months. Outcome measures will include nodule hardness, size and disease progression. The trial will also determine the cost-effectiveness of adalimumb treatment for this group of participants.

Anti-Tumour Necrosis Factor Therapy for Dupuytren's Disease: A Randomised Dose Response Proof of Concept Phase 2a Clinical Trial

“…This phase 2a randomised trial shows that a single intranodular injection of 40 mg adalimumab in 0.4 ml in patients with Dupuytren's disease is safe and leads to down regulation of the myofibroblast phenotype as evidenced by reduced expression of α-SMA and type I procollagen proteins. Having defined the most efficacious dose and preparation and based on these positive proof of concept data we are now proceeding with a phase 2b trial in 138 patients with early stage Dupuytren's disease randomised 1:1 to receive 4 injections of adalimumab or placebo at 3 month intervals and followed for a total of 18 months from baseline [ 21 ]. Our study also illustrates the utility of using early stage fibrotic human tissue to elucidate novel therapeutic targets [ 18 ] that can be translated to the clinic.…”

“…Repurposing anti-TNF for Dupuytren's disease (RIDD) is a two-part phase 2 randomised, double-blinded placebo-controlled dose response study to assess the efficacy of local injection of adalimumab in patients with DD. The protocol was reviewed by the South Central Oxford B Research Ethics Committee (Reference number 15/SC/0259) and the Medicine and Healthcare products Regulatory Authority (EudraCT no: 2015-001780-40) and has been published [ 21 ] (details of subsequent amendments in appendix). The phase 2a dose escalation study reported here was performed at a single centre in the UK at the Edinburgh Department of Plastic Surgery at St John's Hospital, NHS Lothian.…”

A Genome-wide Association Study of Dupuytren Disease Reveals 17 Additional Variants Implicated in Fibrosis

“… 4 Additionally, because DD is associated with other forms of fibrosis, it may serve as an ideal human model system for fibrotic disease, and the routine excision of tissue as a part of treatment facilitates experimental medicine studies. 5 …”

Erosive Arthritis, Fibromatosis, and Keloids: A Rare Dermatoarthropathy

“…Laboratory studies have shown the inhibitory effects of TNFi in Dupuytren's contracture by inhibiting myofibroblast activity and the contractile apparatus [ 17 ]. A phase II clinical trial will assess the role of intralesional adalimumab in early Dupuytren's contracture [ 18 ]. Thus, TNFi could possibly help address both the musculoskeletal and dermatological manifestations.…”