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 . This clinical trial is designed to in vitro 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.

Identification of TNFR2 and IL-33 as therapeutic targets in localized fibrosis

“…Our current clinical trial for early-stage DD involves administration of adalimumab every 3 months ( 9 ). Potentially, combination therapy based on TNFR2 and IL-33 blockade may improve the efficacy of this treatment regimen, possibly permitting less frequent dosing, and at the same time avoid potential adverse effects associated with global TNF inhibition.…”

“…Common to all fibrotic diseases, the key effector cell in DD is the myofibroblast, which is responsible for the deposition, remodeling, and contraction of the excessive matrix ( 1 ) that ultimately compromises hand function. We have previously demonstrated that inhibition of tumor necrosis factor (TNF) down-regulates the myofibroblast phenotype in DD ( 7 ), and following a phase 2a dose-ranging, proof-of-efficacy study ( 8 ), we are now conducting a phase 2b clinical trial to assess the effects of TNF inhibition by injecting adalimumab into nodules of patients with progressive early-stage disease ( 9 ). Although the safety profile of TNF inhibition is well known, it has potential drawbacks, including the reactivation of latent infections such as tuberculosis.…”

Dupuytrenova kontraktura - bolest Vikinga u suvremenom svijetu

“…Nekoliko godina kasnije na temelju ovih otkrića Nanchahal i sur. provode fazu 2a dvostruko slijepe studije u kojoj procjenjuju učinak intranodularnih injekcija od 40 mg anti-TNF protutijela (adalimumaba) u ranim stadijima bolesti gdje je došlo do smanjenja prokolagena tipa 1 i alpha-SMA proteina u nodulima dva tjedna nakon injiciranja 20 . Faza istraživanja 2b objavljena 2022. godine od istih autora pokazala je da adalimumab injiciran intranodularno u tromjesečnim intervalima s ukupno četiri doze dovodi do smekšavanja nodula i regresije bolesti praćene putem ultrazvuka nakon 18 mjeseci, odnosno devet mjeseci nakon zadnje injicirane doze, a autori nastavljaju s praćenjem pacijenata kako bi nakon 10 godina mogli procijeniti učinak na fleksijsku kontrakturu i funkciju šake 21 .…”

Recent advances in the understanding of Dupuytren’s disease

“…In vitro , neutralizing antibodies to TNF resulted in downregulation of myofibroblast contractility in a dose-dependent manner 22 . These data formed the foundation for a phase 2a placebo-controlled dose-ranging trial of anti-TNF (adalimumab) 29, 30 . Direct intranodular injection of 40 mg of adalimumab in a concentrated formulation (0.4 mL) resulted in downregulation of procollagen type 1 and alpha-smooth muscle actin (α-SMA) proteins at 2 weeks post-injection 30 .…”

“…Direct intranodular injection of 40 mg of adalimumab in a concentrated formulation (0.4 mL) resulted in downregulation of procollagen type 1 and alpha-smooth muscle actin (α-SMA) proteins at 2 weeks post-injection 30 . An ongoing phase 2b trial is comparing intranodular adalimumab with placebo in patients with early-stage DD 29 . If the trial is successful, this will represent the first targeted treatment to control the progression of early-stage disease.…”