Healing Refractory Venous Ulcers: New Treatments Offer Hope

Kirsner, Robert S.; Fox, Joshua; Liu, Sophia N.

doi:10.1038/jid.2014.444

Cited by 20 publications

(12 citation statements)

References 22 publications

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“…The results reported here demonstrate that the CTD of Cx43 protein plays pivotal roles in normal chondrocyte function and cartilage structure. Some compounds such as Cx mimetic peptides with conserved homology to the cytoplasmic domains of Cx43 are being considered as candidates to improve the rate of wound repair in connective tissues [70–74]. The potential therapeutic implications of novel tissue repair compounds that modulates the CTD of Cx43 protein is an exciting and promising field for degenerative diseases such as osteoarthritis and other cartilage and bone disorders such as osteoporosis.…”

Section: Discussionmentioning

confidence: 99%

The C-terminal domain of connexin43 modulates cartilage structure via chondrocyte phenotypic changes

et al. 2016

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Chondrocytes in cartilage and bone cells population express connexin43 (Cx43) and gap junction intercellular communication (GJIC) is essential to synchronize cells for coordinated electrical, mechanical, metabolic and chemical communication in both tissues. Reduced Cx43 connectivity decreases chondrocyte differentiation and defective Cx43 causes skeletal defects. The carboxy terminal domain (CTD) of Cx43 is located in the cytoplasmic side and is key for protein functions. Here we demonstrated that chondrocytes from the CTD-deficient mice, K258stop/Cx43KO and K258stop/K258stop, have reduced GJIC, increased rates of proliferation and reduced expression of collagen type II and proteoglycans. We observed that CTD-truncated mice were significantly smaller in size. Together these results demonstrated that the deletion of the CTD negatively impacts cartilage structure and normal chondrocyte phenotype. These findings suggest that the proteolytic cleavage of the CTD under pathological conditions, such as under the activation of metalloproteinases during tissue injury or inflammation, may account for the deleterious effects of Cx43 in cartilage and bone disorders such as osteoarthritis.

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Section: Discussionmentioning

confidence: 99%

The C-terminal domain of connexin43 modulates cartilage structure via chondrocyte phenotypic changes

et al. 2016

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“…New treatment for refractory VLUs is needed. Several ongoing phase 2 trials offer promise but obstacles to development exist . New treatments will hopefully be studied with the rigor of these trials.…”

Section: Discussionmentioning

confidence: 99%

Phase 3 evaluation of HP802‐247 in the treatment of chronic venous leg ulcers

Kirsner

Vanscheidt

Keast

et al. 2016

Wound Repair Regeneration

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In 2012 we reported promising results from a phase 2 clinical trial of HP802-247, a novel spray-applied investigational treatment for chronic venous leg ulcers consisting of human, allogeneic fibroblasts and keratinocytes. We now describe phase 3 clinical testing of HP802-247, its failure to detect efficacy, and subsequent investigation into the root causes of the failure. Two randomized, controlled trials enrolled a total of 673 adult outpatients at 96 centers in North America and Europe. The primary endpoint was the proportion of ulcers with confirmed closure at the end of 12 weeks of treatment. An investigation into the root cause for the failure of HP802-247 to show efficacy in these two phase 3 trials was initiated immediately following the initial review of the North American trial results. Four hundred twenty-one patients were enrolled in the North American (HP802-247, 211; Vehicle 210) and 252 in the European (HP802-247, 131; Vehicle 121) trials. No difference in proportion of closed ulcers at week 12 was observed between treatment groups for either the North American (HP802-247, 61.1%; Vehicle 60.0%; p = 0.5896) or the European (HP802-247, 47.0%; Vehicle 50.0%; p = 0.5348) trials. Thorough investigation found no likelihood that design or execution of the trials contributed to the failure. Variability over time during the trials in the clinical response implicated the quality of the cells comprising HP802-247. Concordance between the two separate, randomized, controlled trials with distinct, nonoverlapping investigative sites and independent monitoring teams renders the possibility of a Type II error vanishingly small and provides strong credibility for the unexpected lack of efficacy observed. The most likely causative factors for the efficacy failure in phase 3 was phenotypic change in the cells (primarily keratinocytes) leading to batch to batch variability due to the age of the cell banks.

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“…Research into the use of novel cell-based therapies, such as allogenic cells and growth factors, is currently in progress. [18][19][20] Owing to their cost and associated side effects, it is thought that such therapies are unlikely to be made widely available. 18 If other treatments were able to reduce the time to healing, this would be a significant breakthrough.…”

Section: Other Therapiesmentioning

confidence: 99%

AVURT: aspirin versus placebo for the treatment of venous leg ulcers – a Phase II pilot randomised controlled trial

Tilbrook

Clark

Cook

et al. 2018

Health Technol Assess

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Background Venous leg ulcers (VLUs) are the most common cause of leg ulceration, affecting 1 in 100 adults. VLUs may take many months to heal (25% fail to heal). Estimated prevalence is between 1% and 3% of the elderly population. Compression is the mainstay of treatment and few additional therapies exist to improve healing. Two previous trials have indicated that low-dose aspirin, as an adjunct to standard care, may improve healing time, but these trials were insufficiently robust. Aspirin is an inexpensive, widely used medication but its safety and efficacy in the treatment of VLUs remains to be established. Objectives Primary objective – to assess the effects of 300 mg of aspirin (daily) versus placebo on the time to healing of the reference VLU. Secondary objectives – to assess the feasibility of leading into a larger pragmatic Phase III trial and the safety of aspirin in this population. Design A multicentred, pilot, Phase II randomised double-blind, parallel-group, placebo-controlled efficacy trial. Setting Community leg ulcer clinics or services, hospital outpatient clinics, leg ulcer clinics, tissue viability clinics and wound clinics in England, Wales and Scotland. Participants Patients aged ≥ 18 years with a chronic VLU (i.e. the VLU is > 6 weeks in duration or the patient has a history of VLU) and who are not regularly taking aspirin. Interventions 300 mg of daily oral aspirin versus placebo. All patients were offered care in accordance with Scottish Intercollegiate Guidelines Network (SIGN) guidance with multicomponent compression therapy aiming to deliver 40 mmHg at the ankle when possible. Randomisation Participants were allocated in a 1 : 1 (aspirin : placebo) ratio by the Research Pharmacy, St George’s University Hospitals NHS Foundation Trust, using a randomisation schedule generated in advance by the investigational medicinal product manufacturer. Randomisation was stratified according to ulcer size (≤ 5cm2 or > 5cm2). Main outcome measure The primary outcome was time to healing of the largest eligible ulcer (reference ulcer). Feasibility results – recruitment 27 patients were recruited from eight sites over a period of 8 months. The target of 100 patients was not achieved and two sites did not recruit. Barriers to recruitment included a short recruitment window and a large proportion of participants failing to meet the eligibility criteria. Results The average age of the 27 randomised participants (placebo, n = 13; aspirin, n = 14) was 62 years (standard deviation 13 years), and two-thirds were male (n = 18). Participants had their reference ulcer for a median of 15 months, and the median size of ulcer was 17.1 cm2. There was no evidence of a difference in time to healing of the reference ulcer between groups in an adjusted analysis for log-ulcer area and duration (hazard ratio 0.58, 95% confidence interval 0.18 to 1.85; p = 0.357). One expected, related serious adverse event was recorded for a participant in the aspirin group. Limitations The trial under-recruited because many patients did not meet the eligibility criteria. Conclusions There was no evidence that aspirin was efficacious in hastening the healing of chronic VLUs. It can be concluded that a larger Phase III (effectiveness) trial would not be feasible. Trial registration Clinical Trials.gov NCT02333123; European Clinical Trials Database (EudraCT) 2014-003979-39. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 55. See the NIHR Journals Library website for further project information.

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Healing Refractory Venous Ulcers: New Treatments Offer Hope

Cited by 20 publications

References 22 publications

The C-terminal domain of connexin43 modulates cartilage structure via chondrocyte phenotypic changes

The C-terminal domain of connexin43 modulates cartilage structure via chondrocyte phenotypic changes

Phase 3 evaluation of HP802‐247 in the treatment of chronic venous leg ulcers

AVURT: aspirin versus placebo for the treatment of venous leg ulcers – a Phase II pilot randomised controlled trial

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