Pyoderma Gangrenosum Study (STOP GAP)

The STOP GAP study consisted of two separate clinical studies – a randomised controlled trial of tablet treatments for pyoderma gangrenosum, and a prospective observational study looking at treatment response in patients treated with creams and ointments.

In the STOP GAP randomised controlled trial, the two most commonly used tablet treatments for pyoderma gangrenosum were tested:

• Prednisolone tablets (0.75mg per kg per day, to a maximum dose of 75mg/day)
• Ciclosporin tablets (4mg per kg per day, to a maximum dose of 400 mg/day)

In the study of creams and ointments, patients used many different treatments, but the most commonly used ones were potent topical corticosteroids (usually clobetosol propionate 0.05%) or calcineurin inhibitors (tacrolimus 0.03% or 0.1%).

Fifty three UK hospitals took part in the study. In total, 121 patients were recruited into the randomised controlled trial, and 66 were recruited into the observational study; making these the largest clinical trials of pyoderma gangrenosum ever done.

Participants in the randomised controlled trial were randomised to receive either prednisolone tablets or ciclosporin tablets, and were followed up for a period of six months. Participants were seen by a dermatologist at the start of the trial, after 2 weeks, 6 weeks and 6 months (or sooner if the ulcer had healed).

Both participants and their doctors knew which treatment they had received and so improvement in the pyoderma gangrenosum was assessed using digital photographs of the ulcer. This meant that the treatment response could be assessed in an unbiased way by investigators who did not know which treatment the participants had received. The two most important outcomes were velocity of healing at 6 weeks and time taken for the ulcer to heal.

Participants in the observational study were not allocated to specific treatments. If they were not suitable (or unwilling to take) tablet treatments, then their doctor prescribed whatever cream or ointment that was felt to be most suitable for that patient. Participants were then followed up in the same way with hospital clinic visits at 2 weeks, 6 weeks and 6 months.

We found no difference between ciclosporin and prednisolone in the speed of healing over 6 weeks, with very narrow confidence intervals: adjusted mean difference 0.00 cm ² /day (95% CI: -0.20, 0.21; p = 0.975). Similarly, there was no difference in the median time to healing: 134 days for ciclosporin compared to 112 days for prednisolone (p=0.84). In both groups, fewer than 50% of ulcers had healed by 6 months, and almost 30% of participants had a recurrence of their pyoderma gangrenosum after initial healing.

Approximately two-thirds of patients experienced adverse reactions, with more serious infections occurring in the prednisolone group and more hypertension and renal dysfunction occurring with ciclosporin. Forty (67.8%) of participants in the ciclosporin group and 35 (66%) in the prednisolone group experienced at least one adverse reaction.

Overall, there were no between group differences for any of the collected outcomes measures.

The primary outcome of speed of healing was assessed using digital images of the ulcers and measuring the size of the ulcers at the start of the trial compared to the size after 6 weeks of treatment. This was felt to be the best measure of treatment success for the STOP GAP trial  as it could be assessed by assessors who did not know what treatment the patient had received (which was important for a trial like this in which the patients and doctors knew what treatments the patients received); because its collection at 6 weeks meant that most people could be included in the analysis; and because previous work in venous leg ulcer patients suggests that speed of healing is a good indicator of subsequent healing. Nevertheless, time to healing of the ulcer was also very important and was included as a secondary outcome. 

The STOP GAP trial found no difference between ciclosporin and prednisolone in the speed of healing over 6 weeks and in the median time to healing. In both groups, fewer than 50% of ulcers had healed by 6 months, and almost 30% of participants had a recurrence of their pyoderma gangrenosum after initial healing.

These results are important as they suggest that clinicians can choose to prescribe either ciclosporin or prednisolone for their patients, with the knowledge that they are likely to be of comparable efficacy.

This means that shared treatment decisions can be made on an individual basis—informed by patient preference and the side-effect profiles of the two drugs.

It is reassuring to know that a bigger trial is unlikely to have shown different results. The confidence intervals around the primary outcome were narrow, suggesting that a clinically meaningful difference between the two interventions is unlikely to have been missed in error.

In a blog in the BMJ following the publication of the STOP GAP trial results, Richard Lehman commented:

"This is the kind of trial we yearn to see. No pharma funding, using cheap old drugs, answering an important clinical question, designed with patients, pragmatic in that it allowed dose adjustment but valid in that it used blinded assessment. More of these, oh many more please."