Study of treatments for pyoderma gangrenosum

ISRCTN	ISRCTN35898459
DOI	https://doi.org/10.1186/ISRCTN35898459
EudraCT/CTIS number	2008-008291-14
Secondary identifying numbers	UKDCTN0901

Submission date: 02/04/2009
Registration date: 26/05/2009
Last edited: 06/02/2017

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Skin and Connective Tissue Diseases

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Background and study aims
Pyoderma gangrenosum is a rare skin disease. It causes painful, rapidly spreading ulcers on the skin, and can take many months to heal. Although there are different medications available to treat pyoderma gangrenosum, there is no information on which of these is best to use. The two most commonly prescribed tablet (oral) medications for pyoderma gangrenosum are ciclosporin and prednisolone. This study compares these treatments head-to-head to find out whether one works better than the other, and the likely side effects of treatment.

Who can participate?
Patients aged 18 or over who have been diagnosed with pyoderma gangrenosum and have a measurable ulceration (e.g. not pustular pyoderma gangrenosum).

What does the study involve?
Participants are randomly allocated to receive either oral prednisolone or oral ciclosporin. Scheduled clinic visits take place at week 0, week 2, week 6 and after 6 months of treatment (or sooner if the ulcer has healed). Ulcer healing is assessed using digital images of the ulcer by a clinician unaware of the treatment allocation.

What are the possible benefits and risks of participating?
Both ciclosporin and prednisolone cause side effects in some people. It is not known whether one medication will be better (more effective) than the other, as that is what our study is looking at.

Where is the study run from?
The trial is being managed through the Nottingham Clinical Trials Unit at the University of Nottingham (UK).

When is the study starting and how long is it expected to run for?
Recruitment is taking place over a four-year period, starting April 2009, in approximately 50 hospitals across the UK.

Who is funding the study?
National Institute for Health Research (NIHR) (UK)

Who is the main contact?
Prof. Hywel Williams
hywel.williams@nottingham.ac.uk

Study website

Contact information

Prof Hywel Williams
Scientific

University of Nottingham
Centre of Evidence Based Dermatology
King's Meadow Campus
Lenton Lane
Nottingham
NG7 2NR
United Kingdom

ORCID ID	0000-0002-5646-3093
Phone	+44 (0)115 8230489
Email	hywel.williams@nottingham.ac.uk

Study information

Study design	Multicentre parallel-group single-blind randomised controlled trial with a parallel observational study
Primary study design	Interventional
Secondary study design	Randomised parallel trial
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	http://www.nottingham.ac.uk/~mszstop/docs/participantinfosheetv3_200309.pdf
Scientific title	Randomised controlled trial of treatments for pyoderma gangrensoum
Study acronym	STOP GAP
Study objectives	Pyoderma gangrenosum (PG) is a mutilating, very painful skin disease that often affects people with an underlying internal disease (such as inflammatory bowel disease, monoclonal gammopathy and rheumatoid arthritis). It starts as a reddish purple bump in the skin that develops into a large, deep, spreading ulcer in a matter of days. People with PG are often misdiagnosed, and spend a long time in hospital waiting for the affected areas to heal (ulcers can last for a variable time on average healing after 3 - 4 months). Patients are not able to work, require daily dressings, have a high need for health care resources, and have very poor quality of life. Patients often have repeat episodes of PG and may have multiple lesions. Treatment of PG usually involves immunosuppression or immunomodulation. The purpose of this trial is to evaluate the efficacy and safety of the two most commonly used systemic treatments for pyoderma gangrenosum (PG). The study aims to test the hypothesis that systemic ciclosporin (4 mg/kg/day) is more effective than systemic prednisolone (0.75 mg/kg/day) for oral therapy of PG. The hypothesis is that ciclosporin gains control of PG more rapidly, and reduces the time to healing for patients with PG compared to treatment with oral prednisolone.
Ethics approval(s)	The Northern and Yorkshire Research Ethics Committee, 15/02/2009, ref: 09/H0903/5
Health condition(s) or problem(s) studied	Pyoderma gangrenosum (PG)
Intervention	Patients entered into the RCT will be randomised to prednisolone (0.75 mg/kg/day) or ciclosporin (4 mg/kg/day), up to a ceiling dose of 75 mg/day prednisolone and 400 mg/day ciclosporin. Patients entered into the observational study will be prescribed topical therapy. Participants will be treated for up to 6 months during the trial and followed up until the end of the trial.
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Phase IV
Drug / device / biological / vaccine name(s)	Ciclosporin, prednisolone
Primary outcome measure	Velocity of healing at 6 weeks. This will be captured for a single target lesion per patient and measured using digital photography and vascular endothelial volume (VEV) computerised planimetry. If multiple lesions are present, the target lesion should be the lesion that is most able to be photographed on a single plane (i.e., not around the curvature of a limb) for study will be the largest of those present. Digital images will be taken at baseline, 6 weeks and when the ulcer has healed (maximum of 6 months). In addition, maximum longitudinal length and maximum perpendicular width will be measured in order to provide some measure of improvement in case of difficulties with the digital images. This will be converted to approximate area by the formula: length x width x 0.785, which approximates to an ellipse for the purpose of randomisation and analysis.
Secondary outcome measures	1. Time to healing - assessed by participants (estimated to the nearest week) based on the time at which sterile dressings are no longer required for the wound. Healing will be confirmed using digital photography at the first opportunity. Information will be provided to participants with instructions on how to report healing of the ulcer. Lesions that remain unhealed after 6 months will be considered to be treatment failures. Time to healing is a more clinically relevant outcome than velocity of healing. It also gives some indication of duration of treatment, which therefore gives an indication of cumulative drug toxicity. 2. Global assessment of improvement (PG specific) - as assessed by the clinician and the patient at 2 weeks, 6 weeks and at 6 months (or healed). This will also be assessed on the digital images by an independent assessor. 3. Inflammation assessment scale - combination scale including erythema, border elevation and exudate based on a scale reported by Foss et al. Assessed at baseline, 2 weeks, 6 weeks and when the ulcer has healed (maximum 6 months). Assessed by the clinician, patient and assessed on digital images. 4. Self-reported pain - assessed daily in diaries for the first 6 weeks 5. Impact on health-related quality of life - assessed at baseline, 6 weeks and 6 months (or healed), using a dermatology specific tool 'Dermatology Life Quality Index', and a general utility measure, the 'EQ-5D' 6. Time to recurrence in each treatment group at the end of the trial. A recurrence is defined as being a repeat episode of PG (at any site) that appears after the lesion has been confirmed as being healed by a physician (or nurse). Self-reported healing that has not been confirmed by a medical professional, and which subsequently recurs, will not be classed as a recurrence and handled as a continuation of the initial episode. 7. Number of treatment failures - treatment failures are defined as being participants who withdraw (or are withdrawn) from their randomised treatment because of treatment intolerance or worsening of the PG, or those who continue to have any unhealed ulcers after 6 months of follow-up 8. Adverse reactions to study medications - adverse events that are classed as possibly, probably or definitely relating to the study medication 9. Cost-effectiveness of the compared treatments
Overall study start date	01/04/2009
Completion date	31/08/2013

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Both
Target number of participants	140
Key inclusion criteria	1. PG as diagnosed by the recruiting dermatologist. An ulcerative lesion may have mixed aetiology, but provided the investigator has confidence that a clinical diagnosis of PG is appropriate then they are eligible. Other contributing factors and atypical features will be captured in the case report form. 2. Must have a measurable ulceration (e.g., not pustular pyoderma gangrenosum) 3. Age over 18 years, either sex 4. Able to provide written, informed consent
Key exclusion criteria	Patients cannot participate in either arms of the trial if they have any of the following: 1. Granulomatous PG - this condition is very rare and may respond differently to treatment 2. Concomitant ciclosporin, prednisolone or intravenous immunoglobulin (IVIG) therapy in the previous month 3. Already participating in another clinical trial Exclusions for the randomised controlled trial only are as follows: 4. Pregnant, lactating or at risk of pregnancy 5. Hypersensitivity to prednisolone or ciclosporin 6. Biopsy not consistent with PG 7. Clinically significant renal impairment that would result in the investigator not normally treating with either study drug 8. Any pre-treatment investigations, the results of which would prompt the investigator not to use either study drug 9. A diagnosis of malignancy or pre-malignant disease where treatments might interfere with ongoing therapy or might cause harm (e.g., history of lymphoma, cervical epithelial neoplasia [CIN], systemic cytotoxic therapy) 10. The patient has a concurrent medical condition that means the investigator would not normally treat the patient with either of the study drugs (for example: a degree of hypertension that would not lead to using either of the study drugs, advanced heart failure, poorly-controlled diabetes, history of peptic ulcer, malignancy in previous years) 11. Administration of a live vaccine (bacillus calmette-guerin [BCG], measles, mumps, rubella, yellow fever, oral polio, oral typhoid) within the last 2 weeks
Date of first enrolment	08/06/2009
Date of final enrolment	31/08/2013

Locations

Countries of recruitment

England
United Kingdom

Study participating centres

University of Nottingham

Nottingham
NG7 2NR
United Kingdom

Approximately 50 hospitals across the UK

-
United Kingdom

Sponsor information

Nottingham University Hospitals NHS Trust (UK)
Hospital/treatment centre

Research & Innovation
Nottingham Integrated Clinical Research Centre
C Floor, South Block
Queen's Medical Centre Campus
Nottingham
NG7 2UH
England
United Kingdom

Phone	+44 (0)115 924 49924
Email	brian.thomson@nuh.ac.uk
Website	http://www.qmc.nhs.uk/
"ROR"	https://ror.org/05y3qh794

Funders

Funder type

Government

National Institute for Health Research (NIHR) (UK) - Programme Grant for Applied Research (PGfAR) (ref: RP-PG-0407-10177): awarded to the Centre of Evidence Based Dermatology at the University of Nottingham

No information available

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
Publication and dissemination plan	Not provided at time of registration
IPD sharing plan

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Protocol article	protocol	28/04/2012		Yes	No
Results article	results	12/06/2015		Yes	No
Results article	results	02/02/2017		Yes	No
HRA research summary			28/06/2023	No	No

Editorial Notes

06/02/2017: Publication reference added.