Effect of rhGM-CSF on the Healing of Venous Leg Ulcers

Study Overview
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Brief Summary
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The objective of this study is to examine whether local administration of the growth factor rhGM-CSF incorporated into a hydrogel, can accelerate wound healing when applied to venous leg ulcers, and whether this is safe.

Official Title
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Effect of Topical rhGM-CSF on the Healing of Venous Leg Ulcers: a Randomized, Placebo-controlled, Double-blind, Clinical Phase II Study

Conditions
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Venous Leg Ulcer

Intervention / Treatment
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* Drug: rhGM-CSF + hydrogel
* Drug: Placebo hydrogel
* Other: Standard care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women aged aged 18 years or older Patients with at least one difficult-to-heal venous leg ulcer on standard care (diagnosed by clinical evaluation) localized between the knee and ankle, including the perimalleolar area. Venous insufficiency confirmed by a venous Doppler/duplex ultrasound scan. A previous scan before randomization can be used. If there is no previous adequate scanning, a new scanning has to be performed before randomization. Ulcer size 2-75 cm2 at randomization day (D0), the upper limit being defined as the largest ulcer in size that fits the area selection criteria Ulcer duration ≥2 months and ≤3 years Negative p-HCG for women of childbearing potential Patient able to understand Danish Patient able to comply with the protocol Patient fully informed about the study and having given written informed consent Exclusion Criteria: Characteristics of the index ulcer: Exposed bone, tendon, ligament, cartilage, joint or muscle Cellulitis or clinical ulcer infection at the screening day D-4, or the day of randomization, D0. Ulcers adjacent to the index ulcer that could interfere with the index ulcer, as judged by investigator Patients that are unsuitable for the compression therapy used in the study Known allergy towards GM-CSF, excipients or any other substances or remedies used in the trial. Vascularization: Ankle-brachial index ≤0.7 Active or history of following diseases: Cancer (past history of well-treated cancer is however accepted after a control period of more than two years). Following autoimmune diseases: rheumatoid arthritis, autoimmune thrombocytopenia, thyroiditis, psoriasis, nephritis or multiple sclerosis. Lower extremity deep venous thrombosis within the last 3 months Any of following active diseases: Serious heart disease, including unstable angina pectoris, a major cardiac event such as myocardial infarction, congestive heart failure NYHA class III-IV within 3 months before the study Neutrophilic dermatoses (e.g. pyoderma gangrenosum and Sweet's syndrome) Severe renal-, hepatic or pulmonary insufficiency or severely dysregulated diabetes, as judged by investigator Myeloproliferative diseases and hematologic diseases (e.g. myelodysplastic syndrome and leukemia). Anemia due to chronic infection or due to deficiency of iron, B12 or folic acid is accepted if Hb >5 mmol/L). Significant dementia Biochemistry with clinically significant abnormalities that could preclude study participation as judged by the investigator, such as: eGFR <20 mL/min/1.73 m2 Hb <5 mmol/L ALAT >1.5 x upper limit of normal value Albumin < 20 g/l Prohibited therapy: Systemic immunosuppressive treatment, immunomodulators, cytotoxic chemotherapy (exception: usage of corticosteroids) on D-4 or D0. Corticosteroids with a daily dose equivalent to >10 mg of prednisolone per day on D-4 or D0. Topical corticosteroids in the index ulcer bed or within 1 cm of the ulcer edge on D-4 or D0. Biologics within 3 months of D-4 (anti-VEGF treatment in the eye in e.g. diabetics is however allowed). Weight <50 kg or BMI >50 Participation in another clinical trial Planned surgery or hospitalization during trial Pregnant or lactating woman. Positive pregnancy test during run-in. Failure to agree to using an adequate method of contraception (having a failure rate of < 1% per year) throughout the study period for heterosexually active males and females of childbearing potential, or disagreement to remain abstinent (refrain from heterosexual intercourse). A woman is considered to be of childbearing potential if she is post-menarche and: Has not reached a postmenopausal state (≥60 years of age and amenorrhea for at least ≥12 months with no identified cause other than menopause, and has not undergone surgical sterilization: removal of ovaries and/or uterus) - OR No menses for over a year and confirmed by follicle-stimulating hormone (FSH) levels elevated into the postmenopausal range Examples of contraceptive methods with a failure rate of <1% per year includes bilateral tubal ligation, male sterilization, proper use of hormonal contraceptives, hormone-releasing intrauterine devices and copper intrauterine devices. Male participants must be abstinent or use a condom during the trial period. Blood or sperm donation during trial Patient has previously been randomized in this study (rescreening is accepted otherwise) Judgment by the investigator that the patient is not suited for study participation

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A randomized, placebo-controlled and double-blind, phase II clinical trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GM-CSF<br>rhGM-CSF (molgramostim) + hydrogel | Drug: rhGM-CSF + hydrogel<br>* The active substance: molgramostim (rhGM-CSF)<br>* Other names: Molgramostim;Other: Standard care<br>* Compression therapy and neutral dressings<br>|
| Placebo Comparator: Placebo<br>Hydrogel | Drug: Placebo hydrogel<br>* Placebo hydrogel<br>Other: Standard care<br>* Compression therapy and neutral dressings<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients reaching a 40% ulcer area reduction, or more, 4 weeks after initiation of the study drug treatment/placebo | Ulcer size (area in cm2) will be assessed on the randomization day (Day 0; initiation of the study drug treatment/placebo) and at the end of the study drug/placebo treatment (D28+1) | 4 weeks after initiation of the study drug treatment/placebo | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute change of the ulcer area | The ulcer size is compared in terms of change in cm2 from the randomization day | 4 and 8 weeks after randomization | 
| Percentage change of the ulcer area | The ulcer size is compared in terms of percentage change from the randomization day | 4 and 8 weeks after randomization | 
| Complete ulcer healing | Number of subjects reaching complete ulcer healing; Full epithelization and no drainage of wound fluid or dressing requirements | 4 and 8 weeks after randomization | 
| Time to complete ulcer healing | Time to complete ulcer healing in days, with the randomization day as baseline | Through study completion (8 weeks) | 
| Clinical improvement of the wound healing process | Semi-quantitatively measured (major improvement, minor improvement, status quo or worsening) | 4 and 8 weeks after randomization | 
| Assessment of the safety profile | All clinical and laboratory adverse events will be assessed and recorded. | Throughout the trial (8 weeks) |