A Multicentre European Study to Evaluate Granulox® Used in the Treatment Pathway of Predominantly Chronic Venous Leg Ulcers (VLUs).

Study Overview
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Brief Summary
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The investigation is designed as an open label, randomized, prospective, assessor blinded, multi centre investigation. 254 evaluable subjects will be randomized to either standard of care group or standard of care with Granulox added as an adjunct therapy in predominantly venous leg ulcer subjects. Standard of care wound management will be completed, including wound cleansing, debridement if necessary and application of a suitable dressing and compression system until complete wound closure. The study will be divided into two phases. Firstly, a two week run-in period to ensure compliance to compression therapy followed by a 20 weeks treatment period starting with randomization and allocation of treatment.

Detailed Description
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The current study is designed to verify previous clinical findings and to pinpoint clinically relevant efficacy, associated to intended use of Granulox® as a therapy added to a defined standard of care in the management of chronic VLUs. The most relevant outcome is considered to be an increase in healing of chronic VLUs over a period of 20 weeks. This is a multi-centre European open label randomised 2-arm parallel group study. The study will include multiple European counties (e.g. France, Germany, UK, Poland, Croatia and Czech Republic), with approximately 2-7 clinics per country. The study will run with a two-phase set-up, with a 14 days run-in period and a an up to 20 weeks treatment period starting with randomization and allocation of treatment. Confirmation of wound closure is further assessed after a 15 day followup period. The primary objective of the study is to compare wound healing between management of chronic VLUs with or without added Granulox®. The main efficacy criterion is Confirmed Complete wound Closure (CCC). Secondary objectives include comparisons of management of chronic VLUs with or without added Granulox® with regards to: Wound healing by means of Possible Complete wound Closure (PCC), Wound Area Regression (WAR), time to healing, trajectories, pressure ulcer scale for healing (PUSH) score, and clinical assessment. Patient Reported Outcomes (PRO) for health-related quality of life (HRQoL)/quality of life (QoL), pain and pain intensity, and impression of change. Acceptability of and compliance to therapy. Cost-effectiveness. Safety by means of Adverse Events (AE) and Serious Adverse Events (SAE) reporting.

Official Title
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Multicentre, Prospective, Randomized, Open-label, Assessor Blinded Study to Evaluate Granulox® Used as Adjunct Therapy to Defined Standard of Care vs. Defined Standard of Care for the Treatment of Predominantly Chronic Venous Leg Ulcers (VLUs)

Conditions
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Venous Leg Ulcer

Intervention / Treatment
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* Device: Venous Leg Ulcer Standard of Care with Granulox


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed consent to participate. No planned hospitalization in the forthcoming 20 weeks. Male or female (women of childbearing age must have an acceptable method of birth control). Age >18 years. Recent (less than 12 months) doppler or duplex colour ultrasonography compatible with chronic venous insufficiency. ABPI (less than 3 months) ≥0.7 for both legs. If ABPI >1.4, then big toe pressure >60mmHg is required or an alternative measurement verifying normal distal arterial flow. At least one or more supra- or peri-malleolar leg ulcers and no foot ulcer or another chronic wound. In case of two or more ulcers, select ulcer with the highest PUSH score at randomization and treat the non-selected ulcer in the same way as ulcers in the control group (standard of care). In case of two or more ulcers on the same limb, ensure that the distance between each ulcer is 3 cm as measured from the margins of each ulcer that are closest to one another. Wound duration ≥ 8 weeks and ≤60 months. At randomization, the ulcer area should be 3 cm2 - 70 cm² and should not have decreased by more than 30% during the 2-week run-in period. Less than 50% of the wound area should be covered with fibrinous tissue at randomization and after debridement. Patients considered as compliant/adherent to the compression device during the run-in period (i.e. no more than 2 days without compression over the 2-week run-in period). No clinically significant comorbidities requiring the use of systemic steroids or any cytotoxic or immunosuppressive agents. Exclusion Criteria: Infected ulcer according to the judgment of the investigator defined as any wound condition requiring the prescription or continuation of systemic antibiotic therapy at randomization. Circumferential wounds. Wound covered fully or partially by necrotic tissue (black tissue). Patients who will have problems following the protocol, especially compression therapy. Patients included in another on-going clinical investigation, or patients who have participated in a clinical investigation during the past 30 days. Wounds treated with dressings containing an active component (e.g. silver, nanooligosaccharide factor (NOSF), charcoal, chlorhexidine, iodine or ibuprofen) 14 days prior to study enrollment. Patient with a systemic infection not controlled by suitable antibiotic treatment. Current treatment with radiotherapy, chemotherapy, immunosuppressant drugs or high doses of oral corticosteroids (>10 mg Predinsolone or equivalent) if any. Patient with deep vein thrombosis within 3 months prior to inclusion. Known allergy/hypersensitivity to the ingredients of the dressings and/or Granulox®. Malignant wounds. Endovenous surgery planned or performed within the past 30 days. Primary lymphoedema caused by congenital/developmental defect, i.e. Milroy's disease (congenital lymphedema), Meige's disease (lymphedema praecox), or Late-onset lymphedema (lymphedema tarda).

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: Multicentre, prospective, randomized, European open label, assessor blinded, 2-arm parallel group study.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Venous Leg Ulcer Standard of Care<br>Subjects will recieve standard of care treatment. | |
| Experimental: Venous Leg Ulcer Standard of Care with Granulox<br>Subjects will recieve standard of care treatment with Granulox added as an adjunct therapy. | Device: Venous Leg Ulcer Standard of Care with Granulox<br>* Granulox will be added as an adjunct therapy to defined standard of care in subjects with predominantly venous leg ulcers.<br>* Other names: Granulox;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of complete confirmed wound closure (CCC) will be measured and compared for 254 subjects divided into standard of care versus standard of care with Granulox. | Derived by two blinded quantifications of 100% re-epithelialization by PictZar, 15 days (+/- 3 days) apart. | 20 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Healing time | Calculated from time in days from baseline to the first observation of CCC. | 20 weeks | 
| Wound status | Wound size measured, i.e. width, length, circumference or perimeter, via PictZar®. Exudate amount and nature. Tissue (i.e. fibrinous, granulation, epithelisation) type, i.e. area and percentage from total wound. Skin condition, i.e. peri-wound, redness/irritation/eczema, maceration, blistering, stripping, trauma. Local infection status, i.e. pain, perilesional skin erythema, oedema, malodour, levels of exudate. Cleansing specification. Debridement specification. | 20 weeks | 
| Wound Area Regression (WAR) | Calculated variables 90WAR (i.e. 90% WAR from baseline, based on wound photos) and 50WAR (i.e. 50% WAR from baseline, based on wound photos). | 20 weeks | 
| Rate of possible confirmed wound closure (PCC) will be measured and compared for 254 subjects divided into standard of care versus standard of care with Granulox. | derived from one measurements of 100% reepithelialization by via PictZar®. | 20 weeks | 
| Healing trajectories | Calculated progression of the re-epithelialization wave over time. | 20 weeks | 
| Pressure Ulcer Scale for Healing tool | Wound changes over time will be captured by the Pressure Ulcer Scale for Healing tool. Total score from 0 to 17 where the lower the score the better the outcome e.g when the wound has closed, score as '0' | 20 weeks | 
| Blind assessment of wound healing | Assessor-blinded clinical verification of CCC and PCC based on patient-series of wound photos assessed by independent and experienced clinicians, unaware of treatment allocation. | 20 weeks | 
| Health related Quality of Life assessment by EQ-5D-5L | Patient report outcome questionnaire to evaluate health and quality of life. The higher the score the better the outcome e.g 100 means the best health. | 20 weeks | 
| Wound specific Quality of Life assessment by Wound-QoL | Patient report outcome questionnaire to evaluate wound specific quality of life. A 5 point scale based on 17 questions of the wound in the last seven days from 'not at all' to 'very much'. The lower the score at 'not at all' the better the outcome e.g my wound hurt (not at all). | 20 weeks | 
| Numerical Rating Scale (NRS) | Patient report outcome questionnaire to evaluate pain. A total score range of 0 - 10. The lower the score the better the outcome e.g 0 is no pain. | 20 weeks | 
| Acceptability of care | Assessment of acceptability of care by means of a 5-item scale (e.g. very poor, poor, average, good, very good) where very good is a better outcome. This will be performed at the final visit only. | 20 weeks | 
| Ease of care | Assessment of ease of care by means of a 5-item scale (e.g. very poor, poor, average, good, very good) where very good is a better outcome. This will be performed at the final visit only. | 20 weeks | 
| Evaluation of patient compliant to venous compression | Evaluation will be based on a 3 point scale from fully compliance, moderately compliance or no compliance to compression therapy where fully compliance is a better outcome. Compliance to compression therapy will be defined as the following: Fully compliance (defined as 7/7 days) = continue in study Moderately compromised compliance (defined as 2 or 3 days maximum without compression) = continue in study No compliance (defined as >3 without compression) = discontinue from study | 20 weeks | 
| Cost Effectiveness | Collection of cost parameters such as micro costing and resource utilization will be made in the study. These include: Wound care consumables associated with dressings (captured both at site by investigator and in the patient specific diary by the study nurse) Frequency of dressings changes (captured both at site by investigator and in the patient specific diary by the study nurse). In addition, reporting of adverse events (i.e. infection and hospitalization) will be used as a basis for economic information together with country-specific costs. | 20 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Granulox, venous ulcers, wound healing, wound reduction