| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10024134 |
| E.1.2 | Term | Leg ulcer (exc varicose) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this study is to assess the safety and effectiveness of Dermagraft® in the promotion of healing of VLUs compared with conventional therapy over the course of the 16-week evaluation. |
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| E.2.2 | Secondary objectives of the trial |
| A secondary, exploratory objective will be time to healing, with healing defined as: 100% closure of the ulcer, 80% closure of the ulcer, 50% closure and 25% closure of the ulcer. Additional objectives which will be analyzed are: net percent ulcer area reduction from baseline, granulation tissue percentage, and the Cardiff Wound Impact Schedule (CWIS) Quality-of-Life (QoL) questionnaire in English speaking subjects. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject is at least 18 years old.
2. Ankle Brachial Pressure Index (ABPI)/Ankle Arm Index (AAI) is > 0.80. Calculations should be made using measurements from both posterior tibial and dorsalis pedis arteries, if possible, to minimize error. The highest ABPI/AAI value from three measurements shall apply.
3. Subject has three or fewer venous leg ulcers, located between the knee and ankle (at the level of and including, the lateral and medial malleolus). The ulcer must extend through the full thickness of the skin but must not extend to muscle, tendon or bone. The largest ulcer will be designated the index ulcer and the only one included in the study. If other ulcerations are present on the same leg they have to be more than 2 cm apart from the index ulcer. Venous disease must be confirmed by Doppler ultrasound (using a Duplex scanner such as Siemens or Philips) to demonstrate reflux of > 0.5 seconds in saphenous (great or small), calf perforators or the deep venous system. Subjects with prior venous surgery (i.e. varicose vein stripping, endovenous laser ablation) may be included if they still demonstrate significant reflux in a remaining venous segment and the ulcer continues to suffer poor healing because of venous hypertension.
4. Subject’s study ulcer (i.e. current episode of ulceration) has been present for at least one month but no more than 24 months prior to the initial screening visit, and is excluded if it has undergone 12 months of continuous high strength compression therapy over its duration.
5. Subject’s ulcer is a minimum of 2 cm2 and a maximum of 15 cm2 at the Week 0 Randomization visit.
6.Ulcer has a clean, granulating base with minimal adherent slough at the Week 0 Randomization visit. Healthy granulation tissue is noted clinically by the presence within the wound bed of brown/red tissue of uneven contour (i.e. “bumps”) that bleed easily upon light stimulation with a scalpel or curette.
7. Subjects with ulcers that are 2.80 cm2 to 21.0 cm2 at the Week -2 visit and heal (reduce in ulcer size) up to a maximum of 40% to reach 2-15 cm2 at the Week 0 Randomization visit are included. Conversely, ulcers that increase in size up to a maximum of 50% but do not exceed 15 cm2 at Week 0 may also be included in the study. The change in ulcer size will be determined using a percent area reduced formula (Appendix I) and confirmed by digital images.
8. Female subjects of childbearing potential must be willing to use acceptable methods of contraception (birth control pills, barriers, or abstinence). A pregnancy test at the Week 0 visit must be administered, and must be negative, for inclusion into the study.
9. Male subjects must be willing to use acceptable methods of contraception (barriers, or abstinence).
10. Subject understands and is willing to participate in the clinical study and can comply with weekly visits and the follow-up regimen.
11. Subject has read and signed the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved Informed Consent Form before screening procedures are undertaken. The informed consent will be used in each country and will include all the required elements. Each informed consent will be translated into all local languages for countries participating in the study and subjects will sign the informed consent in their own language.
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| E.4 | Principal exclusion criteria |
1. Subjects whose ulcers are deemed by the investigator to be caused by a medical condition other than venous insufficiency. These may include, but are not limited to: fungal ulcerations, malignant ulcerations, diabetic ulcerations, and ulcerations due to arterial insufficiency.
2. Subjects with gross morbid obesity (i.e. a Body Mass Index [BMI] > 40).
3. Subjects who suffer from acute or chronic bacterial, viral, or fungal skin diseases that could interfere with ulcer healing.
4. Subjects who have a known allergy to the components of Dermagraft (including excipients) the four-layer compression bandaging (Profore®), or who cannot tolerate fo,ur-layer compression bandaging therapy.
5. Subjects who are non-mobile (i.e. not ambulatory, or have significant impairment of their mobility), making them completely bedridden.
6. Subjects who, in the opinion of the investigator, show evidence of ulcer infection, cellulitis, and/or osteomyelitis are excluded. If clinically indicated, subjects should undergo an ulcer biopsy to rule out a carcinoma of the ulcer, as well as an ulcer culture to eliminate ulcers with infection or heavy colonization.
7. Subjects with a history of more than two weeks treatment with immuno-suppressants (including systemic corticosteroids), cytotoxic chemotherapy, or application of topical steroids to the ulcer surface within one month prior to initial screening, or who receive such medications during the screening period, or who are anticipated to require such medications during the course of the study.
8. Subjects on any investigational drug(s) within 90 days preceding randomization (i.e. Week 0); or subject or physician anticipates use of any of these therapies by the subject during the course of the study.
9. Subjects with:
(i) Severe malnutrition (i.e. BMI ≤ 18, and a serum albumin of < 2.5 g/dL).
(ii) Alcohol abuse as recorded by an average daily intake of > 4 units in females, > 5 units in males (i.e. 1 oz. of spirit, glass of wine, or can of beer).
(iii) Drug abuse as evidenced by the subject’s use of illegal drugs or prescription drugs that have not been prescribed for him/her.
10. Subjects with malignant disease not in remission for five years or more, other than superficial carcinomas of the skin that have been medically or surgically treated without evidence of metastases. Patients currently being treated for skin cancer are excluded.
11. Subjects with a history of radiation at the ulcer site.
12. Subjects with one or more medical conditions, including renal (serum creatinine >3.4 nanomol/L, BUN >44 mmol/L), hepatic (AST, ALT 3 x ULN, Total Bilirubin >3.3 nanomol/L), hematologic (Hgb <6.9 g/L, or Platelet <49 x 109 /L or WBC <1.9, or >22 x 109 /L), active auto-immune or immune diseases that, in the opinion of the Investigator, would make the subject an inappropriate candidate for this ulcer healing study.
13. Subjects with laboratory values that are flagged at Screening Visit #1 (Week -2) as “high” will have these laboratory tests repeated at Screening Visit #2 (Week -1). If the value is still flagged as “high”and in the opinion of the investigator clinically significant, the subject will be excluded from the trial. For hemoglobin, hematocrit, platelet count, and WBC, the same rules will apply if the values are flagged as “low”.
14. Subject with known history of having Acquired Immunodeficiency Syndrome (AIDS) or with a history known to be infected with Human Immunodeficiency Virus (HIV).
15. Subject has previously participated in any Dermagraft® trial.
16. Subjects with a history of bleeding disorders that, in the opinion of the Investigator, would make compliance with the protocol medically unsafe (e.g. debridement).
17. Subject’s study ulcer has been previously treated with other tissue engineered materials (e.g. Apligraf®) within the last 30 days.
18. Subjects who are unable to understand the aims and objectives of the trial.
19. Subject has any condition(s) which seriously compromises the subject's ability to complete this study, or has a known history of poor compliance with medical treatment.
20. Subjects with NYHA Class III and IV congestive heart failure (CHF), as defined by the following criteria (16):
Class I: Asymptomatic
Class II: Symptoms with moderate exertion
Class III: Symptoms with minimal exertion
Class IV: Symptoms at rest
21. Subject has uncontrolled Diabetes Mellitus, as measured by an HbA1c > 8.5.
22. Dorsal foot ulcers are excluded.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary outcome measure will be the complete healing (100% re-epithelialization, with no presence of scab or drainage) of ulcers by 16 weeks. The study will be a success if there is a statistically significant difference between treatments in the primary analysis of the primary variable (number of subjects with study ulcer healed by 16 weeks). This primary analysis will be conducted on the Intention-to-Treat (ITT) population.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Standard treatment comprising CE-marked four-layer compression bandaging therapy sourced from the EU |
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| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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