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A Study to Evaluate Safety and Efficacy of APO-2 at Three Different Doses in Patients With Diabetic Foot Ulcer

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ClinicalTrials.gov Identifier: NCT04277598
Recruitment Status : Not yet recruiting
First Posted : February 20, 2020
Last Update Posted : February 24, 2020
Sponsor:
Collaborator:
FGK Clinical Research GmbH
Information provided by (Responsible Party):
Aposcience AG

Brief Summary:
The MARSYAS II study which will be conducted in patients with diabetic foot ulcer (DFU) consists of a Lead-In Phase for safety assessment of multiple doses of the biologic investigational medicinal product (IMP) APO-2 and of a Main Phase (Phase II Study) to assess the efficacy and safety of the IMP. The phase II study will be a randomized study at multiple clinical centers and it will be double-blind meaning that neither the investigator nor the treated patient know if the IMP or a placebo is applied; the study will investigate the safety and clinical efficacy of multiple dose administrations at three dose levels of APO-2 (low dose, medium dose or high dose) compared with placebo.

Condition or disease Intervention/treatment Phase
Diabetic Foot Ulcer (DFU) Biological: APO-2 Other: Placebo Phase 1 Phase 2

Detailed Description:

APOSEC is a secretome released by cultured, stressed peripheral blood mononuclear cells (PBMC) in medium. Content analysis revealed that APOSEC harbors a myriad of proteins, exosomes, lipids, phospholipids, cholesterols as well as antimicrobial peptides. It was shown that the topical application of APOSEC mixed with a hydrogel, called APO-2, promotes/enhances wound healing.

The MARSYAS II main study will be a multinational, multicenter, randomized, double-blind, placebo-controlled, parallel group, dose-ranging phase II study to investigate the safety and clinical efficacy of multiple dose administrations at three dose levels of APO-2 compared with placebo in patients with diabetic foot ulcer (DFU).

The main study will be preceded by a safety lead-in period evaluating multiple dose safety (25 U/ml APO-2) in patients with DFU in a cohort of 12 patients randomized at a ratio of 3:1 between APO-2 and placebo at 2 to 4 study sites. The minimum duration of an individual patient in the safety lead-in period is 93 days (including screening), with a maximum of approximately 117 days.

In the main study 120 eligible patients will be randomized at a ratio of 1:1:1:1 between APO-2 (three doses) and placebo. Patients will be stratified by wound size (at least one third of patients will need to have wound size > 4 square cm), and randomly assigned to 1 of 4 treatment groups (low dose [12.5 U/ml], medium dose [25 U/ml], high dose [50 U/ml] or placebo). After randomization, patients will receive IMP three times per week during the 4-week active treatment period. 0.5 ml IMP will be applied per square cm wound surface area for each dose group.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 132 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

During Safety Lead In Phase 12 patients will be randomized to one of two study arms at a ratio of 3:1 between APO-2 and placebo.

During the Main Phase 120 patients will be randomized to one of the four study arms at a ratio of 1:1:1:1 between APO-2 (three doses) and placebo.

Masking: Double (Participant, Investigator)
Masking Description: double blind
Primary Purpose: Treatment
Official Title: A Randomized, Placebo-controlled, Double-blind Study to Evaluate Safety and Dose Dependent Clinical Efficacy of APO-2 at Three Different Doses in Patients With Diabetic Foot Ulcer
Estimated Study Start Date : February 2020
Estimated Primary Completion Date : August 2021
Estimated Study Completion Date : November 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Lead In Phase: APO-2: 25U/ml
Topical administration of APO-2, 25 U/ml; 0.5 ml per square cm wound;
Biological: APO-2
APO-2: dose adjusted gel for topical administration.

Placebo Comparator: Lead In Phase: Placebo
Topical administration of placebo; 0.5 ml per square cm wound;
Other: Placebo
Placebo gel for topical administration.

Experimental: Main Phase: APO-2: 12.5 U/ml
Topical administration of APO-2, 12.5 U/ml; 0.5 ml per square cm wound;
Biological: APO-2
APO-2: dose adjusted gel for topical administration.

Experimental: Main Phase: APO-2: 25 U/ml
Topical administration of APO-2, 25 U/ml; 0.5 ml per square cm wound;
Biological: APO-2
APO-2: dose adjusted gel for topical administration.

Experimental: Main Phase: APO-2: 50 U/ml
Topical administration of APO-2, 50 U/ml; 0.5 ml per square cm wound;
Biological: APO-2
APO-2: dose adjusted gel for topical administration.

Placebo Comparator: Main Phase: Placebo
Topical administration of placebo; 0.5 ml per square cm wound;
Other: Placebo
Placebo gel for topical administration.




Primary Outcome Measures :
  1. Wound area reduction after 4 weeks treatment with APO-2 [ Time Frame: week 4 post baseline ]
    Percentage reduction in wound area from visit 2 (baseline) at day 1 to visit 14 (end of treatment) at week 4


Secondary Outcome Measures :
  1. >50 % reduction in wound area [ Time Frame: week 4 post baseline ]
    Proportion of patients with >50 % reduction in wound area from day 1 (baseline) to week 4 (end of treatment)

  2. Wound size [ Time Frame: Day 1 and week 1,2 3,4,6,8,12 post baseline ]
    Wound size at day 1 and 1, 2, 3, 4, 6, 8 and 12 weeks after day 1

  3. Proportion of patients with complete wound closure [ Time Frame: week 4, 6, 8 and 12 post baseline ]
    Proportion of patients with complete wound closure during 12-week follow-up period

  4. Time to complete wound closure [ Time Frame: A priori specification not possible; between baseline and week 12 post baseline ]
    Time point at which complete wound closure is achieved

  5. Recurrence rate of the ulcer [ Time Frame: week 4, 6, 8 and 12 post baseline ]
    Recurrence rate of the ulcer during 12-week follow-up period

  6. Clinical assessment of peripheral neuropathy [ Time Frame: day 1 and week 4 and 12 post baseline ]
    Assessment of severity level of peripheral neuropathy using a 10 g monofilament (Semmes-Weinstein) and a standard 128 Hz tuning fork with scaling (0 = no sense, 8 = good sense)

  7. Assessment of local IMP tolerability [ Time Frame: A priori specification not possible; between baseline and week 12 post baseline ]
    Number of patients with local adverse events or serious adverse events with causal relationship to study medication

  8. Evaluation of wound pain: visual analogue scale [ Time Frame: day 1 and week 4,6, 8 and 12 post baseline ]
    Evaluation of wound pain by visual analogue scale (score of 0 cm = no pain, score of 10 cm = worst pain)

  9. Evaluation of Quality of Life: questionnaire [ Time Frame: day 1 and week 4 and 12 post baseline ]
    Evaluation of Quality of Life (QoL) using Wound QoL questionnaire. Answers to each item are coded with numbers (0='not at all' to 5='very much').



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patient is between 18 and 80 years of age
  2. Patients with Type I or Type II diabetes with a glycosylated hemoglobin (HbA1c) of ≤ 12 %, obtained at enrollment or within 30 days prior to study enrollment
  3. Patients who have a wound defined as diabetic foot ulcer present for ≥ 4 weeks
  4. Foot ulcer Wagner grade I - II or ARMSTRONG grade I-A (superficial, non-infected, non-ischemic wound not involving tendon, capsules, or bone) or II-A (non-infected, non-ischemic wound penetrating to tendon or capsule but not to the bone or joint)
  5. Estimated foot ulcer surface area between ≥ 1 cm2 and ≤ 8 cm2 as measured at day of randomization assessed using the eKARE imaging and measurement device
  6. A patient with more than one diabetic foot ulcer may be included in the study but only one ulcer will be selected for the investigational treatment based on Investigator judgment as far as the ulcer meets the inclusion criteria (the largest ulcer fitting the inclusion criteria will be selected as index ulcer)
  7. Wound area has not changed by more than 30 % between screening visit and randomization visit (at least 14 days)
  8. Adequate arterial blood perfusion (ABI [ankle brachial index] between 0.7 and 1.3 [the highest ABI measured value will be used as reference], or toe pressure > 50 mmHg, or tcPO2 > 40 mmHg) within the past 6 months
  9. Patient must adhere to off-loading of the ulcer area (in mobile patients adherence to off-loading footwear during the study is mandatory)
  10. Patient is able to give written informed consent prior to study start and to comply with the study requirements
  11. Women of childbearing potential agree using adequate birth control methods during the study

Exclusion Criteria:

  1. History of anaphylaxis, known hypersensitivity to sodium alginate, propylene glycol, methylene-blue or chicken-egg
  2. Target ulcer is over a deformity (such as Charcot deformity) that interferes with off-loading based on investigator's opinion
  3. Index wound duration of > 52 weeks without intermittent healing
  4. Clinical evidence of ulcer bed infection or patients requiring intravenous (IV) antibiotics to treat the index wound infection at time of randomization
  5. Current evidence of osteomyelitis, cellulitis, or other evidence of infection including pus drainage from the wound site, or documented history of osteomyelitis at the target wound location during the 6 months preceding the screening visit
  6. Major uncontrolled medical disorder(s) such as severe uncontrolled leg edema, concurrent medication, or other issue that renders the patient unsuitable for participation in the study, including but not limited to: comorbid condition with an estimated life expectancy of ≤ 12 months, hemoglobin A1c (Hba1c) > 12 % at screening, patients on dialysis, patients with severe pulmonary (requiring home oxygen, uncontrolled COPD Gold III/ IV) or cardiovascular conditions (heart failure NYHA IV, uncontrolled hypertension systolic BP by repeated measurement > 180 mmHg)
  7. Raynaud disease or any other severe peripheral microvascular disease, current diagnosis of vasculitis, or current diagnosis of claudication
  8. Dermatologic comorbid disease (e.g. pyoderma gangrenosum, vasculopathy or vasculitic ulcers), history of Systemic Lupus Erythematosus with elevated anti-DNA antibody titers, Buerger's disease (thromboangiitis obliterans)
  9. Patient currently treated for an active malignant disease or prior diagnosis of an active malignant disease who is disease free for less than 1 year. Treatment with anticancer therapy (chemotherapy, immunotherapy, radiotherapy, targeted therapy or gene therapy) within 3 months before the first administration of investigational product or at any time during the study.
  10. Patient with history of malignancy within the wound; history of radiation therapy to the wound region
  11. Patients who have undergone wound treatments with growth factors, dermal substitutes, or other biological therapies within the last 30 days or during the study
  12. Patients who received oral or parenteral corticosteroids, immunosuppressants, or cytotoxic agents within 30 days preceding the first study drug administration, or plan to use these medications during the study period
  13. Patients who are pregnant or breastfeeding
  14. Mental condition rendering the patient (or the patient's legally acceptable representative[s]) unable to understand the nature, scope and possible consequences of the study
  15. Patients who are incarcerated, including prisoners or patients compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness
  16. Therapy with another investigational agent within thirty days of screening, or during the study
  17. Patients who are considered by the investigator to have a significant disease, which can impact the study; patients who are considered not suitable for the study by the investigator
  18. Employee at the study site, spouse/partner or relative of any study staff (e.g. investigator, sub-investigators, or study nurse) or relationship to the sponsor

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04277598


Contacts
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Contact: Alfred Gugerell, Dr. +43 (0)1 40 400 ext 69790 alfred.gugerell@aposcience.com
Contact: Ghazaleh Gouya-Lechner, PD Dr. +43 650 4704206 ghazaleh.gouya-lechner@aposcience.com

Locations
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Austria
A.ö. Krankenhaus der Elisabethinen Klagenfurt GmbH; Abteilung für Chirurgie
Klagenfurt am Wörthersee, Austria, 9020
Contact: Christiane Dreschl, Dr.         
Kepler Universitätsklinikum Linz; Klinik für Dermatologie und Venerologie
Linz, Austria, 4021
Contact: Wolfram Hötzenecker, DDr.         
Sponsors and Collaborators
Aposcience AG
FGK Clinical Research GmbH
Investigators
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Study Director: Hendrik J Ankersmit, Univ.Prof.Dr. Aposcience AG

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Responsible Party: Aposcience AG
ClinicalTrials.gov Identifier: NCT04277598    
Other Study ID Numbers: MARSYAS II
First Posted: February 20, 2020    Key Record Dates
Last Update Posted: February 24, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Diabetic Foot
Foot Ulcer
Ulcer
Pathologic Processes
Diabetic Angiopathies
Vascular Diseases
Cardiovascular Diseases
Leg Ulcer
Skin Ulcer
Skin Diseases
Diabetes Complications
Diabetes Mellitus
Endocrine System Diseases
Diabetic Neuropathies
Foot Diseases