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

Primary Purpose

Diabetic Foot Ulcer (DFU)

Status
Active
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
APO-2
Placebo
Sponsored by
Aposcience AG
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Diabetic Foot Ulcer (DFU)

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 ≥ 0.8 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 measured on the leg with treated wound (ABI [ankle brachial index] ≥0.5 [the lowest ABI measured value will be used as reference], or toe pressure > 40 mmHg, or tcPO2 > 40 mmHg) within the past 6 months including patients with mild to moderate peripheral arterial disease (Fontaine Stage I and II)
  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 > 3 years 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 8 weeks 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

7a. Patients with PAD who

  • have not been assessed by vascular imaging as per standard of care or
  • have acute peripheral artery occlusion of the index extremity or
  • have PAD Fontaine Stage III and IV or
  • have PAD with planned revascularization during the upcoming 6 months or
  • had Angioplasty for re-perfusion in the lower extremity with target ulcer during 3 months preceding the screening visit

    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

Sites / Locations

  • LKH-Universitätsklinikum Graz; Klinische Abteilung für Plastische, Ästhetische und Rekonstruktive Chirurgie
  • Medizinische Universität Innsbruck; Univ.-Klinik für Gefäßchirurgie
  • A.ö. Krankenhaus der Elisabethinen Klagenfurt GmbH; Abteilung für Chirurgie
  • Kepler Universitätsklinikum Linz; Klinik für Dermatologie und Venerologie
  • Clinic Hietzing; Wiener Gesundheitsverbund
  • Klinikum Wels-Grieskirchen; Abteilung für Haut- und Geschlechtskrankheiten
  • University hospital at St. Anny; Fakultní nemocnice u sv. Anny
  • University hospital Vinohrady
  • Central military hospital - Military university hospital Prague
  • Masaryk hospital in Usti nad Labem
  • Universitätsklinikum Essen, Klinik für Endokrinologie und Stoffwechselerkrankungen
  • Podos clinic
  • Pracownia Badań Klinicznych Salus
  • NZOZ "Mikomed"

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Placebo Comparator

Experimental

Experimental

Experimental

Placebo Comparator

Arm Label

Lead In Phase: APO-2: 25U/ml

Lead In Phase: Placebo

Main Phase: APO-2: 12.5 U/ml

Main Phase: APO-2: 25 U/ml

Main Phase: APO-2: 50 U/ml

Main Phase: Placebo

Arm Description

Topical administration of APO-2, 25 U/ml; Approximalety 0.5 ml per square cm wound;

Topical administration of placebo; Approximalety 0.5 ml per square cm wound;

Topical administration of APO-2, 12.5 U/ml; Approximalety 0.5 ml per square cm wound;

Topical administration of APO-2, 25 U/ml; Approximalety 0.5 ml per square cm wound;

Topical administration of APO-2, 50 U/ml; Approximalety 0.5 ml per square cm wound;

Topical administration of placebo; Approximalety 0.5 ml per square cm wound;

Outcomes

Primary Outcome Measures

Wound area reduction after 4 weeks treatment with APO-2
Percentage reduction in wound area from visit 2 (baseline) at day 1 to visit 14 (end of treatment) at week 4

Secondary Outcome Measures

>50 % reduction in wound area
Proportion of patients with >50 % reduction in wound area from day 1 (baseline) to week 4 (end of treatment)
Wound size
Wound size at day 1 and 1, 2, 3, 4, 6, 8 and 12 weeks after day 1
Proportion of patients with complete wound closure
Proportion of patients with complete wound closure during 12-week follow-up period
Time to complete wound closure
Time point at which complete wound closure is achieved
Recurrence rate of the ulcer
Recurrence rate of the ulcer during 12-week follow-up period
Clinical assessment of peripheral neuropathy
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)
Assessment of local IMP tolerability
Number of patients with local adverse events with causal relationship to study medication or serious adverse events with causal relationship to study medication
Evaluation of wound pain: visual analogue scale
Evaluation of wound pain by visual analogue scale (score of 0 cm = no pain, score of 10 cm = worst pain)
Evaluation of Quality of Life: questionnaire
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').

Full Information

First Posted
February 18, 2020
Last Updated
October 4, 2023
Sponsor
Aposcience AG
Collaborators
FGK Clinical Research GmbH
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1. Study Identification

Unique Protocol Identification Number
NCT04277598
Brief Title
A Study to Evaluate Safety and Efficacy of APO-2 at Three Different Doses in Patients With Diabetic Foot Ulcer
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
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
October 9, 2020 (Actual)
Primary Completion Date
December 2023 (Anticipated)
Study Completion Date
December 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Aposcience AG
Collaborators
FGK Clinical Research GmbH

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.
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 20% 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diabetic Foot Ulcer (DFU)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
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 108 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
ParticipantInvestigator
Masking Description
double blind
Allocation
Randomized
Enrollment
159 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Lead In Phase: APO-2: 25U/ml
Arm Type
Experimental
Arm Description
Topical administration of APO-2, 25 U/ml; Approximalety 0.5 ml per square cm wound;
Arm Title
Lead In Phase: Placebo
Arm Type
Placebo Comparator
Arm Description
Topical administration of placebo; Approximalety 0.5 ml per square cm wound;
Arm Title
Main Phase: APO-2: 12.5 U/ml
Arm Type
Experimental
Arm Description
Topical administration of APO-2, 12.5 U/ml; Approximalety 0.5 ml per square cm wound;
Arm Title
Main Phase: APO-2: 25 U/ml
Arm Type
Experimental
Arm Description
Topical administration of APO-2, 25 U/ml; Approximalety 0.5 ml per square cm wound;
Arm Title
Main Phase: APO-2: 50 U/ml
Arm Type
Experimental
Arm Description
Topical administration of APO-2, 50 U/ml; Approximalety 0.5 ml per square cm wound;
Arm Title
Main Phase: Placebo
Arm Type
Placebo Comparator
Arm Description
Topical administration of placebo; Approximalety 0.5 ml per square cm wound;
Intervention Type
Biological
Intervention Name(s)
APO-2
Intervention Description
APO-2: dose adjusted gel for topical administration.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Placebo gel for topical administration.
Primary Outcome Measure Information:
Title
Wound area reduction after 4 weeks treatment with APO-2
Description
Percentage reduction in wound area from visit 2 (baseline) at day 1 to visit 14 (end of treatment) at week 4
Time Frame
week 4 post baseline
Secondary Outcome Measure Information:
Title
>50 % reduction in wound area
Description
Proportion of patients with >50 % reduction in wound area from day 1 (baseline) to week 4 (end of treatment)
Time Frame
week 4 post baseline
Title
Wound size
Description
Wound size at day 1 and 1, 2, 3, 4, 6, 8 and 12 weeks after day 1
Time Frame
Day 1 and week 1,2 3,4,6,8,12 post baseline
Title
Proportion of patients with complete wound closure
Description
Proportion of patients with complete wound closure during 12-week follow-up period
Time Frame
week 4, 6, 8 and 12 post baseline
Title
Time to complete wound closure
Description
Time point at which complete wound closure is achieved
Time Frame
A priori specification not possible; between baseline and week 12 post baseline
Title
Recurrence rate of the ulcer
Description
Recurrence rate of the ulcer during 12-week follow-up period
Time Frame
week 4, 6, 8 and 12 post baseline
Title
Clinical assessment of peripheral neuropathy
Description
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)
Time Frame
day 1 and week 4 and 12 post baseline
Title
Assessment of local IMP tolerability
Description
Number of patients with local adverse events with causal relationship to study medication or serious adverse events with causal relationship to study medication
Time Frame
A priori specification not possible; between baseline and week 12 post baseline
Title
Evaluation of wound pain: visual analogue scale
Description
Evaluation of wound pain by visual analogue scale (score of 0 cm = no pain, score of 10 cm = worst pain)
Time Frame
day 1 and week 4,6, 8 and 12 post baseline
Title
Evaluation of Quality of Life: questionnaire
Description
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').
Time Frame
day 1 and week 4 and 12 post baseline

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patient is between 18 and 80 years of age 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 Patients who have a wound defined as diabetic foot ulcer present for ≥ 4 weeks 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) Estimated foot ulcer surface area between ≥ 0.8 cm2 and ≤ 8 cm2 as measured at day of randomization assessed using the eKare imaging and measurement device 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) Wound area has not changed by more than 30 % between screening visit and randomization visit (at least 14 days) Adequate arterial blood perfusion measured on the leg with treated wound (ABI [ankle brachial index] ≥0.5 [the lowest ABI measured value will be used as reference], or toe pressure > 40 mmHg, or tcPO2 > 40 mmHg) within the past 6 months including patients with mild to moderate peripheral arterial disease (Fontaine Stage I and II) Patient must adhere to off-loading of the ulcer area (in mobile patients adherence to off-loading footwear during the study is mandatory) Patient is able to give written informed consent prior to study start and to comply with the study requirements Women of childbearing potential agree using adequate birth control methods during the study Exclusion Criteria: History of anaphylaxis, known hypersensitivity to sodium alginate, propylene glycol, methylene-blue or chicken-egg Target ulcer is over a deformity (such as Charcot deformity) that interferes with off-loading based on investigator's opinion Index wound duration of > 3 years without intermittent healing Clinical evidence of ulcer bed infection or patients requiring intravenous (IV) antibiotics to treat the index wound infection at time of randomization 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 8 weeks preceding the screening visit 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) Raynaud disease or any other severe peripheral microvascular disease, current diagnosis of vasculitis 7a. Patients with PAD who have not been assessed by vascular imaging as per standard of care or have acute peripheral artery occlusion of the index extremity or have PAD Fontaine Stage III and IV or have PAD with planned revascularization during the upcoming 6 months or had Angioplasty for re-perfusion in the lower extremity with target ulcer during 3 months preceding the screening visit 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Hendrik J Ankersmit, Univ.Prof.Dr.
Organizational Affiliation
Aposcience AG
Official's Role
Study Director
Facility Information:
Facility Name
LKH-Universitätsklinikum Graz; Klinische Abteilung für Plastische, Ästhetische und Rekonstruktive Chirurgie
City
Graz
ZIP/Postal Code
8036
Country
Austria
Facility Name
Medizinische Universität Innsbruck; Univ.-Klinik für Gefäßchirurgie
City
Innsbruck
ZIP/Postal Code
6020
Country
Austria
Facility Name
A.ö. Krankenhaus der Elisabethinen Klagenfurt GmbH; Abteilung für Chirurgie
City
Klagenfurt am Wörthersee
ZIP/Postal Code
9020
Country
Austria
Facility Name
Kepler Universitätsklinikum Linz; Klinik für Dermatologie und Venerologie
City
Linz
ZIP/Postal Code
4021
Country
Austria
Facility Name
Clinic Hietzing; Wiener Gesundheitsverbund
City
Vienna
ZIP/Postal Code
1130
Country
Austria
Facility Name
Klinikum Wels-Grieskirchen; Abteilung für Haut- und Geschlechtskrankheiten
City
Wels
ZIP/Postal Code
4600
Country
Austria
Facility Name
University hospital at St. Anny; Fakultní nemocnice u sv. Anny
City
Brno
ZIP/Postal Code
65691
Country
Czechia
Facility Name
University hospital Vinohrady
City
Prague 10
ZIP/Postal Code
100 34
Country
Czechia
Facility Name
Central military hospital - Military university hospital Prague
City
Prague 6
ZIP/Postal Code
169 02
Country
Czechia
Facility Name
Masaryk hospital in Usti nad Labem
City
Ústí Nad Labem
ZIP/Postal Code
401 13
Country
Czechia
Facility Name
Universitätsklinikum Essen, Klinik für Endokrinologie und Stoffwechselerkrankungen
City
Essen
ZIP/Postal Code
45147
Country
Germany
Facility Name
Podos clinic
City
Warsaw
ZIP/Postal Code
02-541
Country
Poland
Facility Name
Pracownia Badań Klinicznych Salus
City
Wrocław
ZIP/Postal Code
50570
Country
Poland
Facility Name
NZOZ "Mikomed"
City
Łódź
ZIP/Postal Code
94-238
Country
Poland

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
33407796
Citation
Gugerell A, Gouya-Lechner G, Hofbauer H, Laggner M, Trautinger F, Almer G, Peterbauer-Scherb A, Seibold M, Hoetzenecker W, Dreschl C, Mildner M, Ankersmit HJ. Safety and clinical efficacy of the secretome of stressed peripheral blood mononuclear cells in patients with diabetic foot ulcer-study protocol of the randomized, placebo-controlled, double-blind, multicenter, international phase II clinical trial MARSYAS II. Trials. 2021 Jan 6;22(1):10. doi: 10.1186/s13063-020-04948-1.
Results Reference
derived

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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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