Bone Marrow Derived Allogeneic Mesenchymal Stromal Cells to Non-healing Diabetic Foot Wounds

Uncontrolled Non-randomised Single Dose Study of Topically Applied Bone Marrow Derived Allogeneic Mesenchymal Stromal Cells (REDDSTAR (ORBCEL-M)) in Patients With Non-healing Neuroischaemic Diabetic Foot Wounds'

examine safety of topical application of single dose allogeneic bone marrow derived mesenchymal stromal cells to non-healing diabetic foot ulcers

1.1 Trial Phase

Phase 1b

1.2 Trial Aims and Objectives

To examine the safety of topical application of a single dose of allogeneic bone marrow derived mesenchymal stromal cells (REDDSTAR ORBCEL-M) seeded in a collagen scaffold to patients with non-healing neuroischaemic diabetic foot wounds.

1.3 Patient Population

Patients with non-healing neuroischaemic diabetic foot wounds despite standard care.

1.4 Trial Setting

Steno Diabetes Center Copenhagen, Denmark and Zelo Phase I Unit, Bispebjerg Hospital, Copenhagen, Denmark.

1.5 Trial Intervention

Topical application of allogeneic bone marrow derived mesenchymal stromal cells seeded in a collagen scaffold to patients with non-healing neuroischaemic diabetic foot wounds.

1.6 Concurrent Control

Open label, uncontrolled, non-randomised, single dose study.

1.7 Sample Size

9

1.8 Method of Participant Assignment

Administration of a single dose of allogeneic bone marrow-derived mesenchymal stromal cells seeded in a collagen scaffold.

1.9 Examination Points

0, 1 week, 2 weeks, 3 weeks, 4 weeks up until 12 weeks or until complete wound closure. After the week 12 visit, or ulcer closure, whichever occurs first, each patient will return to the clinic 1 (± 2 days), 2 (± 2 days), 4 (± 3 days), 8 (±3 days), and 12 (±3days) weeks later for follow-up visits to for adverse events, assess wound, wound closure and durability.

1.10 Primary Outcome

Serious adverse events that are attributable to intervention.

1.11 Secondary Outcomes

Time to complete wound closure (defined as from treatment day 1 to the first visit when closure is documented). Absolute and percent changes in wound area from baseline, at weekly intervals throughout. Durability of wound closure as measured at 4 week intervals for 12 weeks from date of wound closure.

Inclusion Criteria:

1. Age 18-80 years.
2. Type 1 or Type 2 diabetes mellitus (with any kind or combination of pharmacological treatment for disease and/or complications to disease).
3. HbA1c ≤ 97 mmol/mol (≤ 11%).
4. Males or non-pregnant females.
5. Understand trial information document.
6. Provide written informed consent.
7. Duration of (diabetic foot) wound > 4 but < 52 weeks.
8. Reduction of < 50% area over 4 weeks despite standard care (standard care; off-loading, weekly debridement, dressings, orthotic).
9. Wound area with sharp debridement of ≥ 0.5 but ≤ 4.0 cm2.
10. Clinically non-infected wound.
11. Texas wound stage 1a, 1c or 2a.
12. Location of wound below malleolus.
13. Affected limb toe pressure ≥ 40 mmHg.
14. An ankle-brachial systolic pressure index between 0.7 and 1.3.
15. Diagnosis of peripheral neuropathy using American Diabetes Association guidelines (monofilament/vibration sensation/biothesiometer).
16. Able to adhere to study visit protocol.
17. Adhere to offloading devices/orthotic.

Exclusion Criteria:

1. Life expectancy of less than 12 months.
2. Patients with a definite diagnosis of any immunodeficiency disorder.
3. Viral hepatitis [patient must have negative hepatitis B surface-antigen (HBsAg) and hepatitis C antibody (HepCAb) test results obtained within 2 weeks prior to the Treatment Day (Day 1)].
4. Active, uncontrolled connective tissue disease.
5. Renal failure as defined by serum creatinine > 220 µmol/L.
6. Liver function tests that are > 2.0 times Upper Limit Normal.
7. Poor nutritional status as measured by serum albumin < 30 g/L.
8. Active cancer or a history of cancer in the 5 years prior to signing the informed consent form (history of basal cell carcinoma is allowed).
9. Active wound infection (i.e. recent onset of erythema, oedema, and increased temperature of the foot with normal radiographs).
10. Diabetic Charcot neuroarthropathy or other structural deformity that would prevent adequate off-loading of the study foot.
11. Treatment with any systemic corticosteroid immunosuppressive chemotherapeutic agent, antiviral, or previous/current radiation therapy to lower extremity to be treated within 30 days prior to signing the informed consent form.
12. Having received another investigational drug or biologic within 30 days prior to signing the informed consent form or currently participating in an investigational drug or biologic study.
13. A psychiatric condition or chronic alcohol or drug abuse problem, determined from the patient's medical history, which in the Investigator's opinion may pose a threat to patient compliance.
14. History of non-compliance with treatment or clinical visit attendance (i.e. this study requires that patients will comply with the protocol and ulcer care regimen).
15. Any unstable medical condition judged by the Principal Investigator that would cause the study to be detrimental to the patient.
16. Wounds caused primarily by untreated vascular insufficiency, or where patients are primarily eligible for vascular intervention to promote wound healing.
17. Wounds with an aetiology not related to diabetes.
18. More than three wounds on the target lower extremity.
19. The wound to be studied not anatomically distinct from another wound(s) (separated by < 1 cm from another wound or would interfere with standard of care treatment of another wound. Only one single wound per one study subject can be treated in this study.
20. Wounds which decrease in area by > 50% during the screening 4-week run-in period.
21. Ulcers with underlying osteomyelitis on the leg with the wound to be treated.
22. Patients presenting with the clinical characteristics of cellulitis at the wound site (suppurative inflammation involving particularly the subcutaneous tissue, often mild erythema, tenderness, malaise, chills and fever).
23. Revascularization surgery on the leg with the wound to be treated ≤8 weeks prior to signing the informed consent form.
24. Surgery to lengthen Achilles tendon on the leg with the wound to be treated ≤8 weeks prior to signing the informed consent form.
25. Necrosis, purulence, or sinus tracts that cannot be removed by debridement on foot to be treated.
26. Received dermal substitute or living skin equivalent within 30 days prior to signing the informed consent form.
27. Received prior (Regranex®/becaplermin) therapy within 30 days prior to signing the informed consent form.
28. Has known history of clinical sensitivity reactions to products of bovine origin or to the primary or secondary dressings used in the trial.