Efficacy and Safety of Intramuscular PDA-002 in Subjects Who Have Diabetic Foot Ulcer With and Without Peripheral Arterial Disease

Study Overview
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Brief Summary
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The PDA-002-DFU-002 trial is a Phase 2, multicenter, randomized, double blind, placebo controlled, dose range finding study. The study will enroll approximately 133 subjects in four treatment groups. The primary objective of the study is to assess the efficacy and safety of PDA-002 administered intramuscular (IM) in subjects who have DFU with and without PAD. The secondary objective is to explore potential clinical efficacy by assessing changes in vascular parameters such as Ankle-Brachial Index and Toe-Brachial Index (ABI and/or TBI), Transcutaneous oxygen measurements (TcPO2).

Official Title
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A Phase 2 Multicenter, Randomized, Doubleblind, Placebo-Controlled, Dose Range Finding Study to Evaluate the Efficacy and Safety of Intramuscular Injection of Human Placenta-derived Cells (Pda-002) in Subjects Who Have Diabetic Foot Ulcer With Peripheral Arterial Disease

Conditions
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Peripheral Arterial Disease, Diabetic Foot

Intervention / Treatment
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* Biological: 3 x 10^6 cells
* Biological: 10 x 10^6 cells
* Biological: 30 x 10^6 cells
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females, at least 18 years of age or older at the time of signing the informed consent document. Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures are conducted. Able to adhere to the study visit schedule and other protocol requirements. Diabetes mellitus Type 1 or Type 2. Diabetic foot ulcer with severity of Grade 1 (full thickness only) or Grade 2 on the Wagner Grading Scale (Appendix A) of greater than one month duration which has not adequately responded to conventional ulcer therapy with a size of at least of 1cm2 except if present on the toe. The maximum lesion size range in the index ulcer is ≤ 10cm2. The measurement of the index ulcer is to be evaluated and measured after debridement (if necessary) at the Screening Visit. If located on the plantar aspect of the foot, the index ulcer must be able to be adequately offloaded in the assessment of the investigator. No planned revascularization or amputation over the next 3 months after Screening visit, in the opinion of the Investigator. Screening should not begin until at least 14 days after a failed reperfusion intervention and at least 30 days after a successful reperfusion intervention. Subjects should be receiving appropriate medical therapy for hypertension and diabetes any other chronic medical conditions for which they require ongoing care. A female of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test prior to treatment with study therapy. In addition, sexually active FCBP must agree to use 2 of the following adequate forms of contraception methods simultaneously such as: oral, injectable, or implantable hormonal contraception; tubal ligation; IUD; barrier contraceptive with spermicide or vasectomized partner for the duration of the study and the Follow-up Period. Males (including those who have had a vasectomy) must agree to use barrier contraception (latex condoms) when engaging in reproductive sexual activity with FCBP for the duration of the study and the Follow-up Period. Exclusion Criteria: Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he or she were to participate in the study. Any condition that confounds the ability to interpret data from the study. Pregnant or lactating females. Subjects with a body mass index > 45 kg/m2 at Screening. AST (SGOT) or ALT (SGPT) > 2.5 x the upper limit of normal (ULN) at Screening. Patient on renal dialysis for abnormal kidney function. An ABI < 0.4 and or TBI < 0.3 in the leg with the index ulcer. Bilirubin level > 2 mg/dL (unless subject has known Gilbert's disease) at Screening. Untreated chronic infection or treatment of any infection with systemic antibiotics, including the ulcer site, must be free of antibiotics within 1 week prior to dosing with IP. Active osteomyelitis, infection, or cellulites at or adjacent to the index ulcer. Patients with a history of being treated for an osteomyelitis without a surgical resection. Index ulcer that has decreased or increased in size by ≥ 30% during the Screening/Run-In/ Pre-Treatment Period. Active Charcot Neuroarthropathy in the foot with the index ulcer Pain at rest due to limb ischemia. Uncontrolled hypertension (defined as diastolic blood pressure > 100 mmHg or systolic blood pressure > 180 mmHg during Screening at 2 independent measurements taken while subject is sitting and resting for at least 5 minutes). Poorly controlled diabetes mellitus (hemoglobin A1c > 12% or a screening serum glucose of ≥ 300mg/dl). Untreated proliferative retinopathy. History of malignant ventricular arrhythmia, CCS Class III-IV angina pectoris, myocardial infarction/ percutaneous coronary intervention (PCI) / coronary artery bypass graft (CABG) in the preceding 6 months prior to signing the informed consent form (ICF), pending coronary revascularization in the following 3 months, transient ischemic attack/cerebrovascular accident in the preceding 6 months, prior to signing the ICF, and/or New York Heart Association [NYHA] Stage III or IV congestive heart failure. Abnormal ECG: new right bundle branch block (BBB) ≥ 120 msec in the preceding 3 months prior to signing the ICF. Uncontrolled hypercoagulation syndrome. Life expectancy less than at 2 years at the time of signing the ICF due to concomitant illnesses. In the opinion of the Investigator, the subject is unsuitable for cellular therapy. History of malignancy within 5 years prior to signing the ICF except basal cell or squamous cell carcinoma of the skin or remote history of cancer now considered cured or positive Pap smear with subsequent negative follow-up. History of hypersensitivity to any of the components of the product formulation (including bovine or porcine products, dextran 40, and dimethyl sulfoxide [DMSO]). Subject has received an investigational agent -an agent or device not approved by the US Food and Drug Administration (FDA) for marketed use in any indication- within 90 days (or 5 half-lives, whichever is longer) prior to treatment with study therapy or planned participation in another therapeutic study prior to the completion of this study. Subject has received previous investigational gene or cell therapy.

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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 3 x 10^6 cells<br>Human Placenta Derived cells (PDA-002) administered intramuscularly (IM) on Study Days 1 and 8 | Biological: 3 x 10^6 cells<br>* 3 x 10^6 cells administered on Study Days 1 and 8<br>* Other names: PDA-002;|
| Experimental: 10 x 10^6 cells<br>10 x 10^6 Human Placenta Derived cells (PDA-002) administered intramuscularly on Study Days 1 and 8 | Biological: 10 x 10^6 cells<br>* 10 x 10^6 Human Placenta Derived cells (PDA-002) administered on Study Days 1 and 8<br>* Other names: PDA-002;|
| Experimental: 30 x 10^6 cells<br>30 x 10^6 Human Placenta Derived cells (PDA-002) administered intramuscularly on Study Days 1 and 8 | Biological: 30 x 10^6 cells<br>* 30 x 10^6 Human Placenta Derived cells (PDA-002) administered intramuscularly on Study Days 1 and 8<br>* Other names: PDA-002;|
| Placebo Comparator: Placebo<br>Identically matching placebo administered IM on Study Days 1 and 8 | Other: Placebo<br>* Identical matching placebo administered IM on Study Days 1 and 8<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete wound closure of the index ulcer | Complete wound closure is defined as closure of the index ulcer and retaining wound closure for the subsequent 4 weeks | Up to 4 months | 
| Safety (adverse events [type, frequency, and severity of AEs, and relationship of AEs to study drug], laboratory abnormalities, and hospitalizations | An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study. | Up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to ulcer closure | The time period for the index ulcer to close | Up to 6 months | 
| Ankle Brachial Index (ABI ) and Toe-Brachial Index (TBI) | ABI and TBI will be calculated by dividing the systolic blood pressure at the ankle or toe by the systolic blood pressures (Doppler technique) in the arm | Up to 6 months | 
| 50% Closure of Index Ulcer | The proportion of subjects with at least 50% closure of the index ulcer | Up to 24 months | 
| Transcutaneous oxygen | Transcutaneous oxygen measurements determine the oxygen level in tissue below the skin | Up to 6 months | 
| Time to amputation, ulcer opening closing, gangrene and infection | Time to major amputation (above the ankle) of treated leg, minor amputations, to re-opening of ulcer, time to doubling / halving of index ulcer total surface area from baseline, de novo gangrene and foot wound infection | Up to 24 months | 
| Wagner Grading Scale | The Wagner system assesses ulcer depth and the presence of osteomyelitis or gangrene by using the following grades: grade 0 (pre-or postulcerative lesion), grade 1 (partial/full thickness ulcer), grade 2 (probing to tendon or capsule), grade 3 (deep with osteitis), grade 4 (partial foot gangrene), and grade 5 (whole foot gangrene). | Up to 24 months | 
| Rutherford Criteria | The Rutherford classification is a clinical staging system for describing peripheral arterial disease. | Up to 6 months | 
| 36-item Short Form Health Survey (SF-36) | A validated measurement of health related quality of life | Up to 6 months | 
| Diabetic Foot Ulcer Scale Short Form (DFS-SF) index ulcer | A measurement of the impact of diabetic foot ulcer on a patient's quality of life. | Up to 6 months | 
| Patient Global Impression of Change in Neuropathy (PGICN) | Assessment of changes in neuropathy over time | Up to 24 months | 
| European Quality of Life: EuroQOL-5D- health utility index assessment (EQ-5D) | A standardized instrument used as a measure of health outcome | Up to 6 months | 
| Number of all ulcers | The total number of ulcers | Up to 24 months | 
| Leg rest pain score | A visual analog scale (VAS) graded from 0 (pain free) to Grade 10 (maximum pain) | Up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Peripheral Arterial Disease, Diabetic Foot