Autologous BMMNC Combined With HA Therapy for PAOD

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and efficacy of hyaluronan combined with autologous bone marrow mononuclear cells for the treatment of critical PAOD patients.

Detailed Description
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This is a multicenter, non-blinded and randomized study to evaluate the safety and efficacy of hyaluronan (HA) combined with autologous bone marrow mononuclear cells (BMMNC) therapy for critical peripheral arterial occlusive disease (PAOD) patients. A total of 30 subjects will be recruited into the study. The subjects will be randomized into 3 different arms. During the Phase I study, 9 subjects recruited while another 21 additional subjects will be recruited in Phase II after the review of DSMB and consultation of Taiwan FDA on the results of the Phase I study. Each subject will be administered 5 10 injections of RV-P1501, the number of injections depends on the size of the subject's ischemic leg. Each subject will receive treatment once. Subjects will be assigned to the treatments in random order. Evaluations including ABI, PWT/PFWT, clinical status, EF, CTA, biochemistry and hematology checked during the inclusion and exclusion evaluation, and will be taken at baseline, 1 week, 2 weeks, 4 weeks, 12 weeks, and 24 weeks after the treatment.

Official Title
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Therapeutic Angiogenesis for Peripheral Artery Occlusive Disease Using Hyaluronan Combined With Autologous Bone Marrow Cell Therapy -- Phase I/II Safety and Efficacy Study

Conditions
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Peripheral Arterial Occlusive Disease, Critical Limb Ischemia

Intervention / Treatment
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* Biological: RV-P1501


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient age ≥ 20 Patients with severe PAOD and diagnosed with Rutherford category 3, 4, or 5 Contraindication to angioplasty or bypass surgery, or post-angioplasty or bypass surgery for once but with limited or no effect. Patient without hypertension or hypertensive patient with adequate-controlled blood pressure. With signed informed consent Exclusion Criteria: Patient undergone any organ transplantation Inability to undergo bone marrow aspiration Pregnant woman Life expectancy < 1 year Cognitive impairment Active malignancy in 5 years prior to treatment Bleeding diathesis or pulmonary embolism Patient with active major cardiovascular diseases such as unstable angina, arrhythmia, heart failure, impaired cardiac function (ejection fraction < 45%), or stroke Estimated Glomerular Filtration Rate (eGFR) < 30 Glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) values higher than 80 U/L Patient with severe diabetes mellitus (HbA1C > 8%) Patient with alcohol addiction Patient with drug abuse Patient with infections or skin disease on the ischemic leg. Allergic to HA Patient whose blockage region only occurred in the femoral artery or at foot.

Ages Eligible for Study
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Minimum Age: 20 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
Interventional Model Description: RV-P1501-4: Gel-like product with 10 thousand BMMNCs in each ml of 1% hyaluronan (HA) solution RV-P1501-5: Gel-like product with 100 thousand BMMNCs in each ml of 1% hyaluronan (HA) solution RV-P1501-6: Gel-like product with 1 million BMMNCs in each ml of 1% hyaluronan (HA) solution
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RV-P1501-4<br>Gel-like product with 10 thousand BMMNCs in each ml of 1% hyaluronan (HA) solution | Biological: RV-P1501<br>* Gel-like product with BMMNCs in each ml of hyaluronan (HA) solution<br>|
| Experimental: RV-P1501-5<br>Gel-like product with 100 thousand BMMNCs in each ml of 1% hyaluronan (HA) solution | Biological: RV-P1501<br>* Gel-like product with BMMNCs in each ml of hyaluronan (HA) solution<br>|
| Experimental: RV-P1501-6<br>Gel-like product with 1 million BMMNCs in each ml of 1% hyaluronan (HA) solution | Biological: RV-P1501<br>* Gel-like product with BMMNCs in each ml of hyaluronan (HA) solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ankle Brachial Index (ABI) | The percentage change of ABI from 3 follow-ups with the baseline. | Day 0, Week 4, Week 12, Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical status (Rutherford category) | Improvement in Rutherford scale was recorded at baseline and each follow-up. | Day 0, Week 1, Week 2, Week 4, Week 12, Week 24 | 
| Level of pain at rest | Rest pain was measured using Wong-Baker FACES pain rating scale at baseline and each follow-up visit. | Day 0, Week 1, Week 2, Week 4, Week 12, Week 24 | 
| Ulcer size in cm2 | Ulcer size was assessed and measured at each follow-up interval and compared to baseline. | Day 0, Week 1, Week 2, Week 4, Week 12, Week 24 | 
| Ulcer category | Ulcer status was assessed at each follow-up interval and compared to baseline. | Day 0, Week 1, Week 2, Week 4, Week 12, Week 24 | 
| PWT/PFWT in seconds | Peak walking time and pain-free walking time was measured at baseline and compared to W4, W12 and W24 by treadmill walking tests. | Day 0, Week 4, Week 12, Week 24 | 
| Amputation free | Time to below the knee amputation of the ipsilateral leg after the treatment. | Week 1, Week 2, Week 4, Week 12, Week 24 | 
| Ejection fraction | Ejection fraction was measured by echocardiogram to record the cardiac function at W12 and W24. | Week 12, Week 24 | 
| CT angiography | CT angiography was performed to record the morphology of blood vessel, location, and the vessel cross section percentage. | Week 12, Week 24 | 
| Biochemistry | Biochemistry tests were performed to interpret the health assessment at W12 and W24. | Week 12, Week 24 | 
| Hematology | Hematology tests were performed to interpret the health assessment at W12 and W24. | Week 12, Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hyaluronan, Bone marrow mononuclear cells