Efficacy and Safety of Stempeucel® in Patients With Critical Limb Ischemia (CLI) Due to Peripheral Arterial Disease

Efficacy and Safety of Stempeucel® in Patients With Critical Limb Ischemia (CLI) Due to Peripheral Arterial Disease

An Observational, Practice-Based, Open Label, Feasibility Study to Observe the Efficacy and Safety of Intramuscular Administration of Stempeucel® in Malaysian Patients With Critical Limb Ischemia (CLI) Due to Peripheral Arterial Disease.

The goal of this observational, practice-based feasibility study is to observe the efficacy and safety of intramuscular administration of Stempeucel® in Malaysian patients with critical limb ischemia (CLI) due to peripheral arterial disease. The main questions it aims to answer are: Can intramuscular administration of Stempeucel® reduce symptoms of CLI due to peripheral arterial disease while improving the healing rate and functional outcomes? Does intramuscular administration of Stempeucel® causes any serious adverse events in CLI due to peripheral arterial disease patients? Study patients will be assessed by the PI before administering the Stempeucel® for any other organ with inflammation. The study patients will also be followed up to the duration of 1 year after study treatment administration for safety and efficacy assessment.

Title: An Observational, Practice-Based, Open Label, Feasibility Study to Observe the Efficacy and Safety of Intramuscular Administration of Stempeucel® in Malaysian Patients with Critical Limb Ischemia (CLI) Due to Peripheral Arterial Disease Study Design: Single arm, practice-based, feasibility study Study Duration: Estimated duration for the main protocol (e.g. from starts of screening to last subject processed and end of the study) is approximately 18 months Study Center: Universiti Kebangsaan Malaysia Medical Centre (UKMMMC), Jalan Yaacob Latif, Bandar Tun Razak, 56000 Kuala Lumpur, Wilayah Persekutuan, Malaysia Objectives: To observe the efficacy and safety of Stempeucel® (adult human bone marrow derived, cultured, pooled, allogeneic mesenchymal stromal cells) in Malaysian patients with critical limb ischemia (CLI) due to peripheral arterial disease. Investigational Medicinal Product Description • Ex-vivo cultured allogeneic mesenchymal stem cells (MSCs) supplied in cryo-bags consisting of 150 or 200 million, suspended in 50 ml of Plasmalyte A containing 1.5% human serum albumin (HSA) and 3% dimethyl sulfoxide (DMSO). Dosage • Dosing of Stempeucel® is based on body weight. The recommended dose is 2 million cells/kg body weight. Administration • 40 - 60 injections administered as 0.6 ml/kg (200 million bag) or 0.8 ml/kg (150 million bag) intramuscularly into different points on the muscle. Additional injections of 2 ml (200 million bag) or 3 ml (150 million bag) administered around the ulcer Number of Subjects: 10 patients Data Analysis Data Management: Electronic case record form (eCRF) will be used for data entry. Oracle clinical (or other suitable alternatives with audit trail) will be used for data management. Statistical Method: The SPSS® package (IBM Inc., USA, version 22) will be used for statistical evaluation. All patients in the study with relevant efficacy and safety data will be considered for the analysis. Efficacy analysis will be done using GEE (Generalized Estimating Equations) method or paired t test as appropriate. Adverse events monitored using information voluntarily disclosed by the patients and as observed by the PI will be summarized descriptively by total number of AE(s). AEs will be categorized as: all AEs, all treatment-emergent AEs, all severe AEs, treatment-related AEs and severe treatment-related AEs. These events will be reported as appropriate and summarized.

Stempeucel® (Ex-vivo cultured MSCs) supplied in 15 ml cryo bags consisting of 200 million or 150 million MSCs, 85% PlasmaLyte-A, 5% HSA and 10% DMSO in a total volume of 15 ml. Following thawing, 35 ml of PlasmaLyte A will be added to the Stempeucel® to make a total volume of 50 ml (Refer section 6.6 IMP Preparation and Designation). The final concentration of components will be 1.5% HSA and 3% DMSO.

• Ex-vivo cultured allogeneic mesenchymal stem cells (MSCs) supplied in cryo-bags consisting of 150 or 200 million, suspended in 50 ml of Plasmalyte A containing 1.5% human serum albumin (HSA) and 3% dimethyl sulfoxide (DMSO).

Monitored and recorded as voluntarily disclosed by the patients and as observed by the Investigator throughout the study

The following lab tests will be conducted: serum chemistry, haematology, liver function test. In case of abnormal results, they shall be recorded as an adverse event or excluded from study (screening).

Urine test will be conducted. In case of abnormal results, they shall be recorded as an adverse event or excluded from study (screening).

TNF-α test will be conducted. In case of abnormal results, they shall be recorded as an adverse event or excluded from study (screening).

The following assessments will be conducted: blood pressure, heart rate, respiratory rate and temperature. In case of abnormal results, they shall be recorded as an adverse event or excluded from the study (screening).

The following examinations will be conducted: visual, heart, lungs, abdomen, nervous system, muscoskeletal system and etc. In case of abnormal conditions, they shall be recorded as an adverse event or excluded from the study (screening).

The following assessments will be conducted: 12 lead ECG recordings with long Lead II, and two-dimensional echocardiography (2D ECHO; if needed). In case of abnormal conditions, they shall be recorded as an adverse event or excluded from study (screening).

Chest x-ray will be conducted. In case of abnormal conditions, they shall be recorded as an adverse event or excluded from study (screening).

Inclusion Criteria: Patients between 18-65 years old Patients diagnosed with atherosclerotic peripheral arterial disease Patients not eligible for or have failed surgical or percutaneous revascularization (No option patients) Patients with at least one ulcer (between 0.5 to 10 cm2 size) Ankle brachial pressure index (ABPI) ≤ 0.6 (toe brachial index (TBI) if ABPI out of range; TBI ≤ 0.5) Patients who are able and willing to provide consent and agrees to comply with study procedures and follow-up evaluations Exclusion Criteria: Patients diagnosed with Buerger's disease by Shionoya criteria Patients eligible for surgical or percutaneous revascularization Patients with a history of participating in another stem cell trial or therapy within 3 months Patients who are unsuitable to participate the clinical trial as determined by investigators

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ICH Topic E 2 A: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting-(CPMP/ICH/377/95)

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