Efficacy and Safety of Stempeucel® in Patients With Critical Limb Ischemia (CLI) Due to Buerger's Disease

Efficacy and Safety of Stempeucel® in Patients With Critical Limb Ischemia (CLI) Due to Buerger's 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 Buerger's 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 Buerger's disease. The main questions it aims to answer are: Can intramuscular administration of Stempeucel® reduce symptoms of CLI due to Buerger's disease while improving the healing rate and functional outcomes? Does intramuscular administration of Stempeucel® causes any serious adverse events in CLI due to Buerger's 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 Buerger's 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 Buerger's 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 3 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. 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).

AE(s) will be 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 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 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: Males or females (willing to use accepted methods of contraception during the course of the study) in the age group of 18-65 years. Buerger's disease as diagnosed by Shionoya criteria Patients should have at least one ulcer (target ulcer): area between 0.5 to 10 cm2 (both inclusive) Ankle Brachial Pressure Index (ABPI) ≤ 0.6. If ABPI is ≥ 1.1 then Toe Brachial Index (TBI) will be performed and TBI should be ≤ 0.5 Patients who are able to understand the requirements of the study, and willing to provide voluntary written informed consent, abide by the study requirements, and agree to return for required follow-up visits Exclusion Criteria: Patients diagnosed with atherosclerotic peripheral arterial disease 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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