Safety and Efficacy of Allogeneic Cells for the Treatment of Intermittent Claudication(IC)

A Phase II, Randomized, Double-Blind, Multicenter, Multinational, Placebo-Controlled, Parallel- Groups Study to Evaluate the Safety and Efficacy of Intramuscular Injections of Allogeneic PLX-PAD Cells for the Treatment of Subjects With Intermittent Claudication (IC)

The objective of the study is to establish the safety profile of

Intramuscular PLX-PAD injections and to evaluate the clinical efficacy of it in IC subjects comprising of 4 treatment groups:

1. Double treatment of PLX-PAD low dose
2. Double treatment of PLX-PAD high dose
3. Double treatment of Placebo
4. Single treatment of PLX-PAD high dose and additional treatment of Placebo. Subjects will receive the assigned treatment twice to the affected leg, within 12-weeks interval between each treatment.

The study will be comprised of 5 stages:

Screening period of up to 4 weeks,first treatment of PLX-PAD or placebo followed by additional injection after 12 weeks and with follow-up of 12 months post second injection

Study Overview

• Status: Completed
• Conditions: Intermittent Claudication; Peripheral Artery Disease
• Intervention / Treatment: Biological: PLX-PAD Low dose; Biological: PLX-PAD high doses; Biological: Double Placebo; Biological: high dose +Placebo

• Study Type: Interventional
• Enrollment (Actual): 180
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Bad Krozingen, Germany, 79189
    • Universtiäts-Herzzentrum Freiburg und Bad-Krozingen
  • Berlin, Germany
    • Franziskus-Krankenhaus
  • Dresden, Germany
    • Universitätsklinikum Carl Gustav Carus
  • Hamburg, Germany
    • Asklepios Klinik St. Georg
  • Heidelberg, Germany, 69129
    • Universitätsklinik Heidelberg
  • Jena, Germany, 97747
    • Universitatsklinikum Jena
  • Karlsbad, Germany, 76307
    • SRH Klinikum Karlsbad-Langensteinbach
  • Mainz, Germany, 55131
    • Universitätsmedizin der Johannes Gutenberg-Universität Mainz
  • Münster, Germany, 48149
    • Universitatsklinikum Munster
• Israel
  • Haifa, Israel
    • "Mor" Instituite, Horev M.C
  • Holon, Israel, 58100
    • Edith Wolson Medical Center
• Korea, Republic of
  • Busan, Korea, Republic of, 602-739
    • Dr. Sungwon Chung
  • Gyeonggi-do, Korea, Republic of, 431-796
    • Dr. Weonyong Lee
  • Gyeonggi-do, Korea, Republic of, 463-712
    • Dr. Changyoung Lim
  • Seoul, Korea, Republic of, 110-746
    • Kangbuk Samsung Medical Center
  • Busan
    • Seo-gu, Busan, Korea, Republic of, 602-715
      • Dong-A University Hospital
  • Gyeonggi-do
    • Ansan, Gyeonggi-do, Korea, Republic of, 425-707
      • Korea University Ansan Hospital
    • Ilsandong-gu, Goyang-si, Gyeonggi-do, Korea, Republic of, 410-719
      • National Health Insurance Service Ilsan Hospital
    • Suwon-si, Gyeonggi-do, Korea, Republic of, 443-380
      • Ajou University Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35211
      • Cardiology, P. C. and Center for Therapeutic Angiogenesis
  • Florida
    • Clearwater, Florida, United States, 33761
      • Tampa Bay Medical Research
    • Gainesville, Florida, United States, 32605
      • Florida Researc Network, LLC
    • Pinellas Park, Florida, United States, 33782
      • DMI Research
  • Georgia
    • Evans, Georgia, United States
      • Dr. Nadarajah Janaki
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • Kentucky
    • Lexington, Kentucky, United States, 40506-0057
      • University of Kentucky Research Foundation
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Cardiovascular Division, MMC, University of Minnesota
  • New York
    • New York, New York, United States, 10029
      • Cardiovascular Institute, Mount Sinai School of Medicine
  • North Carolina
    • Durham, North Carolina, United States
      • Duke University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States
      • Dr. Mohler Emile
  • Rhode Island
    • Warwick, Rhode Island, United States, 02886
      • Omega Medical Center
  • Tennessee
    • Knoxville, Tennessee, United States, 10820
      • Turkey Creek Medical Center
  • Texas
    • San Antonio, Texas, United States, 78229
      • Clinical Trials of Texas
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College Of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adult male or female subjects between 45 to 85 years of age (inclusive) at the time of screening visit.

• Subjects with a diagnosis of peripheral artery disease, secondary to atherosclerosis, confirmed by one of the following criteria assessed at the screening visit:

  • Resting ankle-brachial index (ABI) ≤ 0.80 or
  • Resting ABI ≤ 0.90 and >20% decrease in ABI from rest to exercise when measured within 1 minute after treadmill exercise or
  • Toe-brachial index (TBI) ≤ 0.60
• Lifestyle-limiting, moderate to severe claudication (symptoms present and stable for > 6 months and not significantly changed within the past 3 months prior to screening).
• Evidence of significant (>50%) stenosis infra-inguinal occlusive disease as confirmed by documented results from Duplex, MRA, CTA and/or contrast angiogram completed within 3 months prior to screening.
• The longest maximal walking distance (MWD) from the Screening Period exercise treadmill tests (ETT), utilizing a modified Gardner Protocol (Appendix I), must be between 1 and 10 minutes (inclusive).
• Subjects who have persistent claudication symptoms despite having been recommended an exercise program if feasible, and or despite having been on a stable dose of Cilostazol, if indicated. Subjects should be Cilostazol free for at least 2 weeks prior to the first ETT.
• Subjects should be receiving standard of care drugs for vascular disease including anti-platelet agent(s) and statin medication, as well as anti-hypertensive medication(s) and oral hypoglycemic agents/insulin, if indicated.
• Signed written informed consent.

Exclusion Criteria:

• Ischemic rest pain; ulceration or gangrene (Fontaine class III-IV; Rutherford category 4-6).
• Failed lower extremity arterial reconstruction (surgical or endovascular) or sympathectomy within the prior one month of screening.
• Planned revascularization (surgical or endovascular intervention) within 12 months after screening.
• Lower extremity arteries inflow obstruction (defined as a greater than 50% stenosis of aorta, iliac and/or common femoral arteries).
• History of Buerger's disease.
• Uncontrolled hypertension (defined as diastolic blood pressure > 100 mmHg or systolic blood pressure > 180 mmHg during screening).
• Uncontrolled diabetes defined as glucose control HbA1c > 9% at screening.
• Life-threatening ventricular arrhythmia - except in subjects with an implantable cardiac-defibrillator.
• Serum Creatinine level>2.5mg/dl.
• SGPT (ALT), SGOT (AST) >2.5 x upper limit of normal range.
• Hemoglobin < 10 g/dl.
• Unstable cardiovascular disease defined as myocardial infarction (STEMI or NSTEMI) within 3 months prior to screening, or unstable angina - characterized by increasingly frequent episodes with modest exertion or at rest, worsening severity, and prolonged episodes.
• Transient Ischemic Attack (TIA)/Stroke within 3 months prior to screening.
• Subjects with severe congestive heart failure symptoms (i.e. NYHA Stage III to IV).
• Subjects with Implant of mechanical prosthetic heart valve(s).
• Pulmonary disease requiring supplemental oxygen treatment on a daily basis.
• Severe, active infection of the involved extremity(ies), including osteomyelitis, fasciitis, or severe/purulent cellulitis.
• History of malignancy within 5 years prior screening requiring chemotherapy and/or radiotherapy and/or immunotherapy, excluding basal or squamous cell carcinoma of the skin.
• Exercise is limited by any condition other than IC, including but not limited to congestive heart failure, chronic pulmonary disease, angina pectoris, or degenerative joint disease.
• Uninterrupted use of warfarin or non-steroidal anti-inflammatory agents (with the exception of ibuprofen at doses up to 1,200 mg/day or Diclofenac at dose of 75mg/day).
• Subjects who are on oral anticoagulant therapy (warfarin, dabigatran, apixaban, endoxaban and rivaroxaban). Unless, upon primary care physician and/or Investigator's discretion the subjects who are on warfarin treatment can switch to Low Molecular Weight Heparin treatment (such as: Clexane) 5-7 days prior study treatment administration and return to warfarin treatment 24 hours post study treatment administration.
• Subjects who are taking immunosuppressive treatment (including high dose steroids).
• Known allergies to protein products (Bovine serum, or recombinant trypsin) used in the cell production process.
• Known sensitivity to Gentamycin.
• Known sensitivity to antihistamine drugs.
• History of hospitalization due to allergic/hypersensitivity reaction to any substance (e.g. Food or drug).
• Medical history of Human Immunodeficiency Virus (HIV) or syphilis positivity at time of screening.
• Known active Hepatitis B, or Hepatitis C infection at the time of screening.
• Pregnant or breast-feeding women or women of childbearing age not protected by an effective contraceptive method of birth control (such as double barrier, oral or parenteral hormonal, intrauterine device and spermicide).
• In the opinion of the Investigator, the subject is unsuitable for participating in the study.
• Subject is currently enrolled in, or has not yet completed a period of at least 30 days since ending other investigational device or drug trial(s).
• Subjects that have prior exposure to gene or cell based therapy.
• Subjects who are legally detained in an official institute.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PLX-PAD Low dose; PLX-PAD double low doses	Biological: PLX-PAD Low dose
Active Comparator: PLX-PAD high doses; PLX-PAD double high dose	Biological: PLX-PAD high doses
Placebo Comparator: Placebo; Double Placebo doses	Biological: Double Placebo
Experimental: PLX-PAD high dose +Placebo; High dose+Placebo	Biological: high dose +Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Log ratio of week 52 maximal walking distance(MWD)to baseline MWD	12 months

Collaborators and Investigators

• Sponsor: Pluristem Ltd.
• Investigators: Principal Investigator: Douglas Denham, DO, Clinical Trials of Texas, Inc. 7940 Floyd Curl drive, Suite 700, San Antonio, Texas 78229; Principal Investigator: James Hampsey, MD, Tampa Bay Medical research, 3251 McMullen Booth Road, STE 303, Clearwater, FL 33761; Principal Investigator: Schulyer Jones, MD, Duke University,Durham, North Carolina, 27705, USA; Principal Investigator: Bret Weichmann, MD, Florida research Network, LLC 6800NW 9th Blvd Suite1, Gainesville, Florida 32605; Principal Investigator: Jeffrey W Olin, DO, Cardiovascular Institute, Mount Sinai School of Medicine , One Gustave L. Levy Place, New York, NY 10029; Principal Investigator: Alan T Hirsch, MD, Cardiovascular Division, MMC 508, University of Minnesota Medical school, Minneapolis, MN 55455; Principal Investigator: Sibu P. Saha, MD, University of Kentucky, Lexington, KY 40506-0057; Principal Investigator: David L Fried, MD, Omega Medical Research, Warwick, RI 02886; Principal Investigator: Berthold Amann, MD, Franziskus-Krankenhaus, Berlin Germany; Principal Investigator: Norbert Weiss, MD, Universitätsklinikum Carl Gustav Carus, Dresden, Germany; Principal Investigator: Sigrid Nikol, MD, ASKLEPIOS Klinik St. Georg, Hamburg Germany; Principal Investigator: Malcolm Foster, MD, Turkey Creek Medical Center, Knoxville TN 37934; Principal Investigator: Kathleen Cullen, MD, DMI Research, 6699 90th Ave. North, Pinellas Park FL; Principal Investigator: Mohler Emile, M.D, Hospital of the University of Pennsylvania, Philadelphia, PA 19104; Principal Investigator: Nadarajah Janaki, M.D, Aiyan Diabetes Center, Evans, GA 30809; Principal Investigator: Reuven Zimlichman, MD, Edith Wolfson Medical Center,62 HaLohamim Street, Holon, Israel; Principal Investigator: Changyoung Lim, MD, CHA Bundang Medical Center, CHA University, 59 Yatap-ro Bundang-Gu, Seongnam-Si, Gyeonggi-do 463-712, Korea; Principal Investigator: Weonyong Lee, MD, Hallym University Sacred Heart Hospital 22, Gwanpyeong-ro 170beon-gil, Dongan-gu, Anyang-si, Gyeonggi-do, 431-796, Korea; Principal Investigator: Sungwon Chung, MD, Pusan National University Hospital 179 Gudeok-Ro Seo-Gu, Busan, 602-739, Korea; Principal Investigator: Yousun Hong, MD, Ajou University School of Medicine; Principal Investigator: Jaeseung Shin, MD, Korea University; Principal Investigator: Kwangjo Cho, MD, Dong-A University Hospital; Principal Investigator: Dokyun Kim, MD, National Health Insurance Service Ilsan Hospital; Principal Investigator: Joonhyuk Kong, MD, Kangbuk Samsung Hospital; Principal Investigator: Stefan Betge, MD, Universitatsklinikum Jena; Principal Investigator: Holger Reinecke, MD, Universitatsklinikum Munster; Principal Investigator: Oliver Müller, MD, Universitätsklinik Heidelberg; Principal Investigator: Erwin Blessing, MD, Klinikum Karlsbad-Langensteinbach; Principal Investigator: Thomas Zeller, MD, Universtiäts-Herzzentrum Freiburg und Bad-Krozingen; Principal Investigator: Christine Espinola-Klein, MD, Johannes Gutenberg University Mainz

Study record dates

Study Major Dates

• Study Start: November 5, 2012
• Primary Completion (Actual): March 29, 2018
• Study Completion (Actual): February 9, 2019

Study Registration Dates

• First Submitted: September 2, 2012
• First Submitted That Met QC Criteria: September 5, 2012
• First Posted (Estimate): September 6, 2012

Study Record Updates

• Last Update Posted (Actual): February 12, 2019
• Last Update Submitted That Met QC Criteria: February 11, 2019
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Atherosclerosis; Peripheral Vascular Diseases; Peripheral Arterial Disease; Intermittent Claudication
• Other Study ID Numbers: PLX 1204-01