Clinical trial NCT01679990: Safety and Efficacy of Allogeneic Cells for the Treatment of Intermittent Claudication(IC)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Intermittent Claudication
Peripheral Artery Disease
Lead sponsor: Pluristem Ltd.
Sponsor class: INDUSTRY
First posted: 2012-09-06
Enrollment: 180
Sex: ALL
Minimum age (years): 45
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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


Eligibility criteria: 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.

Primary outcomes:
measure: Log ratio of week 52 maximal walking distance(MWD)to baseline MWD
timeFrame: 12 months
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Cardiology, P. C. and Center for Therapeutic Angiogenesis
state: Alabama
city: Clearwater
country: United States
facility: Tampa Bay Medical Research
state: Florida
city: Gainesville
country: United States
facility: Florida Researc Network, LLC
state: Florida
city: Pinellas Park
country: United States
facility: DMI Research
state: Florida
city: Evans
country: United States
facility: Dr. Nadarajah Janaki
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Lexington
country: United States
facility: University of Kentucky Research Foundation
state: Kentucky
city: Minneapolis
country: United States
facility: Cardiovascular Division, MMC, University of Minnesota
state: Minnesota
city: New York
country: United States
facility: Cardiovascular Institute, Mount Sinai School of Medicine
state: New York
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Philadelphia
country: United States
facility: Dr. Mohler Emile
state: Pennsylvania
city: Warwick
country: United States
facility: Omega Medical Center
state: Rhode Island
city: Knoxville
country: United States
facility: Turkey Creek Medical Center
state: Tennessee
city: San Antonio
country: United States
facility: Clinical Trials of Texas
state: Texas
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Bad Krozingen
country: Germany
facility: Universtiäts-Herzzentrum Freiburg und Bad-Krozingen
city: Berlin
country: Germany
facility: Franziskus-Krankenhaus
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus
city: Hamburg
country: Germany
facility: ASKLEPIOS Klinik St. Georg
city: Heidelberg
country: Germany
facility: Universitätsklinik Heidelberg
city: Jena
country: Germany
facility: Universitätsklinikum Jena
city: Karlsbad
country: Germany
facility: SRH Klinikum Karlsbad-Langensteinbach
city: Mainz
country: Germany
facility: Universitätsmedizin der Johannes Gutenberg-Universität Mainz
city: Münster
country: Germany
facility: Universitätsklinikum Münster
city: Haifa
country: Israel
facility: "Mor" Instituite, Horev M.C
city: Holon
country: Israel
facility: Edith Wolson Medical Center
city: Seo-gu
country: Korea, Republic of
facility: Dong-A University Hospital
state: Busan
city: Ansan
country: Korea, Republic of
facility: Korea University Ansan Hospital
state: Gyeonggi-do
city: Ilsandong-gu, Goyang-si
country: Korea, Republic of
facility: National Health Insurance Service Ilsan Hospital
state: Gyeonggi-do
city: Suwon-si
country: Korea, Republic of
facility: Ajou University Hospital
state: Gyeonggi-do
city: Busan
country: Korea, Republic of
facility: Dr. Sungwon Chung
city: Gyeonggi-do
country: Korea, Republic of
facility: Dr. Weonyong Lee
city: Gyeonggi-do
country: Korea, Republic of
facility: Dr. Changyoung Lim
city: Seoul
country: Korea, Republic of
facility: Kangbuk Samsung Medical Center
Study officials:
affiliation: Clinical Trials of Texas, Inc. 7940 Floyd Curl drive, Suite 700, San Antonio, Texas 78229
name: Douglas Denham, DO
role: PRINCIPAL_INVESTIGATOR
affiliation: Tampa Bay Medical research, 3251 McMullen Booth Road, STE 303, Clearwater, FL 33761
name: James Hampsey, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Duke University,Durham, North Carolina, 27705, USA
name: Schulyer Jones, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Florida research Network, LLC 6800NW 9th Blvd Suite1, Gainesville, Florida 32605
name: Bret Weichmann, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Cardiovascular Institute, Mount Sinai School of Medicine , One Gustave L. Levy Place, New York, NY 10029
name: Jeffrey W Olin, DO
role: PRINCIPAL_INVESTIGATOR
affiliation: Cardiovascular Division, MMC 508, University of Minnesota Medical school, Minneapolis, MN 55455
name: Alan T Hirsch, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Kentucky, Lexington, KY 40506-0057
name: Sibu P. Saha, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Omega Medical Research, Warwick, RI 02886
name: David L Fried, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Franziskus-Krankenhaus, Berlin Germany
name: Berthold Amann, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Universitätsklinikum Carl Gustav Carus, Dresden, Germany
name: Norbert Weiss, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: ASKLEPIOS Klinik St. Georg, Hamburg Germany
name: Sigrid Nikol, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Turkey Creek Medical Center, Knoxville TN 37934
name: Malcolm Foster, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: DMI Research, 6699 90th Ave. North, Pinellas Park FL
name: Kathleen Cullen, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital of the University of Pennsylvania, Philadelphia, PA 19104
name: Mohler Emile, M.D
role: PRINCIPAL_INVESTIGATOR
affiliation: Aiyan Diabetes Center, Evans, GA 30809
name: Nadarajah Janaki, M.D
role: PRINCIPAL_INVESTIGATOR
affiliation: Edith Wolfson Medical Center,62 HaLohamim Street, Holon, Israel
name: Reuven Zimlichman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: CHA Bundang Medical Center, CHA University, 59 Yatap-ro Bundang-Gu, Seongnam-Si, Gyeonggi-do 463-712, Korea
name: Changyoung Lim, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hallym University Sacred Heart Hospital 22, Gwanpyeong-ro 170beon-gil, Dongan-gu, Anyang-si, Gyeonggi-do, 431-796, Korea
name: Weonyong Lee, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Pusan National University Hospital 179 Gudeok-Ro Seo-Gu, Busan, 602-739, Korea
name: Sungwon Chung, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Ajou University School of Medicine
name: Yousun Hong, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Korea University
name: Jaeseung Shin, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Dong-A University Hospital
name: Kwangjo Cho, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: National Health Insurance Service Ilsan Hospital
name: Dokyun Kim, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Kangbuk Samsung Hospital
name: Joonhyuk Kong, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Jena University Hospital
name: Stefan Betge, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Universitätsklinikum Münster
name: Holger Reinecke, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Universitätsklinik Heidelberg
name: Oliver Müller, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Klinikum Karlsbad-Langensteinbach
name: Erwin Blessing, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Universtiäts-Herzzentrum Freiburg und Bad-Krozingen
name: Thomas Zeller, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Johannes Gutenberg University Mainz
name: Christine Espinola-Klein, MD
role: PRINCIPAL_INVESTIGATOR
References: