Efficacy, Tolerability and Safety of Intramuscular Injections of PLX PAD for the Treatment of Subjects With Critical Limb Ischemia (CLI) With Minor Tissue Loss Who Are Unsuitable for Revascularization

• ClinicalTrials.gov Identifier: NCT03006770
• Recruitment Status: Active, not recruiting
• First Posted: December 30, 2016
• Last Update Posted: December 28, 2020
• Sponsor: Pluristem Ltd.
• Information provided by (Responsible Party): Pluristem Ltd.

Tracking Information

• First Submitted Date: December 27, 2016
• First Posted Date: December 30, 2016
• Last Update Posted Date: December 28, 2020
• Actual Study Start Date: May 22, 2017
• Estimated Primary Completion Date: March 2021 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: April 24, 2017): Time to major amputation or death (AFS) [ Time Frame: Up to 36 months from enrollment ]
• Original Primary Outcome Measures (submitted: December 27, 2016): Amputation Free Survival (AFS) [ Time Frame: Up to 36 months from enrollment ]

Current Secondary Outcome Measures (submitted: December 23, 2020)

• Time to first occurrence of any of the events (in index leg)-major amputation, revascularization due to worsening of CLI, All-cause mortality. [ Time Frame: Up to 36 months from enrollment ]
• Time to major amputation of the index leg. [ Time Frame: Up to 36 months from enrollment ]
• Change from baseline in ischemic pain as assessed by numerical rating scale (NRS) at 6 months. [ Time Frame: 6 months from enrollment ]
  NRS measures the intensity or magnitude of sensations and subject feelings and the relative strength of attitudes and opinions about specific stimuli, on a scale of 0 to 10 with a score of zero denoting "no pain at all" and a score of 10 denoting "worst possible pain".
• Proportion of subjects with complete healing of all ischemic lesions i.e., ulcers and necroses in the index leg at 12 months. [ Time Frame: 12 months from enrollment ]
• Time (days) from randomization to occurrence of death. [ Time Frame: Up to 36 months from enrollment ]

Original Secondary Outcome Measures (submitted: December 27, 2016)

• Time to first occurrence of any of the events (in index leg)-major amputation,revascularization due to worsening of CLI,doubling of total wound area from baseline,anew gangrene. All-cause mortality. [ Time Frame: Up to 36 months from enrollment ]
• Time to major amputation of the index leg. [ Time Frame: Up to 36 months from enrollment ]
• Complete wound healing in the index leg [ Time Frame: 12 months from enrollment ]
• Ischemic pain (NRS). [ Time Frame: 6 months from enrollment ]
• Time to adjudicated major amputation of the index leg or death [ Time Frame: Up to 36 months from enrollment ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Efficacy, Tolerability and Safety of Intramuscular Injections of PLX PAD for the Treatment of Subjects With Critical Limb Ischemia (CLI) With Minor Tissue Loss Who Are Unsuitable for Revascularization
• Official Title: Efficacy, Tolerability and Safety of Intramuscular Injections of PLX PAD for the Treatment of Subjects With Critical Limb Ischemia (CLI) With Minor Tissue Loss Who Are Unsuitable for Revascularization
• Brief Summary: This will be a randomized, placebo-controlled, parallel group, multicenter, Phase III study.The study aims to evaluate the Efficacy, Tolerability and Safety of Intramuscular Injections of PLX PAD for the Treatment of Subjects with Critical Limb Ischemia (CLI) with Minor Tissue Loss (Rutherford Category 5) who are Unsuitable for Revascularization.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Critical Limb Ischemia (CLI)

Intervention

• Biological: PLX-PAD
  Local intramuscular (IM) injections of PLX-PAD in the index leg.
• Biological: Placebo
  Local intramuscular (IM) injections of Placebo in the index leg.

Study Arms

• Experimental: PLX-PAD
  PLX-PAD will be administered via 30 IM injections (0.5 mL each). Each subject will be treated twice, with an interval of 8 weeks between treatments.
  Intervention: Biological: PLX-PAD
• Placebo Comparator: Placebo
  Placebo will be administered via 30 IM injections (0.5 mL each). Each subject will be treated twice, with an interval of 8 weeks between treatments.
  Intervention: Biological: Placebo

• Publications *: Norgren L, Weiss N, Nikol S, Hinchliffe RJ, Lantis JC, Patel MR, Reinecke H, Ofir R, Rosen Y, Peres D, Aberman Z. PLX-PAD Cell Treatment of Critical Limb Ischaemia: Rationale and Design of the PACE Trial. Eur J Vasc Endovasc Surg. 2019 Apr;57(4):538-545. doi: 10.1016/j.ejvs.2018.11.008. Epub 2019 Jan 25.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: December 23, 2020): 213
• Original Estimated Enrollment (submitted: December 27, 2016): 246
• Estimated Study Completion Date: March 2021
• Estimated Primary Completion Date: March 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Adult male or female subjects between ages 45-99 years of age.
2. CLI, with minor tissue loss up to the ankle level (Rutherford Category 5)
3. Ankle pressure (AP) ≤70 mmHg or TP ≤50 mmHg in the index leg. (If a subject has ABI >1.4 and TP is not measureable, inclusion may be based on TcPO2 ≤30 mmHg)
4. Subject unsuitable for revascularization (by any method) in the index leg.
5. Ischemic lesions in the index leg stable for at least 2 weeks.
6. Ischemic ulcers in the index leg without tendon or bone exposure (unless secondary to a minor amputation).
7. Under treatment for cardiovascular risk factors: hypertension, hyperlipidemia, diabetes, in accordance with applicable guidelines. Concomitant therapy with a statin and an anti-platelet agent for at least 2 weeks prior to randomization.
8. Women of childbearing potential must have a negative serum pregnancy test at screening and must be willing to use at least one highly effective birth control method throughout the study.
9. Subject understood, agreed and provided informed consent. Patients must give written informed consent before any assessment is performed .

Exclusion Criteria:

1. Non-atherosclerotic PAD (e.g. Buerger's disease).
2. CLI with major tissue loss (Rutherford Category 6) in either leg.
3. Evidence of active infection (e.g., cellulitis, osteomyelitis).
4. Subject having undergone surgical revascularization or major amputation less than 1 month prior to screening, or endovascular revascularization or minor amputation less than 2 weeks prior to screening.
5. Planned or potential need for major/minor amputation or any revascularization within 1 month of study entry upon investigator's judgment.
6. Aorto-iliac stenosis or common femoral artery stenosis ≥70%, or otherwise suspicion of inadequate inflow to the leg.
7. Life expectancy of less than 6 months.
8. Stroke or acute myocardial infarction/unstable angina within 3 months prior to screening.
9. Severe congestive heart failure symptoms (New York Heart Association [NYHA] class III-IV).
10. Uncontrolled severe hypertension.
11. Diabetes mellitus with HbA1c >10%.
12. Current or history of proliferative retinopathy.
13. Known Hepatitis B virus or Hepatitis C virus or acquired immunodeficiency syndrome (AIDS) infections.
14. Subjects with international normalized ratio (INR) >2.
15. Subject on renal replacement therapy or planned to start renal replacement therapy within 3 months of first screening visit.
16. Subject is currently enrolled in, or has not yet completed a period of at least 30 days since ending another investigational device or drug trial(s), unless in long-term follow-up phase.
17. Use of hyperbaric oxygen therapy, prostanoids, spinal cord stimulation, lumbar sympathectomy, wound dressing containing cells or growth factors, or topical platelet derived growth factor.
18. Known allergies to any of the following: DMSO, human serum albumin, bovine serum albumin.
19. History of allergic/hypersensitivity reaction to any substance having required hospitalization and/or treatment with IV steroids/epinephrine.
20. Pulmonary disease requiring supplemental oxygen treatment on a daily basis.
21. Active malignancy or history of malignancy within 5 years prior to study entry.
22. In the opinion of the investigator, the subject is unsuitable for participating in the study.
23. Chronic liver disease Child Pugh class B\C

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 45 Years to 99 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Bulgaria, Czechia, Germany, Hungary, Israel, North Macedonia, Poland, United Kingdom, United States
• Removed Location Countries: Austria, Macedonia, The Former Yugoslav Republic of

Administrative Information

• NCT Number: NCT03006770
• Other Study ID Numbers: PLX-CLI-03
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Pluristem Ltd.
• Original Responsible Party: Same as current
• Current Study Sponsor: Pluristem Ltd.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Pluristem Ltd.
• Verification Date: December 2020