The Efficacy and Safety of REX-001 to Treat Ischemic Ulcers in Subjects With CLI Rutherford Category 5 and DM

• ClinicalTrials.gov Identifier: NCT03174522
• Recruitment Status: Terminated
• First Posted: June 2, 2017
• Last Update Posted: March 16, 2023
• Sponsor: Ixaka Ltd
• Collaborator: Andalusian Network for Design and Translation of Advanced Therapies
• Information provided by (Responsible Party): Ixaka Ltd

Study Description

Brief Summary:

This trial is a pivotal, placebo-controlled, double-blind, parallel-group, adaptive trial conducted in subjects with DM and CLI Rutherford Category 5. Minimisation will be used to assign eligible subjects in a 2:1 ratio to receive a single intra-arterial administration of REX-001 or matching placebo into the index limb.

Condition or disease	Intervention/treatment	Phase
Peripheral Arterial Disease (PAD); Diabetes Mellitus (DM); Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Cardiovascular Disease; Critical Limb Ischemia (CLI)	Drug: REX-001; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 49 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: The Efficacy and Safety of Intra-arterial Administration of REX-001 to Treat Ischemic Ulcers in Subjects With Critical Limb Ischemia (CLI) Rutherford Category 5 and Diabetes Mellitus: A Pivotal, Placebo-controlled, Double-blind, Parallel-group, Adaptive Trial
• Actual Study Start Date: April 25, 2017
• Actual Primary Completion Date: February 13, 2023
• Actual Study Completion Date: February 13, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: REX-001; REX-001 is a cell suspension of autologous bone marrow mononuclear cells (BM-MNCs) composed of several mature cell types.	Drug: REX-001; REX-001 is administered through an intra-arterial catheter.
Placebo Comparator: Placebo; The final formulation of the placebo will be a diluted suspension of red blood cells.	Drug: Placebo; Placebo is administered through an intra-arterial catheter.

Outcome Measures

Primary Outcome Measures :

1. Complete healing of all ischemic ulcers on the index leg. [ Time Frame: The primary endpoint for this trial will be assessed at 12 months. ]
   Change in Rutherford classification from CLI Category 5 to Category 4 or lower 12 months. after administration of REX-001 or placebo.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 85 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

INCLUSION CRITERIA:

1. Aged ≥ 18 to ≤ 85 years.
2. Diagnosis of Type I or II DM, established more than one year ago.
3. Glycosylated hemoglobin (HbA1c) < 9%.

4. Subjects with poor or no (surgical or endovascular) revascularization option classified as CLI Rutherford Category 5. For these patients, one of the following must be confirmed and documented at screening:

   • Ankle systolic pressure < 70 mmHg, or
   • Toe systolic pressure < 50 mmHg, or
   • TcpO2 < 30 mmHg (lying down). Subjects with non-compressible or calcified vessels must qualify on toe pressure or tcpO2.

   Poor or no revascularization option means that, in the opinion of the Investigator, revascularization using surgical or endovascular methods are not feasible due to for example the anatomy of existing vessels and/or existing comorbidity and/or previously failed surgical or endovascular revascularization.

5. In the opinion of the Investigator, the subject is controlled on medical therapy indicated for CLI (unless there is a documented contraindication or intolerance) and pain management is optimized.

6. Women of childbearing potential must have a negative pregnancy test at screening. A woman is considered of childbearing potential, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. Men and women who are sexually active shall use effective contraceptive methods for the duration of their participation in this study if the partner of the male participant, or if the female participant is of childbearing potential. Effective contraceptive methods are e.g.:

   • Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal or transdermal),
   • Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable or implantable),
   • Intrauterine device (IUD),
   • Intrauterine hormone-releasing system (IUS),
   • Bilateral tubal occlusion,
   • Vasectomised partner, or
   • Sexual abstinence. The use of this contraceptive method should be continued for at least the duration of participation in the study, and should be continued thereafter as long as indicated by the study doctor.

EXCLUSION CRITERIA:

Subjects meeting any of the following criteria must not be enrolled in the trial:

1. Advanced CLI defined as presence of major tissue loss as significant ulceration/gangrene proximal to the metatarsal heads (CLI Rutherford Category 6). Significant ulceration/gangrene means any ulceration that extends beyond the subcutaneous tissue layer, or any gangrene or tissue necrosis proximal to the metatarsal heads.
2. CLI Rutherford Category 4.
3. Uncontrolled or untreated proliferative retinopathy.
4. Failed surgical or endovascular revascularization on the index leg within 10 days after the procedure.
5. Subjects in whom arterial insufficiency in the lower extremity is the result of acute limb ischemia or an immunological or inflammatory or non-atherosclerotic disorder (e.g., thromboangiitis obliterans (Buerger's Disease), systemic sclerosis (both limited and diffuse forms).
6. Clinical evidence of invasive infection on index leg defined as major tissue loss at the mid-foot or heel involving tendon and/or bone, and/or when intravenous antibiotics are required to treat the infection according to the Investigator.
7. At screening, the presence of only neuropathic ulcers on the index leg.
8. Amputation at or above the talus on the index leg.
9. Planned major amputation within the first month after randomization.
10. On the index leg, use of concomitant wound treatments not currently approved for ischemic wound-healing within 30 days prior to screening or plans to initiate new, nonstandard-of-care treatments to the index leg during the trial.
11. Blood clotting disorder not caused by medication (e.g., thrombophilia).
12. Severe hypertension according to the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. (34)
13. A platelet count < 50,000/μL.
14. International normalized ratio (INR) > 1.5. For patients on anticoagulant medication an INR > 1.5 is allowed, provided that the Investigator and the haematologist consider the patient eligible to collect BM.
15. Evidence of moderate to severe hepatocellular dysfunction according to the treating physician.
16. Positive test for human immunodeficiency virus 1 (HIV 1), HIV 2, hepatitis B virus (HBV), hepatitis C virus (HCV) or Treponema pallidum.

17. Subjects who may not be healthy enough to successfully complete all protocol requirements including BM collection, or who are not expected to survive more than 12 months, or in whom results may be particularly difficult to assess, as assessed by the Investigator. For example:

    1. Concurrent severe congestive heart failure (New York Heart Association Classes III and IV).
    2. Life-threatening ventricular arrhythmias, unstable angina (characterized by increasingly frequent episodes with modest exertion or at rest, worsening severity, and prolonged duration), and/or myocardial infarction within four weeks before screening.
    3. Coronary artery bypass grafting or percutaneous coronary intervention within one month before screening.
    4. A renal and/or carotid revascularization procedure within one month of screening.
    5. Transient ischemic attack within three months prior to screening.
    6. Deep vein thrombosis within three months prior to screening.
    7. Subjects with immunocompromised conditions, organ transplant recipients and/or subjects in need of immunosuppressive therapy.
    8. Neurological dementia (i.e., Alzheimer's Disease).
18. Subjects who participate in another clinical interventional trial.
19. Subjects who have been treated with experimental medication within 30 days of screening.
20. Subjects who participated in other cell therapy trials for CLI.

Contacts and Locations

Locations

Czechia

Fakultní nemocnice Ostrava

Ostrava, Czechia

Hungary

Pécsi Tudományegyetem, PTE-KK I. sz Belgyógyászati Klinika

Pécs, Hungary

Netherlands

Leids Universitair Medisch Centrum

Leiden, Netherlands

Maastricht Universitair Medisch Centrum

Maastricht, Netherlands

Portugal

Hospital Garcia de Orta, EPE

Almada, Portugal

Centro Hospitalar Lisboa Norte, EPE

Lisboa, Portugal

Centro Hospitalar de São João

Porto, Portugal

Spain

Hospital Universitari Germans Trias i Pujol

Badalona, Barcelona, Spain

Hospital Universitari de Bellvitge

L'Hospitalet De Llobregat, Barcelona, Spain

Hospital Universitari Vall d'Hebron

Barcelona, Spain

Hospital Universitario Puerta del Mar

Cadiz, Spain

First site: Hospital Universitario Reina Sofía

Córdoba, Spain

Hospital General Universitario Morales Meseguer

Murcia, Spain

Hospital Regional Universitario

Málaga, Spain

United Kingdom

University Hospital of Wales

Cardiff, United Kingdom

Sponsors and Collaborators

Ixaka Ltd

Andalusian Network for Design and Translation of Advanced Therapies

Investigators

• Study Director: Gilbert Wagener, MD; Ixaka Limited

More Information

• Responsible Party: Ixaka Ltd
• ClinicalTrials.gov Identifier: NCT03174522
• Other Study ID Numbers: REX-001-005
• First Posted: June 2, 2017
• Last Update Posted: March 16, 2023
• Last Verified: March 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Ixaka Ltd:

Autologous; Bone Marrow-derived Mononuclear Cells (BM-MNCs); Advanced Therapy Medicinal Product (ATMP); Tissue-engineered Medicinal Product; Revascularization; Angiogenesis; Vasculogenesis; Arteriogenesis

Additional relevant MeSH terms:

Cardiovascular Diseases; Peripheral Arterial Disease; Peripheral Vascular Diseases; Chronic Limb-Threatening Ischemia; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetes Mellitus, Type 1; Ischemia; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Pathologic Processes; Atherosclerosis; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Autoimmune Diseases; Immune System Diseases; Chronic Disease; Disease Attributes