Clinical trial NCT03174522: The Efficacy and Safety of REX-001 to Treat Ischemic Ulcers in Subjects With CLI Rutherford Category 5 and DM
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Peripheral Arterial Disease (PAD)
Diabetes Mellitus (DM)
Diabetes Mellitus, Type 1
Diabetes Mellitus, Type 2
Cardiovascular Disease
Critical Limb Ischemia (CLI)
Keywords: Autologous
Bone Marrow-derived Mononuclear Cells (BM-MNCs)
Advanced Therapy Medicinal Product (ATMP)
Tissue-engineered Medicinal Product
Revascularization
Angiogenesis
Vasculogenesis
Arteriogenesis
Lead sponsor: Ixaka Ltd
Sponsor class: INDUSTRY
Collaborators: name: Andalusian Network for Design and Translation of Advanced Therapies
First posted: 2017-06-02
Enrollment: 49
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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.

Primary outcomes:
measure: Complete healing of all ischemic ulcers on the index leg.
timeFrame: The primary endpoint for this trial will be assessed at 12 months.
Secondary outcomes:
Other outcomes:
Locations:
city: Ostrava
country: Czechia
facility: Fakultní nemocnice Ostrava
city: Pécs
country: Hungary
facility: Pécsi Tudományegyetem, PTE-KK I. sz Belgyógyászati Klinika
city: Leiden
country: Netherlands
facility: Leids Universitair Medisch Centrum
city: Maastricht
country: Netherlands
facility: Maastricht Universitair Medisch Centrum
city: Almada
country: Portugal
facility: Hospital Garcia de Orta, EPE
city: Lisboa
country: Portugal
facility: Centro Hospitalar Lisboa Norte, EPE
city: Porto
country: Portugal
facility: Centro Hospitalar de São João
city: Badalona
country: Spain
facility: Hospital Universitari Germans Trias i Pujol
state: Barcelona
city: L'Hospitalet De Llobregat
country: Spain
facility: Hospital Universitari de Bellvitge
state: Barcelona
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Cadiz
country: Spain
facility: Hospital Universitario Puerta del Mar
city: Córdoba
country: Spain
facility: First site: Hospital Universitario Reina Sofía
city: Murcia
country: Spain
facility: Hospital General Universitario Morales Meseguer
city: Málaga
country: Spain
facility: Hospital Regional Universitario
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales
Study officials:
affiliation: Ixaka Limited
name: Gilbert Wagener, MD
role: STUDY_DIRECTOR
References: