E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Critical Limb Ischemia in patients with Diabetes Mellitus |
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E.1.1.1 | Medical condition in easily understood language |
Severe obstruction of the arteries in patients with Diabetes Mellitus |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10077142 |
E.1.2 | Term | Limb ischemia |
E.1.2 | System Organ Class | 100000004866 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10058069 |
E.1.2 | Term | Critical limb ischemia |
E.1.2 | System Organ Class | 100000004866 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10012601 |
E.1.2 | Term | Diabetes mellitus |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Study Objective Trial 1
The objective of this trial is to confirm the efficacy and safety of an intra-arterial administration of Rexmyelocel-T to relief ischemic rest pain in subjects with DM and CLI Rutherford Category 4.
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
To be eligible for this trial subjects must satisfy all of the following 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 4.
These subjects must have documentation of severely compromised hemodynamics at screening defined as:
• Ankle systolic pressure < 50 mm Hg, or
• Toe systolic pressure < 30 mm Hg, or
• TcpO2 < 30 mm Hg, and
• Flat or barely pulsatile ankle or metatarsal PVR
The subject should have rest pain without tissue loss, and the rest pain must be persistent and require analgesics for at least two weeks for the subject to be eligibile. 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 poor 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.
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E.4 | Principal 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 5.
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.
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:
a. Concurrent severe congestive heart failure (New York Heart Association Classes III and IV).
b. 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.
c. Coronary artery bypass grafting or percutaneous coronary intervention within one month before screening.
d. A renal and/or carotid revascularization procedure within one month of screening.
e. Transient ischemic attack within three months prior to screening.
f. Deep vein thrombosis within three months prior to screening.
g. Subjects with immunocompromised conditions, organ transplant recipients and/or subjects in need of immunosuppressive therapy.
h. 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.
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Efficacy Endpoints Trial 1:
Change in Rutherford classification from CLI Category 4 to Category 3 or lower 12 months after administration of Rexmyelocel-T or placebo. Success is defined as complete relief of ischemic rest pain with the absence of development of ischemic lesions on the index leg.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Change in Rutherford classification from CLI Category 4 to Category 3 or lower 12 months after administration of Rexmyelocel-T or placebo |
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E.5.2 | Secondary end point(s) |
Secondary Endpoints
The following secondary endpoints at 12 months after administration of Rexmyelocel-T or placebo are defined:
• Change in Rutherford score (Categories 0-6).
• Presence of ischemic ulcers (yes/no).
• Amputation free survival (AFS).
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
12 months post administration of Rexmyelocel-T or placebo
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 37 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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LVLS
All subjects will be followed up until 24 months after the administration of Rexmyelocel-T or placebo. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 15 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |