E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Limb Threatening 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 | 21.1 |
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 | 24.0 |
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 | 20.0 |
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 |
The objective of this trial is to confirm the efficacy and safety of an intra-arterial administration of REX-001 to treat ischaemic ulcers in subjects with CLTI Rutherford Category 5 and DM.
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E.2.2 | Secondary objectives of the trial |
Study Endpoints Primary Efficacy Endpoint Change in Rutherford classification from CLTI Category 5 to Category 4 or lower 12 months after administration of REX-001 or the placebo product (hereafter referred to as Placebo). Success is defined as complete healing of all ischaemic ulcers on the index leg.
Secondary Endpoints The following secondary endpoints at 12 months after administration of REX-001 or Placebo are defined: • Change in Rutherford classification from CLTI Category 5 to Category 3 or lower. • Change from Baseline to Visit 9 (12 months) in TcpO2 • Partial healing of ischaemic ulcers (≥ 50% reduction in size as compared to ulcer size at baseline). • Amputation free survival (AFS).
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Aged ≥ 18 to ≤ 85 years. 2. Diagnosis of Type I or II DM, established more than one year ago. 3. Glycosylated haemoglobin (HbA1c) < 9%. 4. Subjects with poor or no (surgical or endovascular) revascularization option classified as CLTI Rutherford Category 5. The blood circulation in these subjects must be compromised at screening, and can be defined as: • 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, existing comorbidity and/or previously failed surgical or endovascular revascularization. IMPORTANT: All three pressures measurements must be performed and only one may be used to meet this criteria 5. In the opinion of the Investigator, the subject is controlled on medical therapy indicated for CLTI (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. Examples of effective contraceptive methods are: • Combined (oestrogen 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 any contraceptive method should be continued for at least the time the subject participates in the trial, and should be continued thereafter as long as indicated by the Investigator.
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E.4 | Principal exclusion criteria |
1. Advanced CLTI defined as presence of major tissue loss, i.e., significant ulceration/gangrene proximal to the metatarsal heads (CLTI 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. CLTI Rutherford Category 4. 3. Uncontrolled or untreated proliferative retinopathy (this refers to signs of neovascularization or impaired visual acuity due to retinal oedema for which the patient is not receiving appropriate treatment at the time of enrolment; or if the condition of retinopathy is concluded to be refractory to treatment). 4. Failed surgical or endovascular revascularization on the index leg within 10 days prior to screening 5. Subjects in whom arterial insufficiency in the lower extremity is the result of acute limb ischaemia or an immunological or inflammatory or non-atherosclerotic disorder (e.g., thromboangiitis obliterans (Buerger’s Disease), or 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 ischaemic wound-healing within 30 days prior to screening or plans to initiate new treatments (not standard of care) 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 (stage 2 hypertension: Systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg)(16). 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 Investigator . (Subject’s ALT should not exceed >2.5 times that of the normal ALT level) 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 ischaemic 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 were treated with other cell therapies for CLTI within the last 12 months preceding the screening visit.
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E.5 End points |
E.5.1 | Primary end point(s) |
Study Endpoints Primary Endpoint Change in Rutherford classification from CLTI Category 5 to Category 4 or lower 12 months after administration of REX-001 or Placebo. Success is defined as complete healing of all ischaemic ulcers on the index leg. A blinded independent adjudication committee (IAC) will confirm the eligibility of all subjects before a subject is randomized. The IAC will also interpret clinical and haemodynamic data to confirm the Rutherford Category of PAD of each subject at the baseline visit (Visit 3), at six months (Visit 7) and at 12 months (Visit 9) after administration of REX-001 or Placebo. Lastly, if the primary endpoint is met, the IAC will also confirm the Rutherford Category of PAD of each subject at 18 and 24 months.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Change in Rutherford classification from CLTI Category 5 to Category 4 or lower 12 months after administration of REX-001 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 REX-001 or Placebo are defined: • Change in Rutherford classification from CLTI Category 5 to Category 3 or lower. • Change from Baseline to Visit 9 (12 months) in TcpO2 • Partial healing of ischaemic ulcers (≥ 50% reduction in size as compared to ulcer size at baseline). • Amputation Free Survival (AFS). Additional Efficacy Endpoints
The following additional efficacy endpoints at different time points after administration of REX-001 or Placebo are defined: • Change in Rutherford classification at three, six, nine, 18 and 24 months. • Presence of ischaemic ulcers at three, six, nine, 18, and 24 months. • Partial healing of ischaemic ulcers at three, six, nine, 18 and 24 months. • Presence of ischaemic rest pain at three,six, nine, 12, 18, and 24 months. • Six-Minute Walking Test (to assess claudication time and distance) at three, six, nine, 12, 18 and 24 months. The Six-Minute walking test will only be performed if subjects are able to walk. • Ankle pressure, toe pressure, ABI, and TBI at three, six, nine, 12, 18, and 24 months. • TcpO2 at one, two, three, six, nine, 12, 18, and 24 months. • Vasculogenesis/arteriogenesis confirmed by angiography at 12 months. • Disease-specific QoL as assessed by the Vascular Quality of Life Questionnaire (VascuQol) at three, six, nine, 12, 18 and 24 months. • Health-related QoL using the EuroQoL five dimensions questionnaire (EQ-5D-5L) at three, six, nine, 12, 18 and 24 months. • Incidence of minor amputations. • AFS at 24 months. • Cardiovascular morbidity including cardiovascular death, non-fatal myocardial infarction and non-fatal stroke (adjudicated by the IAC, recommended as per the CHMP note for guidance). •Change in WIfI risk score at three, six, nine, 12, 18 and 24 months. WIfI risk stratification is based on three major factors that impact amputation risk and clinical management of Wound, Ischemia and foot Infection. The scale uses grades 0-3, 0=no/none, 1=mild, 2=moderate and 3=severe. The overall grade is the sum of the three signs and symptoms and is calculated for a risk classification (Mills, et al. 2014). • Frequency, extent and type of wound care at three, six, nine, 12, 18 and 24 months. This includes debridement, cleansing and wound dressing changes. Wound care is to be performed according to local standard practice. • Proportion of patients receiving a successful administration of REX-001 or Placebo after BM collection • Overall frequency and type of TEAEs will be assessed at each visit per trial arm and per individual subject.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
12 months post administration of REX-001 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 | 27 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
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 REX-001 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 | 4 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |