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 | 20.0 |
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 | 20.0 |
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 |
Study Objective
To confirm the efficacy and safety of a single intra-arterial administration of REX-001 to treat ischaemic ulcers in subjects with CLI 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 CLI 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 CLI Category 5 to Category 3 or lower.
• 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 |
Trial Population
Main Inclusion Criteria
1. Aged ≥ 18 to ≤ 85 years.
2. Diagnosis of Type I or II DM, established more than one year ago.
3. Subjects with poor or no (surgical or endovascular) revascularization option classified as CLI Rutherford Category 5.
The blood circulation in these subjects must be compromised at screening, defined as:
• Ankle systolic pressure < 70 mmHg, or
• Toe systolic pressure < 50 mmHg, or
• Transcutaneous oxygen pressure (tcpO2) < 30 mmHg (lying down).
Subjects with non-compressible 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 is not feasible due to unsuitable anatomy of existing vessels, existing comorbidity and/or previously failed surgical or endovascular revascularization.
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E.4 | Principal exclusion criteria |
Main Exclusion Criteria
1. Advanced CLI defined as presence of major tissue loss (i.e, significant ulceration and/or 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 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 according to the Investigator intravenous antibiotics are required to treat the infection.
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. 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.
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E.5 End points |
E.5.1 | Primary end point(s) |
Study Endpoints
Primary Efficacy Endpoint
Change in Rutherford classification from CLI 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. 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 CLI 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 score (Categories 0-6).
• Presence of ischemic ulcers (yes/no).
• 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-5L0 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). |
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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 | 3 |
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 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 | 3 |
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 | 3 |
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 |