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    Summary
    EudraCT Number:2016-000240-34
    Sponsor's Protocol Code Number:REX-001-004
    National Competent Authority:Portugal - INFARMED
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-06-07
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedPortugal - INFARMED
    A.2EudraCT number2016-000240-34
    A.3Full title of the trial
    The Efficacy and Safety of Intra-Arterial Administration of REX-001 to Treat Ischaemic Rest Pain in Subjects with Critical Limb Ischaemia Rutherford Category 4 and Diabetes Mellitus: A Pivotal, Placebo-Controlled, Double-Blind, Parallel-Group, Adaptive Trial
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical trial to test the efficacy and safety of a bone marrow cell preparation to treat Critical Limb Ischemia in Subjects with Diabetes Mellitus.
    A.4.1Sponsor's protocol code numberREX-001-004
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorRexgenero Limited
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportRexgenero Limited
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationRexgenero Limited
    B.5.2Functional name of contact pointChief Operating Officer
    B.5.3 Address:
    B.5.3.1Street Address1A Isetta Square, 35 New England Street
    B.5.3.2Town/ cityBrighton
    B.5.3.3Post codeBN1 4GQ
    B.5.3.4CountryUnited Kingdom
    B.5.6E-mailedwin.wagena@rexgenero.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameREX-001 (autologous bone marrow-derived mononuclear cell enriched white blood cells)
    D.3.2Product code N/A
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntraarterial use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNConcentrate of Autologous adult non-expanded bone marrow mononuclear cells
    D.3.9.1CAS number mononuclear
    D.3.9.2Current sponsor codeREX-001
    D.3.9.3Other descriptive namemononuclear cells
    D.3.10 Strength
    D.3.10.1Concentration unit million organisms/ml million organisms/millilitre
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number25 to 50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Yes
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Yes
    D.3.11.3.5.1CAT classification and reference numberTissue engineered product; EMA/CAT/451233/2015
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntraarterial use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Critical Limb Ischemia in patients with Diabetes Mellitus
    E.1.1.1Medical condition in easily understood language
    Severe obstruction of the arteries in patients with Diabetes Mellitus
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10077142
    E.1.2Term Limb ischemia
    E.1.2System Organ Class 100000004866
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10058069
    E.1.2Term Critical limb ischemia
    E.1.2System Organ Class 100000004866
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10012601
    E.1.2Term Diabetes mellitus
    E.1.2System Organ Class 10027433 - Metabolism and nutrition disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Study Objective
    To confirm the efficacy and safety of a single intra-arterial administration of REX-001 to relief ischemic rest pain in subjects with critical limb ischaemia (CLI) Rutherford Category 4 and diabetes mellitus (DM).
    E.2.2Secondary objectives of the trial
    Study Endpoints
    Primary Efficacy Endpoint
    Change in Rutherford classification from CLI Category 4 to Category 3 or lower 12 months after administration of REX-001 or the placebo product (hereafter referred to as the Placebo). Success is defined as complete relief of ischaemic rest pain with the absence of the development of ischaemic lesions 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 score (Categories 0-6).
    • Presence of ischaemic ulcers (yes/no).
    • Amputation free survival (AFS).
    E.2.3Trial contains a sub-study No
    E.3Principal 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. Subjects with poor or no (surgical or endovascular) revascularization option classified as CLI Rutherford Category 4.
    The blood circulation in these subjects must be compromised at screening defined as:
    • Ankle systolic pressure < 50 mm Hg, or
    • Toe systolic pressure < 30 mm Hg, or
    • Transcutaneos oxygen pressure (tcpO2) < 30 mm Hg, and
    • Flat or barely pulsatile ankle or metatarsal pulse volume recording (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 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.
    E.4Principal 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 5.
    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 ischemia 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.
    E.5 End points
    E.5.1Primary end point(s)
    Change in Rutherford classification from CLI Category 4 to Category 3 or lower 12 months after administration of REX-001 or Placebo. Success is defined as complete relief of ischemic rest pain with the absence of development of ischemic lesions on the index leg.
    The term "ischaemic rest pain" has been well characterized and indicates diffuse pedal ischaemia (Cranley 1969). It is a severe pain not readily controlled by analgesics that is in general localized to the
    forefoot and toes or, if more proximal, includes these distal parts. It may also be localized to the vicinity of focal ischaemic lesions. It is brought on or made worse by elevation and relieved by dependency and therefore is often only experienced at night or when lying down. The presence of ischaemic rest pain will be determined by the Investigator through a structured interview (for more details we refer to the Ischaemic Rest Pain Interview form).
    E.5.1.1Timepoint(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 REX-001 or Placebo.
    E.5.2Secondary end point(s)
    The following secondary endpoints at 12 months after administration of REX-001 or Placebo will be used:
    • Change in Rutherford classification (Categories 0-6).
    The change in Rutherford classification from baseline will be determined at six and 12 months after administration of REX-001 or Placebo. The IAC will confirm the Rutherford category of PAD of each subject.
    • Presence of ischaemic ulcers (yes/no).
    The presence of ischaemic ulcers will be determined for each subject at the baseline visit (Visit 3) and at 12 months after the administration of REX-001 or Placebo. These assessments will be confirmed by the IAC using photographs taken of the lower limb and foot for each subject at
    the baseline visit (Visit 3) and of the ulcers (or the lower limb and foot if no ulcers are present) at 12 months (Visit 9).
    • AFS.
    AFS is a composite endpoint which incorporates mortality and major amputation. A major amputation is defined as any procedure that results in amputation at the level of the ankle or above, and is further divided based on its location in relation to the knee. Below the knee amputation is an amputation affecting the tibia at any point below the knee and above the ankle. Above the knee amputation is an amputation above the knee, affecting the femur at any level.

    Additional Efficacy Endpoints

    • Change in Rutherford classification at three, six, nine, 18, and 24 months.
    • Presence of ischaemic ulcers at three, six, nine, 18 and 24 months.
    The IAC will also confirm the presence of ischaemic ulcers using photographs taken of the ulcers, or of the lower limb and foot if no ulcers are present, for each subject at three, six, nine, 18 and 24 months
    when the primary endpoint is met.
    • Presence of ischaemic rest pain at 3, 6, 9, 18, and 24 months.
    • Six-Minute Walking Test at three, six, nine, 12, 18 and 24 months.
    • 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.
    Measurements of tcpO2 reflect the metabolic state of lower limbs with CLI and diabetic feet. Small electrodes consisting of a circular silver - silver chloride anode surrounding a central platinum cathode are placed on the skin. Oxygen diffusing to the surface of the skin is reduced at the cathode to produce a current proportional to the partial pressure of oxygen (pO2) within the sensor. In patients with foot ulcers, tissue loss or rest pain, tcpO2 values can be used to assess the presence and
    severity of vascular disease, the need for revascularization, and to predict the success of healing with or without revascularization. This test is performed by placing probes with electrodes on the foot and the leg, using the chest as a reference site. Common locations for assessment are the dorsum of the foot, the anteromedial aspect of the calf 10 cm below the knee, and the thigh 10 cm above the knee (Cao, et al. 2011).
    • Revascularization confirmed by angiography at 12 months.
    An intra-arterial digital angiographic procedure will be performed using a contrast medium.
    • Disease-specific QoL as assessed by the VascuQol at three, six, nine, 12, 18 and 24 months.
    • EQ-5D-5L at three, six, nine, 12, 18 and 24 months.
    The EQ-5D is the most widely used generic preference based measure assessing health on five dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) across three response levels generating 243 health states in total (Wisløff, et al. 2014). Value sets for use in cost utility analysis (anchored on a full health (1) and dead (0)) have been developed internationally (Szende, Oppe en Devlin 2007). A new version of the EQ-5D with five response levels (EQ-5D-5L; none,
    slight, moderate, severe, extreme/unable) has been developed (Herdman, et al. 2011).
    • Incidence of minor amputations.
    A minor amputation is defined as any procedure that results in amputation of a part of the foot distal to the transverse tarsal joint with preservation of the talus and calcaneus.
    • AFS at 24 months.
    • Cardiovascular morbidity.
    This includes cardiovascular death, non-fatal MI and non-fatal stroke (adjudicated by the IAC, recommended as per CHMP note for guidance).
    E.5.2.1Timepoint(s) of evaluation of this end point
    12 months post administration of REX-001 or Placebo
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA37
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.7Trial 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
    LVLS
    All subjects will be followed up until 24 months after the administration of REX-001 or Placebo.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 32
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 28
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 60
    F.4.2.2In the whole clinical trial 60
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    All subjects will be followed up until 24 months after the administration of REX-001 or Placebo. After that patients will be treated per standard clinical practice.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-12-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-12-11
    P. End of Trial
    P.End of Trial StatusOngoing
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