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    Summary
    EudraCT Number:2018-003000-39
    Sponsor's Protocol Code Number:2018.0158
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2018-11-09
    Trial 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 ConcernedUK - MHRA
    A.2EudraCT number2018-003000-39
    A.3Full title of the trial
    A Multi-centre, Multiple-dose, Open-label Study to Investigate the Safety, Tolerability, Pharmacodynamics, and Efficacy of Erythrocyte Encapsulated Thymidine Phosphorylase (EE-TP) in Patients with Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to evaluate the Safety, Tolerability, Pharmacodynamics, and Efficacy of Erythrocyte Encapsulated Thymidine Phosphorylase (EE-TP) in Patients with Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE)
    A.4.1Sponsor's protocol code number2018.0158
    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 SponsorSt George’s University of London
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportSt George’s University of London
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSt George’s University of London
    B.5.2Functional name of contact pointResearch Governance and Delivery
    B.5.3 Address:
    B.5.3.1Street AddressCranmer Terrace
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeSW17 0RE
    B.5.3.4CountryUnited Kingdom
    B.5.6E-mailresearchgovernance@sgul.ac.uk
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/11/856
    D.3 Description of the IMP
    D.3.1Product nameErythrocyte Encapsulated Thymidine Phosphorylase
    D.3.2Product code EE-TP
    D.3.4Pharmaceutical form Infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTP
    D.3.9.1CAS number 9030-23-3
    D.3.9.2Current sponsor codeTP
    D.3.9.3Other descriptive namerThymidine phosphorylase
    D.3.10 Strength
    D.3.10.1Concentration unit U unit(s)
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number1500
    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) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    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 No
    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 No
    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 Yes
    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 Yes
    D.3.11.13.1Other medicinal product typeAutologous, differentiated cells. But not a ATIMP
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE)
    E.1.1.1Medical condition in easily understood language
    Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a progressive metabolic disorder caused by thymidine phosphorylase (TP) enzyme deficiency.
    E.1.1.2Therapeutic area Body processes [G] - Genetic Phenomena [G05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10058799
    E.1.2Term Mitochondrial encephalomyopathy
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the safety, tolerability, pharmacodynamics (PD), and efficacy (as measured by weight stabilisation) of multiple doses of EE-TP manufactured using the red cell loader (RCL) in patients with MNGIE.
    E.2.2Secondary objectives of the trial
    • To assess the immunogenicity of EE-TP after multiple dose
    administrations.
    • To assess changes in clinical assessments.
    • To assess the PD effect of EE-TP on clinical assessments.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients must be male or female, of any race, aged 18 years or
    older at Screening.
    •Having reviewed the benefit-risk profile and with appropriate approval from ECs and/or regulatory agencies, the age range may be extended to include patients:
    - aged 16 years or older after at least 12 patient-months of exposure in patients aged 18 years or over.
    - aged 12 years or older after at least 12 patient-months of exposure in patients aged <18 years at the time of enrolment.
    2. Patients must be diagnosed with MNGIE by demonstrating ALL of the following:
    •<18% normal TP activity in the buffy coat;
    • >3 μmol/L plasma thymidine;
    • >5 μmol/L plasma deoxyuridine;
    • confirmation of the presence of a pathogenic mutation in TYMP gene by sequencing.
    3. Patients must be able to undergo study procedures. Patients must agree to either remain completely true abstinent (because of the patient’s lifestyle choice; the patient should not become abstinent just for the purpose of study participation) or to use two effective contraceptive methods from Screening until completion of the Follow-up visit:
    •Male patients with partners of childbearing potential must use a male barrier method of contraception (i.e., male condom with spermicide) in addition to a second method of acceptable contraception used by their female partners (refer to Section 4.6.6).
    • Female patients of childbearing potential must be willing to use a highly effective method of birth control (i.e., contraceptive measures with a failure rate of <1% per year):
    - IUD (e.g., Mirena) which was implanted at least 2 months prior to Screening. Steel or copper IUDs are not acceptable.
    - Established use of oral, implanted, transdermal, or hormonal method of contraception associated with inhibition of ovulation.
    - Male sterilisation, with verbal confirmation of surgical success (for female patients on the study, the vasectomised male partner should be the sole partner for that patient).
    - Bilateral tubal ligation.
    5. Patients must be willing to sign and date the written ICF after the benefits and risks of taking part in this study have been explained to them, and to comply with the study restrictions.
    E.4Principal exclusion criteria
    1. Patients who have received a successful liver or bone marrow transplant.
    2. Patients with a known history of human immunodeficiency virus (HIV), hepatitis B infection, or an active hepatitis C infection.
    3. Patients who are severely disabled (e.g., patient bed-bound, incontinent, and unable to carry out any daily activities), or with a life expectancy of less than 12 months at Screening, based on the Investigator’s judgment.
    4. Female patients who are:
    •pregnant, planning a pregnancy, or are unwilling to use contraception
    •breastfeeding or lactating.
    5. Patients who have donated blood in the 90 days prior to Screening.
    6. Patients with a confirmed RBC count of <3.0 × 109 per mL.
    7. Patients who have a significant history of alcoholism or drug/chemical abuse within 1 year prior to Screening, as determined by the Investigator.
    8. Patients who have an abnormality in heart rate, blood pressure, or body temperature at Screening that, in the opinion of the Investigator, increases the risk of participating in the study.
    9. Patients who have an abnormality in the 12-lead electrocardiogram (ECG) at Screening that, in the opinion of the Investigator, increases the risk of participating in the study.
    10. Patients who have, or have a history of, any clinically significant neurological, gastrointestinal, renal, hepatic, cardiovascular, psychiatric, respiratory, metabolic, endocrine, haematological, or other major disorder (except for MNGIE, or disorders associated with MNGIE that, in the Investigator’s opinion, do not constitute a risk when taking study medication and would not interfere with the study objectives) as determined by the Investigator.
    11. Patients with any current malignancy, or a history of malignancy within 5 years prior to Screening, with the exception of adequately treated or excised non-metastatic basal cell or squamous cell cancer of the skin or cervical carcinoma in situ.
    12. Patients who are currently enrolled in, or are planning to participate in, or discontinued within the last 30 days from a clinical study involving an investigational medicinal product (IMP) or concurrently enrolled in medical research judged not to be scientifically or medically compatible with EE-TP.
    13. Patients with any medical condition, which in the opinion of the Investigator, would make the patient unsuitable for enrolment or could interfere with the patient’s participation in, or completion of, the study
    E.5 End points
    E.5.1Primary end point(s)
    •Mean absolute change from baseline in BMI from baseline at 24 months
    E.5.1.1Timepoint(s) of evaluation of this end point
    Please refer to Schedule of Assessments in the protocol.
    E.5.2Secondary end point(s)
    •Mean absolute change from baseline BMI at 3, 6, 9, 12, 15, 18, and 21 months
    •Change from baseline in the proportion of patients who require TPN or have deceased at 3, 6, 9, 12, 15, 18, 21, and 24 months
    •Mean absolute change from baseline handgrip strength measured using handgrip dynamometry (for assessment of distal muscle weakness) employed according to the Southampton protocol for adult grip strength at 6, 12, 18, and 24 months
    •Mean absolute change from baseline disability measured using the I-RODS at 6, 12, 18, and 24 months
    •Mean absolute change from baseline ambulatory function measured using the timed 10-metre walk test at 6, 12, 18, and 24 months
    •Mean absolute change from baseline quality of life measured using EuroQol-5D and CGI-I at 6, 12, 18, and 24 months
    •Mean absolute change from baseline of gastrointestinal (GI) symptoms measured using PROMIS® short form scales (GI belly pain, GI diarrhoea, GI disrupted swallowing, GI gas and bloating, GI gastroesophageal reflux, and GI nausea and vomiting) at 6, 12, 18, and 24 months
    •PGIC at 6, 12, 18, and 24 months, relative to baseline
    •Changes relative to baseline in distal sensory impairment and deep tendon reflexes using neurological exam tests recorded in a standardised fashion
    •Improvement of the most disabling symptom for each patient (assessed using the VAS)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Please refer to Schedule of Assessments in the protocol.
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    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 No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA5
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    France
    Germany
    Israel
    Italy
    Spain
    United Kingdom
    E.8.7Trial 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months5
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 8
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 12
    F.1.3Elderly (>=65 years) No
    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 state2
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 17
    F.4.2.2In the whole clinical trial 20
    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)
    None
    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 Decision2018-12-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-01-09
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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