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    Summary
    EudraCT Number:2019-001061-32
    Sponsor's Protocol Code Number:mRNA-3704-P101
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2019-05-30
    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 ConcernedUK - MHRA
    A.2EudraCT number2019-001061-32
    A.3Full title of the trial
    A Global, Phase 1/2, Open Label, Dose Escalation Study to Evaluate the Safety, Pharmacodynamics, and Pharmacokinetics of mRNA-3704 in Patients with Isolated Methylmalonic Acidemia Due to Methylmalonyl-CoA Mutase Deficiency
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study to evaluate mRNA-3704 in Patients with MMA
    A.4.1Sponsor's protocol code numbermRNA-3704-P101
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03810690
    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 SponsorModernaTX, Inc.
    B.1.3.4CountryUnited States
    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 supportModernaTX, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationModernaTX, Inc.
    B.5.2Functional name of contact pointChief Medical Officer
    B.5.3 Address:
    B.5.3.1Street Address200 Technology Square
    B.5.3.2Town/ cityCambridge
    B.5.3.3Post codeMA 02139
    B.5.3.4CountryUnited States
    B.5.4Telephone number1617209 5906
    B.5.6E-mailTal.Zaks@modernatx.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 Yes
    D.2.5.1Orphan drug designation numberEMA/OD/017/18
    D.3 Description of the IMP
    D.3.1Product namemRNA-3704
    D.3.4Pharmaceutical form Solution for injection
    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 INNNA
    D.3.9.1CAS number NA
    D.3.9.2Current sponsor codemRNA-3704
    D.3.9.3Other descriptive nameNA
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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 Yes
    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 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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Isolated Methylmalonic Acidemia Due to Methylmalonyl-CoA Mutase Deficiency
    E.1.1.1Medical condition in easily understood language
    Deficiency of the enzyme methylmalonyl-coenzyme A (CoA) mutase (MUT)
    E.1.1.2Therapeutic area Body processes [G] - Metabolic Phenomena [G03]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objectives of the study are:
    • To evaluate the safety and tolerability of mRNA-3704 administered via IV infusion to patients with isolated MMA due to MUT deficiency.
    • To characterize the PD response to mRNA-3704 as determined by plasma methylmalonic acid measurement after single and repeated administrations of mRNA-3704.
    E.2.2Secondary objectives of the trial
    The secondary objectives of the study are:
    • To characterize the single-dose and repeat-dose PK of mRNA-3704.
    • To characterize the changes in plasma 2-methylcitrate levels after single and repeated administrations of mRNA-3704.
    • To assess for the presence of anti-drug antibodies (ADAs).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients are eligible to be included in the study only if all of the following criteria apply:
    1. Confirmed diagnosis of isolated MMA due to MUT deficiency based on the following criteria:
    o Elevated plasma methylmalonic acid concentrations of ≥100 ╬╝mol/L, confirmed by 2 values drawn at least 24 hours apart during the Screening Period or within the past 6 months;
    o Presence of normal serum/plasma vitamin B12 and plasma homocysteine levels (local laboratory reference range) confirmed in the Screening Period (values may be from historical data); and
    o Confirmed diagnosis by molecular genetic testing.
    2. Patient must be ≥1 years of age at the time of consent/assent. (inclusion of the first three patients will be restricted to individuals 8 years of age or older).
    3. Patient or legally authorized representative is willing and able to provide informed consent and/or assent as mandated by local regulations.
    4. The patient’s caregiver (and the patient) must be willing and able to comply with study-related assessments.
    5. Values for ALT, AST, and direct serum bilirubin ≤1.25x of ULN.
    6. Platelet count within a range of ≥150,000/mm3 to 450,000/mm3.
    7. Hemoglobin levels >9 g/dL
    8. Sexually active females of childbearing potential and sexually active males of reproductive potential agree to use a highly effective method of contraception during the study and for 12 weeks following study participation.
    E.4Principal exclusion criteria
    Patients are excluded from the study if any of the following criteria apply:
    1. Diagnosis of isolated MMA cblA, cblB, or cblD enzymatic subtypes or methylmalonyl-CoA epimerase deficiency or combined MMA with homocystinuria.
    2. Previously received gene therapy for the treatment of MMA.
    3. Estimated glomerular filtration rate (GFR) <30 mL/min/1.73 m2, as estimated by the Schwartz formula (based on serum creatinine); or patients who receive chronic dialysis.
    4. QTc including Bazett's correction >450 msec.
    5. In female patients of reproductive potential: a positive pregnancy test at Screening or at the end of the Observational Period.
    6. Pregnant or lactating.
    7. aPTT, PT, or INR greater than ULN or history of clinically significant bleeding abnormality.
    8. Absolute neutrophil count (ANC) below the following:
    • 1000/mm3 for patients ≥1 year of age to <2 years of age
    • 1500/mm3 for patients ≥2 years of age
    9. History of organ transplantation.
    10. History of hypersensitivity to any components of the study drug.
    11. Participated in another clinical trial of another investigational agent within 30 days prior to study entry (or within 5 elimination half-lives of the investigational agent), whichever is longer.
    12. Major surgical procedure within 30 days prior to study entry (excludes central line, port, or feeding tube placement).
    13. Known history of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection.
    14. Have any other clinically significant medical condition that in the Investigator’s opinion could interfere with the interpretation of study results or limit the patient’s participation in the study.
    E.5 End points
    E.5.1Primary end point(s)
    - Incidence and severity of treatment-emergent adverse events (TEAEs; including study drugrelated and not related TEAEs regardless of causality), treatment-emergent serious adverse events (SAEs), and TEAEs leading to treatment discontinuation.
    - Change in plasma methylmalonic acid levels from baseline (pre-dose levels) to post-dose levels measured after single and after repeated administrations of mRNA-3704.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Primary endpoints will be evaluated over the entire period of the trial
    E.5.2Secondary end point(s)
    - Pharmacokinetic parameters of hMUT mRNA including, but not limited to, maximum observed concentration (Cmax), time of Cmax (Tmax), area under the plasma concentration-time curve (AUC), terminal elimination half-life (t1/2), clearance (CL), and volume of distribution (Vz).
    - Change in plasma 2-methylctirate levels from baseline (pre-dose levels) to levels measured after single and after repeated administrations of mRNA-3704.
    - Measurement of anti-PEG antibodies
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary endpoints will be evaluated over the entire period of the trial
    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 Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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) Yes
    E.7.1.1First administration to humans Yes
    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.8.3 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 concerned2
    E.8.5The trial involves multiple Member States No
    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
    United States
    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 years4
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months0
    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 Yes
    F.1.1Number of subjects for this age range: 33
    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) Yes
    F.1.1.4.1Number of subjects for this age range: 6
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 24
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 3
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 1
    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 No
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Some patients may be below the age for giving consent and a legally authorized representative will provide informed consent and/or assent as mandated by local regulations
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state8
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 8
    F.4.2.2In the whole clinical trial 34
    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)
    Normal treatment
    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 Decision2019-07-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-10-25
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2020-08-18
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