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    Summary
    EudraCT Number:2019-003529-36
    Sponsor's Protocol Code Number:mRNA-3927-P101
    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:2020-03-03
    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 number2019-003529-36
    A.3Full title of the trial
    A Global, Phase 1/2, Open-label, Dose Optimization Study to Evaluate the Safety, Pharmacodynamics, and Pharmacokinetics of mRNA-3927 in Participants with Propionic Acidemia
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study to evaluate the medicinal product in Patients with Propionic Acidemia
    A.4.1Sponsor's protocol code numbermRNA-3927-P101
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04159103
    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 Kingdom
    B.5.4Telephone number16172095906
    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/0000003207
    D.3 Description of the IMP
    D.3.1Product namemRNA-3927
    D.3.4Pharmaceutical form 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 INNN/A
    D.3.9.1CAS number N/A
    D.3.9.2Current sponsor codeCX-016492
    D.3.9.3Other descriptive nameCX-016492
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3.2
    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 codeCX-017950
    D.3.9.3Other descriptive nameCX-017950
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.4
    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
    Propionic Acidemia- Propionic acidemia is an autosomal recessive disorder caused by loss-of-function mutations in PCCA or PCCB (and in rare instances, mutations in both PCCA and PCCB), resulting in the loss
    of enzymatic activity of the mitochondrial complex PCC
    E.1.1.1Medical condition in easily understood language
    Deficiency of PCCA and PCCB
    E.1.1.2Therapeutic area Body processes [G] - Metabolic Phenomena [G03]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10080615
    E.1.2Term Propionic acidemia
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Evaluate the safety and tolerability of mRNA-3927 in participants with PA
    E.2.2Secondary objectives of the trial
    Characterize the PD responses of mRNA-3927 as determined by changes in plasma 2-MC and 3-HP after single and repeated administrations of mRNA-3927;Characterize the single-dose and repeated-dose PK of mRNA-3927;Assess for the presence of anti-PEG antibodies.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    ≥ 8 years of age at the time of consent/assent if enrolled as 1 of the first 2 participants;≥ 1 year of age at the time of consent/assent if enrolled after the first 2 participants; Confirmed diagnosis of PA based on diagnosis by molecular genetic testing (PCCA and/or PCCB mutations); Participant and/or legally authorized representative is willing and able to provide informed consent and/or assent as mandated by local regulations and willing and able to comply with study-related assessments; Sexually active females of childbearing potential and sexually active males of reproductive potential agree to use a highly effective method of contraception during study treatment and for 3 months following the last administration of study drug.
    E.4Principal exclusion criteria
    Any individual with laboratory abnormalities achieving thresholds;
    Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2, as estimated by Schwartz formula (Schwartz et al 2012); or participants who receive chronic dialysis;
    Corrected QT interval (QTc) > 480 ms using Bazett’s correction;
    In female participants of reproductive potential: a positive pregnancy test at the Screening Visit;
    Pregnant or breastfeeding;
    Grade 3 or 4 heart failure according to the Modified Ross Heart Failure Classification for Children or the New York Heart Association Classification;
    History of organ transplantation or planned organ transplantation during the period ofstudy participation;
    Hypersensitivity to acetaminophen/paracetamol and/or ibuprofen or H1-receptor blockers;
    History of hypersensitivity to any component of the study drug;
    History of anaphylaxis/anaphylactoid reaction or severe hypersensitivity with infusions;
    Participation in another clinical study of another investigational agent within 30 days before study entry or within 5 elimination half-lives of the investigational agent,whichever is longer;
    Major surgical procedure within 30 days before the Screening Visit (excludes central line, port, or feeding tube placement);
    Enrollment in the study is not deemed to be of clinical benefit, in the opinion of the Investigator;
    Other condition that in the Investigator’s opinion could interfere with interpretation of study results or limit the participant’s participation in the study.
    E.5 End points
    E.5.1Primary end point(s)
    Incidence and severity of AEs (including study drug-related and not related AEs), SAEs, and AEs leading to treatment discontinuation
    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)
    Change in plasma 2-MC and 3-HP levels
    from baseline (predose levels) to postdose
    levels measured after single and repeated
    administrations of mRNA-3927;
    Estimation of PD parameters from baseline after single and repeated administration of mRNA-3927, including Emax, AUEC, and duration of response;
    Estimation of PK parameters of PCCA and
    PCCB mRNAs and SM-86, including Cmax,
    tmax, AUC, t½, CL, Vz, and Vss;
    Presence and titers of anti-PEG antibodies;
    Change in other biomarkers, including
    total, free, and acyl carnitines (C2 and C3
    and, if feasible, C17 and C19), propionylglycine, and glycine;
    Estimation of PD parameters for these
    other biomarkers after single and repeated administration of mRNA-3927, including to, Emax, AUEC, and duration of response;
    Association of Cmax and AUC and Emax and AUEC of biomarkers across dose levels with PA-related clinical events;
    Antibodies to PCC;
    Incidence and severity of pretreatment and posttreatment AEs and SAEs;
    Changes in CSEs pretreatment and
    posttreatment. CSE, is defined as a
    composite of the following:Hospitalization (excluding
    hospitalizations for chronic diseases not
    related to PA or elective hospitalizations for conditions not related to PA), Emergency room visits, Emergency interventions outside of health care settings to prevent an MDE
    (sick-day diets and fluid resuscitation at
    home), Complications of cardiomyopathy
    treated outside of hospital (documented
    arrhythmia, emergent changes in
    diuretic therapy due to increasing fluid
    overload);
    Changes in MDEs pretreatment and
    posttreatment;
    Changes in health care resource utilization
    pretreatment and posttreatment;
    Changes in disease impact on missed
    school and work days pretreatment and
    posttreatment;
    Ammonia and lactate levels in participants
    with PA;
    Cardiac parameters evaluating for
    cardiomyopathy, including ECHO and
    NT-BNP;
    eGFR;
    Changes in PedsQL™ and PedsQL Family
    Impact Module™;
    Relationship between dietary changes and
    PD biomarkers.
    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 No
    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.8.2.4Number of treatment arms in the trial1
    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 concerned3
    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
    Canada
    United Kingdom
    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 months3
    E.8.9.1In the Member State concerned days10
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months7
    E.8.9.2In all countries concerned by the trial days20
    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: 36
    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: 8
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 18
    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: 2
    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 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 state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 6
    F.4.2.2In the whole clinical trial 36
    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)
    Participants may participate in an mRNA-3927 extension study if they complete the treatment period.
    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 Decision2020-12-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-12-18
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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