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NCT04159103PHASE1, PHASE2Recruiting

Open-Label Study of mRNA-3927 in Participants With Propionic Acidemia

ModernaTX, Inc.

Start Date

4/15/2021

Completion Date

8/31/2027

Summary

This 3-part, Phase 1/2 study is designed to characterize the safety, tolerability, and pharmacological activity (as assessed by biomarker measurements) and to determine the selected dose of mRNA-3927 in participants with genetically confirmed propionic acidemia (PA). After establishing a dose with an acceptable safety and pharmacodynamic (PD) response for participants ≥1 year of age in Part 1, participants will be enrolled in Part 2 (which will serve as the pivotal study) to allow for determination of the efficacy, safety, and PD of mRNA-3927. Part 3 will evaluate the safety, efficacy and PD response of mRNA-3927 in infants (\<1 year of age).

Detailed Description

During the Dose Optimization Stage, after each dose cohort is fully enrolled (≥1 year of age), and the dose-limiting toxicity (DLT) observation window of at least 14 days is complete for the final participant in that cohort, the Sponsor will review the totality of available safety data in conjunction with all available PK/PD data. Based on this review, the Sponsor will recommend a revised dose and/or dosing interval. The Sponsor will abide by predefined constraints as to the maximum percentage change in dose and dose interval. A maximum of 9 cohorts will be enrolled in Part 1 (Dose Optimization). Upon establishment of a dose with an acceptable safety and PD activity in Part 1 (participants ≥1 year of age), additional participants will be enrolled into the study in Part 2 (participants ≥1 year of age) to allow for determination of the safety, efficacy, and PD of mRNA-3927. Part 3 will evaluate the safety, efficacy and PD response in infants (\<1 year of age). Participants in all the phases will participate in a predosing observational period, followed by a treatment period, and then a follow-up period after withdrawal of treatment.

Eligibility Criteria

Age Range: No minimum to No maximum

Inclusion Criteria: Participants ≥1 year of age are eligible to be included in the study only if all of the following criteria apply: * ≥ 8 years of age at the time of consent/assent if enrolled as 1 of the first 2 participants in Part 1. * ≥1 year of age at the time of consent/assent if enrolled after the first 2 participants in Part 1. * Confirmed diagnosis of PA based on diagnosis by molecular genetic testing via central laboratory (PCCA and/or PCCB mutations). * Part 2 only: At least one documented MDE in the 12-month period before consent. Participants \<1 Year of Age : * Identification by newborn screening shortly after birth or having suspected PA by presenting with a spectrum of metabolic symptoms, and having a sibling diagnosed with PA. Participant may enter the Screening Period while awaiting genetic testing results, provided that all other eligibility criteria are met but would not be enrolled until diagnosis of PA is confirmed. * For infants in the neonatal intensive care unit (NICU) only: ≥37 weeks gestational age at the time of birth without other conditions/comorbidities that in the opinion of the Investigator may interfere with the interpretation of study results. * Body weight ≥3 kilograms (kg) at Screening. * At least 1 documented PA-related event prior to Screening defined as the following criteria: * Clinical signs of metabolic deterioration consistent with PA (for example, vomiting, not feeding well/poor suck, heavy breathing, lethargy, absence of proper perfusion, abnormal movements including bicycling, abnormal tone, low body temperature, seizure\[s\]), OR * Meeting the criteria of MDE definition, OR * Evidence of laboratory abnormalities as evidenced by at least one of the following: * Metabolic acidosis with elevated anion gap. * Acute hyperammonemia. * Neutropenia or thrombocytopenia. Exclusion Criteria: Participants of all ages are excluded from the study if during Screening any of the following criteria apply: * Any individual with laboratory abnormalities considered to be clinically significant (for example, markedly out of range, associated with clinical symptoms) in the Investigator or Sponsor's opinion that could interfere with or limit the participation in the study. * Estimated glomerular filtration rate (eGFR) \<30 milliliters (mL)/minute/1.73 square meter (m\^2) for participants of all ages receiving chronic dialysis. * History of organ transplantation or planned organ transplantation during the period of study participation. * Corrected QT interval (QTc) \>480 milliseconds (ms) using Bazett's correction. * Grade 3 or 4 heart failure according to the Modified Ross Heart Failure Classification for Children or the New York Heart Association Classification. * Pregnant or breastfeeding. * Other clinically significant conditions that in the Investigator's opinion could interfere with the safety of the participant, the interpretation of study results, or limit the participation in the study.

Interventions

BIOLOGICAL

mRNA-3927

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Conditions

Propionic Acidemia

Locations

UCSD Altman Clinical and Transalational Research Institute Building

Los Angeles, California 90027

United States

Ronald Reagan UCLA Medical Center

Los Angeles, California 90095

United States

Lucile Packard Children's Hospital Stanford

Stanford, California 94304

United States

Nicklaus Children's Hospital

Miami, Florida 33155

United States

University of South Florida - 12901 Bruce B Downs

Tampa, Florida 33606-3603

United States

Ann and Robert H Lurie Childrens Hospital of Chicago

Chicago, Illinois 60611

United States

Johns Hopkins Hospital, Adult Outpatient Clinical Research Unit

Baltimore, Maryland 21287

United States

Boston Children's Hospital

Boston, Massachusetts 02115

United States

University of Michigan Hospitals

Ann Arbor, Michigan 48109

United States

Icahn School of Medicine at Mount Sinai - Clinical Research Unit

New York, New York 10029

United States

Duke University Medical System (Duke Health)

Durham, North Carolina 27710

United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio 45229

United States

University Hospitals Cleveland Medical Center - 11100 Euclid Ave

Cleveland, Ohio 44106-2624

United States

Children's Hospital of Philadelphia (CHOP)

Philadelphia, Pennsylvania 19104

United States

Texas Children's Hospital

Houston, Texas 77030

United States

Stollery Children's Hospital University of Alberta

Edmonton, Alberta T6G 2R7

Canada

Hospital For Sick Children

Toronto, Ontario M5G 1X8

Canada

CHU de Marseille - Hôpital de la Timone

Marseille, 13005

France

Hôpital Necker - Enfants Malades

Paris, 75019

France

Fujita Health University Hospital

Toyoake-shi, Aichi-ken 470-1192

Japan

Tohoku University Hospital

Sendai, Miyagi 980-8574

Japan

National Center for Child Health and Development

Tokyo, 113-8519

Japan

Erasmus MC

Rotterdam, South Holland 3015 GD

Netherlands

Universitair Medisch Centrum Utrecht - PPDS

Utrecht, 3584 CX

Netherlands

King Faisal Specialist Hospital & Research Center - Riyadh

Riyadh, Ar Riya 11211

Saudi Arabia

King Fahad Medical City

Riyadh, Ar Riya 11564

Saudi Arabia

King Abdullah Children's Specialist Hospital

Riyadh, Ar Riya 14611

Saudi Arabia

Hospital Sant Joan de Deu - PIN

Esplugues de Llobregat, Barcelona 8950

Spain

Hospital Universitario Cruces

Barakaldo, Biscay 48903

Spain

Hospital Universitario 12 de Octubre

Madrid, 28041

Spain

Hospital Universitario Virgen del Rocio - PPDS

Seville, 41013

Spain

University Hospital Birmingham NHS Foundation Trust

Birmingham, B15 2TH

United Kingdom

Birmingham Children's Hospital

Birmingham, B4 6NH

United Kingdom

Great Ormond Street Hospital for Children NHS Foundation Trust

London, WC1N 3JH

United Kingdom

Willink Biochemical Genetics Unit - PPDS

Manchester, M13 9WL

United Kingdom