<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03810690</url>
  </required_header>
  <id_info>
    <org_study_id>mRNA-3704-P101</org_study_id>
    <nct_id>NCT03810690</nct_id>
  </id_info>
  <brief_title>Open Label Study of mRNA-3704 in Patients With Isolated Methylmalonic Acidemia</brief_title>
  <official_title>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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>ModernaTX, Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>ModernaTX, Inc.</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This First-in-Human (FIH) Phase 1/2 study will evaluate mRNA-3704 in patients with&#xD;
      methylmalonic acidemia/aciduria (MMA) due to methylmalonyl-coenzyme A mutase (MUT) deficiency&#xD;
      between 1 to 18 years of age with elevated plasma methylmalonic acid. The study is designed&#xD;
      to characterize baseline biomarker levels followed by assessment of safety, pharmacokinetics,&#xD;
      and pharmacodynamics of different doses of mRNA-3704 in patients affected by MMA as part of&#xD;
      the Dose Escalation phase.&#xD;
&#xD;
      During the Dose Escalation phase, three dose levels of mRNA-3704 are planned to be&#xD;
      investigated in this study among patients with MMA due to MUT deficiency: low dose, mid dose,&#xD;
      and high dose. An additional cohort to evaluate a fourth dose level may be considered jointly&#xD;
      by the independent SMC and the Sponsor.&#xD;
&#xD;
      Upon establishment of a dose with acceptable safety and pharmacodynamic activity, additional&#xD;
      patients will be enrolled in a Dose Expansion phase to allow for further characterization of&#xD;
      the safety and pharmacodynamics of mRNA-3704.&#xD;
&#xD;
      Patients in both phases of study will participate in a pre-dosing observational period,&#xD;
      followed by a treatment period, and then a follow-up period after withdrawal of treatment.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Study was terminated before the start of dosing due to a business decision and not due to&#xD;
    safety or efficacy reasons.&#xD;
  </why_stopped>
  <start_date type="Actual">May 28, 2019</start_date>
  <completion_date type="Actual">August 18, 2020</completion_date>
  <primary_completion_date type="Actual">August 18, 2020</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence of treatment-emergent adverse events</measure>
    <time_frame>Day 1 (initial mRNA-3704 dose) through 52 weeks after final mRNA-3704 dose</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in plasma methylmalonic acid levels</measure>
    <time_frame>Week -4 through 36 weeks after initial mRNA-3704 dose</time_frame>
    <description>Baseline (pre-dose levels) to post-dose levels measured after single and after repeated administrations of mRNA-3704</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Maximum observed concentration (Cmax) after administration of mRNA-3704</measure>
    <time_frame>Baseline through 36 weeks after initial mRNA-3704 dose</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time of Cmax (Tmax)</measure>
    <time_frame>Baseline through 36 weeks after initial mRNA-3704 dose</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under the plasma concentration-time curve (AUC)</measure>
    <time_frame>Baseline through 36 weeks after initial mRNA-3704 dose</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in plasma 2-methylcitrate levels</measure>
    <time_frame>Week -4 through 36 weeks after initial mRNA-3704 dose</time_frame>
    <description>Baseline (pre-dose levels) to levels measured after single and after repeated administrations of mRNA-3704</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measurement of anti-PEG antibodies</measure>
    <time_frame>Pre-dose through up to 52 weeks after final mRNA-3704 dose</time_frame>
  </secondary_outcome>
  <number_of_arms>5</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Methylmalonic Acidemia (MMA)</condition>
  <condition>Metabolism, Inborn Errors</condition>
  <arm_group>
    <arm_group_label>Dose Escalation Phase: Dose Level 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>mRNA-3704</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Dose Escalation Phase: Dose Level 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>mRNA-3704</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Dose Escalation Phase: Dose Level 3</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>mRNA-3704</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Dose Escalation Phase: Dose Level 4 (optional)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>mRNA-3704</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Dose Expansion Phase: mRNA-3704</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>mRNA-3704</intervention_name>
    <description>mRNA-3704 dispersion for intravenous (IV) infusion</description>
    <arm_group_label>Dose Escalation Phase: Dose Level 1</arm_group_label>
    <arm_group_label>Dose Escalation Phase: Dose Level 2</arm_group_label>
    <arm_group_label>Dose Escalation Phase: Dose Level 3</arm_group_label>
    <arm_group_label>Dose Escalation Phase: Dose Level 4 (optional)</arm_group_label>
    <arm_group_label>Dose Expansion Phase: mRNA-3704</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Patients are eligible to be included in the study only if all of the following criteria&#xD;
        apply:&#xD;
&#xD;
          -  Confirmed diagnosis of isolated MMA due to MUT deficiency based on the following&#xD;
             criteria:&#xD;
&#xD;
               -  Elevated plasma methylmalonic acid concentrations (≥ 100 µmol/L)&#xD;
&#xD;
               -  Presence of normal serum/plasma Vitamin B12 and plasma homocysteine levels&#xD;
&#xD;
               -  Confirmed diagnosis by molecular genetic testing&#xD;
&#xD;
          -  Patient must be ≥ 1 year of age at the time of consent/assent (Inclusion of the first&#xD;
             three patients will be restricted to individuals age ≥ 8 years)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Patients are excluded from the study if any of the following criteria apply:&#xD;
&#xD;
          -  Diagnosis of isolated MMA cblA, cblB, or cblD enzymatic subtypes or methylmalonyl-CoA&#xD;
             epimerase deficiency or combined MMA with homocystinuria&#xD;
&#xD;
          -  History of organ transplantation&#xD;
&#xD;
          -  Previously received gene therapy for the treatment of MMA.&#xD;
&#xD;
          -  Estimated glomerular filtration rate (GFR) &lt; 30 mL/min/1.73 m2; or patients who&#xD;
             receive chronic dialysis&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Year</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <removed_countries>
    <country>United States</country>
  </removed_countries>
  <verification_date>November 2020</verification_date>
  <study_first_submitted>January 14, 2019</study_first_submitted>
  <study_first_submitted_qc>January 16, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 22, 2019</study_first_posted>
  <last_update_submitted>November 10, 2020</last_update_submitted>
  <last_update_submitted_qc>November 10, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">November 13, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Metabolism, Inborn Errors</mesh_term>
    <mesh_term>Amino Acid Metabolism, Inborn Errors</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03810690
org study id: mRNA-3704-P101
nct id: NCT03810690
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This First-in-Human (FIH) Phase 1/2 study will evaluate mRNA-3704 in patients with
      methylmalonic acidemia/aciduria (MMA) due to methylmalonyl-coenzyme A mutase (MUT) deficiency
      between 1 to 18 years of age with elevated plasma methylmalonic acid. The study is designed
      to characterize baseline biomarker levels followed by assessment of safety, pharmacokinetics,
      and pharmacodynamics of different doses of mRNA-3704 in patients affected by MMA as part of
      the Dose Escalation phase.

      During the Dose Escalation phase, three dose levels of mRNA-3704 are planned to be
      investigated in this study among patients with MMA due to MUT deficiency: low dose, mid dose,
      and high dose. An additional cohort to evaluate a fourth dose level may be considered jointly
      by the independent SMC and the Sponsor.

      Upon establishment of a dose with acceptable safety and pharmacodynamic activity, additional
      patients will be enrolled in a Dose Expansion phase to allow for further characterization of
      the safety and pharmacodynamics of mRNA-3704.

      Patients in both phases of study will participate in a pre-dosing observational period,
      followed by a treatment period, and then a follow-up period after withdrawal of treatment.
allocation: Non-Randomized
intervention model: Sequential Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Incidence of treatment-emergent adverse events
time frame: Day 1 (initial mRNA-3704 dose) through 52 weeks after final mRNA-3704 dose
measure: Change in plasma methylmalonic acid levels
time frame: Week -4 through 36 weeks after initial mRNA-3704 dose
description: Baseline (pre-dose levels) to post-dose levels measured after single and after repeated administrations of mRNA-3704
measure: Maximum observed concentration (Cmax) after administration of mRNA-3704
time frame: Baseline through 36 weeks after initial mRNA-3704 dose
measure: Time of Cmax (Tmax)
time frame: Baseline through 36 weeks after initial mRNA-3704 dose
measure: Area under the plasma concentration-time curve (AUC)
time frame: Baseline through 36 weeks after initial mRNA-3704 dose
measure: Change in plasma 2-methylcitrate levels
time frame: Week -4 through 36 weeks after initial mRNA-3704 dose
description: Baseline (pre-dose levels) to levels measured after single and after repeated administrations of mRNA-3704
measure: Measurement of anti-PEG antibodies
time frame: Pre-dose through up to 52 weeks after final mRNA-3704 dose
arm group label: Dose Escalation Phase: Dose Level 1
arm group type: Experimental
description: mRNA-3704
arm group label: Dose Escalation Phase: Dose Level 2
arm group type: Experimental
description: mRNA-3704
arm group label: Dose Escalation Phase: Dose Level 3
arm group type: Experimental
description: mRNA-3704
arm group label: Dose Escalation Phase: Dose Level 4 (optional)
arm group type: Experimental
description: mRNA-3704
arm group label: Dose Expansion Phase: mRNA-3704
arm group type: Experimental
intervention type: Biological
intervention name: mRNA-3704
description: mRNA-3704 dispersion for intravenous (IV) infusion
arm group label: Dose Escalation Phase: Dose Level 1
arm group label: Dose Escalation Phase: Dose Level 2
arm group label: Dose Escalation Phase: Dose Level 3
arm group label: Dose Escalation Phase: Dose Level 4 (optional)
arm group label: Dose Expansion Phase: mRNA-3704
criteria: 
gender: All
minimum age: 1 Year
maximum age: N/A
healthy volunteers: No
country: United States
responsible party type: Sponsor
mesh term: Metabolism, Inborn Errors
mesh term: Amino Acid Metabolism, Inborn Errors
sharing ipd: No