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Safety, Tolerability and PK/PD Evaluation of Intravenous Administration of MRT5201 in Patients With OTC Deficiency (STEP-OTC)

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ClinicalTrials.gov Identifier: NCT03767270
Recruitment Status : Not yet recruiting
First Posted : December 6, 2018
Last Update Posted : December 6, 2018
Sponsor:
Information provided by (Responsible Party):
Translate Bio, Inc.

Brief Summary:
This Phase 1/2, first-in-human study will evaluate the safety and tolerability of single and multiple escalating doses of MRT5201 administered intravenously to subjects with OTC Deficiency (OTCD). This study will also evaluate the effect of a single dose or multiple doses of MRT5201 on metabolic markers of OTCD and ureagenesis; and determine an acceptable dosing interval of MRT5201.

Condition or disease Intervention/treatment Phase
Ornithine Transcarbamylase Deficiency Biological: MRT5201 Other: Placebo Comparator Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Multiple-Part Phase 1/2 Study Evaluating the Safety, Tolerability, PK, and PD of Intravenously Administered MRT5201 in Subjects With Ornithine Transcarbamylase Deficiency, Comprising Single Ascending Dose and Multiple Dose Parts
Estimated Study Start Date : March 2019
Estimated Primary Completion Date : June 2022
Estimated Study Completion Date : June 2022


Arm Intervention/treatment
Experimental: Part A
Single Ascending Low, Mid, and High doses of MRT5201 with placebo comparator.
Biological: MRT5201
Codon-optimized human ornithine transcarbamylase messenger ribonucleic acid complexed with lipid-based nanoparticles

Other: Placebo Comparator
5% Dextrose in Water

Experimental: Part B
Multiple (five) Ascending Low, Mid, and High doses of MRT5201 with placebo comparator.
Biological: MRT5201
Codon-optimized human ornithine transcarbamylase messenger ribonucleic acid complexed with lipid-based nanoparticles

Other: Placebo Comparator
5% Dextrose in Water




Primary Outcome Measures :
  1. The incidence of treatment-emergent adverse events by treatment group (Part A) [ Time Frame: Week 24 ]
    The incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) for each dosing cohort by treatment group, assessed by severity and relationship to study product.

  2. The incidence of treatment-emergent adverse events by treatment group (Part B) [ Time Frame: Week 56 ]
    The incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) for each dosing cohort by treatment group, assessed by severity and relationship to study product.


Secondary Outcome Measures :
  1. Pharmacokinetics parameters of MRT5201 [ Time Frame: 1 month after single dose (Part A); 3 months after last dose (Part B) ]
    Pharmacokinetics of MRT5201, as measured by levels of mRNA

  2. Pharmacokinetics parameters of MRT5201 [ Time Frame: 1 month after single dose (Part A); 3 months after last dose (Part B) ]
    Pharmacokinetics of MRT5201, as measured by levels of lipid nanoparticle

  3. Effect of a single dose or multiple doses of MRT5201 on ureagenesis [ Time Frame: Up to 1 month after single dose (Part A); 1 month after last dose (Part B) ]
    Change from Baseline in 4-hour ureagenesis AUC at weeks 2, 3, 4, and 5 after a single dose of MRT5201 (Part A). Change from Baseline in 4-hour ureagenesis AUC at Week 12 (Part B).

  4. Effect of single or multiple doses of MRT5201 on metabolic markers of OTCD [ Time Frame: 6 months after single and last dose ]
    Change from Baseline in 8-hour ammonia AUC



Information from the National Library of Medicine

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Ages Eligible for Study:   12 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Have a documented diagnosis of OTCD.
  • Documented history of ≥1 symptomatic hyperammonemia event with ammonia ≥100 µmol/L in the 2 years prior to signing informed consent
  • Subject's OTCD is stable as evidenced by meeting the following criteria:

    • Ammonia level <175 µmol/L during the Screening Period and at Baseline (Day Hard hyphen1)
    • No clinical symptoms of hyperammonemia during the Screening Period and at Baseline (Day -1)
  • If using nitrogen scavenger therapy, must be on a stable regimen for ≥28 days prior to signing informed consent
  • Subject has, in the opinion of the Investigator, maintained a stable protein restricted diet (which may or may not include medical foods) and/or amino acid supplementation with no changes in calorie or protein goals and no changes in medical food and/or amino acid supplementation for ≥ 28 days prior to signing informed consent.

Exclusion Criteria:

  • Any laboratory abnormality that may put the subject at increased risk by participating in this study.
  • Have any significant concurrent or past medical condition that would represent an unacceptable risk to the subject or might jeopardize the collection of high-quality data from the study. These include but are not limited to:

    • History of liver transplant, including hepatocyte therapy/transplant
    • History of liver disease
    • Positive viral serology test results for HIV type 1 or 2 antibodies, hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibody
    • Type I or Type II diabetes that is poorly controlled, in the opinion of the Investigator
    • Poorly controlled hypertension (defined as systolic blood pressure [BP] > 150 mm Hg or diastolic BP > 90 mm Hg)
    • Use of anticoagulants or platelet inhibitors, including but not limited to heparin and non-steroidal anti-inflammatory drugs (NSAIDS). Acetaminophen is permitted
  • Participation in previous clinical studies evaluating investigational OTCD therapies directed at expressing functional OTC protein (eg, OTC gene therapy studies)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03767270


Contacts
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Contact: Michelle Grossman, MS 781-918-6223 mgrossman@translate.bio
Contact: Caroline O'Hara 857-209-2450 cohara@translate.bio

Sponsors and Collaborators
Translate Bio, Inc.

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Responsible Party: Translate Bio, Inc.
ClinicalTrials.gov Identifier: NCT03767270     History of Changes
Other Study ID Numbers: MRT5201-101
2018-004095-35 ( EudraCT Number )
First Posted: December 6, 2018    Key Record Dates
Last Update Posted: December 6, 2018
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Translate Bio, Inc.:
OTC
Urea Cycle Disorder
UCD

Additional relevant MeSH terms:
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Ornithine Carbamoyltransferase Deficiency Disease
Urea Cycle Disorders, Inborn
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Genetic Diseases, X-Linked
Genetic Diseases, Inborn
Amino Acid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Metabolic Diseases