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

Primary Purpose

Ornithine Transcarbamylase Deficiency

Status

Withdrawn

Phase

Phase 1

Locations

Study Type

Interventional

Intervention

MRT5201

Placebo

About this trial

This is an interventional treatment trial for Ornithine Transcarbamylase Deficiency focused on measuring OTC, Urea Cycle Disorder, UCD

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Have a documented diagnosis of OTCD.
Documented history of ≥1 symptomatic hyperammonemia event with ammonia ≥100 µmol/L
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 -1)
- 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 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, other mRNA replacement therapy) that has led to the presence of anti-OTC antibodies.

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

MRT5201

Placebo

Arm Description

Single Ascending Low, Mid, and High doses of MRT5201

Placebo comparator using 5% dextrose in water at the same administration rate as study drug.

Outcomes

Primary Outcome Measures

The incidence of treatment-emergent adverse events by treatment group

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

Pharmacokinetics parameters of MRT5201

Pharmacokinetics of MRT5201 as measured by levels of mRNA

Effect of a single dose of MRT5201 on ureagenesis

Change from Baseline in 4-hour ureagenesis AUC at weeks 2, 3, 4, and 5 after a single dose of MRT5201

Effect of single dose of MRT5201 on metabolic markers of OTCD

Change from Baseline in 8-hour ammonia AUC

Full Information

NCT ID

NCT03767270

First Posted

November 28, 2018

Last Updated

September 12, 2019

Sponsor

Translate Bio, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT03767270

Brief Title

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

Acronym

STEP-OTC

Official Title

A Phase 1/2 Single Ascending Dose Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Intravenously Administered MRT5201 in Subjects With Ornithine Transcarbamylase Deficiency

Study Type

Interventional

2. Study Status

Record Verification Date

September 2019

Overall Recruitment Status

Withdrawn

Why Stopped

Program was discontinued.

Study Start Date

December 2019 (Anticipated)

Primary Completion Date

July 2022 (Anticipated)

Study Completion Date

July 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Translate Bio, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Ornithine Transcarbamylase Deficiency

Keywords

OTC, Urea Cycle Disorder, UCD

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Sequential Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

MRT5201

Arm Type

Experimental

Arm Description

Single Ascending Low, Mid, and High doses of MRT5201

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Placebo comparator using 5% dextrose in water at the same administration rate as study drug.

Intervention Type

Biological

Intervention Name(s)

MRT5201

Intervention Description

Codon-optimized human ornithine transcarbamylase messenger ribonucleic acid with lipid-based nanoparticles

Intervention Type

Other

Intervention Name(s)

Placebo

Intervention Description

5% dextrose in water

Primary Outcome Measure Information:

Title

The incidence of treatment-emergent adverse events by treatment group

Description

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.

Time Frame

Week 24

Secondary Outcome Measure Information:

Title

Pharmacokinetics parameters of MRT5201

Description

Pharmacokinetics of MRT5201 as measured by levels of mRNA

Time Frame

1 month after single dose

Title

Effect of a single dose of MRT5201 on ureagenesis

Description

Change from Baseline in 4-hour ureagenesis AUC at weeks 2, 3, 4, and 5 after a single dose of MRT5201

Time Frame

Up to 1 month after single dose

Title

Effect of single dose of MRT5201 on metabolic markers of OTCD

Description

Change from Baseline in 8-hour ammonia AUC

Time Frame

6 months after single dose

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Have a documented diagnosis of OTCD. Documented history of ≥1 symptomatic hyperammonemia event with ammonia ≥100 µmol/L 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 -1) 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 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, other mRNA replacement therapy) that has led to the presence of anti-OTC antibodies.

12. IPD Sharing Statement

Plan to Share IPD

Undecided

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

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