Orphan Europe Carbaglu® Surveillance Protocol

The purpose of this study is to conduct post-marketing surveillance of carglumic acid (Carbaglu) to obtain long-term clinical safety information. Carglumic acid was approved by the United States Food and Drug Administration (FDA) for treatment of acute hyperammonemia due to N-acetylglutamate synthase (NAGS) deficiency. Much of the FDA-required data is already collected through the Longitudinal Study of Urea Cycle Disorders (RDCRN Protocol #5101). This study will collect additional data on adverse events (interim events), adverse reactions, pregnancy, and fetal outcomes.

Study Overview

• Status: Recruiting
• Conditions: N-acetylglutamate Synthase (NAGS) Deficiency

Detailed Description

Among the urea cycle disorders, N-acetylglutamate synthase (NAGS) deficiency is the rarest type. In 2010, carglumic acid (Carabglu) was approved by the United States Food and Drug Administration (FDA) "as an adjunctive therapy for the treatment of acute hyperammonemia due to the deficiency of the hepatic enzyme NAGS, and as maintenance therapy for chronic hyperammonemia due to NAGS deficiency." As post-marketing requirements, the US FDA requests that Orphan Europe (OE) conduct:

1604-2: A registry of patients, with NAGS deficiency being treated with carglumic acid to obtain long-term clinical safety information. Data will include patient demographics, details of treatment with carglumic acid, other therapies for hyperammonemia, dietary protein management, clinical status, neurocognitive and psychomotor status, growth and development status, and adverse events. Information from this registry is submitted to the FDA annually (in annual reports) with a final report submitted at 15 years post-approval.

1604-3: A study of the effects of carglumic acid on pregnancy and fetal outcomes. This study can be performed as a sub-study within the registry for all patients with NAGS deficiency. Information on pregnancy and fetal outcomes should be submitted annually (in annual reports) with a final report submission at 15 years post-approval.

This patient registry or surveillance protocol will be facilitated by collaboration with the existing National Institutes of Health (NIH) sponsored Urea Cycle Disorders Consortium (UCDC) Longitudinal Study of Urea Cycle Disorders (RDCRN Protocol #5101) (including NAGS deficiency) in the United States. The Longitudinal Study is sponsored by the NIH and other philanthropic sources. It is an academically governed network with the objective to conduct a longitudinal multidisciplinary investigation of the natural history, morbidity and mortality in people with UCD. It therefore aims to collect data on all patients with NAGS deficiency in the US. Measures in the Longitudinal Study are compatible with a Carbaglu post-marketing study including: developmental outcome, medical history, interval medical history, adverse events (interim events), pregnancy history, physical exam, vital signs, laboratory evaluation, dietary history, and medication records. Additional data on drug related adverse events and pregnancy outcomes will is collected for OE for FDA reporting.

• Study Type: Observational
• Enrollment (Estimated): 30

Contacts and Locations

• Study Contact: Name: Jennifer Seminara, MPH; Phone Number: 2023066489; Email: jseminar@childrensnational.org

Study Locations

• United States
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Recruiting
      • Children's National Medical Center
      • Contact: Kara Simpson, MS, CGC; Phone Number: 202-476-6216; Email: ksimpson@childrensnational.org
      • Principal Investigator: Nicholas Ah Mew, MD
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Children's Hospital Boston (UCDC New England Center)
      • Sub-Investigator: Harvey Levy, MD
      • Contact: Debbie Fu; Phone Number: 617-919-7631; Email: Yu-Ting.Fu@childrens.harvard.edu
      • Principal Investigator: Gerry Berry, MD
  • New York
    • New York, New York, United States, 10029
      • Recruiting
      • Icahn School of Medicine at Mount Sinai
      • Principal Investigator: Margo Breilyn, MD
      • Contact: Alison Horn; Phone Number: 212-659-8540; Email: alison.tiao@mssm.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Confirmed diagnosis of NAGS deficiency or suspicion of NAGS deficiency, taking Carbaglu for the treatment of NAGS, and enrolled in the Longitudinal Study of Urea Cycle Disorders (RDCRN protocol #5101)

Description

Inclusion Criteria:

• Confirmed diagnosis of NAGS deficiency or suspicion of NAGS deficiency
• Carbaglu intake for the treatment of NAGS
• Enrolled in the Longitudinal Study of Urea Cycle Disorders (RDCRN protocol #5101)

Exclusion Criteria:

• Cases of hyperammonemia caused by other urea cycle disorders
• Organic acidemia, lysinuric protein intolerance
• Mitochondrial disorders
• Congenital lactic acidemia,
• Fatty acid oxidation defects
• Primary liver disease will be excluded
• Individuals with extreme low birth weight (<1,500 grams) will be also excluded.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Carbaglu related adverse events and adverse reactions	The primary outcome measure is to monitor adverse events and adverse reactions, which will be reported to the FDA to fulfill post-marketing surveillance requirements.	15 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of hyperammonemic events	The number of hyperammonemic events (ammonia > 100 umol/L) will be monitored in participants taking Carbaglu to ensure there are no significant adverse changes	15 years
IQ	IQ will be monitored in participants taking Carbaglu to ensure there are no significant adverse changes	15 years
Height	Height (cm) will be monitored in participants taking Carbaglu to ensure there are no significant adverse changes	15 years
Weight	Weight (kg) will be monitored in participants taking Carbaglu to ensure there are no significant adverse changes	15 years
Abnormal physical and neurological findings	Any abnormal physical and neurological findings reported will be investigated as potential adverse reactions/adverse events (see primary outcome measure). Investigators conducts a review of systems and indicates whether findings are normal, abnormal or not assessed. Each abnormal finding is coded using SNOMED codes.	15 years

Collaborators and Investigators

• Sponsor: Nicholas Ah Mew
• Collaborators: Icahn School of Medicine at Mount Sinai; Boston Children's Hospital
• Investigators: Principal Investigator: Nicholas Ah Mew, MD, Children's National Health System

Publications and helpful links

Helpful Links

• 5111: Orphan Europe Carbaglu® Surveillance Protocol In Collaboration with the Longitudinal Study of Urea Cycle Disorders
• Orphan Europe Products - Carbaglu

Study record dates

Study Major Dates

• Study Start: April 1, 2012
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): January 1, 2027

Study Registration Dates

• First Submitted: November 18, 2016
• First Submitted That Met QC Criteria: January 17, 2018
• First Posted (Actual): January 24, 2018

Study Record Updates

• Last Update Posted (Estimated): February 7, 2024
• Last Update Submitted That Met QC Criteria: February 6, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: urea cycle disorder
• Other Study ID Numbers: UCDC5111

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: This is a post-marketing surveillance study being performed so that Orphan Europe (OE) can meet its post FDA approval reporting obligations. Data will be shared with OE who will then report to the FDA. There are no other plans to make this data available to other researchers.