A Non-interventional, Post-Marketing Study to Describe Outcome of Nitisinone Treatment in HT-1 Patients

A Prospective, Non-interventional, Post-Marketing Study to Describe Outcome of Nitisinone Treatment in Hereditary Tyrosinemia Type 1 (HT-1) Patients in Routine Clinical Care in China

This is a prospective, non-interventional, non-comparative, multicenter study to collect data on HT-1 patients in China treated with Nitisinone in a routine clinical setting. No tests or examinations are mandated in the study.

Study Overview

• Status: Recruiting
• Conditions: Hereditary Tyrosinemia, Type I
• Intervention / Treatment: Drug: Nitisinone

Detailed Description

This is a prospective, non-interventional, non-comparative, multicenter study to collect data on HT-1 patients in China treated with Nitisinone in a routine clinical setting. No tests or examinations are mandated in the study, though the expectation is that most of the tests and examinations listed in the protocol will be performed in the context of routine clinical care and relevant data will be captured. At enrollment, data on patient treatment, medical and surgical history together with other patient characteristics will be captured.Patients enrolled in the study will be followed for at least 1 year and for a maximum of 3.5 years.

The study aims to enroll at least 15 HT-1 patients aged 0-18 years. If adult patients are enrolled the study population will be larger as all eligible patients will be invited to participate. However, the enrollment will close when the target of 15 patients aged 0-18 years has been reached.

• Study Type: Observational
• Enrollment (Estimated): 15

Contacts and Locations

• Study Contact: Name: Ioannis Kottakis, MD, PhD; Phone Number: +41 61 508 72 13; Email: Ioannis.Kottakis@sobi.com
• Study Contact Backup: Name: Catrine Berlin, MSc; Phone Number: +46(0)86972000; Email: Catrine.Berlin@sobi.com

Study Locations

• China
  • Beijing, China
    • Not yet recruiting
    • Swedish Orphan Biovitrum Research Site
  • Chongqing, China
    • Not yet recruiting
    • Swedish Orphan Biovitrum Research Site
  • Hefei, China
    • Recruiting
    • Swedish Orphan Biovitrum Research Site
  • Wuhan, China
    • Recruiting
    • Swedish Orphan Biovitrum Research Site

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Non-Probability Sample

Study Population

Investigators at selected sites in China will attempt to consecutively enroll all eligible patients who present for a routine clinical visit.

Description

Inclusion Criteria:

1. Patients with a confirmed diagnosis of HT-1 treated with, or at enrollment prescribed, Nitisinone treatment (product manufactured by Sobi) in a routine clinical care setting. The decision to initiate treatment shall be made by the treating physician independently from the decision to include the patient in the study.
2. Signed and dated informed consent provided by the patient, or the patient's legally authorized representative(s) for patients under the legal age, should be obtained before any study-related activities are undertaken. Assent should be obtained from pediatric patients according to local regulations

Exclusion Criteria:

1. Enrollment in a concurrent clinical interventional study, or intake of an Investigational Medicinal Product (IMP), within three months prior to inclusion in this study

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Full Analysis Set (FAS); The Full Analysis Set (FAS) will include all patients with a confirmed HT-1 diagnosis on Nitisinone treatment in routine clinical care, who provide signed informed consent. Patients must be either on treatment with Nitisinone at study entry or they must have been prescribed Nitisinone at enrollment. No specific exclusion criteria from the analysis set will be applied. The FAS will be used for all analyses.

Drug: Nitisinone; According to prescription; Other Names: Orfadin®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrence of hepatic, renal or hematological adverse events (AEs) or death	Number and percent of patients with occurrence and number of occurrences per 100 patient years.	Data will be collected for all routine visits completed during the study period which is at least 12 months but no more than 3.5 years.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrence of death	Number and percent of patients with occurrence and number of occurrences per 100 patient years.	Data will be collected for all routine visits completed during the study period which is at least 12 months but no more than 3.5 years.
Occurrence of liver transplantation	Number and percent of patients with occurrence and number of occurrences per 100 patient years.	Data will be collected for all routine visits completed during the study period which is at least 12 months but no more than 3.5 years.
Occurrence of hepatic malignancy	Number and percent of patients with occurrence and number of occurrences per 100 patient years.	Data will be collected for all routine visits completed during the study period which is at least 12 months but no more than 3.5 years.
Occurrence of other (non-hepatic) malignancies	Number and percent of patients with occurrence and number of occurrences per 100 patient years.	Data will be collected for all routine visits completed during the study period which is at least 12 months but no more than 3.5 years.
Occurrence of ophthalmic events	Number and percent of patients with occurrence and number of occurrences per 100 patient years.	Data will be collected for all routine visits completed during the study period which is at least 12 months but no more than 3.5 years.
Occurrence of neurological events	Number and percent of patients with occurrence and number of occurrences per 100 patient years.	Data will be collected for all routine visits completed during the study period which is at least 12 months but no more than 3.5 years.
Occurrence of cognitive, developmental function AEs	Cognitive, developmental function AEs will be recorded in the eCRF.	Data will be collected for all routine visits completed during the study period which is at least 12 months but no more than 3.5 years.
Occurrence of any reportable AEs	Number and percent of patients with occurrence and number of occurrences per 100 patient years. Reportable AEs are defined as: All Serious Adverse Events (SAEs) irrespective of causality with Nitisinone; Non-serious Adverse Events (AEs) assessed as causally related to treatment with Nitisinone; All Adverse Events leading to subject discontinuation from the study	Data will be collected for all routine visits completed during the study period which is at least 12 months but no more than 3.5 years.
Treatment and diet compliance	Rated from 1 ("very good") to 4 ("very poor") and "unknown". Number and percent of patients in each group.	Data will be collected for all routine visits completed during the study period which is at least 12 months but no more than 3.5 years.
Extent of exposure	Extent of exposure as measured by: Prescribed daily dose of Nitisinone; Changes in prescribed doses of Nitisinone	Data will be collected for all routine visits completed during the study period which is at least 12 months but no more than 3.5 years.
Extent of Exposure	Extent of exposure as measured by: Nitisinone trough concentrations in dried blood spot; Nitisinone trough concentrations in serum or plasma (depending on method)	Data will be collected for all routine visits completed during the study period which is at least 12 months but no more than 3.5 years.
Overall clinical condition as assessed by the investigator	Overall clinical condition will be assessed by the investigator on a 4-point scale; normal, mildly ill, moderately ill, markedly ill. Number and percent of patients in each group.	Data will be collected for all routine visits completed during the study period which is at least 12 months but no more than 3.5 years.
Ophthalmic status as assessed by the investigator	As assessed by the investigator ("yes, normal", "no, not normal", and "unknown"). Number and percent of patients in each group.	Data will be collected for all routine visits completed during the study period which is at least 12 months but no more than 3.5 years.
Neurocognitive/developmental status as assessed by the investigator	As assessed by the investigator ("yes, normal", "no, not normal", and "unknown"). Number and percent of patients in each group.	Data will be collected for all routine visits completed during the study period which is at least 12 months but no more than 3.5 years.
Laboratory investigations - Blood Coagulation (1)	Mean, median, standard deviation, minimum, and maximum time for ad-hoc specified age groups will be calculated for: • Prothrombin time (International Normalized Ratio)	Data will be collected for all routine visits completed during the study period which is at least 12 months but no more than 3.5 years.
Laboratory investigations - Blood Coagulation (2)	Mean, median, standard deviation, minimum, and maximum time for ad-hoc specified age groups will be calculated for: • Partial thromboplastin time (milliseconds)	Data will be collected for all routine visits completed during the study period which is at least 12 months but no more than 3.5 years.
Laboratory investigations - Blood Coagulation (3)	Mean, median, standard deviation, minimum, and maximum time for ad-hoc specified age groups will be calculated for: • Activated partial thromboplastin time (seconds per ration)	Data will be collected for all routine visits completed during the study period which is at least 12 months but no more than 3.5 years.
Laboratory investigations - Blood Chemistry (1)	Mean, median, standard deviation, minimum, and maximum concentration for ad-hoc specified age groups will be calculated for blood concentrations of: Tyrosine (µmol/L); Phenylalanine (µmol/L); Succinylacetone (µmol/L); Creatinine (µmol/L); Aspartate transaminase (µmol/L); Serum bilirubin (µmol/L)	Data will be collected for all routine visits completed during the study period which is at least 12 months but no more than 3.5 years.
Laboratory investigations - Blood Chemistry (2)	Mean, median, standard deviation, minimum, and maximum concentration for ad-hoc specified age groups will be calculated for blood concentrations of: • Alpha-fetoprotein (ng/mL)	Data will be collected for all routine visits completed during the study period which is at least 12 months but no more than 3.5 years.
Laboratory investigations - Blood Chemistry (3)	Mean, median, standard deviation, minimum, and maximum concentration for ad-hoc specified age groups will be calculated for blood concentrations of: Alanine transaminase (international units per liter); Alkaline phosphatase (international units per liter); Gamma-glutamyl transferase (international units per liter)	Data will be collected for all routine visits completed during the study period which is at least 12 months but no more than 3.5 years.
Laboratory investigations - Blood Chemistry (4)	Mean, median, standard deviation, minimum, and maximum concentration for ad-hoc specified age groups will be calculated for blood concentrations of: • Albumin (g/L)	Data will be collected for all routine visits completed during the study period which is at least 12 months but no more than 3.5 years.

Collaborators and Investigators

• Sponsor: Swedish Orphan Biovitrum
• Investigators: Study Director: Ioannis Kottakis, MD, PhD, Swedish Orphan Biovitrum; Principal Investigator: Xiaoping Luo, MD, PhD, Tongji Hospital, Tongji Medical College of Huazhong University of Science & Technology

Study record dates

Study Major Dates

• Study Start (Actual): December 14, 2023
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): June 30, 2027

Study Registration Dates

• First Submitted: December 19, 2023
• First Submitted That Met QC Criteria: January 17, 2024
• First Posted (Actual): January 26, 2024

Study Record Updates

• Last Update Posted (Estimated): February 7, 2024
• Last Update Submitted That Met QC Criteria: February 5, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: China; liver failure; observational research; phase IV; rare diseases; drug treatment; pediatric patient; nitisinone; fumarylacetoacetate hydrolase (FAH) deficiency
• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Amino Acid Metabolism, Inborn Errors; Tyrosinemias; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Nitisinone
• Other Study ID Numbers: Sobi.NTBC-008

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: According to Sobi's data sharing policy Sobi may share anonymized clinical study data with qualified researchers. Sobi commits to sharing clinical study data on participant level and summary data for medicines and indications approved by the European Medicines Agency (EMA) and/or the Food and Drug Administration (FDA). Data access will be granted in response to qualified research requests. All requests are evaluated by a cross functional panel of experts within Sobi.
• IPD Sharing Time Frame: Evaluated on a case by case basis

IPD Sharing Access Criteria

A decision on data sharing will be based on the following:

• The scientific merit of the proposal - i.e. the proposal should be scientifically sound, ethical, and have the potential to contribute to the advancement of public health.
• The feasibility of the research proposal - i.e. the requesting research team must be scientifically qualified and have the resources to conduct the proposed project.
• Maintenance of personal integrity - i.e. Sobi will not consider sharing individual data if there is a risk of re-identification of individuals despite a proper anonymisation. Moreover, the patients' informed consent will always be respected. Sobi reserves the right to reject the proposal if the anonymisation process will render unusable data.
• Publication of results - the applicants should commit to submit their findings to a peer-reviewed scientific journal, alternatively to present the results at a congress (poster or similar), regardless of the research outcome