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Safety Evaluation of Gene Therapy Drug in the Treatment of Primary Hypertriglyceridemic Patients With Recurrent Pancreatitis

Primary Purpose

Hypertriglyceridemia, Familial

Status
Not yet recruiting
Phase
Phase 1
Locations
China
Study Type
Interventional
Intervention
GC304
Sponsored by
GeneCradle Inc
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hypertriglyceridemia, Familial

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Diagnosed as primary hypertriglyceridemia poorly managed by regular treatment and dietary control, with episode of acute pancreatitis twice or once of severe acute pancreatitis within 5 years; Fasting plasma triglycerides (TG) levels above 5.65 mmol/L (intake of dietary fat <30 g within 24 hours before blood taken); Homozygous or heterozygous mutations in GPIHBP1 or LPL genes by genetic screening; The patients within reproductive age take effective contraceptive measures voluntarily entering screening stage until 6 months after the trial; The patients fully understand and are able to comply with the requirements of the treatment and are willing to complete the trial as planned, including voluntary compliance with the trial procedures, acceptance of low-fat dietary requirements, and provide of biological samples. Be able to understand the procedures and methods of the trial and voluntarily participate with the signature of the informed consent by the patient or his/her guardian. Exclusion Criteria: Patient who is known to be allergic to any ingredient of a trial drug (including immunosuppressants) or has any disease prohibited from the treatment; Patient who is having active bacteria, fungi, viruses or other infections; Patient who is intolerant of immunosuppressive drugs or steroids; Patient who is with any of the following clinical history of serious illness or existing serious illness: unrelieved abdominal pain caused by acute onset of pancreatitis or by other causes; disease history of malignancy or currently suffering from any malignant tumor; autoimmune diseases; disease history of epilepsy or mental illness (e.g. schizophrenia, depression, mania, anxiety, etc.); heart diseases: cardiomyopathy and myocarditis; structural heart diseases; coronary heart disease (acute coronary syndrome, myocardial infarction); pericardial disease; severe arrhythmias (severe tachycardia requiring pacemakers, severe rapid arrhythmias, and other arrhythmias beyond the control of medications) ; New York Heart Association (NYHA) classification heart function grading ≥III or Left Ventricular Ejection Fraction (LVEF) ≤50%; poorly controlled diabetes (fasting blood glucose ≥11.1mmol/L); with systolic blood pressure (SBP) > 150mmHg and/or diastolic blood pressure (DBP) > 100mmHg after treatment with a stable dose (at least 4 weeks) of antihypertensive drugs; The results of the laboratory examination at screening meet either of the following: Aspartate transaminase (AST) or alanine transaminase (ALT) > 2 × upper limit of normals (ULN); Total bilirubin > upper limit of normals (ULN); Creatinine > upper limit of normals (ULN); Phosphatase kinase > 2 × upper limit of normals (ULN); Glomerular filtration rate estimate < 50 mL/min (estimated by the Cockroft-Gault formula); Positive hepatitis B surface antigen, positive hepatitis C antibody, positive HIV antibody or positive syphilis spiral antibody before or during screening; A positive blood pregnancy test; AAV5 neutralizing antibody levels above 1:100 Person who has used a clinical trial drug within 1 month (30 days) prior to screening, or who plans to participate in other clinical trials during the trial period; Blood loss/donation of more than 400 mL (except for female physiological blood loss) within 3 months (90 days) before screening, and receiving blood transfusion or using blood products; Person who has undergone major surgery within 3 months (90 days) prior to screening, or who has undergone surgery that could significantly affect the course or safety evaluation of the trial drug; Alcohol consumption was high in the first 3 months (90 days), i.e. the average alcohol intake was greater than 3 units/day (Male) or 2 units/days (female) (1 unit = 18ml alcohol, such as beer 360 ml with 5% alcohol, 12% wine 150ml, 40% liquor 45ml); or who cannot abstain from drinking during the trial; Women who are pregnant, pregnant or breastfeeding, or all persons of reproductive age who are unable to take effective contraceptives until 3 months after the completion of the study; Patients who have poor compliance or who may not be able to complete the test for other reasons, or whom the investigator considers inappropriate to participate in the trial.

Sites / Locations

  • Affiliated Jinling Hospital, Medical School, Nanjing University

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Cohort 1

Cohort 2

Cohort 3

Arm Description

1.0x10^13 vg/kg of GC304 delivered one-time intravenously (n=3)

3.0x10^13 vg/ kg of GC304 delivered one-time i intravenously (n=3)

5.0x10^13 vg/ kg of GC304 delivered one-time i intravenously (n=3)

Outcomes

Primary Outcome Measures

Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability])
Frequency of treatment-related adverse events (AEs), serious adverse events (SAEs), and changes from baseline in relevant clinical laboratory tests

Secondary Outcome Measures

Changes of plasma triglyceride levels from baseline
The proportion of patients who stop taking hypolipidemic drugs;
Copy numbers of viral vector DNA [Shedding of viral vectors];
Titers of antibody against viral vector
The proportion of patients treated with GC304 who achieve 40% reduction of plasma triglyceride levels;
Titers of antibody against LPL (lipoprotein lipase) protein

Full Information

First Posted
April 23, 2023
Last Updated
May 5, 2023
Sponsor
GeneCradle Inc
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1. Study Identification

Unique Protocol Identification Number
NCT05860569
Brief Title
Safety Evaluation of Gene Therapy Drug in the Treatment of Primary Hypertriglyceridemic Patients With Recurrent Pancreatitis
Official Title
A Multi-center, Open Label, Multi-arm, Dose Ascending Clinical Trial for Evaluation of Safety and Tolerance of Gene Therapy Drug GC304 in the Treatment of Primary Hypertriglyceridemia Patients With History of Acute Pancreatitis
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
December 2023 (Anticipated)
Primary Completion Date
December 2025 (Anticipated)
Study Completion Date
December 2028 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
GeneCradle Inc

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The study will evaluate safety and tolerance of intravenous delivery of GC304 gene therapy drug as a treatment of primary hypertriglyceridemic patients with previous onset of acute pancreatitis.
Detailed Description
The purpose of this trial is to evaluate safety and tolerance of gene therapy drug GC304 in primary hypertriglyceridemic patients who have loss of function mutations in GPIHBP1 or LPL genes, with previous onset of acute pancreatitis. Open-label, dose-escalation clinical trial of GC304 will be conducted in China. GC304 will be administrated intravenously. Short-term safety will be evaluated in 52 weeks and enter long-term follow-up study of 5 years at will. Patients will be tested at baseline and followed up on various time points.

6. Conditions and Keywords

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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
12 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Cohort 1
Arm Type
Experimental
Arm Description
1.0x10^13 vg/kg of GC304 delivered one-time intravenously (n=3)
Arm Title
Cohort 2
Arm Type
Experimental
Arm Description
3.0x10^13 vg/ kg of GC304 delivered one-time i intravenously (n=3)
Arm Title
Cohort 3
Arm Type
Experimental
Arm Description
5.0x10^13 vg/ kg of GC304 delivered one-time i intravenously (n=3)
Intervention Type
Genetic
Intervention Name(s)
GC304
Intervention Description
Self-complementary adeno-associated virus serotype 5 (AAV5) carrying a codon-optimized LPL coding sequence(coLPL) driven by a liver-specific promoter (LP)
Primary Outcome Measure Information:
Title
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability])
Description
Frequency of treatment-related adverse events (AEs), serious adverse events (SAEs), and changes from baseline in relevant clinical laboratory tests
Time Frame
12 weeks
Secondary Outcome Measure Information:
Title
Changes of plasma triglyceride levels from baseline
Time Frame
12 weeks
Title
The proportion of patients who stop taking hypolipidemic drugs;
Time Frame
12 weeks
Title
Copy numbers of viral vector DNA [Shedding of viral vectors];
Time Frame
12 weeks
Title
Titers of antibody against viral vector
Time Frame
12 weeks
Title
The proportion of patients treated with GC304 who achieve 40% reduction of plasma triglyceride levels;
Time Frame
12 weeks
Title
Titers of antibody against LPL (lipoprotein lipase) protein
Time Frame
12 weeks
Other Pre-specified Outcome Measures:
Title
Changes of LPL activity in post-heparin plasma from baseline;
Time Frame
52 weeks
Title
Frequency of onset of acute pancreatitis after administration of GC304;
Time Frame
52 weeks
Title
Changes of plasma triglyceride levels from baseline;
Time Frame
52 weeks
Title
The proportion of patients who stop taking hypolipidemic drugs;
Time Frame
52 weeks
Title
The proportion of patients treated with GC304 who achieve 40% reduction of plasma triglyceride levels.
Time Frame
52 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Diagnosed as primary hypertriglyceridemia poorly managed by regular treatment and dietary control, with episode of acute pancreatitis twice or once of severe acute pancreatitis within 5 years; Fasting plasma triglycerides (TG) levels above 5.65 mmol/L (intake of dietary fat <30 g within 24 hours before blood taken); Homozygous or heterozygous mutations in GPIHBP1 or LPL genes by genetic screening; The patients within reproductive age take effective contraceptive measures voluntarily entering screening stage until 6 months after the trial; The patients fully understand and are able to comply with the requirements of the treatment and are willing to complete the trial as planned, including voluntary compliance with the trial procedures, acceptance of low-fat dietary requirements, and provide of biological samples. Be able to understand the procedures and methods of the trial and voluntarily participate with the signature of the informed consent by the patient or his/her guardian. Exclusion Criteria: Patient who is known to be allergic to any ingredient of a trial drug (including immunosuppressants) or has any disease prohibited from the treatment; Patient who is having active bacteria, fungi, viruses or other infections; Patient who is intolerant of immunosuppressive drugs or steroids; Patient who is with any of the following clinical history of serious illness or existing serious illness: unrelieved abdominal pain caused by acute onset of pancreatitis or by other causes; disease history of malignancy or currently suffering from any malignant tumor; autoimmune diseases; disease history of epilepsy or mental illness (e.g. schizophrenia, depression, mania, anxiety, etc.); heart diseases: cardiomyopathy and myocarditis; structural heart diseases; coronary heart disease (acute coronary syndrome, myocardial infarction); pericardial disease; severe arrhythmias (severe tachycardia requiring pacemakers, severe rapid arrhythmias, and other arrhythmias beyond the control of medications) ; New York Heart Association (NYHA) classification heart function grading ≥III or Left Ventricular Ejection Fraction (LVEF) ≤50%; poorly controlled diabetes (fasting blood glucose ≥11.1mmol/L); with systolic blood pressure (SBP) > 150mmHg and/or diastolic blood pressure (DBP) > 100mmHg after treatment with a stable dose (at least 4 weeks) of antihypertensive drugs; The results of the laboratory examination at screening meet either of the following: Aspartate transaminase (AST) or alanine transaminase (ALT) > 2 × upper limit of normals (ULN); Total bilirubin > upper limit of normals (ULN); Creatinine > upper limit of normals (ULN); Phosphatase kinase > 2 × upper limit of normals (ULN); Glomerular filtration rate estimate < 50 mL/min (estimated by the Cockroft-Gault formula); Positive hepatitis B surface antigen, positive hepatitis C antibody, positive HIV antibody or positive syphilis spiral antibody before or during screening; A positive blood pregnancy test; AAV5 neutralizing antibody levels above 1:100 Person who has used a clinical trial drug within 1 month (30 days) prior to screening, or who plans to participate in other clinical trials during the trial period; Blood loss/donation of more than 400 mL (except for female physiological blood loss) within 3 months (90 days) before screening, and receiving blood transfusion or using blood products; Person who has undergone major surgery within 3 months (90 days) prior to screening, or who has undergone surgery that could significantly affect the course or safety evaluation of the trial drug; Alcohol consumption was high in the first 3 months (90 days), i.e. the average alcohol intake was greater than 3 units/day (Male) or 2 units/days (female) (1 unit = 18ml alcohol, such as beer 360 ml with 5% alcohol, 12% wine 150ml, 40% liquor 45ml); or who cannot abstain from drinking during the trial; Women who are pregnant, pregnant or breastfeeding, or all persons of reproductive age who are unable to take effective contraceptives until 3 months after the completion of the study; Patients who have poor compliance or who may not be able to complete the test for other reasons, or whom the investigator considers inappropriate to participate in the trial.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
GeneCradle, Inc. China
Phone
86-13501380583
Email
ind@bj-genecradle.com
Facility Information:
Facility Name
Affiliated Jinling Hospital, Medical School, Nanjing University
City
Nanjing
Country
China
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Weiqin Li

12. IPD Sharing Statement

Plan to Share IPD
No

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Safety Evaluation of Gene Therapy Drug in the Treatment of Primary Hypertriglyceridemic Patients With Recurrent Pancreatitis

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