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An open, phase I/II, investigator initiated trial to evaluate the safety and efficacy of high dose ambroxol in combination with enzyme replacement therapy in Gaucher disease patients

Status Approved

  • First Submitted Date

    2018/09/10

  • Registered Date

    2018/09/26

  • Last Updated Date

    2018/10/17

  • 1. Background

    Background - CRIS Registration Number, Unique Protocol ID, Public/Brief Title, Scientific Title, Acronym, MFDS Regulated Study, IND/IDE Protocol, Registered at Other Registry, Name of Registry/Registration Number
    CRIS
    Registration Number
    KCT0003218
    Unique Protocol ID GD-AMBX-02
    Public/Brief Title The trial to evaluate the safety and efficacy of high dose ambroxol in combination with enzyme replacement therapy in Gaucher disease patients
    Scientific Title An open, phase I/II, investigator initiated trial to evaluate the safety and efficacy of high dose ambroxol in combination with enzyme replacement therapy in Gaucher disease patients
    Acronym
    MFDS Regulated Study Yes
    IND/IDE Protocol Yes
    Registered at Other Registry No
    Healthcare Benefit Approval Status Not applicable
  • 2. Institutional Review Board / Ethics Committee

    Institutional Review Board Information
    Board Approval Status Submitted approval
    Board Approval Number 2014-1113
    Approval Date 2014-11-13
    Institutional Review Board Name Asan Medical Center Institutional Review Board
    Institutional Review Board Address 88, Olympic-ro 43-gil, Songpa-gu, Seoul
    Institutional Review Board Telephone 02-3010-7166
    Data Monitoring Committee Yes
    Data and Safety Monitoring Board
  • 3. Contact Details

    Contact Details Information - Contact Person for Principal Investigator / Scientific Queries, Contact Person for Public Queries, Contact Person for Updating Information의 Name, Title, Email, Telephone, Cellular Phone, Affiliation, Address
    Contact Person for Principal Investigator / Scientific Queries
    Name Yoo Han Wook
    Title Professor
    Telephone +82-2-3010-3374
    Affiliation Asan Medical Center
    Address 88, Olympic-ro 43-gil, Songpa-gu, Seoul, Republic of Korea
    Contact Person for Public Queries
    Name Yoo Han Wook
    Title Professor
    Telephone +82-2-3010-3374
    Affiliation Asan Medical Center
    Address 88, Olympic-ro 43-gil, Songpa-gu, Seoul, Republic of Korea
    Contact Person for Updating Information
    Name Yoo Han Wook
    Title Professor
    Telephone +82-2-3010-3374
    Affiliation Asan Medical Center
    Address 88, Olympic-ro 43-gil, Songpa-gu, Seoul, Republic of Korea
  • 4. Status

    Status Information - Study Site, Overall Recruitment Status, Date of First Enrollment, Status of First Enrollment, Target Number of Participant, Primary Completion Date, Recruitment Status by Participating Study Site, Name of Study Site, Recruitment Status, Date of First Enrollment, Status of First Enrollemnt
    Study Site Multi-center Number of center : 3
    Overall Recruitment Status Recruiting
    Date of First Enrollment 2015-03-30 Actual
    Target Number of Participant 10
    Primary Completion Date 2022-09-05 , Anticipated
    Study Completion Date 2023-03-05 , Anticipated
    Recruitment Status by Participating Study Site 1
    Name of Study Asan Medical Center
    Recruitment Status Recruiting
    Date of First Enrollment 2015-03-30 ,
    Recruitment Status by Participating Study Site 2
    Name of Study Seoul National University Hospital
    Recruitment Status Recruiting
    Date of First Enrollment 2015-09-14 ,
    Recruitment Status by Participating Study Site 3
    Name of Study Samsung Changwon Medical Center
    Recruitment Status Completed
    Date of First Enrollment 2016-09-12 ,
  • 5. Source of Monetary / Material Support

    Source of Monetary / Material Support Information - Organization Name, Organization Type, Project ID
    1. Source of Monetary/Material Support
    Organization Name ISU ABXIS
    Organization Type Pharmaceutical Company
    Project ID 해당사항 없음
  • 6. Sponsor Organization

    Sponsor Organization Information - Organization Name, Organization Type
    1. Sponsor Organization
    Organization Name Asan Medical Center
    Organization Type Medical Institute
  • 7. Study Summary

    Study Summary Information
    Lay Summary
    Gaucher’s disease is typical lysosomal storage disease, which is characterized by deficiency of β glucocerebrosidase (GBA), a hydrolytic enzyme of lysosomes, which is caused that accumulation of glucocerebroside that kind of sphingolipid in the multiple organs like liver, spleen, central nervous system, skeleton and lung. That disease is typical disease with proven efficacy of enzyme replacement therapy (ERT), ERT is known to be very helpful in improving hepatosplenomegaly and hematologic findings in Gaucher’s disease. About 1,400 in the libraries of approved from FDA screened that can improve the residual enzyme activity of GBA utilized the thermal denaturation assay. Among them, only ambroxol(ABX) is described to increase enzyme efficacy significantly.
    The objective of this study is to evaluate the safety and impact of oral administration of high-dose ambroxol in combination with enzyme replacement therapy on enzyme activities and neurological symptoms in Gaucher disease patients thereby providing grounds for the future use of adjunctive treatment for Gaucher disease patients who are on enzyme replacement therapy. Additionally, it is to evaluate the pharmacokinetics of oral administration of high-dose ambroxol in combination with enzyme replacement
    therapy in Gaucher disease patients.
    The sample size is up to 10 subjects of this study. Gaucher disease patients who have been treated with standard-of-care therapy for the disease, i.e., enzyme replacement therapy (imiglucerase, Abcertin Inj. etc.), will continue to be treated with the same dose of the enzyme replacement therapy for 192 weeks (48 months). The patients divided into 2 group: patients who have been treated with ambroxol or not, and applies to the each method about the usage and dosage.
  • 8. Study Design

    Study Design Information - Study Type, Study Purpose, Phase, Intervention Model, Blinding/Masking, Blinded Subject, Allocation, Intervention Type, Intervention Description, Number of Arms, Arm Label, Target Number of Participant, Arm Type, Arm Description
    Study Type Interventional Study
    Study Purpose
    Treatment
    Phase Phase1/Phase2
    Intervention Model Single Group  
    Blinding/Masking Open
    Allocation Non-RCT
    Intervention Type Drug  
    Intervention Description
    Ambroxol is an oral administration drug.
    1. Gaucher disease patients who have been treated with standard-of-care therapy for the disease, i.e., enzyme replacement therapy (imiglucerase, Abcertin Inj. etc.), will continue to be treated with the same dose of the enzyme replacement therapy for 192 weeks (48 months).
    2. The patients divided into 2 group: patients who have been treated with ambroxol or not, and applies to the each method about the usage and dosage. Both group can be escalated by 3 mg/kg/day every 4-8 weeks (1-2 months) up to 35 mg/kg /day (dose should not exceed 1,300 mg/day). Given the objective of this study, ambroxol will be administered to subjects at the age of 17 or older at a dose that does not exceed 1,300 mg/day for at least 6 months, and then drug tolerability and status of serious adverse events (SAEs) will be determined.
    Ambroxol dose will be maintained at a blood concentration of 10 µmol/L or below.
    Number of Arms 1
    Arm 1

    Arm Label

    Gaucher disease patients who are on enzyme replacement therapy

    Target Number of Participant

    10

    Arm Type

    Experimental

    Arm Description

    Ambroxol is an oral administration drug.
    1. Gaucher disease patients who have been treated with standard-of-care therapy for the disease, i.e., enzyme replacement therapy (imiglucerase, Abcertin Inj. etc.), will continue to be treated with the same dose of the enzyme replacement therapy for 192 weeks (48 months).
    2. The patients divided into 2 group: patients who have been treated with ambroxol or not, and applies to the each method about the usage and dosage. Both group can be escalated by 3 mg/kg/day every 4-8 weeks (1-2 months) up to 35 mg/kg /day (dose should not exceed 1,300 mg/day). Given the objective of this study, ambroxol will be administered to subjects at the age of 17 or older at a dose that does not exceed 1,300 mg/day for at least 6 months, and then drug tolerability and status of serious adverse events (SAEs) will be determined.
    Ambroxol dose will be maintained at a blood concentration of 10 µmol/L or below.
  • 9. Subject Eligibility

    Subject Eligibility Information
    Condition(s)/Problem(s) * (E00-E90)Endocrine, nutritional and metabolic diseases 
       (E75.2)Other sphingolipidosis 
    Rare Disease Yes
    Inclusion Criteria

    Gender

    Both

    Age

    2Year~60Year

    Description

    1) Male and female subjects aged between 2 and 60 years old, inclusive
    2) Patients diagnosed with Gaucher disease by genetic testing or enzyme activity assay
    3) Voluntarily signed written informed consent by patients or by both patients and their representatives
    Exclusion Criteria
    1) Patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2)
    2) Patients with severe hepatic impairment (Child-Pugh class C)
    3) Patients with genetic predisposition to lactose intolerance, galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption
    4) Patients with known active hepatitis, HIV positive, or other uncontrolled infectious diseases
    5) Patients who are unable to orally administer the study drug 
    6) Patients with hypersensitivities to the study drug or any of its components 
    7) Pregnant and lactating women, men and women of childbearing potential who are not willing to practice abstinence or use appropriate methods of contraception during the study
    8) Patients who participated in any clinical trials other than GD-AMBX-01 within 90 days from treatment with the investigational product
    9) Patients who are unable to participate in the study for other reasons, according to the investigator
    Healthy Volunteers No
  • 10. Outcome Measure(s)

    Outcome Measure(s) Information - Type of Primary Outcome, Primary Outcome, Outcome, Timepoint, Secondary Outcome, Outcome, Timepoint
    Type of Primary Outcome Safety
    Primary Outcome(s) 1
    Outcome
    Adverse events (AEs) (Renal dysfunction, hepatic disease, digestive disorder, allergy and anaphylactoid reaction, Stevens-Johnson syndrome, Lyell syndrome, purulent rhinitis, etc.)
    Timepoint
    Whole period of study
    Primary Outcome(s) 2
    Outcome
    Laboratory tests (hematology, blood chemistry, blood coagulation, and urinalysis)
    Timepoint
    Whole period of study
    Primary Outcome(s) 3
    Outcome
    Vital signs (blood pressure, pulse, body temperature) and body measurements (body mass index)
    Timepoint
    Whole period of study
    Primary Outcome(s) 4
    Outcome
    Electrocardiogram (ECG) and chest X-ray
    Timepoint
    Whole period of study
    Secondary Outcome(s) 1
    Outcome
    Primary efficacy endpoint_Change in modified severity scoring tool (mSST) score
    Timepoint
    Screening and each visits after administrative IP
    Secondary Outcome(s) 2
    Outcome
    Secondary efficacy endpoints_Change in residual enzyme activity of GBA before treatment with enzyme replacement therapy
    Timepoint
    Screening and each visits after administrative IP
    Secondary Outcome(s) 3
    Outcome
    Secondary efficacy endpoints_Change in residual enzyme activity of GBA after treatment with enzyme replacement therapy
    Timepoint
    Screening and each visits after administrative IP
    Secondary Outcome(s) 4
    Outcome
    Secondary efficacy endpoints_Change in latency and threshold of brainstem auditory evoked response (BAER)
    Timepoint
    Screening and each visits after administrative IP
    Secondary Outcome(s) 5
    Outcome
    Secondary efficacy endpoints_Change in N-acetyl acid/creatinine (NAA/Cr) and choline/creatinine (Cho/Cr) on brain magnetic resonance spectroscopy (MRS)
    Timepoint
    Screening and each visits after administrative IP
    Secondary Outcome(s) 6
    Outcome
    Secondary efficacy endpoints_Improvement rate of ocular motility disorders
    Timepoint
    Screening and each visits after administrative IP
    Secondary Outcome(s) 7
    Outcome
    Secondary efficacy endpoints_Change in angle of esotropia
    Timepoint
    Screening and each visits after administrative IP
    Secondary Outcome(s) 8
    Outcome
    Secondary efficacy endpoints_Change in biomarkers of Gaucher disease (acid phosphatase, angiotensin converting enzyme, and chitotriosidase)
    Timepoint
    Screening and each visits after administrative IP
    Secondary Outcome(s) 9
    Outcome
    Secondary efficacy endpoints_Change in hemoglobin concentrations
    Timepoint
    Screening and each visits after administrative IP
    Secondary Outcome(s) 10
    Outcome
    Secondary efficacy endpoints_Change in platelet levels
    Timepoint
    Screening and each visits after administrative IP
    Secondary Outcome(s) 11
    Outcome
    Secondary efficacy endpoints_Change in bone mineral density (BMD)
    Timepoint
    Screening and each visits after administrative IP
    Secondary Outcome(s) 12
    Outcome
    Secondary efficacy endpoints_Change in intelligence test scores
    Timepoint
    Screening and each visits after administrative IP
    Secondary Outcome(s) 13
    Outcome
    Secondary efficacy endpoints_Change in the frequency of seizures
    Timepoint
    every visit except of screening visit
    Secondary Outcome(s) 14
    Outcome
    Secondary efficacy endpoints_Change in the size of liver and spleen
    Timepoint
    Screening and each visits after administrative IP
    Secondary Outcome(s) 15
    Outcome
    Exploratory endpoints_Transfer ratio of ambroxol (CSF to serum ambroxol concentration ratio)
    Timepoint
    At the discretion of the investigator, a maximum of 2 times
    Secondary Outcome(s) 16
    Outcome
    Exploratory endpoints_Pharmacokinetic parameter: serum Cmax, Tmax, t1/2, CL, AUCτau, etc.
    Timepoint
    At the discretion of the investigator, a maximum of 2 times
  • 11. Study Results and Publication

    Study Results and Publication Information - Result Registered, Final Enrollment Number, Number of Publication, Publications, Results Upload, Date of Posting Results, Protocol URL or File Upload, Brief Summary
    Result Registered No
  • 12. Sharing of Study Data(Deidentified Individual-Patient Data, IPD)

    Sharing of Study Data Information - Sharing Statement, Time of Sharing, Way of Sharing
    Sharing Statement Not provided at time of Registration

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