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criskorea@korea.kr
  • Status : Approved
    • First Submitted Date : 2018/09/10
    • Registered Date : 2018/09/26
    • Last Updated Date : 2018/09/10
Background Information
1.Background  
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
Institutional Review Board Information
2. Institutional Review Board/Ethics Committee  
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  
- Address 88, Olympic-ro 43-gil, Songpa-gu, Seoul 
- Telephone 02-3010-7166 
Data Monitoring Committee Yes
Data and Safety Monitoring Board    
Contact Details
3.Contact Details  
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 
Status
4. Status Status  
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 Site Asan Medical Center 
- Recruitment Status Recruiting  
- Date of First Enrollment 2015-03-30 , Actual
Recruitment Status by Participating Study Site 2 
- Name of Study Site Seoul National University Hospital 
- Recruitment Status Recruiting  
- Date of First Enrollment 2015-09-14 , Actual
Recruitment Status by Participating Study Site 3 
- Name of Study Site Samsung Changwon Medical Center 
- Recruitment Status Completed  
- Date of First Enrollment 2016-09-12 , Actual
Source of Monetary / Material Support 정보
5. Source of Monetary/Material Support  
Source of Monetary/Material Support1 
- Organization Name ISU ABXIS 
- Organization Type Pharmaceutical Company  
- Project ID 해당사항 없음 
Sponsor Organization
6. Sponsor Organization  
Sponsor Organization 1 
- Organization Name Asan Medical Center 
- Organization Type Medical Institute  
Study Summary
7. Study Summary  
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.  
Study Design 정보
8. Study Design  
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
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. 
Subject Eligibility Information
9. Subject  
Condition(s)/Problem(s) * Endocrine, nutritional and metabolic disease
 
Rare Disease Yes
Inclusion
Criteria
Gender Both 
Age 2 Year ~ 60 Year
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
Outcome Measure(s) Information
10. Outcome Measure(s)  
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 
Study Results and Publication Information
11. Study Results and Publication
Result Registerd No
Sharing of Study Data Information
12. Sharing of Study Data(Deidentified Individual-Patient Data, IPD)
Sharing Statement Not provided at time of Registration