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Ambroxol Therapy for Patients With Type 1 Gaucher Disease and Suboptimal Response to Enzyme Replacement Therapy

Primary Purpose

Gaucher Disease, Type 1

Status
Completed
Phase
Phase 2
Locations
Israel
Study Type
Interventional
Intervention
Ambroxol
Sponsored by
Shaare Zedek Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Gaucher Disease, Type 1

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

*Adult patients ≥ 18 years with type 1 GD and suboptimal response to ERT defined as one or more than one of the following: platelet count < 100 x 103/mm3 bone mineral density < -2 T score Lyso-GB1 > 200 ng/ml.

*No change in dose or preparation of ERT in the last 12 months (Except for Naive patients)

Exclusion Criteria:

  • Patients with comorbidity that may impact on the primary and/or secondary endpoint.
  • Pregnant women will be excluded from the study.
  • Inability to cooperate with the study procedure
  • Hypersensitivity or any other contraindication listed in the local labeling of ambroxol
  • Refusal of patients to participate in the study.

Sites / Locations

  • Shaare Zedek Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Ambroxol

Arm Description

Ambroxol therapy will be dosed up to 600 mg/day divided to twice a day starting 150 mg for the first month, 300 mg for the following month and 600 mg for the following month. The study was conducted in accordance with the provisions of the Declaration of Helsinki, Good Clinical Practice guidelines, and local laws and regulations.

Outcomes

Primary Outcome Measures

Platelets count
Increase in platelet count
bone mineral density evaluated by Dual Energy X-ray Absorptiometry (DEXA)
Bone Mineral Densitometry (BMD)
Lyso-GB1 biomarker for Gaucher disease
decrease in Lyso-GB1.

Secondary Outcome Measures

Patient-reported outcomes (PRO)
Improve in PRO from baseline
Fatigue Severity Scale (FSS)
Improve in FSS from baseline

Full Information

First Posted
August 6, 2018
Last Updated
February 12, 2023
Sponsor
Shaare Zedek Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT03950050
Brief Title
Ambroxol Therapy for Patients With Type 1 Gaucher Disease and Suboptimal Response to Enzyme Replacement Therapy
Official Title
Ambroxol Therapy for Patients With Type 1 Gaucher Disease and Suboptimal Response to Enzyme Replacement Therapy
Study Type
Interventional

2. Study Status

Record Verification Date
May 2022
Overall Recruitment Status
Completed
Study Start Date
March 1, 2019 (Actual)
Primary Completion Date
November 30, 2022 (Actual)
Study Completion Date
December 30, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Shaare Zedek Medical Center

4. Oversight

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

5. Study Description

Brief Summary
Ambroxol hydrochloride, an over-the-counter antitussive available in many markets , was identified as an interesting pharmacological chaperone. In addition to a mucolytic action, ambroxol has antioxidant and anti-inflammatory properties. Importantly, ambroxol therapy was found safe when given to pregnant women for prevention of neonatal respiratory distress syndrome . Thus, ambroxol, an oral available drug on the market, may be a safe option for GD patients with potential disease-specific efficacy and should be expanded into a clinical trial using higher doses and placebo-controlled design. The investigators propose to start with a phase II study for patients with type 1 GD and suboptimal response to ERT. In addition the investigators plan to open an international registry of patients with GD currently receiving ambroxol (off study).
Detailed Description
Introduction: Description of the Problem: Enzyme replacement therapy (ERT) makes a significant impact on the clinical manifestations and quality of life of patients with Gaucher disease (GD) . The goals of therapy focus mainly on platelets, hemoglobin, spleen, liver, bones and growth parameters for children. ERT is mostly effective in patients with type 1 GD; still some patients don't achieve normalization or near normalization of the therapeutic targets . Glucosylsphingosine (LysoGb1) is the most specific and sensitive, and hence is probably the best currently available GD biomarker. A level of LysoGB1 < 140 ng/ml is considered a marker for controlled GD (personal communication). Patients with GD may also experience chronic fatigue that causes functional disability and adversely affects quality of life . The fatigue severity scale (FSS) is a 9-item tool; each item is scored on a scale from 1 to 7, with a mean score of 4 or higher considered to represent significant fatigue . Patients with GD have improvements in fatigue within 6 months of starting ERT, and that it may be among the first symptoms to show significant improvement. Using the FSS, no association was identified between fatigue and time on ERT (P = 0.57). In a survey of patients with Type 1 GD and physicians, patients ascribed greater importance to fatigue than other disease parameters, while physicians placed more emphasis on objective measures of visceral and hematologic disease manifestations. B. Pharmacological chaperones: The underlying pathology in GD is not only due to the lysosomal accumulation of glucosylceramide in the tissue macrophages. There is a broader spectrum of lysosomal dysfunction and various intracellular and molecular changes that could lead to additional disease manifestations that are not affected by ERT. In particular, the retention of the mutant glucocerebrosidase within the endoplasmic reticulum (ER) which causes ER stress, unfolding protein response (UPR) and early ER associated degradation (ERAD) . These ER related changes are the rationale behind the use of pharmacological chaperones which are capable of partially removing the misfolded proteins from the ER, thereby relieving ER stress, avoiding ERAD and preventing consequent complications . Pharmacological chaperones increase glucocerebrosidase activity by stabilizing the enzyme in the lysosome. C. The Therapy to be Examined: Ambroxol hydrochloride, an over-the-counter antitussive available in many markets, was identified as an interesting pharmacological chaperone. In addition to a mucolytic action, ambroxol has antioxidant and anti-inflammatory properties . Importantly, ambroxol therapy was found safe when given to pregnant women for prevention of neonatal respiratory distress syndrome. In skin fibroblasts derived from Type 1 and Type 2 GD patients, ambroxol increases both the lysosomal fraction and the enzymatic activity of several mutant glucocerebrosidase variants with low toxicity . Incubation of human induced pluripotent stem cell macrophages from patients with type I-III GD with ambroxol corrected the abnormal phenotypes of GD macrophages. Ambroxol, has a small molecule chaperone, has been shown in healthy nonhuman primates to cross the blood-brain barrier, and increase brain glucocerebrosidase activity . In Drosophila neuropathic model, ambroxol was show to alleviate the neuronopathic phenotype through reducing ER stress ]. The investigators have performed a pilot study to test the tolerability and efficacy of ambroxol as a pharmacological chaperone in patients with symptomatic, type 1 GD who present with measurable disease parameters but are not receiving ERT in order to provide proof of concept and/or ascertain the suitability of ambroxol for a larger clinical trial [29] . The Israeli Ministry of Health Form 29c was employed to prescribe ambroxol for off-label use. Twelve patients were dispensed 2 capsules of 75 mg of ambroxol daily for 6 months. One patient withdrew because of a hypersensitivity reaction, one because of elective splenectomy. No patient experienced clinically relevant deterioration in disease parameters measured. One patient achieved a robust response relative to baseline: +16.2% hemoglobin; +32.9% platelets; -2.8% liver volume; and -14.4% spleen volume. Three patients elected to continue on ambroxol for a further 6 months: hemoglobin levels and liver volumes were relatively stable, but platelet counts further increased in the above patient (+52.6% from baseline) and spleen volumes decreased further in all three patients (-6.4%, -18.6%, and -23.4% from baseline) . More recently, a pilot study of ambroxol was done in five patients with neuronopathic GD in combination with enzyme replacement therapy [30]. High-dose oral Ambroxol had good safety and tolerability with clinical and laboratory signs of activity. Thus, ambroxol, an oral available drug on the market, may be a safe option for GD patients with potential disease-specific efficacy and should be expanded into a clinical trial using higher doses and placebo-controlled design [31]. The investigators propose to start with a phase II study for patients with type 1 GD and suboptimal response to ERT. In addition the investigators plan to open an international registry of patients with GD currently receiving ambroxol (off study).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Gaucher Disease, Type 1

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Model Description
The aim of this single arm, phase II study is to evaluate the efficacy and safety of adding ambroxol to patients with type 1 GD and suboptimal response to ERT. HYPOTHESIS The addition of ambroxol will improve the disease related symptoms and disease impact of patients with GD with suboptimal response to ERT.
Masking
None (Open Label)
Allocation
N/A
Enrollment
40 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Ambroxol
Arm Type
Experimental
Arm Description
Ambroxol therapy will be dosed up to 600 mg/day divided to twice a day starting 150 mg for the first month, 300 mg for the following month and 600 mg for the following month. The study was conducted in accordance with the provisions of the Declaration of Helsinki, Good Clinical Practice guidelines, and local laws and regulations.
Intervention Type
Drug
Intervention Name(s)
Ambroxol
Other Intervention Name(s)
Ambroxol Hydrochloride
Intervention Description
Ambroxol Hydrochloride therapy will be dosed up to 600 mg/day divided to twice a day starting 150 mg for the first month, 300 mg for the following month and 600 mg for the following month. The study was conducted in accordance with the provisions of the Declaration of Helsinki, Good Clinical Practice guidelines, and local laws and regulations.
Primary Outcome Measure Information:
Title
Platelets count
Description
Increase in platelet count
Time Frame
12 months.
Title
bone mineral density evaluated by Dual Energy X-ray Absorptiometry (DEXA)
Description
Bone Mineral Densitometry (BMD)
Time Frame
12 months.
Title
Lyso-GB1 biomarker for Gaucher disease
Description
decrease in Lyso-GB1.
Time Frame
12 months
Secondary Outcome Measure Information:
Title
Patient-reported outcomes (PRO)
Description
Improve in PRO from baseline
Time Frame
12 months
Title
Fatigue Severity Scale (FSS)
Description
Improve in FSS from baseline
Time Frame
12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: *Adult patients ≥ 18 years with type 1 GD and suboptimal response to ERT defined as one or more than one of the following: platelet count < 100 x 103/mm3 bone mineral density < -2 T score Lyso-GB1 > 200 ng/ml. *No change in dose or preparation of ERT in the last 12 months (Except for Naive patients) Exclusion Criteria: Patients with comorbidity that may impact on the primary and/or secondary endpoint. Pregnant women will be excluded from the study. Inability to cooperate with the study procedure Hypersensitivity or any other contraindication listed in the local labeling of ambroxol Refusal of patients to participate in the study.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ari Zimran
Organizational Affiliation
Ari Zimran - Shaare Zedek
Official's Role
Principal Investigator
Facility Information:
Facility Name
Shaare Zedek Medical Center
City
Jerusalem
Country
Israel

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
27866808
Citation
Ishay Y, Zimran A, Szer J, Dinur T, Ilan Y, Arkadir D. Combined beta-glucosylceramide and ambroxol hydrochloride in patients with Gaucher related Parkinson disease: From clinical observations to drug development. Blood Cells Mol Dis. 2018 Feb;68:117-120. doi: 10.1016/j.bcmd.2016.10.028. Epub 2016 Nov 12.
Results Reference
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Ambroxol Therapy for Patients With Type 1 Gaucher Disease and Suboptimal Response to Enzyme Replacement Therapy

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