Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03950050
Recruitment Status : Recruiting
First Posted : May 15, 2019
Last Update Posted : September 24, 2019
Sponsor:
Information provided by (Responsible Party):
Shaare Zedek Medical Center

Tracking Information
First Submitted Date  ICMJE August 6, 2018
First Posted Date  ICMJE May 15, 2019
Last Update Posted Date September 24, 2019
Actual Study Start Date  ICMJE March 1, 2019
Estimated Primary Completion Date July 1, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 13, 2019)
  • Platelets count [ Time Frame: 12 months. ]
    Increase in platelet count
  • bone mineral density evaluated by Dual Energy X-ray Absorptiometry (DEXA) [ Time Frame: 12 months. ]
    Bone Mineral Densitometry (BMD)
  • Lyso-GB1 biomarker for Gaucher disease [ Time Frame: 12 months ]
    decrease in Lyso-GB1.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03950050 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 13, 2019)
  • Patient-reported outcomes (PRO) [ Time Frame: 12 months ]
    Improve in PRO from baseline
  • Fatigue Severity Scale (FSS) [ Time Frame: 12 months ]
    Improve in FSS from baseline
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Ambroxol Therapy for Patients With Type 1 Gaucher Disease and Suboptimal Response to Enzyme Replacement Therapy
Official Title  ICMJE Ambroxol Therapy for Patients With Type 1 Gaucher Disease and Suboptimal Response to Enzyme Replacement Therapy
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).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Intervention 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)
Primary Purpose: Treatment
Condition  ICMJE Gaucher Disease, Type 1
Intervention  ICMJE Drug: Ambroxol

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.

Other Name: Ambroxol Hydrochloride
Study Arms  ICMJE Experimental: Ambroxol

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: Drug: Ambroxol
Publications * 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. Review.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 13, 2019)
60
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 1, 2021
Estimated Primary Completion Date July 1, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Joleen Istaiti, B.Sc. +97226555143 joleenist@szmc.org.il
Contact: Ari Zimran, MD +97226555143 azimran@gmail.com
Listed Location Countries  ICMJE Israel
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03950050
Other Study ID Numbers  ICMJE 0005-18-SZMC
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Shaare Zedek Medical Center
Study Sponsor  ICMJE Shaare Zedek Medical Center
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Ari Zimran Ari Zimran - Shaare Zedek
PRS Account Shaare Zedek Medical Center
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP