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ID
Source
Brief title
Health condition
Gaucher disease type 3
Sponsors and support
Intervention
Outcome measures
Primary outcome
Change in cerebrospinal fluid (CSF) Lyso-GL1, from GD3 patients receiving ambroxol.
Secondary outcome
- Change in plasma Lyso-GL1, GL-1, chitotriosidase and Lyso-GM3, from GD3 patients receiving ambroxol;
- Change in CSF GL-1 and Lyso-GM3, from GD3 patients receiving ambroxol;
- Change in GCase activity in leukocytes, from GD3 patients receiving ambroxol;
- Effect of ambroxol on functional/developmental outcomes using the Goal Attainment Scaling (GAS) in GD3 patients;
- Effect of ambroxol on quality of life using the Pediatric Quality of Life Inventory (PedsQL) in GD3 patients;
- Effect of ambroxol on ataxia using the Scale for the Assessment and Rating of Ataxia (SARA) in GD3 patients;
- Effect of ambroxol on neuropsychological outcomes using the Attention Network Task (ANT) and/or Wechsler scale in GD3 patients;
- If epilepsy: effect of ambroxol on seizure control using the Unified Myoclonus Rating Scale (UMRS) and a seizure log book in GD3 patients.
Background summary
Gaucher disease (GD) is an autosomal recessive lysosomal storage disease (LSD), caused by bi-allelic mutations in GBA1 resulting in a deficiency of the lysosomal enzyme glucocerebrosidase (GCase). GD is biochemically characterized by lysosomal accumulation of glucosylceramide (GL-1) and its deacylated form, glucosylsphinogosine (Lyso-GL1). Clinically, GD is classified intro three subtypes (GD1-3). All present with multisystemic disease manifestations (i.e. enlarged liver and spleen, anaemia). GD2 and GD3 are less common and include involvement of the central nervous system (CNS). GD3 patients present with untreatable progressive neurodegenerative disease, i.e. progressive developmental delay, myoclonic epilepsy, supranuclear gaze palsy and ataxia. The systemic manifestations of GD can be treated by enzyme replacement therapy (ERT). However, ERT is not able to cross the blood-brain barrier (BBB) and hence no treatment for the devastating neurological symptoms is available. Ambroxol is a small molecule chaperone that has been shown to increase GCase activity in vitro and is able to cross the BBB. Because classical randomized controlled trials (RCTs) are unfit to perform due to a low prevalence and heterogeneity of GD3, we will combine the results of several n-of-1 trials. The purpose of this study is to evaluate the neurological efficacy of ambroxol in patients with GD3, using an n-of-1 series.
Study objective
Based on previous studies, we will expect that ambroxol improves neurological manifestations in patients with GD3.
Study design
Outcome measures will be assessed during the baseline period and during the whole trial period every 3 or 6 months. A follow-up visit will be scheduled 6 weeks and 3 months after the end of the trial.
Intervention
Each patient receives multiple blocks consisting of three time daily ambroxol (25 mg/kg/day) alternated with placebo and washout periods.
Bibiche den Hollander
+31630238642
b.denhollander@amsterdamumc.nl
Bibiche den Hollander
+31630238642
b.denhollander@amsterdamumc.nl
Inclusion criteria
1) The patient or the parent(s)/legal guardian(s) must provide written informed consent before start of the study
2) Male and female patients with documented deficiency of GCase activity and GBA genotype fitting GD3
3) All ages
4) Able to travel to the study site
5) Patients receive ERT with treatment ongoing at the time of enrollment
6) There are no sufficient data for the use of ambroxol in pregnant women (see Summary of product characteristics (SPC), section 4.6). This particularly concerns the period up to the 28th week of pregnancy. Postmenarchal female patients must be willing to practice true abstinence in line with their preferred and usual lifestyle, or use a medically accepted form of contraception throughout the study (barrier method such as condom or diaphragm+spermicide or non-barrier method such as oral, injected, or implanted hormonal contraceptive with ethinylestradiol and norethindrone or similar active components
Exclusion criteria
1) The patient is transfusion dependent
2) The patient has received an investigational product within 30 days prior to enrollment
3) Known hypersensitivity reactions, intolerance or adverse reactions to ambroxol or to the inactive ingredients
4) The patient is lactating. Ambroxol crosses into the breast milk. As there is no adequate experience in humans to date, ambroxol should not be used in lactation in a study setting (see SPC, section 4.6)
5) Pregnancy
6) The patient is unwilling or, in the investigator’s opinion, unable to adhere to the requirements of the study
7) The patient is unable to swallow powder and has no other enteral access (e.g. gastrostomy)
8) Any condition or abnormality which may, in the opinion of the investigator, compromise the safety of patients
Design
Recruitment
IPD sharing statement
Followed up by the following (possibly more current) registration
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Other (possibly less up-to-date) registrations in this register
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In other registers
| Register | ID |
|---|---|
| NTR-new | NL9550 |
| Other | METC AMC : METC 2021_152 |