Status:
Recruiting
Clinicaltrials.gov identifier:
Sponsor:
Lawson Health Research Institute
Enrollment:
75
Study Design:
Randomized, double-blind, parallel assignment, with a treatment time of 52 weeks, carried out at a single center. There are three arms in the study: Arm 1: Ambroxol high dose (1050mg per day); Arm 2: Ambroxol low dose (525mg per day); and Arm 3: Placebo. Participants with a MoCA score between 16 and 24 and age >50 are being recruited. The GBA1 gene in each participant will be sequenced, but the mutation status is not an inclusion or exclusion criterion.
Rationale:
Primary outcome measures, taken at baseline, 26 weeks and 52 weeks are: 1. Changes in the Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog); and 2. Changes in the ADCS-Clinician’s Global Impression of Change (CGIC). Secondary outcome measures include a spectrum of scales measuring motor and non-motor disability, specific domains of cognition, CSF and peripheral ambroxol PK profile, and GCAse levels. The study also includes MRI imaging outcomes measuring brain ventricle volume and hippocampal atrophy (baseline and week 52): 1. Changes in the MoCA (baseline, week 26 and week 52); 2. Changes in the Clinical Dementia Rating Scale (CDR) (baseline, week 26 and week 52); 3. Changes in the Trail Making Test (baseline, week 26 and week 52); 4. Change in the Parkinson’s Disease-Cognitive Rating Scale (PD-CRS) (baseline, week 26 and week 52); 5. Changes in the Stroop Test (baseline, week 26 and week 52); 6. Changes in the Unified Parkinson’s disease Rating Scale motor subsection (UP-DRS-III) (baseline, week 26 and week 52); 7. Changes in the Purdue Pegboard (baseline, week 26 and week 52); 8. Changes in the Timed Up and Go (baseline, week 26 and week 52); 9. Change in Quantitative Movement Testing - gait assessment on electronic mat (Zeno Walkway System) (baseline, week 26 and week 52); 10. Changes in Cerebrospinal Fluid (CSF) biomarkers - levels of ±-synuclein (pg/ml), Tau (pg/ml), phospho-Tau (pg/ml) and beta amyloid-42 (pg/ml) (baseline, week12 and week 52); 11. Changes in Magnetic Resonance Imaging (MRI) - brain ventricle volume (cm3) and hippocampal atrophy (cm3) (baseline and week 52); 12. Changes in the Mini-Mental State Examination (screening, baseline, week 4, week 6, week 12, week 18, week 26, week 34, week 42, week 52); 13. Changes in GCase in lymphocytes (baseline, week 2, week 4, week 6, week 8, week 12, week 18, week 26, week 34, week 42, week 52); 14. Changes in Plasma Ambroxol levels (baseline, week 2, week 4, week 6, week 8, week 12, week 18, week 26, week 34, week 42, week 52); 15. Mayo Fluctuation Questionnaire (baseline, 26 weeks and 52 weeks).
Comments:
A more detailed description of the trial has been published. Targeting the GBA pathway is of great interest, and a number of programs are in development. This study focuses specifically on the impact on cognition. The secondary outcome measures are comprehensive and require a high number of participant visits (11) and procedures, including three lumbar punctures. The dose of ambroxol under evaluation is 1,050mg per day, approximately 15mg/kg/day. This is much higher than the OTC dose. An even higher dose, 1,260mg, was used in the phase 2 efficacy trial described by Mullins et al. [4]. In the Lawson Health study, the number of 75mg tablets per day is up to 14 per day for the higher dose. The number of tablets to be taken each day by participants with PDD or MCI may thus be a challenge for compliance. However, one inclusion criterion requires the presence of a responsible caregiver for at least 4 days per week.
