Ambroxol as a Treatment for Parkinson's Disease Dementia

NCT02914366 | Active Not Recruiting Phase 2 DMC

• 3 other identifiers: R15-006105234181033
• Study Type: interventional
• Target: 55
• Locations: 1 country
• Sites: 1

Brief Summary

The present study will test the hypothesis that the medication Ambroxol is safe and well tolerated and will improve cognitive and motor symptoms of Parkinson's Disease Dementia (PDD). Ambroxol has been shown to raise the levels of the enzyme beta-glucocerebrosidase resulting in lower the levels of the protein alpha-synuclein, both of which have been shown to improve cognition in mouse models. This will be a 52 week trial of Ambroxol in 75 individuals with PDD. Participants will undergo clinical, neuropsychological and neuroimaging assessment throughout the study to assess changes.

Conditions

Parkinson's Disease Dementia

Keywords

Ambroxol; Dementia; Parkinson's disease; Disease modifying treatment; Pharmacological Chaperone; GBA1

Outcome Measures

Primary Outcomes (2)

• Changes in the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog)

  This 70-point test examines language, recall, word finding, comprehension, naming, drawing, praxis, orientation, and word recognition. Although designed for Alzheimer's disease where it is considered a gold standard, the ADAS-Cog has been used effectively in many clinical trials of PDD including large randomized trials. This scale has been recommended for the assessment of Parkinson's dementia in "Diagnostic Procedures for Parkinson's Disease Dementia: Recommendations from the Movement Disorder Society Task Force"

  baseline, week 26, and week 52

• Changes in the ADCS-Clinician's Global Impression of Change (CGIC)

  This is a 7-point scale for rating patient function in cognition behavior and activities of daily living, and this test is standard in clinical trials in Alzheimer's disease and has been useful in trials with PDD.

  baseline, week 26, and week 52

Secondary Outcomes (15)

• Changes in the Montreal Cognitive Assessment

  baseline, week 26, and week 52

• Changes in the Clinical Dementia Rating Scale (CDR)

  baseline, week 26, and week 52

• Changes in the Trail Making Test (TRAILS)

  baseline, week 26, and week 52

• Changes in the Parkinson's Disease-Cognitive Rating Scale (PD-CRS)

  baseline, week 26, and week 52

• Changes in the Stroop Test

  baseline, week 26, and week 52

Study Arms (2)

Ambroxol high dose (1050 mg)

EXPERIMENTAL

Participants randomized to the 1050 mg/day group will begin with a dose of 225mg (3 mg/kg/day), increasing bi-weekly by \~3mg/kg to a dose of 1050 mg/day (\~l5 mg/kg/day).

Drug: Ambroxol

Placebo

PLACEBO COMPARATOR

Participants receive capsules visually identical to the experimental groups but without active ingredients.

Other: Placebo

Interventions

Ambroxol DRUG

Also known as: Mucosolvon

Ambroxol high dose (1050 mg)

Placebo OTHER

Placebo

Eligibility Criteria

• Age: 50 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age \>50,
• Mild to Moderate Dementia (established by an upper cut off of a Montreal Cognitive Assessment score of 24 or below, and the lower bound by a Mini Mental State Exam of 16 or greater),
• Parkinson's Disease (Hoehn \& Yahr stage 2 - 3.5) clearly established more than 1 year before the onset of dementia
• Patients must have a responsible caregiver = 4 days/wk
• Must be on stable doses of medications for Parkinson's disease mood and cognition (Cholinesterase Inhibitor) for at least 3 months prior to the study.

You may not qualify if:

• Evidence of clinically significant stroke or other neurological condition
• Any other serious underlying condition (i.e. cancer or unstable cardiac disease etc.
• Concurrent treatment with oral anticoagulants (including Vitamin K agonists and Novel Oral Anticoagulants (NOACs)) within 4 weeks of screening or anticipated during the 52 week double-blind and open label periods. Specifically, Apixaban, Dabigatran, Edoxaban, Fondaparinux, Rivaroxaban, and Warfarin are prohibited concomitant medications.
• Exceptions: antiplatelet agents such as Aspirin, Clopidogrel, and Aggrenox are allowed.

Sponsors & Collaborators

• London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's: lead
• Weston Brain Institute: collaborator
• Western University, Canada: collaborator
• London Health Sciences Centre: collaborator

Study Sites (1)

Parkwood Institute

London, Ontario, N6C 0A7, Canada

Location

Related Publications (16)

• Lang AE, Obeso JA. Challenges in Parkinson's disease: restoration of the nigrostriatal dopamine system is not enough. Lancet Neurol. 2004 May;3(5):309-16. doi: 10.1016/S1474-4422(04)00740-9.

  PMID: 15099546 BACKGROUND

• Balducci C, Pierguidi L, Persichetti E, Parnetti L, Sbaragli M, Tassi C, Orlacchio A, Calabresi P, Beccari T, Rossi A. Lysosomal hydrolases in cerebrospinal fluid from subjects with Parkinson's disease. Mov Disord. 2007 Jul 30;22(10):1481-1484. doi: 10.1002/mds.21399.

  PMID: 17546678 BACKGROUND

• Gegg ME, Burke D, Heales SJ, Cooper JM, Hardy J, Wood NW, Schapira AH. Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains. Ann Neurol. 2012 Sep;72(3):455-63. doi: 10.1002/ana.23614.

  PMID: 23034917 BACKGROUND

• Sardi SP, Clarke J, Viel C, Chan M, Tamsett TJ, Treleaven CM, Bu J, Sweet L, Passini MA, Dodge JC, Yu WH, Sidman RL, Cheng SH, Shihabuddin LS. Augmenting CNS glucocerebrosidase activity as a therapeutic strategy for parkinsonism and other Gaucher-related synucleinopathies. Proc Natl Acad Sci U S A. 2013 Feb 26;110(9):3537-42. doi: 10.1073/pnas.1220464110. Epub 2013 Jan 7.

  PMID: 23297226 BACKGROUND

• Malerba M, Ragnoli B. Ambroxol in the 21st century: pharmacological and clinical update. Expert Opin Drug Metab Toxicol. 2008 Aug;4(8):1119-29. doi: 10.1517/17425255.4.8.1119.

  PMID: 18680446 BACKGROUND

• Maegawa GH, Tropak MB, Buttner JD, Rigat BA, Fuller M, Pandit D, Tang L, Kornhaber GJ, Hamuro Y, Clarke JT, Mahuran DJ. Identification and characterization of ambroxol as an enzyme enhancement agent for Gaucher disease. J Biol Chem. 2009 Aug 28;284(35):23502-16. doi: 10.1074/jbc.M109.012393. Epub 2009 Jul 3.

  PMID: 19578116 BACKGROUND

• Luan Z, Li L, Higaki K, Nanba E, Suzuki Y, Ohno K. The chaperone activity and toxicity of ambroxol on Gaucher cells and normal mice. Brain Dev. 2013 Apr;35(4):317-22. doi: 10.1016/j.braindev.2012.05.008. Epub 2012 Jun 7.

  PMID: 22682976 BACKGROUND

• Laoag-Fernandez JB, Fernandez AM, Maruo T. Antenatal use of ambroxol for the prevention of infant respiratory distress syndrome. J Obstet Gynaecol Res. 2000 Aug;26(4):307-12. doi: 10.1111/j.1447-0756.2000.tb01327.x.

  PMID: 11049243 BACKGROUND

• Luerti M, Lazzarin A, Corbella E, Zavattini G. An alternative to steroids for prevention of respiratory distress syndrome (RDS): multicenter controlled study to compare ambroxol and betamethasone. J Perinat Med. 1987;15(3):227-38. doi: 10.1515/jpme.1987.15.3.227.

  PMID: 3323457 BACKGROUND

• Wauer RR, Schmalisch G, Hammer H, Buttenberg S, Weigel H, Huth M. Ambroxol for prevention and treatment of hyaline membrane disease. Eur Respir J Suppl. 1989 Mar;3:57S-65S.

  PMID: 2662997 BACKGROUND

• Schmalisch G, Wauer RR, Bohme B. Changes in pulmonary function in preterm infants recovering from RDS following early treatment with ambroxol: results of a randomized trial. Pediatr Pulmonol. 1999 Feb;27(2):104-12. doi: 10.1002/(sici)1099-0496(199902)27:23.0.co;2-t.

  PMID: 10088933 BACKGROUND

• Narita A, Kubota N, Takayama R, Takahashi Y, Maegaki Y, Suzuki Y, & Ohno K. Chaperone therapy for neuronopathic Gaucher disease. Molecular Genetics and Metabolism, 108(2): S69, 2013.

  BACKGROUND

• Abstracts of the 12th International Child Neurology Congress and the 11th Asian and Oceanian Congress of Child Neurology. May 27-June 1, 2012. Brisbane, Australia. Dev Med Child Neurol. 2012 Jun;54 Suppl 4:5-220. No abstract available.

  PMID: 22606700 BACKGROUND

• Zimran A, Altarescu G, Elstein D. Pilot study using ambroxol as a pharmacological chaperone in type 1 Gaucher disease. Blood Cells Mol Dis. 2013 Feb;50(2):134-7. doi: 10.1016/j.bcmd.2012.09.006. Epub 2012 Oct 22.

  PMID: 23085429 BACKGROUND

• Silveira CRA, Coleman KKL, Borron K, Tirona RG, Rupar CA, Zou G, Hegele RA, Wellington C, Stukas S, Finger EC, Bartha R, Morrow SA, Wells JL, Borrie MJ, Mahuran D, MacDonald PA, Jenkins ME, Jog MS, Dresser G, Fox S, Camicioli R, Feagan B, Mendonca DA, Mayich M, Sharma MD, Pandey SK, Pasternak SH. Ambroxol as a Treatment for Parkinson Disease Dementia: A Randomized Clinical Trial. JAMA Neurol. 2025 Jun 30;82(8):797-807. doi: 10.1001/jamaneurol.2025.1687. Online ahead of print.

  PMID: 40587145 DERIVED

• Silveira CRA, MacKinley J, Coleman K, Li Z, Finger E, Bartha R, Morrow SA, Wells J, Borrie M, Tirona RG, Rupar CA, Zou G, Hegele RA, Mahuran D, MacDonald P, Jenkins ME, Jog M, Pasternak SH. Ambroxol as a novel disease-modifying treatment for Parkinson's disease dementia: protocol for a single-centre, randomized, double-blind, placebo-controlled trial. BMC Neurol. 2019 Feb 9;19(1):20. doi: 10.1186/s12883-019-1252-3.

  PMID: 30738426 DERIVED

MeSH Terms

Conditions

Dementia; Parkinson Disease

Interventions

Ambroxol

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Mental Disorders; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases

Intervention Hierarchy (Ancestors)

Bromhexine; Aniline Compounds; Amines; Organic Chemicals; Cyclohexylamines

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: M.D., Ph.D.

Study Record Dates

• First Submitted: September 8, 2016
• First Posted: September 26, 2016
• Study Start: November 1, 2015
• Primary Completion: December 1, 2025
• Study Completion: December 1, 2025
• Last Updated: February 28, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will share

Locations

CA (1)