<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04405596</url>
  </required_header>
  <id_info>
    <org_study_id>REB:115252</org_study_id>
    <nct_id>NCT04405596</nct_id>
  </id_info>
  <brief_title>Ambroxol as a Novel Disease Modifying Treatment for Lewy Body Dementia</brief_title>
  <official_title>Ambroxol as a Novel Disease Modifying Treatment for Lewy Body Dementia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Lawson Health Research Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Lawson Health Research Institute</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a randomized, placebo-controlled, double-blind study investigating whether the&#xD;
      medication Ambroxol is safe,effectiveness and well tolerated for the treatment of Lewy Body&#xD;
      Dementia (LBD). Currently the main treatments for patients with LBD target symptom&#xD;
      management. However, none of the medications treat the underlying cause of the disease, which&#xD;
      includes the accumulation of protein in the brain. Therefore, even if patients respond well&#xD;
      to symptomatic treatment, they continue to deteriorate. Therefore, the purpose of the current&#xD;
      study is to make sure Ambroxol is safe to take long term and to test the effects of Ambroxol&#xD;
      in treating the cognitive impairments associated with LBD by modifying the underlying causes&#xD;
      of the disease.&#xD;
&#xD;
      There will be a total of 15 people participating this this study, which will last 52 weeks.&#xD;
      Over the study period patients will undergo clinical, neuropsychological and neuroimaging&#xD;
      assessment to assess changes.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The increasing prevalence of dementia is a serious threat to our medical system and our&#xD;
      society. About 500,000 Canadians are affected with dementia, and this number will rise to&#xD;
      more than 1 million in the next 20 years. Dementia already costs our economy 15 billion&#xD;
      dollars per year. While much of the focus of dementia is on Alzheimer's disease, autopsy&#xD;
      studies suggest that up to 30% of dementia is due to diseases caused by abnormal&#xD;
      alpha-synuclein accumulation (Synucleinopathies). In healthy brains, alpha-synuclein plays a&#xD;
      number of important roles, especially in the process by which brain cells (neurons)&#xD;
      communicate. However, when alpha-synuclein abnormally accumulates into clumps inside the&#xD;
      neurons it forms Lewy bodies. Eventually, as a result, brain neurons will die causing&#xD;
      widespread damage to specific brain regions.&#xD;
&#xD;
      Until the 1980's, cortical Lewy bodies were thought to be relatively rare. However, with&#xD;
      improved alpha-synuclein immunostaining techniques, Lewy body dementias are now recognized as&#xD;
      the second most common neurodegenerative dementia, after Alzheimer's disease. Lewy&#xD;
      body-related disorders include idiopathic Parkinson's disease (PD), Parkinson's disease&#xD;
      dementia (PDD) and Lewy Body Dementia (LBD). In LBD, alpha- synuclein accumulation is found&#xD;
      in the brainstem, limbic and neocortical regions, giving rise to autonomic, cognitive and&#xD;
      motor impairments.&#xD;
&#xD;
      Cognitive Symptoms: Progressive cognitive decline typically begins early in the course of the&#xD;
      disease in advance of parkinsonism, but by consensus may follow the development of motor&#xD;
      signs up to 1 year. Impaired cognitive domains include executive and visual-spatial&#xD;
      functions, attention and short-term memory. For example, patients may have difficulty&#xD;
      multi-tasking, following conversations, episodes of staring and perturbed flow of ideas.&#xD;
      Regarding short-term memory, patients with LBD experience impairment in memory retrieval,&#xD;
      which can be improved by cueing, which is in contrast to memory encoding seen in AD. The&#xD;
      early presence of recurrent visual hallucinations is also common in patients with LBD and&#xD;
      therefore diagnostically useful. Later in the course of the disease, delusions can be present&#xD;
      giving rise to paranoia.&#xD;
&#xD;
      Motor symptoms: Parkinsonian motor signs in LBD are often symmetric, with bradykinesia and&#xD;
      gait impairments being more common than resting tremor. Importantly, patients with LBD will&#xD;
      often show limited or no response to typical Parkinson's disease pharmacological intervention&#xD;
      such as levodopa/carbidopa. LBD patients however do show reduced dopamine transporter&#xD;
      activity on single-photon emission computed tomography (SPECT) or positron emission&#xD;
      tomography (PET) imaging.&#xD;
&#xD;
      Other Associated symptoms can include: loss of olfaction, autonomic dysfunction (i.e.&#xD;
      neurogenic orthostatic hypotension, constipation, neurogenic urinary frequency and urgency),&#xD;
      high sensitivity to medications and rapid eye movement sleep behaviour disorder typically&#xD;
      reported by a sleep partner as kicking, punching, yelling and acting out their dreams.&#xD;
&#xD;
      Mechanism for targeting Lewy bodies: A potential target for disease-modifying treatment is&#xD;
      the enzyme β-Glucocerebrosidase (GCase; gene name GBA1). Glucocerebrosidase (GCase) is a&#xD;
      degradative enzyme that resides in a subcellular compartment called the lysosome, and cleaves&#xD;
      a neutral glycolipid, glucocerebroside, present in the plasma membrane of most cells. GCase&#xD;
      is intimately linked with Parkinson's disease - a Lewy body-related disorder. Being an&#xD;
      &quot;asymptomatic carrier&quot; of a GCase mutation is currently the highest genetic risk factor for&#xD;
      Parkinson's disease, Parkinson's disease dementia and Lewy Body Dementia, with some studies&#xD;
      suggesting up to 1/3 of patients carry mutations. Reductions in GCase activity most likely&#xD;
      also play a role in sporadic Parkinson's disease, as these patients have lower levels of&#xD;
      GCase in their brain and cerebrospinal fluid, even when they do not carry a mutant GCase&#xD;
      allele. Laboratory studies have demonstrated a direct link between GCase activity and&#xD;
      α-synuclein accumulation. In cultured cells, loss of GCase results in α-synuclein&#xD;
      accumulation and this process feeds back upon itself, with overexpression of α-synuclein&#xD;
      further inhibiting GCase function, and increasing GCase expression reducing α-synuclein.&#xD;
      Moreover, reducing GCase genetically or pharmacologically in animal studies results in&#xD;
      increased α-synuclein aggregates. Remarkably, overexpressing GCase in the brain of a&#xD;
      Parkinson's disease mouse model reduces α-synuclein and improves cognition. Taken together,&#xD;
      these findings suggest that increasing GCase levels could be a therapy that addresses the&#xD;
      underlying pathophysiology of Lewy body-related disorders such as Lewy Body dementia to&#xD;
      modify the course of disease progression.&#xD;
&#xD;
      Background on Ambroxol Studies: Ambroxol is an expectorant that has been available over the&#xD;
      counter in more than 50 countries for over 30 years. The Mahuran Lab identified Ambroxol by&#xD;
      screening a library of compounds as an agent that stabilizes wild-type (normal) GCase. By&#xD;
      stabilizing GCase, Ambroxol is able to markedly increase GCase protein and activity in normal&#xD;
      and Gaucher disease fibroblasts at doses of 10 µM. Ambroxol can also increase GCase in normal&#xD;
      mouse neuronal cultures to more than 150% of normal at a dose of 30 µM. Ambroxol has good&#xD;
      lipophilicity (cLogP = 2.8) and low polar surface area (PSA 58 Å2), predicting good CNS&#xD;
      penetration. Unpublished studies performed by ExSAR corporation demonstrate that in single&#xD;
      and multiple dose experiments in rats, Ambroxol crossed rapidly into the brain and exhibited&#xD;
      brain to plasma concentration ratios of greater than 10 indicating outstanding CNS&#xD;
      penetration. In pilot studies, Ambroxol was effective at improving GCase function in humans.&#xD;
      In a trial aimed at non-neurological Gaucher disease, 12 patients received 150 mg/day for 6&#xD;
      months, and all but one had some measurable improvement. The best response was in the&#xD;
      lightest patient (who received 3 mg/kg/day), suggesting that Ambroxol was under dosed.&#xD;
      Ambroxol has also been administered to three Japanese Gaucher disease patients with severe&#xD;
      neurological disease, at 1000-3000 mg/day for 12-31 months. These patients had improvements&#xD;
      in seizure frequency and neurological symptoms; one patient regained the ability to sit&#xD;
      unsupported and to walk. Importantly, in a recent study of Ambroxol in 18 Parkinson's disease&#xD;
      patients, the authors observed a 35% increase in CSF GCase protein levels at a daily dose of&#xD;
      1260mg with no serious adverse events.&#xD;
&#xD;
      Safety: Ambroxol has an excellent safety record, and has been studied in &gt;15,000 patients in&#xD;
      more than 100 trials. Ambroxol is sold over the counter in much of the world as an&#xD;
      expectorant at doses of 75-120 mg/day. Ambroxol is considered so safe that it is approved for&#xD;
      intravenous use in pregnant women at a dose of 1000 mg/day IV (15 mg/kg) to improve fetal&#xD;
      lung maturation before preterm delivery. Clinical trials in more than 390 pregnant women have&#xD;
      been performed using doses up to 3000 mg in one day and 1300 mg/day for up to 33 days.&#xD;
      Critically ill neonates have also been given doses as high as 30 mg/kg for respiratory&#xD;
      distress. The fact that Ambroxol has been used at very high doses in pregnant women and&#xD;
      neonates suggests that these doses are safe.&#xD;
&#xD;
      Project Summary: This is a proof of principle randomized, placebo-controlled, double-blind&#xD;
      study investigating whether the medication Ambroxol (dose: 1350mg/day) is safe, well&#xD;
      tolerated and will raise GCase levels in the CSF and plasma of patients diagnosed with&#xD;
      probable Lewy Body Dementia (LBD). Additionally, increased levels of the enzyme&#xD;
      β-glucocerebrosidase (GCase) and lower the levels of the protein α-synuclein have both been&#xD;
      shown to improve cognition in mouse models. Therefore, as secondary aim will be to&#xD;
      investigate whether Ambroxol will improve cognitive symptoms in patients diagnosed with Lewy&#xD;
      Body Dementia (LBD). This will be a 52-week trial of Ambroxol in 15 patients diagnosed with&#xD;
      probable LBD. Patients will undergo clinical, neuropsychological and neuroimaging assessment&#xD;
      throughout the study to assess changes. Ambroxol has never been examined in LBD patients;&#xD;
      however, trials of pharmacological chaperone therapy have been suggested in a recent review&#xD;
      in the journal &quot;The Proceedings of the National Academy of Sciences&quot;. A successful outcome of&#xD;
      this trial will greatly accelerate the development of therapeutics for neurodegenerative&#xD;
      disease. This proposal outlines a completely novel pharmacological target for LBD, namely the&#xD;
      GCase enzyme. The investigators also propose a completely novel therapy using the drug&#xD;
      Ambroxol, an agent considered safe enough to give to pregnant women, which has improved GCase&#xD;
      function in pilot studies in humans. This strategy could stabilize the underlying pathology&#xD;
      of Lewy Body Dementia; it might allow patients to get better. Furthermore, repurposing an&#xD;
      existing medication with excellent safety record will greatly shorten the time to bring this&#xD;
      therapy to general use, allowing us to leapfrog the normally decades-long drug development&#xD;
      process.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Not yet recruiting</overall_status>
  <start_date type="Anticipated">November 2023</start_date>
  <completion_date type="Anticipated">November 2025</completion_date>
  <primary_completion_date type="Anticipated">November 2024</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Mini Mental State Examination score from baseline over time</measure>
    <time_frame>Baseline, week 4, week 10, week 18, week 26, week 34, week 42, week 52</time_frame>
    <description>Monitor safety using frequent cognitive evaluations using the mini mental state examination. Lower scores are indicative of worsening cognitive impairment [score range: 0-30]</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in the incidence, nature and severity of AE's and SAE's from baseline</measure>
    <time_frame>Baseline, week 4, week 10, week 18, week 26, week 34, week 42, week 52</time_frame>
    <description>Change in the number of participants with AE's and SAE's</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in the number of participants with treatment discontinuations and study discontinuation due to AEs from baseline</measure>
    <time_frame>Baseline, week 4, week 10, week 18, week 26, week 34, week 42, week 52</time_frame>
    <description>Change from baseline in the number of participants with treatment and/or study discontinuation will be used to demonstrate safety and tolerability</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in the number of participants with electrocardiogram (ECG) abnormalities</measure>
    <time_frame>Baseline, week 4, week 10, week 18, week 26, week 34, week 42, week 52</time_frame>
    <description>Change from baseline in the number of participants with clinically significant ECG abnormalities (QT interval) to demonstrate safety</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change from baseline the number of participants with abnormal changes in hemodynamic values while seated</measure>
    <time_frame>Baseline, week 4, week 10, week 18, week 26, week 34, week 42, week 52</time_frame>
    <description>Changes in hemodynamic values from baseline over time to demonstrate safety</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change from baseline the number of participants with abnormal changes in hemodynamic values while standing</measure>
    <time_frame>Baseline, week 4, week 10, week 18, week 26, week 34, week 42, week 52</time_frame>
    <description>Changes in hemodynamic values from baseline over time to demonstrate safety</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in blood analyses from baseline over time</measure>
    <time_frame>Baseline, week 4, week 10, week 18, week 26, week 34, week 42, week 52</time_frame>
    <description>Change from baseline in number of participants with abnormal changes in clinical laboratory blood tests from baseline over time for safety</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in urine analyses from baseline over time</measure>
    <time_frame>Baseline, week 4, week 10, week 18, week 26, week 34, week 42, week 52</time_frame>
    <description>Change from baseline in number of participants with abnormal changes in clinical laboratory urine tests from baseline over time for safety</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change from baseline in plasma concentrations of Ambroxol from blood sample</measure>
    <time_frame>Baseline, week 4, week 10, week 26, week 52</time_frame>
    <description>Change in plasma Ambroxol concentrations from blood sample from baseline</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change from baseline in cerebrospinal fluid (CSF) concentrations of Ambroxol at specified time points</measure>
    <time_frame>Baseline, week 10, week 52</time_frame>
    <description>Change in Ambroxol concentrations from cerebrospinal fluid sample from baseline</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change from baseline in enzyme β-Glucocerebrosidase (GCase) concentration levels in CSF</measure>
    <time_frame>Baseline, week 10, week 52</time_frame>
    <description>Change in GCase concentration in the CSF from baseline</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change from baseline in enzyme β-Glucocerebrosidase (GCase) concentration levels in white blood cells</measure>
    <time_frame>Baseline, week 4, week 10, week 26, week 52</time_frame>
    <description>Change in white blood cell GCase concentrations from baseline</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)</measure>
    <time_frame>Baseline, week 26, and week 52</time_frame>
    <description>Demonstrate the efficacy of Ambroxol in improving, or slowing the progression of cognitive deficits. Lower scores are indicative of worsening cognitive function [score range: 40-160]</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinician's Global Impression of Change (CGIC)</measure>
    <time_frame>Baseline, week 26, and week 52</time_frame>
    <description>Demonstrate the efficacy of Ambroxol in improving, or slowing the progression of cognitive deficits. Patients are assessed as: no change, minimal, moderate and marked worsening, minimal, moderate and marked improvement</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Montreal Cognitive Assessment (MoCA)</measure>
    <time_frame>Baseline, week 26, and week 52</time_frame>
    <description>Demonstrate the efficacy of Ambroxol in improving, or slowing the progression of cognitive deficits. Lower scores are indicative of worsening cognitive impairment [score range: 0-30]</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Trail making test A and B to assess cognitive function</measure>
    <time_frame>Baseline, week 26, and week 52</time_frame>
    <description>Demonstrate the efficacy of Ambroxol in improving, or slowing the progression of cognitive deficits: Higher times to complete are indicative of worsening cognitive function [Max time: 300 seconds]</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Parkinson's disease - Cognitive rating scale to assess cognitive function</measure>
    <time_frame>Baseline, week 26, and week 52</time_frame>
    <description>Demonstrate the efficacy of Ambroxol in improving, or slowing the progression of cognitive deficits. Lower scores are indicative of higher cognitive dysfunction [Score range: 0-134]</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in regional brain magnetic resonance imaging atrophy measures</measure>
    <time_frame>Baseline, week 52</time_frame>
    <description>Change in hippocampal atrophy (cm3)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in global brain magnetic resonance imaging atrophy measures</measure>
    <time_frame>Baseline, week 52</time_frame>
    <description>Change in brain ventricle volume (cm3)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in plasma biomarkers</measure>
    <time_frame>Baseline, week 4, week 10, week 18, week 26, week 34, week 42, week 52</time_frame>
    <description>Change in levels of plasma biomarkers: α-synuclein (pg/ml), Tau (pg/ml), phospho-Tau (pg/ml) and beta amyloid-42 (pg/ml) in plasma</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Cerebrospinal Fluid (CSF) biomarkers</measure>
    <time_frame>Baseline, week 10, week 52</time_frame>
    <description>Change in levels of CSF biomarkers: α-synuclein (pg/ml), Tau (pg/ml), phospho-Tau (pg/ml) and beta amyloid-42 (pg/ml) in CSF</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neuropsychological Inventory (NPI)</measure>
    <time_frame>Baseline, week 26, and week 52</time_frame>
    <description>Demonstrate change or slowed progression in standard tests of mood and neuropsychiatric symptoms. Assesses frequency and severity of neuropsychological symptoms with higher scores indicative of more symptoms, higher frequency and more severe. [Score range: 0-144]</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Geriatric Depression Scale</measure>
    <time_frame>Baseline, week 26, and week 52</time_frame>
    <description>Demonstrate change or slowed progression in standard tests of mood and neuropsychiatric symptoms: Higher scores indicate more severe depression [score range: 0-15]</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The Motor subscale of Unified Parkinson's Disease Rating Scale (UPDRS-III)</measure>
    <time_frame>Baseline, week 26, and week 52</time_frame>
    <description>Demonstrate change or slowed progression in tests of motor function/Parkinsonism: Higher scores indicate more dysfunction [score range: 0-108]</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Timed Up and Go</measure>
    <time_frame>Baseline, week 26, and week 52</time_frame>
    <description>Demonstrate change or slowed progression in tests of motor function/Parkinsonism. Higher times indicate slower movement and more motor impairment</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">15</enrollment>
  <condition>Lewy Body Disease</condition>
  <arm_group>
    <arm_group_label>Ambroxol</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants randomized to the 1350 mg/day group will begin with a dose of 450 mg, increasing bi-weekly to a dose of 1350 mg/day.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Participants receive capsules visually identical to the experimental groups but without active ingredients.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ambroxol Hydrochloride</intervention_name>
    <description>The treatment regimen consists of a titration phase and a maintenance phase. Participants begin the titration phase (Weeks 1 and 2) taking 6 capsules a day (450mg or 0 mg) divided BID (3 capsules in the morning and 3 capsules in the evening). The first medication dose will be taken at the end of Baseline visit and in the presence of the study Neurologist. Possible side effects will be observed for 30 minutes. Medication dose will increase bi-weekly to 12 capsules on Weeks 3 and 4, and 18 capsules on Weeks 5 and 6 divided BID. At the end of titration (Week 5) participants will have reached a maximum of 1350mg or 0mg per day, depending on group allocation. In the maintenance phase, participants will remain in their maximum dose (1350mg or 0mg) from Week 5 to Week 52 (End of Trial).</description>
    <arm_group_label>Ambroxol</arm_group_label>
    <other_name>Mucosolvan</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>The treatment regimen consists of a titration phase and a maintenance phase. Participants begin the titration phase (Weeks 1 and 2) taking 6 capsules a day (450mg or 0 mg) divided BID (3 capsules in the morning and 3 capsules in the evening). The first medication dose will be taken at the end of Baseline visit and in the presence of the study Neurologist. Possible side effects will be observed for 30 minutes. Medication dose will increase bi-weekly to 12 capsules on Weeks 3 and 4, and 18 capsules on Weeks 5 and 6 divided BID. At the end of titration (Week 5) participants will have reached a maximum of 1350mg or 0mg per day, depending on group allocation. In the maintenance phase, participants will remain in their maximum dose (1350mg or 0mg) from Week 5 to Week 52 (End of Trial).</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Probable diagnosis of Lewy Body Dementia&#xD;
&#xD;
          2. Age greater than 50 years old&#xD;
&#xD;
          3. Montreal Cognitive Assessment (MoCA) score: 24-18&#xD;
&#xD;
          4. Patients must have a responsible caregiver = 4days/week&#xD;
&#xD;
          5. Must be on a stable dose of medications for parkinsonism (levodopa, dopaminergic&#xD;
             agonist) and cognition (cholinesterase inhibitors) and psychiatric (i.e.&#xD;
             antidepressants, antipsychotic) for at least 3 months prior to the study&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Evidence of stroke or other neurological condition&#xD;
&#xD;
          2. Any other serious underlying condition or brain disorder that can account in part of&#xD;
             in full for the clinical presentation (i.e. cancer or unstable cardiac disease etc.)&#xD;
&#xD;
          3. Contraindication to MRI e.g. presence of metal fragments in head or eye, implanted&#xD;
             electrical devices or conductive implants or devices (pacemakers, neurostimulators).&#xD;
&#xD;
          4. Unable to undergo DAT-scan&#xD;
&#xD;
          5. Depression that is, in the opinion of the investigator, significant enough to&#xD;
             interfere with neuropsychology and safety assessments&#xD;
&#xD;
          6. Females who are pregnant or breastfeeding, or planning to conceive within the study&#xD;
             period&#xD;
&#xD;
          7. Concurrent treatment with oral anticoagulants (including Vitamin K agonists and Novel&#xD;
             Oral Anticoagulants (NOACs)) within 4 weeks of screening or anticipated during the 52&#xD;
             week double-blind and open label periods. Specifically, Apixaban, Dabigatran,&#xD;
             Edoxaban, Fondaparinux, Rivaroxaban, and Warfarin are prohibited concomitant&#xD;
             medications. Exceptions: antiplatelet agents such as Aspirin, Clopidogrel, and&#xD;
             Aggrenox.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>50 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Stephen Pasternak, MD, PhD</last_name>
    <phone>519-646-6000</phone>
    <phone_ext>66032</phone_ext>
    <email>spasternak@robarts.cs</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Carolina Silveira, PhD</last_name>
    <phone>519-646-6100</phone>
    <phone_ext>42367</phone_ext>
    <email>Carolina.Silveira@sjhc.london.ca</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Parkwood Institute</name>
      <address>
        <city>London</city>
        <state>Ontario</state>
        <zip>N6C0A7</zip>
        <country>Canada</country>
      </address>
    </facility>
    <contact>
      <last_name>Carolina Silveira, PhD</last_name>
      <phone>519-646-6100</phone>
      <phone_ext>42367</phone_ext>
      <email>Carolina.Silveira@sjhc.london.ca</email>
    </contact>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <reference>
    <citation>Bendor JT, Logan TP, Edwards RH. The function of alpha-synuclein. Neuron. 2013 Sep 18;79(6):1044-66. doi: 10.1016/j.neuron.2013.09.004.</citation>
    <PMID>24050397</PMID>
  </reference>
  <reference>
    <citation>Gomperts SN. Lewy Body Dementias: Dementia With Lewy Bodies and Parkinson Disease Dementia. Continuum (Minneap Minn). 2016 Apr;22(2 Dementia):435-63. doi: 10.1212/CON.0000000000000309.</citation>
    <PMID>27042903</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>17546678</PMID>
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  </reference>
  <verification_date>August 2022</verification_date>
  <study_first_submitted>April 29, 2020</study_first_submitted>
  <study_first_submitted_qc>May 22, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 28, 2020</study_first_posted>
  <last_update_submitted>August 29, 2022</last_update_submitted>
  <last_update_submitted_qc>August 29, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">September 1, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Lawson Health Research Institute</investigator_affiliation>
    <investigator_full_name>Stephen Pasternak</investigator_full_name>
    <investigator_title>Neurologist</investigator_title>
  </responsible_party>
  <keyword>Lewy Body Disease</keyword>
  <keyword>Ambroxol</keyword>
  <keyword>Cognition</keyword>
  <keyword>Dementia</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dementia</mesh_term>
    <mesh_term>Lewy Body Disease</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ambroxol</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04405596
org study id: REB:115252
nct id: NCT04405596
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This is a randomized, placebo-controlled, double-blind study investigating whether the
      medication Ambroxol is safe,effectiveness and well tolerated for the treatment of Lewy Body
      Dementia (LBD). Currently the main treatments for patients with LBD target symptom
      management. However, none of the medications treat the underlying cause of the disease, which
      includes the accumulation of protein in the brain. Therefore, even if patients respond well
      to symptomatic treatment, they continue to deteriorate. Therefore, the purpose of the current
      study is to make sure Ambroxol is safe to take long term and to test the effects of Ambroxol
      in treating the cognitive impairments associated with LBD by modifying the underlying causes
      of the disease.

      There will be a total of 15 people participating this this study, which will last 52 weeks.
      Over the study period patients will undergo clinical, neuropsychological and neuroimaging
      assessment to assess changes.
The increasing prevalence of dementia is a serious threat to our medical system and our
      society. About 500,000 Canadians are affected with dementia, and this number will rise to
      more than 1 million in the next 20 years. Dementia already costs our economy 15 billion
      dollars per year. While much of the focus of dementia is on Alzheimer's disease, autopsy
      studies suggest that up to 30% of dementia is due to diseases caused by abnormal
      alpha-synuclein accumulation (Synucleinopathies). In healthy brains, alpha-synuclein plays a
      number of important roles, especially in the process by which brain cells (neurons)
      communicate. However, when alpha-synuclein abnormally accumulates into clumps inside the
      neurons it forms Lewy bodies. Eventually, as a result, brain neurons will die causing
      widespread damage to specific brain regions.

      Until the 1980's, cortical Lewy bodies were thought to be relatively rare. However, with
      improved alpha-synuclein immunostaining techniques, Lewy body dementias are now recognized as
      the second most common neurodegenerative dementia, after Alzheimer's disease. Lewy
      body-related disorders include idiopathic Parkinson's disease (PD), Parkinson's disease
      dementia (PDD) and Lewy Body Dementia (LBD). In LBD, alpha- synuclein accumulation is found
      in the brainstem, limbic and neocortical regions, giving rise to autonomic, cognitive and
      motor impairments.

      Cognitive Symptoms: Progressive cognitive decline typically begins early in the course of the
      disease in advance of parkinsonism, but by consensus may follow the development of motor
      signs up to 1 year. Impaired cognitive domains include executive and visual-spatial
      functions, attention and short-term memory. For example, patients may have difficulty
      multi-tasking, following conversations, episodes of staring and perturbed flow of ideas.
      Regarding short-term memory, patients with LBD experience impairment in memory retrieval,
      which can be improved by cueing, which is in contrast to memory encoding seen in AD. The
      early presence of recurrent visual hallucinations is also common in patients with LBD and
      therefore diagnostically useful. Later in the course of the disease, delusions can be present
      giving rise to paranoia.

      Motor symptoms: Parkinsonian motor signs in LBD are often symmetric, with bradykinesia and
      gait impairments being more common than resting tremor. Importantly, patients with LBD will
      often show limited or no response to typical Parkinson's disease pharmacological intervention
      such as levodopa/carbidopa. LBD patients however do show reduced dopamine transporter
      activity on single-photon emission computed tomography (SPECT) or positron emission
      tomography (PET) imaging.

      Other Associated symptoms can include: loss of olfaction, autonomic dysfunction (i.e.
      neurogenic orthostatic hypotension, constipation, neurogenic urinary frequency and urgency),
      high sensitivity to medications and rapid eye movement sleep behaviour disorder typically
      reported by a sleep partner as kicking, punching, yelling and acting out their dreams.

      Mechanism for targeting Lewy bodies: A potential target for disease-modifying treatment is
      the enzyme β-Glucocerebrosidase (GCase; gene name GBA1). Glucocerebrosidase (GCase) is a
      degradative enzyme that resides in a subcellular compartment called the lysosome, and cleaves
      a neutral glycolipid, glucocerebroside, present in the plasma membrane of most cells. GCase
      is intimately linked with Parkinson's disease - a Lewy body-related disorder. Being an
      "asymptomatic carrier" of a GCase mutation is currently the highest genetic risk factor for
      Parkinson's disease, Parkinson's disease dementia and Lewy Body Dementia, with some studies
      suggesting up to 1/3 of patients carry mutations. Reductions in GCase activity most likely
      also play a role in sporadic Parkinson's disease, as these patients have lower levels of
      GCase in their brain and cerebrospinal fluid, even when they do not carry a mutant GCase
      allele. Laboratory studies have demonstrated a direct link between GCase activity and
      α-synuclein accumulation. In cultured cells, loss of GCase results in α-synuclein
      accumulation and this process feeds back upon itself, with overexpression of α-synuclein
      further inhibiting GCase function, and increasing GCase expression reducing α-synuclein.
      Moreover, reducing GCase genetically or pharmacologically in animal studies results in
      increased α-synuclein aggregates. Remarkably, overexpressing GCase in the brain of a
      Parkinson's disease mouse model reduces α-synuclein and improves cognition. Taken together,
      these findings suggest that increasing GCase levels could be a therapy that addresses the
      underlying pathophysiology of Lewy body-related disorders such as Lewy Body dementia to
      modify the course of disease progression.

      Background on Ambroxol Studies: Ambroxol is an expectorant that has been available over the
      counter in more than 50 countries for over 30 years. The Mahuran Lab identified Ambroxol by
      screening a library of compounds as an agent that stabilizes wild-type (normal) GCase. By
      stabilizing GCase, Ambroxol is able to markedly increase GCase protein and activity in normal
      and Gaucher disease fibroblasts at doses of 10 µM. Ambroxol can also increase GCase in normal
      mouse neuronal cultures to more than 150% of normal at a dose of 30 µM. Ambroxol has good
      lipophilicity (cLogP = 2.8) and low polar surface area (PSA 58 Å2), predicting good CNS
      penetration. Unpublished studies performed by ExSAR corporation demonstrate that in single
      and multiple dose experiments in rats, Ambroxol crossed rapidly into the brain and exhibited
      brain to plasma concentration ratios of greater than 10 indicating outstanding CNS
      penetration. In pilot studies, Ambroxol was effective at improving GCase function in humans.
      In a trial aimed at non-neurological Gaucher disease, 12 patients received 150 mg/day for 6
      months, and all but one had some measurable improvement. The best response was in the
      lightest patient (who received 3 mg/kg/day), suggesting that Ambroxol was under dosed.
      Ambroxol has also been administered to three Japanese Gaucher disease patients with severe
      neurological disease, at 1000-3000 mg/day for 12-31 months. These patients had improvements
      in seizure frequency and neurological symptoms; one patient regained the ability to sit
      unsupported and to walk. Importantly, in a recent study of Ambroxol in 18 Parkinson's disease
      patients, the authors observed a 35% increase in CSF GCase protein levels at a daily dose of
      1260mg with no serious adverse events.

      Safety: Ambroxol has an excellent safety record, and has been studied in >15,000 patients in
      more than 100 trials. Ambroxol is sold over the counter in much of the world as an
      expectorant at doses of 75-120 mg/day. Ambroxol is considered so safe that it is approved for
      intravenous use in pregnant women at a dose of 1000 mg/day IV (15 mg/kg) to improve fetal
      lung maturation before preterm delivery. Clinical trials in more than 390 pregnant women have
      been performed using doses up to 3000 mg in one day and 1300 mg/day for up to 33 days.
      Critically ill neonates have also been given doses as high as 30 mg/kg for respiratory
      distress. The fact that Ambroxol has been used at very high doses in pregnant women and
      neonates suggests that these doses are safe.

      Project Summary: This is a proof of principle randomized, placebo-controlled, double-blind
      study investigating whether the medication Ambroxol (dose: 1350mg/day) is safe, well
      tolerated and will raise GCase levels in the CSF and plasma of patients diagnosed with
      probable Lewy Body Dementia (LBD). Additionally, increased levels of the enzyme
      β-glucocerebrosidase (GCase) and lower the levels of the protein α-synuclein have both been
      shown to improve cognition in mouse models. Therefore, as secondary aim will be to
      investigate whether Ambroxol will improve cognitive symptoms in patients diagnosed with Lewy
      Body Dementia (LBD). This will be a 52-week trial of Ambroxol in 15 patients diagnosed with
      probable LBD. Patients will undergo clinical, neuropsychological and neuroimaging assessment
      throughout the study to assess changes. Ambroxol has never been examined in LBD patients;
      however, trials of pharmacological chaperone therapy have been suggested in a recent review
      in the journal "The Proceedings of the National Academy of Sciences". A successful outcome of
      this trial will greatly accelerate the development of therapeutics for neurodegenerative
      disease. This proposal outlines a completely novel pharmacological target for LBD, namely the
      GCase enzyme. The investigators also propose a completely novel therapy using the drug
      Ambroxol, an agent considered safe enough to give to pregnant women, which has improved GCase
      function in pilot studies in humans. This strategy could stabilize the underlying pathology
      of Lewy Body Dementia; it might allow patients to get better. Furthermore, repurposing an
      existing medication with excellent safety record will greatly shorten the time to bring this
      therapy to general use, allowing us to leapfrog the normally decades-long drug development
      process.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Change in Mini Mental State Examination score from baseline over time
time frame: Baseline, week 4, week 10, week 18, week 26, week 34, week 42, week 52
description: Monitor safety using frequent cognitive evaluations using the mini mental state examination. Lower scores are indicative of worsening cognitive impairment [score range: 0-30]
measure: Change in the incidence, nature and severity of AE's and SAE's from baseline
time frame: Baseline, week 4, week 10, week 18, week 26, week 34, week 42, week 52
description: Change in the number of participants with AE's and SAE's
measure: Change in the number of participants with treatment discontinuations and study discontinuation due to AEs from baseline
time frame: Baseline, week 4, week 10, week 18, week 26, week 34, week 42, week 52
description: Change from baseline in the number of participants with treatment and/or study discontinuation will be used to demonstrate safety and tolerability
measure: Change in the number of participants with electrocardiogram (ECG) abnormalities
time frame: Baseline, week 4, week 10, week 18, week 26, week 34, week 42, week 52
description: Change from baseline in the number of participants with clinically significant ECG abnormalities (QT interval) to demonstrate safety
measure: Change from baseline the number of participants with abnormal changes in hemodynamic values while seated
time frame: Baseline, week 4, week 10, week 18, week 26, week 34, week 42, week 52
description: Changes in hemodynamic values from baseline over time to demonstrate safety
measure: Change from baseline the number of participants with abnormal changes in hemodynamic values while standing
time frame: Baseline, week 4, week 10, week 18, week 26, week 34, week 42, week 52
description: Changes in hemodynamic values from baseline over time to demonstrate safety
measure: Change in blood analyses from baseline over time
time frame: Baseline, week 4, week 10, week 18, week 26, week 34, week 42, week 52
description: Change from baseline in number of participants with abnormal changes in clinical laboratory blood tests from baseline over time for safety
measure: Change in urine analyses from baseline over time
time frame: Baseline, week 4, week 10, week 18, week 26, week 34, week 42, week 52
description: Change from baseline in number of participants with abnormal changes in clinical laboratory urine tests from baseline over time for safety
measure: Change from baseline in plasma concentrations of Ambroxol from blood sample
time frame: Baseline, week 4, week 10, week 26, week 52
description: Change in plasma Ambroxol concentrations from blood sample from baseline
measure: Change from baseline in cerebrospinal fluid (CSF) concentrations of Ambroxol at specified time points
time frame: Baseline, week 10, week 52
description: Change in Ambroxol concentrations from cerebrospinal fluid sample from baseline
measure: Change from baseline in enzyme β-Glucocerebrosidase (GCase) concentration levels in CSF
time frame: Baseline, week 10, week 52
description: Change in GCase concentration in the CSF from baseline
measure: Change from baseline in enzyme β-Glucocerebrosidase (GCase) concentration levels in white blood cells
time frame: Baseline, week 4, week 10, week 26, week 52
description: Change in white blood cell GCase concentrations from baseline
measure: Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)
time frame: Baseline, week 26, and week 52
description: Demonstrate the efficacy of Ambroxol in improving, or slowing the progression of cognitive deficits. Lower scores are indicative of worsening cognitive function [score range: 40-160]
measure: Clinician's Global Impression of Change (CGIC)
time frame: Baseline, week 26, and week 52
description: Demonstrate the efficacy of Ambroxol in improving, or slowing the progression of cognitive deficits. Patients are assessed as: no change, minimal, moderate and marked worsening, minimal, moderate and marked improvement
measure: Montreal Cognitive Assessment (MoCA)
time frame: Baseline, week 26, and week 52
description: Demonstrate the efficacy of Ambroxol in improving, or slowing the progression of cognitive deficits. Lower scores are indicative of worsening cognitive impairment [score range: 0-30]
measure: Trail making test A and B to assess cognitive function
time frame: Baseline, week 26, and week 52
description: Demonstrate the efficacy of Ambroxol in improving, or slowing the progression of cognitive deficits: Higher times to complete are indicative of worsening cognitive function [Max time: 300 seconds]
measure: Parkinson's disease - Cognitive rating scale to assess cognitive function
time frame: Baseline, week 26, and week 52
description: Demonstrate the efficacy of Ambroxol in improving, or slowing the progression of cognitive deficits. Lower scores are indicative of higher cognitive dysfunction [Score range: 0-134]
measure: Change in regional brain magnetic resonance imaging atrophy measures
time frame: Baseline, week 52
description: Change in hippocampal atrophy (cm3)
measure: Change in global brain magnetic resonance imaging atrophy measures
time frame: Baseline, week 52
description: Change in brain ventricle volume (cm3)
measure: Change in plasma biomarkers
time frame: Baseline, week 4, week 10, week 18, week 26, week 34, week 42, week 52
description: Change in levels of plasma biomarkers: α-synuclein (pg/ml), Tau (pg/ml), phospho-Tau (pg/ml) and beta amyloid-42 (pg/ml) in plasma
measure: Change in Cerebrospinal Fluid (CSF) biomarkers
time frame: Baseline, week 10, week 52
description: Change in levels of CSF biomarkers: α-synuclein (pg/ml), Tau (pg/ml), phospho-Tau (pg/ml) and beta amyloid-42 (pg/ml) in CSF
measure: Neuropsychological Inventory (NPI)
time frame: Baseline, week 26, and week 52
description: Demonstrate change or slowed progression in standard tests of mood and neuropsychiatric symptoms. Assesses frequency and severity of neuropsychological symptoms with higher scores indicative of more symptoms, higher frequency and more severe. [Score range: 0-144]
measure: Geriatric Depression Scale
time frame: Baseline, week 26, and week 52
description: Demonstrate change or slowed progression in standard tests of mood and neuropsychiatric symptoms: Higher scores indicate more severe depression [score range: 0-15]
measure: The Motor subscale of Unified Parkinson's Disease Rating Scale (UPDRS-III)
time frame: Baseline, week 26, and week 52
description: Demonstrate change or slowed progression in tests of motor function/Parkinsonism: Higher scores indicate more dysfunction [score range: 0-108]
measure: Timed Up and Go
time frame: Baseline, week 26, and week 52
description: Demonstrate change or slowed progression in tests of motor function/Parkinsonism. Higher times indicate slower movement and more motor impairment
arm group label: Ambroxol
arm group type: Experimental
description: Participants randomized to the 1350 mg/day group will begin with a dose of 450 mg, increasing bi-weekly to a dose of 1350 mg/day.
arm group label: Placebo
arm group type: Placebo Comparator
description: Participants receive capsules visually identical to the experimental groups but without active ingredients.
intervention type: Drug
intervention name: Ambroxol Hydrochloride
description: The treatment regimen consists of a titration phase and a maintenance phase. Participants begin the titration phase (Weeks 1 and 2) taking 6 capsules a day (450mg or 0 mg) divided BID (3 capsules in the morning and 3 capsules in the evening). The first medication dose will be taken at the end of Baseline visit and in the presence of the study Neurologist. Possible side effects will be observed for 30 minutes. Medication dose will increase bi-weekly to 12 capsules on Weeks 3 and 4, and 18 capsules on Weeks 5 and 6 divided BID. At the end of titration (Week 5) participants will have reached a maximum of 1350mg or 0mg per day, depending on group allocation. In the maintenance phase, participants will remain in their maximum dose (1350mg or 0mg) from Week 5 to Week 52 (End of Trial).
arm group label: Ambroxol
other name: Mucosolvan
intervention type: Other
intervention name: Placebo
description: The treatment regimen consists of a titration phase and a maintenance phase. Participants begin the titration phase (Weeks 1 and 2) taking 6 capsules a day (450mg or 0 mg) divided BID (3 capsules in the morning and 3 capsules in the evening). The first medication dose will be taken at the end of Baseline visit and in the presence of the study Neurologist. Possible side effects will be observed for 30 minutes. Medication dose will increase bi-weekly to 12 capsules on Weeks 3 and 4, and 18 capsules on Weeks 5 and 6 divided BID. At the end of titration (Week 5) participants will have reached a maximum of 1350mg or 0mg per day, depending on group allocation. In the maintenance phase, participants will remain in their maximum dose (1350mg or 0mg) from Week 5 to Week 52 (End of Trial).
arm group label: Placebo
criteria: 
gender: All
minimum age: 50 Years
maximum age: N/A
healthy volunteers: No
last name: Stephen Pasternak, MD, PhD
phone: 519-646-6000
phone ext: 66032
email: spasternak@robarts.cs
last name: Carolina Silveira, PhD
phone: 519-646-6100
phone ext: 42367
email: Carolina.Silveira@sjhc.london.ca
facility: 
contact: 
country: Canada
citation: Bendor JT, Logan TP, Edwards RH. The function of alpha-synuclein. Neuron. 2013 Sep 18;79(6):1044-66. doi: 10.1016/j.neuron.2013.09.004.
PMID: 24050397
citation: Gomperts SN. Lewy Body Dementias: Dementia With Lewy Bodies and Parkinson Disease Dementia. Continuum (Minneap Minn). 2016 Apr;22(2 Dementia):435-63. doi: 10.1212/CON.0000000000000309.
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responsible party type: Principal Investigator
investigator affiliation: Lawson Health Research Institute
investigator full name: Stephen Pasternak
investigator title: Neurologist
mesh term: Dementia
mesh term: Lewy Body Disease
mesh term: Ambroxol