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Ambroxol in New and Early DLB, A Phase IIa Multicentre Randomized Controlled Double Blind Clinical Trial (ANeED)

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ClinicalTrials.gov Identifier: NCT04588285
Recruitment Status : Recruiting
First Posted : October 19, 2020
Last Update Posted : May 19, 2021
Sponsor:
Collaborators:
Klinbeforsk
Helse-Bergen HF
Information provided by (Responsible Party):
Helse Fonna

Brief Summary:
This is a confirmatory investigational medicinal product (IMP) study to investigate the effects on cognition, functional decline and on neuropsychiatric symptoms of the Glucocerebrosidase (GCase) enhancing chaperone ambroxol in participants diagnosed with prodromal and early dementia with Lewybodies (DLB).

Condition or disease Intervention/treatment Phase
Dementia With Lewy Bodies Drug: Ambroxol Drug: Placebo Phase 2

Detailed Description:
Participants will be recruited through established network of Norwegian Memory Clinics. Patients will be randomised to ambroxol with proven effect on the lysosomal and glucocerebrosidase pathology in DLB or placebo. The randomization will be stratified based on APOE e4 and on the concentration of A-beta in CSF. The frequency of GBA genotypes in the active treatment and placebo groups will be calculated at study end. The blinded phase will last for 18 months and an open extension with ambroxol will be offered to all participants for one additional year. The primary outcomes will be cognition, global function, disease stage, progression, and neuropsychiatric symptoms. Secondary outcomes will be on sleep disturbances, falls, fluctuations and parkinsonism, and exploratory outcomes will be impact on the potential biomarkers for drug effects defined as qEEG, DaTSCAN, MRI and α-synuclein in CSF. One hundred seventy-two participants will be recruited in total. Each participant will orally self-administer or administer by a caregiver ambroxol or placebo at 5 intra-participant dose escalations at 60 mg TID (day 1-7), 120 mg TID (day 8- 14), 315 BID (day 15-21), 315 mg TID (day 22-28) and 420 mg TID (day 29-550)).Participants will be subjected to clinical and laboratory assessments to assess the safety, tolerability effects of ambroxol on blood biomarkers and MRI, DaTSCAN, ECG, EEG and lumbar puncture. Each participant will undergo 8 hospital visits and 16 telephone visits for the blinded phase of the study during the first 18 months. Hospital visits will additionally include 1 or 2 screening appointments within 60 days of Day 1 hospital visit (at which participants will receive the first dose of ambroxol), followed by visits at week 4, week 8, week 24, week 36, week 52, month 15 and month 18. Participants will receive a telephone call 3 days after lumbar puncture to record any complaints. Participants will receive 16 telephone calls to record any drug related adverse events in between hospital visits, between 1-3 days before and after each dose escalation (day 1, 8, 15, 22 and 29, week 12,16, 20, 28, 32, 40, 44, 48 and month 13, 14, 16 and 17). All participants will be offered treatment with the IMP for 12 additional months from month 18 - month 30.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 172 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Each participant will receive 5 intra-participant dose escalations at 60 mg TID (day 1-7), 120 mg TID (day 8-14), 315 BID (day 15-21), 315 mg TID (day 22-28) and 420 mg TID (day 29-550) with ambroxol or placebo for the duration of 18 months.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: The blinded phase (placebo or ambroxol) will last for 18 months and an open extension with ambroxol will be offered to all participants for one additional year. Randomisation to placebo or ambroxol will be done by the system Viedoc.
Primary Purpose: Treatment
Official Title: A Clinical Trial to Demonstrate Clinical Efficacy on Cognitive, Neuropsychiatric and Functional Outcomes of Ambroxol in New and Early Patients With Prodromal and Mild Dementia With Lewybodies
Actual Study Start Date : May 4, 2021
Estimated Primary Completion Date : April 1, 2022
Estimated Study Completion Date : December 1, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Dementia

Arm Intervention/treatment
Experimental: Ambroxol
Oral ambroxol medication, from day 1 to study end (at 60 mg TID (day 1-7), 120 mg TID (day 8- 14), 315 mg BID (day 15-21), 315 mg TID (day 22-28) and 420 mg TID (day 29-550)).
Drug: Ambroxol
Oral ambroxol medication (60 mg) from day 1 to study end (at 60 mg TID (day 1-7), 120 mg TID (day 8- 14), 315 mg BID (day 15-21), 315 mg TID (day 22-28) and 420 mg TID (day 29-550)
Other Name: Mucosolvan

Experimental: Placebo
Oral placebo medication, from day 1 to study end (at 60 mg TID (day 1-7), 120 mg TID (day 8- 14), 315 mg BID (day 15-21), 315 mg TID (day 22-28) and 420 mg TID (day 29-550)).
Drug: Placebo
Oral placebo medication (60 mg) from day 1 to study end (at 60 mg TID (day 1-7), 120 mg TID (day 8- 14), 315 mg BID (day 15-21), 315 mg TID (day 22-28) and 420 mg TID (day 29-550)




Primary Outcome Measures :
  1. Change in the incidence, nature and severity of AE's and SAE's from baseline. [ Time Frame: All patient visits including phonecalls trough study completion, planned duration 18 months ]
    Change in the number of participants with AE's and SAE's.

  2. Change in the number of participants with treatment discontinuations and study discontinuation due to AEs from baseline. [ Time Frame: All patient visits including phonecalls trough study completion, planned duration 18 months ]
    Change from baseline in the number of participants with treatment and/or study discontinuation will be used to demonstrate safety and tolerability

  3. Change in the number of participants with electrocardiogram (ECG) abnormalities. [ Time Frame: Through study completion at the following visits: Screening, Baseline, week 4, week 24, week 36, week 52, month 15, and month 18. ]
    Including QTc interval.

  4. Change in blood analyses from baseline over time abnormalities. [ Time Frame: Through study completion at the following visits: Screening, week 4, week 8, week 24, week 36, week 52, month 15, and month 18. ]
    Change from baseline in number of participants with abnormal changes in clinical laboratory blood tests from baseline over time for safety.

  5. Change in MMSE-NR3 (Mini Mental Status Examination, Norwegian revised version) over time. [ Time Frame: Through study completion at the following visits: Screening, week 24, week 36, week 52, Month 18. ]

    To confirm the effect of the IMP ambroxol in participants diagnosed with DLB measured by a defined battery of cognitive tests defining MMSE-NR3 as the primary outcome.

    The MMSE-NR3 is a screening test for cognitive impairment that spans the visuospatial/executive, naming, memory, attention, language, delayed recall and orientation domains (score range from 0 to 30 points).


  6. ADCS-CGIC (Clinician's Global Impression of Change) [ Time Frame: Through study completion at the following visits: Screening, week 24, week 36, week 52, month 18. ]
    To confirm the effect of the IMP Ambroxol on the rate of functional decline in DLB.

  7. Change in CDR-SB (Clinical Dementia Rating-Sum of Boxes). [ Time Frame: Through study completion at the following visits: Screening, week 24, week 36 week 52, Month 18. ]
    Measure Rate of decline from screening to study completion at month 18 using CDR-SB.

  8. Change NPI (neuropsychiatric inventory) [ Time Frame: Through study completion at the following visits: Screening, week 24, week 36, week 52, month 18. ]

    To confirm the effect of the IMP Ambroxol on neuropsychiatric symptoms in DLB from screening to study completion at month 18 by using NPI.

    The NPI is a semistructured clinician interview of caretakers in which the severity and frequency of disturbance in 12 symptom domains is rated. The scoring reflects not only the effect on the patient, but also the extent to which the symptom causes distress in the caregiver.

    Score 0-144. The higher the score the more disease progression.


  9. GDS (geriatric depression scale) - 15 items [ Time Frame: Through study completion at the following visits: Screening, week 24, week 36, week 52, month 18. ]

    To confirm the effect of the IMP Ambroxol on neuropsychiatric symptoms in DLB from screening to study completion at month 18 by using GDS.

    The Geriatric Depression Scale (GDS) is a 15-item self-report assessment used to identify depression in the elderly. A high score usually always indicates depression and more severe depression.



Secondary Outcome Measures :
  1. Mayo Sleep Questionnaire (MSQ). [ Time Frame: Through study completion at the following visits: Screening, week 24, week 36, week 52, Month 18. ]

    To confirm the effect of The IMP Ambroxol in DLB measured on MSQ for evaluating sleep disturbances.

    MSQ is developed and validated in English version to detect Rapid Eye Movement - (REM) Sleep Behavior Disorder - (RBD) and several other sleep disorders in people with dementia and Parkinson's disease. RBD is part of the diagnosis of dementia with Lewy bodies.

    No score - only yes/no questions.


  2. Mayo Fluctuation Scale (MFS) [ Time Frame: Through study completion at the following visits: Screening, week 24, week 36, week 52, Month 18. ]

    To confirm the effect of The IMP Ambroxol in DLB measured on MFS for evaluating fluctuations.

    The Mayo Fluctuations Scale is a short questionnaire that evaluates cognitive fluctuation.

    Three or four points shows cognitive fluctuation. Scale 0-4.The higher the score the more disease progression


  3. Unified Parkinson Disease Rating Scale (UPDRS-III) [ Time Frame: Through study completion at the following visits: Screening, week 8, week 24, week 36, week 52, Month 18. ]

    To confirm the effect of The IMP Ambroxol in DLB measured on UPDRS-III for evaluating Parkinsonism.

    The unified Parkinson's disease rating scale (UPDRS) is used to follow the longitudinal course of Parkinson's disease. The UPD rating scale is the most commonly used scale in the clinical study of Parkinson's disease. Following the UPDRS scores over time provides insight into the patient's disease progression.

    Scale 0-138 points. The higher the score the more disease progression


  4. Number of falls and related injury [ Time Frame: Through study completion at the following visits: Screening, week 24, week 36, week 52, Month 18. ]
    To confirm the effect of The IMP Ambroxol in DLB measured on questions evaluating number of falls and related injury.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   50 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or female.
  2. Age ≥ 50 and ≤ 85 years of age.
  3. Confirmed diagnosis of Dementia with Lewy Bodies (DLB) or Mild Cognitive Impairment in DLB (DLB-MCI).
  4. MMSE score>=15
  5. Able and willing to provide informed consent prior to any study related assessments and procedures at screening visit 1.
  6. Capable of complying with all study procedures.
  7. Willing to provide blood samples for genetic analyses of APOE and GBA.
  8. Willing and able to self-administer or administer by a caregiver oral ambroxol medication, from day 1 to study end (at 60 mg TID (day 1-7), 120 mg TID (day 8- 14), 315 BID (day 15-21), 315 mg TID (day 22-28) and 420 mg TID (day 29-550)).
  9. Able to travel to the participating study site.
  10. A female participant is eligible to participate if she is of:

    Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 consecutive months of spontaneous amenorrhea, at least 6 weeks post-surgical bilateral oophorectomy (with or without hysterectomy) or post tubal ligation. In questionable cases, menopausal status will be confirmed by demonstrating levels of follicle stimulating hormone (FSH) 25.8 - 134.8 IU/L and oestradiol < 201 pmol/l at entry.

    Women of child-bearing potential must use accepted contraceptive methods (listed below), and must have a negative serum at screening visit 1 and urine pregnancy tests at subsequent visits if applicable. An additional pregnancy test will be performed, and results obtained, prior to administration of the first dose of ambroxol.

  11. A female participant is eligible to participate if she is of:

Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 consecutive months of spontaneous amenorrhea, at least 6 weeks post-surgical bilateral oophorectomy (with or without hysterectomy) or post tubal ligation. In questionable cases, menopausal status will be confirmed by demonstrating levels of follicle stimulating hormone (FSH) 25.8 - 134.8 IU/L and oestradiol < 201 pmol/l at entry.

Women of child-bearing potential must use accepted contraceptive methods (listed below), and must have a negative serum at screening visit 1 and urine pregnancy tests at subsequent visits if applicable. An additional pregnancy test will be performed, and results obtained, prior to administration of the first dose of ambroxol.

Exclusion Criteria:

  1. Current treatment with anticoagulants (e.g. warfarin) that might preclude safe completion in the opinion of the Investigator.
  2. Current use of investigational medicinal product or participation in another interventional clinical trial or who have done so within 30 days prior to the first dose in the current study.
  3. Exposure to more than three investigational medicinal products within 12 months prior to the first dose in the current study;
  4. Confirmed dysphagia that would preclude self-administration of ambroxol up to 6 tablets daily for the duration of day 1 to day 550/Month 18.
  5. Significant known lower spinal malformations or other spinal abnormalities that would preclude lumbar puncture.
  6. History of known sensitivity to the study medication, ambroxol or its excipients (lactose monohydrate, granulated microcrystalline cellulose, copovidone and magnesium stearate) in the opinion of the investigator that contraindicates their participation.
  7. History of known rare hereditary disorders of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.
  8. History of illegal substance abuse, drug abuse or alcoholism in the opinion of the Investigator that would preclude participation in the study.
  9. Donation of blood (one unit or 350 ml) within three months prior to receiving the first dose of the study drug.
  10. Pregnant or breastfeeding; All participants of child bearing potential in the opinion of the Investigator that would preclude participation in the study and who do not agree to use double-barrier birth control or abstinence while participating in the study and for two weeks following the last dose of study drug;
  11. Any clinically significant or unstable psychiatric, medical or surgical condition that in the opinion of the PI or PI-delegated clinician may put the participant at risk when participating in the study or may influence the results of the study or affect the participant's ability to take part in the study, as determined by medical history, physical examinations, electrocardiogram (ECG), or laboratory tests.

    Such conditions may include:

    1. Impaired renal function
    2. Moderate/Severe hepatic impairment
    3. A major cardiovascular event (e.g. myocardial infarction, acute coronary syndrome, decompensated congestive heart failure, pulmonary embolism, coronary revascularisation that occurred within 6 months prior to the screening visit.
    4. Major depression, delirium or psychosis not related to DLB.
    5. Metastatic cancer or terminal illness.
  12. Planned major surgery or other major treatments during study period that will interfere with study-obligations.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04588285


Contacts
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Contact: Arvid Rongve, Phd 90548749 arvid.rongve@helse-fonna.no

Locations
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Norway
Helse Fonna Recruiting
Haugesund, Norway, 5504
Contact: Arvid Rongve, Phd    90548749    arvid.rongve@helse-fonna.no   
Principal Investigator: Dag Årsland, Professor         
Principal Investigator: Tormod Fladby, Professor         
Principal Investigator: Geir Selbæk, Professor         
Principal Investigator: Ragnhild Eide Skogseth, Resident         
Principal Investigator: Geir Bråthen, MD         
Principal Investigator: Knut Waterloo, Professor         
Principal Investigator: Minna Kia Hynninen, MD         
Principal Investigator: Sverre Bergh, Postdoc         
Sponsors and Collaborators
Helse Fonna
Klinbeforsk
Helse-Bergen HF
Investigators
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Principal Investigator: Arvid Rongve, Phd arvid.rongve@helse-fonna.no
Additional Information:
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Responsible Party: Helse Fonna
ClinicalTrials.gov Identifier: NCT04588285    
Other Study ID Numbers: 1.0 Date: April 7th 2020
First Posted: October 19, 2020    Key Record Dates
Last Update Posted: May 19, 2021
Last Verified: May 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Helse Fonna:
Cognitive
Neuropsychiatric
Functional Outcomes
New and Early Patients
Prodromal
Mild Dementia
Lewybodies
Additional relevant MeSH terms:
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Dementia
Lewy Body Disease
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neurocognitive Disorders
Mental Disorders
Parkinsonian Disorders
Basal Ganglia Diseases
Movement Disorders
Synucleinopathies
Neurodegenerative Diseases
Ambroxol
Expectorants
Respiratory System Agents