Phase IIa Multicenter RCT on Ambroxol Efficacy in Prodromal and Mild Dementia with Lewy Bodies

Trial ID: 2024-510720-38-00
Protocol: 2019-002855-41
Sponsor: Helse Fonna HF

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Diseases & Conditions

Dementia with Lewy bodies

Objectives

The primary objective of this phase IIa multicentre randomized controlled double-blind clinical trial is to confirm the effect of **Ambroxol** in participants diagnosed with **Dementia with Lewy Bodies** (DLB), as measured by the Mini-Mental State Examination (MMSE-NR3) as the primary outcome measure. This is clinically relevant as it aims to establish the cognitive efficacy of Ambroxol in improving or stabilizing cognitive function in patients with DLB, a condition characterized by progressive cognitive decline and neuropsychiatric symptoms.

Secondary objectives include evaluating the effect of Ambroxol on sleep disturbances, falls, fluctuations, and parkinsonism in DLB patients, using specific questionnaires. These secondary measures are important for understanding the broader impact of Ambroxol on the quality of life and daily functioning of individuals with DLB, beyond cognitive outcomes.

Participants

The clinical trial focuses on participants diagnosed with **Dementia with Lewy Bodies** (DLB), including those with Mild Cognitive Impairment in DLB (DLB-MCI). The study population comprises both male and female subjects aged between 50 and 85 years. Participants are required to have a confirmed diagnosis of DLB and a **Mini-Mental State Examination** (MMSE) score of 15 or higher at screening. The trial includes individuals who are capable of complying with all study procedures and are willing to provide informed consent. Participants must be able to self-administer or have a caregiver administer oral ambroxol medication. The trial population selection criteria emphasize the ability to travel to the study site and maintain regular contact with a caregiver. The sponsor has not provided information regarding the total number of participants in the study.

Plans and Procedures

The clinical trial is designed as a **randomized**, **double-blind**, and **controlled** study to evaluate the efficacy of **Ambroxol** in patients with prodromal and mild **Dementia with Lewy Bodies**. The trial aims to confirm the effect of Ambroxol, with the primary outcome measure being the mean score on the Mini-Mental State Examination (MMSE) from screening to 18 months. The study will involve participants aged 50 to 85 years, who have a confirmed diagnosis of Dementia with Lewy Bodies, including Mild Cognitive Impairment in DLB. The trial is expected to run until December 31, 2028, with recruitment having started on May 1, 2021.

Participants will be involved in the study for a total duration of 18 months. The sequence of study visits includes an initial screening visit to assess eligibility based on inclusion criteria such as age, cognitive status, and ability to comply with study procedures. Following the screening, participants will undergo regular follow-up visits to monitor their cognitive, neuropsychiatric, and functional outcomes. These visits will also include assessments such as the clock drawing test, COWAT, and the Clinician’s Global Impression of Change. The end-of-study visit will conclude the trial, where final assessments will be conducted to evaluate the long-term effects of the treatment.

Participants will be required to self-administer or have a caregiver administer oral Ambroxol, with the dosage escalating from 60 mg three times daily to 420 mg three times daily over the course of the study. Conditions that may lead to early termination from the study include inability to comply with the study protocol, adverse reactions to the medication, or withdrawal of consent. The trial will also include a placebo group to ensure the reliability of the results, with the placebo matching the active treatment in appearance. The study is not classified as a low-intervention trial and is categorized as a Phase II therapeutic exploratory and confirmatory clinical trial.

Treatment

The clinical trial involves the administration of **Ambroxol**, an experimental medication, to evaluate its efficacy in patients with prodromal and mild **Dementia with Lewy bodies**. Ambroxol is provided in a **tablet** form and contains the active substance **ambroxol hydrochloride**. The medication is administered orally. The dosing regimen includes a maximum daily dose of 1260 mg, with a total maximum dose of 420 mg per administration. The treatment period is set for a maximum of 30 days. The pharmaceutical product is classified as an expectorant and is not a paediatric formulation. The chemical origin of the active substance is confirmed, and the product is authorized under the marketing authorization number PRD11535660.

In addition to the experimental treatment, a **placebo** matching the active treatment is utilized in the study. The placebo is designed to mimic the appearance and administration route of the Ambroxol tablets, ensuring blinding in the randomized controlled trial. The placebo does not contain any active substances and serves as a comparator to assess the efficacy of Ambroxol. The administration of the placebo follows the same oral route and dosing schedule as the active treatment, maintaining consistency in the trial protocol.

Efficacy

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the mean score on the **Mini-Mental State Examination (MMSE)** from screening to 18 months in the intervention group compared to the control group. This endpoint will evaluate the cognitive function of participants diagnosed with Dementia with Lewy bodies (DLB) and will be measured using the MMSE-NR3 as the primary outcome measure.

Secondary endpoints include various cognitive, neuropsychiatric, and functional outcomes. These will be assessed by comparing mean scores at 18 months between the ambroxol and placebo groups. Specific assessments include the clock drawing test, Controlled Oral Word Association Test (COWAT) immediate and delayed recall, Trail Making Test A&B, Visual Object and Space Perception (VOSP) silhouettes, and the FAS test. Additionally, the Clinician’s Global Impression of Change (ADCS-CGIC) score, total Neuropsychiatric Inventory (NPI) score, and Unified Parkinson's Disease Rating Scale (UPDRS) part III motor part and MAYO fluctuation scores will be evaluated. The number of participants with Rapid Eye Movement Sleep Behavior Disorder (RBD) as defined by the Mayo Sleep Questionnaire and the number of falls will also be recorded at month 18.

These efficacy parameters will be collected and analyzed at specified timepoints, with the primary and secondary outcomes being assessed at the 18-month mark. The trial aims to confirm the effect of ambroxol in participants with DLB, with a focus on cognitive and functional improvements as measured by these validated scales and tests.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Age ≥ 50 and ≤ 85 years of age, both genders
Confirmed diagnosis of Dementia with Lewybodies (DLB) including Mild Cognitive Impairment in DLB (DLB-MCI).
MMSE score>=15 at screening
Able and willing to provide informed consent prior to any study related assessments and procedures.
Capable of complying with all study procedures.
Willing to provide blood samples for genetic analyses of APOE and GBA.
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 mg BID (day 15-21), 315 mg TID (day 22-28) and 420 mg TID (day 29-550)).
Contact with caregiver at least 3 times a week, to ensure sufficient information from the caregiver regarding participants status and possible change in condition.
Able to travel to the participating study site.
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.
Caregiver needs to be > 18 years when signing the informed consent form.

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Exclusion Criteria

Current treatment with anticoagulants (e.g. warfarin, argatroban, dabigatraneteksilat, rivaroksaban, apiksaban, edoksaban).
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.
Exposure to more than three investigational medicinal products within 12 months prior to the first dose in the current study.
Confirmed dysphagia that would preclude self-administration of ambroxol up to 6 tablets daily for the duration of this study.
History of known sensitivity to the study medication, ambroxol or its excipients (lactose monohydrate, granulated microcrystalline cellulose, silicon dioxide,magnesium stearate and Bitrex/Denatonium Benzoate in the opinion of the investigator that contraindicates their participation.
History of known rare hereditary disorders of galactose Intolerance: Lapp lactase deficiency or glucose-galactose malabsorption.
History of illegal substance abuse, drug abuse or alcoholism in the opinion of the Investigator that would preclude participation in the study.
Donation of blood (one unit or 350 ml) within three months prior to receiving the first dose of the study drug.
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 2 weeks following the last dose of the study drug.
clinically significant or unstable 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: a) Impaired renal function defined by eGFR<=30 b) Moderate/Severe hepatic impairment defined by Child-Pugh score >1 c) 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. d) Major stroke e) Major depression defined clinically or by GDS-15 >=11 points or delirium or psychotic disorder unrelated to DLB. f) Cancer, history of metastatic cancer, terminal illness or clinically significant disease within ≤5 years, except for adequately treated basal cell skin cancer.
Planned major surgical treatment during the study period.