A phase IIa multicentre randomized controlled double blind 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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Helse Fonna HF

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10], Psychiatry and Psychology [F] - Mental Disorders [F03]

Trial duration

12 Jan 2021 → ongoing

Decision date (initial)

2024-10-22

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

KLINBEFORSK

External identifiers

EU CT number

2024-510720-38-00

EudraCT number

2019-002855-41

ClinicalTrials.gov

NCT04588285

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Therapy

To confirm the effect of the IMP ambroxol in participants diagnosed with DLB measured by MMSE-NR3 as the primary outcome measure.

Secondary objectives 1

1. Evaluate the effect of Ambroxol in DLB measured on questionnaires for evaluating sleep disturbances, falls, fluctuations and parkinsonism.

Conditions and MedDRA coding

Dementia with Lewy Bodies

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. 1. Age ≥ 50 and ≤ 85 years of age, both genders
2. Confirmed diagnosis of Dementia with Lewybodies (DLB) including Mild Cognitive Impairment in DLB (DLB-MCI).
3. MMSE score>=15 at screening
4. Able and willing to provide informed consent prior to any study related assessments and procedures.
5. Capable of complying with all study procedures.
6. Willing to provide blood samples for genetic analyses of APOE and GBA.
7. 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)).
8. Contact with caregiver at least 3 times a week, to ensure sufficient information from the caregiver regarding participants status and possible change in condition.
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. Caregiver needs to be > 18 years when signing the informed consent form.

Exclusion criteria 12

1. Current treatment with anticoagulants (e.g. warfarin, argatroban, dabigatraneteksilat, rivaroksaban, apiksaban, edoksaban).
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 this study.
5. 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.
6. History of known rare hereditary disorders of galactose Intolerance: Lapp lactase deficiency or glucose-galactose malabsorption.
7. History of illegal substance abuse, drug abuse or alcoholism in the opinion of the Investigator that would preclude participation in the study.
8. Donation of blood (one unit or 350 ml) within three months prior to receiving the first dose of the study drug.
9. Pregnant or breastfeeding.
10. 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.
11. 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.
12. Planned major surgical treatment during the study period.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Mean score on the MMSE at screening to 18 months in the intervention group compared to the control group.

Secondary endpoints 7

1. Mean score in MMSE at 18 months in the ambroxol group compared to the placebo group in subgroups defined by APOE and GBA genotypes and A-Beta in CSF.
2. Mean score at 18 months between the ambroxol group compared to the placebo group for the clock drawing test, COWAT immediate and delayed recall, Trail making test A&B, VOSP siluettes and FAS test.
3. Mean score in the Clinician’s Global Impression of Change (ADCS-CGIC) score at Month 18 in the ambroxol and placebo groups.
4. Mean score in the total NPI score at Month 18 in the ambroxol group compared to the placebo group.
5. Mean score on the UPDRS-part III motor part and the MAYO fluctuation scores at month 18
6. The number of participants with RBD defined from the Mayo Sleep Questionnaire at month 18 in ambroxol and placebo groups.
7. The number of falls at month 18 in the ambroxol and in the placebo groups.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Helse Fonna HF

Sponsor organisation

Helse Fonna HF

Address

Karmsundgata 120

City

Haugesund

Postcode

5528

Country

Norway

Scientific contact point

Organisation

Helse Fonna HF

Contact name

Arvid Rongve

Public contact point

Organisation

Helse Fonna HF

Contact name

Arvid Rongve

Locations

1 EU/EEA country · 8 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 10 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications