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Trial registered on ANZCTR


Registration number
ACTRN12623000004662
Ethics application status
Approved
Date submitted
14/12/2022
Date registered
9/01/2023
Date last updated
4/09/2023
Date data sharing statement initially provided
9/01/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase II pilot study to determine protocol feasibility, and potential efficacy for disease modification of combined Doxycycline and Ambroxol in Dementia with Lewy Bodies
Scientific title
A Phase II pilot study to determine protocol feasibility, and potential efficacy for disease modification of combined Doxycycline and Ambroxol in Dementia with Lewy Bodies
Secondary ID [1] 308605 0
Nil known
Universal Trial Number (UTN)
Trial acronym
AXON
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Dementia with Lewy Bodies 328495 0
Condition category
Condition code
Neurological 325522 325522 0 0
Dementias

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants in the treatment arm will receive two oral capsules containing 300mg ambroxol, and one oral tablet containing doxycycline 100mg in the morning (three pills total in the morning). They will also receive two oral capsules containing 300mg ambroxol in the evening.
Participants will take these treatments for a total of 26 weeks, and compliance will be monitored via participant diary and capsule / tablet count at each face to face visit.
Intervention code [1] 325063 0
Treatment: Drugs
Intervention code [2] 326925 0
Treatment: Drugs
Comparator / control treatment
Participants in the placebo arm will receive three oral placebo (dicaclium phosphate) pills in the morning and two oral placebo pills in the evening.
Control group
Placebo

Outcomes
Primary outcome [1] 333373 0
Feasibility of a clinical trial protocol which repurposes doxycyline and ambroxol for disease modification in participants with Dementia with Lewy Bodies (DLB), as assessed by participant recruitment / rates of attrition (study recruitment and enrolment logs), compliance with treatment (dispensing logs and participant diaries), and completion rates (compliance with study schedule).
Timepoint [1] 333373 0
Baseline, Week 4, Week 15, Week 26 (primary endpoint), Week 38 follow up
Primary outcome [2] 333410 0
Tolerability of a clinical trial protocol which repurposes doxycyline and ambroxol for disease modification in participants with Dementia with Lewy Bodies (DLB) as assessed by participant adverse event (AE) reporting (e.g. rash or hives) and other safety data.
Timepoint [2] 333410 0
Baseline, Week 4, Week 15, Week 26 (primary endpoint), Week 38 follow up
Secondary outcome [1] 416827 0
Changes in motor parkinsonism as per Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS part III)
Timepoint [1] 416827 0
Baseline, Week 26, Week 38 follow up
Secondary outcome [2] 416828 0
Changes in cognition as per Mini Mental State Examination (MMSE)
Timepoint [2] 416828 0
Baseline, Week 26, Week 38 follow up
Secondary outcome [3] 416829 0
Changes in psychiatric symptoms as per Hospital Anxiety and Depression Scale (HADS)
Timepoint [3] 416829 0
Baseline, Week 26, Week 38 follow up
Secondary outcome [4] 416830 0
Changes in sleep-wake disturbances as per Scale For Outcomes in Parkinson's Disease - Sleep (SCOPA-S)
Timepoint [4] 416830 0
Baseline, Week 26, Week 38 follow up
Secondary outcome [5] 416831 0
Changes in quality of life as per Parkinson's Disease Questionnaire (PDQ-39)
Timepoint [5] 416831 0
Baseline, Week 26, Week 38 follow up
Secondary outcome [6] 416832 0
Exploratory outcomes will evaluate the percentage change of total and pathological -alpha synuclein levels, GCase activity in peripheral blood mononuclear cells (PBMCs), as well as markers of neuronal injury (plasma neurofilament light (NfL) protein, Glial fibrillary acidic protein (GFAP) and Ubiquitin carboxyl-terminal esterase L1 (UCHL1). As these outcomes are exploratory, they will be assessed as a composite.
Timepoint [6] 416832 0
Baseline, Week 26, Week 38 follow up
Secondary outcome [7] 416952 0
Changes in cognition as per Montreal Cognitive Assessment (MoCA)
Timepoint [7] 416952 0
Baseline, Week 26, Week 38 follow up
Secondary outcome [8] 416953 0
Changes in cognition as per Trail Making Tests - Part A and B
Timepoint [8] 416953 0
Baseline, Week 26, Week 38 follow up
Secondary outcome [9] 416954 0
Changes in cognition as per Clock Drawing test
Timepoint [9] 416954 0
Baseline, Week 26, Week 38 follow up
Secondary outcome [10] 416955 0
Changes in cognition as per Sustained Attention Response Task (SART)
Timepoint [10] 416955 0
Baseline, Week 26, Week 38 follow up
Secondary outcome [11] 416956 0
Changes in psychiatric symptoms as per Psychosis and Hallucinations Questionnaire (PsycH-Q)
Timepoint [11] 416956 0
Baseline, Week 26, Week 38 follow up
Secondary outcome [12] 416957 0
Changes in sleep-wake disturbances as per Epworth Sleepiness Scale (ESS)
Timepoint [12] 416957 0
Baseline, Week 26, Week 38 follow up
Secondary outcome [13] 416958 0
Changes in sleep-wake disturbances as per the REM Sleep Behaviour Disorder Questionnaire (RBD-Q)
Timepoint [13] 416958 0
Baseline, Week 26, Week 38 follow up
Secondary outcome [14] 416959 0
Changes in quality of life as per Patient Global Impression of Change (PGIC)
Timepoint [14] 416959 0
Baseline, Week 26, Week 38 follow up
Secondary outcome [15] 416960 0
Changes in quality of life as per Lewy Body Dementia - Disability Rating Scale (LBD-DRS)
Timepoint [15] 416960 0
Baseline, Week 26, Week 38 follow up
Secondary outcome [16] 416964 0
Change in cognitive fluctuations as per Clinical Assessment of Fluctuations (CAFS)
Timepoint [16] 416964 0
Baseline, Week 26, Week 38 follow up
Secondary outcome [17] 416965 0
Change in cognitive fluctuations as per Dementia Cognitive Fluctuation Scale (DCFS)
Timepoint [17] 416965 0
Baseline, Week 26, Week 38 follow up

Eligibility
Key inclusion criteria
1. Diagnosis of probable DLB according to the Fourth Consensus Report of the DLB Consortium
2. Ability to provide written informed consent in accordance with International Conference on Harmonisation - Good Clinical Practice (ICH-GCP) and local regulations
3. Male or female aged 60 years or over as of the date of Baseline visit
4. Stabilised on optimal symptomatic treatment for a minimum of 4 weeks prior to the screening visit, with no changes expected throughout the study
5. Liver Function Tests (LFTs): alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to 3 × upper limit of normal (ULN); total bilirubin less than or equal to 1.5 × ULN; serum albumin less than or equal to 2.8 g/dL
6. Men must agree to use highly effective, double barrier contraception during the study. Double barrier contraception is defined as a condom and one other form of the following: a. Contraceptive pill b. Depot or injectable birth control c. Intrauterine Device (IUD) d. Birth control patch (e.g. Ortho Evra) e. NuvaRing® f. Documented evidence of surgical sterilization at least 6 months prior to the screening visit, i.e., tubal ligation or hysterectomy for women or vasectomy for men. Must be willing to remain on their current form of contraception for the duration of the study.
7. Willing and able to undergo trial assessments (e.g. venepuncture, ECG)
8. Willing and able to take oral drug therapy according to the study protocol
Minimum age
60 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Participation in a clinical trial within the past 3 months, or current use of study IP
2. Known hypersensitivity to any of the IPs or their constituents
3. BMI < 18.5
4. History of significant medical event/s within 6 months prior to the screening visit, at the discretion of the PI
5. Use of typical or atypical antipsychotics or other dopamine blocking agents within 6 months prior to screening that in the opinion of the PI might account for parkinsonism
6. Gastrointestinal conditions that may affect the absorption of IP (e.g., ulcerative colitis, gastric bypass)
7. Serious neurological disorder (e.g., epilepsy) other than DLB
8. History of head trauma with loss of consciousness for more than 5 minutes within the past 6 months
9. Sustained supine hypertension greater than or equal to 180 mmHg systolic or 110 mmHg diastolic; sustained is defined as the average of 3 observations, each at least 10 minutes apart, with the participant having been supine and at rest for at least 5 minutes prior to each measurement
10. Abnormal 12-lead ECG results, which in the opinion of the investigator would preclude participation in the study
11. Prior diagnosis of cancer and evidence of continued malignancy within the past three years (with the exception of adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer or in situ prostate cancer with normal prostate-specific antigens post resection)
12. Any major surgical procedure within 30 days prior to the screening visit
13. Severely impaired renal function with creatinine clearance < 30 mL/min
14. Active alcohol or substance use disorder within the past 12 months
15. Depression of moderate severity or more on the Patient Health Questionnaire (PHQ-9) greater than or equal to score of 10 at the screening visit.
16. History of uncontrolled psychotic symptoms or history of a suicidal attempt/s within the prior 6 months.
17. Any condition or laboratory test result, which in the investigator's judgment might result in an increased risk to the participant or would affect their participation in the study.
18. Participation in any trial of a device [including, but not limited to Transcranial magnetic stimulation (TMS)], Near infrared light (NIr) and red light therapy (lambda = 600–1070 nm), investigational medicinal product, supplement, surgical treatment, cognitive/behavioural therapy, physiotherapy, health food supplements or active exercise study within 30 days prior to the screening visit

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Randomisation will occur via computerised blocked randomisation performed by an unblinded clinical trial coordinator who will not be involved with recruitment, screening, or assessment of trial participants.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
In a sample size of 24 randomised to the treatment arm, if the observed attrition rate is less than 20%, the one sided 90% confidence interval for the true attrition rate will exclude rates of higher than 35%. Eight participants randomised to the placebo arm is considered sufficient to maintain blinding and provide additional safety data.
Although the primary objective is to assess feasibility, the sample standard deviation (SD) for secondary endpoints (i.e. changes in participant related outcome scales) and exploratory endpoints (changes in blood biomarkers) may be used in power calculations for future studies. If a sample SD is calculated with observations from at least 25 participants (across both arms, allowing for 20% attrition), then using this sample SD as the true SD in future power calculations with target power of 90% will ensure that the true power will be over 80% with around 80% assurance.
Primary Analysis
Attrition rates and compliance rates (for both assessments and IP combined) will be estimated in each arm and overall, together with confidence intervals.
Secondary and Exploratory Analyses
For each secondary and exploratory endpoint, summary statistics (n, mean, SD, minimum and maximum) will be presented at each time point for each group. Summary statistics will also be calculated for the change from baseline in each measure at each timepoint for each group. A pooled SD estimate across groups will also be calculated for potential use in powering future studies. To provide a preliminary assessment of the magnitude of change within each treatment group, confidence intervals for the change at each timepoint with each group will be calculated, together with the p-value from a paired t-test.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/08/2023
Actual
Date of last participant enrolment
Anticipated
31/12/2023
Actual
Date of last data collection
Anticipated
30/09/2024
Actual
Sample size
Target
32
Accrual to date
0
Final
Recruitment in Australia
Recruitment state(s)
NSW

Funding & Sponsors
Funding source category [1] 312850 0
University
Name [1] 312850 0
University of Sydney
Country [1] 312850 0
Australia
Primary sponsor type
University
Name
University of Sydney
Address
c/o Brain and Mind Centre
94-100 Mallett Street
Camperdown NSW 2050
Country
Australia
Secondary sponsor category [1] 314514 0
None
Name [1] 314514 0
Address [1] 314514 0
Country [1] 314514 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312127 0
Bellberry Ltd.
Ethics committee address [1] 312127 0
123 Glen Osmond Rd
Eastwood SA 5063
Ethics committee country [1] 312127 0
Australia
Date submitted for ethics approval [1] 312127 0
Approval date [1] 312127 0
05/12/2022
Ethics approval number [1] 312127 0

Summary
Brief summary
The purpose of this study is to determine the feasibility of the research protocol, as well as assess the potential effectiveness of the study medication (combination of doxycyline and ambroxol) in slowing the progression of Dementia with Lewy Bodies. Treatment effectiveness will be evaluated by means of clinical disease rating scales and questionnaires that evaluate participants’ DLB-related symptoms, quality of life and general health. The results of this study may help identify future disease modifying strategies for DLB, as well as provide the clinical trial framework with which to further investigate their effects on the disease. Participants will be assigned to either the active treatment group, or a placebo group. To try to ensure the groups are allocated fairly, each participant is put into a group by chance (randomisation).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 123574 0
Prof Simon Lewis
Address 123574 0
Brain and Mind Centre
University of Sydney
94 Mallett Street
Camperdown NSW 2050
Country 123574 0
Australia
Phone 123574 0
+61 02 9351 0702
Fax 123574 0
Email 123574 0
simon.lewis@sydney.edu.au
Contact person for public queries
Name 123575 0
Miss Stacey West
Address 123575 0
Brain and Mind Centre
University of Sydney
94 Mallett Street
Camperdown NSW 2050
Country 123575 0
Australia
Phone 123575 0
+61 02 9114 4172
Fax 123575 0
Email 123575 0
stacey.west@sydney.edu.au
Contact person for scientific queries
Name 123576 0
Prof Simon Lewis
Address 123576 0
Brain and Mind Centre
University of Sydney
94 Mallett Street
Camperdown NSW 2050
Country 123576 0
Australia
Phone 123576 0
+61 02 9351 0702
Fax 123576 0
Email 123576 0
simon.lewis@sydney.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.