Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000843651
Ethics application status
Approved
Date submitted
7/06/2023
Date registered
4/08/2023
Date last updated
4/08/2023
Date data sharing statement initially provided
4/08/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
A Clinical Trial of Ambroxol and Doxycycline in Moderate Severity Parkinson’s Disease
Scientific title
A Randomised, Double-Blind, Parallel-Group, Placebo-Controlled, 60-Week, Phase II Clinical Trial of Ambroxol and Doxycycline for Motor Symptoms in Moderate Severity Parkinson’s Disease
Secondary ID [1] 309671 0
APM002
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Parkinson’s Disease 330024 0
Condition category
Condition code
Neurological 326931 326931 0 0
Parkinson's disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study consists of four arms. Participants in each stratum will be randomised to the three active treatment arms and the placebo arm in a 1:1:1:1 ratio.

Arm 1: Ambroxol
Route of Administration: Orally
Dosage form: Capsule
Ambroxol, a repurposed mucolytic agent, has shown neuroprotective effects in preclinical studies, including significantly enhanced glucocerebrosidase (GCase) activity and decreased levels of tau and a-synuclein.
- Participants will receive 2 pills of 300 mg of Ambroxol twice daily in morning and evening and 1 pill of Matching placebo to ambroxol once daily in the morning on visit 1 (Baseline) and the 12, 24, and 48-week visits.

Arm 2: Doxycycline
Route of Administration: Orally
Dosage form: Tablet
Doxycycline, an established antibiotic, has been shown to reshape a-synuclein oligomers into off-pathway, high molecular weight species that are unable to convert into the fibrils that form Lewy bodies in Parkinson's Disease (PD).
- Participants will receive 1 pill of 100 mg of Doxycycline once daily in morning and 2 pills of Matching placebo to Doxycycline twice daily in the morning and evening on visit 1 (Baseline) and the 12, 24, and 48-week visits

Arm 3: Combination of Ambroxol and Doxycycline
Route of Administration: Orally
Dosage form: Ambroxol is in the form of capsule and Doxycycline is in the form of tablet
- In morning, participants will receive 1 pill of 110 mg of Doxycycline along with 2 pills of 300 mg of Ambroxol on visit 1 (Baseline) and the 12, 24, and 48-week visits
- In evening, participants will receive 2 pills of 300 mg of Ambroxol on visit 1 (Baseline) and the 12, 24, and 48-week visits

Arm 4: Placebo
- In morning, participants will receive 1 pill of Matching placebo to Doxycycline along with 2 pills of Matching placebo to Ambroxol on visit 1 (Baseline) and the 12, 24, and 48-week visits
- In evening, participants will receive 2 pills of Matching placebo to Ambroxol on visit 1 (Baseline) and the 12, 24, and 48-week visits

All four arms participants will be taking medication continuosly for 48 weeks. They will have a 12 weeks washout period after 48 week visit.
Each arm will enrol distinct group of participants.
Pill count method and Patient Diary will be used to check for treatment compliance at every visit. Patient Diary are paper booklets which are given to patients at study visits and completed by the patient each day to capture details of IP taken, including the timing.
Intervention code [1] 326112 0
Treatment: Drugs
Comparator / control treatment
There are two placebo in the study.
- Matching placebo to Doxycycline
- Matching placebo to Ambroxol
Composition of Placebo: Micro crystalline cellulose, colloidal silicon dioxide, sodium starch glycolate and sodium stearyl fumarate.

Arm 1: Participants will receive matching placebo to ambroxol once daily in the morning on visit 1 (Baseline) and the 12, 24, and 48-week visits.
Arm 2: Participants will receive matching placebo to Doxycycline twice daily in the morning and evening on visit 1 (Baseline) and the 12, 24, and 48-week visits.
Arm 4: Placebo
- In morning, participants will receive 1 pill of Matching placebo to Doxycycline along with 2 pills of Matching placebo to Ambroxol on visit 1 (Baseline) and the 12, 24, and 48-week visits
- In evening, participants will receive 2 pills of Matching placebo to Ambroxol on visit 1 (Baseline) and the 12, 24, and 48-week visits
Control group
Placebo

Outcomes
Primary outcome [1] 334768 0
Change in motor symptoms measured by the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS).
The motor symptoms will be measured by the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), which is a comprehensive and flexible tool to monitor the course of PD and the associated degree of disability
Timepoint [1] 334768 0
Once at Baseline and at 24, 48, and 60 weeks post-baseline
Secondary outcome [1] 422015 0
To compare the change in motor symptoms in the "OFF" usual PD medication state using the MDS-UPDRS Part III score
Timepoint [1] 422015 0
At 60 weeks (after the IP has been removed for 12 weeks) with the 24- and 48-week post-baseline score in the “OFF” usual PD medication state.
Secondary outcome [2] 422016 0
To assess any improvement by determining the change from Baseline MDS-UPDRS Part I, II, III, and IV scores. This will be assessed as a composite outcome.
Change in non-motor and motor symptoms of PD in the "ON" usual medication state assessed using the MDS-UPDRS Part I, II, III, and IV scores
Timepoint [2] 422016 0
At 12, 24, 48, and 60 weeks post-baseline in the “ON” usual PD medication state
Secondary outcome [3] 422017 0
To compare the changes in MDS-UPDRS Parts I, II, III, and IV scores at 48 weeks compared to the scores at 60 weeks in the “ON” usual PD medication state
Timepoint [3] 422017 0
Once at 60 weeks (after IP has been removed for 12 weeks), the 48 weeks post-baseline will be compared to 60 weeks post-baseline in the "ON" usual PD medication state.
Secondary outcome [4] 422018 0
To assess for cognitive performance Montreal Cognitive Assessment (MoCA)
Timepoint [4] 422018 0
Once at 48 and 60 weeks post-baseline compared to Baseline
Secondary outcome [5] 422019 0
To determine the patient’s overall global impression of status using the Patient’s Global Impression of Change (PGIC)
Timepoint [5] 422019 0
12, 24, 48, and 60 weeks post-baseline compared to Baseline

Eligibility
Key inclusion criteria
1. Ability to provide written informed consent in accordance with GCP, ICH, and local regulations.
2. Male or female aged 25 to 80 (inclusive) as of the date of Baseline Visit.
3. Diagnosis of idiopathic PD according to Queen Square Brain Bank (QSBB) criteria.
4. PD Modified Hoehn and Yahr stage less than or equal to 2.5 in the “ON” usual PD medication state.
5. Must be stabilised on optimal dopaminergic PD treatment for a minimum of 4 weeks prior to the Screening Visit with no changes in dosing or PD medication expected throughout the study.
6. Liver function tests (LFTs): alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than 3 × upper limit of normal (ULN); total bilirubin less than or equal to 1.5 × ULN; serum albumin greater than 2.8 g/dL.
7. Willing to avoid use of potent CYP3A4 inducers (including phenobarbital, phenytoin, rifampicin, St. John's Wort, and glucocorticoids) and potent CYP3A4 inhibitors (including clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, verapamil, goldenseal, and grapefruit) during the study that, in the Investigator’s judgement, are likely to impact hepatic metabolism.
8. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test (human chorionic gonadotropin [hCG]) at Screening. WOCBP and 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. Contraceptive skin implant, eg, Implanon NXT®
e. Hormonal vaginal ring, eg, NuvaRing®
f. Documented evidence of surgical sterilisation at least 6 months prior to the Screening Visit, ie, 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.
9. Willing and able to have the types of diagnostic procedures required by the protocol, such as phlebotomy and other testing.
10. Willing and able to take oral drug therapy according to the study protocol.
11. Willing to practice adequate sun protection throughout the study (use of sunscreen or sun-protective clothing or limitation of sun exposure), as instructed by the Investigator or designee.
Minimum age
25 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Confirmed or suspected atypical or Parkinsonian syndromes due to drugs, metabolic disorders, encephalitis, cerebrovascular disease, or neurodegenerative diseases.
2. Females who are pregnant or breastfeeding.
3. Body mass index less than 18.5 kg/m2.
4. Prior surgical intervention for PD (including but not limited to deep brain stimulation [DBS], transcranial direct-current stimulation [tDCS], near infrared light [NIR] therapy, or cell transplantation) or active continuous infusion therapy (including but not limited to Duodopa® and/or apomorphine). Patients who have used the following therapies may be considered if the relevant washout period is completed:
a. Over the counter therapies (eg, vitamin supplements) would require a washout period of 1 month (30 days) from the Screening Visit
b. Other therapies where there might be a symptomatic effect (eg, red light therapy, tDCS) would require a washout period of a minimum of 12 weeks from the Screening Visit
c. Previous disease-modifying or systematic IPs would require a washout period of at least five times the half-life of the treatment.
Therapeutic use of cannabidiol is permitted if not part of a clinical trial.
5. History of psychotic symptoms requiring antipsychotic treatment or exposure to typical or atypical antipsychotics or other dopamine blocking agents within 6 months prior to Screening.
6. History of suicide attempt(s) within the 6 months prior to Screening.
7. Gastrointestinal conditions that may affect the absorption of IP (eg, ulcerative colitis, gastric bypass).
8. Diagnosis of insulin-dependent Type 1 diabetes mellitus (T1DM).
9. History of significant medical event(s) within 6 months prior to the Screening Visit, at the discretion of the Investigator. This includes, but is not limited to, a cerebrovascular event or a myocardial infarction.
10. Serious neurological disorder other than PD.
11. History of head trauma with loss of consciousness for more than 5 minutes within the past 6 months.
12. Sustained supine hypertension greater than or equal to 180 mmHg systolic or 110 mmHg diastolic; sustained is defined as the average of three observations, each at least 10 minutes apart, with the patient having been supine and at rest for at least 5 minutes prior to each measurement.
13. History of symptomatic orthostatic hypotension (OH) which interferes with the patient’s day-to-day level of functioning. OH is defined as a decrease of greater than or equal 20 mmHg systolic or greater than or equal 10 mmHg diastolic when changing from supine to standing position, after having been in supine position for at least 5 minutes.
14. Any significant uncontrolled cardiac arrhythmia, including but not limited to second and third degree atrioventricular (AV) block.
15. Current unstable angina.
16. Congestive heart failure (New York Heart Association [NYHA] Class 3 or 4).
17. Heart rate less than 50 bpm as tested on three occasions, 10 minutes apart.
18. Abnormal 12-lead electrocardiogram (ECG) results which, in the opinion of the Investigator, will prevent participation in the study.
19. Prior difficulties with swallowing solid oral IPs.
20. Prior diagnosis of cancer and evidence of continued malignancy within the past 3 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).
21. Any major surgical procedure within 30 days prior to the Screening Visit.
22. Diagnosis of dementia as defined by Movement Disorder Society (MDS) PD
Dementia criteria or treatment with any centrally-acting agents targeting cognition (eg, cholinesterase inhibitors, memantine).
23. Active alcohol or substance use disorder within the past 12 months, at the discretion of the Investigator.
24. Depression of moderate severity or more on the Patient Health Questionnaire (PHQ-9), defined as score greater than or equal 10, at the Screening Visit.
25. Any condition or laboratory test result which, in the Investigator's judgement, might result in an increased risk to the patient or would affect their participation in the study.
26. Participation in any trial of a device (including, but not limited to transcranial magnetic stimulation [TMS]), NIR and red light therapy (lambda = 600–1070 nm), IP, supplement, surgical treatment, cognitive/behavioural therapy, physiotherapy, or active exercise study within 30 days prior to the Screening Visit. Patients who have used the following therapies may be considered if the relevant washout period is completed:
a. Over the counter therapies (eg, vitamin supplements) would require a washout period of 1 month (30 days) from the Screening Visit
b. Other therapies where there might be a symptomatic effect (eg, red light therapy, tDCS) would require a washout period of a minimum of 12 weeks from the Screening Visit
c. Previous disease-modifying or systematic IPs would require a washout period of at least five times the half-life of the treatment.
27. Known allergy or sensitivity to ambroxol or doxycycline or any of their components:
a. Sucrose intolerance: Patients with rare hereditary problems of fructose intolerance, glucose galactose malabsorption, or sucrose-isomaltase insufficiency should not take doxycycline.
b. Patients with histamine intolerance should not take ambroxol.
28. Severely impaired renal function (creatinine clearance less than 30 mL/min) or severely impaired hepatic function (any LFT 3 × ULN).

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
7/09/2023
Actual
Date of last participant enrolment
Anticipated
7/03/2025
Actual
Date of last data collection
Anticipated
30/05/2026
Actual
Sample size
Target
240
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,TAS,VIC
Recruitment hospital [1] 24775 0
Brain and Mind Centre - University of Sydney - Camperdown
Recruitment hospital [2] 24776 0
The Alfred - Melbourne
Recruitment hospital [3] 24777 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [4] 24778 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [5] 24779 0
Southern Neurology - Kogarah
Recruitment hospital [6] 24780 0
Gold Coast University Hospital - Southport
Recruitment hospital [7] 24781 0
John Hunter Hospital - New Lambton
Recruitment hospital [8] 24782 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment postcode(s) [1] 40412 0
2050 - Camperdown
Recruitment postcode(s) [2] 40413 0
3004 - Melbourne
Recruitment postcode(s) [3] 40414 0
2010 - Darlinghurst
Recruitment postcode(s) [4] 40415 0
5000 - Adelaide
Recruitment postcode(s) [5] 40416 0
2217 - Kogarah
Recruitment postcode(s) [6] 40417 0
4215 - Southport
Recruitment postcode(s) [7] 40418 0
2305 - New Lambton
Recruitment postcode(s) [8] 40420 0
7000 - Hobart
Recruitment postcode(s) [9] 40421 0
3050 - Parkville

Funding & Sponsors
Funding source category [1] 313863 0
University
Name [1] 313863 0
University of Sydney
Country [1] 313863 0
Australia
Primary sponsor type
University
Name
University of Sydney
Address
Brain and Mind Centre
100 Mallett St,
Camperdown NSW 2050
Country
Australia
Secondary sponsor category [1] 315698 0
None
Name [1] 315698 0
Address [1] 315698 0
Country [1] 315698 0
Other collaborator category [1] 282684 0
Commercial sector/Industry
Name [1] 282684 0
Novotech (Australia) Pty Limited
Address [1] 282684 0
Level 3, 235 Pyrmont Street Sydney, NSW Australia - 2009
Country [1] 282684 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313010 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 313010 0
Ethics committee country [1] 313010 0
Australia
Date submitted for ethics approval [1] 313010 0
10/05/2023
Approval date [1] 313010 0
12/05/2023
Ethics approval number [1] 313010 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 126674 0
Prof Simon Lewis
Address 126674 0
Brain and Mind Centre, 94 Mallett St, Camperdown, NSW, 2050
Country 126674 0
Australia
Phone 126674 0
+6102 9114 4121
Fax 126674 0
Email 126674 0
[email protected]
Contact person for public queries
Name 126675 0
Emma Masango
Address 126675 0
Novotech (Australia) Pty Limited, Level 2, 15- 31 Pelham Street Carlton Victoria 3053 Australia
Country 126675 0
Australia
Phone 126675 0
+613 9341 1998
Fax 126675 0
Email 126675 0
[email protected]
Contact person for scientific queries
Name 126676 0
Jyotsna Das
Address 126676 0
Novotech (Australia) Pty Limited, Level 3, 235 Pyrmont Street Pyrmont, NSW, 2009 Australia
Country 126676 0
Australia
Phone 126676 0
+612 9171 3283
Fax 126676 0
Email 126676 0
[email protected]

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.