None listed
Conditions
Brief summary
This study aims to establish the efficacy of ambroxol and doxycycline, administered individually or in combination for 48 weeks, in slowing the progression of motor symptoms of moderate severity PD and in maintaining this effect for 12 weeks after the IP is discontinued. Who is it for? You may be eligible for this study if you aged between 25 and 80 years old. Please note that this study will be enrolling patients with Parkinson’s Disease. Study details Participation will involve 48 weeks of treatment and a 12 follow up period. Patients will be randomized to one of the 2 IPs (Ambroxol or Doxcycycline), placebo or combination (Ambroxol and Doxycycline) arm. The 2 IPs will be administered with matching placebos for blinding purposes. All patients will received 5 oral pills per day according to the following schedule: -Twice daily (BID) Ambroxol pills will be taken at breakfast time and dinner time and 1 Doxycycline placebo pill will be taken once daily (QD) at breakfast time -Twice daily (BID) Ambroxol placebo pills will be taken at breakfast time and dinner time and 1 Doxycycline pill will be taken once daily (QD) at breakfast time -Twice daily (BID) Ambroxol placebo pills will be taken at breakfast time and dinner time and 1 Doxycycline placebo pill will be taken once daily (QD) at breakfast time -Twice daily (BID) Ambroxol pills will be taken at breakfast time and dinner time and 1 Doxycycline pill will be taken once daily (QD) at breakfast time It is hoped this research will determine the efficacy of ambroxol and doxycycline for motor symptoms in moderate severity Parkinson's disease.
Interventions
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 twi
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.
Sponsors
University of Sydney
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Blinded (masking used) (Subject, Caregiver)
Eligibility
Sex/Gender
All
Age
25 Years to 80 Years
Healthy volunteers
No
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.
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).
Outcome results
None listed