A Clinical Trial of Ambroxol and Doxycycline in Moderate Severity Parkinson’s Disease

INTERVENTION: 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 pla CONDITION: Neurological ‐ Parkinson's disease Parkinson’s Disease; ; Parkinson’s Disease PRIMARY OUTCOME: 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[Once at Baseline and at 24, 48, and 60 weeks post‐baseline] SECONDARY OUTCOME: 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[At 12, 24, 48, and 60 weeks post‐baseline in the “ON” usual PD medication state] To assess for cognitive performance Montreal Cognitive Assessment (MoCA) [Once at 48 and 60 weeks post‐baseline compared to Baseline] To compare the change in motor symptoms in the "OFF" usual PD medication state using the MDS‐UPDRS Part III score[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.] 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 [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. ] To determine the patient’s overall global impression of status using the Patient’s Global Impression of Change (PGIC)[12, 24, 48, and 60 weeks post‐baseline compared to Baseline] 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 c