The purpose of this study is to determine if hydroxychloroquine is safe to take and whether there is potential for it to slow the progression of PD symptoms. This will be done by comparing how PD symptoms progress throughout the study compared to how people with PD typically progress. Within PD, it is thought that an inflammation response is associated with abnormal forms of a protein called alpha-synuclein in the brain. Individuals who have taken this medication for other conditions have been shown to be less likely to develop PD than people who have not taken this medication. Therefore, it is hoped that the study drug may interrupt the inflammation response and in turn stop/delay the progression of PD.
Parkinson disease (PD) is a progressive neurodegenerative disorder pathologically characterized by the loss of dopaminergic neurons in the substantia nigra and the presence of α-synuclein protein inclusions termed Lewy bodies. There is increasing evidence of the important role of inflammation in the pathophysiology in PD. Studies of the innate and adaptive immune systems provide evidence that immune dysregulation in both the periphery and brain can cause upregulation of inflammatory cytokines that initiate a cascade of pro-inflammatory signaling events that ultimately result in the neurotoxicity. Post-mortem studies reveal activated microglia and T-cells and immunoglobulin deposition in brain tissue from PD subjects. Alterations in immune cells are detected in living PD subjects, with most consistent findings pointing to T-cell and monocyte changes. Peptides derived from αsynuclein, the key protein that aggregates in PD and the primary component of Lewy bodies, can activate T-cells from PD patients. Pro-inflammatory cytokines and chemokines are elevated in blood and cerebrospinal fluid (CSF) specimens from PD subjects. In vivo evaluation of microglial activity has been performed using positron emission tomography (PET) ligands to measure and shown evidence of neuroinflammation in the brains of patients with PD. Mutations in more than 20 genes have been identified that cause PD with many of them (e.g. LRRK2, SNCA, GBA, PRKN, PINK1) encoding proteins that modulate immune function. Animal PD models show inflammatory changes, and manipulation of inflammation can alter neurodegeneration in animal models. A wide range of epidemiologic studies have supported the role of inflammation in PD that includes data to suggest that ibuprofen and treatment of inflammatory bowel disease with anti- tumor necrosis factor (TNF) biologics are associated with reduced PD risk. The repurposing of generic drugs is a strategy to identify new treatment options for PD because of their known safety profile. Hydroxychloroquine (HCQ) was approved for medical use for over 50 years as a treatment for malaria, systemic lupus erythematosus, and rheumatoid arthritis and is on the World Health Organization's List of Essential Medicines. It belongs to a class of medications known as disease-modifying antirheumatic drug that can reduce skin problems in lupus and prevent swelling/pain in arthritis. It has been shown to interfere with lysosomal activity and autophagy, interact with membrane stability and alter signaling pathways and transcriptional activity, which can result in inhibition of cytokine production and modulation of certain co-stimulatory molecules. HCQ has been studied in multiple sclerosis (MS) which is an inflammatory and neurodegenerative disease of the central nervous. In mice models of MS, HCQ has been shown to inhibit microglia activation and attenuate the severity of disease. Hydroxychloroquine reduces microglial activity and attenuates experimental autoimmune encephalomyelitis. A phase II futility trial of 200 mg bid HCQ in 35 patients with primary progressive MS was associated with reduced disability worsening over 18 months. HCQ was well tolerated overall, with adverse events in 82% and serious adverse events in 12% of participants. All serious adverse events were felt to be unlikely related to HCQ. In this study, HCQ treatment attenuated the increase of neurofilament-light (NfL) after 6 months of treatment and up to 18 months of follow-up, suggesting a treatment effect of HCQ over these biomarkers
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
40
The intervention involves hydroxychloroquine (HCQ), administered orally in 200 mg tablets, with a dosing schedule of 200 mg twice daily (400 mg per day). The treatment duration is 48 weeks, after which participants will enter a 4-week safety follow-up period. HCQ will be taken alongside stable doses of Parkinson's disease (PD) medications, with no anticipated changes during the study. Monitoring for adverse events, laboratory assessments, and efficacy evaluations will occur regularly throughout the 12-month period. The study does not include a placebo group or other treatment arms.
The Ottawa Hospital
Ottawa, Ontario, Canada
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
All participants exposed to HCQ at least once will be assessed for: * Incidence and severity of treatment-emergent adverse events (TEAEs) * Relationship of TEAEs to HCQ * Percentage of discontinuations due to adverse events (AEs)
Time frame: Throughout enrollment (4 weeks of screening) to the end of treatment at 48 weeks and 4-week safety follow-up.
Efficacy of Hydroxychloroquine (HCQ) in Delaying Clinical Motor Progression Using MDS-UPDRS Part III
Another primary clinical outcome is assess change in motor symptom severity, specifically using the movement disorder society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III. A ≥4-point increase (one standard deviation) over 48 weeks will be used as a threshold to assess whether HCQ delays clinical motor progression of PD when compared to historical controls.
Time frame: Throughout enrollment to the end of treatment at 48 weeks. MDS-UPDRS Part III will be evaluated at baseline, 24 weeks and 48 weeks.
Efficacy of Hydroxychloroquine (HCQ) in Delaying Clinical PD Progression Using CGI-C Scale
The Clinical Global Impression of Change (CGI-C) scale assesses the clinician's perception of the change in a patient's condition. It ranges from 1 (very much improved) to 7 (very much worse). A score of 1-3 indicates improvement, while a score of 5-7 indicates worsening of the condition. This study will identify the number of participants with worsening CGI-C scale by the end of the study.
Time frame: Throughout enrollment to the end of treatment at 48 weeks. CGI-C will be evaluated at baseline, 24 weeks and 48 weeks.
Efficacy of Hydroxychloroquine (HCQ) in Delaying Clinical PD Progression Using CGI-S Scale
The Clinical Global Impression-Severity (CGI-S) scale will be used to assess the severity of Parkinson's disease symptoms based on clinician judgment. The scale ranges from 1 (normal, not at all ill) to 7 (extremely ill). A higher score indicates more severe symptoms. A reduction in score will indicate an improvement in disease severity. This study will identify the number of participants with worsening CGI-S scale by the end of the study.
Time frame: Throughout enrollment to the end of treatment at 48 weeks. CGI-S will be evaluated at baseline, 24 weeks and 48 weeks.
Efficacy of Hydroxychloroquine (HCQ) in Delaying Clinical PD Progression Using PGI-S Scale
The Patient Global Impression-Severity (PGI-S) scale measures the patient's assessment of the severity of their Parkinson's disease symptoms at the time of the assessment. The scale ranges from 1 (not at all ill) to 7 (extremely ill). A higher score indicates greater severity, and a decrease in score over time indicates improvement. This study will identify the number of participants with worsening PGI-S scale by the end of the study.
Time frame: Throughout enrollment to the end of treatment at 48 weeks. PGI-S will be evaluated at baseline, 24 weeks and 48 weeks.
Efficacy of Hydroxychloroquine (HCQ) in Delaying Clinical PD Progression Using PGI-C Scale
The Patient Global Impression of Change (PGI-C) measures the patient's own perception of how much their condition has changed since the beginning of the study. The scale ranges from 1 (very much improved) to 7 (very much worse), with 1-3 indicating improvement and 5-7 indicating worsening. This study will identify the number of participants with worsening PGI-C scale by the end of the study.
Time frame: Throughout enrollment to the end of treatment at 48 weeks. PGI-C will be evaluated at baseline, 24 weeks and 48 weeks.
Change in Quality of Life (QoL) as assessed by the PDQ-8
The Parkinson's Disease Questionnaire-8 (PDQ-8) will be used to assess changes in quality of life (QoL) over the 48-week treatment period. The PDQ-8 is a shorter version of the PDQ-39 and includes 8 items measuring physical functioning, emotional well-being, and social participation. Scores range from 0 to 32, where a higher score indicates worse quality of life. A decrease in the score reflects an improvement in QoL.
Time frame: Throughout enrollment to the end of treatment at 48 weeks. QoL will be evaluated at baseline, 24 weeks and 48 weeks.
Efficacy of Hydroxychloroquine (HCQ) Using Change in Modified Hoehn and Yahr Scale
The Modified Hoehn and Yahr Scale is widely recognized for tracking the progression of Parkinson's disease and is crucial for evaluating treatment effects on motor symptoms. It will measure disease severity in Parkinson's patients, ranging from 0 (no signs of disease) to 5 (wheelchair-bound or bedridden unless aided). A decrease in score indicates an improvement in motor function and disease severity.
Time frame: Throughout enrollment to the end of treatment at 48 weeks. Modified Hoehn and Yahr Scale will be evaluated at baseline, 24 weeks and 48 weeks.
Efficacy of Hydroxychloroquine (HCQ) in Slowing Clinical Disease Progression as Assessed by the MDS-UPDRS
Movement Disorder Society-Unified Parkinson's Disease Rating Scale ( MDS-UPDRS) is a comprehensive scale for assessing both motor and non-motor aspects of Parkinson's disease. The efficacy of HCQ in slowing clinical disease progression will be measured by the change from baseline to Week 48 in various MDS-UPDRS sub-scales: MDS-UPDRS Part I score (Non-motor aspects of PD) MDS-UPDRS Part II score (Motor experiences of daily living) MDS-UPDRS Part III score (Motor examination) MDS-UPDRS Part II + Part III (Tremor items) MDS-UPDRS Part II + Part III (Non-Tremor items)
Time frame: Throughout enrollment to the end of treatment at 48 weeks. MDS-UPDRS will be evaluated at baseline, 24 weeks and 48 weeks.
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