Safety and Biomarker Study of PTC-589 in Participants With Parkinson's Disease

Study Overview
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Brief Summary
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Open-label study with 30-day run-in phase and adaptive design component to include more participants if deemed appropriate by investigators.

Detailed Description
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This is a within-subject, controlled open-label study seeking to determine if PTC-589 can alter the biochemical signature of Parkinson's disease as assessed by peripheral blood biomarkers, central nervous system (CNS) biomarkers, and urine biomarker analysis. In addition, data on a number of disease-relevant clinical measures will be collected.

Official Title
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A Phase 2A Safety and Biomarker Study of EPI-589 in Mitochondrial Subtype and Idiopathic Parkinson's Disease Subjects

Conditions
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Parkinson's Disease

Intervention / Treatment
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* Drug: PTC-589


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Hoehn and Yahr stage ≤3.0 Ambulatory with or without assistance Sexually active fertile participants and their partners must agree to use medically accepted methods of contraception (such as, hormonal methods, including oral, subcutaneous, and intrauterine; barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for 3 months after the last dose of study treatment. Willingness and ability to comply with study procedures If on medications for Parkinson's disease drugs, then medication regimen must be stable for 60 days prior to enrollment Abstention from use of other investigative or non-approved drugs for the duration of the trial For Idiopathic Participants A diagnosis of idiopathic Parkinson's disease confirmed by the presence of bradykinesia plus one or both of the following symptoms: rigidity or resting tremor; and with an abnormal DaTscan consistent with a dopaminergic deficit Age 40 to 75 years Within 5 years of diagnosis of Parkinson's disease For Genetic Subtype Participants A confirmed diagnosis of Parkinson's disease plus a genetic diagnosis consistent with Parkinson's disease, specifically PTEN-induced kinase 1 (PINK1), parkin, Leucine-rich repeat kinase 2 (LRRK2) or other mitochondrial genetic subtype Age 21 to 75 years Exclusion Criteria: Allergy to PTC-589 or other components of the PTC-589 tablet formulation Use of antioxidant supplements, specifically vitamins E and C beyond the recommended daily allowance Other Parkinsonian disorders Montreal Cognitive Assessment (MoCA) score of <24 Revised Hamilton Rating Scale for Depression ≥11 Parkinsonism due to drugs or toxins Diagnosis of any other clinically significant neurologic disease that will confound the assessment of effect of study drug on disease progression Malignancy within past 2 years Pregnant or plans to become pregnant or breast feeding History of stroke History of brain surgery Hepatic insufficiency with liver function tests (LFTs) >3 times upper limit of normal Renal insufficiency as defined by creatinine >1.5 times normal End stage cardiac failure Participation within past 3 months and for duration of study in a trial of a device, drug, or other therapy for Parkinson's disease

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PTC589<br>Participants with Parkinson's disease (idiopathic and mitochondrial genetic subtype participants) will receive PTC589 at a dose of 500 milligrams (mg) (2 tablets of 250 mg each) orally twice daily (BID) for up to 3 months unless discontinued for safety or tolerability issues. | Drug: PTC-589<br>* PTC-589 is a redox active molecule and will be provided in a 250 mg tablet formulation.<br>* Other names: (R)-Troloxamide quinone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Drug-Related Serious Adverse Events (SAEs) | An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'. | Baseline up to 30 days after last dose of study drug (up to 4 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Movement Disorder Society Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Score at Month 3 | The MDS-UPDRS is a tool for monitoring the impact of Parkinson's disease, the degree of disability caused, and complications from treatment. Part I (13 items) evaluates nonmotor experiences of daily living (nM-EDL); Part II (13 items) evaluates motor experiences of daily living (M-EDL; Part III (18 items) is a motor examination; Part IV (6 items) examines motor complications (for example, motor fluctuations and dyskinesias). Each item was rated on a 5-point scale, ranging from 0 (normal) to 4 (severe), with higher score indicating greater severity and more impairment. Total score for Part I (nM-EDL) and Part II (M-EDL) each ranges from 0-52; for Part III (motor examination) ranges from 0-72; and for Part IV (motor complications) ranges from 0-24; with higher scores in each range for all 4 parts reflecting greater severity. | Baseline, Month 3 | 
| Change From Baseline in Non-motor Symptoms Scale (NMSS) Total Score at Month 3 | Non-motor symptoms were evaluated using the NMSS which was divided into 30 questions in 9 different domains including such symptoms as dribbling saliva, constipation, depression, sleep disorders, apathy, hallucinations and dementia. Symptoms were quantified based on their severity (using a scale of 0 [none] to 3 [severe]) and frequency (using a scale of 0 [rarely] to 4 [very frequent]). Total score derived from adding up the product of the frequency score times severity score for each of the 30 questions. Total score ranged from 0 to 360, with a lower score indicating fewer symptoms. | Baseline, Month 3 | 
| Change From Baseline in Parkinson's Disease Questionnaire - 39 (PDQ-39) Score at Month 3 | The PDQ-39 is a self-administered questionnaire for participants with Parkinson's disease that has 39 questions grouped in 8 dimensions: mobility (items 1-10), activities of daily living (items 11-16), emotional well-being (items 17-22), stigma (items 23-26), social support (items 27-29), cognitions (items 30-33), communication (items 34-36), and bodily discomfort (items 37-39). Each item was scored on a 5-point Likert scale (0 to 4) to indicate the frequency of each event; 0 = never, 1 = occasionally, 2 = sometimes, 3 = often, and 4 = always or cannot do at all. Each dimension's total score ranged from 0-100, with lower scores indicating better health, and higher scores indicating more severe symptoms. | Baseline, Month 3 | 
| Change From Baseline in EuroQol-5 Dimension (EQ-5D) Score at Month 3 | EQ-5D is a questionnaire designed to provide measures of health-related quality of life states, consisting of 5 domains (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Each dimension has a 3 point response scale designed to indicate the level of the problem: 1 = no problems, 2 = some problems, 3 = extreme problems. A higher score indicated an increase in the level of problem. The EQ-5D also contains a visual analog scale (EQ-VAS), which records the respondent's self-rated health status on a vertical graduated visual analog scale ranging from 0 (worst imaginable health state) to 100 (best imaginable health state). Higher score indicated improvement. | Baseline, Month 3 | 
| Montreal Cognitive Assessment (MoCA) Score | MoCA is a 30-point questionnaire for cognitive dysfunction. It assesses different cognitive domains: attention and concentration, executive functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and orientation. Scores on the MoCA range from 0-30 with 26-30 indicating normal global cognition; 18-25 mild cognitive impairment; 10-17 moderate cognitive impairment; and <10 severe cognitive impairment. | Month 3 | 
| Beck Depression Inventory (BDI) Score | The BDI is a self-reporting 21-item scoring tool that measures characteristic attitudes and symptoms of depression, including physical symptoms. Each of the 21 items on BDI tool represent a depressive symptom. The symptoms are each scored on a 4-point Likert scale of 0 (symptom is absent) to 3 (symptom is severe). Scores for each symptom are added up to obtain the total scores for all 21 items, which are interpreted as follows 1-10 (normal); 11-16 (mild mood disturbance); 17-20 (borderline clinical depression); 21-30 (moderate depression); 31-40 (severe depression); and >40 (extreme depression). Participants with symptom score of 0 were not included in the summary. | Month 3 | 
| Change From Baseline in Montgomery and Asberg Depression Rating Scale (MADRS) Total Score at Month 3 | The MADRS is a clinician-rated tool for measuring changes in depressive symptom severity. Ten core symptoms and cognitive features (feelings of sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep or appetite, difficulty concentrating, and a lack of interest) were rated on a severity scale of 0 (no symptoms)) to 6 (symptoms of maximum severity). The total score was the sum of the scores on the 10 items, ranging from 0 to 60 with a higher score indicating increasing depressive symptoms. | Baseline, Month 3 | 
| Change From Baseline in Time to Complete Time Up and Go (TUG) Test in ON State at Month 3 | Timed motor tests are simple, objective, quantitative measures for the assessment of Parkinson's disease. They include, in on-medication and off-medication state, timed recorded physical movements. Time Up and Go Test (TUG) is one of timed motor tests which is used to assess a person's mobility and requires both static and dynamic balance. This is a walking assessment. Participants start in the seated position, stand up, walk 7 meters, turn around, and sit back down. The entire process from leaving the chair to returning to the chair was timed. The total time was summarized under ON state with participants on dopamine therapy. | Baseline, Month 3 | 
| Maximum Observed Plasma Concentration (Cmax) of PTC589 |  | 0 hour (predose) and 0.5, 1, 2, 4, 6, 8, and 12 hours postdose at Month 1 and 3 | 
| Level of Disease-Related Biomarker (Glutathione) in Plasma | Glutathione lowest limit of quantification (LLOQ) = 0.01 micromoles (uM) and upper limit of quantification (ULOQ) = 27.83 uM in plasma. | Month 3 | 
| Level of Disease-Related Biomarker (Glutathione) in Cerebrospinal Fluid (CSF) | Glutathione LLOQ = 0.002 uM and ULOQ = 0.35 uM in CSF. | Month 3 | 
| Level of Disease-Related Biomarker (Glutathione) in Urine | Glutathione LLOQ = 0.01 uM, and ULOQ = 1.39 uM in urine. | Month 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PD, Parkinson's Disease, EPI-589, EPI589