Clinical Trial Results:
A Phase 2A Safety and Biomarker Study of EPI-589 in Mitochondrial Subtype and Idiopathic Parkinson's Disease Subjects
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Summary
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EudraCT number |
2015-001786-10 |
Trial protocol |
GB DE |
Global end of trial date |
08 Jan 2019
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Results information
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Results version number |
v1(current) |
This version publication date |
11 Nov 2023
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First version publication date |
11 Nov 2023
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
EPI589-15-002
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02462603 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
PTC Therapeutics, Inc.
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Sponsor organisation address |
100 Corporate Court, South Plainfield, United States, NJ 07080
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Public contact |
Medical Information, PTC Therapeutics, Inc., +011 44 1-866-562-4620, medinfo@ptcbio.com
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Scientific contact |
Medical Information, PTC Therapeutics International Limited, +353 19068700, medinfo@ptcbio.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
08 Jan 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
08 Jan 2019
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Global end of trial reached? |
Yes
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Global end of trial date |
08 Jan 2019
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective of this study was to evaluate the safety of PTC589 as assessed by occurrence of drug-related serious adverse events (SAEs) in participants with Parkinson's Disease (PD).
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Protection of trial subjects |
This study was conducted in full accordance with all applicable research policies and procedures, all applicable United States (US) federal and local laws and regulations including 45 Code of Federal Regulations (CFR) 46, 21 CFR Parts 50, 54, 56, 312 and 314, and the International Conference on Harmonisation (ICH) Guideline for good clinical practice E6(R2)(2016).
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
17 May 2016
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Germany: 7
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Country: Number of subjects enrolled |
United Kingdom: 8
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Country: Number of subjects enrolled |
United States: 29
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Worldwide total number of subjects |
44
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EEA total number of subjects |
7
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
15
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From 65 to 84 years |
29
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||
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Pre-assignment
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Screening details |
Forty-four participants (28 idiopathic and 16 genetically diagnosed) were enrolled into the study and 41 participants received treatment | ||||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||
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Arms
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Arm title
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PTC589 | ||||||||||||||||||
Arm description |
Participants with Parkinson's disease (idiopathic and mitochondrial genetic subtype participants) received 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. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
PTC589
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
PTC589 was administered per schedule specified in the arm description.
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Baseline characteristics reporting groups
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Reporting group title |
PTC589
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Reporting group description |
Participants with Parkinson's disease (idiopathic and mitochondrial genetic subtype participants) received 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
PTC589
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Reporting group description |
Participants with Parkinson's disease (idiopathic and mitochondrial genetic subtype participants) received 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. | ||
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End point title |
Number of Participants With Drug-Related Serious Adverse Events (SAEs) [1] | ||||||
End point description |
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'. Safety population included any participant who received at least 1 dose of PTC589.
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End point type |
Primary
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End point timeframe |
Baseline up to 30 days after last dose of study drug (up to 4 months)
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The analysis is descriptive in nature. |
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| No statistical analyses for this end point | |||||||
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End point title |
Change From Baseline in Movement Disorder Society Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Score at Month 3 | ||||||||||||||||||||||||
End point description |
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. Efficacy intent-to-treat (EITT) population included any participant who received at least 1 dose of PTC589 and had a minimum of the Month 3 assessment.
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End point type |
Secondary
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End point timeframe |
Baseline, Month 3
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Change From Baseline in Non-motor Symptoms Scale (NMSS) Total Score at Month 3 | ||||||||||||
End point description |
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. EITT population included any participant who received at least 1 dose of PTC589 and had a minimum of the Month 3 assessment.
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End point type |
Secondary
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End point timeframe |
Baseline, Month 3
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in Parkinson’s Disease Questionnaire - 39 (PDQ-39) Score at Month 3 | ||||||||||||||||||||||||||||||||||||||||
End point description |
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. EITT population included any participant who received at least 1 dose of PTC589 and had a minimum of the Month 3 assessment.
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End point type |
Secondary
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End point timeframe |
Baseline, Month 3
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||
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End point title |
Change From Baseline in EuroQol-5 Dimension (EQ-5D) Score at Month 3 | ||||||||||||||||||||||||||||||||
End point description |
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. EITT population included any participant who received at least 1 dose of PTC589 and had a minimum of the Month 3 assessment.
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End point type |
Secondary
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End point timeframe |
Baseline, Month 3
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||
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End point title |
Montreal Cognitive Assessment (MoCA) Score | ||||||||||||||||
End point description |
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. EITT population included any participant who received at least 1 dose of PTC589 and had a minimum of the Month 3 assessment. Here, 'Number analyzed' = participants with normal, mild, moderate, or severe cognition impairment. 'n' = participants evaluable for specified category. Data for a specific severity level was not collected if no evaluable participants were available. '99999' = data not available due to no participants.
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End point type |
Secondary
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End point timeframe |
Month 3
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Beck Depression Inventory (BDI) Score | ||||||||||||||||||||
End point description |
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. EITT population included any participant who received at least 1 dose of PTC589 and had a minimum of Month 3 assessment. 'Number analyzed' = participants with symptom score >1 for normal, mild, borderline, moderate, severe, or extreme depression. 'n' = participants evaluable for specified category. Data for a specific severity level was not collected if no evaluable participants were available. '99999' = data not available due to no participants.
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End point type |
Secondary
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End point timeframe |
Month 3
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Change From Baseline in Montgomery and Asberg Depression Rating Scale (MADRS) Total Score at Month 3 | ||||||||||||
End point description |
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. EITT population included any participant who received at least 1 dose of PTC589 and had a minimum of the Month 3 assessment.
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End point type |
Secondary
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End point timeframe |
Baseline, Month 3
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in Time to Complete Time Up and Go (TUG) Test in ON State at Month 3 | ||||||||||||
End point description |
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. EITT population included any participant who received at least 1 dose of PTC589 and had a minimum of the Month 3 assessment. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure.
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End point type |
Secondary
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End point timeframe |
Baseline, Month 3
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Level of Disease-Related Biomarker (Glutathione) in Plasma | ||||||||
End point description |
Glutathione lowest limit of quantification (LLOQ) = 0.01 micromoles (uM) and upper limit of quantification (ULOQ) = 27.83 uM in plasma. EITT population included any participant who received at least 1 dose of EPI-589.
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End point type |
Secondary
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End point timeframe |
Month 3
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| No statistical analyses for this end point | |||||||||
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End point title |
Maximum Observed Plasma Concentration (Cmax) of PTC589 | ||||||||||||
End point description |
EITT population included any participant who received at least 1 dose of PTC589 and had a minimum of the Month 3 assessment. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure.
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End point type |
Secondary
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End point timeframe |
0 hour (predose) and 0.5, 1, 2, 4, 6, 8, and 12 hours postdose at Month 1 and 3
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Level of Disease-Related Biomarker (Glutathione) in Cerebrospinal Fluid (CSF) | ||||||||
End point description |
Glutathione LLOQ = 0.002 uM and ULOQ = 0.35 uM in CSF. EITT population included any participant who received at least 1 dose of EPI-589. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure.
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End point type |
Secondary
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End point timeframe |
Month 3
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| No statistical analyses for this end point | |||||||||
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End point title |
Level of Disease-Related Biomarker (Glutathione) in Urine | ||||||||
End point description |
Glutathione LLOQ = 0.01 uM, and ULOQ = 1.39 uM in urine. EITT population included any participant who received at least 1 dose of EPI-589.
Due to database limitations, the Arithmetic Mean and the Full Range (min-max) cannot be reported in the table below and “0.0000” are reported as placeholders. The Arithmetic Mean is: 0.000006051 and the Full Range (min-max) is: 0.00000034 to 0.00003283.
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End point type |
Secondary
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End point timeframe |
Month 3
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| No statistical analyses for this end point | |||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Baseline up to 30 days after last dose of study drug (up to 4 months)
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Adverse event reporting additional description |
Safety population included any participant who received at least 1 dose of PTC589.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
15.0
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Reporting groups
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Reporting group title |
PTC589
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Reporting group description |
Participants with Parkinson's disease (idiopathic and mitochondrial genetic subtype participants) received PTC589 at a dose of 500 mg (2 tablets of 250 mg each) orally BID for up to 3 months unless discontinued for safety or tolerability issues. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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09 Sep 2015 |
The key changes were:
• Study title, objectives, and endpoints were modified;
• Central nervous system (CNS) and urine biomarker assessments added;
• DaTscan removed from Month-3 visit;
• The Columbia Suicide Severity Scale has been added to the clinical safety assessments;
• Deoxyribonucleic acid (DNA) genetic analysis has been removed from Screening assessments;
• Mattis Dementia Rating Scale has been removed from efficacy
variables. |
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04 Jan 2016 |
The key changes were:
• Numerically indicated the ± day range of study treatment administration;
• Additional detail for adaptive design rationale;
• Added examples of contraception;
• Added a post-treatment follow-up visit;
• Added details of study withdrawal criteria;
• Added warning about possible drug-associated phototoxicity since no data are yet available. |
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10 Oct 2016 |
The key changes were:
• Added the new list of investigators and investigative sites;
• Revision of inclusion and exclusion criteria regarding disease severity and prohibited meds;
• Added the term “for idiopathic participantd” to DaTscan, “fasting” for blood-based glutathione cycle biomarkers in schedule of assessments;
• Changed the MDS-UPDRS assessment from run-in to screening visit;
• Changes in laboratory evaluations, National Institutes of Health common terminology criteria, etc.;
• Dose modifications guidelines. |
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17 Feb 2017 |
The key change was:
• Change in Company Name from Edison Pharmaceuticals to BioElectron Technology Corporation. |
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29 Sep 2017 |
The key changes were:
• Fasting conditions for biomarker samples;
• Added the term morning and evening dose to BID;
• Non-clinical studies language;
• Changed the language under pharmacokinetics (PK) section
• Changed the timed motor test as ON state only (for participants on dopamine therapy);
• Dose limiting toxicity;
• Administration of clinical assessment;
• Washout period for subjects on high doses of Vitamin E or C;
• Complete blood count (CBC) differential as absolute or percentages;
• Carbon dioxide (CO2) for serum chemistry;
• Day 1 first dose language;
• Changed the height measurement to screening visit only;
• Included breast exam as part of screening physical exam;
• Removed language in adverse event reporting;
• Changed the AE language under post-treatment follow-up. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
