| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10013113 |
| E.1.2 | Term | Disease Parkinson's |
| E.1.2 | System Organ Class | 100000004852 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the safety and tolerability of tozadenant in levodopa-treated PD patients experiencing motor fluctuations |
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| E.2.2 | Secondary objectives of the trial |
| To evaluate the effects of tozadenant on the occurrence of daytime drowsiness, impulsive behavior, and suicidality. |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| PK sub-study - not conducted in European sites |
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| E.3 | Principal inclusion criteria |
1. Provide written informed consent.
2. Patient is considered reliable and capable of adhering to the protocol according to the judgment of the investigator.
3. Patient has a documented history of idiopathic Parkinson’s disease consistent with the UK Parkinson’s Disease Society Brain Bank Diagnostic criteria prior to the Screening Visit.
4. Patient has a PD duration of at least 3 years from diagnosis.
5. Patient has a modified Hoehn and Yahr stage 2–4 when in OFF state (estimated) and ≤ 3 in ON state.
6. Patient is male or female and 30–80 years old (inclusive) at Screening.
7. Patient must have a good response to levodopa in the opinion of the investigator, be taking at least four doses of a levodopa-containing medication per day, and at least one other concomitant anti PD medication (dopamine agonists, MAO-B inhibitors, anticholinergic agents, amantadine or entacapone).
8. Patient is maintained on a regimen of permitted anti-PD medications that has been stable for at least 4 weeks prior to Screening.
9. Patients must have been taking a levodopa-containing anti-PD medication continuously for at least the previous 12 months and must be currently experiencing end-of-dose “wearing-off” with at least 2.5 hours of OFF time per day as confirmed by a 3-day Baseline diary.
10. Patient must have achieved the following results for PD diary training, practice diary collection, and Baseline diary recordings:
a. During a diary concordance session with an approved PD diary trainer/rater (minimum 2.5 hours), patient achieved at least 80% overall diary concordance including at least 1 OFF interval.
b. Returned a valid 3 day (i.e., 3 consecutive 24 hour periods) practice diary.
c. Returned valid diary recordings for each of the 3 consecutive days preceding the Baseline Visit that indicated at least 2.5 hours of OFF time on each of the 3 days.
11. Contraception:
a. Women of childbearing potential must use an acceptable method of contraception starting 4 weeks prior to study drug administration and for a minimum of 1 month after study completion. Otherwise, women must be postmenopausal (at least 1year absence of vaginal bleeding or spotting, and confirmed by follicle stimulating hormone [FSH] ≥ 40 mIU/mL [or ≥ 40 IU/L] if less than 2 years postmenopausal) or be surgically sterile.
b. Men with a potentially fertile partner must have had a vasectomy or be willing to use an acceptable method of contraception for the duration of the study and for 3 months after study drug discontinuation.
For men and women: Acceptable methods of contraception include use of a condom with spermicide; oral, implantable or injectable contraceptives; intrauterine device (IUD); diaphragm with spermicide; or, diaphragm with condom. |
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| E.4 | Principal exclusion criteria |
1. Patient previously participated in any study with tozadenant.
2. Patient is currently participating in or has participated in another study and received an IMP within 5 half-lives of the IMP.
3. Patient has any form of secondary or atypical parkinsonism (e.g., drug-induced, post stroke).
4. Body mass index (BMI) greater than 40.
5. QTcF interval of ≥ 500 msec at Screening (Visit 1) or the patient has an average QTcF interval ≥ 450 msec for males or ≥ 470 msec for females at Baseline (Visit 2).
6. Known diagnosis of malignant melanoma.
7. History of neurosurgical intervention for PD, except for the placement of deep brain stimulator electrodes at least 12 months or greater prior to screening; subjects with DBS must not be experiencing any clinically meaningful side effects related to the procedure, the device, or stimulation.
8. Grade 2 hypertension (supine systolic BP ≥ 160 or diastolic BP ≥ 100 mmHg), treated or untreated
9. Patient with a history of hypertensive crisis unless the underlying cause has been removed (e.g. stenting for renal artery stenosis).
10. Patient has a history of chronic alcohol or drug abuse within the last 2 years.
11. Patient is taking apomorphine, budipine, istradefylline, tolcapone, or DUOPA™/Duodopa®, within 4 weeks prior to Screening or is likely to require any of these drugs during the study.
12. Current treatment with antipsychotics; however, quetiapine administered at doses of ≤ 100 mg per day and pimavanserin are permitted if the patient has been on a stable daily dose for at least 4 weeks before Screening. PRN (as needed) dosing is not permitted.
13. Patient has taken digoxin within 4 weeks prior to Screening or is likely to require digoxin during the study.
14. Hyperthyroidism or hypothyroidism, unless all of the following conditions are met:
a. Patient has received a stable dose of thyroid medication for at least 3 months before the Baseline Visit.
b. TSH concentrations are in the normal range (± 10% as a window either side of the normal range).
c. Patient is clinically euthyroid.
15. Any out-of-range laboratory values at Screening that have not been reviewed and documented as not clinically significant by the investigator.
16. A score of < 26 on the Mini-Mental State Examination, Second Edition (MMSE-II) at the Screening Visit.
17. Patients with a current episode of major depression. Patients receiving treatment for depression with antidepressants may be enrolled if they have been on a stable daily dose of the antidepressant for at least 8 weeks before the Baseline Visit.
18. Patient has a recent history of suicide attempt (defined as an active, interrupted or aborted attempt within the past 5 years), or reports suicidal ideation in the past 6 months as indicated by a positive response (‘Yes’) to either Question 4 or Question 5 of the C-SSRS performed at the Screening or Baseline Visit.
19. Patient has evidence of an impulse control disorder (ICD) (i.e., one or more positive modules) according to the Modified Minnesota Impulse Disorders Interview (mMIDI) unless a structured clinical interview performed during Screening confirms that the patient does not have an ICD.
20. Patient is currently lactating or pregnant or planning to become pregnant during the duration of the study.
21. Patient has a known hypersensitivity to any components of the IMP or excipients.
22. Any other condition or clinically significant abnormal findings on the physical or neurological examination, psychiatric and medical history, at Screening or at Baseline that, in the opinion of the investigator, would make the patient unsuitable for the study or put the patient at additional risk or prejudice evaluation of safety and efficacy of the IMP.
23. Patients with alanine transaminase (ALT) or aspartate transaminase (AST) ≥3x upper limit of normal (ULN), or total bilirubin ≥1.5x ULN, at Screening.
24. Patients with a history of hepatic dysfunction secondary to viral infection (hepatitis B or C; Epstein Barr virus [EBV]; or cytomegalovirus [CMV]), or a history of diagnosed drug- or alcohol-induced hepatic toxicity or frank hepatitis.
25. Patients with moderate to severe hepatic or renal impairment.
26. Patients who have taken strong cytochrome P450 subtype 3A4 (CYP3A4) inhibitors or inducers within 4 weeks prior to Baseline (Visit 2) or who anticipate requiring use of strong CYP3A4 inhibitors or inducers during the study |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Treatment emergent Adverse Events.
2. Vital signs
3. ECGs
4. Clinical Laboratory tests
5. Physical and neurological examinations |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| End of treatment, assumed to be 52 weeks |
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| E.5.2 | Secondary end point(s) |
Epworth Sleepiness Scale ESS
modified Minnesota Impulse Disorders Interview mMIDI
Columbia Suicide Severity Rating Scale C-SSRS
Unified Parkinson’s Disease Rating Scale (UPDRS) Part I - IV
Clinical Global Impression of Improvement (CGI-I).
Patient’s Global Impression of Improvement (PGI-I).
Parkinson’s Disease Quality of Life Questionnaire (PDQ-39; total score and individual domain scores).
Non-motor Symptom Questionnaire.
EuroQol 5D-5L Health Questionnaire (EQ-5D-5L).
Patient-completed diaries (Change from Baseline in the number of hours per day spent as follows: OFF time, ON time without troublesome dyskinesia, total ON time, ON time with troublesome dyskinesia and asleep time).
Healthcare Resource Utilization. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| End of treatment, assumed to be 52 weeks |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| European Union |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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