| 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 |
| Gradually developing disorder of the nervous system that affects movement. |
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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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061536 |
| E.1.2 | Term | Parkinson's disease |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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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 effect of PF 06649751 administered once daily on motor symptoms in subjects with early stage Parkinson’s disease. |
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| E.2.2 | Secondary objectives of the trial |
- To evaluate the safety and tolerability of PF 06649751 administered once daily in subjects with early stage Parkinson’s disease.
- To evaluate the effect of PF 06649751 administered once daily on other domains relevant in early Parkinson’s disease (eg, depression, daytime sleepiness, and cognition).
- To characterize steady state plasma concentrations of PF 06649751.
- To explore the relationship between PF 06649751 plasma exposures and relevant study endpoints.
- Pooled or exploratory analyses, if conducted, utilizing the biobanked exploratory genomic and biomarker samples across PF 06649751 studies or across multiple programs will be documented in a separate protocol and/or statistical analysis plan.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
2. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
3. Females of non childbearing potential and/or male subjects between the ages of 45 and 80 years, inclusive.
4. Male subjects able to father children must agree to use a highly effective method of contraception throughout the study and for at least 28 days after the last dose of assigned treatment.
5. Female subjects of non childbearing potential (ie, meet at least 1 of the following criteria):
- Have undergone a documented hysterectomy and/or bilateral oophorectomy;
- Have medically confirmed ovarian failure; or
- Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; and have a serum follicle stimulating hormone (FSH) level confirming the post menopausal state.
6. Clinical diagnosis of Parkinson’s disease consistent with the United Kingdom (UK) Parkinson’s Disease Society Brain Bank Clinical Diagnostic Criteria (Appendix 4).
7. Parkinson’s Disease Hoehn & Yahr Stage I III inclusive.
8. Parkinson’s disease subjects deemed appropriate for treatment of motor symptoms with a MDS UPDRS Part III score >=10.
9. Treatment naïve or history of prior incidental treatment with dopaminergic agents (including L Dopa and dopamine receptor agonist medications) for no more than 28 days and not within at least 7 days prior to Visit 1 (Randomization) as outlined in Section 5.8, Concomitant Treatment(s), and Appendix 2 in the protocol.
10. Willing and able to refrain from any Parkinson’s disease medication not permitted by the protocol (including dopaminergic agents) throughout participation in the study as outlined in Appendix 2 in the protocol.
11. A score of >=26 on the Mini Mental State Examination (MMSE).
12. Body Mass Index (BMI) of 17.5 to 35 kg/m2; and a total body weight >= 45 kg.
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|
| E.4 | Principal exclusion criteria |
1. History or clinical features consistent with an atypical Parkinsonian syndrome (including but not limited to Progressive Supranuclear Palsy, Multiple System Atrophy, Cortico Basal Degeneration, etc).
2. Any Parkinson’s disease related feature or symptom that could interfere with the study conduct and results as assessed by the sponsor or Investigator.
3. Presence of acute or chronic clinically significant medical, including fever, or psychiatric condition or cognitive impairment or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
4. Presence or history of brain tumor, past history of hospitalization for head trauma with loss of consciousness, epilepsy (as defined by the International League Against Epilepsy)E31, including childhood seizures, or conditions that lower seizure threshold, seizures of any etiology (including substance or drug withdrawal), or known increased risk of seizures.
5. Any significant AXIS I psychiatric disease as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th edition Revised (DSM IV TR, American Psychiatric Association, 2000) including subjects with clinically significant depression (PHQ 8 total score >=15) (refer to Section 7.1.6 of the protocol, Depression Assessment (PHQ 8). Presence of minor depression or treated, stable depressive disorder is acceptable.
6. Subjects who have made a suicide attempt within the last 5 years. Subjects who, in the investigator’s judgment, pose a significant suicide risk. Subjects who have suicidal ideation associated with actual intent and a method or plan in the past 6 months (ie, “Yes” answers on items 4 or 5 of the C-SSRS; refer to Section 7.3 Assessment of Suicidal Ideation and Behavior (C-SSRS).
7. History of clinically significant alcohol or substance dependency (other than caffeine or nicotine), as defined in DSM IV TR, within 1 year before Screening.
8. In the opinion of the investigator (or caregiver, as applicable), has signs/symptoms suggestive of clinically significant cognitive impairment that would interfere with the ability to comply with study procedures.
9. Any condition possibly affecting drug absorption, past surgery of the gastrointestinal tract (eg, gastrectomy, colectomy), except cholecystectomy.
10. History of vasculitis.
11. History of Human Immunodeficiency Virus (HIV) infection.
12. History of malignancy other than:
• Non-metastatic basal or squamous cell carcinoma of the skin or carcinoma in situ that was surgically removed in total >1 year before screening and has not recurred.
• Other type of malignancy which has been in remission 5 years or more before screening and has not recurred.
13. Subjects with first degree family history of unexplained sudden death, or of Long QT syndrome (LQTS).
14. Within 1 year of Screening or between Screening and Visit 1 (Randomization), any of the following: myocardial infarction; moderate or severe congestive heart failure, NYHA class III or IV; hospitalization for, or symptoms of, unstable angina; syncope due to orthostatic hypotension or unexplained syncope; known significant structural heart disease (eg, significant valvular disease, hypertrophic cardiomyopathy); or hospitalization for arrhythmia.
15. Currently receiving moderate or strong CYP3A4 inducers or CYP3A4 inhibitors (except for topical administration) as outlined in Section 5.8 Concomitant Treatment(s), Appendix 2, and Appendix 3.
16. Currently receiving an antipsychotic, metoclopramide, reserpine, or amphetamine as outlined in Section 5.8 Concomitant Treatment(s) and Appendix 2.
17. Prohibited concomitant medications as outlined in Section 5.8, Concomitant Treatment(s), and Appendix 2.
18. Pregnant female subjects; breastfeeding female subjects; females of childbearing potential (assessed at Screening); male subjects with partners currently pregnant; male subjects able to father children who are unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 28 days after the last dose of investigational product or longer based upon the compound’s half life characteristics.
19. Screening supine blood pressure >=160 mm Hg (systolic) or >=95 mm Hg (diastolic), on a single measurement. If abnormal, up to 2 repeats are permitted following at least 5 minutes of rest. The screening value in that case will be the average of the 2 values closest to the normal range.
Please refer to the study protocol for full list of exclusion criteria |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
(Efficacy) Change from baseline in the Modified Unified Parkinson’s Disease Rating Scale (MDS UPDRS) Score Part III
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
(Safety and Tolerability)
- Adverse events.
- Clinical laboratory parameters.
- Vital signs.
- Electrocardiogram (ECG) parameters.
- Columbia Suicide Severity Rating Scale (C-SSRS).
- Questionnaire for Impulsive Compulsive Disorders in Parkinson’s Disease – Rating Scale (QUIP RS).
- Physician Withdrawal Checklist (PWC 20).
(Exploratory endpoints)
- Beck Depression Inventory – II (BDI II).
- Epworth Sleepiness Scale (ESS).
- Patient Global Impression Severity (PGI S).
- Patient Global Impression – Improvement (PGI I).
- Parkinson’s Disease Questionnaire (PDQ 39).
- EuroQol 5 Dimension (EQ 5D 5L).
- Oral Symbol Digit Modality Test.
- Modified Clinical Global Impression-Severity (MCGI S).
- Modified Clinical Global Impression-Improvement (MCGI I).
- MDS – UPDRS Part I.
- MDS – UPDRS Part II.
- MDS – UPDRS Parts II + III.
- MDS – UPDRS Parts I + II + III.
- MDS – UPDRS Total Score (Parts I + II + III + IV).
- Average plasma PF-06649751 concentrations
- Exploratory exposure response relationship with relevant endpoints.
- Serum Prolactin level at Visit 14.
- Banked biospecimens for possible follow up analysis. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety and tolerability endpoints are assessed throughout the course of the study
Exploratory endpoints:
- Change from baseline at Weeks 10 and 15: BDI II, ESS, PGI S, PGI I, PDQ 39, EQ 5D 5L, Symbol Digit Modality Test, MCGI S, MCGI I, MDS - UPDRS Part I and Part II, Parts II+III, Parts I+II+III, Total Score - Parts I+II+III+IV
- PF-06649751 plasma concentrations - Visit 4, 6, 10, 12 and 14
- Serum prolaction level |
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 13 |
| 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 |
| France |
| Germany |
| Israel |
| Spain |
| United States |
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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