| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients (40 to 80 years age) who have diagnosis of Parkinson's Disease with Motor Fluctuations |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients (40 to 80 years age) with Parkinson' s |
|
| 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 |
|
| 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 assess the effect of tavapadon on the change from baseline in total daily hours of “on” time without troublesome dyskinesia in L Dopa treated subjects with PD who are experiencing motor fluctuations |
|
| E.2.2 | Secondary objectives of the trial |
| To assess the effect of tavapadon on the change from baseline in total daily hours of “off” time in L Dopa treated subjects with PD who are experiencing motor fluctuations |
|
| 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 |
| Optional Future Biospecimen Research |
|
| E.3 | Principal inclusion criteria |
1. Male and female subjects aged 40 to 80 years, inclusive, at the time of signing the ICF.
2. Sexually active men or women of childbearing potential must agree to must agree to use acceptable (at minimum) or highly effective birth control, or remain abstinent during the trial and for 4 weeks after the last dose of trial treatment.
3. Subjects who are capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
4. Subjects who are able, in the opinion of the investigator, to understand the nature of the trial and comply with protocol requirements, including the prescribed dosage regimens, scheduled visits, laboratory tests, and other trial procedures.
5. Subjects with a diagnosis of PD that is consistent with the UK Parkinson’s Disease Society Brain Bank diagnostic criteria.
6. Subjects with modified Hoehn and Yahr stage 2, 2.5, or 3 in the “on” state.
7. Subjects with a good response to L-Dopa in the judgment of the investigator.
Note: Subjects using levodopa/carbidopa intestinal gel are not eligible to participate in the trial.
8. Subjects who return a completed self-reported home diary for motor function status (Hauser diary) during the screening period (after diary training and concordance testing has occurred), with recordings for 2 consecutive days (ie, 2 consecutive 24 hour periods) showing at least 2½ hours of “off” time on each of the 2 days.
9. Subjects who are on a stable dose of L Dopa for at least 4 weeks prior to screening and are taking a minimum total daily dose of 400 mg divided in at least 4 doses per day of standard carbidopa/levodopa or divided in at least 3 doses per day of extended release carbidopa/levodopa capsules. The carbidopa/levodopa dose and frequency must be maintained for the duration of the trial.
Standard or extended-release levodopa/benserazide is allowed as an alternative to levodopa/carbidopa, where available. The minimum dose
and frequency requirements for levodopa still apply.
10. Prior and concurrent use of COMT inhibitors, MAO B inhibitors, amantadine, istradefylline, or anticholinergic drugs is permitted if use
was initiated >90 days before the Baseline Visit and the dosage will remain stable for for the duration of the trial (ie, no change in the COMT, MAO B inhibitor, amantadine, istradefylline, or anticholinergic dose is permitted during the trial). |
|
| E.4 | Principal exclusion criteria |
1. Subjects with a history or clinical features consistent with essential tremor, atypical or secondary parkinsonian syndrome (including, but not limited to, progressive supranuclear palsy, multiple system atrophy, cortico-basal degeneration, or drug induced or poststroke parkinsonism).
2. Subjects with a history of nonresponse or insufficient response to L Dopa at therapeutic dosages.
3. Subjects who have had previous surgical intervention (eg, deep brain stimulation) for PD or for whom such a procedure is planned or anticipated during the trial period.
4. Subjects with an acute or chronic, clinically significant medical or psychiatric condition, cognitive impairment, or laboratory abnormality that might increase the risk associated with trial participation or administration of trial treatment or interfere with the interpretation of the trial results or that, in the judgment of the investigator, would make the subject inappropriate for entry into this trial. Medical conditions that are minor or well controlled may be considered acceptable if the condition does not expose the subject to an undue risk of a significant AE or interfere with the assessments of safety or efficacy during the course of the trial. Subjects with symptoms of anxiety or depression that are not debilitating and that are stable or adequately controlled with non-prohibited medication are considered acceptable. The medical monitor should be contacted in any instance where the investigator is uncertain regarding the stability of a subject’s medical conditions(s) and the potential impact of the condition(s) on trial participation.
5. Subjects with a history or current diagnosis of a clinically significant impulse control disorder (Disruptive, Impulse Control, and Conduct Disorder per DSM 5)
6. Subjects with the presence of or history of brain tumor, hospitalization for severe head trauma, epilepsy (as defined by the International League Against Epilepsy), or seizures.
7. Subjects with a history of psychosis or hallucinations within the previous 12 months.
8. Subjects who answer “yes” on the C-SSRS Suicidal Ideation Item 4 or Item 5 (Active Suicidal Ideation with Some Intent to Act, Without Specific Plan, or Active Suicidal Ideation with Specific Plan and Intent) and whose most recent episode meeting the criteria for C SSRS Item 4 or Item 5 occurred within the last 6 months, OR
Subjects who answer “yes” on any of the 5 C-SSRS Suicidal Behavior Items (actual attempt, interrupted attempt, aborted attempt, preparatory acts, or behavior) and whose most recent episode meeting the criteria for any of these 5 C-SSRS Suicidal Behavior Items occurred within the last 2 years, OR
Subjects who, in the opinion of the investigator, present a serious risk of suicide.
9. Subjects with substance abuse or dependence disorder, including alcohol, benzodiazepines, and opioids, but excluding nicotine, within the past 6 months (180 days).
10. Subjects with dementia or cognitive impairment that, in the judgement of the investigator, would exclude the subject from understanding the ICF or participating in the trial.
11. Subjects with any condition that could possibly affect drug absorption, including bowel resections, bariatric weight loss surgery, or gastrectomy (this does not include gastric banding).
12. Subjects who have a positive result for HIV antibodies, HbsAg, or HCV antibodies at screening.
Note: Subjects who were previously infected with hepatitis C but have been successfully treated (defined as a sustained virologic response or
undetectable hepatitis C viral RNA levels at 12 or more weeks after the end of treatment) may be enrolled after discussion with the medical
monitor.
13. Subjects with a 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 signing the ICF and had not recurred
- Another type of malignancy that had been in remission for ≥5 years before signing the ICF and had not recurred
14. Subjects with a history of myocardial infarction with residual atrial, nodal, or ventricular arrhythmias that are not controlled with medical and/or surgical intervention; second or third degree atrioventricular block; sick sinus syndrome; severe or unstable angina; or congestive heart failure within the last 12 months. A recent (≤12 months) history of myocardial infarction with secondary arrhythmias is exclusionary regardless of the therapeutic control.
15. Subjects with a history of neuroleptic malignant syndrome.
16. Female subjects who are breastfeeding and/or who have a positive pregnancy test result prior to receiving IMP.
17. Subjects who are currently receiving moderate or strong CYP3A4 inducers or CYP3A4 inhibitors (except for topical administration).
Please see Section 5.2 of protocol for the full list. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary efficacy endpoint:
Change from baseline to endpoint the total “on” time without troublesome dyskinesia based on the 2 day average of the self-completed home diary for motor functional status (Hauser diary)
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Key Secondary Efficacy Endpoints
- Change from baseline to endpoint in total daily “off” time based on the 2 day average of the self completed home diary for motor function status (Hauser diary)
- Change from baseline in the total “on” time without troublesome dyskinesia based on the 2 day average of the self-completed home diary for motor function status (Hauser diary)
- Change from baseline in the total “off” time without troublesome dyskinesia based on the 2 day average of the self-completed home diary for motor function status (Hauser diary)
- Change from baseline in the MDS-UPDRS Part I score
- Change from baseline in the MDS-UPDRS Part II score
- Change from baseline in the MDS-UPDRS Part III score
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 73 |
| 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 |
| Ukraine |
| Australia |
| Canada |
| Israel |
| Serbia |
| United States |
| Bulgaria |
| Czechia |
| France |
| Germany |
| Hungary |
| Italy |
| Poland |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| LVLS (Last visit of last subject) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 4 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 4 |
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