| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Excessive daytime sleepiness associated with Parkinson’s disease |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with Parkinson disease (PD) suffering and complaining of daytime sleepiness |
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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 | SOC |
| E.1.2 | Classification code | 10029205 |
| E.1.2 | Term | Nervous system disorders |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| 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 | 10041349 |
| E.1.2 | Term | Somnolence |
| 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 safety profile of THN102 (modafinil/flecainide combination) at two doses (200 mg/18 mg and 200 mg/2 mg) versus placebo in subjects with excessive daytime sleepiness associated with Parkinson’s disease (PD). |
|
| E.2.2 | Secondary objectives of the trial |
1. To quantify the efficacy of THN102 versus placebo in improving sleepiness.
2. To quantify the efficacy of THN102 versus placebo in improving
a. attention, vigilance
b. cognition
3. To determine the dose response profile of THN102 versus placebo on efficacy parameters.
4. To determine the plasma levels of modafinil and flecainide at steady state.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion criteria:
1. Subjects with a diagnosis of idiopathic Parkinson’s disease as defined by the Movement Disorders Society (MDS).
2. Subjects with Hoehn and Yahr scale score ≤ 4.
3. Males or females, aged between 18 and 80 years.
4. Body mass index > 18 kg/m2 and < 35 kg/m2.
5. Subjects should have a complaint of daytime sleepiness impacting their quality of life and/or daytime functioning (e.g. falling asleep while reading or watching TV, while eating or talking with other people).
6. Epworth Sleepiness Scale (ESS) score ≥ 14.
7. Women of childbearing potential (not surgically sterile or < 2 years postmenopausal), must use a highly effective method of contraception, and must continue for the duration of the trial (and for 2 months after participation in the trial). Highly effective methods of contraception include hormonal contraception associated with inhibition of ovulation (combined estrogen/progestogen: oral, intravaginal, transdermal; progestogen-only: oral, implanted, and injected) in conjunction with a barrier method (preferably male condom)., Highly effective methods further include intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomised partner (provided that the partner is the sole sexual partner of the subject and the vasectomised partner has received medical assessment of the surgical success) and sexual abstinence, i.e. when this is in line with the preferred and usual lifestyle of the subject.
8. Subjects willing and able to follow trial procedures (including to swallow IMP capsules) and to regularly attend scheduled clinic visits as specified in the protocol, and who have signed the informed consent prior to any screening procedure.
All above-mentioned inclusion criteria will be checked at VS1.
At VR the following inclusion criteria will be re-checked: 5, 6, 7, 8. |
|
| E.4 | Principal exclusion criteria |
Exclusion criteria
1. Subjects with known or with a suspected sleep apnea syndrome or who have any other cause of excessive daytime sleepiness, such as shift work sleep disorder.
2. Psychiatric and neurological disorders (other than Parkinson’s disease), such as idiopathic narcolepsy, Alzheimer’s disease, Huntington’s Chorea, multiple sclerosis, epilepsy, psychosis, bipolar disorder, severe clinical anxiety or depression, multiple system atrophy (Shy-Drager syndrome) or other problem that in the investigator’s opinion would preclude the subject’s participation and completion of this trial or comprise reliable representation of subjective symptoms.
3. Cardiovascular disorders such
a. Uncontrolled moderate to severe hypertension
b. ECG QTcF duration ≥ 450 ms (men) or ≥ 470 (women)
c. ECG signs of left ventricular hypertrophy (exclusion if at least one of the three indices is abnormal):
• Sokolow-Lyon voltage (sum of amplitude of the S wave in lead V1 and the R wave in lead V5 or V6 ≥ 3.5 mV), or
• Cornell voltage (S wave in V3 + R wave in aVL > 2.8 mV in men or > 2.0 mV in women), or
• Modified Cornell (R wave in aVL > 1.1 mV)
d. Recent (less than three months before screening visit VS1) myocardial infarction
e. Stable or unstable angina pectoris
f. Cardiac insufficiency
g. Previous history of heart failure
h. Previous history of cardiac valvular surgery
i. Ventricular arrhythmias considered as clinically significant
j. Atrial fibrillation unless it is stable and controlled by stable doses of amiodarone, calcium channel blocker or beta-blocker
k. 2nd or 3rd grade atrioventricular block or chronic bifascicular block, unless an adequate pacemaker is present
l. Sinus node dysfunction
m. Documented Brugada syndrome
4. Subjects with current impulse control disorder.
5. Subjects showing dementia or with MoCA < 23.
6. Subjects with current suicidal risk, based on investigator’s clinical judgement or with a “yes” answer to item 4 and/or 5 of the Columbia-Suicide Severity Rating Scale (C-SSRS) at VS1, referring to the last month before screening.
7. Current or recent (within one year) history of substance abuse or dependence disorder as defined in Diagnostic and Statistical Manual of Mental Disorders (DSM-V), e. g. alcohol. Tobacco use is accepted.
8. Other active clinically significant illness, including unstable cardiovascular, or malignant patholog, significant abnormality in physical examination or clinical laboratory results at VS1, which could interfere with the trial conduct or counter-indicate the trial treatments or place the subject at risk during the trial or compromise the trial participation.
9. Subjects with hepatic impairment (serum total bilirubin ≥ 34 mg/dL, except in patients diagnosed with Gilbert’s syndrome, or prothrombin time [PT] ≥ 4 s (except in patients on therapeutic anti-coagulation), or serum albumin < 3.5 g/dL)), or renal impairment (glomerular filtration rate [GFR] < 60 mL/min/1.73 m2, according to Kidney Disease Improving Global Outcomes (KDIGO)).
10. Known hypersensitivity to IMP (active ingredients or excipients of modafinil or flecainide capsules).
11. Subjects currently (or within 6 weeks before VS1) under one of the following medications (isolated intake up to 1 week can be accepted):
a. Neuroleptics, anxiolytics, anticonvulsants. Benzodiazepines and benzodiazepine-like drugs are only authorised if used regularly at stable indicated doses with an evening intake as sleep promoting agents.
b. Flecainide or other class I antiarrhythmic drugs.
c. Psychostimulants (except caffeine if no abuse and stable consumption) such as, but not limited to, modafinil, methylphenidate, amphetamine.
d. Antidepressants except if maintained at stable dose for at least 6 weeks before visit VS1 and anticipated to remain stable during the trial in subjects with mild or moderate unipolar depression.
e. Antiemetic medications (except domperidone), myo-relaxing drugs and opioids.
f. Dopaminergic medications, unless they have been used at stable doses for at least 4 weeks before screening and it is anticipated that the doses will not be changed throughout the trial. Efficacious medication for Parkinson's disease should not be discontinued for the sole purpose of the subject's enrolment into this clinical trial but must be maintained at stable dosage levels.
g. Centrally acting anti-obesity drugs.
h. TNF-alpha inhibitors.
12. Pregnancy or lactation. Women of childbearing potential who intend to be pregnant during the next few months.
13. Subjects protected by the law (legal guardianship).
14. Subjects participating in any other clinical trial within 60 days prior to visit VS1 in this trial or still in the protected period imposed by a previous trial.
15. Subjects working in an occupation requiring variable shift work or routine night shifts.
16. Subjects who plan to travel involving time zone changes.
All above-mentioned exclusion criteria will be checked at VS1. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety endpoints
1. Adverse events
2. Safety laboratory
3. Vital signs change
4. Electrocardiogram assessments
5. Columbia-Suicide Severity Rating Scale (C-SSRS)
6. MDS-UPDRS
7. QUIP-RS
Efficacy endpoints
Key efficacy endpoint
8. Mean ESS score change from baseline at the end of each treatment period
Secondary efficacy endpoints
9. ESS score responder rate, defined as the proportion of subjects with at least 25% ESS improvement from baseline, at the end of each treatment period
10. Absence of residual somnolence, i.e. ESS < 11 at the end of each treatment period
11. Psychomotor Vigilance Test (PVT) variables change from baseline at the end of each treatment period
12. MoCA score change from baseline at the end of each treatment period
13. Actimetry change (inactivity) from baseline at the end of each treatment period
14. Number and duration of diurnal involuntary sleep attacks (subject diaries) change from baseline at the end of each treatment period
15. Episodes of somnolence (subject diaries) change from baseline at the end of each treatment period |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
|
| 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 | No |
| 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 | Yes |
| 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) | 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 | No |
| E.8.1.6 | Cross over | Yes |
| 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 | 3 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| 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 |
| Czech Republic |
| France |
| Germany |
| Hungary |
| United States |
|
| 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
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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 | 1 |
| 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 | 1 |
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