Riluzole Orodispersible Film Replicate Bioavailability

Study Overview
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Brief Summary
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The objective of the study is to compare the pharmacokinetic profile of riluzole after replicate single dose of the novel orodispersible film test formulation and of the marketed reference Rilutek® tablets and to evaluate their bioequivalence. The subjects will receive single oral doses of 50 mg of riluzole, as test orodispersible film and reference film-coated tablets under fasting conditions, in each of 4 subsequent periods separated by wash-out intervals of at least 7 days between consecutive administrations, according to a 2-treatment, 4-period, replicate cross-over design.

Official Title
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Comparative Bioavailability Study of a New Riluzole Orodispersible Film vs. a Marketed Oral Reference (Rilutek® Tablets) in Healthy Male and Female Volunteers

Conditions
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Bioequivalence

Intervention / Treatment
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* Drug: Riluzole 50 mg Oral Film
* Drug: Rilutek 50Mg Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent: signed written informed consent before inclusion in the study Sex and Age: men/women, 18-55 years old inclusive Tobacco: non-smokers for at least 6 months prior to study screening Body Mass Index (BMI): 18.5-29 kg/m2 inclusive Vital signs: systolic blood pressure (SBP) 100-139 mmHg, diastolic blood pressure (DBP) 50-89 mmHg, heart rate 50-90 bpm, measured after 5 min at rest in the sitting position Full comprehension: ability to comprehend the full nature and purpose of the study, including possible risks and side effects; ability to co-operate with the investigator and to comply with the requirements of the entire study Contraception and fertility (women only): women of child-bearing potential must be using at least one of the following reliable methods of contraception: A non-hormonal intrauterine device or female condom with spermicide or contraceptive sponge with spermicide or diaphragm with spermicide or cervical cap with spermicide for at least 2 months before the screening visit A male sexual partner who agrees to use a male condom with spermicide A sterile sexual partner Female participants of non-child-bearing potential or in post-menopausal status for at least 1 year will be admitted. For all women, pregnancy test result must be negative at screening. Exclusion Criteria: Electrocardiogram (ECG) 12-leads: (supine position) clinically significant abnormalities; corrected QT interval > 450 msec Physical findings: clinically significant abnormal physical findings which could interfere with the objectives of the study Laboratory analyses: clinically significant abnormal laboratory values indicative of physical illness Cotinine: positive cotinine test at screening Allergy: ascertained or presumptive hypersensitivity to the active principle and/or formulations' ingredients; history of anaphylaxis to drugs or allergic reactions in general, which the investigator considers may affect the outcome of the study Diseases: clinically significant history or presence of renal, hepatic, gastrointestinal, cardiovascular, cerebrovascular, immunological, musculoskeletal, respiratory, skin, haematological, endocrine, psychiatric or neurological diseases or surgeries that may interfere with the aim of the study. Gastrointestinal pathologies include any clinically significant disorder of the mouth, e.g. impairment of swallowing, lesions, ulcerations, deformities, untreated dental caries Dentures: presence of mouth jewellery, dentures, braces, piercings that may interfere with successful completion of the dosing Medications: medications, including over the counter medications and herbal remedies for 2 weeks before study screening; central nervous system depressants, including opioids, benzodiazepines, general anaesthetics and anticonvulsants, or cytochrome C inhibitors, including cimetidine, fluoxetine, quinidine, erythromycin, ciprofloxacin, fluconazole, ketoconazole, diltiazem and antiretroviral agents, or strong cytochrome C inducers, including barbiturates, carbamazepine, glucocorticoids, phenytoin, St John's wort and rifampin, or hormonal oral or transdermal contraceptives for 30 days before study screening; implanted, injected, intravaginal or intrauterine hormonal contraceptives for 6 months before study screening Investigative drug studies: participation in the evaluation of any investigational product for 3 months before this study. The 3-month interval is calculated as the time between the first calendar day of the month that follows the last visit of the previous study and the first day of the present study Blood donation: blood donations for 3 months before this study Drug, alcohol, caffeine, tobacco: history of drug, alcohol [>1 drink/day for females and >2 drinks/day for males, defined according to the Dietary Guidelines 2015 ], caffeine (>5 cups coffee/tea/day) or tobacco use including any tobacco product like e-cigarettes and vamping products Drug test: positive result at the drug test at screening or Day -1 Alcohol test: positive alcohol breath test at Day -1 Diet: abnormal diets (<1600 or >3500 kcal/day) or substantial changes in eating habits in the 4 weeks before this study; vegetarians and vegans Pregnancy (women only): positive or missing pregnancy test at screening or Day -1, pregnant or lactating women

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: The study was designed in agreement with the EMA guideline Guidance on the investigation of bioequivalence, CPMP/EWP/QWP/1401/98 Rev. 1 January 2010 (9).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Riluzole orodispersible film (Test)<br>The subjects will be treated with one orodispersible film containing 50 mg of riluzole in two out of the four study periods according to the randomisation sequence | Drug: Riluzole 50 mg Oral Film<br>* Before each administration, the subjects will drink 20 mL of still mineral water in order to wet their mouth. Afterwards, using gloves, the investigator or deputy will take the orodispersible film (32.0x22.0 mm) out of the provided pouch and place the product directly on the top surface (dorsal aspect) of the subjects' tongue.<br>|
| Active Comparator: Rilutek® (Reference)<br>The subjects will be treated with one film-coated table containing 50 mg of riluzole in two out of the four study periods according to the randomisation sequence | Drug: Rilutek 50Mg Tablet<br>* One film-coated tablet will be swallowed (without chewing) with 150 mL of still mineral water.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of the bioequivalent rate (Cmax) of absorption of riluzole after replicate single dose administration of test and reference. | Acceptance criterion will be that the 90% Confidential Interval of this ratio has to lie within the range 80.00-125.00%. | 36 hours after the drug treatment | 
| Evaluation of the bioequivalent extent (AUC0-t) of absorption of riluzole after replicate single dose administration of test and reference. | Acceptance criterion will be that the 90% Confidential Interval of this ratio has to lie within the range 80.00-125.00%. | 36 hours after the drug treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Description tmax: Time to achieve Cmax reference | The results will be displayed and summarised in tables and figures. | 36 hours after the drug treatment | 
| Description t1/2: Half-life, calculated, if feasible, as ln2/λz | The results will be displayed and summarised in tables and figures. | 36 hours after the drug treatment | 
| Description AUC(0-∞) | The results will be displayed and summarised in tables and figures. | 36 hours after the drug treatment | 
| Evaluation of the test product palatability | Test product palatability scores will be listed: very unpleasant 0 unpleasant 1 acceptable 2 good 3 very good 4 | immediately after administration | 
| Blood pressure | Subjects blood pressure (BP) measured at rest (5 min in sitting position) | 36 hours after the drug treatment | 
| Mouth visual inspections | check for mucosal irritation | 1hour post dose | 
| Incidence of Treatment-Emergent Adverse Events | Individual events will be listed in subject data listings. | 2 months | 
| Heart rate | Subjects heart rate (HR) measured at rest (5 min in sitting position) | 36 hours after the drug treatment | 
| Laboratory data interpretation | Overall investigator's interpretation (as normal or abnormal and, if abnormal, clinically significant or not clinically significant) | 2 months |