Riluzole Orodispersible Film Replicate Bioavailability

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

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.

Study Overview

• Status: Completed
• Conditions: Healthy Participants
• Intervention / Treatment: Drug: Riluzole 50 mg orodispersible film; Drug: Rilutek® 50 mg riluzole tablets

Detailed Description

The new formulation riluzole orodispersible film is expected to fill an important medical need, since the medication can be easily administered without water and may improve patient care. Riluzole orodispersible film is easily administered, because the patient or caregiver needs only to place the film on the tongue, where it can immediately dissolve into the saliva and be ingested with intentional swallowing or during the normal reflex of swallowing, thus eliminating the need for swallowing a tablet with liquid or crushing it into soft food.

Zambon S.p.A., Italy, is sponsoring the present bioequivalence study in order to investigate the bioequivalence of the novel unit-dose product versus Rilutek® tablets, commercially available in Europe as 50 mg tablets. The dose strength for the test formulation is 50 mg, matching the 50 mg strength of the reference formulation.

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.

• Study Type: Interventional
• Enrollment (Actual): 54
• Phase: Phase 1

Contacts and Locations

Study Locations

• Switzerland
  • Ticino
    • Arzo, Ticino, Switzerland, 6864
      • CROSS Research SA Phase 1 Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Informed consent: signed written informed consent before inclusion in the study
2. Sex and Age: men/women, 18-55 years old inclusive
3. Tobacco: non-smokers for at least 6 months prior to study screening
4. Body Mass Index (BMI): 18.5-29 kg/m2 inclusive
5. 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
6. 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

7. Contraception and fertility (women only): women of child-bearing potential must be using at least one of the following reliable methods of contraception:

   1. 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
   2. A male sexual partner who agrees to use a male condom with spermicide
   3. 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:

1. Electrocardiogram (ECG) 12-leads: (supine position) clinically significant abnormalities; corrected QT interval > 450 msec
2. Physical findings: clinically significant abnormal physical findings which could interfere with the objectives of the study
3. Laboratory analyses: clinically significant abnormal laboratory values indicative of physical illness
4. Cotinine: positive cotinine test at screening
5. 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
6. 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
7. Dentures: presence of mouth jewellery, dentures, braces, piercings that may interfere with successful completion of the dosing
8. 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
9. 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
10. Blood donation: blood donations for 3 months before this study
11. 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
12. Drug test: positive result at the drug test at screening or Day -1
13. Alcohol test: positive alcohol breath test at Day -1
14. Diet: abnormal diets (<1600 or >3500 kcal/day) or substantial changes in eating habits in the 4 weeks before this study; vegetarians and vegans
15. Pregnancy (women only): positive or missing pregnancy test at screening or Day -1, pregnant or lactating women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Reference/Test/Reference/Test; Riluzole orodispersible film (test): 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 Rilutek® (reference): The subjects will be treated with one film-coated tablet containing 50 mg of riluzole in two out of the four study periods according to the randomisation sequence.	Drug: Riluzole 50 mg orodispersible film; 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.; Other Names: Test product (T); Drug: Rilutek® 50 mg riluzole tablets; One film-coated tablet will be swallowed (without chewing) with 150 mL of still mineral water.; Other Names: Reference product (R)
Experimental: Test/Reference/Test/Reference; Riluzole orodispersible film (test): 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 Rilutek® (reference): The subjects will be treated with one film-coated tablet containing 50 mg of riluzole in two out of the four study periods according to the randomisation sequence.	Drug: Riluzole 50 mg orodispersible film; 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.; Other Names: Test product (T); Drug: Rilutek® 50 mg riluzole tablets; One film-coated tablet will be swallowed (without chewing) with 150 mL of still mineral water.; Other Names: Reference product (R)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluation of the Bioequivalent Rate of Absorption (Cmax) of Riluzole After Replicate Single Dose Administration of Test and Reference	For each individual, the maximum plasma concentration (Cmax) of riluzole after replicate single dose administration of Test and Reference was measured. The Cmax 90% confidence interval of the ratio Test/Reference of the population means was calculated. The bioequivalence is demonstrated when the 90% confidence Interval of this ratio lies within the range 80.00-125.00% (acceptance interval).	0 h (pre-dose) and 15, 30, 45 min, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 12, 24 and 36 h after the drug administration
Evaluation of the Bioequivalent Extent of Absorption (AUC0-t) of Riluzole After Replicate Single Dose Administration of Test and Reference.	For each individual, the area under the concentration-time curve from single dose Test and Reference administration to the last observed concentration time t (AUC0-t) of riluzole was measured. The AUC0-t 90% confidence interval of the ratio Test/Reference of the population means was calculated. The bioequivalence is demonstrated when the 90% confidence Interval of this ratio lies within the range 80.00-125.00% (acceptance interval).	0 h (pre-dose), 15, 30, 45 min, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 12, 24 and 36 h after drug administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To Describe the t1/2 (Half-life) of Riluzole After Replicate Single Dose Administration of Test and Reference	To Describe the half-life of riluzole, calculated, if feasible, as ln2/λz, After Replicate Single Dose Administration of Test and Reference.	0 h (pre-dose), 15, 30, 45 min, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 12, 24 and 36 h after drug administration
To Describe the AUC0-∞ of Riluzole After Replicate Single Dose Administration of Test and Reference	For each individual, the area under the concentration-time curve extrapolated to infinity after single dose administration of Test and Reference (AUC0-∞) was measured. The AUC0-∞ 90% confidence interval of the ratio Test/Reference of the population means was calculated. The bioequivalence is demonstrated when the 90% confidence Interval of this ratio lies within the range 80.00-125.00% (acceptance interval).	0 h (pre-dose), 15, 30, 45 min, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 12, 24 and 36 h after drug administration
Description Tmax: Time to Achieve Cmax Reference	The results will be displayed and summarised in tables and figures.	0 h (pre-dose), 15, 30, 45 min, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 12, 24 and 36 h after drug administration
Evaluation of the Test Product Palatability	Palatability was scored according to the following scale. Palatability evaluation description and scores (between brackets): Very unpleasant (0), Unpleasant (1), Acceptable (2), Good (3), Very good (4). Minimun value is 0, maximum value is 4. An higher score mean a better outcome.	Immediately after 1st Test product administration, approximately within 5 minutes after administration
Evaluation of the Test Product Palatability	Palatability was scored according to the following scale. Palatability evaluation description and scores (between brackets): Very unpleasant (0), Unpleasant (1), Acceptable (2), Good (3), Very good (4). Minimun value is 0, maximum value is 4. An higher score mean a better outcome.	Immediately after 2nd Test product administration, approximately within 5 minutes after administration
Number of Participants With Mucosal Irritation	Mouth inspections were performed before the Test administration and 30 min and 1 h after administrations of Test, to check the mucosal irritation at the application site. The outcome number shows the overall number of subjects with mucosal irritation.	pre-dose (0), 0.5 and 1 h after the drug administration
Haematology, Blood Chemistry and Urinalysis Laboratory Tests Interpretation	Overall investigator's interpretation (as normal or abnormal and, if abnormal, clinically significant or not clinically significant). The following analyses were performed at screening: Leukocytes, erythrocytes, haemoglobin, haematocrit, MCV, MCH, MCHC, thrombocytes, electrolytes, enzymes (alkaline phosphatase, γ-GT, AST, ALT), total bilirubin, creatinine, glucose, urea, uric acid, total cholesterol, triglycerides, cotinine, total proteins. Serum pregnancy test (women). Urine analysis: pH, specific weight, appearance, colour, nitrites, proteins, glucose, urobilinogen, bilirubin, ketones, haematic pigments, leukocytes. Urine sediment (analysis performed only if positive): leukocytes, erythrocytes, flat cells, round cells, crystals, cylinders, mucus, bacteria. Hepatitis B (HBs antigen), Hepatitis C (HCV antibodies), HIV 1/2 (HIV Ag/Ab combo). The same analyses, with the exception of cotinine, urine drug test, virology and pregnancy test, were performed at the final visit	At screening (initial visit) and at final visit (approximately 1 month)

Collaborators and Investigators

• Sponsor: Cross Research S.A.
• Collaborators: Zambon SpA
• Investigators: Principal Investigator: Milko Radicioni, MD, CROSS Research SA

Study record dates

Study Major Dates

• Study Start (Actual): January 15, 2021
• Primary Completion (Actual): March 14, 2021
• Study Completion (Actual): March 14, 2021

Study Registration Dates

• First Submitted: March 8, 2021
• First Submitted That Met QC Criteria: March 25, 2021
• First Posted (Actual): March 29, 2021

Study Record Updates

• Last Update Posted (Actual): May 2, 2025
• Last Update Submitted That Met QC Criteria: April 16, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: Bioequivalence; Riluzole; Orodispersible film
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Protective Agents; Anticonvulsants; Neuroprotective Agents; Excitatory Amino Acid Agents; Excitatory Amino Acid Antagonists; Riluzole
• Other Study ID Numbers: Z7251J01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No