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| Name | Class |
|---|---|
| Zambon SpA | INDUSTRY |
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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 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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Reference/Test/Reference/Test | Experimental | 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. |
|
| Test/Reference/Test/Reference | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Riluzole 50 mg orodispersible film | Drug | 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. |
| 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 |
| 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 |
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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:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Milko Radicioni, MD | CROSS Research SA | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| CROSS Research SA Phase 1 Unit | Arzo | Canton Ticino | 6864 | Switzerland |
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Fifty-four (54) subjects were randomised in the study and 53 of them received at least one dose of investigational product, while one subject discontinued the study before receiving any treatment due to adverse event.
Participants were recruited at the Phase I Unit from January 2021 to February 2021.
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| ID | Title | Description |
|---|---|---|
| FG000 | Riluzole 50mg (Test) / Rilutek 50mg (Reference) / Riluzole 50mg (Test) / Rilutek 50mg (Reference) | Riluzole 50 mg Orodispersible Film (Test, T): The subjects were treated with one orodispersible film containing 50 mg of riluzole in two out of the four study periods according to the randomisation sequence. Before each administration, the subjects drank 20 mL of still mineral water in order to wet their mouth. Afterwards, using gloves, the investigator or deputy took the orodispersible film (32.0x22.0 mm) out of the provided pouch and placed the product directly on the top surface (dorsal aspect) of the subjects' tongue. Rilutek 50 mg Tablet (Reference, R): The subjects were treated with one film-coated table containing 50 mg of riluzole in two out of the four study periods according to the randomisation sequence. One film-coated tablet was swallowed (without chewing) with 150 mL of still mineral water. |
| FG001 | Rilutek 50mg (Reference) / Riluzole 50mg (Test) / Rilutek 50mg (Reference) / Riluzole 50mg (Test) | Riluzole 50 mg Orodispersible Film (Test, T): The subjects were treated with one orodispersible film containing 50 mg of riluzole in two out of the four study periods according to the randomisation sequence. Before each administration, the subjects drank 20 mL of still mineral water in order to wet their mouth. Afterwards, using gloves, the investigator or deputy took the orodispersible film (32.0x22.0 mm) out of the provided pouch and placed the product directly on the top surface (dorsal aspect) of the subjects' tongue. Rilutek 50 mg Tablet (Reference, R): The subjects were treated with one film-coated tablet containing 50 mg of riluzole in two out of the four study periods according to the randomisation sequence. One film-coated tablet was swallowed (without chewing) with 150 mL of still mineral water. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | All Study Participants | 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. 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. The subjects received 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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). | Posted | Mean | Standard Deviation | ng/mL | 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 |
|
36 days
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Riluzole Orodispersible Film (Test) | The subjects were treated with one orodispersible film containing 50 mg of riluzole in two out of the four study periods according to the randomisation sequence Riluzole 50 mg Oral Film: Before each administration, the subjects drank 20 mL of still mineral water in order to wet their mouth. Afterwards, using gloves, the investigator or deputy took the orodispersible film (32.0x22.0 mm) out of the provided pouch and placed the product directly on the top surface (dorsal aspect) of the subjects' tongue. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hypoaesthesia oral | Gastrointestinal disorders | MedDRA (24.0) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Mathias Knecht, Chief Medical Officer | Zambon S.p.A. | +41.91.960.4187 | mathias.knecht@zambongroup.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Apr 28, 2020 | Apr 26, 2022 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | May 31, 2021 | Apr 26, 2022 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D019782 | Riluzole |
| ID | Term |
|---|---|
| D013844 | Thiazoles |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
| D052160 | Benzothiazoles |
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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).
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| Rilutek® 50 mg riluzole tablets | Drug | One film-coated tablet will be swallowed (without chewing) with 150 mL of still mineral water. |
|
|
| 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) |
| Protocol Violation |
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| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Body weight | Mean | Standard Deviation | kilograms |
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| Height | Mean | Standard Deviation | centimeters |
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| Body mass index | Mean | Standard Deviation | kilograms/square meters |
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| OG001 | Rilutek® Tablet (Reference) | 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. |
|
|
|
| Primary | 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). | Posted | Mean | Standard Deviation | h*ng/mL | 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 |
|
|
|
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| Secondary | 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. | Posted | Mean | Standard Deviation | h | 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 | 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). | Posted | Mean | Standard Deviation | h*ng/mL | 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 |
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| Secondary | Description Tmax: Time to Achieve Cmax Reference | The results will be displayed and summarised in tables and figures. | Posted | Median | Full Range | h | 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 |
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|
|
| Secondary | 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. | Data for this outcome measure were only collected after administration of the Test product (Riluzole orodispersible film). The overall number of participants analyzed is the number of subjects who received Riluzole 50 mg orodispersible film (T) at the 1st administration. | Posted | Count of Participants | Participants | Immediately after 1st Test product administration, approximately within 5 minutes after administration |
|
|
|
| Secondary | 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. | Data for this outcome measure were only collected after administration of the Test product (Riluzole orodispersible film). The overall number of participants analyzed is the number of subjects who received Riluzole 50 mg orodispersible film (T) at the 2nd administration. | Posted | Count of Participants | Participants | Immediately after 2nd Test product administration, approximately within 5 minutes after administration |
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|
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| Secondary | 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. | Data for this outcome measure were only collected for the Test product (Riluzole orodispersible film). No mouth inspection was performed after Reference (Rilutek®) administration. The overall number of participants analyzed is the number of subjects who received Riluzole 50 mg orodispersible film (T). | Posted | Count of Participants | Participants | pre-dose (0), 0.5 and 1 h after the drug administration |
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| Secondary | 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 | Posted | Count of Participants | Participants | At screening (initial visit) and at final visit (approximately 1 month) |
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| 0 |
| 52 |
| 0 |
| 52 |
| 52 |
| 52 |
| EG001 | Rilutek® (Reference) | The subjects were treated with one film-coated table containing 50 mg of riluzole in two out of the four study periods according to the randomisation sequence Rilutek 50Mg Tablet: One film-coated tablet was swallowed (without chewing) with 150 mL of still mineral water. | 0 | 53 | 0 | 53 | 14 | 53 |
| Headache | Nervous system disorders | MedDRA (24.0) | Systematic Assessment |
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| D001393 |
| Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| Title | Measurements |
|---|---|
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| 3 - good |
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| 4 - very good |
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| Title | Measurements |
|---|---|
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| 3 - good |
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| 4 - very good |
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| Final visit (approximately 1 month) |
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