A Study to Assess if Epanutin Infatabs 50 mg From Germany Are Similar to Dilantin Infatabs 50 mg From Australia

• Sponsor: Pfizer's Upjohn has merged with Mylan to form Viatris Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01355068
• Collaborator: (none)
• Enrollment: 26
• Location: 1
• Arms: 2
• Duration (Months): 1
• Patients Per Site Per Month: 25.5

Study Details

Study Description

Brief Summary

In this study, the bioequivalence of Epanutin Infatabs® 50 mg (sourced from Germany) and Dilantin Infatabs® 50 mg (sourced from Australia) will be assessed. This is intended to be a pivotal bioequivalence study.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Epanutin Infatabs (Phenytoin); Drug: Dilantin Infatabs (Phenytoin)	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 26 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: An Open Label, Randomized, Single Dose, Crossover Pivotal Bioequivalence Study of Epanutin Infatabs 50 mg (Sourced From Germany) Verses Dilantin Infatabs 50 mg (Sourced From Australia) in Healthy Subjects
• Study Start Date: May 1, 2011
• Actual Primary Completion Date: Jun 1, 2011
• Actual Study Completion Date: Jun 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Treatment A Epanutin Infatabs 50 mg (sourced from Germany), 1 x 50 mg (REFERENCE)	Drug: Epanutin Infatabs (Phenytoin); Chewable Tablet, 50 mg, Single dose
Experimental: Treatment B Dilantin Infatabs 50 mg (sourced from Australia), 1 x 50 mg (TEST)	Drug: Dilantin Infatabs (Phenytoin); Chewable Tablet, 50 mg, Single dose

Outcome Measures

Primary Outcome Measures

1. Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) [0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, and 72 hours (hrs) post-dose]

   Area under the plasma concentration time-curve from zero (pre-dose) to the last measured concentration (AUClast).

2. Maximum Observed Plasma Concentration (Cmax) [0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 hrs post-dose]

Secondary Outcome Measures

1. Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC [0-∞]) [0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 hrs post-dose]

   AUC (0-∞) = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-∞). It is obtained from AUC (0-t) plus AUC (t-∞).

2. Extrapolated Area Under the Curve (AUC Percent [%] Extrap) [0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 hrs post-dose]

   AUC%extrap is the percentage of AUC [0-∞] obtained by forward extrapolation. It is calculated as (AUC [0-∞] minus AUClast)*100/ AUC [0-∞], where AUC [0-∞] = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0-∞) and AUClast is area under the plasma concentration time-curve from zero (pre-dose) to the last measured concentration.

3. Plasma Decay Half Life (t1/2) [0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 hrs post-dose]

   Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.

4. Time to Reach Maximum Observed Plasma Concentration (Tmax) [0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 hrs post-dose]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Healthy male and/or female subjects between the ages of 21 and 55 years, inclusive.

• An informed consent document signed and dated by the subject.

Exclusion Criteria:

• Evidence or history of clinically significant abnormalities.

• Any condition possibly affecting drug absorption (e.g. gastrectomy).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pfizer Investigational Site	Singapore		Singapore	188770

Sponsors and Collaborators

• Pfizer's Upjohn has merged with Mylan to form Viatris Inc.

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• To obtain contact information for a study center near you, click here.

Publications

None provided.

• Responsible Party: Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
• ClinicalTrials.gov Identifier: NCT01355068
• Other Study ID Numbers: A4121010
• First Posted: May 17, 2011
• Last Update Posted: Jan 28, 2021
• Last Verified: Nov 1, 2011

• Keywords provided by Pfizer's Upjohn has merged with Mylan to form Viatris Inc.: phenytoin; chewable tablets; dilantin; epanutin; infatabs; bioequivalence; Partial seizure; Tonic-clonic seizure
• Additional relevant MeSH terms: Phenytoin

Study Results

Participant Flow

Arm/Group Title	Epanutin Infatabs 50 mg First, Then Dilantin Infatabs 50 mg	Dilantin Infatabs 50 mg First, Then Epanutin Infatabs 50 mg
Arm/Group Description	Single oral dose of Epanutin (phenytoin) infatabs 50 milligram (mg) chewable tablet in first intervention period; and single oral dose of Dilantin (phenytoin) infatabs 50 mg chewable tablet in second intervention period. A washout period of at least 7 days was maintained between each period.	Single oral dose of Dilantin (phenytoin) infatabs 50 mg chewable tablet in first intervention period; and single oral dose of Epanutin (phenytoin) infatabs 50 mg chewable tablet in second intervention period. A washout period of at least 7 days was maintained between each period.
Period Title: First Intervention Period
STARTED	13	13
COMPLETED	13	11
NOT COMPLETED	0	2
Period Title: First Intervention Period
STARTED	13	11
COMPLETED	13	11
NOT COMPLETED	0	0
Period Title: First Intervention Period
STARTED	13	11
COMPLETED	13	11
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Entire Study Population
Arm/Group Description	Includes participants randomized to receive Epanutin (phenytoin) infatabs 50 mg first and Dilantin (phenytoin) infatabs 50 mg first.
Overall Participants	26
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	31.8 (8.3)
Sex: Female, Male (Count of Participants)
Female	1 3.8%
Male	25 96.2%

Outcome Measures

1. Primary Outcome

Title	Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast)
Description	Area under the plasma concentration time-curve from zero (pre-dose) to the last measured concentration (AUClast).
Time Frame	0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, and 72 hours (hrs) post-dose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) parameter analysis population included all randomized and treated participants who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.

Arm/Group Title	Epanutin Infatabs 50 mg	Dilantin Infatabs 50 mg
Arm/Group Description	Single oral dose of Epanutin (phenytoin) infatabs 50 mg chewable tablet (Reference) in either first intervention period or second intervention period.	Single oral dose of Dilantin (phenytoin) infatabs 50 mg chewable tablet (Test) in either first intervention period or second intervention period.
Measure Participants	24	26
Geometric Mean (Standard Deviation) [ng*hr/mL]	21380.0 (6043.0)	21370.0 (5571.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Epanutin Infatabs 50 mg, Dilantin Infatabs 50 mg
	Comments	Natural log transformed AUClast was analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. The adjusted mean differences and 90% confidence intervals (CIs) for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Adjusted Means
	Estimated Value	101.33
	Confidence Interval	(2-Sided) 90%; 97.85 to 104.94
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Maximum Observed Plasma Concentration (Cmax)
Time Frame	0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 hrs post-dose

Outcome Measure Data

Analysis Population Description

PK parameter analysis population included all randomized and treated participants who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.

Arm/Group Title	Epanutin Infatabs 50 mg	Dilantin Infatabs 50 mg
Arm/Group Description	Single oral dose of Epanutin (phenytoin) infatabs 50 mg chewable tablet (Reference) in either first intervention period or second intervention period.	Single oral dose of Dilantin (phenytoin) infatabs 50 mg chewable tablet (Test) in either first intervention period or second intervention period.
Measure Participants	24	26
Geometric Mean (Standard Deviation) [ng/mL]	952.10 (229.25)	976.50 (214.78)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Epanutin Infatabs 50 mg, Dilantin Infatabs 50 mg
	Comments	Natural log transformed Cmax was analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. The adjusted mean differences and 90% CIs for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Adjusted Means
	Estimated Value	102.20
	Confidence Interval	(2-Sided) 90%; 97.18 to 107.47
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC [0-∞])
Description	AUC (0-∞) = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-∞). It is obtained from AUC (0-t) plus AUC (t-∞).
Time Frame	0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 hrs post-dose

Outcome Measure Data

Analysis Population Description

PK parameter analysis population included all randomized and treated participants who had at least 1 of the PK parameters of primary interest in at least 1 treatment period. Here, the 'N' (number of participants analyzed) is signifying those participants who were evaluable for this measure.

Arm/Group Title	Epanutin Infatabs 50 mg	Dilantin Infatabs 50 mg
Arm/Group Description	Single oral dose of Epanutin (phenytoin) infatabs 50 mg chewable tablet (Reference) in either first intervention period or second intervention period.	Single oral dose of Dilantin (phenytoin) infatabs 50 mg chewable tablet (Test) in either first intervention period or second intervention period.
Measure Participants	23	25
Geometric Mean (Standard Deviation) [ng*hr/mL]	21730.0 (6345.9)	21740.0 (5816.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Epanutin Infatabs 50 mg, Dilantin Infatabs 50 mg
	Comments	Natural log transformed AUC (0-∞) was analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. The adjusted mean differences and 90% CIs for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Adjusted Means
	Estimated Value	101.43
	Confidence Interval	(2-Sided) 90%; 97.56 to 105.47
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Extrapolated Area Under the Curve (AUC Percent [%] Extrap)
Description	AUC%extrap is the percentage of AUC [0-∞] obtained by forward extrapolation. It is calculated as (AUC [0-∞] minus AUClast)*100/ AUC [0-∞], where AUC [0-∞] = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0-∞) and AUClast is area under the plasma concentration time-curve from zero (pre-dose) to the last measured concentration.
Time Frame	0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 hrs post-dose

Outcome Measure Data

Analysis Population Description

PK parameter analysis population included all randomized and treated participants who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.

Arm/Group Title	Epanutin Infatabs 50 mg	Dilantin Infatabs 50 mg
Arm/Group Description	Single oral dose of Epanutin (phenytoin) infatabs 50 mg chewable tablet (Reference) in either first intervention period or second intervention period.	Single oral dose of Dilantin (phenytoin) infatabs 50 mg chewable tablet (Test) in either first intervention period or second intervention period.
Measure Participants	24	26
Geometric Mean (Standard Deviation) [Percent AUC]	3.321 (4.884)	3.198 (4.805)

5. Secondary Outcome

Title	Plasma Decay Half Life (t1/2)
Description	Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
Time Frame	0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 hrs post-dose

Outcome Measure Data

Analysis Population Description

PK parameter analysis population included all randomized and treated participants who had at least 1 of the PK parameters of primary interest in at least 1 treatment period. Here, the 'N' (number of participants analyzed) is signifying those participants who were evaluable for this measure.

Arm/Group Title	Epanutin Infatabs 50 mg	Dilantin Infatabs 50 mg
Arm/Group Description	Single oral dose of Epanutin (phenytoin) infatabs 50 mg chewable tablet (Reference) in either first intervention period or second intervention period.	Single oral dose of Dilantin (phenytoin) infatabs 50 mg chewable tablet (Test) in either first intervention period or second intervention period.
Measure Participants	23	26
Mean (Standard Deviation) [hr]	14.380 (3.247)	14.970 (4.777)

6. Secondary Outcome

Title	Time to Reach Maximum Observed Plasma Concentration (Tmax)
Time Frame	0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 hrs post-dose

Outcome Measure Data

Analysis Population Description

PK parameter analysis population included all randomized and treated participants who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.

Arm/Group Title	Epanutin Infatabs 50 mg	Dilantin Infatabs 50 mg
Arm/Group Description	Single oral dose of Epanutin (phenytoin) infatabs 50 mg chewable tablet (Reference) in either first intervention period or second intervention period.	Single oral dose of Dilantin (phenytoin) infatabs 50 mg chewable tablet (Test) in either first intervention period or second intervention period.
Measure Participants	24	26
Median (Full Range) [hr]	3.51	4.00

Adverse Events

Adverse Event Reporting Description	The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Arm/Group Title	Epanutin Infatabs 50 mg		Dilantin Infatabs 50 mg
Arm/Group Description	Single oral dose of Epanutin (phenytoin) infatabs 50 mg chewable tablet (Reference) in either first intervention period or second intervention period.		Single oral dose of Dilantin (phenytoin) infatabs 50 mg chewable tablet (Test) in either first intervention period or second intervention period.
All Cause Mortality
	Epanutin Infatabs 50 mg		Dilantin Infatabs 50 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Epanutin Infatabs 50 mg		Dilantin Infatabs 50 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		0/26 (0%)
Other (Not Including Serious) Adverse Events
	Epanutin Infatabs 50 mg		Dilantin Infatabs 50 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/24 (16.7%)		2/26 (7.7%)
Infections and infestations
Upper respiratory tract infection	1/24 (4.2%)		1/26 (3.8%)
Nervous system disorders
Dizziness	1/24 (4.2%)		0/26 (0%)
Headache	2/24 (8.3%)		0/26 (0%)
Skin and subcutaneous tissue disorders
Rash	0/24 (0%)		1/26 (3.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.