Study Evaluating the Pharmacokinetics of Keppra Extended Release (XR) in Children and Adults With Epilepsy

• ClinicalTrials.gov Identifier: NCT00961441
• Recruitment Status: Completed
• First Posted: August 19, 2009
• Results First Posted: May 25, 2011
• Last Update Posted: August 6, 2015
• Sponsor: UCB BIOSCIENCES, Inc.
• Information provided by (Responsible Party): UCB Pharma ( UCB BIOSCIENCES, Inc. )

• Study Type: Interventional
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Epilepsy
• Intervention: Drug: Keppra XR
• Enrollment: 25

Participant Flow

Recruitment Details	Intent-to-treat (ITT) population includes all enrolled patients who received at least one dose of study medication.Pharmacokinetic Per-Protocol (PK-PP) population is a subset of the ITT population, consisting of those patients who had no major protocol deviations affecting the pharmacokinetic parameters.
Pre-assignment Details	Participant Flow and Baseline characteristics refer to the Intention-to-treat (ITT) population.

Arm/Group Title	Keppra XR in Children (12-16 Years Old)	Keppra XR in Adults (18-55 Years Old)
Arm/Group Description	Drug: Keppra XR Keppra XR 500 mg tablets and Keppra XR 750 mg tablets Dosage: Keppra XR 1000-3000 mg/day taken once daily Duration: 4-7 days	Drug: Keppra XR Keppra XR 500 mg tablets and Keppra XR 750 mg tablets Dosage: Keppra XR 1000-3000 mg/day taken once daily Duration: 4-7 days
Period Title: Overall Study
Started	12	13
Pharmacokinetic (PK-PP) Population	12	10 [1]
Completed	12	13
Not Completed	0	0
[1] Two subjects were excluded due to study medication noncompliance, one due to wrong dosing regimen.

Baseline Characteristics

Arm/Group Title		Keppra XR in Children (12-16 Years Old)	Keppra XR in Adults (18-55 Years Old)	Total
Arm/Group Description		Drug: Keppra XR Keppra XR 500 mg tablets and Keppra XR 750 mg tablets Dosage: Keppra XR 1000-3000 mg/day taken once daily Duration: 4-7 days	Drug: Keppra XR Keppra XR 500 mg tablets and Keppra XR 750 mg tablets Dosage: Keppra XR 1000-3000 mg/day taken once daily Duration: 4-7 days	Total of all reporting groups
Overall Number of Baseline Participants		12	13	25
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	12 participants	13 participants	25 participants
		14.88 (1.37)	41.78 (9.21)	28.87 (15.21)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	12 participants	13 participants	25 participants
	Female	6 50.0%	8 61.5%	14 56.0%
	Male	6 50.0%	5 38.5%	11 44.0%
Weight; Mean (Standard Deviation); Unit of measure: Kilogram (kg)
	Number Analyzed	12 participants	13 participants	25 participants
		77.2 (24.1)	82.5 (23.0)	80.0 (23.2)
Height; Mean (Standard Deviation); Unit of measure: Centimeter (cm)
	Number Analyzed	12 participants	13 participants	25 participants
		165.9 (8.8)	169.3 (10.3)	167.7 (9.6)
Body Mass Index (BMI); Mean (Standard Deviation); Unit of measure: Kg/m^2
	Number Analyzed	12 participants	13 participants	25 participants
		27.62 (7.01)	28.63 (7.14)	28.14 (6.95)
Body Surface Area (BSA); Mean (Standard Deviation); Unit of measure: M^2
	Number Analyzed	12 participants	13 participants	25 participants
		1.87 (0.34)	1.95 (0.32)	1.91 (0.32)
Race; Measure Type: Number; Unit of measure: Participants	Number Analyzed	12 participants	13 participants	25 participants
Black		4	3	7
Caucasian		8	9	17
Other / mixed		0	1	1

Outcome Measures

1. Primary Outcome

Title	Maximum Concentration at Steady State (Cmax) of Keppra XR Normalized by Dose and by Body Weight and Dose During up to 7 Days of Administration
Description	The Cmax is the maximum plasma concentration normalized by dose and by body weight and dose. Cmax normalized by 1000 mg dose was calculated as: Cmax/(mg dose taken/ 1000 mg Keppra XR). Cmax normalized by body weight and dose (1 mg Keppra XR/kg) was calculated as: Cmax/(bodyweight (kg)/ mg dose Keppra XR taken). Pharmacokonetic (PK) samples were taken predose and 1h, 2.5h, 4h, 6h and 10h after study medication at day 4, 5, 6 or 7 of Keppra XR administration.
Time Frame	6 pharmacokinetic samples were taken pre-dose, 1, 2.5, 4, 6 and 10 hours after administration, at Day 4, 5, 6, or 7 of Keppra XR administration.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Per-Protocol (PK-PP) population

Arm/Group Title	Keppra XR in Children (12-16 Years Old)	Keppra XR in Adults (18-55 Years Old)
Arm/Group Description:	Drug: Keppra XR Keppra XR 500 mg tablets and Keppra XR 750 mg tablets Dosage: Keppra XR 1000-3000 mg/day taken once daily Duration: 4-7 days	Drug: Keppra XR Keppra XR 500 mg tablets and Keppra XR 750 mg tablets Dosage: Keppra XR 1000-3000 mg/day taken once daily Duration: 4-7 days
Overall Number of Participants Analyzed	12	10
Geometric Mean (95% Confidence Interval); Unit of Measure: µg/mL
Dose norm. ( Keppra XR 1000mg)	17.3; (14.3 to 21.0)	14.9; (12.1 to 18.5)
Dose and weight norm. ( Keppra XR 1 mg/kg)	1.27; (1.12 to 1.44)	1.24; (1.08 to 1.42)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Keppra XR in Children (12-16 Years Old), Keppra XR in Adults (18-55 Years Old)
	Comments	An ANOVA for log-transformed values has been used as the basis for calculation of point estimates and Confidence Intervals (CIs).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	ANOVA
	Comments	Point estimates for the geometric means ratios children/adults for Cmax normalized by dose and body weight and 90% CIs have been calculated.
Method of Estimation	Estimation Parameter	Point estimate for ratio
	Estimated Value	1.0271
	Confidence Interval	(2-Sided) 90%; 0.8817 to 1.1964
	Estimation Comments	[Not Specified]

2. Primary Outcome

Title	Area Under the Plasma Concentration Curve Over a Dosing Interval of 24 Hours (AUCtau) of Keppra XR Normalized by Dose, and by Body Weight and Dose During up to 7 Days of Administration
Description	AUCtau normalized by 1000 mg dose was calculated as: AUCtau/(mg dose taken/ 1000 mg Keppra XR). AUCtau normalized by body weight and dose (1 mg Keppra XR/kg) was calculated as: AUCtau/(bodyweight (kg)/ mg dose Keppra XR taken). 6 PK samples were taken pre-dose, 1, 2.5, 4, 6 and 10 hours after administration, at Day 4, 5, 6, or 7 of Keppra XR administration. At steady state, reached after 2 days of administration of Keppra XR, the concentrations at 24h postdose is equal to the predose concentration. The predose concentration was used as the 24h concentration to calculate AUCτau.
Time Frame	6 pharmacokinetic samples were taken pre-dose, 1, 2.5, 4, 6 and 10 hours after administration, at Day 4, 5, 6, or 7 of Keppra XR administration.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Per-Protocol (PK-PP) population

Arm/Group Title	Keppra XR in Children (12-16 Years Old)	Keppra XR in Adults (18-55 Years Old)
Arm/Group Description:	Drug: Keppra XR Keppra XR 500 mg tablets and Keppra XR 750 mg tablets Dosage: Keppra XR 1000-3000 mg/day taken once daily Duration: 4-7 days	Drug: Keppra XR Keppra XR 500 mg tablets and Keppra XR 750 mg tablets Dosage: Keppra XR 1000-3000 mg/day taken once daily Duration: 4-7 days
Overall Number of Participants Analyzed	12	10
Geometric Mean (95% Confidence Interval); Unit of Measure: µg*h/mL
Dose norm. (Keppra XR 1000mg)	265; (214 to 327)	236; (187 to 298)
Dose and weight norm. (Keppra XR 1 mg/kg)	19.4; (16.5 to 22.9)	19.6; (16.4 to 23.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Keppra XR in Children (12-16 Years Old), Keppra XR in Adults (18-55 Years Old)
	Comments	An ANOVA for log-transformed values has been used as the basis for calculation of point estimates and Confidence Intervals (CIs).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	ANOVA
	Comments	Point estimates for the geometric means ratios children/adults for AUCtau normalized by dose and body weight and 90% CIs have been calculated.
Method of Estimation	Estimation Parameter	Point estimate for ratio
	Estimated Value	0.9914
	Confidence Interval	(2-Sided) 90%; 0.8110 to 1.2118
	Estimation Comments	[Not Specified]

3. Primary Outcome

Title	Time of Maximum Plasma Concentration (Tmax) of Keppra XR During up to 7 Days of Administration
Description	The Tmax is the time corresponding to the maximum plasma concentration of Keppra XR. It was directly obtained from the observed concentration versus time curve. 6 pharmacokinetic samples were taken pre-dose, 1, 2.5, 4, 6 and 10 hours after administration, at Day 4, 5, 6, or 7 of Keppra XR administration.
Time Frame	6 pharmacokinetic samples were taken pre-dose, 1, 2.5, 4, 6 and 10 hours after administration, at Day 4, 5, 6, or 7 of Keppra XR administration.

Outcome Measure Data

Analysis Population Description

PK-PP population

Arm/Group Title	Keppra XR in Children (12-16 Years Old)	Keppra XR in Adults (18-55 Years Old)
Arm/Group Description:	Drug: Keppra XR Keppra XR 500 mg tablets and Keppra XR 750 mg tablets Dosage: Keppra XR 1000-3000 mg/day taken once daily Duration: 4-7 days	Drug: Keppra XR Keppra XR 500 mg tablets and Keppra XR 750 mg tablets Dosage: Keppra XR 1000-3000 mg/day taken once daily Duration: 4-7 days
Overall Number of Participants Analyzed	12	10
Median (Full Range); Unit of Measure: hours (h)
	5.90; (2.50 to 6.07)	5.93; (2.45 to 6.05)

4. Primary Outcome

Title	Apparent Total Body Clearance (CL/F) of Keppra XR During up to 7 Days of Administration
Description	The Apparent Total Body Clearance (CL/F) was calculated as Dose/ AUCtau. 6 pharmacokinetic samples were taken pre-dose, 1, 2.5, 4, 6 and 10 hours after administration, at Day 4, 5, 6, or 7 of Keppra XR administration.
Time Frame	6 pharmacokinetic samples were taken pre-dose, 1, 2.5, 4, 6 and 10 hours after administration, at Day 4, 5, 6, or 7 of Keppra XR administration.

Outcome Measure Data

Analysis Population Description

PK-PP population

Arm/Group Title	Keppra XR in Children (12-16 Years Old)	Keppra XR in Adults (18-55 Years Old)
Arm/Group Description:	Drug: Keppra XR Keppra XR 500 mg tablets and Keppra XR 750 mg tablets Dosage: Keppra XR 1000-3000 mg/day taken once daily Duration: 4-7 days	Drug: Keppra XR Keppra XR 500 mg tablets and Keppra XR 750 mg tablets Dosage: Keppra XR 1000-3000 mg/day taken once daily Duration: 4-7 days
Overall Number of Participants Analyzed	12	10
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: L/h
	3.78; (31.4%)	4.23; (41.8%)

5. Secondary Outcome

Title	Occurrence of Treatment-Emergent Adverse Events From Starting Study Drug Treatment (Day 1) to up to 14 Days
Description	An Adverse Event (AE) is any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. Treatment emergent means that an AE has begun or got worse after start of Keppra XR administration.
Time Frame	From Starting Study Drug Treatment (Day 1) to up to 14 days

Outcome Measure Data

Analysis Population Description

Safety Set includes all subjects who took at least one dose of study medication. The Safety Set is identical to the Intention-to-treat (ITT) population in this study.

Arm/Group Title	Keppra XR in Children (12-16 Years Old)	Keppra XR in Adults (18-55 Years Old)
Arm/Group Description:	Drug: Keppra XR Keppra XR 500 mg tablets and Keppra XR 750 mg tablets Dosage: Keppra XR 1000-3000 mg/day taken once daily Duration: 4-7 days	Drug: Keppra XR Keppra XR 500 mg tablets and Keppra XR 750 mg tablets Dosage: Keppra XR 1000-3000 mg/day taken once daily Duration: 4-7 days
Overall Number of Participants Analyzed	12	13
Measure Type: Number; Unit of Measure: Count
Total number of AEs	7	11
Patients with at least 1 AE	3	3
Patients with severe AEs	0	1
Patients with serious AEs	0	0

Adverse Events

Time Frame	From Starting Study Drug Treatment (Day 1) to up to 14 days.
Adverse Event Reporting Description	Treatment-Emergent AEs were collected and refer to the Safety Set. Safety Set includes all subjects who took at least one dose of study medication. Treatment emergent means that an Adverse Event has begun or got worse after start of Keppra XR administration.
Arm/Group Title	Keppra XR in Children (12-16 Years Old)		Keppra XR in Adults (18-55 Years Old)
Arm/Group Description	Drug: Keppra XR Keppra XR 500 mg tablets and Keppra XR 750 mg tablets Dosage: Keppra XR 1000-3000 mg/day taken once daily Duration: 4-7 days		Drug: Keppra XR Keppra XR 500 mg tablets and Keppra XR 750 mg tablets Dosage: Keppra XR 1000-3000 mg/day taken once daily Duration: 4-7 days
All-Cause Mortality
	Keppra XR in Children (12-16 Years Old)		Keppra XR in Adults (18-55 Years Old)
	Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--
Serious Adverse Events
	Keppra XR in Children (12-16 Years Old)		Keppra XR in Adults (18-55 Years Old)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0.00%)		0/13 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Keppra XR in Children (12-16 Years Old)		Keppra XR in Adults (18-55 Years Old)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/12 (25.00%)		3/13 (23.08%)
Blood and lymphatic system disorders
Lymphadenopathy * 1	1/12 (8.33%)	1	0/13 (0.00%)	0
Gastrointestinal disorders
Nausea * 1	1/12 (8.33%)	1	1/13 (7.69%)	1
Vomiting * 1	1/12 (8.33%)	1	1/13 (7.69%)	2
General disorders
Fatigue * 1	1/12 (8.33%)	1	0/13 (0.00%)	0
Irritability * 1	0/12 (0.00%)	0	1/13 (7.69%)	1
Infections and infestations
Pharyngitis streptococcal * 1	1/12 (8.33%)	1	0/13 (0.00%)	0
Musculoskeletal and connective tissue disorders
Arthralgia * 1	0/12 (0.00%)	0	1/13 (7.69%)	1
Nervous system disorders
Somnolence * 1	1/12 (8.33%)	1	1/13 (7.69%)	1
Paraesthesia * 1	0/12 (0.00%)	0	1/13 (7.69%)	1
Psychiatric disorders
Abnormal behaviour * 1	1/12 (8.33%)	1	0/13 (0.00%)	0
Reproductive system and breast disorders
Dysmenorrhoea * 1	0/12 (0.00%)	0	1/13 (7.69%)	1
Skin and subcutaneous tissue disorders
Hypoaesthesia facial * 1	0/12 (0.00%)	0	1/13 (7.69%)	1
Pruritus * 1	0/12 (0.00%)	0	1/13 (7.69%)	1
Rash * 1	0/12 (0.00%)	0	1/13 (7.69%)	1
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA 13.0

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

UCB has > 60 days but <= 180 days to review results communications prior to public release and may delete information that compromises ongoing studies or is considered proprietary. This restriction is not intended to compromise the objective scientific integrity of the manuscript, it being understood that results shall be published regardless of outcome.

Results Point of Contact

• Name/Title: UCB Clinical Trial Call Center
• Organization: UCB
• Phone: +1 877 822 9493 (UCB)

• Responsible Party: UCB Pharma ( UCB BIOSCIENCES, Inc. )
• ClinicalTrials.gov Identifier: NCT00961441
• Other Study ID Numbers: N01340; 2014-004376-39 ( EudraCT Number )
• First Submitted: August 17, 2009
• First Posted: August 19, 2009
• Results First Submitted: March 15, 2011
• Results First Posted: May 25, 2011
• Last Update Posted: August 6, 2015