A Bioavailability Crossover Study of Two Formulations of Lamotrigine Extended Release Tablets in Healthy Subjects

• Sponsor: Food and Drug Administration (FDA) (U.S. Fed)
• Overall Status: Completed
• CT.gov ID: NCT02821338
• Collaborator: Vince & Associates Clinical Research, Inc. (Other), Algorithme Pharma Inc (Industry)
• Enrollment: 30
• Location: 1
• Arms: 2
• Actual Duration (Months): 10
• Patients Per Site Per Month: 3

Study Details

Study Description

Brief Summary

The objective of this study is to determine bioequivalence between two different formulations of lamotrigine extended release tablets (one reference product and one generic product) in a healthy adult population, following a single oral dose under fed conditions.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Lamotrigine Extended Release	Phase 1

Detailed Description

This is a single center, randomized, open-label, single dose, two treatment, four-period, two-sequence, fully replicated crossover design in the fed state.

The study will include two treatments:

• Treatment-A: One dose of Lamotrigine extended-release tablet (Test) administered in the morning after a 10-hour overnight fast and 30 minutes after the start of a high-fat, high-calorie breakfast.

• Treatment-B: One dose of Lamictal XR extended-release tablet (Reference) administered in the morning after a 10 hour overnight fast and 30 minutes after the start of a high-fat, high-calorie breakfast.

A total of 30 healthy subjects will be dosed to ensure that at least 24 subjects will complete the 4-period replicate design. For each treatment period, subjects will be confined from the day prior to dosing until approximately 48 hours post-dose. Subjects will return to the clinical site for the remaining blood samples. There will be a minimum 14-day washout between doses.

Subject participation from the Screening Visit to the Follow-Up Visit will be approximately 71 days.

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: A Randomized, 2-Sequence, 2-Treatment, 4-Period, Open-Label, Single Dose, Fully Replicated Comparative Bioavailability Crossover Study of Two Formulations of Lamotrigine Extended Release Tablets in Healthy Subjects Under Fed Conditions
• Actual Study Start Date: Jun 1, 2016
• Actual Primary Completion Date: Sep 1, 2016
• Actual Study Completion Date: Apr 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Sequence 1 The treatments will be administered according to a randomly assigned pre-generated sequence involving the randomized, four-period, two sequence, fully replicate crossover design. Two study drugs involved are: Lamotrigine Extended Release (generic) and Lamictal XR (brand).	Drug: Lamotrigine Extended Release; Lamotrigine Extended Release (generic) and Lamictal XR (brand).; Other Names: Lamictal XR
Active Comparator: Sequence 2 The treatments will be administered according to a randomly assigned pre-generated sequence involving the four-period, two sequence, fully replicate crossover design. Two study drugs involved are: Lamotrigine Extended Release (generic) and Lamictal XR (brand).	Drug: Lamotrigine Extended Release; Lamotrigine Extended Release (generic) and Lamictal XR (brand).; Other Names: Lamictal XR

Outcome Measures

Primary Outcome Measures

1. Area Under the Lamotrigine Concentration vs. Time Curve From Sample Time Point 0 Hour to Sample Time Point 144 Hour. [144 hours]

   Pre-dose, and post-dose 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 27, 30, 33, 36, 48, 72, 96, 120, 144 hours Lamotrigine and Lamictal have the same active ingredient "Lamotrigine."

2. AUC 0-Inf [144 hours]

   Area Under the Lamotrigine Concentrations vs. time curve from sample time point 0 hour to sample time point 144hours plus extrapolation to infinity of the terminal concentration slope. This describes the total exposure to Lamotrigine. Sampling times include: Pre-dose, and post-dose 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 27, 30, 33, 36, 48, 72, 96, 120, 144 hours. Lamotrigine and Lamictal have the same active ingredient.

3. Cmax [2 to 144 hours]

   The maximum concentration of the Lamotrigine achieved in specified time frame for each treatment. Sampling times include: post-dose 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 27, 30, 33, 36, 48, 72, 96, 120, 144 hours. Lamotrigine and Lamictal have the same active ingredient.

Other Outcome Measures

1. Tmax [2 to 144 hours]

   Time from 0 concentration sample point to the Cmax sample point. Sampling times include: post-dose 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 27, 30, 33, 36, 48, 72, 96, 120, 144 hours.

2. λZ [2 to 144 hours]

   Apparent elimination rate constant, estimated by linear regression of the terminal linear portion of the log concentration versus time curve. Sampling times include: post-dose 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 27, 30, 33, 36, 48, 72, 96, 120, 144 hours.

3. Thalf [2 to 144 hours]

   It is the terminal elimination half-life, calculated as ln(2)/λZ. Sampling times include: post-dose 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 27, 30, 33, 36, 48, 72, 96, 120, 144 hours.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. Healthy male or female subjects ≥18 to ≤50 years of age

2. Subject is willing and able to provide informed consent

3. Body mass index (BMI) greater than or equal to 18.00 kg/m2 and below 30.00 kg/m2 at screening

4. Body weight greater than or equal to 50 kg at screening

5. Subject is a non-smoker and has not used any nicotine containing products within 6 months prior to screening

6. Subjects who are considered generally healthy upon completion of medical history, physical examination, vital signs, screening laboratory results and screening ECG in the opinion of the Investigator

7. Subjects who are willing and able to comply with the visit schedule, laboratory tests, pharmacokinetic sampling schedule and other study procedures

8. Subjects who are willing and able to maintain their eligibility throughout the study.

9. A female study subject must meet one of the following criteria:

• If of childbearing potential - agrees to use one of the accepted contraceptive regimens from at least 30 days prior to the first administration of the study medication, during the study, and for at least 30 days after the last dose of the study medication. An acceptable method of contraception includes one of the following:

• Abstinence from heterosexual intercourse

• Progestogen-containing hormonal contraceptives (birth control pills, injectable/implant/insertable hormonal birth control products, transdermal patch)

• Intrauterine device (without hormones)

• Condom with spermicide

• If a female of non-childbearing potential - should be surgically sterile (i.e. has undergone complete hysterectomy, bilateral oophorectomy, or tubal ligation) or in a menopausal state (at least 1 year without menses), as confirmed by FSH levels (post menopausal must be confirmed by the subject having a serum follicle stimulating hormone greater than 40mIU/ml at screening). Females of non-childbearing potential must present a proof of partial or total hysterectomy; if such proof is not available, the female will be considered to be of childbearing potential.

1. A male study subject must agree to use one of the accepted contraceptive regimens during the study and for at least 90 days after the last dose of the study medication;

• Abstinence from heterosexual intercourse

• Female partner with hormonal contraceptives (birth control pills, injectable/implant/insertable hormonal birth control products, transdermal patch)

• Female partner with intrauterine device (with or without hormones)

• Female partner with condom with spermicide used by male study subject

• Female partner of non-childbearing potential

• Male sterilization with absence of sperm in the post vasectomy ejaculate

1. A male study subject must agree not to donate sperm during the study and for at least 90 days after the last dose of the study medication

Exclusion Criteria:

1. Females who are pregnant or are breastfeeding

2. Females who are using any estrogen-containing hormonal contraceptives

3. History of known clinically significant drug allergies or reactions to lamotrigine, or any related products (including excipients of the formulations) as well as severe hypersensitivity reactions (like angioedema) to any drugs in the opinion of the Investigator

4. Clinically significant history or evidence of gastrointestinal, hepatic, renal, endocrine, pulmonary, neurological, psychiatric, cardiovascular, hematologic, dermatologic, immunologic disease or any other condition known to interfere with the absorption, distribution, metabolism or distribution of drugs that in the opinion of the Investigator would jeopardize the safety of the subject or impact validity of study results

5. Presence of observed abnormality (evidenced from physical examination, ECG, vital signs, or laboratory evaluation) that would be clinically significant in the opinion of the Investigator

6. History of regular alcohol consumption exceeding 7 drinks per week for females and 14 drinks per week for males within 6 months of screening

7. Has current or recent history (within the past year) of alcohol or drug abuse or dependence

8. Any clinically significant illness in the previous 30 days prior to screening

9. Use of any enzyme-modifying drugs, including strong inhibitors of CYP enzymes (such as cimetidine, fluoxetine, quinidine, erythromycin, ciprofloxacin, fluconazole, ketoconazole, diltiazem, and HIV antivirals) and strong inducers of CYP enzymes (such as barbiturates, carbamazepine, glucocorticoids, phenytoin, rifampin, St John's Wort) in the previous 30 days prior to screening

10. Known presence of rare hereditary problems of galactose and /or lactose intolerance or glucose-galactose malabsorption

11. Unusual dietary habits (e.g., vegan, Atkins), dietary restrictions, and/or food allergies.

12. Any planned surgery from the screening visit until the end of the study

13. Positive urine screen for alcohol, cotinine and/or drugs of abuse at screening and at each admission of each treatment period

14. Positive test results for HIV-1/HIV-2 Antibodies, Hepatitis B surface Antigen (HBsAg) or Hepatitis C Antibody (HCVAb)

15. Albumin values less than 4 g/dL at screening

16. Triglyceride values greater than 200 mg/dL at screening

17. Treatment with any investigational drug 30 days prior to screening

18. Participation in other clinical studies within 30 days prior to screening

19. Blood donation (excluding plasma donation) of approximately 500 mL within 56 days prior to screening

20. Subject is unlikely to comply with the study protocol or, in the opinion of the Investigator, would not be a suitable candidate for participation in the trial

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Vince and Associates Clinical Research, Inc	Overland Park	Kansas	United States	66212

Sponsors and Collaborators

• Food and Drug Administration (FDA)
• Vince & Associates Clinical Research, Inc.
• Algorithme Pharma Inc

Investigators

• Principal Investigator: Bradley Vince, D.O., Vince and Associates Clinical Research

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Clinical site

Publications

None provided.

• Responsible Party: Food and Drug Administration (FDA)
• ClinicalTrials.gov Identifier: NCT02821338
• Other Study ID Numbers: 15-099D
• First Posted: Jul 1, 2016
• Last Update Posted: May 1, 2020
• Last Verified: Apr 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Keywords provided by Food and Drug Administration (FDA): Bioequivalence; Lamotrigine Extended Release; Generic; Pharmacokinetic
• Additional relevant MeSH terms: Lamotrigine

Study Results

Participant Flow

Arm/Group Title	Sequence 1 (Test-Ref-Test-Ref)	Sequence 2 (Ref-Test-Ref-Test)
Arm/Group Description	Sequence 1 - ABAB. The study was a single center, randomized, open-label, single dose, 2-treatment, 4-period, 2-sequence, fully replicated, crossover design in healthy male and female subjects. All completed subjects received two rounds of Lamictal and Lamotrigine. The following investigational products were administered in the fed state: Treatment A: A single 1-tablet dose of Lamotrigine 200 mg extended-release tablet (Test) Treatment B: A single 1-tablet dose of Lamictal XR 200 mg extended-release tablet (Reference)	Sequence 2 - BABA. The study was a single center, randomized, open-label, single dose, 2-treatment, 4-period, 2-sequence, fully replicated, crossover design in healthy male and female subjects. All completed subjects received two rounds of Lamictal and Lamotrigine. The following investigational products were administered in the fed state: Treatment A: A single 1-tablet dose of Lamotrigine 200 mg extended-release tablet (Test) Treatment B: A single 1-tablet dose of Lamictal XR 200 mg extended-release tablet (Reference)
Period Title: Overall Study
STARTED	15	15
COMPLETED	12	13
NOT COMPLETED	3	2

Baseline Characteristics

Arm/Group Title	All Participants
Arm/Group Description	30 participants Completed subjects received two rounds of Lamictal and Lamotrigine.
Overall Participants	30
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	32
Sex: Female, Male (Count of Participants)
Female	11 36.7%
Male	19 63.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 3.3%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	15 50%
White	14 46.7%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	30 100%
BMI (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	26.05 (2.54)

Outcome Measures

1. Primary Outcome

Title	Area Under the Lamotrigine Concentration vs. Time Curve From Sample Time Point 0 Hour to Sample Time Point 144 Hour.
Description	Pre-dose, and post-dose 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 27, 30, 33, 36, 48, 72, 96, 120, 144 hours Lamotrigine and Lamictal have the same active ingredient "Lamotrigine."
Time Frame	144 hours

Outcome Measure Data

Analysis Population Description

Fully replicated crossover study (all completed subjects received two rounds of Lamictal and Lamotrigine). Completed participants contributed two data points for each treatment, however, some subjects provided one or partial data point.

Arm/Group Title	Generic Lamotrigine Extended Release Tablet	Brand Lamictal XR Tablet
Arm/Group Description	Lamotrigine Extended Release (generic)	Lamictal XR (brand)
Measure Participants	24	24
Measure data points	44	45
Mean (Standard Deviation) [h*ng/mL]	119966.6 (32391.0)	121969.5 (33663.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Generic Lamotrigine Extended Release Tablet, Brand Lamictal XR Tablet
	Comments	90% confidence interval of the geometric mean ratio of test/reference
	Type of Statistical Test	Equivalence
	Comments	90% confidence interval falls within 80.00-125.00%
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Test/Reference ratio
	Estimated Value	0.9863
	Confidence Interval	(2-Sided) 90%; 0.9598 to 1.0134
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	AUC 0-Inf
Description	Area Under the Lamotrigine Concentrations vs. time curve from sample time point 0 hour to sample time point 144hours plus extrapolation to infinity of the terminal concentration slope. This describes the total exposure to Lamotrigine. Sampling times include: Pre-dose, and post-dose 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 27, 30, 33, 36, 48, 72, 96, 120, 144 hours. Lamotrigine and Lamictal have the same active ingredient.
Time Frame	144 hours

Outcome Measure Data

Analysis Population Description

Fully replicated crossover design (all completed subjects received two rounds of Lamictal and Lamotrigine). Completed participants contributed two data points for each treatment, however, some subjects provided one or partial data point.

Arm/Group Title	Generic Lamotrigine Extended Release Tablet	Brand Lamictal XR Tablet
Arm/Group Description	Lamotrigine Extended Release (generic)	Lamictal XR (brand)
Measure Participants	24	24
Measure data points	43	44
Mean (Standard Deviation) [h*ng/mL]	128824.9 (39291.6)	134410.3 (47446.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Generic Lamotrigine Extended Release Tablet, Brand Lamictal XR Tablet
	Comments
	Type of Statistical Test	Equivalence
	Comments	90% confidence interval falls within 80.00-125.00%
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Test/Reference Ratio
	Estimated Value	0.9785
	Confidence Interval	(2-Sided) 90%; 0.9484 to 1.0095
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Cmax
Description	The maximum concentration of the Lamotrigine achieved in specified time frame for each treatment. Sampling times include: post-dose 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 27, 30, 33, 36, 48, 72, 96, 120, 144 hours. Lamotrigine and Lamictal have the same active ingredient.
Time Frame	2 to 144 hours

Outcome Measure Data

Analysis Population Description

Fully replicated crossover design (all completed subjects received two rounds of Lamictal and Lamotrigine). Completed participants contributed two data points for each treatment, however, some subjects provided one or partial data point.

Arm/Group Title	Generic Lamotrigine Extended Release Tablet	Brand Lamictal XR Tablet
Arm/Group Description	Lamotrigine Extended Release (generic)	Lamictal XR (brand)
Measure Participants	24	24
Measure Data points	45	46
Mean (Standard Deviation) [ng/mL]	2338.9 (353.2)	2244.6 (341.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Generic Lamotrigine Extended Release Tablet, Brand Lamictal XR Tablet
	Comments
	Type of Statistical Test	Equivalence
	Comments	90% confidence interval falls within 80.00-125.00%
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Test/Reference Ratio
	Estimated Value	1.0470
	Confidence Interval	(2-Sided) 90%; 1.0079 to 1.0877
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Other Pre-specified Outcome

Title	Tmax
Description	Time from 0 concentration sample point to the Cmax sample point. Sampling times include: post-dose 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 27, 30, 33, 36, 48, 72, 96, 120, 144 hours.
Time Frame	2 to 144 hours

Outcome Measure Data

Analysis Population Description

Fully replicate crossover design (all completed subjects received two rounds of Lamictal and Lamotrigine). Completed participants contributed two data points for each treatment, however, some subjects provided one or partial data point.

Arm/Group Title	Generic Lamotrigine Extended Release Tablet	Brand Lamictal XR Tablet
Arm/Group Description	Lamotrigine Extended Release (generic)	Lamictal XR (brand)
Measure Participants	24	24
Measure data points	45	46
Median (Full Range) [hours]	10	22

5. Other Pre-specified Outcome

Title	λZ
Description	Apparent elimination rate constant, estimated by linear regression of the terminal linear portion of the log concentration versus time curve. Sampling times include: post-dose 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 27, 30, 33, 36, 48, 72, 96, 120, 144 hours.
Time Frame	2 to 144 hours

Outcome Measure Data

Analysis Population Description

Fully replicated crossover design (all completed subjects received two rounds of Lamictal and Lamotrigine). Completed participants contributed two data points for each treatment, however, some subjects provided one or partial data point.

Arm/Group Title	Generic Lamotrigine Extended Release Tablet	Brand Lamictal XR Tablet
Arm/Group Description	Lamotrigine Extended Release (generic)	Lamictal XR (brand)
Measure Participants	24	24
Measure data points	43	44
Mean (Standard Deviation) [per hour]	0.0218 (0.0067)	0.0221 (0.0067)

6. Other Pre-specified Outcome

Title	Thalf
Description	It is the terminal elimination half-life, calculated as ln(2)/λZ. Sampling times include: post-dose 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 27, 30, 33, 36, 48, 72, 96, 120, 144 hours.
Time Frame	2 to 144 hours

Outcome Measure Data

Analysis Population Description

Fully replicated crossover design (all completed subjects received two rounds of Lamictal and Lamotrigine). Completed participants contributed two data points for each treatment, however, some subjects provided one or partial data point.

Arm/Group Title	Generic Lamotrigine Extended Release Tablet	Brand Lamictal XR Tablet
Arm/Group Description	Lamotrigine Extended Release (generic)	Lamictal XR (brand)
Measure Participants	24	24
Measure data points	43	44
Mean (Standard Deviation) [hours]	34.77 (10.57)	34.56 (11.34)

Adverse Events

Arm/Group Title	Generic Lamotrigine Extended Release Tablet		Brand Lamictal XR Tablet
Arm/Group Description	Lamotrigine Extended Release (generic)		Lamictal XR (brand)
All Cause Mortality
	Generic Lamotrigine Extended Release Tablet		Brand Lamictal XR Tablet
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/30 (0%)		0/30 (0%)
Serious Adverse Events
	Generic Lamotrigine Extended Release Tablet		Brand Lamictal XR Tablet
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/30 (0%)		0/30 (0%)
Other (Not Including Serious) Adverse Events
	Generic Lamotrigine Extended Release Tablet		Brand Lamictal XR Tablet
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/30 (30%)		11/30 (36.7%)
Cardiac disorders
Tachycardia	2/30 (6.7%)	2	1/30 (3.3%)	1
Bradycardia	0/30 (0%)	0	1/30 (3.3%)	1
Gastrointestinal disorders
Diarrhoea	1/30 (3.3%)	1	2/30 (6.7%)	2
Nausea	1/30 (3.3%)	1	0/30 (0%)	0
General disorders
Vessel Puncture Site Pain	0/30 (0%)	0	1/30 (3.3%)	1
Infections and infestations
Gastroenteritis	0/30 (0%)	0	1/30 (3.3%)	1
Upper Respiratory Tract Infection	0/30 (0%)	0	1/30 (3.3%)	1
Injury, poisoning and procedural complications
Laceration	0/30 (0%)	0	1/30 (3.3%)	1
Skin Abrasion	1/30 (3.3%)	1	0/30 (0%)	0
Investigations
Blood Pressure Systolic Increased	2/30 (6.7%)	2	1/30 (3.3%)	1
Drug Screen Positive	2/30 (6.7%)	2	1/30 (3.3%)	1
Heart Rate Increased	1/30 (3.3%)	1	1/30 (3.3%)	1
Liver Function Test Increased	0/30 (0%)	0	1/30 (3.3%)	1
Musculoskeletal and connective tissue disorders
Musculoskeletal Pain	1/30 (3.3%)	1	1/30 (3.3%)	1
Nervous system disorders
Headache	2/30 (6.7%)	3	0/30 (0%)	0
Paraesthesia	1/30 (3.3%)	1	1/30 (3.3%)	1
Respiratory, thoracic and mediastinal disorders
Nasal Congestion	1/30 (3.3%)	1	1/30 (3.3%)	1
Skin and subcutaneous tissue disorders
Acne	1/30 (3.3%)	1	0/30 (0%)	0
Ecchymosis	0/30 (0%)	0	1/30 (3.3%)	1
Rash	0/30 (0%)	0	1/30 (3.3%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.