A Pharmacokinetic Evaluation of Two Nicotine Patches in Smokers

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01702519
• Collaborator: (none)
• Enrollment: 40
• Location: 1
• Arms: 2

Study Details

Study Description

Brief Summary

Bioequivalence study to confirm that a NTS with a polyisobutylene (PIB) adhesive from an alternative supplier delivers the same nicotine blood profile as that of the currently approved NTS with a polyisobutylene adhesive from the current supplier.

Condition or Disease	Intervention/Treatment	Phase
Smoking	Drug: nicotine	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Single (Outcomes Assessor)
• Official Title: A Pharmacokinetic Evaluation of Two Nicotine Patches in Smokers
• Study Start Date: Mar 1, 2012
• Actual Primary Completion Date: Mar 1, 2012
• Actual Study Completion Date: Mar 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Reference nicotine transdermal patch with the existing polyisobutylene adhesive	Drug: nicotine; nicotine transdermal patch
Active Comparator: Treatement nicotine transdermal patch with the alternate polyisobutylene adhesive	Drug: nicotine; nicotine transdermal patch

Outcome Measures

Primary Outcome Measures

1. Area Under the Curve From Time 0 to the Last Quantifiable Sample, AUC(0-t) [Baseline to 32 hours]

   Following randomization, the nicotine patches; reference nicotine patch or test nicotine patch (as per the assigned sequence), were applied on participant's upper back or arm. Area under the plasma concentration time curve from zero and extrapolated to the time of last quantifiable sample was determined by plasma concentration time profile of nicotine. Blood samples were drawn at the following time intervals: immediately pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 20, 24, 25, 26, 28, and 32 hours after the application of the patch. Patch was then removed after the collection of 24 hour blood sample. AUC(0 -t) was based on the baseline adjusted nicotine plasma concentration data.

2. Maximum Measured Plasma Concentration (Cmax) [Baseline to 32 hours]

   Following randomization, the nicotine patches; reference nicotine patch or test nicotine patch (as per the assigned sequence), were applied on participant's upper back or arm. Maximum plasma nicotine concentration was determined from plasma concentration time profiles. Blood samples were drawn at various time points: immediately pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 20, 24, 25, 26, 28, and 32 hours after application the patch. Patch was then removed after the collection of 24 hour blood sample. Cmax was based on the baseline adjusted nicotine plasma concentration data.

Secondary Outcome Measures

1. Area Under the Concentration Time Curve Between Zero and Infinity, AUC (0-inf) [Baseline to 32 hours]

   Following randomization, the nicotine patches; reference nicotine patch or test nicotine patch (as per the assigned sequence), were applied on participant's upper back or arm. Area under the plasma nicotine concentration time curve from zero extrapolated to infinity was determined by plasma concentration time profile of nicotine. Blood samples drawn at various time points including: immediately pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 20, 24, 25, 26, 28, and 32 hours after wearing the patch. Patch was then removed after the collection of 24 hour blood sample. AUC(0 -inf) was based on the baseline adjusted nicotine plasma concentration data.

2. Time to Maximum Plasma Concentration (Tmax) [Baseline to 32 hours]

   Following randomization, the nicotine patches; reference nicotine patch or test nicotine patch (as per the assigned sequence), were applied on participant's upper back or arm. Time to Maximum Plasma Concentration was determined from plasma concentration time profiles. Blood samples were drawn at various time points; immediately pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 20, 24, 25, 26, 28, and 32 hours after application of the patch. Patch was then removed after the collection of 24 hour blood sample. Tmax was based on the baseline adjusted nicotine plasma concentration data.

3. Plasma Half-life (t1/2) [Baseline to 32 hours]

   Following randomization, the nicotine patches; reference nicotine patch or test nicotine patch (as per the assigned sequence), were applied on participant's upper back or arm. The elimination half-life of nicotine was determined by from plasma concentration time profiles. Blood samples were drawn at several time points: immediately pre-dose, and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 20, 24, 25, 26, 28, and 32 hours after the application of the patch. Patch was then removed after the collection of 24 hour blood sample. Plasma half-life (t1/2) was based on the baseline adjusted nicotine plasma concentration data

4. Rate of Elimination (Kel) [Baseline to 32 hours]

   Following randomization, the nicotine patches; reference nicotine patch or test nicotine patch (as per the assigned sequence), were applied on participant's upper back or arm. Elimination rate constant for nicotine was determined from plasma concentration time profiles. Blood samples were drawn at several time points: immediately pre-dose, and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 20, 24, 25, 26, 28, and 32 hours the application of the patch. Patch was then removed after the collection of 24 hour blood sample. Elimination rate constant for nicotine was based on the baseline adjusted nicotine plasma concentration data.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 19 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• BMI 19-27 kg/m2

• smokes >10 cigarettes per day for preceeding 6 months

Exclusion Criteria:

• inability to stop smoking during study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Celerion NEBRASKA	Lincoln	Nebraska	United States	68502

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT01702519
• Other Study ID Numbers: RH01418
• First Posted: Oct 8, 2012
• Last Update Posted: Mar 20, 2015
• Last Verified: Feb 1, 2015

• Additional relevant MeSH terms: Nicotine

Study Results

Participant Flow

Recruitment Details	Participants were recruited at a single clinical site in the US.
Pre-assignment Detail	A total of 128 participants were screened, of which only 40 were randomized into the study. 71 participants did not meet the study eligibility criteria, 4 were lost to follow up, 6 withdrew consent while the remaining 7 were not randomized due to the other reason.

Arm/Group Title	Test Then Reference Patch	Reference Then Test Patch
Arm/Group Description	Participants first applied a test nicotine patch (21 mg) containing test adhesive for 24 hours, and then entered a washout period of 48 hours. Post-washout, they applied reference nicotine patch containing Reference adhesive (21 mg) for additional 24 hours.	Participants first applied the Reference nicotine patch (21 mg) containing test adhesive for 24 hours, and then entered a washout period of 48 hours. Post-washout, they applied the Test nicotine patch containing reference adhesive (21 mg) for additional 24 hours.
Period Title: Period 1
STARTED	20	20
COMPLETED	20	20
NOT COMPLETED	0	0
Period Title: Period 1
STARTED	20	20
COMPLETED	19	18
NOT COMPLETED	1	2
Period Title: Period 1
STARTED	19	18
COMPLETED	19	18
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Test Then Reference Patch	Reference Then Test Patch	Total
Arm/Group Description	Participants first applied a test nicotine patch (21 mg) containing test adhesive for 24 hours, and then entered a washout period of 48 hours. Post-washout, they applied reference nicotine patch containing Reference adhesive (21 mg) for additional 24 hours.	Participants first applied the Reference nicotine patch (21 mg) containing test adhesive for 24 hours, and then entered a washout period of 48 hours. Post-washout, they applied the Test nicotine patch containing reference adhesive (21 mg) for additional 24 hours.	Total of all reporting groups
Overall Participants	20	20	40
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	36.3 (11.33)	31.4 (11.59)	33.8 (11.58)
Sex: Female, Male (Count of Participants)
Female	6 30%	6 30%	12 30%
Male	14 70%	14 70%	28 70%

Outcome Measures

1. Primary Outcome

Title	Area Under the Curve From Time 0 to the Last Quantifiable Sample, AUC(0-t)
Description	Following randomization, the nicotine patches; reference nicotine patch or test nicotine patch (as per the assigned sequence), were applied on participant's upper back or arm. Area under the plasma concentration time curve from zero and extrapolated to the time of last quantifiable sample was determined by plasma concentration time profile of nicotine. Blood samples were drawn at the following time intervals: immediately pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 20, 24, 25, 26, 28, and 32 hours after the application of the patch. Patch was then removed after the collection of 24 hour blood sample. AUC(0 -t) was based on the baseline adjusted nicotine plasma concentration data.
Time Frame	Baseline to 32 hours

Outcome Measure Data

Analysis Population Description

Per Protocol Population, which consisted of all randomized participants who took at least one dose of the study treatment, did not have any protocol deviation, and provided enough pharmacokinetic data as determined by the pharmacokineticist.

Arm/Group Title	Test Patch	Reference Patch
Arm/Group Description	Participants were instructed to wear transdermal nicotine patch (21 mg) with test adhesive, for 24 hours.	Participants were instructed to wear transdermal nicotine patch (21 mg) with the reference adhesive, for 24 hours.
Measure Participants	38	38
Mean (Standard Deviation) [nanogram (ng)*hour (hr)/milliliter (mL)]	494.54 (115.075)	528.43 (129.762)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Test Patch, Reference Patch
	Comments	Null hypothesis considered no difference between the two treatments.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Bio-equivalence was established if 90% confidence interval (CI) of the ratio (Test/Ref) of geometric means was included in the limit of 0.80 - 1.25
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment Ratio
	Estimated Value	0.946
	Confidence Interval	(2-Sided) 90%; 0.912 to 0.982
	Parameter Dispersion	Type: Value:
	Estimation Comments	The ratio between the geometric means of the test and reference formulations was calculated

2. Primary Outcome

Title	Maximum Measured Plasma Concentration (Cmax)
Description	Following randomization, the nicotine patches; reference nicotine patch or test nicotine patch (as per the assigned sequence), were applied on participant's upper back or arm. Maximum plasma nicotine concentration was determined from plasma concentration time profiles. Blood samples were drawn at various time points: immediately pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 20, 24, 25, 26, 28, and 32 hours after application the patch. Patch was then removed after the collection of 24 hour blood sample. Cmax was based on the baseline adjusted nicotine plasma concentration data.
Time Frame	Baseline to 32 hours

Outcome Measure Data

Analysis Population Description

Per Protocol Population, which consisted of all randomized participants who took at least one dose of the study treatment, did not have any protocol deviation, and provided enough pharmacokinetic data as determined by the pharmacokineticist.

Arm/Group Title	Test Patch	Reference Patch
Arm/Group Description	Participants were instructed to wear transdermal nicotine patch (21 mg) with test adhesive, for 24 hours.	Participants were instructed to wear transdermal nicotine patch (21 mg) with the reference adhesive, for 24 hours.
Measure Participants	38	38
Mean (Standard Deviation) [ng/mL]	22.31 (4.986)	23.50 (5.917)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Test Patch, Reference Patch
	Comments	Null hypothesis considered no difference between the treatments.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Bioequivalence was established if 90% confidence interval (CI) of the ratio (Test/Ref) of geometric means was included in the limit of 0.80 - 1.25.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment Ratio
	Estimated Value	0.962
	Confidence Interval	(2-Sided) 90%; 0.92 to 1.00
	Parameter Dispersion	Type: Value:
	Estimation Comments	The ratio between the geometric means of the test and reference formulations was calculated

3. Secondary Outcome

Title	Area Under the Concentration Time Curve Between Zero and Infinity, AUC (0-inf)
Description	Following randomization, the nicotine patches; reference nicotine patch or test nicotine patch (as per the assigned sequence), were applied on participant's upper back or arm. Area under the plasma nicotine concentration time curve from zero extrapolated to infinity was determined by plasma concentration time profile of nicotine. Blood samples drawn at various time points including: immediately pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 20, 24, 25, 26, 28, and 32 hours after wearing the patch. Patch was then removed after the collection of 24 hour blood sample. AUC(0 -inf) was based on the baseline adjusted nicotine plasma concentration data.
Time Frame	Baseline to 32 hours

Outcome Measure Data

Analysis Population Description

Per Protocol Population, which consisted of all randomized participants who took at least one dose of the study treatment, did not have any protocol deviation, and provided enough pharmacokinetic data as determined by the pharmacokineticist.

Arm/Group Title	Test Patch	Reference Patch
Arm/Group Description	Participants were instructed to wear transdermal nicotine patch (21 mg) with test adhesive, for 24 hours	Participants were instructed to wear transdermal nicotine patch (21 mg) with reference adhesive, for 24 hours
Measure Participants	38	38
Mean (Standard Deviation) [ng*h/mL]	505.13 (118.939)	541.15 (134.854)

4. Secondary Outcome

Title	Time to Maximum Plasma Concentration (Tmax)
Description	Following randomization, the nicotine patches; reference nicotine patch or test nicotine patch (as per the assigned sequence), were applied on participant's upper back or arm. Time to Maximum Plasma Concentration was determined from plasma concentration time profiles. Blood samples were drawn at various time points; immediately pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 20, 24, 25, 26, 28, and 32 hours after application of the patch. Patch was then removed after the collection of 24 hour blood sample. Tmax was based on the baseline adjusted nicotine plasma concentration data.
Time Frame	Baseline to 32 hours

Outcome Measure Data

Analysis Population Description

Per protocol population, which included all randomized participants who took at least one dose of the drug, did not have any protocol deviations and whose data was considered evaluable by the pharmacokineticist.

Arm/Group Title	Test Patch	Reference Patch
Arm/Group Description	Participants were instructed to wear transdermal nicotine patch with test adhesive, for 24 hours.	Participants were instructed to wear transdermal nicotine patch with reference adhesive, for 24 hours.
Measure Participants	38	38
Median (Full Range) [hrs]	10.00	17.99

5. Secondary Outcome

Title	Plasma Half-life (t1/2)
Description	Following randomization, the nicotine patches; reference nicotine patch or test nicotine patch (as per the assigned sequence), were applied on participant's upper back or arm. The elimination half-life of nicotine was determined by from plasma concentration time profiles. Blood samples were drawn at several time points: immediately pre-dose, and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 20, 24, 25, 26, 28, and 32 hours after the application of the patch. Patch was then removed after the collection of 24 hour blood sample. Plasma half-life (t1/2) was based on the baseline adjusted nicotine plasma concentration data
Time Frame	Baseline to 32 hours

Outcome Measure Data

Analysis Population Description

Per-prorocol population, which included all randomized participants who received at least one dose of the study treatment, had no protocol violation, and whose data was considered evaluable by the pharmacokineticist.

Arm/Group Title	Test Patch	Reference Patch
Arm/Group Description	Participants were instructed to wear transdermal nicotine patch with test adhesive, for 24 hours.	Participants were instructed to wear transdermal nicotine patch with reference adhesive, for 24 hours.
Measure Participants	38	38
Median (Full Range) [Hrs]	2.55	2.59

6. Secondary Outcome

Title	Rate of Elimination (Kel)
Description	Following randomization, the nicotine patches; reference nicotine patch or test nicotine patch (as per the assigned sequence), were applied on participant's upper back or arm. Elimination rate constant for nicotine was determined from plasma concentration time profiles. Blood samples were drawn at several time points: immediately pre-dose, and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 20, 24, 25, 26, 28, and 32 hours the application of the patch. Patch was then removed after the collection of 24 hour blood sample. Elimination rate constant for nicotine was based on the baseline adjusted nicotine plasma concentration data.
Time Frame	Baseline to 32 hours

Outcome Measure Data

Analysis Population Description

Per protocol population, which included all randomized participants who took at least one dose of the study medications, had no protocol violations, and whose data was considered evaluable by the pharmacokineticist.

Arm/Group Title	Test Patch	Reference Patch
Arm/Group Description	Participants were instructed to wear transdermal nicotine patch with test adhesive, for 24 hours.	Participants were instructed to wear transdermal nicotine patch with reference adhesive, for 24 hours.
Measure Participants	38	38
Median (Full Range) [1/hr]	0.27	0.27

Adverse Events

Time Frame	AEs were collected from the start of the smoking abstinence sequestration period and until five days following last administration of the study treatments
Arm/Group Title	Test Patch		Reference Patch
Arm/Group Description	Participants were instructed to wear transdermal nicotine patch with test adhesive, for 24 hours.		Participants were instructed to wear transdermal nicotine patch with reference adhesive, for 24 hours
All Cause Mortality
	Test Patch		Reference Patch
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Test Patch		Reference Patch
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/38 (0%)		0/39 (0%)
Other (Not Including Serious) Adverse Events
	Test Patch		Reference Patch
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/38 (57.9%)		26/39 (66.7%)
General disorders
Application Site Erythema	15/38 (39.5%)	15	20/39 (51.3%)	20
Application Site Pruritus	5/38 (13.2%)	5	7/39 (17.9%)	7
Nervous system disorders
Headache	2/38 (5.3%)	2	4/39 (10.3%)	4
Psychiatric disorders
Abnormal Dreams	0/38 (0%)	0	4/39 (10.3%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.