Buprenorphine 8 mg Sublingual Tablets Under Fasting Conditions

• Sponsor: Teva Pharmaceuticals USA (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01157169
• Collaborator: (none)
• Enrollment: 40
• Location: 1
• Arms: 2
• Duration (Months): 1
• Patients Per Site Per Month: 39.3

Study Details

Study Description

Brief Summary

The object of this study is to compare the rate and extent of absorption of an investigational formulation of buprenorphine 8 mg sublingual tablets manufactured by Barr Laboratories, Inc. to an equivalent oral dose of the commercially available reference product, Subutex® manufactured by Reckitt Benckiser, following and overnight fast of at least 10 hours.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Buprenorphine; Drug: Buprenorphine	Phase 1

Detailed Description

Criteria for Evaluation: FDA Bioequivalence Criteria

Statistical Methods: FDA Bioequivalence Statistical Methods

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: A Single-Dose, 2-Period, 2-Treatment, 2-Way Crossover Bioequivalence Study of Buprenorphine 8 mg Sublingual Tablets Under Fasting Conditions.
• Study Start Date: Aug 1, 2007
• Actual Primary Completion Date: Sep 1, 2007
• Actual Study Completion Date: Sep 1, 2007

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Investigational Test Product Buprenorphine 8 mg Sublingual Tablets	Drug: Buprenorphine; 8 mg Sublingual Tablets
Active Comparator: Reference Listed Drug Subutex® 8 mg Sublingual Tablets	Drug: Buprenorphine; 8 mg Sublingual Tablets; Other Names: Subutex®

Outcome Measures

Primary Outcome Measures

1. Cmax of Buprenorphine. [Blood samples collected over a 144 hour period.]

   Bioequivalence based on Buprenorphine Cmax (maximum observed concentration of drug substance in plasma).

2. AUC0-t for Buprenorphine. [Blood samples collected over a 144 hour period.]

   Bioequivalence based on Buprenorphine AUC0-t (area under the concentration-time curve from time zero to time of last measurable concentration).

3. AUC0-inf for Buprenorphine. [Blood samples collected over a 144 hour period.]

   Bioequivalence based on Buprenorphine AUC0-inf (area under the concentration-time curve from time zero to infinity).

Secondary Outcome Measures

1. Cmax for Norbuprenorphine. [Blood samples collected over a 144 hour period.]

   Informational comparison of Cmax (maximum observed concentration of drug substance in plasma) values for the metabolite Norbuprenorphine.

2. AUC0-t for Norbuprenorphine. [Blood samples collected over a 144 hour period.]

   Informational comparison of AUC0-t (area under the concentration-time curve from time zero to time of last measurable concentration) values for the metabolite Norbuprenorphine.

3. AUC0-inf for Norbuprenorphine. [Blood samples collected over a 144 hour period.]

   Informational comparison of AUC0-inf (area under the concentration-time curve from time zero to infinity) values for the metabolite Norbuprenorphine.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Subject must be a male or non-pregnant, non-breastfeeding female.

• Subject must be between 18 and 45 years of age (inclusive).

• Subject's Body Mass Index (BMI) must be between 18 and 30 (inclusive), and subject must weigh a minimum of 50 kg (110 lbs).

• Female subjects must agree to utilize one of the following forms of contraception from screening through 4 weeks after completion of the study. Approved forms of contraception are abstinence, double barrier, IUD in place at least 30 days prior to study drug administration, vasectomized partner, surgically sterile for at least 6 months, or at least 2 years postmenopausal.

• Subject must voluntarily consent to participate in this study and provide their written informed consent prior to completion of any study-specific procedures.

• Subject is willing and able to remain in the study unit for the entire duration of the confinement period and return for all scheduled outpatient visits.

Exclusion Criteria:

• History or presence of any clinically significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, oncologic, or psychiatric disease or any other condition that, in the opinion of the investigator, would jeopardize the safety of the subject or the validity of the study results.

• History or presence of pancreatitis, bowel obstruction, glaucoma, enlargement of the prostate, adrenal disease, hyperthyroidism, or gallbladder disease. Subjects with a history of cholecystectomy for the treatment of gallbladder disease will be excluded.

• Females taking any oral contraceptives including estrogen and progestin combined pills, progestin-only pills, patch, or vaginal ring within 28 days prior to the first dose of study medication; using injectable contraceptives within 6 months of first dose; or who have ever had progestational hormone implants.

• Females taking hormone replacement therapy within 60 days prior to the first dose of study medication.

• Has a clinically significant abnormal finding on the physical exam, medical history, ECG, or clinical laboratory results at screening.

• History or presence of allergic or adverse response to buprenorphine, naltrexone, or any comparable or similar product.

• Has been on a significantly abnormal diet during the 4 weeks preceding the first dose of study medication.

• Has donated blood or plasma within 30 days prior to the first dose of study medication.

• Has participated in another clinical trial within 30 days prior to the first dose of study medication.

• Has used any over-the-counter (OTC) medication, including cough and cold preparations, vitamins, and herbal supplements, within 7 days prior to the first dose of study medication.

• Has used any prescription medication within 14 days prior to the first dose of study medication.

• Has consumed beverages or food containing alcohol, caffeine/xanthine, or poppy seeds from 48 hours prior to the first dose of study medication or has consumed beverages or foods containing grapefruit from 14 days prior to the first dose of study medication.

• Has been treated with any known enzyme-altering drugs, such as barbiturates, phenothiazines, cimetidine, carbamazepine, etc., within 30 days prior to the first dose of study medication.

• Has smoked or used tobacco products within 60 days prior to the first dose of study medication.

• Has a history of treatment for substance abuse (including alcohol) in the past 5 years.

• Is a female with a positive pregnancy test result.

• Has any piercing of the tongue or has a lip piercing within 30 days prior to the first dose of study medication.

• Has a positive urine screen for drugs of abuse.

• Has a positive urine alcohol test or ethanol breath test.

• Has a positive test for or has been treated for hepatitis B, hepatitis C, or HIV.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	CEDRA Clinical Research, LLC	Austin	Texas	United States	78759

Sponsors and Collaborators

• Teva Pharmaceuticals USA

Investigators

• Principal Investigator: Frederick A Bieberdorf, M.D., CPI, CEDRA Clinical Research, LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT01157169
• Other Study ID Numbers: 20-A63-AU
• First Posted: Jul 5, 2010
• Last Update Posted: Jan 18, 2020
• Last Verified: Jan 1, 2020

• Keywords provided by , ,: Bioequivalence; Healthy
• Additional relevant MeSH terms: Buprenorphine

Study Results

Participant Flow

Arm/Group Title	Buprenorphine (Test) First	Subutex® (Reference) First
Arm/Group Description	8 mg Buprenorphine Sublingual Tablets test product dosed in first period followed by 8 mg Subutex® Sublingual Tablets reference product dosed in the second period.	8 mg Subutex® Sublingual Tablets reference product dosed in first period followed by 8 mg Buprenorphine Sublingual Tablets test product dosed in the second period.
Period Title: First Intervention
STARTED	20	20
COMPLETED	16	18
NOT COMPLETED	4	2
Period Title: First Intervention
STARTED	16	18
COMPLETED	16	18
NOT COMPLETED	0	0
Period Title: First Intervention
STARTED	16	18
COMPLETED	16	17
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Buprenorphine (Test) First	Subutex® (Reference) First	Total
Arm/Group Description	8 mg Buprenorphine Sublingual Tablets test product dosed in first period followed by 8 mg Subutex® Sublingual Tablets reference product dosed in the second period.	8 mg Subutex® Sublingual Tablets reference product dosed in first period followed by 8 mg Buprenorphine Sublingual Tablets test product dosed in the second period.	Total of all reporting groups
Overall Participants	20	20	40
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	20 100%	20 100%	40 100%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	9 45%	6 30%	15 37.5%
Male	11 55%	14 70%	25 62.5%
Race/Ethnicity, Customized (participants) [Number]
Asian	1 5%	1 5%	2 5%
Black	3 15%	1 5%	4 10%
Caucasian	9 45%	12 60%	21 52.5%
Hispanic	7 35%	5 25%	12 30%
American Indian	0 0%	1 5%	1 2.5%
Region of Enrollment (participants) [Number]
United States	20 100%	20 100%	40 100%

Outcome Measures

1. Primary Outcome

Title	Cmax of Buprenorphine.
Description	Bioequivalence based on Buprenorphine Cmax (maximum observed concentration of drug substance in plasma).
Time Frame	Blood samples collected over a 144 hour period.

Outcome Measure Data

Analysis Population Description

All participants that completed the study had their samples analyzed.

Arm/Group Title	Buprenorphine (Test)	Subutex® (Reference)
Arm/Group Description	8 mg Buprenorphine Sublingual Tablets test product dosed in either period.	8 mg Subutex® Sublingual Tablets reference product dosed in either period.
Measure Participants	33	33
Mean (Standard Deviation) [ng/mL]	4.40 (2.16)	3.88 (1.82)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Buprenorphine (Test), Subutex® (Reference)
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of the T/R geometric mean x 100
	Estimated Value	110.49
	Confidence Interval	(2-Sided) 90%; 101.67 to 120.07
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence is established if the 90% confidence interval for the ln-transformed geometric mean between the reference (R) and test (T) product fall within the interval of 80-125%.

2. Primary Outcome

Title	AUC0-t for Buprenorphine.
Description	Bioequivalence based on Buprenorphine AUC0-t (area under the concentration-time curve from time zero to time of last measurable concentration).
Time Frame	Blood samples collected over a 144 hour period.

Outcome Measure Data

Analysis Population Description

All participants that completed the study had their samples analyzed.

Arm/Group Title	Buprenorphine (Test)	Subutex® (Reference)
Arm/Group Description	8 mg Buprenorphine Sublingual Tablets test product dosed in either period.	8 mg Subutex® Sublingual Tablets reference product dosed in either period.
Measure Participants	33	33
Mean (Standard Deviation) [ng*h/mL]	35.12 (12.55)	32.92 (12.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Buprenorphine (Test), Subutex® (Reference)
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of the T/R geometric mean x 100
	Estimated Value	105.91
	Confidence Interval	(2-Sided) 90%; 99.74 to 112.45
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence is established if the 90% confidence interval for the ln-transformed geometric mean between the reference (R) and test (T) product fall within the interval of 80-125%.

3. Primary Outcome

Title	AUC0-inf for Buprenorphine.
Description	Bioequivalence based on Buprenorphine AUC0-inf (area under the concentration-time curve from time zero to infinity).
Time Frame	Blood samples collected over a 144 hour period.

Outcome Measure Data

Analysis Population Description

All participants that completed the study had their samples analyzed.

Arm/Group Title	Buprenorphine (Test)	Subutex® (Reference)
Arm/Group Description	8 mg Buprenorphine Sublingual Tablets test product dosed in either period.	8 mg Subutex® Sublingual Tablets reference product dosed in either period.
Measure Participants	33	33
Mean (Standard Deviation) [ng*h/mL]	37.19 (13.39)	35.73 (13.93)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Buprenorphine (Test), Subutex® (Reference)
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of the T/R geometric mean x 100
	Estimated Value	103.97
	Confidence Interval	(2-Sided) 90%; 97.18 to 111.24
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence is established if the 90% confidence interval for the ln-transformed geometric mean between the reference (R) and test (T) product fall within the interval of 80-125%.

4. Secondary Outcome

Title	Cmax for Norbuprenorphine.
Description	Informational comparison of Cmax (maximum observed concentration of drug substance in plasma) values for the metabolite Norbuprenorphine.
Time Frame	Blood samples collected over a 144 hour period.

Outcome Measure Data

Analysis Population Description

All participants that completed the study had their samples analyzed.

Arm/Group Title	Buprenorphine (Test)	Subutex® (Reference)
Arm/Group Description	8 mg Buprenorphine Sublingual Tablets test product dosed in either period.	8 mg Subutex® Sublingual Tablets reference product dosed in either period.
Measure Participants	33	33
Mean (Standard Deviation) [ng/mL]	1.58 (0.719)	1.64 (0.643)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Buprenorphine (Test), Subutex® (Reference)
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of the T/R geometric mean x 100
	Estimated Value	93.28
	Confidence Interval	(2-Sided) 90%; 85.37 to 101.93
	Parameter Dispersion	Type: Value:
	Estimation Comments	This analysis was for informational purposes only and was not used to establish bioequivalence.

5. Secondary Outcome

Title	AUC0-t for Norbuprenorphine.
Description	Informational comparison of AUC0-t (area under the concentration-time curve from time zero to time of last measurable concentration) values for the metabolite Norbuprenorphine.
Time Frame	Blood samples collected over a 144 hour period.

Outcome Measure Data

Analysis Population Description

All participants that completed the study had their samples analyzed.

Arm/Group Title	Buprenorphine (Test)	Subutex® (Reference)
Arm/Group Description	8 mg Buprenorphine Sublingual Tablets test product dosed in either period.	8 mg Subutex® Sublingual Tablets reference product dosed in either period.
Measure Participants	33	33
Mean (Standard Deviation) [ng*h/mL]	45.34 (18.72)	47.58 (17.91)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Buprenorphine (Test), Subutex® (Reference)
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of the T/R geometric mean x 100
	Estimated Value	94.19
	Confidence Interval	(2-Sided) 90%; 87.44 to 101.46
	Parameter Dispersion	Type: Value:
	Estimation Comments	This analysis was for informational purposes only and was not used to establish bioequivalence.

6. Secondary Outcome

Title	AUC0-inf for Norbuprenorphine.
Description	Informational comparison of AUC0-inf (area under the concentration-time curve from time zero to infinity) values for the metabolite Norbuprenorphine.
Time Frame	Blood samples collected over a 144 hour period.

Outcome Measure Data

Analysis Population Description

All participants that completed the study had their samples analyzed.

Arm/Group Title	Buprenorphine (Test)	Subutex® (Reference)
Arm/Group Description	8 mg Buprenorphine Sublingual Tablets test product dosed in either period.	8 mg Subutex® Sublingual Tablets reference product dosed in either period.
Measure Participants	33	33
Mean (Standard Deviation) [ng*h/mL]	50.77 (28.99)	51.04 (22.12)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Buprenorphine (Test), Subutex® (Reference)
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of the T/R geometric mean x 100
	Estimated Value	95.06
	Confidence Interval	(2-Sided) 90%; 86.56 to 104.39
	Parameter Dispersion	Type: Value:
	Estimation Comments	This analysis was for informational purposes only and was not used to establish bioequivalence.

Adverse Events

Time Frame	Adverse event data was collected over the course of the study, which was approximately 3 weeks in duration.
Adverse Event Reporting Description	Volunteers were monitored throughout the study for any adverse experiences. AEs were collected through both solicited and unsolicited methods. The volunteers were encouraged to report signs, symptoms, and any changes in health to the clinic staff.
Arm/Group Title	Buprenorphine (Test) First		Subutex® (Reference) First
Arm/Group Description	8 mg Buprenorphine Sublingual Tablets test product dosed in first period followed by 8 mg Subutex® Sublingual Tablets reference product dosed in the second period.		8 mg Subutex® Sublingual Tablets reference product dosed in first period followed by 8 mg Buprenorphine Sublingual Tablets test product dosed in the second period.
All Cause Mortality
	Buprenorphine (Test) First		Subutex® (Reference) First
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Buprenorphine (Test) First		Subutex® (Reference) First
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/40 (0%)		0/40 (0%)
Other (Not Including Serious) Adverse Events
	Buprenorphine (Test) First		Subutex® (Reference) First
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/40 (55%)		13/40 (32.5%)
General disorders
Nausea	15/40 (37.5%)	15	8/40 (20%)	8
Dizziness	8/40 (20%)	8	3/40 (7.5%)	3
Headache	6/40 (15%)	6	6/40 (15%)	6
Emesis	9/40 (22.5%)	9	3/40 (7.5%)	3
Fatigue	2/40 (5%)	2	2/40 (5%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The Principal Investigator is not permitted to discuss or publish trial results.