Peer Review, Research
Conditions
Keywords
Bioequivalence, Therapeutic Equivalency
Brief summary
This is an Open-label, Non-Randomized, 3-way Crossover Bioequivalence Study to compare fentanyl release after heating of a brand name (Duragesic) and generic (Apotex and Mylan) fentanyl (transdermal delivery system)TDSs in healthy adults.
Detailed description
This research study is intended to determine the effect of heat on FDA-approved fentanyl TDSs and whether the heat applied will result in more fentanyl being absorbed through the skin than without applying heat. This is important given that little is known about how the release of fentanyl is affected by heat, particularly for generic products. This study will use fentanyl TDSs (brand name and generic TDSs) that have been approved by the Food and Drug Administration (FDA) and are already prescribed to customers in the United States, and will not include any placebos.
Interventions
DRUGDuragesic reference fentanyl TDS
25 µg/hour
DRUGApotex generic fentanyl TDS
25 µg/hour
DRUGMylan generic fentanyl TDS
25 µg/hour
Sponsors
Food and Drug Administration (FDA)
University of Maryland, Baltimore
Study design
Allocation
NON_RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
HEALTH_SERVICES_RESEARCH
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* 1\. Men or non-pregnant women of any ethnic background between the age of 18 and 45 years old. * 2\. Subjects must be non-smokers (must have refrained from the use of nicotine-containing substances, including tobacco products (e.g., cigarettes, cigars, chewing tobacco, gum, patch or electronic cigarettes) over the previous 2 months and are not currently using tobacco products. * 3\. Provide written informed consent before initiation of any study procedures. * 4\. Available for follow-up for the planned duration of the study. * 5\. Able to communicate well with the investigators. * 6\. Able to adhere to the study protocol schedule. * 7\. Subjects who are within their ideal body weight (BMI\>17 and ≤ 28). * 8\. Demonstrate comprehension of the protocol procedures and knowledge of study by passing (\>70% correct responses) a written examination containing 20 multiple choice and true false questions covering all aspects of the study including the purpose, procedures, risks and benefits. * 9\. Subjects deemed to be healthy as judged by the Medically Accountable Investigator (MAI) and determined by medical history, physical examination, and medication history. * 10\. Negative urine drug screening test. * 11\. Have a normal blood pressure (systolic: 90-140 mmHg; diastolic: 50-90 mmHg) and heart rate (55-100 bpm). * 12\. Have normal screening laboratories for WBC, Hgb, platelets, sodium, potassium, chloride, bicarbonate, BUN, creatinine, ALT, AST and total bilirubin. * 13\. Have normal screening laboratories for urine protein and urine glucose. * 14\. Female subjects must be of non-childbearing potential (as defined as surgically sterile \[i.e. history of hysterectomy or tubal ligation\] or postmenopausal for more than 1 year), or if of childbearing potential must be non-pregnant at the time of enrollment and on the morning of each procedure, and must agree to use hormonal or barrier birth control such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence, or a vasectomized partner. * 15\. Agrees not to participate in another clinical study during the study period. * 16\. Agrees not to donate blood to a blood bank throughout participation in the study and for at least 3 months after last procedure day. * 17\. Have a normal ECG.
Exclusion criteria
* 1\. Women who are pregnant, lactating, breast feeding or have a positive serum pregnancy test at enrollment or on the morning of any procedure day. * 2\. Smokers (current use or use over the previous 2 months of nicotine-containing substances, including tobacco products (e.g., cigarettes, cigars, chewing tobacco, gum, patch or electronic cigarettes). * 3\. Participation in any ongoing investigational drug trial or clinical drug trial. * 4\. Abnormal Vital signs, defined as: * Hypertension (systolic blood pressure \>140 mm Hg or diastolic blood pressure \>90 mm Hg) at rest on 2 separate days) * Heart rate \<55 at rest on 2 separate days * Respiratory rate \>20 * 5\. Temperature \> 38.0°C (100.4°F) or symptoms of an acute self-limited illness such as an upper respiratory infection or gastroenteritis within 7 days of application of the fentanyl TDS. * 6\. History of chronic obstructive pulmonary disease. * 7\. Active positive Hepatitis B, C, and HIV serologies. * 8\. Positive urine drug screening test. * 9\. Use of any prescription medication during the period 0 to 30 days or over-the counter medication (vitamin, herbal supplements and birth control medications not included) during the period 0 to 3 days before entry to the study. * 10\. Donation or loss of greater than one pint of blood within 60 days of entry to the study. * 11\. Any prior serious adverse reaction or hypersensitivity to fentanyl, naltrexone or naloxone or any of the inactive ingredients in the TDS (alcohol, ethylene vinyl acetate-copolymer membrane and hydroxyethyl cellulose, polyester, silicone adhesive, isopropyl myristate, octyldodecanol, polybutene, polyisobutene, dimethicone NF, or polyolefin). * 12\. Have a diagnosis of schizophrenia or other major psychiatric diagnosis or mental illness (e.g. major depression). * 13\. Received an experimental agent (vaccine, drug, biologic, device, blood product or medication) within 1 month before enrollment in this study or expects to receive an experimental agent during the study. * 14\. Any condition that would, in the opinion of the Medically Accountable Investigator (MAI), place the subject at an unacceptable risk of injury or render the subject unable to meet the requirements of the protocol. * 15\. Inability to communicate or co-operate with the investigators. * 16\. History of consumption of alcohol within 24 hours prior to dose administration. * 17\. Within 72 hours prior to dosing, use of antihistamines or use of topical drugs at TDS site. * 18\. Subject has an obvious difference in skin color between arms or the presence of a skin condition, open sore, scar tissue, tattoo, or coloration that would interfere with placement of test articles, skin assessment, or reactions to drug. * 19\. Use of monoamine oxidase inhibitors 21 days prior to study. * 20\. Failure to pass opioid dependence challenge test on each procedure day before application of the fentanyl TDS. Each subject will be injected subcutaneously with naloxone HCl (0.8 mg injection) and will be observed for 45 minutes for signs and symptoms of opioid withdrawal.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Partial Area Under the Curve (AUC) Attained With Early and Late Heat in Each of the Three Fentanyl TDSs (Reference and Generic) | six procedure days for each participant | Partial area under the flux-time curve of fentanyl calculated from 11 to 14 h for Early Heat and 18 to 21 h for Late Heat study designs Blood samples obtained at 15 min prior to patch application \[baseline\], and at 1:00, 10:00, 10:55, 11:05, 11:15, 11:25, 11:35, 11:45, 12:00, 13:00, 14:00, 16:00, 17:00, 17:55, 18:05, 18:15, 18:25, 18:35, 18:45, 19:00, 20:00, 21:00, and 22:00 h post-patch application |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Fentanyl TDS Each volunteer participates in six procedure days.
1. Apotex generic fentanyl TDS (25 µg/h) with heat applied at 11 h for one hour
2. Apotex generic fentanyl TDS (25 µg/h) with heat at 18 h for one hour
3. Duragesic fentanyl TDS (25 µg/h) with heat applied at 11 h for one hour
4. Duragesic fentanyl TDS (25 µg/h) with heat at 18 h for one hour
5. Mylan generic fentanyl TDS (25 µg/h) with heat applied at 11 h for one hour
6. Mylan generic fentanyl TDS (25 µg/h) with heat at 18 h for one hour
Two week wash out period between each procedure day. | 10 |
| Total | 10 |
Baseline characteristics
| Characteristic | Fentanyl TDS |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 2 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 10 | 0 / 10 |
| other Total, other adverse events | 10 / 10 | 10 / 10 | 10 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 | 0 / 10 |
Outcome results
Primary
Partial Area Under the Curve (AUC) Attained With Early and Late Heat in Each of the Three Fentanyl TDSs (Reference and Generic)
Partial area under the flux-time curve of fentanyl calculated from 11 to 14 h for Early Heat and 18 to 21 h for Late Heat study designs Blood samples obtained at 15 min prior to patch application \[baseline\], and at 1:00, 10:00, 10:55, 11:05, 11:15, 11:25, 11:35, 11:45, 12:00, 13:00, 14:00, 16:00, 17:00, 17:55, 18:05, 18:15, 18:25, 18:35, 18:45, 19:00, 20:00, 21:00, and 22:00 h post-patch application
Time frame: six procedure days for each participant
Population: Partial area under the flux-time curve of fentanyl from 11 to 14 h for Early Heat and 18 to 21 h for Late Heat study designs. Each was corrected to account for different TDS sizes. Comparison was early heat to late heat differences.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Apotex Generic Fentanyl TDS | Partial Area Under the Curve (AUC) Attained With Early and Late Heat in Each of the Three Fentanyl TDSs (Reference and Generic) | Early Heat (11 h) | 2.2 h*ng/mL | Standard Deviation 1.4 |
| Apotex Generic Fentanyl TDS | Partial Area Under the Curve (AUC) Attained With Early and Late Heat in Each of the Three Fentanyl TDSs (Reference and Generic) | Late Heat (18 h) | 2.7 h*ng/mL | Standard Deviation 1.4 |
| Duragesic Reference Fentanyl TDS | Partial Area Under the Curve (AUC) Attained With Early and Late Heat in Each of the Three Fentanyl TDSs (Reference and Generic) | Early Heat (11 h) | 1.7 h*ng/mL | Standard Deviation 1.4 |
| Duragesic Reference Fentanyl TDS | Partial Area Under the Curve (AUC) Attained With Early and Late Heat in Each of the Three Fentanyl TDSs (Reference and Generic) | Late Heat (18 h) | 2.4 h*ng/mL | Standard Deviation 1 |
| Mylan Generic Fentanyl TDS | Partial Area Under the Curve (AUC) Attained With Early and Late Heat in Each of the Three Fentanyl TDSs (Reference and Generic) | Early Heat (11 h) | 2.1 h*ng/mL | Standard Deviation 1.8 |
| Mylan Generic Fentanyl TDS | Partial Area Under the Curve (AUC) Attained With Early and Late Heat in Each of the Three Fentanyl TDSs (Reference and Generic) | Late Heat (18 h) | 2.9 h*ng/mL | Standard Deviation 1.5 |