Evaluation of Bioavailability of Diclofenac Dermal Products

• Sponsor: University of Maryland, Baltimore (Other)
• Overall Status: Completed
• CT.gov ID: NCT03145259
• Collaborator: Food and Drug Administration (FDA) (U.S. Fed)
• Enrollment: 12
• Location: 1
• Arms: 3
• Actual Duration (Months): 36.9
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The study will utilize already FDA-approved marketed diclofenac products in healthy adults to generate data for establishing rate of drug delivery comparisons between diclofenac epolamine patches and diclofenac sodium solution in healthy adults and to determine skin concentrations.

Condition or Disease	Intervention/Treatment	Phase
Bioavailability	Drug: Diclofenac Epolamine Patch; Drug: diclofenac sodium solution	Early Phase 1

Detailed Description

The study will utilize already FDA-approved marketed diclofenac products in healthy adults to generate data for establishing rate of drug delivery comparisons between diclofenac epolamine patches and diclofenac sodium solution in healthy adults and to determine skin concentrations. This study supports FDA's continuing effort to identify the most accurate, sensitive, reproducible and efficient methods to evaluate topical dermatological drug products.

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: Non-Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: The same 12 volunteers received all treatments in three separate study arms.The same 12 volunteers received all treatments in three separate study arms.
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: Evaluation of Bioavailability of Diclofenac Dermal Products
• Actual Study Start Date: Apr 19, 2017
• Actual Primary Completion Date: Aug 29, 2019
• Actual Study Completion Date: May 15, 2020

Arms and Interventions

Arm	Intervention/Treatment
Other: Diclofenac patch Study Session 1: diclofenac epolamine patches (PK) [51 h study duration]	Drug: Diclofenac Epolamine Patch; patch; Other Names: patch
Other: Diclofenac solution Study Session 2: diclofenac sodium solution (PK) [47 h study duration]	Drug: diclofenac sodium solution; solution; Other Names: solution
Other: Diclofenac patch and solution Study Session 3: diclofenac epolamine patch pieces and diclofenac sodium solution (no PK, for skin tape stripping) [51 h study duration]	Drug: Diclofenac Epolamine Patch; patch; Other Names: patch ; Drug: diclofenac sodium solution; solution; Other Names: solution

Outcome Measures

Primary Outcome Measures

1. Serum Diclofenac Concentrations [blood samples obtained over 51 hour time period for study session 1 and over 47 hour time period for study session 2; through study completion]

   Study Session 1: within 60 min prior to dosing, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 24, 27, 30, 32, 51 h Study Session 2: within 60 min prior to dosing, 1, 2, 3, 4, 5, 6, 7, 23, 26, 29, 31, 47 h Study Session 3: no blood samples obtained

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Men or non-pregnant, women who are of any ethnic background between the age of 18 to 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, snuff, gum, patches or electronic cigarettes) over the previous 2 months and are not currently using tobacco products

3. Provide written informed consent before initiation of any of the study procedures

4. Agree not to participate in another clinical trial/study during the study period or to participate in an investigational drug study for at least 1 month after the last study session

5. Able to adhere to the study protocol and study restrictions

6. Able to participate in all study sessions

7. Has a volar forearm of either at least 24 cm (9.45 inches) in length or of sufficient size that can accommodate the products to be tested in a study area that begins at least 5 cm (1.97 inches) above the wrist and ends a minimum of 0.5 cm (0.197 inches) below the antecubital fossa (i.e., the bend in the arm at the elbow).

8. Subjects have upper arms large enough to allow for placement of two 140 cm2 [21.7 in2] patches (distance from acromion process of the scapula to olecranon process should be a minimum of 35 cm [13.8 inches]; circumference of upper arms should be a minimum of 28 cm [11.02 inches] and 200 cm2 [31 in2] area for application of solution

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 (cannabinoids, amphetamines, barbiturates, benzodiazepine, cocaine, methadone, opiates, PCP)

11. Have normal screening laboratories for white blood cells (WBC), hemoglobin (Hgb), platelets, sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), creatinine, alanine transaminase (ALT) and aspartate aminotransferase (AST)

12. Have normal screening laboratories for urine protein and urine glucose

13. 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 study session, 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

14. Agrees not to donate blood to a blood bank throughout participation in the study and for at least 3 months after last study session

15. Have a normal ECG; must not have the following to be acceptable: pathologic Q wave abnormalities, significant ST-T wave changes, left ventricular hypertrophy, right bundle branch block, left bundle branch block. (sinus rhythm is between 55-100 beats per minute)

16. Have normal vital signs:

• Temperature 35-37.9°C (95-100.3°F)

• Systolic blood pressure 90-165 mmHg

• Diastolic blood pressure 60-100 mmHg

• Heart rate 55-100 beats per minute

• Respiration rate 12-20 breaths per minute

Exclusion Criteria:

1. Women who are pregnant, lactating, breast feeding or have a positive serum pregnancy test at enrollment or positive urine pregnancy test on the morning of the first day of each study session

2. Smokers (current use or use over the previous 2 months of nicotine-containing substances, including tobacco products (e.g., cigarettes, cigars, chewing tobacco, snuff, gum, patch or electronic cigarettes)

3. Participation in any ongoing investigational drug trial/study or clinical drug trial/study

4. History as either reported by the subject or evident to the Medically Accountable Investigator (MAI) of infectious disease or skin infection or of chronic skin disease (e.g., psoriasis, atopic dermatitis)

5. History of diabetes

6. History of significant skin cancers (e.g., melanoma, squamous cell carcinoma) except basal cell carcinomas that were superficial and did not involve the investigative sites

7. Body Mass Index (BMI) ≥30 kg/m2

8. History of chronic obstructive pulmonary disease or cor pulmonale, or substantially decreased respiratory reserve, hypoxia, hypercapnia or pre-existing respiratory depression

9. Active positive Hepatitis B, C and/or HIV serologies

10. Positive urine drug screening test

11. Use of chronic prescription medications during the period 0 to 30 days; or over-the-counter medication (e.g. antihistamines, topical corticosteroids) and short term (<30 days) prescription medications during the period 0-3 days before a study session (vitamins, herbal supplements and birth control medications not included)

12. Currently taking daily oral nonsteroidal anti-inflammatory drug [NSAIDs] (aspirin, ibuprofen, naproxen, etc…)

13. Currently taking daily anticoagulants or within the past month prior to entry into the study (warfarin, heparin, rivaroxaban, dabigatran, etc…), ACE-inhibitors, cyclosporine, diuretics, lithium or methotrexate

14. Donation or loss of greater than one pint of blood within 60 days of entry to the study

15. Any prior adverse reaction or hypersensitivity to diclofenac, aspirin, ibuprofen, naproxen or other nonsteroidal anti-inflammatory drug (NSAID), other inactive ingredients in the patch or topical solution or to adhesives or tapes used to cover or tape strip the treatment sites

16. 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

17. Eat or drink anything containing alcohol within 24 hours prior to dose administration

18. 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

19. Subject has an obvious difference in skin color between arms or the presence of a skin condition, excessive hair at the application site (upper arms/volar forearms), sunburn, raised moles or scars, open sores at application site (upper arms/volar forearms), scar tissue, tattoo, or coloration that would interfere with placement of diclofenac products, skin assessment, or reactions to diclofenac

20. History of asthma or urticaria,, hypertension, myocardial infarction, thrombotic events, stroke, congestive heart failure, impaired renal function or liver disease

21. History of gastrointestinal bleeding or peptic ulcer disease

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	General Clinical Research Center (GCRC) at the University of Maryland Medical Center	Baltimore	Maryland	United States	21201

Sponsors and Collaborators

• University of Maryland, Baltimore
• Food and Drug Administration (FDA)

Investigators

• Principal Investigator: Audra L Stinchcomb, PhD, University of Maryland Baltimore School of Pharmacy
• Principal Investigator: Hazem E Hassan, PhD, University of Maryland Baltimore School of Pharmacy

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 7, 2019

More Information

Publications

None provided.

• Responsible Party: Audra Stinchcomb, Professor, University of Maryland, Baltimore
• ClinicalTrials.gov Identifier: NCT03145259
• Other Study ID Numbers: HP-00067047
• First Posted: May 9, 2017
• Last Update Posted: Jun 30, 2020
• Last Verified: Jun 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Diclofenac; Diclofenac hydroxyethylpyrrolidine; Pharmaceutical Solutions

Study Results

Participant Flow

Arm/Group Title	Diclofenac
Arm/Group Description	Study Session 1. diclofenac epolamine patch Study Session 2. diclofenac sodium solution Study Session 3. diclofenac epolamine patch pieces and diclofenac sodium solution
Period Title: Overall Study
STARTED	12
COMPLETED	12
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Diclofenac
Arm/Group Description	Study Session 1. diclofenac epolamine patch Study Session 2. diclofenac sodium solution Study Session 3. diclofenac epolamine patch pieces and diclofenac sodium solution
Overall Participants	12
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	12 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	36 (6.8)
Sex: Female, Male (Count of Participants)
Female	4 33.3%
Male	8 66.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 8.3%
Asian	3 25%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	3 25%
White	4 33.3%
More than one race	1 8.3%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Serum Diclofenac Concentrations
Description	Study Session 1: within 60 min prior to dosing, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 24, 27, 30, 32, 51 h Study Session 2: within 60 min prior to dosing, 1, 2, 3, 4, 5, 6, 7, 23, 26, 29, 31, 47 h Study Session 3: no blood samples obtained
Time Frame	blood samples obtained over 51 hour time period for study session 1 and over 47 hour time period for study session 2; through study completion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Diclofenac Epolamine Patches	Diclofenac Sodium Solution
Arm/Group Description	diclofenac epolamine patches Diclofenac Epolamine Patch: patch	diclofenac sodium solution diclofenac sodium solution: solution
Measure Participants	12	12
Mean (Standard Deviation) [ng/mL]	5.6 (10.8)	40.0 (54.3)

Adverse Events

Time Frame	From the beginning of the study (10/04/17) through when the last adverse event resolved (05/15/20) [2 years, 7 months] TDCLO-001 (431 days), TDCLO-003 (156 days), TDCLO-004 (740 days), TDCLO-010 (37 days), TDCLO-011 (162 days), TDCLO-012 (306 days), TDCLO-013 (500 days), TDCLO-016 (76 days), TDCLO-019 (52 days), TDCLO-020 (213 days), TDCLO-024 (79 days), TDCLO-029 (58 days)
Arm/Group Title	Diclofenac Epolamine Patches		Diclofenac Sodium Solution		Diclofenac Epolamine Patches and Diclofenac Sodium Solution
Arm/Group Description	diclofenac epolamine patches Diclofenac Epolamine Patch: patch		diclofenac sodium solution diclofenac sodium solution: solution		patch pieces and solution Diclofenac Epolamine Patch: patch diclofenac sodium solution: solution
All Cause Mortality
	Diclofenac Epolamine Patches		Diclofenac Sodium Solution		Diclofenac Epolamine Patches and Diclofenac Sodium Solution
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/12 (0%)		0/12 (0%)
Serious Adverse Events
	Diclofenac Epolamine Patches		Diclofenac Sodium Solution		Diclofenac Epolamine Patches and Diclofenac Sodium Solution
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/12 (0%)		0/12 (0%)
Other (Not Including Serious) Adverse Events
	Diclofenac Epolamine Patches		Diclofenac Sodium Solution		Diclofenac Epolamine Patches and Diclofenac Sodium Solution
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/12 (100%)		12/12 (100%)		12/12 (100%)
Eye disorders
decreased blood pressure	5/12 (41.7%)	5	5/12 (41.7%)	5	5/12 (41.7%)	5
General disorders
Menstrual flow	1/12 (8.3%)	1	0/12 (0%)	0	0/12 (0%)	0
increased heart rate	1/12 (8.3%)	1	1/12 (8.3%)	1	0/12 (0%)	0
raised skin	0/12 (0%)	0	0/12 (0%)	0	1/12 (8.3%)	1
skin hyperpigmentation	0/12 (0%)	0	1/12 (8.3%)	1	9/12 (75%)	9
abrasions	0/12 (0%)	0	0/12 (0%)	0	1/12 (8.3%)	1
scabs	0/12 (0%)	0	0/12 (0%)	0	2/12 (16.7%)	2
skin dryness	0/12 (0%)	0	3/12 (25%)	3	0/12 (0%)	0
skin itching	0/12 (0%)	0	6/12 (50%)	6	4/12 (33.3%)	4
skin burning sensation	0/12 (0%)	0	1/12 (8.3%)	1	1/12 (8.3%)	1
skin tingly sensation	0/12 (0%)	0	2/12 (16.7%)	2	0/12 (0%)	0
skin peeling	0/12 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0
urticaria	0/12 (0%)	0	1/12 (8.3%)	2	0/12 (0%)	0
upset stomach/indigestion	0/12 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0
diarrhea	0/12 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0
hematoma	1/12 (8.3%)	1	0/12 (0%)	0	0/12 (0%)	0
skin erythema (redness)	5/12 (41.7%)	5	10/12 (83.3%)	10	12/12 (100%)	12

Limitations/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.