Effect of Heat on Rivastigmine TDS Products

• Sponsor: University of Maryland, Baltimore (Other)
• Overall Status: Completed
• CT.gov ID: NCT03915626
• Collaborator: Food and Drug Administration (FDA) (U.S. Fed)
• Enrollment: 7
• Location: 1
• Arms: 4
• Actual Duration (Months): 19
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This research study is designed to measure the amount of medicine in blood over time after the patch is placed on the skin with and without external heat application.

Condition or Disease	Intervention/Treatment	Phase
Bioavailability	Drug: Rivastigmine (RLD) transdermal patch; Drug: Rivastigmine (generic) transdermal patch	Early Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 7 participants
• Allocation: Non-Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: The same healthy subjects are assigned to all four treatments.The same healthy subjects are assigned to all four treatments.
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: Determination of Serum Rivastigmine Levels After Using Rivastigmine Transdermal Delivery Systems With and Without Standardized Heat Application in Healthy Human Volunteers
• Actual Study Start Date: Oct 4, 2019
• Actual Primary Completion Date: May 4, 2021
• Actual Study Completion Date: May 4, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: RLD patch RLD rivastigmine patch (4.6 mg/24 hours); worn for 9 hours	Drug: Rivastigmine (RLD) transdermal patch; brand name patch; Other Names: brand name patch
Experimental: generic patch generic rivastigmine patch (4.6 mg/24 hours); worn for 9 hours	Drug: Rivastigmine (generic) transdermal patch; generic patch; Other Names: generic patch
Experimental: RLD patch with heat RLD rivastigmine patch (4.6 mg/24 hours); worn for 9 hours; 90 min heat application	Drug: Rivastigmine (RLD) transdermal patch; brand name patch; Other Names: brand name patch
Experimental: generic patch with heat generic rivastigmine patch (4.6 mg/24 hours); worn for 9 hours; 90 min heat application	Drug: Rivastigmine (generic) transdermal patch; generic patch; Other Names: generic patch

Outcome Measures

Primary Outcome Measures

1. Total Area Under the Curve (AUC) 0-12 Hours [0-12 hours for each subject for each of the four study sessions]

   Blood samples were obtained at the following time points: -60 min (before patch application) and then 2 h, 3 h, 4 h, 5 h, 5 h 15 min, 5 h 30 min, 5 h 45 min, 6 h, 6 h 15 min, 6 h 30 min, 6 h 45 min, 7 h, 7 h 30 min, 8 h, 8 h 30 min, 9 h, 9 h 15 min, 9 h 30 min, 10 h, 11 h, 12 h post patch administration.

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, non-lactating women who are of any ethnic background between the age of 18 to 45 years old

2. Subjects must be non-smokers/tobacco users (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 or to participate in an investigational drug study for at least one month after the last study session

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

6. Able to participate in all study sessions

7. Subjects deemed to be healthy as judged by the Medically Accountable Investigator (MAI) and determined by medical history, physical examination and medication history

8. Negative urine drug screening test (cannabinoids, amphetamines, barbiturates, benzodiazepine, cocaine, methadone, opiates, PCP)

9. 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)

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

11. 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 day, and must agree to use reliable hormonal or barrier birth control such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence or a vasectomized partner

12. Agree not to donate blood to a blood bank throughout participation in the study and for at least three months after last procedure day

13. 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)

14. Have normal vital signs:

• Temperature 35-37.9°C (95-100.3°F)

• Systolic blood pressure 90-140 mmHg

• Diastolic blood pressure 60-90 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 any study session

2. Smokers/tobacco users (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 of lung, heart, respiratory or blood disease

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

6. Positive urine drug screening test

7. Use of chronic prescription medications during the period 0 to 30 days; or over-the-counter medications (e.g. cholinomimetic drugs [used to treat diseases like acid reflux in children, glaucoma, dry mouth associated with Sjögren's Syndrome], anticholinergics [used to treat diseases like asthma, incontinence, gastrointestinal cramps, and muscular spasms], antihistamines, topical corticosteroids) and short term (<30 days) prescription medications during the period 0-3 days before a study session vitamin, herbal supplements and birth control medications not included)

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

9. Any prior allergies to rivastigmine, other carbamate derivatives, other ingredients in the patch, to medical tape products or other skin patches

10. Subject has problems with urinary retention, gastric retention or gastrointestinal obstruction

11. Subject has continuous spasms, muscle contractions, motor restlessness, rigidity, slowness of movement, tremors or irregular jerky movements

12. Subject has ulcers or gastrointestinal bleeding

13. Subject has asthma or blocked airflow making it hard to breathe (COPD)

14. Received an experimental agent (vaccine, drug, biologic, device, blood product or medication) within one month before enrollment in this study or expects to receive an experimental agent during the study

15. 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

16. Consumption (food or drink) of alcohol within 24 h prior to dose administration

17. History as either reported by the subject or evident to the investigator of infectious disease or skin infection or of chronic skin disease (e.g., psoriasis, atopic dermatitis)

18. History of diabetes

19. Hereditary skin disorders or any skin inflammatory conditions as reported by the subject or evident to the MAI

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

21. 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), sunburn, raised moles and scars, open sores at application site (upper arms), scar tissue, tattoo, or coloration that would interfere with placement of products, skin assessment, or reactions to rivastigmine

22. BMI ≥30 kg/m2

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

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 5, 2020

More Information

Publications

None provided.

• Responsible Party: Audra Stinchcomb, Professor, University of Maryland, Baltimore
• ClinicalTrials.gov Identifier: NCT03915626
• Other Study ID Numbers: HP-00076010
• First Posted: Apr 16, 2019
• Last Update Posted: Apr 4, 2022
• Last Verified: Apr 1, 2022

• 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: Rivastigmine

Study Results

Participant Flow

Arm/Group Title	Rivastigmine RLD and Generic Patches
Arm/Group Description	Session 1: RLD patch worn for 9 hours, then at least one week wash out period, Session 2: Generic patch worn for 9 hours, then at least one week wash out period, Session 3: RLD patch worn for 9 hours includes 90 minute heat application (5 h-6 h 30 min), then at least one week wash out period Session 4: Generic patch worn for 9 hours includes 90 minute heat application (5 h-6 h 30 min)
Period Title: Overall Study
STARTED	7
COMPLETED	6
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Rivastigmine RLD and Generic Patches
Arm/Group Description	Session 1: RLD patch worn for 9 hours, then at least one week wash out period, Session 2: Generic patch worn for 9 hours, then at least one week wash out period, Session 3: RLD patch worn for 9 hours includes 90 minute heat application (5 h-6 h 30 min), then at least one week wash out period Session 4: Generic patch worn for 9 hours includes 90 minute heat application (5 h-6 h 30 min)
Overall Participants	7
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	7 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	28.57 (4.43)
Sex: Female, Male (Count of Participants)
Female	2 28.6%
Male	5 71.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 14.3%
Not Hispanic or Latino	6 85.7%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	5 71.4%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	1 14.3%
More than one race	1 14.3%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	7 100%

Outcome Measures

1. Primary Outcome

Title	Total Area Under the Curve (AUC) 0-12 Hours
Description	Blood samples were obtained at the following time points: -60 min (before patch application) and then 2 h, 3 h, 4 h, 5 h, 5 h 15 min, 5 h 30 min, 5 h 45 min, 6 h, 6 h 15 min, 6 h 30 min, 6 h 45 min, 7 h, 7 h 30 min, 8 h, 8 h 30 min, 9 h, 9 h 15 min, 9 h 30 min, 10 h, 11 h, 12 h post patch administration.
Time Frame	0-12 hours for each subject for each of the four study sessions

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RLD Patch	Generic Patch	RLD Patch With Heat	Generic Patch With Heat
Arm/Group Description	RLD rivastigmine patch (4.6 mg/24 hours); worn for 9 hours Rivastigmine (RLD) transdermal patch: brand name patch	generic rivastigmine patch (4.6 mg/24 hours); worn for 9 hours Rivastigmine (generic) transdermal patch: generic patch	RLD rivastigmine patch (4.6 mg/24 hours); worn for 9 hours; 90 min heat application Rivastigmine (RLD) transdermal patch: brand name patch	generic rivastigmine patch (4.6 mg/24 hours); worn for 9 hours; 90 min heat application Rivastigmine (generic) transdermal patch: generic patch
Measure Participants	6	6	6	6
Mean (Standard Deviation) [ng*h/mL]	19.99 (14.35)	19.22 (11.41)	19.22 (11.41)	16.57 (9.66)

Adverse Events

Time Frame	Subjects were observed for the 12 hours during product administration and then were followed up with a phone call up to 72 h after product removal; ~4 days for each of the four study sessions.
Arm/Group Title	RLD Patch		Generic Patch		RLD Patch With Heat		Generic Patch With Heat
Arm/Group Description	RLD rivastigmine patch (4.6 mg/24 hours); worn for 9 hours Rivastigmine (RLD) transdermal patch: brand name patch		generic rivastigmine patch (4.6 mg/24 hours); worn for 9 hours Rivastigmine (generic) transdermal patch: generic patch		RLD rivastigmine patch (4.6 mg/24 hours); worn for 9 hours; 90 min heat application Rivastigmine (RLD) transdermal patch: brand name patch		generic rivastigmine patch (4.6 mg/24 hours); worn for 9 hours; 90 min heat application Rivastigmine (generic) transdermal patch: generic patch
All Cause Mortality
	RLD Patch		Generic Patch		RLD Patch With Heat		Generic Patch With Heat
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)
Serious Adverse Events
	RLD Patch		Generic Patch		RLD Patch With Heat		Generic Patch With Heat
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/7 (0%)		0/6 (0%)		0/6 (0%)
Other (Not Including Serious) Adverse Events
	RLD Patch		Generic Patch		RLD Patch With Heat		Generic Patch With Heat
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/7 (100%)		7/7 (100%)		4/6 (66.7%)		6/6 (100%)
Cardiac disorders
Decreased heart rate	0/7 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0	0/6 (0%)	0
Increased heart rate	0/7 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Decreased blood pressure	3/7 (42.9%)	3	1/7 (14.3%)	1	1/6 (16.7%)	1	0/6 (0%)	0
Increased blood pressure	1/7 (14.3%)	1	1/7 (14.3%)	1	0/6 (0%)	0	1/6 (16.7%)	1
Investigations
Dizziness	0/7 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
SOMNOLENCE (SLEEPINESS)	0/7 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Skin and subcutaneous tissue disorders
ERYTHEMA (skin reddening)	7/7 (100%)	7	7/7 (100%)	7	4/6 (66.7%)	6	6/6 (100%)	6

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.