PK/PD Comparison of Guanfacine ER and IR

• Sponsor: Yale University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01904526
• Collaborator: National Institute on Drug Abuse (NIDA) (NIH)
• Enrollment: 5
• Location: 1
• Arm: 1
• Duration (Months): 41
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Evaluate whether a 4mg/day or 6/mg day dose of extended-release guanfacine produces pharmacokinetic/dynamic (PK/PD) properties similar to 3mg/day immediate release guanfacine.

Condition or Disease	Intervention/Treatment	Phase
Smoking	Drug: Guanfacine	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 5 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: Pharmacokinetic/Dynamic (PK/PD) Comparison of Guanfacine Extended Release (ER) and Immediate Release (IR) in Smokers
• Study Start Date: Jul 1, 2013
• Actual Primary Completion Date: Dec 1, 2016
• Actual Study Completion Date: Dec 1, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Guanfacine Guanfacine 3 mg/day immediate release followed by Guanfacine 4mg/day extended release followed by Guanfacine 6 mg/day extended release

Drug: Guanfacine; 3mg/day IR with 3-week lead-in period. Maintained at steady state to complete lab session. After completion of lab session, 1-week lead-in medication period to 4mg/day ER. Maintained at steady state to complete lab session. After completion of lab session, 1-week lead-in medication period to 6mg/day ER. Maintained at steady state to complete lab session. 5-day taper after lab.; Other Names: Tenex Intuniv

Outcome Measures

Primary Outcome Measures

1. Plasma Trough Levels of Guanfacine [+24 hours on Lab Session days (Days 22, 49, 58)]

   Evaluate whether a 4mg/day or 6mg/day dose of extended-release guanfacine produces pharmacokinetic (PK) properties similar to 3mg/day immediate release guanfacine by measuring plasma trough levels of guanfacine for each dose

Secondary Outcome Measures

1. Heart Rate [Last day of titration period 1 (Day 21) to the last day of titration period 3 (Day 57)]

   Evaluate the safety and tolerability of guanfacine by measuring physiologic reactivity (e.g., heart rate)

2. Systolic Blood Pressure [Last day of titration period 1 (Day 21) to the last day of titration period 3 (Day 57)]

   Evaluate the safety and tolerability of guanfacine by measuring physiologic reactivity (e.g., systolic blood pressure)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Age 18-65

• Able to read, write and comprehend English

• Smoker

• Able to take oral medications and willing to adhere to medication regimen

• Provide evidence of a stable living residence in the last 2 months, have reasonable transportation to the study site, and have no plans to move within the next 3 months or unresolved legal problems.

Exclusion Criteria:

• Any significant current medical conditions that would contraindicate smoking

• Current Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) abuse or dependence of other substances, other than nicotine dependence or alcohol abuse

• Positive test results at intake appointment on urine drug screens for illicit drugs

• Past 30 day use of psychoactive drugs including anxiolytics and antidepressants

• Women who are pregnant or nursing

• Suicidal, homicidal or evidence of current mental illness such as schizophrenia, bipolar disorder or major depression, or anxiety disorders

• Meeting DSM-IV criteria for current attention deficit hyperactivity disorder (ADHD)

• Individuals who are currently taking medications known to be effective for smoking cessation or are regular users of other tobacco products in the past 30 days

• Only one member per household can participate in the study

• Specific exclusions for administration of guanfacine not already specified include:

• EKG evidence at baseline screening of any clinically significant conduction abnormalities or arrhythmias

• Known intolerance for guanfacine or any alpha blocker

• History of fainting, syncopal attacks

• Heart failure or myocardial infarction

• Impaired liver (as indicated by aspartate aminotransferase (AST), alanine aminotransferase (ALT) >3x normal)

• Renal function (as indicated by estimated creatinine clearance <60cc/min)

• Treatment with any antihypertensive drug or any alpha-adrenergic blocker

• Use of any central nervous system depressant (e.g., phenothiazines, barbiturates, benzodiazepines)

• Use of strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ketoconazole) or inducers (e.g., rifampin), or consumption of grapefruit juice

• Subjects may have not donated blood in the past 8 weeks or have been involved in other investigational studies that involve substantial blood draws or medications unknown to us

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Yale Center for Clinical Investigations, Yale University	New Haven	Connecticut	United States	06519

Sponsors and Collaborators

• Yale University
• National Institute on Drug Abuse (NIDA)

Investigators

• Principal Investigator: Sherry A McKee, PhD, Yale University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Sherry McKee, Associate Professor of Psychiatry, Yale University
• ClinicalTrials.gov Identifier: NCT01904526
• Other Study ID Numbers: 1110009133; R01DA035001; P50DA033945
• First Posted: Jul 22, 2013
• Last Update Posted: Mar 6, 2020
• Last Verified: Mar 1, 2020

• Keywords provided by Sherry McKee, Associate Professor of Psychiatry, Yale University: Guanfacine; PK/PD; Smokers
• Additional relevant MeSH terms: Guanfacine

Study Results

Participant Flow

Arm/Group Title	Guanfacine
Arm/Group Description	Guanfacine: 3mg/day immediate release (IR) with 3-week lead-in period. Maintained at steady state to complete lab session. After completion of lab session, 1-week lead-in medication period to 4mg/day extended release (ER). Maintained at steady state to complete lab session. After completion of lab session, 1-week lead-in medication period to 6mg/day ER. Maintained at steady state to complete lab session. 5-day taper after lab.
Period Title: Overall Study
STARTED	5
COMPLETED	5
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Guanfacine
Arm/Group Description	Guanfacine: 3mg/day IR with 3-week lead-in period. Maintained at steady state to complete lab session. After completion of lab session, 1-week lead-in medication period to 4mg/day ER. Maintained at steady state to complete lab session. After completion of lab session, 1-week lead-in medication period to 6mg/day ER. Maintained at steady state to complete lab session. 5-day taper after lab.
Overall Participants	5
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	45.8 (2.49)
Sex: Female, Male (Count of Participants)
Female	2 40%
Male	3 60%

Outcome Measures

1. Primary Outcome

Title	Plasma Trough Levels of Guanfacine
Description	Evaluate whether a 4mg/day or 6mg/day dose of extended-release guanfacine produces pharmacokinetic (PK) properties similar to 3mg/day immediate release guanfacine by measuring plasma trough levels of guanfacine for each dose
Time Frame	+24 hours on Lab Session days (Days 22, 49, 58)

Outcome Measure Data

Analysis Population Description

3 mg/day IR (Day 22) followed by 4mg/day ER (Day 49) followed by 6mg/day ER (Day 58)

Arm/Group Title	Guanfacine 3mg/Day Immediate Release	Guanfacine 4mg/Day Extended Release	Guanfacine 6mg/Day Extended Release
Arm/Group Description	Guanfacine: 3mg/day immediate release	Guanfacine: 4mg/day extended release	Guanfacine: 6mg/day extended release
Measure Participants	5	5	5
Mean (Standard Error) [ng/ml]	3.40 (0.33)	3.46 (0.67)	5.92 (1.02)

2. Secondary Outcome

Title	Heart Rate
Description	Evaluate the safety and tolerability of guanfacine by measuring physiologic reactivity (e.g., heart rate)
Time Frame	Last day of titration period 1 (Day 21) to the last day of titration period 3 (Day 57)

Outcome Measure Data

Analysis Population Description

Last day of titration period: 3 mg/day IR (Day 21) followed by 4mg/day ER (Day 48) followed by 6mg/day ER (Day 57)

Arm/Group Title	Guanfacine 3mg/Day Immediate Release	Guanfacine 4mg/Day Extended Release	Guanfacine 6mg/Day Extended Release
Arm/Group Description	Guanfacine: 3mg/day immediate release	Guanfacine: 4mg/day extended release	Guanfacine: 6mg/day extended release
Measure Participants	5	5	5
Mean (Standard Error) [beats per minute]	59.6 (1.75)	58.8 (3.97)	61.6 (5.30)

3. Secondary Outcome

Title	Systolic Blood Pressure
Description	Evaluate the safety and tolerability of guanfacine by measuring physiologic reactivity (e.g., systolic blood pressure)
Time Frame	Last day of titration period 1 (Day 21) to the last day of titration period 3 (Day 57)

Outcome Measure Data

Analysis Population Description

Last day of titration period: 3 mg/day IR (Day 21) followed by 4 mg/kg ER (Day 48) followed by 6 mg/day ER (Day 57)

Arm/Group Title	Guanfacine 3mg/Day Immediate Release	Guanfacine 4mg/Day Extended Release	Guanfacine 6mg/Day Extended Release
Arm/Group Description	Guanfacine: 3mg/day immediate release	Guanfacine: 4mg/day extended release	Guanfacine: 6mg/day extended release
Measure Participants	5	5	5
Mean (Standard Error) [mmHg]	101.0 (3.73)	107.4 (7.51)	108.4 (7.16)

Adverse Events

Arm/Group Title	Guanfacine 3mg/Day Immediate Release		Guanfacine 4mg/Day Extended Release		Guanfacine 6mg/Day Extended Release
Arm/Group Description	Guanfacine: 3mg/day immediate release		Guanfacine: 4mg/day extended release		Guanfacine: 6mg/day extended release
All Cause Mortality
	Guanfacine 3mg/Day Immediate Release		Guanfacine 4mg/Day Extended Release		Guanfacine 6mg/Day Extended Release
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/5 (0%)		0/5 (0%)
Serious Adverse Events
	Guanfacine 3mg/Day Immediate Release		Guanfacine 4mg/Day Extended Release		Guanfacine 6mg/Day Extended Release
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/5 (0%)		0/5 (0%)
Other (Not Including Serious) Adverse Events
	Guanfacine 3mg/Day Immediate Release		Guanfacine 4mg/Day Extended Release		Guanfacine 6mg/Day Extended Release
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/5 (60%)		4/5 (80%)		4/5 (80%)
Cardiac disorders
Chest pain	1/5 (20%)		0/5 (0%)		0/5 (0%)
Gastrointestinal disorders
Constipation	2/5 (40%)		2/5 (40%)		2/5 (40%)
Gas pains	2/5 (40%)		2/5 (40%)		3/5 (60%)
Diarrhea	1/5 (20%)		0/5 (0%)		0/5 (0%)
Abdominal pain	1/5 (20%)		0/5 (0%)		0/5 (0%)
General disorders
Dry mouth	2/5 (40%)		4/5 (80%)		4/5 (80%)
Drowsiness	3/5 (60%)		3/5 (60%)		3/5 (60%)
Dizziness	2/5 (40%)		2/5 (40%)		2/5 (40%)
Fatigue	3/5 (60%)		3/5 (60%)		3/5 (60%)
Headache	2/5 (40%)		1/5 (20%)		0/5 (0%)
Insomnia	0/5 (0%)		1/5 (20%)		0/5 (0%)
Loss of appetite	1/5 (20%)		0/5 (0%)		1/5 (20%)
Runny nose	1/5 (20%)		0/5 (0%)		1/5 (20%)
Weakness	1/5 (20%)		0/5 (0%)		2/5 (40%)
Nausea/vomiting	0/5 (0%)		0/5 (0%)		0/5 (0%)
Shortness of breath	0/5 (0%)		0/5 (0%)		0/5 (0%)
Skin rash	0/5 (0%)		0/5 (0%)		0/5 (0%)
Swelling of hands or feet	0/5 (0%)		0/5 (0%)		0/5 (0%)
Blurred vision	0/5 (0%)		0/5 (0%)		0/5 (0%)
Yellowing of the eyes or skin	0/5 (0%)		0/5 (0%)		0/5 (0%)
Mental/mood changes	0/5 (0%)		0/5 (0%)		0/5 (0%)
Tingling of the hands or feet	0/5 (0%)		0/5 (0%)		0/5 (0%)
Impotence	2/5 (40%)		0/5 (0%)		1/5 (20%)
Decreased sexual desire	1/5 (20%)		0/5 (0%)		1/5 (20%)
Vision changes	0/5 (0%)		0/5 (0%)		0/5 (0%)
Taste changes	1/5 (20%)		1/5 (20%)		1/5 (20%)
Ringing in ears	1/5 (20%)		1/5 (20%)		1/5 (20%)
Leg cramps	0/5 (0%)		0/5 (0%)		1/5 (20%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT 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.