Proof-Of-Concept Investigation With a Neurosteroid Analog (Ganaxolone) as a Smoking Cessation Candidate

• Sponsor: Jed E. Rose (Other)
• Overall Status: Completed
• CT.gov ID: NCT01857531
• Collaborator: National Institute on Drug Abuse (NIDA) (NIH)
• Enrollment: 36
• Locations: 4
• Arm: 1
• Duration (Months): 8
• Patients Per Site: 9
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

The purpose of this research study is to evaluate whether the investigational drug ganaxolone can help smokers quit smoking. Ganaxolone is a drug that has been investigated (in other research studies) for the treatment of seizures and migraines. This drug is considered investigational in the US.

Condition or Disease	Intervention/Treatment	Phase
Smoking Cessation	Drug: Ganaxolone; Drug: Nicotine Patch	Phase 2

Detailed Description

The purpose of this proof-of-concept study is to evaluate whether expired air carbon monoxide (CO) will be reduced and smoking cessation success rates enhanced for smokers who receive the neurosteroid analog ganaxolone. The trial will be seeking preliminary indications of efficacy and tolerability in the smoking population and allow us to estimate effect sizes for future controlled trials.

Study Design

• Study Type: Interventional
• Actual Enrollment: 36 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Proof-Of-Concept Investigation With a Neurosteroid Analog (Ganaxolone) as a Smoking Cessation Candidate
• Study Start Date: Jun 1, 2013
• Actual Primary Completion Date: Jul 1, 2013
• Actual Study Completion Date: Feb 1, 2014

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Ganaxolone -- Nicotine Patch Pre-Quit Period: Ganaxolone -- 400mg daily for the first 3 days, 800mg daily for the next 3 days and 1200mg daily for the remainder of the first 2 wks. Nicotine Patches -- 21mg/24h nicotine patches applied daily during wks. 3 and 4. Post-Quit Period: Ganaxolone -- 1200mg daily for wk. 5, 800mg daily for 3 days, and 400mg daily for 3 days. Nicotine Patches -- 21mg/24h for 4 wks., 14mg/24h for 1 wk., and 7mg/24h for 1 wk.

Drug: Ganaxolone; Pre-Quit Period: Beginning at Session P1, subjects will receive ganaxolone at a dose of 400mg total daily (200mg bid) for the first three days, 800mg total daily (400mg bid) for the next three days and 1200mg total daily (600mg bid) for the remainder of the first four weeks. Post-Quit Period: Following the quit-day, subjects will receive ganaxolone at a dose of (1200mg total daily) for the next week. Down-titration of ganaxolone will begin at post-quit week two. Subjects will receive ganaxolone at a dose of 800mg total daily (400mg bid) to take for three days and 400mg total daily (200mg bid) to take for three.; Drug: Nicotine Patch; Pre-Quit Period: Beginning at Session P2, subjects will receive active 21mg/24h nicotine patches to apply daily for the next two weeks. Post-Quit Period: Following the quit-day, subjects will continue to apply active nicotine patches daily for the remainder of the study (21mg/24h for four weeks, 14mg/24h for one week, and 7mg/24h for one week).; Other Names: nicoderm

Outcome Measures

Primary Outcome Measures

1. Percentage of Change in Expired Air Carbon Monoxide (CO) at End of Week 2 [Baseline and 2 Weeks]

   To evaluate the effects of ganaxolone on ad lib smoking by looking at the percent change in expired air CO at the end of week two (relative to baseline).

Secondary Outcome Measures

1. Percentage of Change in Expired Air Carbon Monoxide (CO) at End of Week 4 [Baseline and 4 Weeks]

   To evaluate the effects of ganaxolone as an augmentation treatment in conjunction with nicotine patch by looking at the percent change in expired air CO at the end of week four (relative to baseline).

Other Outcome Measures

1. Number of Participants Completing Continuous 2-week Abstinence From Smoking [2 Weeks post quit]

   Continuous two week abstinence from smoking at the first post-quit visit (approximately 2 weeks post quit date), based on self-reported abstinence confirmed by expired air CO.

2. Number of Participants Completing Point Abstinence From Smoking Two Weeks After Quitting [7 day point abstinence from smoking at 2 weeks post quit]

   Point abstinence from smoking two weeks post quit, based on self-reported abstinence during last seven days confirmed by expired air CO at first post-quit visit.

3. Number of Participants Completing Continuous 6-week Abstinence From Smoking [6 Weeks post quit]

   Continuous six week abstinence from smoking at final study visit (approximately 6 weeks post quit date), based on self-reported abstinence confirmed by expired air CO

4. Number of Participants Completing Abstinence From Smoking During the Last Four Weeks of Treatment [4 Week abstinence from smoking at 6 weeks post quit]

   End of treatment abstinence from smoking during the last four weeks of treatment, based on self-reported abstinence during last four weeks confirmed by expired air CO

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Have no known serious medical conditions;

• Are 18-65 years old;

• Smoke an average of at least 10 cigarettes per day;

• Have smoked at least one cumulative year;

• Have an expired air CO reading of at least 10ppm;

• Able to read and understand English;

• Express a desire to quit smoking in the next thirty days.

Potential subjects must agree to use acceptable contraception during their participation in this study.

Potential subjects must agree to avoid the following during their participation in this study:

• participation in any other nicotine-related modification strategy outside of this protocol;

• use of tobacco products other than cigarettes, including pipe tobacco, cigars, e-cigarettes, snuff, and chewing tobacco;

• use of experimental (investigational) drugs or devices;

• use of illegal drugs;

• use of opiate medications;

• consumption of grapefruit or grapefruit juice for the first six weeks of study participation;

• use of melatonin;

• use of sedating antihistamines for the first six weeks of study participation;

• use of alcohol during the first six weeks of study participation.

• use of benzodiazepines

Exclusion Criteria:

• Inability to attend all required experimental sessions;

• Inability to take oral drugs or adhere to medication regimens;

• Hypertension (systolic >140 mm Hg, diastolic >90 mm Hg);

• Hypotension with symptoms (systolic <90 mm Hg, diastolic <60 mm Hg).

• Coronary heart disease;

• Lifetime history of heart attack;

• Clinically significant cardiac rhythm disorder (irregular heart rhythm);

• Chest pains;

• Cardiac (heart) disorder;

• Extensive active skin disorder;

• Liver or kidney disorder;

• Gastrointestinal disease other than gastroesophageal reflux or heartburn;

• Active ulcers in the past 30 days;

• Currently symptomatic lung disorder/disease;

• Brain abnormality;

• Migraine headaches that occur more frequently than once per week;

• History of seizures;

• Recent, unexplained fainting spells;

• Problems giving blood samples;

• Diabetes (unless treated with diet and exercise alone);

• Current cancer or treatment for cancer in the past six months (except basal or squamous cell skin cancer);

• Other major medical condition;

• Current symptomatic psychiatric disease;

• Current depression;

• Current suicidal ideation or history of suicide attempt (in the past 5 years);

• Pregnant or nursing mothers;

• Use (within the past 30 days) of:

• Illegal drugs (or if the urine drug screen is positive),

• Experimental (investigational) drugs;

• Psychiatric medications including antidepressants, antipsychotics or any other medications that are known to affect smoking cessation (e.g. clonidine);

• Corticosteroids;

• Cytochrome P450 341 (CYP3A4) inhibitors and inducers;

• Smokeless tobacco (chewing tobacco, snuff), pipes or e-cigarettes;

• Wellbutrin, bupropion, Zyban, Chantix, varenicline, nicotine replacement therapy or any other smoking cessation aid.

• Use (within the past 14 days) of:

• dehydroepiandrosterone (DHEA), Pregnenolone or ganaxolone;

• Opiate medications for pain or sleep;

• Benzodiazepines or other drugs with significant sedating or anticholinergic activity;

• Use of more than one cigar a month;

• Regular alcohol use;

• Significant adverse reaction to nicotine patches in the past.

• Significant past adverse reaction to ganaxolone in the past.

• Current participation or recent participation (in the past 30 days) in another smoking study at our center or another research facility.

• Current participation in another research study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Duke Center for Smoking Cessation	Charlotte	North Carolina	United States	28210
2	Duke Center for Smoking Cessation	Durham	North Carolina	United States	27705
3	Duke Center for Smoking Cessation	Raleigh	North Carolina	United States	27609
4	Duke Center for Smoking Cessation	Winston-Salem	North Carolina	United States	27103

Sponsors and Collaborators

• Jed E. Rose
• National Institute on Drug Abuse (NIDA)

Investigators

• Principal Investigator: Jed E Rose, Ph.D., Duke University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Jed E. Rose, Professor, Department of Psychiatry and Behavioral Sciences, Duke University
• ClinicalTrials.gov Identifier: NCT01857531
• Other Study ID Numbers: Pro00041533; 1P50DA027840-01A1
• First Posted: May 20, 2013
• Last Update Posted: Sep 8, 2014
• Last Verified: Sep 1, 2014

• Keywords provided by Jed E. Rose, Professor, Department of Psychiatry and Behavioral Sciences, Duke University: Smoking Cessation; Quit Smoking; Ganaxolone; Nicotine Patch
• Additional relevant MeSH terms: Nicotine; Ganaxolone

Study Results

Participant Flow

Arm/Group Title	Ganaxolone -- Nicotine Patch
Arm/Group Description	Pre-Quit Period: Ganaxolone -- 400mg daily (200mg bid) for the first 3 days, 800mg daily (400mg bid) for the next 3 days and 1200mg daily (600mg bid) for the remainder of the first 2 wks. Nicotine Patches -- 21mg/24h nicotine patches applied daily during wks. 3 and 4. Post-Quit Period: Ganaxolone -- 1200mg daily for wk. 5, 800mg daily for 3 days, and 400mg daily for 3 days. Nicotine Patches -- 21mg/24h for 4 wks., 14mg/24h for 1 wk., and 7mg/24h for 1 wk.
Period Title: Overall Study
STARTED	16
COMPLETED	12
NOT COMPLETED	4

Baseline Characteristics

Arm/Group Title	Ganaxolone -- Nicotine Patch
Arm/Group Description	Pre-Quit Period: Ganaxolone -- 400mg daily for the first 3 days, 800mg daily for the next 3 days and 1200mg daily for the remainder of the first 2 wks. Nicotine Patches -- 21mg/24h nicotine patches applied daily during wks. 3 and 4. Post-Quit Period: Ganaxolone -- 1200mg daily for wk. 5, 800mg daily for 3 days, and 400mg daily for 3 days. Nicotine Patches -- 21mg/24h for 4 wks., 14mg/24h for 1 wk., and 7mg/24h for 1 wk.
Overall Participants	16
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	47.44 (9.94)
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	16 100%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	14 87.5%
Male	2 12.5%
Region of Enrollment (participants) [Number]
United States	16 100%

Outcome Measures

1. Primary Outcome

Title	Percentage of Change in Expired Air Carbon Monoxide (CO) at End of Week 2
Description	To evaluate the effects of ganaxolone on ad lib smoking by looking at the percent change in expired air CO at the end of week two (relative to baseline).
Time Frame	Baseline and 2 Weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ganaxolone -- Nicotine Patch
Arm/Group Description	Pre-Quit Period: Ganaxolone -- 400mg daily (200mg bid) for the first 3 days, 800mg daily (400mg bid) for the next 3 days and 1200mg daily (600mg bid) for the remainder of the first 2 wks. Nicotine Patches -- 21mg/24h nicotine patches applied daily during wks. 3 and 4. Post-Quit Period: Ganaxolone -- 1200mg daily for wk. 5, 800mg daily for 3 days, and 400mg daily for 3 days. Nicotine Patches -- 21mg/24h for 4 wks., 14mg/24h for 1 wk., and 7mg/24h for 1 wk.
Measure Participants	16
Mean (Standard Error) [percentage change]	-0.52 (7.38)

2. Secondary Outcome

Title	Percentage of Change in Expired Air Carbon Monoxide (CO) at End of Week 4
Description	To evaluate the effects of ganaxolone as an augmentation treatment in conjunction with nicotine patch by looking at the percent change in expired air CO at the end of week four (relative to baseline).
Time Frame	Baseline and 4 Weeks

Outcome Measure Data

Analysis Population Description

Three of the original 16 subjects dropped out prior to week 4, so only 13 subjects had a week 4 CO reading and could be included in this analysis.

Arm/Group Title	Ganaxolone -- Nicotine Patch
Arm/Group Description	Pre-Quit Period: Ganaxolone -- 400mg daily (200mg bid) for the first 3 days, 800mg daily (400mg bid) for the next 3 days and 1200mg daily (600mg bid) for the remainder of the first 2 wks. Nicotine Patches -- 21mg/24h nicotine patches applied daily during wks. 3 and 4. Post-Quit Period: Ganaxolone -- 1200mg daily for wk. 5, 800mg daily for 3 days, and 400mg daily for 3 days. Nicotine Patches -- 21mg/24h for 4 wks., 14mg/24h for 1 wk., and 7mg/24h for 1 wk.
Measure Participants	13
Mean (Standard Error) [percentage change]	-39.40 (8.96)

3. Other Pre-specified Outcome

Title	Number of Participants Completing Continuous 2-week Abstinence From Smoking
Description	Continuous two week abstinence from smoking at the first post-quit visit (approximately 2 weeks post quit date), based on self-reported abstinence confirmed by expired air CO.
Time Frame	2 Weeks post quit

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ganaxolone -- Nicotine Patch
Arm/Group Description	Pre-Quit Period: Ganaxolone -- 400mg daily (200mg bid) for the first 3 days, 800mg daily (400mg bid) for the next 3 days and 1200mg daily (600mg bid) for the remainder of the first 2 wks. Nicotine Patches -- 21mg/24h nicotine patches applied daily during wks. 3 and 4. Post-Quit Period: Ganaxolone -- 1200mg daily for wk. 5, 800mg daily for 3 days, and 400mg daily for 3 days. Nicotine Patches -- 21mg/24h for 4 wks., 14mg/24h for 1 wk., and 7mg/24h for 1 wk.
Measure Participants	16
Number (95% Confidence Interval) [participants]	3 18.8%

4. Other Pre-specified Outcome

Title	Number of Participants Completing Point Abstinence From Smoking Two Weeks After Quitting
Description	Point abstinence from smoking two weeks post quit, based on self-reported abstinence during last seven days confirmed by expired air CO at first post-quit visit.
Time Frame	7 day point abstinence from smoking at 2 weeks post quit

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ganaxolone -- Nicotine Patch
Arm/Group Description	Pre-Quit Period: Ganaxolone -- 400mg daily (200mg bid) for the first 3 days, 800mg daily (400mg bid) for the next 3 days and 1200mg daily (600mg bid) for the remainder of the first 2 wks. Nicotine Patches -- 21mg/24h nicotine patches applied daily during wks. 3 and 4. Post-Quit Period: Ganaxolone -- 1200mg daily for wk. 5, 800mg daily for 3 days, and 400mg daily for 3 days. Nicotine Patches -- 21mg/24h for 4 wks., 14mg/24h for 1 wk., and 7mg/24h for 1 wk.
Measure Participants	16
Number (95% Confidence Interval) [participants]	4 25%

5. Other Pre-specified Outcome

Title	Number of Participants Completing Continuous 6-week Abstinence From Smoking
Description	Continuous six week abstinence from smoking at final study visit (approximately 6 weeks post quit date), based on self-reported abstinence confirmed by expired air CO
Time Frame	6 Weeks post quit

Outcome Measure Data

Analysis Population Description

Because 6-week abstinence is counted backward from the final study visit, one additional subject (n=4) qualified as abstinent than at 2-weeks post-quit (n=3) due to the fact that the day(s) that one of the subjects smoked did not fall into the range evaluated at 6 weeks.

Arm/Group Title	Ganaxolone -- Nicotine Patch
Arm/Group Description	Pre-Quit Period: Ganaxolone -- 400mg daily (200mg bid) for the first 3 days, 800mg daily (400mg bid) for the next 3 days and 1200mg daily (600mg bid) for the remainder of the first 2 wks. Nicotine Patches -- 21mg/24h nicotine patches applied daily during wks. 3 and 4. Post-Quit Period: Ganaxolone -- 1200mg daily for wk. 5, 800mg daily for 3 days, and 400mg daily for 3 days. Nicotine Patches -- 21mg/24h for 4 wks., 14mg/24h for 1 wk., and 7mg/24h for 1 wk.
Measure Participants	16
Number (95% Confidence Interval) [participants]	4 25%

6. Other Pre-specified Outcome

Title	Number of Participants Completing Abstinence From Smoking During the Last Four Weeks of Treatment
Description	End of treatment abstinence from smoking during the last four weeks of treatment, based on self-reported abstinence during last four weeks confirmed by expired air CO
Time Frame	4 Week abstinence from smoking at 6 weeks post quit

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ganaxolone -- Nicotine Patch
Arm/Group Description	Pre-Quit Period: Ganaxolone -- 400mg daily (200mg bid) for the first 3 days, 800mg daily (400mg bid) for the next 3 days and 1200mg daily (600mg bid) for the remainder of the first 2 wks. Nicotine Patches -- 21mg/24h nicotine patches applied daily during wks. 3 and 4. Post-Quit Period: Ganaxolone -- 1200mg daily for wk. 5, 800mg daily for 3 days, and 400mg daily for 3 days. Nicotine Patches -- 21mg/24h for 4 wks., 14mg/24h for 1 wk., and 7mg/24h for 1 wk.
Measure Participants	16
Number (95% Confidence Interval) [participants]	5 31.3%

Adverse Events

Time Frame	Subjects were receiving study drugs for ten weeks. At each study session during this period subjects completed a questionnaire about side effects. Subjects were also told to contact us between study sessions if side effects were bothersome.
Arm/Group Title	Ganaxolone -- Nicotine Patch
Arm/Group Description	Pre-Quit Period: Ganaxolone -- 400mg daily (200mg bid) for the first 3 days, 800mg daily (400mg bid) for the next 3 days and 1200mg daily (600mg bid) for the remainder of the first 2 wks. Nicotine Patches -- 21mg/24h nicotine patches applied daily during wks. 3 and 4. Post-Quit Period: Ganaxolone -- 1200mg daily for wk. 5, 800mg daily for 3 days, and 400mg daily for 3 days. Nicotine Patches -- 21mg/24h for 4 wks., 14mg/24h for 1 wk., and 7mg/24h for 1 wk.
All Cause Mortality
	Ganaxolone -- Nicotine Patch
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Ganaxolone -- Nicotine Patch
	Affected / at Risk (%)	# Events
Total	0/16 (0%)
Other (Not Including Serious) Adverse Events
	Ganaxolone -- Nicotine Patch
	Affected / at Risk (%)	# Events
Total	16/16 (100%)
General disorders
Thirst	3/16 (18.8%)	4
Mouth irritation	1/16 (6.3%)	2
Dry mouth	1/16 (6.3%)	1
Musculoskeletal and connective tissue disorders
Muscle / joint pain	1/16 (6.3%)	1
Nervous system disorders
Headache	2/16 (12.5%)	2
Fatigue	11/16 (68.8%)	15
Dizziness	4/16 (25%)	5
Loss of balance	1/16 (6.3%)	1
Irritability	1/16 (6.3%)	1
Insomnia	1/16 (6.3%)	3
Nightmares	1/16 (6.3%)	1
Vivid dreams	3/16 (18.8%)	5
Psychiatric disorders
Anxiety	2/16 (12.5%)	2
Depression	1/16 (6.3%)	1
Skin and subcutaneous tissue disorders
Itching at patch site	5/16 (31.3%)	7
Rash at patch site	2/16 (12.5%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.