Efficacy Safety, and Tolerability of Topical Terbinafine in Patients With Mild to Moderate Toenail Fungus of the Big Toenail

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00443820
• Collaborator: (none)
• Enrollment: 526
• Locations: 23
• Arms: 4
• Duration (Months): 18
• Patients Per Site: 22.9
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

This study is designed to assess the efficacy, safety and tolerability of a topical formulation of terbinafine solution applied daily in patients with toenail fungus. This trial will study patients with mild to moderate toenail fungus disease of the big toenail and their responses to two treatment durations, 24 or 48 weeks.

Condition or Disease	Intervention/Treatment	Phase
Onychomycosis	Drug: terbinafine; Drug: Placebo; Drug: terbinafine; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 526 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Vehicle-controlled, Multicenter, Parallel Group Study to Assess the Efficacy, Safety, and Tolerability of Topical Terbinafine Hydrogen Chloride (HCl) Formulation for 24 or 48 Weeks of Treatment in Patients With Mild to Moderate Toenail Onychomycosis
• Study Start Date: Dec 1, 2006
• Actual Primary Completion Date: Jun 1, 2008
• Actual Study Completion Date: Jun 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Terbinafine hydrochloride (HCl) 10 % Nail Solution for Onychomycosis (NSO) for 48 weeks	Drug: terbinafine; Terbinafine hydrochloride (HCl) 10 % nail solution for onychomycosis (NSO) once daily for 48 weeks; Other Names: Lamisil
Placebo Comparator: 2 Vehicle (placebo) for 48 weeks	Drug: Placebo; Vehicle (placebo) once daily for 48 weeks
Experimental: 3 Terbinafine hydrochloride (HCl) 10 % Nail Solution for Onychomycosis (NSO) for 24 weeks	Drug: terbinafine; Terbinafine hydrochloride (HCl) 10 % Nail Solution for Onychomycosis once daily for 24 weeks; Other Names: Lamisil
Placebo Comparator: 4 Vehicle (placebo) for 24 weeks	Drug: Placebo; Vehicle (placebo) once daily for 24 weeks

Outcome Measures

Primary Outcome Measures

1. Efficacy Assessed by the Percentage of Participants With Complete Cure at the End of Study (Week 52) After Treating for 24 or 48 Weeks [52 weeks]

   Complete cure is defined as negative KOH microscopy and negative culture for dermatophytes and no residual involvement of the target toenail.

Secondary Outcome Measures

1. Efficacy Assessed by the Percentage of Participants With Mycological Cure at the End of Study After Treating Participants for 24 or 48 Weeks [52 weeks]

   Mycological cure is defined as negative KOH microscopy and negative culture for dermatophytes.

2. Efficacy Assessed by the Percentage of Participants With Clinical Effectiveness at the End of Study After Treating Participants for 24 or 48 Weeks [52 weeks]

   Clinical effectiveness is defined as negative KOH microscopy and negative culture for dermatophytes and <= 10% residual involvement of the target toenail. Clinical effectiveness was a composite binary variable defined as "Yes" if: If mycological cure (negative KOH and negative culture for dermatophytes) and = 10% residual involvement of the target toenail "No" if otherwise

3. Safety and Tolerability Assessed by the Number of Participants With Adverse Events [52 weeks]

   Safety and tolerability data as assessed by the number of participants with Adverse Events (AE), Serious Adverse Events, Drug discontinuation due to an AE and death. Additional details can be found in the Adverse Event Section.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male and females 12 - 75 years of age

• Fungal toenail infection of one or both of the large (great) toenails

• The nail infection must be due to a dermatophyte, (mixed infections dermatophyte and non-dermatophyte] are not allowed)

Exclusion Criteria:

• Target foot must not have severe plantar (moccasin) tinea pedis that would require systemic therapy. Mild to moderate tinea pedis (athlete's foot) infection should be treated with terbinafine prior to baseline or at any time during the trial. Other topical treatments for athlete's foot may be recommended at the discretion of the investigator.

• Subjects must not have abnormalities of the nail that could prevent a normal appearing nail if clearing of infection is achieved

• No administration of systemic antifungal medications within 6 months prior to screening visit

• No application of prescription topical antifungal medications for toenail fungus within 3 months or other commercially available topical medications for toenail fungus applied directly to the toenails within 1 month prior to screening visit

• No professional pedicures or application of any nail polish product or nail cosmetic to the toenails after the screening visit

• Known pregnancy or lactation at time of enrollment

Other protocol-defined inclusion/exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Dr. Fred D. Youngswick	Novato	California	United States	94945
2	Dr. Larry Doehring	Northglenn	Colorado	United States	80234
3	Dr. Robert P. Dunne	Melbourne	Florida	United States	32935
4	Dr. Mark Ling	Newnan	Georgia	United States	30263
5	Dr. Jesse Plasencia	Chicago	Illinois	United States	60632
6	Dr. John Mallory	Overland Park	Kansas	United States	66215
7	Dr. Jeffrey Conrow	Topeka	Kansas	United States	66606
8	Dr.Michael Kaye	Covington	Louisiana	United States	70433
9	Dr. Max Weisfeld	Baltimore	Maryland	United States	21214
10	Dr. Linda Stein-Gold	Detroit	Michigan	United States	48202
11	Dr. Anna Glaser	St. Louis	Missouri	United States	63104
12	Dr. Richard Scher	New York	New York	United States	10032
13	Dr. Joseph Jorrizo	Winston Salem	North Carolina	United States	27157
14	Dr. Anne Lucky	Cincinnati	Ohio	United States	45230
15	Dr. Rich Phoebe	Portland	Oregon	United States	97210
16	Dr. Patricia Westmorland	Simpsonville	South Carolina	United States	29681
17	Dr. David Horowitz	Nashville	Tennessee	United States	37203
18	Dr. Jay Lifshen	Irving,	Texas	United States	75061
19	Dr. Richard Pollak	San Antonio	Texas	United States	78229
20	Dr. Patrick Agnew	Virginia Beach	Virginia	United States	23464
21	Novartis Investigative Site	Various Cities		France
22	Novartis	Investigative Site		Germany
23	Novartis Investigative Site	Various cities		Germany

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00443820
• Other Study ID Numbers: CSFO327N2302
• First Posted: Mar 6, 2007
• Last Update Posted: Apr 19, 2011
• Last Verified: Mar 1, 2011

• Keywords provided by , ,: Toenail fungus; Onychomycosis; Nail fungus; Toenail fungal infection; Tinea unguium; Dermatophytes; Foot dermatoses
• Additional relevant MeSH terms: Onychomycosis; Terbinafine

Study Results

Participant Flow

Recruitment Details	This randomized, double -blind, vehicle -controlled, multicenter, parallel group study was designed to assess the efficacy, safety and tolerability of a topical formulation of terbinafine hydrogen chloride 10% topical solution (TTS10%) applied daily in patients with toenail onychomycosis. Started 07 DEC 2006 and ending 27 JUN 2008.

Arm/Group Title	Terbinafine 24 Weeks	Vehicle 24 Weeks	Terbinafine 48 Weeks	Vehicle 48 Weeks
Arm/Group Description	Terbinafine hydrochloride (HCl) 10 % Nail Solution for Onychomycosis (NSO) for 24 weeks	Vehicle (placebo) for 24 weeks	Terbinafine hydrochloride (HCl) 10 % Nail Solution for Onychomycosis (NSO) for 48 weeks	Vehicle (placebo) for 48 weeks
Period Title: Overall Study
STARTED	133	130	135	128
Safety Population	131	129	134	126
COMPLETED	112	111	117	111
NOT COMPLETED	21	19	18	17

Baseline Characteristics

Arm/Group Title	Terbinafine 24 Weeks	Vehicle 24 Weeks	Terbinafine 48 Weeks	Vehicle 48 Weeks	Total
Arm/Group Description	Terbinafine hydrochloride (HCl) 10 % Nail Solution for Onychomycosis (NSO) for 24 weeks	Vehicle (placebo) for 24 weeks	Terbinafine hydrochloride (HCl) 10 % Nail Solution for Onychomycosis (NSO) for 48 weeks	Vehicle (placebo) for 48 weeks	Total of all reporting groups
Overall Participants	133	130	135	128	526
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	1 0.8%	1 0.2%
Between 18 and 65 years	93 69.9%	103 79.2%	95 70.4%	97 75.8%	388 73.8%
>=65 years	40 30.1%	27 20.8%	40 29.6%	30 23.4%	137 26%
Sex: Female, Male (Count of Participants)
Female	34 25.6%	39 30%	41 30.4%	35 27.3%	149 28.3%
Male	99 74.4%	91 70%	94 69.6%	93 72.7%	377 71.7%

Outcome Measures

1. Primary Outcome

Title	Efficacy Assessed by the Percentage of Participants With Complete Cure at the End of Study (Week 52) After Treating for 24 or 48 Weeks
Description	Complete cure is defined as negative KOH microscopy and negative culture for dermatophytes and no residual involvement of the target toenail.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Intent to treat (ITT) population, Last observation carried forward (LOCF)

Arm/Group Title	Terbinafine 24 Weeks	Vehicle 24 Weeks	Terbinafine 48 Weeks	Vehicle 48 Weeks
Arm/Group Description	Terbinafine hydrochloride (HCl) 10 % Nail Solution for Onychomycosis (NSO) for 24 weeks	Vehicle (placebo) for 24 weeks	Terbinafine hydrochloride (HCl) 10 % Nail Solution for Onychomycosis (NSO) for 48 weeks	Vehicle (placebo) for 48 weeks
Measure Participants	133	130	135	128
Number [Percentage of participants]	1.50 1.1%	0.77 0.6%	2.96 2.2%	0 0%

2. Secondary Outcome

Title	Efficacy Assessed by the Percentage of Participants With Mycological Cure at the End of Study After Treating Participants for 24 or 48 Weeks
Description	Mycological cure is defined as negative KOH microscopy and negative culture for dermatophytes.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Intent to treat (ITT) population, Last observation carried forward (LOCF)

Arm/Group Title	Terbinafine 24 Weeks	Vehicle 24 Weeks	Terbinafine 48 Weeks	Vehicle 48 Weeks
Arm/Group Description	Terbinafine hydrochloride (HCl) 10 % Nail Solution for Onychomycosis (NSO) for 24 weeks	Vehicle (placebo) for 24 weeks	Terbinafine hydrochloride (HCl) 10 % Nail Solution for Onychomycosis (NSO) for 48 weeks	Vehicle (placebo) for 48 weeks
Measure Participants	133	130	135	128
Number [Percentage of participants]	15.04 11.3%	6.15 4.7%	22.22 16.5%	7.81 6.1%

3. Secondary Outcome

Title	Efficacy Assessed by the Percentage of Participants With Clinical Effectiveness at the End of Study After Treating Participants for 24 or 48 Weeks
Description	Clinical effectiveness is defined as negative KOH microscopy and negative culture for dermatophytes and <= 10% residual involvement of the target toenail. Clinical effectiveness was a composite binary variable defined as "Yes" if: If mycological cure (negative KOH and negative culture for dermatophytes) and = 10% residual involvement of the target toenail "No" if otherwise
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Intent to treat (ITT) population, Last observation carried forward (LOCF)

Arm/Group Title	Terbinafine 24 Weeks	Vehicle 24 Weeks	Terbinafine 48 Weeks	Vehicle 48 Weeks
Arm/Group Description	Terbinafine hydrochloride (HCl) 10 % Nail Solution for Onychomycosis (NSO) for 24 weeks	Vehicle (placebo) for 24 weeks	Terbinafine hydrochloride (HCl) 10 % Nail Solution for Onychomycosis (NSO) for 48 weeks	Vehicle (placebo) for 48 weeks
Measure Participants	133	130	135	128
Number [Percentage of participants]	3.01 2.3%	0.77 0.6%	5.93 4.4%	0.78 0.6%

4. Secondary Outcome

Title	Safety and Tolerability Assessed by the Number of Participants With Adverse Events
Description	Safety and tolerability data as assessed by the number of participants with Adverse Events (AE), Serious Adverse Events, Drug discontinuation due to an AE and death. Additional details can be found in the Adverse Event Section.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Terbinafine 24 Weeks	Vehicle 24 Weeks	Terbinafine 48 Weeks	Vehicle 48 Weeks
Arm/Group Description	Terbinafine hydrochloride (HCl) 10 % Nail Solution for Onychomycosis (NSO) for 24 weeks	Vehicle (placebo) for 24 weeks	Terbinafine hydrochloride (HCl) 10 % Nail Solution for Onychomycosis (NSO) for 48 weeks	Vehicle (placebo) for 48 weeks
Measure Participants	131	129	134	126
At least 1 AE	80 60.2%	72 55.4%	94 69.6%	87 68%
At least 1 SAE	8 6%	3 2.3%	9 6.7%	7 5.5%
Study drug discontinued due to an AE	0 0%	1 0.8%	1 0.7%	0 0%
Death	0 0%	0 0%	1 0.7%	0 0%

Adverse Events

Time Frame	52 weeks
Adverse Event Reporting Description	Safety population consisting of all participants who had at least one dose of study drug and had at least one post-baseline safety assessment.
Arm/Group Title	Terbinafine 24 Weeks		Vehicle 24 Weeks		Terbinafine 48 Weeks		Vehicle 48 Weeks
Arm/Group Description	Terbinafine hydrochloride (HCl) 10 % Nail Solution for Onychomycosis (NSO) for 24 weeks		Vehicle (placebo) for 24 weeks		Terbinafine hydrochloride (HCl) 10 % Nail Solution for Onychomycosis (NSO) for 48 weeks		Vehicle (placebo) for 48 weeks
All Cause Mortality
	Terbinafine 24 Weeks		Vehicle 24 Weeks		Terbinafine 48 Weeks		Vehicle 48 Weeks
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Terbinafine 24 Weeks		Vehicle 24 Weeks		Terbinafine 48 Weeks		Vehicle 48 Weeks
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/131 (6.1%)		3/129 (2.3%)		9/134 (6.7%)		7/126 (5.6%)
Cardiac disorders
Acute coronary syndrome	1/131 (0.8%)		0/129 (0%)		0/134 (0%)		0/126 (0%)
Angina pectoris	1/131 (0.8%)		0/129 (0%)		0/134 (0%)		0/126 (0%)
Arrhythmia	1/131 (0.8%)		0/129 (0%)		0/134 (0%)		0/126 (0%)
Myocardial infarction	1/131 (0.8%)		0/129 (0%)		1/134 (0.7%)		0/126 (0%)
Tachycardia	0/131 (0%)		0/129 (0%)		0/134 (0%)		1/126 (0.8%)
Gastrointestinal disorders
Constipation	0/131 (0%)		0/129 (0%)		0/134 (0%)		1/126 (0.8%)
Gastric ulcer	0/131 (0%)		1/129 (0.8%)		0/134 (0%)		0/126 (0%)
Infections and infestations
Cellulitis	0/131 (0%)		0/129 (0%)		1/134 (0.7%)		0/126 (0%)
Pneumonia	0/131 (0%)		0/129 (0%)		0/134 (0%)		1/126 (0.8%)
Injury, poisoning and procedural complications
Near drowning	0/131 (0%)		0/129 (0%)		1/134 (0.7%)		0/126 (0%)
Subdural haematoma	0/131 (0%)		0/129 (0%)		1/134 (0.7%)		0/126 (0%)
Metabolism and nutrition disorders
Hypocalcaemia	0/131 (0%)		0/129 (0%)		0/134 (0%)		1/126 (0.8%)
Musculoskeletal and connective tissue disorders
Back pain	0/131 (0%)		0/129 (0%)		1/134 (0.7%)		1/126 (0.8%)
Intervertebral disc protrusion	0/131 (0%)		0/129 (0%)		1/134 (0.7%)		0/126 (0%)
Osteoarthritis	0/131 (0%)		0/129 (0%)		1/134 (0.7%)		0/126 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder cancer	1/131 (0.8%)		0/129 (0%)		0/134 (0%)		0/126 (0%)
Bladder neoplasm	1/131 (0.8%)		0/129 (0%)		0/134 (0%)		0/126 (0%)
Breast cancer	0/131 (0%)		0/129 (0%)		1/134 (0.7%)		0/126 (0%)
Cervix carcinoma	0/131 (0%)		0/129 (0%)		1/134 (0.7%)		0/126 (0%)
Malignant melanoma	1/131 (0.8%)		0/129 (0%)		0/134 (0%)		0/126 (0%)
Malignant melanoma in situ	0/131 (0%)		0/129 (0%)		0/134 (0%)		1/126 (0.8%)
Meningioma	0/131 (0%)		1/129 (0.8%)		0/134 (0%)		0/126 (0%)
Prostate cancer	2/131 (1.5%)		0/129 (0%)		0/134 (0%)		0/126 (0%)
Nervous system disorders
Sciatica	0/131 (0%)		0/129 (0%)		0/134 (0%)		1/126 (0.8%)
Renal and urinary disorders
Bladder prolapse	0/131 (0%)		0/129 (0%)		0/134 (0%)		1/126 (0.8%)
Dysuria	0/131 (0%)		0/129 (0%)		0/134 (0%)		1/126 (0.8%)
Micturition disorder	0/131 (0%)		0/129 (0%)		0/134 (0%)		1/126 (0.8%)
Renal failure	0/131 (0%)		1/129 (0.8%)		0/134 (0%)		0/126 (0%)
Reproductive system and breast disorders
Epididymitis	0/131 (0%)		0/129 (0%)		0/134 (0%)		1/126 (0.8%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/131 (0%)		0/129 (0%)		1/134 (0.7%)		0/126 (0%)
Other (Not Including Serious) Adverse Events
	Terbinafine 24 Weeks		Vehicle 24 Weeks		Terbinafine 48 Weeks		Vehicle 48 Weeks
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	37/131 (28.2%)		38/129 (29.5%)		54/134 (40.3%)		52/126 (41.3%)
Infections and infestations
Influenza	2/131 (1.5%)		1/129 (0.8%)		13/134 (9.7%)		10/126 (7.9%)
Nasopharyngitis	13/131 (9.9%)		11/129 (8.5%)		15/134 (11.2%)		15/126 (11.9%)
Sinusitis	3/131 (2.3%)		0/129 (0%)		4/134 (3%)		7/126 (5.6%)
Upper respiratory tract infection	4/131 (3.1%)		4/129 (3.1%)		4/134 (3%)		10/126 (7.9%)
Musculoskeletal and connective tissue disorders
Back pain	8/131 (6.1%)		7/129 (5.4%)		6/134 (4.5%)		12/126 (9.5%)
Nervous system disorders
Headache	21/131 (16%)		21/129 (16.3%)		28/134 (20.9%)		23/126 (18.3%)
Vascular disorders
Hypertension	1/131 (0.8%)		3/129 (2.3%)		8/134 (6%)		4/126 (3.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.