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: NCT00443898
• Collaborator: (none)
• Enrollment: 518
• Locations: 22
• Arms: 4
• Patients Per Site: 23.5

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: 518 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

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Efficacy Assessed by Complete Cure Rate 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. The complete cure was a composite binary variable defined as "Yes" if: Mycological cure (negative KOH and negative culture for dermatophytes) and No residual involvement of the target toenail "No" if otherwise

Secondary Outcome Measures

1. Efficacy Assessed by Mycological Cure (Negative Culture and Negative KOH Microscopy) at the End of Study After Treating Patients for 24 or 48 Weeks. [52 weeks]

   Mycological cure is defined as negative KOH microscopy and negative culture for dermatophytes. Mycological cure was a composite binary variable defined as "Yes"if : Negative microscopy and Negative culture for dermatophytes "No" if otherwise.

2. Efficacy Assessed by Clinical Efficacy at the End of Study After Treating Patients 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 Mycological cure (negative KOH and negative culture for dermatophytes) and = 10% residual involvement of the target toenail "No" if otherwise

3. Number of Participants Assessed With Adverse Events and Serious Adverse Events [52 weeks]

   An adverse event (AE) is any adverse change in health or side effect that occurs while the participant is receiving the treatment or within a previously specified period of time after the treatment has been completed. A Serious Adverse Event (SAE) is any untoward medical occurrence that results in death, is life-threatening requires, inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or requires intervention to prevent permanent impairment or damage.

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 terbinifine 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. Boni Elewski	Birmingham	Alabama	United States	35233
2	Dr. Stacy Smith	San Diego	California	United States	92123
3	Dr. James Swinehart	Denver	Colorado	United States	80210
4	Dr. David G. Armstrong	North Chicago	Illinois	United States	60064
5	Dr. Kevin Terry	Lutherville	Maryland	United States	21093
6	Dr. Anthony Puopolo	Milford	Massachusetts	United States	01757
7	Dr. John Fenyk	Chaska	Minnesota	United States	55318
8	Dr. Joel Schlessinger	Omaha	Nebraska	United States	68144
9	Dr. AnneMarie Uliasz	New York	New York	United States	10029
10	Dr. Willard Niemi	Raleigh	North Carolina	United States	27615
11	Dr. Diane Baker	Lake Oswego	Oregon	United States	97035
12	Dr. John Barnes	Portland	Oregon	United States	97205
13	Dr. Harry Penny	Altoona	Pennsylvania	United States	16602
14	Dr. Lawrence Parish	Philadelphia	Pennsylvania	United States	19103
15	Dr. Cynthia Strout	Mt. Pleasant	South Carolina	United States	29464
16	Dr. Teresa Coats	Austin	Texas	United States	78705
17	Dr. Scott J. Ashton	Dallas	Texas	United States	75243
18	Dr. Amit Pandya	Dallas	Texas	United States	75390-8802
19	Dr. Lawrence Harkless	San Antonio	Texas	United States	78207
20	Dr. Robert Shouey	Harrisonburg	Virginia	United States	22801
21	Novartis Investigative Site	Various cities		Canada
22	Novartis Investigative Site	Various cities		Iceland

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00443898
• Other Study ID Numbers: CSFO327N2301
• First Posted: Mar 7, 2007
• Last Update Posted: May 3, 2012
• Last Verified: May 1, 2012

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

Study Results

Participant Flow

Arm/Group Title	Terbinafine 24 w	Vehicle 24 w	Terbinafine 48 w	Vehicle 48 w
Arm/Group Description	Active terbinafine hydrochloride (HCl) 10 % Nail Solution for Onychomycosis (NSO) applied once daily for 24 weeks	vehicle (placebo) applied once daily for 24 weeks	Active terbinafine hydrochloride (HCl) 10 % Nail Solution for Onychomycosis (NSO) applied once daily for 48 weeks	vehicle (placebo) applied once daily for 48 weeks
Period Title: Overall Study
STARTED	126	128	136	128
COMPLETED	102	103	107	110
NOT COMPLETED	24	25	29	18

Baseline Characteristics

Arm/Group Title	Terbinafine 24 w	Vehicle 24 w	Terbinafine 48 w	Vehicle 48 w	Total
Arm/Group Description	Active terbinafine hydrochloride (HCl) 10 % Nail Solution for Onychomycosis (NSO) applied once daily for 24 weeks	vehicle (placebo) applied once daily for 24 weeks	Active terbinafine hydrochloride (HCl) 10 % Nail Solution for Onychomycosis (NSO) applied once daily for 48 weeks	vehicle (placebo) applied once daily for 48 weeks	Total of all reporting groups
Overall Participants	126	128	136	128	518
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	107 84.9%	101 78.9%	116 85.3%	100 78.1%	424 81.9%
>=65 years	19 15.1%	27 21.1%	20 14.7%	28 21.9%	94 18.1%
Sex: Female, Male (Count of Participants)
Female	25 19.8%	29 22.7%	26 19.1%	27 21.1%	107 20.7%
Male	101 80.2%	99 77.3%	110 80.9%	101 78.9%	411 79.3%

Outcome Measures

1. Primary Outcome

Title	Efficacy Assessed by Complete Cure Rate 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. The complete cure was a composite binary variable defined as "Yes" if: Mycological cure (negative KOH and negative culture for dermatophytes) and No residual involvement of the target toenail "No" if otherwise
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

All participants were included in the intention to treat (ITT) population, defined as all participants who were randomized and received study drug. The Last Observation was Carried Forward (LOCF).

Arm/Group Title	Terbinafine 24 w	Vehicle 24 w	Terbinafine 48 w	Vehicle 48 w
Arm/Group Description	Active terbinafine hydrochloride (HCl) 10 % Nail Solution for Onychomycosis (NSO) applied once daily for 24 weeks	vehicle (placebo) applied once daily for 24 weeks	Active terbinafine hydrochloride (HCl) 10 % Nail Solution for Onychomycosis (NSO) applied once daily for 48 weeks	vehicle (placebo) applied once daily for 48 weeks
Measure Participants	126	128	136	128
Number [Percentage of Participants]	0.79 0.6%	0.78 0.6%	1.47 1.1%	0.00 0%

2. Secondary Outcome

Title	Efficacy Assessed by Mycological Cure (Negative Culture and Negative KOH Microscopy) at the End of Study After Treating Patients for 24 or 48 Weeks.
Description	Mycological cure is defined as negative KOH microscopy and negative culture for dermatophytes. Mycological cure was a composite binary variable defined as "Yes"if : Negative microscopy and Negative culture for dermatophytes "No" if otherwise.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

All participants were included in the intention to treat (ITT) population, defined as all participants who were randomized and received study drug. The Last Observation was Carried Forward (LOCF).

Arm/Group Title	Terbinafine 24 w	Vehicle 24 w	Terbinafine 48 w	Vehicle 48 w
Arm/Group Description	Active terbinafine hydrochloride (HCl) 10 % Nail Solution for Onychomycosis (NSO) applied once daily for 24 weeks	vehicle (placebo) applied once daily for 24 weeks	Active terbinafine hydrochloride (HCl) 10 % Nail Solution for Onychomycosis (NSO) applied once daily for 48 weeks	vehicle (placebo) applied once daily for 48 weeks
Measure Participants	126	128	136	128
Number [Percentage of Participants]	10.32 8.2%	6.25 4.9%	15.44 11.4%	3.13 2.4%

3. Secondary Outcome

Title	Efficacy Assessed by Clinical Efficacy at the End of Study After Treating Patients 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 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

All participants were included in the intention to treat (ITT) population, defined as all participants who were randomized and received study drug. The Last Observation was Carried Forward (LOCF).

Arm/Group Title	Terbinafine 24 w	Vehicle 24 w	Terbinafine 48 w	Vehicle 48 w
Arm/Group Description	Active terbinafine hydrochloride (HCl) 10 % Nail Solution for Onychomycosis (NSO) applied once daily for 24 weeks	vehicle (placebo) applied once daily for 24 weeks	Active terbinafine hydrochloride (HCl) 10 % Nail Solution for Onychomycosis (NSO) applied once daily for 48 weeks	vehicle (placebo) applied once daily for 48 weeks
Measure Participants	126	128	136	128
Number [Percentage of Participants]	1.59 1.3%	2.34 1.8%	3.68 2.7%	1.56 1.2%

4. Secondary Outcome

Title	Number of Participants Assessed With Adverse Events and Serious Adverse Events
Description	An adverse event (AE) is any adverse change in health or side effect that occurs while the participant is receiving the treatment or within a previously specified period of time after the treatment has been completed. A Serious Adverse Event (SAE) is any untoward medical occurrence that results in death, is life-threatening requires, inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or requires intervention to prevent permanent impairment or damage.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Safety Population was defined as all participants who received at least one dose of study drug and had at least one post-baseline safety assessment. All except 4 participants who were randomized to the vehicle 24 w group and one participant randomized to the terbinafine 48 w group, were included in the safety population.

Arm/Group Title	Terbinafine 24 w	Vehicle 24 w	Terbinafine 48 w	Vehicle 48 w
Arm/Group Description	Active terbinafine hydrochloride (HCl) 10 % Nail Solution for Onychomycosis (NSO) applied once daily for 24 weeks	vehicle (placebo) applied once daily for 24 weeks	Active terbinafine hydrochloride (HCl) 10 % Nail Solution for Onychomycosis (NSO) applied once daily for 48 weeks	vehicle (placebo) applied once daily for 48 weeks
Measure Participants	126	124	135	128
Number [Participants]	126 100%	124 96.9%	135 99.3%	128 100%

Adverse Events

Time Frame	52 weeks
Adverse Event Reporting Description	Safety Population was defined as all participants who received at least one dose of study drug and had at least one post-baseline safety assessment. All except 4 participants who were randomized to the vehicle 24 w group and one participant randomized to the terbinafine 48 w group, were included in the safety population.
Arm/Group Title	Terbinafine 24 w		Vehicle 24 w		Terbinafine 48 w		Vehicle 48 w
Arm/Group Description	Active terbinafine hydrochloride (HCl) 10 % Nail Solution for Onychomycosis (NSO) applied once daily for 24 weeks		vehicle (placebo) applied once daily for 24 weeks		Active terbinafine hydrochloride (HCl) 10 % Nail Solution for Onychomycosis (NSO) applied once daily for 48 weeks		vehicle (placebo) applied once daily for 48 weeks
All Cause Mortality
	Terbinafine 24 w		Vehicle 24 w		Terbinafine 48 w		Vehicle 48 w
	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 w		Vehicle 24 w		Terbinafine 48 w		Vehicle 48 w
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/126 (1.6%)		7/124 (5.6%)		7/135 (5.2%)		4/128 (3.1%)
Cardiac disorders
Cardiac failure congestive	0/126 (0%)		0/124 (0%)		0/135 (0%)		1/128 (0.8%)
Gastrointestinal disorders
Gastric ulcer perforation	0/126 (0%)		0/124 (0%)		1/135 (0.7%)		0/128 (0%)
General disorders
Accidental death	0/126 (0%)		1/124 (0.8%)		0/135 (0%)		0/128 (0%)
Chest discomfort	0/126 (0%)		0/124 (0%)		1/135 (0.7%)		0/128 (0%)
Infections and infestations
Appendicitis	0/126 (0%)		0/124 (0%)		2/135 (1.5%)		0/128 (0%)
Cellulitis	0/126 (0%)		0/124 (0%)		0/135 (0%)		1/128 (0.8%)
Pneumonia	0/126 (0%)		1/124 (0.8%)		0/135 (0%)		0/128 (0%)
Injury, poisoning and procedural complications
Lower limb fracture	0/126 (0%)		0/124 (0%)		1/135 (0.7%)		1/128 (0.8%)
Tendon rupture	0/126 (0%)		1/124 (0.8%)		0/135 (0%)		0/128 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Endometrial cancer	0/126 (0%)		1/124 (0.8%)		0/135 (0%)		0/128 (0%)
Metastatic malignant melanoma	0/126 (0%)		1/124 (0.8%)		0/135 (0%)		0/128 (0%)
Multiple myeloma	0/126 (0%)		0/124 (0%)		0/135 (0%)		1/128 (0.8%)
Prostate cancer	1/126 (0.8%)		1/124 (0.8%)		1/135 (0.7%)		0/128 (0%)
Nervous system disorders
Cerebral haemorrhage	0/126 (0%)		0/124 (0%)		1/135 (0.7%)		0/128 (0%)
Convulsion	1/126 (0.8%)		0/124 (0%)		0/135 (0%)		0/128 (0%)
Headache	0/126 (0%)		0/124 (0%)		1/135 (0.7%)		0/128 (0%)
Syncope	0/126 (0%)		1/124 (0.8%)		0/135 (0%)		0/128 (0%)
Syncope vasovagal	0/126 (0%)		1/124 (0.8%)		0/135 (0%)		0/128 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/126 (0%)		0/124 (0%)		1/135 (0.7%)		0/128 (0%)
Other (Not Including Serious) Adverse Events
	Terbinafine 24 w		Vehicle 24 w		Terbinafine 48 w		Vehicle 48 w
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	35/126 (27.8%)		38/124 (30.6%)		47/135 (34.8%)		56/128 (43.8%)
General disorders
Influenza like illness	2/126 (1.6%)		1/124 (0.8%)		0/135 (0%)		8/128 (6.3%)
Infections and infestations
Nasopharyngitis	7/126 (5.6%)		9/124 (7.3%)		18/135 (13.3%)		18/128 (14.1%)
Upper respiratory tract infection	4/126 (3.2%)		6/124 (4.8%)		8/135 (5.9%)		8/128 (6.3%)
Musculoskeletal and connective tissue disorders
Back pain	7/126 (5.6%)		7/124 (5.6%)		9/135 (6.7%)		10/128 (7.8%)
Nervous system disorders
Headache	23/126 (18.3%)		24/124 (19.4%)		23/135 (17%)		29/128 (22.7%)

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.