Onychomycosis
Conditions
Keywords
Nail fungus, Onychomycosis, Itraconazole, Toenail
Brief summary
Onychomycosis is a common condition accounting for approximately half of all nail disorders. It is most commonly caused by dermatophytes. Itraconazole has been approved for the treatment of onychomycosis in the United States with an approved dosage regimen for the treatment of onychomycosis of the toenail of once daily (QD) treatment with 200mg of itraconazole (two 100 mg capsules) for 12 weeks. Barrier Therapeutics has developed a 200 mg tablet which could be used in a more convenient one-tablet-per-day dosing regimen. This clinical trial will compare the efficacy and safety of this new tablet formulation with itraconazole capsules and placebo.
Detailed description
Onychomycosis is common and accounts for about half of all nail disorders. Usually the cause is due to dermatophytes, either Trichophyton rubrum (71%) or Trichophyton mentagrophytes (20%) but may also be due to yeast infection, usually Candida albicans. The prevalence of onychomycosis in the United States population as a whole is 13% and is more prevalent in the elderly (60%). Onychomycosis of the toenail recurs and is thought to have a genetic component. Onychomycosis can result in permanent nail deformity. This disease has a significant impact on the patient's quality of life (e.g., concern with the appearance of the toenails and fingernails, interference with wearing shoes, walking and sports activities). Itraconazole has been approved for the treatment of onychomycosis in the United States since the mid-nineteen-nineties. The approved dosage regimen for treatment of onychomycosis of the toenail is once daily (QD) treatment with 200 mg of itraconazole (Sporanox®, Janssen Pharmaceutical Products, L.P., Titusville, NJ, USA) for 12 weeks. The approved dosage form is a 100mg capsule. Barrier Therapeutics has developed a 200mg tablet which could be used in a more convenient one-tablet-per-day dosing regimen. This clinical trial will compare the efficacy and safety of this new tablet formulation with itraconazole capsules and placebo.
Interventions
DRUGItraconazole 100mg capsules
Subjects took two 100mg capsules once per day after a full meal. The dose dose was taken the day before the Week 12 visit.
DRUGItraconazole 200mg tablets
Subjects took one 200mg tablet once per day after a full meal. The last dose was taken the day before the Week 12 visit.
DRUGPlacebo tablets
Placebo tablets are the same as the Itraconazole tablets but without the active drug included. Subjects took one tablet once per day after a full meal. The last tablet was taken the day before the Week 12 visit.
Sponsors
GlaxoSmithKline
Stiefel, a GSK Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Investigator)
Eligibility
Sex/Gender
ALL
Age
16 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Clinical diagnosis of onychomycosis of at least one great toenail * Percent Nail Involvement Score of the more severely affected great toenail (the Target Toenail) must be between 2 and 3 (25-75% of the nail unit). * Length of Unaffected Part of the Target Toenail ≥2mm * Direct microscopic examination with KOH that is positive for the hyphae associated with dermatophytes on the target toenail * Subjects must have signed informed consent * If the subject is woman of childbearing potential, she must have a negative urine pregnancy test and agree to use an effective form of birth control until the first menses after 60 days following the last dose of study medication.
Exclusion criteria
* Onychomycosis caused by Candida spp. without the presence of a dermatophyte * Participation in a clinical trial for the systemic treatment of onychomycosis of the toenail within 24 weeks prior to Visit 1 * Use of systemic antifungals within 12 weeks prior to Visit 1 * Use of topical antifungal nail lacquer within 30 days prior to Visit 1 * Use of any other topical onychomycosis treatment on any toenail within 7 days prior to Visit 1 * Evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF * Known liver disease or a history of liver toxicity with other drugs * Use of systemic immunosuppressants
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical and Mycological Cure of Target Toenail | 1 year | This study was designed to evaluate the superiority of itraconazole tablets to placebo tablets. Clinical Cure was defined as an IGA score of 0 for the target toenail; Mycological Cure was defined as a negative potassium hydroxide (KOH) exam and a negative culture for dermatophytes of the target toenail. |
| Complete Cure - Itraconazole Tablets Compared to Itraconazole Capsules | 12 months | The primary efficacy endpoint was Compete Cure (consisting of a Clinical Cure and a Mycological Cure) at week 52. In this study, Clinical Cure was defined as an Investigator's Global Assessment (IGA) score of 0 for the target toenail; Mycological Cure was defined as a negative potassium hydroxide (KOH) examination and a negative culture outcome for dermatophytes of the target toenail. The efficacy analyses were conducted to demonstrate the non-inferiority of 1 itraconazole 200-mg tablet to 2 itraconazole 100-mg capsule. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Improvement of the Target Toenail | 12 months | Clinical Improvement consisted of a mycological cure and an Investigator's Global Assessment (IGA) score less than or equal to 1 at week 52. The Investigator's Global Assessment (IGA) assesses the overall severity of onychomycosis on the target toenail and takes into consideration, onycholysis, hyperkeratosis and percent nail involvement. 0 = Clinical Cure: No evidence of onychomycosis. 1 = Clinical Improvement: Minimal evidence of onychomycosis. 2 = Mild: ≤25% dystrophy and/or onycholysis. 3 = Moderate: ≤50% dystrophy with onycholysis. 4 = Severe: \>50% dystrophy with onycholysis. |
| Clinical Improvement Compared to Placebo | 12 months | Clinical Improvement consisted of a mycological cure and an Investigator's Global Assessment (IGA) score less than or equal to 1 at week 52. The Investigator's Global Assessment(IGA)assesses the overall severity of onychomycosis on the target toenail and takes into consideration, onycholysis, hyperkeratosis and percent nail involvement. 0 = Clinical Cure: No evidence of onychomycosis. 1 = Clinical Improvement: Minimal evidence of onychomycosis. 2 = Mild: ≤25% dystrophy and/or onycholysis. 3 = Moderate: ≤50% dystrophy with onycholysis. 4 = Severe: \>50% dystrophy with onycholysis. |
Countries
Canada, Dominican Republic, Ecuador, Honduras, Panama, South Africa, United States
Participant flow
Recruitment details
Subjects were recruited from clinics in the US, Canada, South America, Ecuador, Dominican Republic, Panama, and Honduras.
Pre-assignment details
Subjects were screened prior to randomization and had to have a positive result from a mycological culture of their toe nail (ie, culture that was positive for dermatophytes). If the culture was negative, they were not randomized to receive treatment and were discontinued from the study.
Participants by arm
| Arm | Count |
|---|---|
| Itraconazole Tablets Itraconazole 200 mg tablets. Subjects took one 200 mg tablet once per day after a full meal. The last dose was taken the day before the Week 12 visit. | 593 |
| Itraconazole Capsules Itraconazole 100 mg capsules | 590 |
| Placebo Tablets Tablets that were the same as the Itraconazole tables except that they did not contain the active drug (Itraconazole). | 198 |
| Total | 1,381 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Administrative Decision | 0 | 0 | 1 |
| Overall Study | Adverse Event | 21 | 31 | 8 |
| Overall Study | Lack of Efficacy | 0 | 0 | 3 |
| Overall Study | Lost to Follow-up | 27 | 34 | 14 |
| Overall Study | Miscellaneous reasons | 11 | 8 | 3 |
| Overall Study | Non compliance | 1 | 2 | 1 |
| Overall Study | Physician Decision | 0 | 2 | 0 |
| Overall Study | Protocol Violation | 2 | 3 | 2 |
| Overall Study | Withdrawal by Subject | 14 | 14 | 10 |
Baseline characteristics
| Characteristic | Itraconazole Capsules | Placebo Tablets | Itraconazole Tablets | Total |
|---|---|---|---|---|
| Age, Continuous | 47 years STANDARD_DEVIATION 12.67 | 49.2 years STANDARD_DEVIATION 11.12 | 47.1 years STANDARD_DEVIATION 11.86 | 47.4 years STANDARD_DEVIATION 12.13 |
| Gender Female | 440 Participants | 153 Participants | 441 Participants | 1034 Participants |
| Gender Male | 150 Participants | 45 Participants | 152 Participants | 347 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 7 Participants | 4 Participants | 7 Participants | 18 Participants |
| Race/Ethnicity, Customized Asian | 4 Participants | 2 Participants | 5 Participants | 11 Participants |
| Race/Ethnicity, Customized Black or African American | 48 Participants | 18 Participants | 48 Participants | 114 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 41 Participants | 7 Participants | 25 Participants | 73 Participants |
| Race/Ethnicity, Customized White | 493 Participants | 169 Participants | 512 Participants | 1174 Participants |
| Region of Enrollment Canada | 21 participants | 8 participants | 23 participants | 52 participants |
| Region of Enrollment Dominican Republic | 9 participants | 2 participants | 7 participants | 18 participants |
| Region of Enrollment Ecuador | 8 participants | 3 participants | 6 participants | 17 participants |
| Region of Enrollment Honduras | 9 participants | 3 participants | 9 participants | 21 participants |
| Region of Enrollment Panama | 9 participants | 3 participants | 9 participants | 21 participants |
| Region of Enrollment South Africa | 11 participants | 3 participants | 12 participants | 26 participants |
| Region of Enrollment United States | 523 participants | 176 participants | 527 participants | 1226 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 19 / 582 | 16 / 581 | 6 / 191 | 19 / 535 | 36 / 515 | 8 / 168 |
| serious Total, serious adverse events | 2 / 582 | 2 / 581 | 2 / 191 | 10 / 535 | 9 / 515 | 1 / 168 |
Outcome results
Primary
Clinical and Mycological Cure of Target Toenail
This study was designed to evaluate the superiority of itraconazole tablets to placebo tablets. Clinical Cure was defined as an IGA score of 0 for the target toenail; Mycological Cure was defined as a negative potassium hydroxide (KOH) exam and a negative culture for dermatophytes of the target toenail.
Time frame: 1 year
Population: Intent to treat (ITT).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Itraconazole Tablets | Clinical and Mycological Cure of Target Toenail | 22.3 Percentage of participants |
| Placebo Tablets | Clinical and Mycological Cure of Target Toenail | 1 Percentage of participants |
Comparison: P-Value from a Cochran-Mantel-Haenszel test, . The superiority analysis was restricted to the itraconazole 200-mg tablets and placebo tablets dosing groups.p-value: <0.001Cochran-Mantel-Haenszel
Primary
Complete Cure - Itraconazole Tablets Compared to Itraconazole Capsules
The primary efficacy endpoint was Compete Cure (consisting of a Clinical Cure and a Mycological Cure) at week 52. In this study, Clinical Cure was defined as an Investigator's Global Assessment (IGA) score of 0 for the target toenail; Mycological Cure was defined as a negative potassium hydroxide (KOH) examination and a negative culture outcome for dermatophytes of the target toenail. The efficacy analyses were conducted to demonstrate the non-inferiority of 1 itraconazole 200-mg tablet to 2 itraconazole 100-mg capsule.
Time frame: 12 months
Population: Intent to treat (ITT).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Itraconazole Tablets | Complete Cure - Itraconazole Tablets Compared to Itraconazole Capsules | 22.3 Percentage of participants |
| Placebo Tablets | Complete Cure - Itraconazole Tablets Compared to Itraconazole Capsules | 21.7 Percentage of participants |
| Placebo Tablets | Complete Cure - Itraconazole Tablets Compared to Itraconazole Capsules | 1.0 Percentage of participants |
Comparison: Comparison between the 2 itraconazole groups was based on lower bound of the 97.5% confidence interval for the difference. The non-inferiority analysis was restricted to the active dosing groups.Wald's CI
Secondary
Clinical Improvement Compared to Placebo
Clinical Improvement consisted of a mycological cure and an Investigator's Global Assessment (IGA) score less than or equal to 1 at week 52. The Investigator's Global Assessment(IGA)assesses the overall severity of onychomycosis on the target toenail and takes into consideration, onycholysis, hyperkeratosis and percent nail involvement. 0 = Clinical Cure: No evidence of onychomycosis. 1 = Clinical Improvement: Minimal evidence of onychomycosis. 2 = Mild: ≤25% dystrophy and/or onycholysis. 3 = Moderate: ≤50% dystrophy with onycholysis. 4 = Severe: \>50% dystrophy with onycholysis.
Time frame: 12 months
Population: Intent to treat (ITT)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Itraconazole Tablets | Clinical Improvement Compared to Placebo | 33.7 percentage of participants |
| Placebo Tablets | Clinical Improvement Compared to Placebo | 2 percentage of participants |
Comparison: The superiority analysis was restricted to the itraconazole 200-mg tablets and placebo tablets dosing groups.p-value: <0.001Cochran-Mantel-Haenszel
Secondary
Clinical Improvement of the Target Toenail
Clinical Improvement consisted of a mycological cure and an Investigator's Global Assessment (IGA) score less than or equal to 1 at week 52. The Investigator's Global Assessment (IGA) assesses the overall severity of onychomycosis on the target toenail and takes into consideration, onycholysis, hyperkeratosis and percent nail involvement. 0 = Clinical Cure: No evidence of onychomycosis. 1 = Clinical Improvement: Minimal evidence of onychomycosis. 2 = Mild: ≤25% dystrophy and/or onycholysis. 3 = Moderate: ≤50% dystrophy with onycholysis. 4 = Severe: \>50% dystrophy with onycholysis.
Time frame: 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Itraconazole Tablets | Clinical Improvement of the Target Toenail | 33.7 percentage of participants |
| Placebo Tablets | Clinical Improvement of the Target Toenail | 29.3 percentage of participants |
Comparison: The test for demonstrating non-inferiority was based on a margin of 10%. Thus, non-inferiority was established if the lower limit of the one-sided, 97.5% CI in the observed difference between the proportions of subjects by study drug with Complete Cure at week 52 (itraconazole 200-mg tablets minus itraconazole 100-mg capsules) was greater than -10%. The non-inferiority analysis was restricted to the active dosing groups.p-value: <0.001Wald's CI