Onychomycosis
Conditions
Keywords
Onychomycosis
Brief summary
The objective of this study is to compare the relative efficacy and safety of SUBA™-Itraconazole Capsules (HalcyGen Ltd) to an already marketed oral formulation of itraconazole SPORANOX® (itraconazole) capsules (Janssen Pharma) in the treatment of onychomycosis of the toenail. Both the test and the reference formulations will also be compared to a placebo formulation to test for superiority.
Detailed description
Randomized, Double-Blind, Multiple-Site, Placebo-Controlled, Parallel designed study comparing a dosing regimen of 100 mg approximately 30 minutes prior to breakfast for 12 weeks of SUBA™-Itraconazole 50 mg capsules (HalcyGen Ltd) to the approved dosing regimen of 200 mg taken with breakfast of SPORANOX® (itraconazole) 100 mg capsules (Janssen Pharma). Patients will be randomly assigned in a 3:3:1 ratio to the test product 100 mg once-a-day: reference product 200 mg once-a-day: placebo once-a-day. respectively. The patients will complete 5 visits: baseline/screening (within 28 days of randomization), Day 1 (randomization), Week 6, Week 12 and Week 24.
Interventions
100 mg approximately 30 minutes prior to breakfast for 12 weeks of SUBA™-Itraconazole 50 mg capsules (HalcyGen Ltd)
DRUGItraconazole
200 mg taken with breakfast of SPORANOX® (itraconazole) 100 mg capsules (Janssen Pharma).
DRUGPlacebo
Two placebo capsules taken approximately 30 minutes prior to breakfast
Sponsors
Halcygen Pharmaceuticals Limited
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or non-pregnant, non lactating females 18 years of age or older. 2. Signed informed consent form, which meets all criteria of current FDA regulations. 3. If female and of child bearing potential, have a negative urine pregnancy test at the baseline and randomization visits and prepared to abstain from sexual intercourse or use a reliable method of contraception during the study (e.g., condom with spermicide, inter-uterine device, oral, injected, transdermal or implanted hormonal contraceptives). 4. Clinical diagnosis of onychomycosis of at least one great toenail 5. Clinical signs and symptoms of onychomycosis of the most severely affected great toenail of at least moderate severity as defined by at least 25% but no more than 75% of the most infected toenail and a combined severity score of at least 4 using the Nail Infection Rating Scale (see Appendix A). 6. At least 2mm of clear nail on the most affected toe between the proximal nail fold and the deepest extend of the onychomycosis. 7. Positive potassium hydroxide (KOH) stain for confirmation of fungal nail infection 8. Positive mycological culture for known fungal dermatophyte consistent with onychomycosis infection of at least one of the great toenails.
Exclusion criteria
1. Females who are pregnant, lactating or likely to become pregnant during the study. 2. Negative KOH stain 3. Negative mycological culture for fungal dermatophytes consistent with onychomycosis infection. 4. Combined score of less than 4 on the Nail Infection Rating Scale for the most severely affected great toenail. 5. Patient has superficial onychomycosis or significant dystrophy of the target toenail that in the Investigators opinion would impair the evaluation of onychomycosis. 6. Patient has total dystrophic or proximal subungual onychomycosis of the target toenail. 7. Presence of mycotic spikes or patient has exclusively lateral groove involvement of the target toenail. 8. Less than 25% or more than 75% of the most severely infected great toenail affected. 9. Target toenail thickness is greater than 3mm. 10. No new nail growth in the target nail over the previous 6 months. 11. Onychomycosis not caused by a dermatophyte (e.g. mold infection, Candida spp or bacterial infection). 12. Previous treatment for onychomycosis of the toenail within the last 12 months that was unresponsive to treatment. 13. Previous treatment within the previous 2 months with any systemic antifungal therapy or within the previous 2 weeks with any topical antifungal therapy. 14. Significant history or current evidence of chronic infectious disease, system disorder, organ disorder or other medical condition that in the Investigator's opinion would place the study patient at undue risk by participation or could jeopardize the integrity of the study evaluations. 15. Immunocompromised either because of concomitant disease (e.g. HIV), or ongoing treatment (e.g. chemotherapy). 16. Current or history of psoriasis within the previous 12 months. 17. Evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. 18. History of diabetes. 19. Previous hypersensitivity to imidazole or azole compounds. 20. Liver Function Test results at screening more than twice the upper limit of normal range or other hematology or clinical chemistry test results that would contraindicate dosing with itraconazole. 21. Use within the previous 3 months or anticipated use during the study of any drugs that are known to affect the bioavailability of oral itraconazole or are otherwise contraindicated to be taken with itraconazole as detailed in the product labeling for SPORANOX® (Appendix B). 22. Receipt of any drug as part of a research study within 30 days prior to dosing. 23. Previous dosing in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Non-inferiority Will be Determined by Evaluating the Difference Between the Proportion of Patients in the Test and Reference Treatment Groups Who Are Considered a Mycological Cure at the End of Study Visit (Week 24) | Week 24 | If the lower bound 95% confidence interval of the difference between the proportion of patients in the Test group compared to the Reference group considered a Mycological Cure at Visit 7 was greater than 20 then non-inferiority was considered to have been demonstrated |
| Non-inferiority Will be Determined by Evaluating the Difference Between the Proportion of Patients in the Test and Reference Treatment Groups Who Are Considered a Therapeutic Cure at the End of Study Visit (Week 24) | Week 24 | If the lower bound 95% confidence interval of the difference between the proportion of patients in the Test group compared to the Reference group considered a Therapeutic Cure at Visit 7 was greater than 20 then non-inferiority was considered to have been demonstrated |
| Non-inferiority Will be Determined by Evaluating the Difference Between the Proportion of Patients in the Test and Reference Treatment Groups Who Are Considered a Clinical Cure at the End of Study Visit (Week 24) | Week 24 | If the lower bound 95% confidence interval of the difference between the proportion of patients in the Test group compared to the Reference group considered a Clinical Cure at Visit 7 was greater than 20 then non-inferiority was considered to have been demonstrated |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Non-inferiority Will be Determined by Evaluating the Difference Between the Proportion of Patients in the Test and Reference Treatment Groups Who Are Considered a Clinical Cure at the End of Study Visit (Week 12) | week 12 | If the lower bound 95% confidence interval of the difference between the proportion of patients in the test group compared to the reference group considered a cure at the visit being analyzed was greater than -20 then non-inferiority was considered to have been demonstrated |
| The Proportion of Patients in Each Treatment Group Who Are Considered a Therapeutic Cure at the End of Treatment Visit (Week 12) 12). | Week 12 | If the lower bound 95% confidence interval of the difference between the proportion of patients in the test group compared to the reference group considered a cure at the visit being analyzed was greater than -20 then non-inferiority was considered to have been demonstrated |
| Non-inferiority Will be Determined by Evaluating the Difference Between the Proportion of Patients in the Test and Reference Treatment Groups Who Are Considered a Mycological Cure at the End of Study Visit (Week 12) | week 12 | If the lower bound 95% confidence interval of the difference between the proportion of patients in the test group compared to the reference group considered a cure at the visit being analyzed was greater than -20 then non-inferiority was considered to have been demonstrated |
Other
| Measure | Time frame | Description |
|---|---|---|
| Superiority of Test Treatment Over Placebo for Mycological Cure | week 6 | All primary and secondary endpoints were tested for superiority against Placebo. The intent to treat (ITT) was used for all superiority testing. For the three primary endpoints and all four dichotomous secondary endpoints, if the difference between the proportion of patients considered a cure in the Test or Reference group was statistically greater (p \< 0.05) than the proportion of patients considered a cure in the Placebo group, then superiority of that treatment over placebo was considered to have been demonstrated. A one-sided continuity corrected Z-test was used for superiority testing. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Two placebo capsules taken approximately 30 minutes prior to breakfast
Placebo: Two placebo capsules taken approximately 30 minutes prior to breakfast | 24 |
| Test 100 mg approximately 30 minutes prior to breakfast for 12 weeks of SUBA™-Itraconazole 50 mg capsules (HalcyGen Ltd)
SUBA-itraconazole: 100 mg approximately 30 minutes prior to breakfast for 12 weeks of SUBA™-Itraconazole 50 mg capsules (HalcyGen Ltd) | 76 |
| Reference 200 mg taken with breakfast of SPORANOX® (itraconazole) 100 mg capsules (Janssen Pharma).
Itraconazole: 200 mg taken with breakfast of SPORANOX® (itraconazole) 100 mg capsules (Janssen Pharma). | 75 |
| Total | 175 |
Baseline characteristics
| Characteristic | Test | Total | Placebo | Reference |
|---|---|---|---|---|
| Age, Continuous | 47.41 years of age | 48.78 years of age | 50.29 years of age | 48.64 years of age |
| Infecting organism - T.rubrum | 72 participants | 165 participants | 24 participants | 69 participants |
| Percentage of toe infected | 55.08 percentage STANDARD_DEVIATION 15.7 | 58.27 percentage STANDARD_DEVIATION 15.56 | 61.42 percentage STANDARD_DEVIATION 15.99 | 58.32 percentage STANDARD_DEVIATION 14.99 |
| Presence of infecting organism - T.mentagrophytes | 3 participants | 9 participants | 0 participants | 6 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 9 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 74 Participants | 164 Participants | 21 Participants | 69 Participants |
| Region of Enrollment United States | 76 participants | 175 participants | 24 participants | 75 participants |
| Sex: Female, Male Female | 25 Participants | 49 Participants | 4 Participants | 20 Participants |
| Sex: Female, Male Male | 51 Participants | 126 Participants | 20 Participants | 55 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 24 | 0 / 76 | 0 / 75 |
| other Total, other adverse events | 13 / 24 | 42 / 76 | 35 / 75 |
| serious Total, serious adverse events | 0 / 24 | 2 / 76 | 1 / 75 |
Outcome results
Primary
Non-inferiority Will be Determined by Evaluating the Difference Between the Proportion of Patients in the Test and Reference Treatment Groups Who Are Considered a Clinical Cure at the End of Study Visit (Week 24)
If the lower bound 95% confidence interval of the difference between the proportion of patients in the Test group compared to the Reference group considered a Clinical Cure at Visit 7 was greater than 20 then non-inferiority was considered to have been demonstrated
Time frame: Week 24
Population: The Efficacy evaluation was performed on the intent to treat population, which included all patients that met all the following criteria; positive baseline mycological culture, dosed with the study drug at least once and had at least one post-baseline evaluation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Non-inferiority Will be Determined by Evaluating the Difference Between the Proportion of Patients in the Test and Reference Treatment Groups Who Are Considered a Clinical Cure at the End of Study Visit (Week 24) | 0 Participants |
| Test | Non-inferiority Will be Determined by Evaluating the Difference Between the Proportion of Patients in the Test and Reference Treatment Groups Who Are Considered a Clinical Cure at the End of Study Visit (Week 24) | 12 Participants |
| Reference | Non-inferiority Will be Determined by Evaluating the Difference Between the Proportion of Patients in the Test and Reference Treatment Groups Who Are Considered a Clinical Cure at the End of Study Visit (Week 24) | 4 Participants |
Comparison: To demonstrate non-inferiority an upper bound 95% confidence interval approach comparing the difference between the cure rate in the Test and the Reference groups was used. If the lower bound 95% confidence interval of the difference between the proportion of patients in the Test group compared to the Reference group considered a Therapeutic Cure, Clinical Cure and Mycological Cure as appropriate, at Week 24 was greater than -20 then non-inferiority was considered to have been demonstrated
Comparison: The ITT was used for all superiority testing. For the three primary endpoints and all four secondary endpoints, if the difference between the proportion of patients considered a cure was statistically greater (p\<0.05) than the proportion of patients considered a cure in the Placebo group, then superiority was considered to have been demonstrated. A one-sided continuity corrected Z-test was used for superiority testingp-value: <0.05one-sided continuity corrected Z-test
Primary
Non-inferiority Will be Determined by Evaluating the Difference Between the Proportion of Patients in the Test and Reference Treatment Groups Who Are Considered a Mycological Cure at the End of Study Visit (Week 24)
If the lower bound 95% confidence interval of the difference between the proportion of patients in the Test group compared to the Reference group considered a Mycological Cure at Visit 7 was greater than 20 then non-inferiority was considered to have been demonstrated
Time frame: Week 24
Population: The Efficacy evaluation was performed on the intent to treat population, which included all patients that met all the following criteria; positive baseline mycological culture, dosed with the study drug at least once and had at least one post-baseline evaluation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Non-inferiority Will be Determined by Evaluating the Difference Between the Proportion of Patients in the Test and Reference Treatment Groups Who Are Considered a Mycological Cure at the End of Study Visit (Week 24) | 1 Participants |
| Test | Non-inferiority Will be Determined by Evaluating the Difference Between the Proportion of Patients in the Test and Reference Treatment Groups Who Are Considered a Mycological Cure at the End of Study Visit (Week 24) | 25 Participants |
| Reference | Non-inferiority Will be Determined by Evaluating the Difference Between the Proportion of Patients in the Test and Reference Treatment Groups Who Are Considered a Mycological Cure at the End of Study Visit (Week 24) | 22 Participants |
Comparison: The ITT was used for all superiority testing. For the three primary endpoints and all four secondary endpoints, if the difference between the proportion of patients considered a cure was statistically greater (p\<0.05) than the proportion of patients considered a cure in the Placebo group, then superiority was considered to have been demonstrated. A one-sided continuity corrected Z-test was used for superiority testingp-value: <0.05one-sided continuity corrected Z-test
Primary
Non-inferiority Will be Determined by Evaluating the Difference Between the Proportion of Patients in the Test and Reference Treatment Groups Who Are Considered a Therapeutic Cure at the End of Study Visit (Week 24)
If the lower bound 95% confidence interval of the difference between the proportion of patients in the Test group compared to the Reference group considered a Therapeutic Cure at Visit 7 was greater than 20 then non-inferiority was considered to have been demonstrated
Time frame: Week 24
Population: The Efficacy evaluation was performed on the intent to treat population, which included all patients that met all the following criteria; positive baseline mycological culture, dosed with the study drug at least once and had at least one post-baseline evaluation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Non-inferiority Will be Determined by Evaluating the Difference Between the Proportion of Patients in the Test and Reference Treatment Groups Who Are Considered a Therapeutic Cure at the End of Study Visit (Week 24) | 0 Participants |
| Test | Non-inferiority Will be Determined by Evaluating the Difference Between the Proportion of Patients in the Test and Reference Treatment Groups Who Are Considered a Therapeutic Cure at the End of Study Visit (Week 24) | 8 Participants |
| Reference | Non-inferiority Will be Determined by Evaluating the Difference Between the Proportion of Patients in the Test and Reference Treatment Groups Who Are Considered a Therapeutic Cure at the End of Study Visit (Week 24) | 3 Participants |
Comparison: The ITT was used for all superiority testing. For the three primary endpoints and all four secondary endpoints, if the difference between the proportion of patients considered a cure was statistically greater (p\<0.05) than the proportion of patients considered a cure in the Placebo group, then superiority was considered to have been demonstrated. A one-sided continuity corrected Z-test was used for superiority testingp-value: <0.05one-sided continuity corrected Z-test
Secondary
Non-inferiority Will be Determined by Evaluating the Difference Between the Proportion of Patients in the Test and Reference Treatment Groups Who Are Considered a Clinical Cure at the End of Study Visit (Week 12)
If the lower bound 95% confidence interval of the difference between the proportion of patients in the test group compared to the reference group considered a cure at the visit being analyzed was greater than -20 then non-inferiority was considered to have been demonstrated
Time frame: week 12
Population: The Efficacy evaluation was performed on the intent to treat population, which included all patients that met all the following criteria; positive baseline mycological culture, dosed with the study drug at least once and had at least one post-baseline evaluation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Non-inferiority Will be Determined by Evaluating the Difference Between the Proportion of Patients in the Test and Reference Treatment Groups Who Are Considered a Clinical Cure at the End of Study Visit (Week 12) | 0 Participants |
| Test | Non-inferiority Will be Determined by Evaluating the Difference Between the Proportion of Patients in the Test and Reference Treatment Groups Who Are Considered a Clinical Cure at the End of Study Visit (Week 12) | 1 Participants |
| Reference | Non-inferiority Will be Determined by Evaluating the Difference Between the Proportion of Patients in the Test and Reference Treatment Groups Who Are Considered a Clinical Cure at the End of Study Visit (Week 12) | 0 Participants |
Secondary
Non-inferiority Will be Determined by Evaluating the Difference Between the Proportion of Patients in the Test and Reference Treatment Groups Who Are Considered a Mycological Cure at the End of Study Visit (Week 12)
If the lower bound 95% confidence interval of the difference between the proportion of patients in the test group compared to the reference group considered a cure at the visit being analyzed was greater than -20 then non-inferiority was considered to have been demonstrated
Time frame: week 12
Population: The Efficacy evaluation was performed on the intent to treat population, which included all patients that met all the following criteria; positive baseline mycological culture, dosed with the study drug at least once and had at least one post-baseline evaluation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Non-inferiority Will be Determined by Evaluating the Difference Between the Proportion of Patients in the Test and Reference Treatment Groups Who Are Considered a Mycological Cure at the End of Study Visit (Week 12) | 3 Participants |
| Test | Non-inferiority Will be Determined by Evaluating the Difference Between the Proportion of Patients in the Test and Reference Treatment Groups Who Are Considered a Mycological Cure at the End of Study Visit (Week 12) | 16 Participants |
| Reference | Non-inferiority Will be Determined by Evaluating the Difference Between the Proportion of Patients in the Test and Reference Treatment Groups Who Are Considered a Mycological Cure at the End of Study Visit (Week 12) | 16 Participants |
Comparison: If the lower bound 95% confidence interval of the difference between the proportion of patients in the Test group compared to the Reference group considered a Therapeutic Cure, Clinical Cure or Mycological Cure as appropriate at Visit 7 was greater than -20 then non-inferiority was considered to have been demonstrated
Secondary
The Proportion of Patients in Each Treatment Group Who Are Considered a Therapeutic Cure at the End of Treatment Visit (Week 12) 12).
If the lower bound 95% confidence interval of the difference between the proportion of patients in the test group compared to the reference group considered a cure at the visit being analyzed was greater than -20 then non-inferiority was considered to have been demonstrated
Time frame: Week 12
Population: The Efficacy evaluation was performed on the intent to treat population, which included all patients that met all the following criteria; positive baseline mycological culture, dosed with the study drug at least once and had at least one post-baseline evaluation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | The Proportion of Patients in Each Treatment Group Who Are Considered a Therapeutic Cure at the End of Treatment Visit (Week 12) 12). | 0 Participants |
| Test | The Proportion of Patients in Each Treatment Group Who Are Considered a Therapeutic Cure at the End of Treatment Visit (Week 12) 12). | 0 Participants |
| Reference | The Proportion of Patients in Each Treatment Group Who Are Considered a Therapeutic Cure at the End of Treatment Visit (Week 12) 12). | 0 Participants |
Other Pre-specified
Superiority of Test Treatment Over Placebo for Mycological Cure
All primary and secondary endpoints were tested for superiority against Placebo. The intent to treat (ITT) was used for all superiority testing. For the three primary endpoints and all four dichotomous secondary endpoints, if the difference between the proportion of patients considered a cure in the Test or Reference group was statistically greater (p \< 0.05) than the proportion of patients considered a cure in the Placebo group, then superiority of that treatment over placebo was considered to have been demonstrated. A one-sided continuity corrected Z-test was used for superiority testing.
Time frame: week 6
Population: The Efficacy evaluation was performed on the intent to treat population, which included all patients that met all the following criteria; positive baseline mycological culture, dosed with the study drug at least once and had at least one post-baseline evaluation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Superiority of Test Treatment Over Placebo for Mycological Cure | 0 Participants |
| Test | Superiority of Test Treatment Over Placebo for Mycological Cure | 11 Participants |
| Reference | Superiority of Test Treatment Over Placebo for Mycological Cure | 5 Participants |
Comparison: For the three primary endpoints and all four dichotomous secondary endpoints, if the difference between the proportion of patients considered a cure in the Test or Reference group was statistically greater (p \< 0.05) than the proportion of patients considered a cure in the Placebo group, then superiority of that treatment over placebo was considered to have been demonstrated. A one-sided continuity corrected Z-test was used for superiority testing.p-value: <0.05A one-sided continuity corrected Z-test
Comparison: For the three primary endpoints and all four dichotomous secondary endpoints, if the difference between the proportion of patients considered a cure in the Test or Reference group was statistically greater (p \< 0.05) than the proportion of patients considered a cure in the Placebo group, then superiority of that treatment over placebo was considered to have been demonstrated. A one-sided continuity corrected Z-test was used for superiority testing.p-value: <0.05A one-sided continuity corrected Z-test