Study Comparing SUBA™-Itraconazole With SPORANOX® (Itraconazole) in the Treatment of Onychomycosis

• Sponsor: Halcygen Pharmaceuticals Limited (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00791219
• Collaborator: (none)
• Enrollment: 175
• Locations: 8
• Arms: 3
• Duration (Months): 25
• Patients Per Site: 21.9
• Patients Per Site Per Month: 0.9

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Onychomycosis	Drug: SUBA-itraconazole; Drug: Itraconazole; Drug: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 175 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double Blind, Multiple-site, Placebo-Controlled Study, Comparing the Efficacy and Safety of SUBA™-Itraconazole Capsules Compared to SPORANOX® (Itraconazole) Capsules in the Treatment of Onychomycosis of the Toenail
• Study Start Date: Nov 1, 2008
• Actual Primary Completion Date: Jul 1, 2010
• Actual Study Completion Date: Dec 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Test 100 mg approximately 30 minutes prior to breakfast for 12 weeks of SUBA™-Itraconazole 50 mg capsules (HalcyGen Ltd)	Drug: SUBA-itraconazole; 100 mg approximately 30 minutes prior to breakfast for 12 weeks of SUBA™-Itraconazole 50 mg capsules (HalcyGen Ltd); Other Names: itraconazole 50 mg capsules
Active Comparator: Reference 200 mg taken with breakfast of SPORANOX® (itraconazole) 100 mg capsules (Janssen Pharma).	Drug: Itraconazole; 200 mg taken with breakfast of SPORANOX® (itraconazole) 100 mg capsules (Janssen Pharma).; Other Names: Sporanox
Placebo Comparator: Placebo Two placebo capsules taken approximately 30 minutes prior to breakfast	Drug: Placebo; Two placebo capsules taken approximately 30 minutes prior to breakfast; Other Names: placebo capsules

Outcome Measures

Primary Outcome Measures

1. 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

2. 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

3. 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

Secondary Outcome Measures

1. 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

2. 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

3. 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 Outcome Measures

1. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Synergyst Research	Altamonte Springs	Florida	United States	32701
2	FXM Research Corp	Miami	Florida	United States	33175
3	Northwest Clinical Trials	Boise	Idaho	United States	83704
4	PMG Research	Salisbury	North Carolina	United States	28144
5	Oregon Medical Research Center, P.C	Portland	Oregon	United States	97223
6	Coastal Carolina Research	Mount Pleasant	South Carolina	United States	29464
7	JS Studies	College Station	Texas	United States	77845
8	Endeavor Clinical Trials	San Antonio	Texas	United States	78229

Sponsors and Collaborators

• Halcygen Pharmaceuticals Limited

Investigators

• Study Chair: Roger Aston, Halcygen Pharmaceuticals Limited

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Halcygen Pharmaceuticals Limited
• ClinicalTrials.gov Identifier: NCT00791219
• Other Study ID Numbers: 70850702; HGN06
• First Posted: Nov 14, 2008
• Last Update Posted: Aug 25, 2020
• Last Verified: Aug 1, 2020

• Keywords provided by Halcygen Pharmaceuticals Limited: Onychomycosis
• Additional relevant MeSH terms: Onychomycosis; Itraconazole; Hydroxyitraconazole

Study Results

Participant Flow

Arm/Group Title	Placebo	Test	Reference
Arm/Group Description	Two placebo capsules taken approximately 30 minutes prior to breakfast Placebo: Two placebo capsules taken approximately 30 minutes prior to breakfast	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)	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).
Period Title: Overall Study
STARTED	24	76	75
COMPLETED	19	60	61
NOT COMPLETED	5	16	14

Baseline Characteristics

Arm/Group Title	Placebo	Test	Reference	Total
Arm/Group Description	Two placebo capsules taken approximately 30 minutes prior to breakfast Placebo: Two placebo capsules taken approximately 30 minutes prior to breakfast	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)	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).	Total of all reporting groups
Overall Participants	24	76	75	175
Age (years of age) [Mean (Full Range) ]
Mean (Full Range) [years of age]	50.29	47.41	48.64	48.78
Sex: Female, Male (Count of Participants)
Female	4 16.7%	25 32.9%	20 26.7%	49 28%
Male	20 83.3%	51 67.1%	55 73.3%	126 72%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	1 4.2%	0 0%	0 0%	1 0.6%
Native Hawaiian or Other Pacific Islander	0 0%	1 1.3%	0 0%	1 0.6%
Black or African American	2 8.3%	1 1.3%	6 8%	9 5.1%
White	21 87.5%	74 97.4%	69 92%	164 93.7%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	24 100%	76 100%	75 100%	175 100%
Percentage of toe infected (percentage) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage]	61.42 (15.99)	55.08 (15.70)	58.32 (14.99)	58.27 (15.56)
Infecting organism - T.rubrum (participants) [Number]
Number [participants]	24 100%	72 94.7%	69 92%	165 94.3%
Presence of infecting organism - T.mentagrophytes (participants) [Number]
Number [participants]	0 0%	3 3.9%	6 8%	9 5.1%

Outcome Measures

1. Primary Outcome

Title	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)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Test	Reference
Arm/Group Description	Two placebo capsules taken approximately 30 minutes prior to breakfast Placebo: Two placebo capsules taken approximately 30 minutes prior to breakfast	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)	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).
Measure Participants	24	76	74
Count of Participants [Participants]	0 0%	8 10.5%	3 4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Test, Reference
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	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
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	-20
	Estimated Value	6.47
	Confidence Interval	(1-Sided) 95%; -1.77 to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Test
	Comments	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 testing
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	one-sided continuity corrected Z-test
	Comments

2. Primary Outcome

Title	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)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Test	Reference
Arm/Group Description	Two placebo capsules taken approximately 30 minutes prior to breakfast Placebo: Two placebo capsules taken approximately 30 minutes prior to breakfast	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)	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).
Measure Participants	24	76	74
Count of Participants [Participants]	0 0%	12 15.8%	4 5.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Test, Reference
	Comments	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
	Type of Statistical Test	Non-Inferiority
	Comments	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
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	-20
	Estimated Value	10.38
	Confidence Interval	(1-Sided) 95%; 0.92 to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Test
	Comments	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 testing
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	one-sided continuity corrected Z-test
	Comments

3. Primary Outcome

Title	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)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Test	Reference
Arm/Group Description	Two placebo capsules taken approximately 30 minutes prior to breakfast Placebo: Two placebo capsules taken approximately 30 minutes prior to breakfast	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)	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).
Measure Participants	24	76	74
Count of Participants [Participants]	1 4.2%	25 32.9%	22 29.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Test, Reference
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	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
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	-20
	Estimated Value	3.17
	Confidence Interval	(1-Sided) 95%; -10.62 to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Test
	Comments	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 testing
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	one-sided continuity corrected Z-test
	Comments

4. Secondary Outcome

Title	The Proportion of Patients in Each Treatment Group Who Are Considered a "Therapeutic Cure" at the End of Treatment Visit (Week 12) 12).
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Test	Reference
Arm/Group Description	Two placebo capsules taken approximately 30 minutes prior to breakfast Placebo: Two placebo capsules taken approximately 30 minutes prior to breakfast	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)	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).
Measure Participants	24	76	74
Count of Participants [Participants]	0 0%	0 0%	0 0%

5. Secondary Outcome

Title	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)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Test	Reference
Arm/Group Description	Two placebo capsules taken approximately 30 minutes prior to breakfast Placebo: Two placebo capsules taken approximately 30 minutes prior to breakfast	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)	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).
Measure Participants	24	76	74
Count of Participants [Participants]	0 0%	1 1.3%	0 0%

6. Secondary Outcome

Title	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)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Test	Reference
Arm/Group Description	Two placebo capsules taken approximately 30 minutes prior to breakfast Placebo: Two placebo capsules taken approximately 30 minutes prior to breakfast	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)	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).
Measure Participants	24	76	74
Count of Participants [Participants]	3 12.5%	16 21.1%	16 21.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Test, Reference
	Comments	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
	Type of Statistical Test	Non-Inferiority
	Comments	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
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	-20
	Estimated Value	-0.57
	Confidence Interval	(1-Sided) 95%; -12.91 to
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Other Pre-specified Outcome

Title	Superiority of Test Treatment Over Placebo for Mycological Cure
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Test	Reference
Arm/Group Description	Two placebo capsules taken approximately 30 minutes prior to breakfast Placebo: Two placebo capsules taken approximately 30 minutes prior to breakfast	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)	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).
Measure Participants	24	76	74
Count of Participants [Participants]	0 0%	11 14.5%	5 6.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Test
	Comments	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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments	It 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.
	Method	A one-sided continuity corrected Z-test
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.0018
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Reference
	Comments	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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	A one-sided continuity corrected Z-test
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.0853
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	The safety profile of each treatment group was evaluated by comparing adverse events, monitoring vital signs, EKG parameters, audiology testing, and changes in clinical laboratory results obtained throughout the study, which included the 12 week treatment period and the End of Study Visit at Week 24.
Arm/Group Title	Placebo		Test		Reference
Arm/Group Description	Two placebo capsules taken approximately 30 minutes prior to breakfast Placebo: Two placebo capsules taken approximately 30 minutes prior to breakfast		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)		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).
All Cause Mortality
	Placebo		Test		Reference
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		0/76 (0%)		0/75 (0%)
Serious Adverse Events
	Placebo		Test		Reference
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		2/76 (2.6%)		1/75 (1.3%)
Musculoskeletal and connective tissue disorders
Lumbar Spinal Stenosis	0/24 (0%)	0	0/76 (0%)	0	1/75 (1.3%)	1
Intervertebral disc protusion	0/24 (0%)	0	1/76 (1.3%)	1	0/75 (0%)	0
Vascular disorders
Pulmonary Embolism	0/24 (0%)	0	1/76 (1.3%)	1	0/75 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Test		Reference
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/24 (54.2%)		42/76 (55.3%)		35/75 (46.7%)
Ear and labyrinth disorders
Acoustic Stimulation Tests Abnormal	0/24 (0%)	0	2/76 (2.6%)	2	3/75 (4%)	3
Tinnitus	1/24 (4.2%)	1	0/76 (0%)	0	2/75 (2.7%)	2
Gastrointestinal disorders
Abdominal Pain	0/24 (0%)	0	2/76 (2.6%)	2	0/75 (0%)	0
Constipation	0/24 (0%)	0	1/76 (1.3%)	1	2/75 (2.7%)	2
Gastroesophageal Reflux Disease	1/24 (4.2%)	1	1/76 (1.3%)	1	0/75 (0%)	0
Nausea	0/24 (0%)	0	2/76 (2.6%)	2	0/75 (0%)	0
Ooropharyngeal Pain	0/24 (0%)	0	2/76 (2.6%)	2	0/75 (0%)	0
Injury, poisoning and procedural complications
Arthropod Bite	1/24 (4.2%)	1	0/76 (0%)	0	0/75 (0%)	0
Investigations
Alanine Aminotransferase Increased	0/24 (0%)	0	3/76 (3.9%)	3	2/75 (2.7%)	2
Aspartate Aminotransferase Increased	0/24 (0%)	0	3/76 (3.9%)	3	1/75 (1.3%)	1
Metabolism and nutrition disorders
Hyperglycaemia	1/24 (4.2%)	1	0/76 (0%)	0	0/75 (0%)	0
Musculoskeletal and connective tissue disorders
Back Pain	1/24 (4.2%)	1	1/76 (1.3%)	1	1/75 (1.3%)	1
Pain in Extremity	1/24 (4.2%)	1	2/76 (2.6%)	2	4/75 (5.3%)	4
Nervous system disorders
Dizziness	1/24 (4.2%)	1	1/76 (1.3%)	1	0/75 (0%)	0
Headache	2/24 (8.3%)	2	7/76 (9.2%)	7	8/75 (10.7%)	8
Insomnia	0/24 (0%)	0	2/76 (2.6%)	2	0/75 (0%)	0
Sinus Headache	0/24 (0%)	0	2/76 (2.6%)	2	0/75 (0%)	0
Tension Headache	1/24 (4.2%)	1	0/76 (0%)	0	1/75 (1.3%)	1
Vertigo	1/24 (4.2%)	1	0/76 (0%)	0	1/75 (1.3%)	1
Psychiatric disorders
Depressed Mood	1/24 (4.2%)	1	0/76 (0%)	0	0/75 (0%)	0
Reproductive system and breast disorders
Erectile Dysfunction	1/24 (4.2%)	1	0/76 (0%)	0	0/75 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	0/24 (0%)	0	2/76 (2.6%)	2	3/75 (4%)	3
Nasal Congestion	0/24 (0%)	0	0/76 (0%)	0	2/75 (2.7%)	2
Nasopharyngitis	2/24 (8.3%)	2	7/76 (9.2%)	7	5/75 (6.7%)	5
Rhinitis	1/24 (4.2%)	1	2/76 (2.6%)	2	0/75 (0%)	0
Sinusitis	1/24 (4.2%)	1	2/76 (2.6%)	2	0/75 (0%)	0
Upper Respiratory Tract Congestion	1/24 (4.2%)	1	1/76 (1.3%)	1	0/75 (0%)	0
Upper Respiratory Tract Infection	0/24 (0%)	0	0/76 (0%)	0	3/75 (4%)	3
Skin and subcutaneous tissue disorders
Dermatitis	1/24 (4.2%)	1	0/76 (0%)	0	0/75 (0%)	0
Dermatitis Contact	1/24 (4.2%)	1	0/76 (0%)	0	0/75 (0%)	0
Vascular disorders
Hypertension	1/24 (4.2%)	1	1/76 (1.3%)	1	2/75 (2.7%)	2

Limitations/Caveats

Subjects were followed for 12 weeks after the 12 week treatment period, typically subjects would be followed for at least 24 weeks post-treatment to allow sufficient time for the nail to grow out and therefore maximizing rates of clinical cure

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Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.