A Study to Evaluate Efficacy and Safety of Four Posaconazole Regimens With Placebo and Terbinafine in the Treatment of Toenail Onychomycosis (Study P05082AM2)(COMPLETED)

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00491764
• Collaborator: (none)
• Enrollment: 218
• Arms: 6
• Duration (Months): 18

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy, safety, and tolerability of oral administration of four dosing regimens of posaconazole relative to placebo and terbinafine, in the treatment of toenail onychomycosis.

Condition or Disease	Intervention/Treatment	Phase
Onychomycosis	Drug: SCH 56592; Drug: SCH 56592; Drug: SCH 56592; Drug: SCH 56592; Drug: Terbinafine; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 218 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Investigator)
• Primary Purpose: Treatment
• Official Title: An Investigator-Blinded Study Evaluating the Efficacy and Safety of Four Posaconazole Treatment Regimens With Placebo and Terbinafine in the Treatment of Onychomycosis of the Toenail
• Study Start Date: Jun 1, 2007
• Actual Primary Completion Date: Dec 1, 2008
• Actual Study Completion Date: Dec 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Posaconazole 100 mg QD for 24 weeks. Posaconazole oral suspension (40 mg/mL) 100 mg QD for 24 weeks.	Drug: SCH 56592; Posaconazole oral suspension (40 mg/mL) 100 mg QD for 24 weeks.; Other Names: Posaconazole Noxafil
Experimental: Posaconazole 200 mg QD for 24 weeks. Posaconazole oral suspension (40 mg/mL) 200 mg QD for 24 weeks.	Drug: SCH 56592; Posaconazole oral suspension (40 mg/mL) 200 mg QD for 24 weeks.; Other Names: Posaconazole Noxafil
Experimental: Posaconazole 400 mg QD for 24 weeks. Posaconazole oral suspension (40 mg/mL) 400 mg QD for 24 weeks.	Drug: SCH 56592; Posaconazole oral suspension (40 mg/mL) 400 mg QD for 24 weeks.; Other Names: Posaconazole Noxafil
Experimental: Posaconazole 400 mg QD for 12 weeks. Posaconazole oral suspension (40 mg/mL) 400 mg QD for 12 weeks.	Drug: SCH 56592; Posaconazole oral suspension (40 mg/mL) 400 mg QD for 12 weeks.; Other Names: Posaconazole Noxafil
Active Comparator: Terbinafine Terbinafine 250 mg QD for 12 weeks.	Drug: Terbinafine; Terbinafine 250 mg QD for 12 weeks.
Placebo Comparator: Placebo Placebo for 24 weeks.	Drug: Placebo; Placebo for 24 weeks.

Outcome Measures

Primary Outcome Measures

1. Complete Cure of Onychomycosis at Week 48. [Measured at Day 1, Week 2, Week 4, and Every 4 Weeks Thereafter Until Week 48]

   Complete cure is defined as negative mycology (negative culture and KOH [potassium hydroxide]) and 0% nail involvement (defined as absence of onycholysis and subungual hyperkeratosis).

Secondary Outcome Measures

1. Effective Treatment of Onychomycosis at Week 48. [Measured at Day 1, Week 2, Week 4, and Every 4 Weeks Thereafter Until Week 48]

   Effective treatment is defined as negative mycology (negative culture and KOH) and either 0% nail involvement or >5 mm growth of unaffected nail

2. Treatment Success of Onychomycosis at Week 48 [Measured at Day 1, Week 2, Week 4, and Every 4 Weeks Thereafter Until Week 48]

   Treatment success was defined as negative mycology (negative culture and negative KOH) and =<10% nail involvement.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• The subject must meet ALL the criteria listed below for entry:

• Subject must be between 18 and 75 years of age inclusive, of either sex, and of any race;

• Subject must have distal subungual infection that affects approximately 25% to 75% of at least one great toenail, both clinically and mycologically diagnosed;

• Subject must have at least 2 mm of the proximal end of the target toenail free of infection;

• Subject must have a target toenail that is assessed as capable of growing approximately 1 mm/month, (eg, the subject needs to report cutting his or her toenails at least once per month);

• Subject must have liver function tests within 1.5 x the upper limit of normal (bilirubin and transaminases);

• Subject must have normal serum creatinine levels;

• Subject must be able to take study medication orally;

• Subject must have no history of current narcotic or alcohol addiction;

• Subject must be willing to give written informed consent and able to adhere to dose, procedures, and visit schedules;

• Woman of childbearing potential who is currently sexually active must agree to use a medically accepted method of contraception while receiving protocol-specified medication and for 30 days after stopping the medication. Methods include condoms (male or female) with or without a spermicidal agent, diaphragm or cervical cap with spermicide, medically prescribed intrauterine device, oral or systemic hormonal contraceptive (plus an additional reliable barrier method), and surgical sterilization (eg, hysterectomy or tubal ligation).

Woman of child-bearing potential who is not currently sexually active must agree to use a medically accepted method of contraception should she become sexually active while participating in the study.

• Woman of childbearing potential must have a negative serum pregnancy test within 72 hours prior to start of study drug.

Exclusion Criteria:

• The subject will be excluded from entry if ANY of the criteria listed below are met:

• Subject with one or more of the following conditions on the target toenail:

• proximal subungual onychomycosis,

• white superficial onychomycosis,

• dermatophytoma or "yellow spike/streak",

• exclusively lateral disease,

• inability to become normal in the opinion of the investigator.

• Subject with psoriasis, severe moccasin-type tinea pedis requiring treatment, symptomatic interdigital tinea pedis, lichen planus, or other abnormalities that could result in a clinically abnormal nail;

• Subject with peripheral vascular disease or peripheral circulatory impairment;

• Subject with history of uncontrolled diabetes mellitus;

• Subject with known chronic or active liver disease;

• Subject with any known immunodeficiency;

• Subject with a family history of long QT syndrome;

• Subject with an electrocardiogram with QTc interval prolongation greater than 450 msec for males and 470 msec for females;

• Subject with potassium or magnesium lower than the lower limit of normal;

• Subject with any clinically significant condition or situation, other than the condition being studied that, in the opinion of the investigator, would interfere with study evaluations or optimal participation in the study;

• Subject who has received systemic antifungal therapy within 3 months or topical antifungal therapy applied to the foot or toenails within 1 month of study entry;

• Subject who has received radiation therapy, chemotherapy, and/or immunosuppressive drugs within 6 months of Randomization, and/or oral corticosteroids for >1 month within the 6 months of Randomization (exception: inhaled steroids);

• Subject using medications known to interact with azoles such as terfenadine, pimozide, quinidine, halofantrine, astemizole, alfentanil, cisapride, HMG-Co A (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors that are metabolized by CYP3A4, and ebastine, within 7 days prior to Randomization; and pravastatin within 14 days prior to Randomization;

• Subject using medications known to lower the serum concentration/efficacy of azoles including rifampin, rifabutin, cimetidine, carbamazepine, phenytoin, barbiturates, and isoniazid, 3 doses or more within 7 days prior to Randomization;

• Subject with a known sensitivity to azoles, POS and/or its excipients, terbinafine and/or its excipients;

• Subject who has been previously enrolled in this study or any other POS investigational trial;

• Subject known to have received treatment with investigational drugs within 30 days prior to enrollment into this study;

• Woman who is breastfeeding, pregnant, or intends to become pregnant;

• Subject who is part of the staff personnel directly involved with this study;

• Subject who is a family member of the investigational study staff.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Merck Sharp & Dohme LLC

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT00491764
• Other Study ID Numbers: P05082
• First Posted: Jun 26, 2007
• Last Update Posted: Apr 7, 2017
• Last Verified: Mar 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Onychomycosis; Posaconazole; Terbinafine

Study Results

Participant Flow

Pre-assignment Detail	A total of 690 subjects were enrolled in the study and screened for eligibility. A total of 472 were screen-failures, leaving 218 subjects randomized to treatment.

Arm/Group Title	Posaconazole 100 mg QD for 24 Weeks	Posaconazole 200 mg QD for 24 Weeks.	Posaconazole 400 mg QD for 24 Weeks.	Posaconazole 400 mg QD for 12 Weeks.	Terbinafine 250 mg QD for 12 Weeks.	Placebo for 24 Weeks
Arm/Group Description	Posaconazole oral suspension (40 mg/mL) 100 mg daily (QD) for 24 weeks.	Posaconazole oral suspension (40 mg/mL) 200 mg QD for 24 weeks.	Posaconazole oral suspension (40 mg/mL) 400 mg QD for 24 weeks.	Posaconazole oral suspension (40 mg/mL) 400 mg QD for 12 weeks.	Terbinafine 250 mg QD for 12 weeks.	Placebo for 24 weeks.
Period Title: Overall Study
STARTED	37	37	36	36	36	36
COMPLETED	32	30	28	28	33	27
NOT COMPLETED	5	7	8	8	3	9

Baseline Characteristics

Arm/Group Title	Posaconazole 100 mg QD for 24 Weeks	Posaconazole 200 mg QD for 24 Weeks.	Posaconazole 400 mg QD for 24 Weeks.	Posaconazole 400 mg QD for 12 Weeks.	Terbinafine 250 mg QD for 12 Weeks.	Placebo for 24 Weeks	Total
Arm/Group Description	Posaconazole oral suspension (40 mg/mL) 100 mg daily (QD) for 24 weeks.	Posaconazole oral suspension (40 mg/mL) 200 mg QD for 24 weeks.	Posaconazole oral suspension (40 mg/mL) 400 mg QD for 24 weeks.	Posaconazole oral suspension (40 mg/mL) 400 mg QD for 12 weeks.	Terbinafine 250 mg QD for 12 weeks.	Placebo for 24 weeks.	Total of all reporting groups
Overall Participants	37	37	36	36	36	36	218
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	49.0 (13.0)	53.6 (10.8)	49.9 (13.2)	53.5 (11.8)	50.1 (12.2)	48.4 (14.8)	50.8 (12.7)
Sex: Female, Male (Count of Participants)
Female	10 27%	6 16.2%	8 22.2%	7 19.4%	7 19.4%	7 19.4%	45 20.6%
Male	27 73%	31 83.8%	28 77.8%	29 80.6%	29 80.6%	29 80.6%	173 79.4%

Outcome Measures

1. Primary Outcome

Title	Complete Cure of Onychomycosis at Week 48.
Description	Complete cure is defined as negative mycology (negative culture and KOH [potassium hydroxide]) and 0% nail involvement (defined as absence of onycholysis and subungual hyperkeratosis).
Time Frame	Measured at Day 1, Week 2, Week 4, and Every 4 Weeks Thereafter Until Week 48

Outcome Measure Data

Analysis Population Description

This analysis was based on all randomized subjects who had a baseline assessment and at least one post-baseline assessment available, and who had been exposed to at least one dose of study medication

Arm/Group Title	Posaconazole 100 mg QD for 24 Weeks	Posaconazole 200 mg QD for 24 Weeks.	Posaconazole 400 mg QD for 24 Weeks.	Posaconazole 400 mg QD for 12 Weeks.	Terbinafine 250 mg QD for 12 Weeks.	Placebo for 24 Weeks
Arm/Group Description	Posaconazole oral suspension (40 mg/mL) 100 mg daily (QD) for 24 weeks.	Posaconazole oral suspension (40 mg/mL) 200 mg QD for 24 weeks.	Posaconazole oral suspension (40 mg/mL) 400 mg QD for 24 weeks.	Posaconazole oral suspension (40 mg/mL) 400 mg QD for 12 weeks.	Terbinafine 250 mg QD for 12 weeks.	Placebo for 24 weeks.
Measure Participants	35	37	33	35	35	32
Number [Participants]	8 21.6%	20 54.1%	15 41.7%	7 19.4%	13 36.1%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Posaconazole 100 mg QD for 24 Weeks, Placebo for 24 Weeks
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	22.9
	Confidence Interval	() 95%; 8.9 to 36.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is in the proportion for Yes responders. Confidence Interval is around the difference in proportions.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Posaconazole 200 mg QD for 24 Weeks., Placebo for 24 Weeks
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	54.1
	Confidence Interval	() 95%; 38.0 to 70.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is in the proportion for Yes responders. Confidence Interval is around the difference in proportions.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Posaconazole 400 mg QD for 24 Weeks., Placebo for 24 Weeks
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	45.5
	Confidence Interval	() 95%; 28.5 to 62.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is in the proportion for Yes responders. Confidence Interval is around the difference in proportions.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Posaconazole 400 mg QD for 12 Weeks., Placebo for 24 Weeks
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.012
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	20.0
	Confidence Interval	() 95%; 6.7 to 33.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is in the proportion for Yes responders. Confidence Interval is around the difference in proportions.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Terbinafine 250 mg QD for 12 Weeks., Placebo for 24 Weeks
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	37.1
	Confidence Interval	() 95%; 21.1 to 53.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is in the proportion for Yes responders. Confidence Interval is around the difference in proportions.

2. Secondary Outcome

Title	Effective Treatment of Onychomycosis at Week 48.
Description	Effective treatment is defined as negative mycology (negative culture and KOH) and either 0% nail involvement or >5 mm growth of unaffected nail
Time Frame	Measured at Day 1, Week 2, Week 4, and Every 4 Weeks Thereafter Until Week 48

Outcome Measure Data

Analysis Population Description

This analysis was based on all randomized subjects who had a baseline assessment and at least one post-baseline assessment available, and who had been exposed to at least one dose of study medication

Arm/Group Title	Posaconazole 100 mg QD for 24 Weeks	Posaconazole 200 mg QD for 24 Weeks.	Posaconazole 400 mg QD for 24 Weeks.	Posaconazole 400 mg QD for 12 Weeks.	Terbinafine 250 mg QD for 12 Weeks.	Placebo for 24 Weeks
Arm/Group Description	Posaconazole oral suspension (40 mg/mL) 100 mg daily (QD) for 24 weeks.	Posaconazole oral suspension (40 mg/mL) 200 mg QD for 24 weeks.	Posaconazole oral suspension (40 mg/mL) 400 mg QD for 24 weeks.	Posaconazole oral suspension (40 mg/mL) 400 mg QD for 12 weeks.	Terbinafine 250 mg QD for 12 weeks.	Placebo for 24 weeks.
Measure Participants	35	37	33	35	35	32
Number [Participants]	9 24.3%	24 64.9%	16 44.4%	11 30.6%	19 52.8%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Posaconazole 100 mg QD for 24 Weeks, Placebo for 24 Weeks
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	25.7
	Confidence Interval	() 95%; 11.2 to 40.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is in the proportion for Yes responders. Confidence Interval is around the difference in proportions.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Posaconazole 200 mg QD for 24 Weeks., Placebo for 24 Weeks
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	64.9
	Confidence Interval	() 95%; 49.5 to 80.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is in the proportion for Yes responders. Confidence Interval is around the difference in proportions.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Posaconazole 400 mg QD for 24 Weeks., Placebo for 24 Weeks
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	48.5
	Confidence Interval	() 95%; 31.4 to 65.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is in the proportion for Yes responders. Confidence Interval is around the difference in proportions.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Posaconazole 400 mg QD for 12 Weeks., Placebo for 24 Weeks
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	31.4
	Confidence Interval	() 95%; 16.0 to 46.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is in the proportion for Yes responders. Confidence Interval is around the difference in proportions.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Terbinafine 250 mg QD for 12 Weeks., Placebo for 24 Weeks
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	54.3
	Confidence Interval	() 95%; 37.8 to 70.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is in the proportion for Yes responders. Confidence Interval is around the difference in proportions.

3. Secondary Outcome

Title	Treatment Success of Onychomycosis at Week 48
Description	Treatment success was defined as negative mycology (negative culture and negative KOH) and =<10% nail involvement.
Time Frame	Measured at Day 1, Week 2, Week 4, and Every 4 Weeks Thereafter Until Week 48

Outcome Measure Data

Analysis Population Description

This analysis was based on all randomized subjects who had a baseline assessment and at least one post-baseline assessment available, and who had been exposed to at least one dose of study medication

Arm/Group Title	Posaconazole 100 mg QD for 24 Weeks	Posaconazole 200 mg QD for 24 Weeks.	Posaconazole 400 mg QD for 24 Weeks.	Posaconazole 400 mg QD for 12 Weeks.	Terbinafine 250 mg QD for 12 Weeks.	Placebo for 24 Weeks
Arm/Group Description	Posaconazole oral suspension (40 mg/mL) 100 mg daily (QD) for 24 weeks.	Posaconazole oral suspension (40 mg/mL) 200 mg QD for 24 weeks.	Posaconazole oral suspension (40 mg/mL) 400 mg QD for 24 weeks.	Posaconazole oral suspension (40 mg/mL) 400 mg QD for 12 weeks.	Terbinafine 250 mg QD for 12 weeks.	Placebo for 24 weeks.
Measure Participants	35	37	33	35	35	32
Number [Participants]	11 29.7%	24 64.9%	22 61.1%	11 30.6%	20 55.6%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Posaconazole 100 mg QD for 24 Weeks, Placebo for 24 Weeks
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	31.4
	Confidence Interval	() 95%; 16.0 to 46.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is in the proportion for Yes responders. Confidence Interval is around the difference in proportions.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Posaconazole 200 mg QD for 24 Weeks., Placebo for 24 Weeks
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	64.9
	Confidence Interval	() 95%; 49.5 to 80.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is in the proportion for Yes responders. Confidence Interval is around the difference in proportions.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Posaconazole 400 mg QD for 24 Weeks., Placebo for 24 Weeks
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	66.7
	Confidence Interval	() 95%; 50.6 to 82.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is in the proportion for Yes responders. Confidence Interval is around the difference in proportions.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Posaconazole 400 mg QD for 12 Weeks., Placebo for 24 Weeks
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	31.4
	Confidence Interval	() 95%; 16.0 to 46.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is in the proportion for Yes responders. Confidence Interval is around the difference in proportions.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Terbinafine 250 mg QD for 12 Weeks., Placebo for 24 Weeks
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	57.1
	Confidence Interval	() 95%; 40.7 to 73.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is in the proportion for Yes responders. Confidence Interval is around the difference in proportions.

Adverse Events

Adverse Event Reporting Description	Number of participants at risk included the 216 subjects who received treatment. Of the 218 subjects randomized, 1 subject in the posaconazole 100 mg and 1 subject in the placebo group were not treated.
Arm/Group Title	Posaconazole 100 mg QD for 24 Weeks		Posaconazole 200 mg QD for 24 Weeks		Posaconazole 400 mg QD for 24 Weeks		Posaconazole 400 mg QD for 12 Weeks		Terbinafine 250 mg QD for 12 Weeks		Placebo for 24 Weeks
Arm/Group Description	Posaconazole oral suspension (40 mg/mL) 100 mg QD for 24 weeks		Posaconazole oral suspension (40 mg/mL) 200 mg QD for 24 weeks		Posaconazole oral suspension (40 mg/mL) 400 mg QD for 24 weeks		Posaconazole oral suspension (40 mg/mL) 400 mg QD for 12 weeks		Terbinafine 250 mg QD for 12 weeks		Placebo for 24 weeks
All Cause Mortality
	Posaconazole 100 mg QD for 24 Weeks		Posaconazole 200 mg QD for 24 Weeks		Posaconazole 400 mg QD for 24 Weeks		Posaconazole 400 mg QD for 12 Weeks		Terbinafine 250 mg QD for 12 Weeks		Placebo for 24 Weeks
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Posaconazole 100 mg QD for 24 Weeks		Posaconazole 200 mg QD for 24 Weeks		Posaconazole 400 mg QD for 24 Weeks		Posaconazole 400 mg QD for 12 Weeks		Terbinafine 250 mg QD for 12 Weeks		Placebo for 24 Weeks
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/36 (2.8%)		1/37 (2.7%)		1/36 (2.8%)		1/36 (2.8%)		0/36 (0%)		3/35 (8.6%)
Cardiac disorders
ATRIAL FIBRILLATION	1/36 (2.8%)	1	0/37 (0%)	0	0/36 (0%)	0	0/36 (0%)	0	0/36 (0%)	0	0/35 (0%)	0
MYOCARDIAL INFARCTION	0/36 (0%)	0	0/37 (0%)	0	0/36 (0%)	0	0/36 (0%)	0	0/36 (0%)	0	1/35 (2.9%)	1
Gastrointestinal disorders
UMBILICAL HERNIA	0/36 (0%)	0	0/37 (0%)	0	0/36 (0%)	0	0/36 (0%)	0	0/36 (0%)	0	1/35 (2.9%)	1
General disorders
NON-CARDIAC CHEST PAIN	0/36 (0%)	0	1/37 (2.7%)	1	0/36 (0%)	0	0/36 (0%)	0	0/36 (0%)	0	0/35 (0%)	0
Infections and infestations
ABSCESS LIMB	0/36 (0%)	0	0/37 (0%)	0	1/36 (2.8%)	1	0/36 (0%)	0	0/36 (0%)	0	0/35 (0%)	0
APPENDICITIS	0/36 (0%)	0	0/37 (0%)	0	0/36 (0%)	0	0/36 (0%)	0	0/36 (0%)	0	1/35 (2.9%)	1
CELLULITIS	0/36 (0%)	0	0/37 (0%)	0	1/36 (2.8%)	1	0/36 (0%)	0	0/36 (0%)	0	1/35 (2.9%)	1
Metabolism and nutrition disorders
DEHYDRATION	0/36 (0%)	0	0/37 (0%)	0	0/36 (0%)	0	1/36 (2.8%)	1	0/36 (0%)	0	0/35 (0%)	0
Other (Not Including Serious) Adverse Events
	Posaconazole 100 mg QD for 24 Weeks		Posaconazole 200 mg QD for 24 Weeks		Posaconazole 400 mg QD for 24 Weeks		Posaconazole 400 mg QD for 12 Weeks		Terbinafine 250 mg QD for 12 Weeks		Placebo for 24 Weeks
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	26/36 (72.2%)		21/37 (56.8%)		20/36 (55.6%)		18/36 (50%)		20/36 (55.6%)		21/35 (60%)
Cardiac disorders
VENTRICULAR EXTRASYSTOLES	2/36 (5.6%)	2	0/37 (0%)	0	0/36 (0%)	0	0/36 (0%)	0	0/36 (0%)	0	0/35 (0%)	0
Gastrointestinal disorders
DIARRHOEA	0/36 (0%)	0	2/37 (5.4%)	2	1/36 (2.8%)	1	4/36 (11.1%)	7	1/36 (2.8%)	1	2/35 (5.7%)	2
DYSPEPSIA	2/36 (5.6%)	2	0/37 (0%)	0	0/36 (0%)	0	0/36 (0%)	0	0/36 (0%)	0	1/35 (2.9%)	1
FLATULENCE	1/36 (2.8%)	1	1/37 (2.7%)	1	0/36 (0%)	0	2/36 (5.6%)	2	0/36 (0%)	0	0/35 (0%)	0
HYPERCHLORHYDRIA	1/36 (2.8%)	1	0/37 (0%)	0	0/36 (0%)	0	2/36 (5.6%)	2	0/36 (0%)	0	0/35 (0%)	0
NAUSEA	1/36 (2.8%)	1	3/37 (8.1%)	3	2/36 (5.6%)	6	0/36 (0%)	0	1/36 (2.8%)	1	2/35 (5.7%)	2
VOMITING	1/36 (2.8%)	6	2/37 (5.4%)	2	1/36 (2.8%)	4	0/36 (0%)	0	1/36 (2.8%)	2	0/35 (0%)	0
General disorders
FATIGUE	3/36 (8.3%)	3	1/37 (2.7%)	1	1/36 (2.8%)	2	0/36 (0%)	0	2/36 (5.6%)	2	1/35 (2.9%)	1
PAIN	3/36 (8.3%)	3	0/37 (0%)	0	0/36 (0%)	0	0/36 (0%)	0	1/36 (2.8%)	1	2/35 (5.7%)	2
Immune system disorders
SEASONAL ALLERGY	2/36 (5.6%)	6	1/37 (2.7%)	1	1/36 (2.8%)	1	1/36 (2.8%)	1	0/36 (0%)	0	0/35 (0%)	0
Infections and infestations
BRONCHITIS	0/36 (0%)	0	2/37 (5.4%)	2	1/36 (2.8%)	1	0/36 (0%)	0	2/36 (5.6%)	2	1/35 (2.9%)	1
GASTROENTERITIS VIRAL	3/36 (8.3%)	3	1/37 (2.7%)	1	0/36 (0%)	0	1/36 (2.8%)	1	1/36 (2.8%)	1	2/35 (5.7%)	2
INFLUENZA	3/36 (8.3%)	3	1/37 (2.7%)	1	2/36 (5.6%)	2	0/36 (0%)	0	3/36 (8.3%)	3	0/35 (0%)	0
LARYNGITIS	2/36 (5.6%)	2	0/37 (0%)	0	0/36 (0%)	0	0/36 (0%)	0	0/36 (0%)	0	0/35 (0%)	0
NASOPHARYNGITIS	4/36 (11.1%)	6	3/37 (8.1%)	3	6/36 (16.7%)	7	2/36 (5.6%)	4	3/36 (8.3%)	3	6/35 (17.1%)	6
SINUSITIS	2/36 (5.6%)	3	1/37 (2.7%)	1	0/36 (0%)	0	2/36 (5.6%)	2	0/36 (0%)	0	2/35 (5.7%)	2
TINEA PEDIS	0/36 (0%)	0	1/37 (2.7%)	1	0/36 (0%)	0	0/36 (0%)	0	0/36 (0%)	0	3/35 (8.6%)	3
UPPER RESPIRATORY TRACT INFECTION	5/36 (13.9%)	5	1/37 (2.7%)	1	3/36 (8.3%)	3	6/36 (16.7%)	7	5/36 (13.9%)	5	1/35 (2.9%)	1
Investigations
ALANINE AMINOTRANSFERASE INCREASED	0/36 (0%)	0	1/37 (2.7%)	1	2/36 (5.6%)	3	1/36 (2.8%)	1	1/36 (2.8%)	1	0/35 (0%)	0
BLOOD GLUCOSE INCREASED	1/36 (2.8%)	1	1/37 (2.7%)	1	0/36 (0%)	0	2/36 (5.6%)	2	3/36 (8.3%)	3	0/35 (0%)	0
HEPATIC ENZYME INCREASED	1/36 (2.8%)	1	0/37 (0%)	0	2/36 (5.6%)	2	0/36 (0%)	0	0/36 (0%)	0	0/35 (0%)	0
Musculoskeletal and connective tissue disorders
ARTHRALGIA	2/36 (5.6%)	2	1/37 (2.7%)	1	0/36 (0%)	0	0/36 (0%)	0	0/36 (0%)	0	0/35 (0%)	0
MUSCULOSKELETAL PAIN	2/36 (5.6%)	2	1/37 (2.7%)	1	0/36 (0%)	0	0/36 (0%)	0	1/36 (2.8%)	1	0/35 (0%)	0
MYALGIA	1/36 (2.8%)	2	2/37 (5.4%)	2	0/36 (0%)	0	1/36 (2.8%)	1	0/36 (0%)	0	1/35 (2.9%)	1
PAIN IN EXTREMITY	2/36 (5.6%)	2	1/37 (2.7%)	1	0/36 (0%)	0	0/36 (0%)	0	0/36 (0%)	0	0/35 (0%)	0
Nervous system disorders
AGEUSIA	0/36 (0%)	0	0/37 (0%)	0	0/36 (0%)	0	0/36 (0%)	0	2/36 (5.6%)	2	0/35 (0%)	0
DIZZINESS	0/36 (0%)	0	5/37 (13.5%)	5	0/36 (0%)	0	1/36 (2.8%)	1	1/36 (2.8%)	2	0/35 (0%)	0
HEADACHE	4/36 (11.1%)	4	1/37 (2.7%)	1	1/36 (2.8%)	13	3/36 (8.3%)	3	3/36 (8.3%)	3	0/35 (0%)	0
Respiratory, thoracic and mediastinal disorders
COUGH	3/36 (8.3%)	4	1/37 (2.7%)	1	0/36 (0%)	0	0/36 (0%)	0	1/36 (2.8%)	1	0/35 (0%)	0
RESPIRATORY TRACT CONGESTION	1/36 (2.8%)	1	0/37 (0%)	0	0/36 (0%)	0	3/36 (8.3%)	3	0/36 (0%)	0	0/35 (0%)	0
SINUS CONGESTION	2/36 (5.6%)	3	2/37 (5.4%)	2	0/36 (0%)	0	4/36 (11.1%)	5	2/36 (5.6%)	3	1/35 (2.9%)	1
Skin and subcutaneous tissue disorders
INGROWING NAIL	2/36 (5.6%)	2	0/37 (0%)	0	4/36 (11.1%)	5	0/36 (0%)	0	0/36 (0%)	0	0/35 (0%)	0
ONYCHALGIA	2/36 (5.6%)	2	0/37 (0%)	0	0/36 (0%)	0	0/36 (0%)	0	0/36 (0%)	0	0/35 (0%)	0
Vascular disorders
HYPERTENSION	0/36 (0%)	0	0/37 (0%)	0	0/36 (0%)	0	2/36 (5.6%)	2	1/36 (2.8%)	1	0/35 (0%)	0

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

PI must provide to sponsor 45 days prior to submission for publication/presentation, review copies of content to be presented that contains any results of the study. The sponsor has the right to review/comment with regard to proprietary information, accuracy, and fair balance. If disagreements arise concerning appropriateness of content to be presented, investigator must meet with sponsor prior to submission for publication to make good faith efforts to discuss/resolve any issues/disagreement.