Onychomycosis
Conditions
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.
Interventions
DRUGSCH 56592
Posaconazole oral suspension (40 mg/mL) 100 mg QD for 24 weeks.
DRUGTerbinafine
Terbinafine 250 mg QD for 12 weeks.
DRUGPlacebo
Placebo for 24 weeks.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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. |
Participant flow
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Posaconazole 100 mg QD for 24 Weeks Posaconazole oral suspension (40 mg/mL) 100 mg daily (QD) for 24 weeks. | 37 |
| Posaconazole 200 mg QD for 24 Weeks. Posaconazole oral suspension (40 mg/mL) 200 mg QD for 24 weeks. | 37 |
| Posaconazole 400 mg QD for 24 Weeks. Posaconazole oral suspension (40 mg/mL) 400 mg QD for 24 weeks. | 36 |
| Posaconazole 400 mg QD for 12 Weeks. Posaconazole oral suspension (40 mg/mL) 400 mg QD for 12 weeks. | 36 |
| Terbinafine 250 mg QD for 12 Weeks. Terbinafine 250 mg QD for 12 weeks. | 36 |
| Placebo for 24 Weeks Placebo for 24 weeks. | 36 |
| Total | 218 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Administrative | 1 | 0 | 2 | 1 | 0 | 0 |
| Overall Study | Adverse Event | 1 | 2 | 4 | 4 | 0 | 1 |
| Overall Study | Did not Meet Protocol Eligibility | 0 | 1 | 1 | 0 | 1 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 | 0 | 1 | 0 | 3 |
| Overall Study | Non Compliance with the Protocol | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 3 | 1 | 2 | 2 | 4 |
Baseline characteristics
| Characteristic | 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 |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 49.0 years STANDARD_DEVIATION 13 | 53.6 years STANDARD_DEVIATION 10.8 | 49.9 years STANDARD_DEVIATION 13.2 | 53.5 years STANDARD_DEVIATION 11.8 | 50.1 years STANDARD_DEVIATION 12.2 | 48.4 years STANDARD_DEVIATION 14.8 | 50.8 years STANDARD_DEVIATION 12.7 |
| Sex: Female, Male Female | 10 Participants | 6 Participants | 8 Participants | 7 Participants | 7 Participants | 7 Participants | 45 Participants |
| Sex: Female, Male Male | 27 Participants | 31 Participants | 28 Participants | 29 Participants | 29 Participants | 29 Participants | 173 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 26 / 36 | 21 / 37 | 20 / 36 | 18 / 36 | 20 / 36 | 21 / 35 |
| serious Total, serious adverse events | 1 / 36 | 1 / 37 | 1 / 36 | 1 / 36 | 0 / 36 | 3 / 35 |
Outcome results
Primary
Complete Cure of Onychomycosis at 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).
Time frame: Measured at Day 1, Week 2, Week 4, and Every 4 Weeks Thereafter Until Week 48
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Posaconazole 100 mg QD for 24 Weeks | Complete Cure of Onychomycosis at Week 48. | 8 Participants |
| Posaconazole 200 mg QD for 24 Weeks. | Complete Cure of Onychomycosis at Week 48. | 20 Participants |
| Posaconazole 400 mg QD for 24 Weeks. | Complete Cure of Onychomycosis at Week 48. | 15 Participants |
| Posaconazole 400 mg QD for 12 Weeks. | Complete Cure of Onychomycosis at Week 48. | 7 Participants |
| Terbinafine 250 mg QD for 12 Weeks. | Complete Cure of Onychomycosis at Week 48. | 13 Participants |
| Placebo for 24 Weeks | Complete Cure of Onychomycosis at Week 48. | 0 Participants |
p-value: 0.00595% CI: [8.9, 36.8]Fisher Exact
p-value: <0.00195% CI: [38, 70.1]Fisher Exact
p-value: <0.00195% CI: [28.5, 62.4]Fisher Exact
p-value: 0.01295% CI: [6.7, 33.3]Fisher Exact
p-value: <0.00195% CI: [21.1, 53.2]Fisher Exact
Secondary
Effective Treatment of Onychomycosis at 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
Time frame: Measured at Day 1, Week 2, Week 4, and Every 4 Weeks Thereafter Until Week 48
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Posaconazole 100 mg QD for 24 Weeks | Effective Treatment of Onychomycosis at Week 48. | 9 Participants |
| Posaconazole 200 mg QD for 24 Weeks. | Effective Treatment of Onychomycosis at Week 48. | 24 Participants |
| Posaconazole 400 mg QD for 24 Weeks. | Effective Treatment of Onychomycosis at Week 48. | 16 Participants |
| Posaconazole 400 mg QD for 12 Weeks. | Effective Treatment of Onychomycosis at Week 48. | 11 Participants |
| Terbinafine 250 mg QD for 12 Weeks. | Effective Treatment of Onychomycosis at Week 48. | 19 Participants |
| Placebo for 24 Weeks | Effective Treatment of Onychomycosis at Week 48. | 0 Participants |
p-value: 0.00295% CI: [11.2, 40.2]Fisher Exact
p-value: <0.00195% CI: [49.5, 80.2]Fisher Exact
p-value: <0.00195% CI: [31.4, 65.5]Fisher Exact
p-value: <0.00195% CI: [16, 46.8]Fisher Exact
p-value: <0.00195% CI: [37.8, 70.8]Fisher Exact
Secondary
Treatment Success of Onychomycosis at Week 48
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Posaconazole 100 mg QD for 24 Weeks | Treatment Success of Onychomycosis at Week 48 | 11 Participants |
| Posaconazole 200 mg QD for 24 Weeks. | Treatment Success of Onychomycosis at Week 48 | 24 Participants |
| Posaconazole 400 mg QD for 24 Weeks. | Treatment Success of Onychomycosis at Week 48 | 22 Participants |
| Posaconazole 400 mg QD for 12 Weeks. | Treatment Success of Onychomycosis at Week 48 | 11 Participants |
| Terbinafine 250 mg QD for 12 Weeks. | Treatment Success of Onychomycosis at Week 48 | 20 Participants |
| Placebo for 24 Weeks | Treatment Success of Onychomycosis at Week 48 | 0 Participants |
p-value: <0.00195% CI: [16, 46.8]Fisher Exact
p-value: <0.00195% CI: [49.5, 80.2]Fisher Exact
p-value: <0.00195% CI: [50.6, 82.8]Fisher Exact
p-value: <0.00195% CI: [16, 46.8]Fisher Exact
p-value: <0.00195% CI: [40.7, 73.5]Fisher Exact