E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Mild to moderate distal subungual Onychomycosis due to Dermatophytes. |
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E.1.1.1 | Medical condition in easily understood language |
Fungal infection ot the nails |
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E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10030338 |
E.1.2 | Term | Onychomycosis |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
- To evaluate the effect of different doses of P-3058 compared to placebo in the treatment of onychomycosis at the end of the follow up (week 76)
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E.2.2 | Secondary objectives of the trial |
- To evaluate the shape and the location of the dose response curve of the efficacy outcome (responders rate)
-To determine the maximal dose beyond which additional benefit would be unlikely to occur |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
“Pharmacokinetics evaluation in blood and nail samples of 3 doses of P-3058 nail lacquer (5% o.d., 10% o.d., and 10% o.w.) given for 52 weeks in patients with onychomycosis”.
Revised version: 2010/01/13
Objective: to evaluate nail concentrations and systemic exposure to the test products after multiple applications in a long-term study.
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E.3 | Principal inclusion criteria |
• Written informed consent before starting any study related procedures
• Patients aged ≥12 up to 80 years old
• Males or females, outpatients
• Patients with established clinical diagnosis of mild-to-moderate distal sub-ungual onychomycosis (i.e. involving ≥ 25% to ≤ 60% of the distal bed-adherent nail plate without involvement of the lunula) caused by dermatophytes, affecting at least one big toenail
• Patients with positive KOH examination from the target big toenail obtained at screening
• Patients with positive culture for dermatophyte/s in screening nail sample
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E.4 | Principal exclusion criteria |
• Patients with history of cardiovascular, renal, neurologic, liver, immunologic or endocrine dysfunction if they are clinically significant.
A clinically significant disease is defined as one which in the opinion of the investigator may either put the patient at risk because of participation in the study or a disease which may influence the results of the study or the patient’s ability to participate in the study.
• Patients with a recent history (< 1 year) of myocardial infarction and/or (< 3 years) of heart failure or patients with any cardiac arrhythmia requiring drug therapy
• Patients with liver function impairment AST, ALT more than twice above the upper limit of reference range
• Patients with kidney function impairment serum creatinine more than twice above the upper limit of reference range
• History of cancer within the past 5 years, excluding treated basal cell carcinoma
• Chemotherapy, immunosuppressive therapy in the 12 weeks prior to screening visit
• Systemic glucocorticosteroids, antimetabolites and immunostimulants therapy in the 4 weeks prior to screening visit
•Alcohol or substance abuse
• HIV infection or any other immunodeficiency
• Patients unable to understand the procedures and purposes of the study
• Patients with history of allergic reactions to terbinafine or its excipients
• Use of an investigational drug or participation in an investigational study within 30 days prior to administration of study medication
• Patients using nail polish or other nail cosmetic product on the concerned nails from at least 24 hours prior to study drug administration until the end of the study
• Patients with target nail hyperkeratosis exceeding 4 mm in thickness
• Patients with proximal subungual involvement (marker of immunosuppressed patient)
• Disease involving <25% or >60% of distal bed-adherent nail plate
• Patients with mucocutaneous candidiasis
• Patients with white superficial onychomycosis
• Patients with onychomycosis caused by yeasts or non-dermatophytes mould
• Patients with "Yellow spikes" on the target nail (extension of fungal infection from distal to proximal part of nail)
• Patients with lunula involvement (marker of immunosuppressed patient)
• Patients with negative KOH examination at screening
• Patients with severe plantar or moccasin tinea pedis (defined by blistering, pustules or inability to ambulate)
• Patients with nail abnormalities due to conditions like psoriasis or lichen planus
• Patients with uncontrolled diabetes
• Patients with recurrent erysipela at screening visit [If erysipela infection occurs during the study, the patient is allowed to continue the study and to be treated with antibiotic therapy (penicillin)]
• Use of systemic antifungal drugs in the 6 months prior to screening visit
• Use of topical products containing terbinafine in the 3 months prior to screening visit
•Use of topical antifungal drugs (other than terbinafine) in the four weeks prior to screening visit
•Breast-feeding patients
•Positive urine pregnancy test at screening
•Women of child-bearing potential or in menopause for less than 1 year not using a reliable method of contraception.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary end-point is the responders rate as evaluated by the central, blinded Assessor at week 76 (end of follow-up) This is defined as patients with conversion to negative of culture and of microscopic KOH examination and with decrease of affected nail area to ≤10% of total |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
week 76 (at the end of the follow up period) |
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E.5.2 | Secondary end point(s) |
- Cure rate defined as complete replacement of the affected nail by new healthy nail, as evaluated by a central, blinded Assessor, accompanied by conversion to negative of culture and of microscopic KOH examination at week 16, 28, 40, 52
(end of treatment), 64 and 76
- Conversion to negative of culture at week 4, 16, 28, 40, 52, 64 and 76
- Conversion to negative of microscopic finding on KOH preparation at week 4, 16, 28, 40, 52, 64 and 76
- Determination of growth rate of healthy nail at week 16, 28, 40, 52, 64 and 76 by the central, blinded Assessor
- Responders as evaluated by the central, blinded Assessor at week 16, 28, 40, 52 and 64
- Responders as evaluated by the local Investigator at week 16, 28, 40, 52, 64 and 76
- Decrease of the affected nail area to ≤ 10% of the total at week 4, 16, 28, 40, 52, 64 and 76
- Time to reach the efficacy outcome responder
- Time to reach the efficacy outcome cure
- Rate of relapse at week 76 (at least one among the following: affected target nail area >10%, culture positive, KOH positive), in patients responders at week 52
- Rate of responders at weeks 64 and 76 among patients non-responders at week 52
- Acceptance of therapy by patient
- Overall safety evaluation |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Cure rate at week 16, 28, 40, 52, 64 and 76
- conversion to negative of culture at week 4, 16, 28, 40, 52, 64 and 76
- conversion to negative of KOH microscopy at week 4, 16, 28, 40, 52, 64 and 76
- growth rate of healthy nail at week 16, 28, 40, 52, 64 and 76
- responders, evaluated by the Blinded Assessor at week 16, 28, 40, 52 and 64
- responders, evaluated by the local Investigator at week 16, 28, 40, 52, 64 and 76
- decrease of the affected nail area to <=10% of the total at week 4, 16, 28, 40, 52, 64 and 76
-rate of relapse at week 76 in patients responders at week 52
-rate of responders at week 64 and 76 among patients non-responders at week 52
-therapy acceptance at week 52 or at the discontinuation
-overall safety evaluation at all time points |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 5 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 34 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the trial corresponds to the last visit performed by the last patient included in the trial |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |