| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Onychomycosis and associated Tinea Pedis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Fungal infection of the nail and associated athlete's foot |
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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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10043873 |
| E.1.2 | Term | Tinea pedis |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| 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 |
|
| 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 |
| The primary objective of the study is to assess the systemic exposure of the API terbinafine as assessed by systemic pharmacokinetics after treatment with topical BB2603 in subjects with onychomycosis and associated tinea pedis compared to Lamisil® Spray and BB2603 vehicle spray. |
|
| E.2.2 | Secondary objectives of the trial |
1. Safety, local tolerability and skin sensitization of topically applied BB2603 / Lamisil® Spray / BB2603 vehicle.
2. Efficacy. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Males or females of 18 years old or older.
2. Clinical diagnosis of onychomycosis in at least one toenail with Onychomycosis Severity Index (OSI) 1-15 at Screening and Baseline (pre-dose D1) and PCR positive at screening.
3. Clinical diagnosis of TP with lesions localized to the interdigital spaces or predominantly interdigital, but may extend to other areas of the foot (the non-interdigital lesions should not be hyperkeratotic i.e. should not have the characteristics of tinea pedis moccasin), and confirmed by a positive potassium hydroxide (KOH) wet mount preparation Screening and Baseline (pre-dose D1).
4. Sum of the clinical signs and symptom scores of the target TP lesion is at least 2, including a minimum score of at least 1 for erythema AND a minimum score of 1 for either scaling or pruritus (on a scale of 0-3, where 1 indicated mild severity).
5. Non-menopausal or non-surgically sterilized childbearing potential female subjects must have a negative urine HCG at the time of entry into the study with no intentions of becoming pregnant during the study.
6. Non-menopausal or non-surgically sterilized childbearing potential female subjects must use a medically acceptable form of birth control.
7. Subjects must have the mental, literate, and legal ability to give a written informed consent, which must comply with the International Council for Harmonisation (ICH), guidelines and local requirements.
8. Non-menopausal or non-surgically sterilized childbearing potential female subjects must have a negative serum HCG at the time of entry into the study with no intentions of becoming pregnant during the study (See Study protocol section 6d).
9. Non-menopausal or non-surgically sterilized childbearing potential female subjects must use a medically acceptable form of birth control. Reliable contraception is defined as a method which results in a low failure rate, i.e., less than 1% per year when used consistently and correctly, such as implants, injectables, some intrauterine contraceptive devices (IUDs), complete sexual abstinence, or a vasectomised partner. Oral contraceptive medications are allowed in this study. Female subjects who are surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy) or postmenopausal (defined as no menstrual period within 1 year of screening) are also allowed to participate.
Subjects must have the mental, literate, and legal ability to give a written informed consent, which must comply with the International Council for Harmonisation (ICH) guidelines and local requirements.
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|
| E.4 | Principal exclusion criteria |
1. PCR negative OM.
2. OSI ≥16.
3. KOH negative tinea pedis.
4. Known history of hypersensitivity or allergy to or known contraindication to the use of Lamisil® Spray, terbinafine, BB2603 or any of its components/excipients.
5. Pregnancy or planning to become pregnant during the study period.
6. Breast feeding.
7. Severe renal or hepatic impairment with parameters of Grade 3 or higher on the corresponding CTCAE scale.
8. Presence of other known clinically significant medical and/or psychological illnesses precluding participation.
9. Any dermatological condition that could mimic the signs and symptoms of TP or OM.
10. Progression of OM by >50% nail manifestation during the last 2 months before enrolment.
11. Use of any systemic (oral) or topical anti-fungal treatment for onychomycosis in the previous 3 months.
12. Use of systemic (oral) antipruritics, including antihistamines, within 72 hours prior to first dosing in the study (Day 1).
13. Use of systemic (oral or injectable) corticosteroid or antibiotic therapy within 1 month prior to first dosing in the study (Day 1).
14. Use of oral terbinafine or itraconazole (or other oral anti-fungal) within 3 months prior to first dosing in the study.
15. Use of topical corticosteroid, antibiotics or antifungal therapy for tinea pedis within 2 weeks prior to first dosing in the study.
16. Use of immunosuppressive medication or radiation therapy within 2 months prior to study entry.
17. Use of laser therapy, photodynamic therapy, chemical, surgical, relevant mechanical removal for onychomycosis within the last 3 months.
18. Confluent, diffuse moccasin-type tinea pedis associated of the entire plantar surface.
19. Presence of any other infection of the foot or other disease process that might confound the treatment evaluation.
20. History of dermatophyte infections unresponsive to systemic or topical antifungal drugs (other than onychomycosis).
21. Use of any investigational agent within 30 days or 5 halflives prior to randomization, whichever is longer.
22. Screening blood parameters >2 times upper limit of normal.
23. Unable or unwilling to complete the follow-up evaluations required for the study.
24. Any other condition that, in the opinion of the Investigator, would prevent the subject from effectively participating in the study, place the subject at risk or affect the assessment of efficacy and safety of the study medication.
25. Vulnerable subjects (such as those kept in detention).
26. Individuals involved in the planning and/or conduct of the study (i.e. Sponsor or employees of Sponsor, CRO employees and relatives thereof).
Any other condition that, in the opinion of the Investigator, would prevent the subject from effectively participating in the study, place the subject at risk or affect the assessment of efficacy and safety of the study medication.
Terbinafine resistance should be noted. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. PHARMACOKINETIC
The primary PK endpoints for this study will be:
• Terbinafine in plasma, compared between spray treatment-allocation groups in Part 1 and Part 2 using appropriate PK analyses/parameters suitable for the emerging analytical data from the study. This may include Cmax, Cmin, tmax, AUClast, AUC∞, λz, t½.
Systemic terbinafine exposure will be compared to that for the marketed product, Lamisil® Spray (active control).
2. EFFICACY
•Tinea Pedis Efficacy
Complete cure of TP at D42, defined as eradication of dermatophyte infection confirmed clinically (no clinical signs or symptoms of TP) and from skin scrapings (KOH and culture).
Other efficacy endpoints will be:
2.1. TP response at D7, D14, D21, D28, D42, D46/W0, W4, W8, W12, W16, W20, W24,
W36, W48 and W52 (FFU) defined as eradication of dermatophyte infection
confirmed clinically and from skin scrapings if clinically present (KOH and culture).
2.2. Tinea pedis KOH at D1, D2, D3, D4, D5, D6, D7, D14, D21, D28, D42, D46/W0, W4, W8, W12, W16, W20, W24, W36 and W48.
2.3. Time to “total mycological cure day” for TP (based on clinical and KOH results) from D1, D2, D3, D4, D5, D6, D7.
2.4. TP Response at D42 (KOH, culture and clinical score).
• Onychomycosis Efficacy
Combined endpoint of negative culture for dermatophytes and an OSI of zero (0) - assessed at D28, D46/W0, W4, W8, W12, W16, W20, W24, W36, W48 and W52 (FFU) and defined as eradication of dermatophyte infection confirmed clinically (no clinical signs or symptoms of OM, OSI=0) and from nail scrapings (for culture).
At W52, nail PCR will also be taken and should be negative for OM.
Partial cure of OM will be assessed at D28, D46/W0, W4, W8, W12, W16, W20, W24, W36, W48 and W52 (FFU). Partial cure is defined as eradication of dermatophyte infection on BBT120126032001 culture from nail scrapings and with less than or equal to 10% of the target nail still with a clinical diagnosis of OM.
“OM improvement” will also be assessed at D28, D46/W0, W4, W8, W12, W16, W20, W24, W36, W48 and W52 (FFU). OM improvement will be defined as eradication of dermatophyte infection on culture from nail scrapings and with a reduction in OSI score by at least 40% from baseline (D1).
Change from baseline in OSI and new nail growth (mm) will be assessed at D28, D46/W0, W4, W8, W12, W16, W20, W24, W36, W48 and W52.
Patient reported outcome (OnyCOE-t) at Baseline (D1), D28, D46/W0, W12, W24, W36, W48 and W52. The Occupational, Environmental and Lifestyle questionnaire will also be assessed at either W4, W8, W12, W16, W20, W24, W36, W48 or W52. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Plasma sampling for terbinafine levels will be performed at T= 0 (baseline sample), 1hr, 2hr, 4hr, 8hr, 12hr, 24hr (D2), D3, D4, D5, D6, D7, D14, D21, D28 and D42 in all subjects for Part 1 of the study. For Part 2 of the study, plasma sampling for terbinafine levels will be performed at D46/W0, W4, W8, W12, W16, W20, W24, W36, W48 and W52 in all subjects.
Systemic terbinafine exposure will be compared to that for the marketed product, Lamisil® Spray (active control). Timings for PK sampling may be adjusted depending on emerging safety and PK data. No additional samples will be taken.
Local target nail PK samples will be taken at T=0 (D1, baseline sample), D28, D46/W0, W12, W24, W36, W48 and W52.
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|
| E.5.2 | Secondary end point(s) |
1. SAFETY
Safety endpoints will include:
1. Treatment-emergent Adverse Events (AEs)
2. Treatment-emergent Serious Adverse Events (SAEs)
3. Treatment-emergent Adverse Events leading to premature discontinuation of study drug/PK assessments
4. Common Terminology Criteria Adverse Events (CTCAE) version 3 grading for skin and other dermatological assessments (see Study Protocol Appendix e)
5. Skindex-16 (see Study Protocol Appendix d) assessments
6. Skin Irritation assessments (see Appendix f)
7. Skin Irritation of patch application started D42 and assessed on D44 and D46 (after patch removal)
8. Routine clinical laboratory safety blood and urinalysis data
9. Vital signs (BP and heart rate)
10. Concomitant medications
Safety data will be listed and summarized by individual, dose-group and overall. Full details will be specified in the Analysis Plan prior to database lock.
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Local tolerability will be assessed by the CTCAE v3.0 criteria
(Study protocol-Appendix e) and irritancy score (Study protocol-Appendix f) at baseline, 1hr, 2hr, 4hr, 8hr, 12hr, 24hr (D2), D3, D4, D5, D6, D7, D14, D21, D28, D42, D46/W0, W4, W8, W12, W16, W20, W24, W36, W48 and W52.
Local tolerability will also be assessed by Skindex-16 (Study protocol-Appendix d) at baseline, D7, D14, D21, D28, D42, D46/W0, W4, W8, W12, W16, W20, W24, W36, W48 and W52.
Skin sensitization will be assessed for all groups in the study using a skin patch test started on Day 42. This will be assessed after 48 hours (Day 44) by an experienced observer when the patches are removed. Subjects return 48 hours (+/- 2 hours) after patch removal (D46) for skin reading by an experienced observer. |
|
| 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 | No |
| 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) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| 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 | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Arm A and C will be double-blind. B is open label |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
| This study is anticipated to complete (end of study, EOS), defined as Last Subject Last Visit (LSLV) within 18-20 months of site initiation visit and commencement of screening. The actual EOS will be dependent on the rate of subject recruitment. The end of clinical trial (EOT) will be notified to authorities within 90 days after the LPLV has occurred. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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