| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Distal Subungual Onychomycosis (DSO) of the Toenail |
|
| E.1.1.1 | Medical condition in easily understood language |
| Fungal infection of the toenail |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
| MedDRA Classification |
| 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 |
| Establish early clinical and mycological efficacy of BB2603-10 vs. vehicle assessed at 16 weeks (Early Response Assessment), 4 weeks after having completed a 12-week treatment schedule for clinically and mycologically confirmed onychomycosis (OM) caused by dermatophytes. |
|
| E.2.2 | Secondary objectives of the trial |
-Complete Cure at W52, 40w after having completed a 12-w treatment with BB2603-10 vs. vehicle
-Completely Clear Nail,Almost Clear Nail, negative microscopy or negative dermatophyte culture at W52, 40w after having completed a 12-w treatment with BB2603-10 vs. vehicle
-Evaluate plasma pharmacokinetics of BB2603
-Safety and tolerability of different doses of BB2603 at 4, 12 and 16W after having started a 12-w treatment
-Early clinical and mycological efficacy of BB2603-1 and BB2603-3, respectively vs. vehicle at 16w (Early Response Assessment), 4w after having completed a 12-w treatment for clinically and mycologically confirmed OM caused by dermatophytes
-Establish Complete Cure at W52, 40w after having completed a 12-w treatment with BB2603-1 and BB2603-3, respectively vs. vehicle.
-Completely Clear Nail, Almost Clear Nail, negative microscopy or negative dermatophyte culture at W52, 40w after having completed a 12-w treatment with BB2603-1 and BB2603-3, respectively vs. vehicle. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1 Male or female ≥18 (and ≤99) at the time of Informed Consent.
2 Clinically and mycologically (KOH and culture positive for dermatophytes [microbial infection with fungus belonging to the genus Trichophyton, Microsporum, Epidermophyton]) confirmed diagnoses of DSO of the target toenail affecting ≥25% to ≤60% of the target toenail as determined through clinimetric measurement.
3 Signed written informed consent form (ICF) prior to any trial related activity (subjects must have the mental, literate, and legal ability to give a written informed consent, which must comply with the ICH GCP guidelines and local requirements).
4 Subjects must be willing and able to comply with trial requirements.
5 Females must be either postmenopausal for ≥1 year (ie 12 consecutive months of amenorrhea, for which there is no other obvious pathologic or physiologic cause), or surgically sterile (tubal ligation, hysterectomy, or bilateral oophorectomy) for at least 6 months or, if of childbearing potential must use either highly effective birth control methods such as:
•Oral, intravaginal or transdermal oestrogen- and progestogen-containing hormonal contraception associated with inhibition of ovulation
•Oral, injectable or implantable progestogen-only hormonal contraception associated with inhibition of ovulation
•Intrauterine device or intrauterine hormone-releasing system
•Bilateral tubal occlusion
•Vasectomised partner provided that the partner is the sole sexual partner and that the vasectomised partner has received medical assessment of the surgical success
•Sexual abstinence, ie, refraining from heterosexual intercourse during the entire period of risk associated with the trial treatments
OR
Acceptable birth control methods such as:
•Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of action
•Male or female condom with or without spermicide
•Cap, diaphragm or sponge with spermicide
•A combination of male condom with either cap, diaphragm or sponge with spermicide (double barrier methods) are also considered acceptable birth control methods
while using trial medication and 28 days after last dose of IMP.
Birth control methods which are considered unacceptable: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea method. Female condom and male condom should not be used together.
Treatment with the IMP will be discontinued in case of pregnancy.
The criteria with respect to pregnancy and contraception are in line with the CTFG Recommendations, v1.1, Sept 2020. |
|
| E.4 | Principal exclusion criteria |
1 Any other form of OM except DSO.
2 Nails with clinical evidence of no or low distal growth.
3 DSO of the target toenail where involvement has extended into the proximal portion of the target nail (unaffected proximal nail is ≤3mm) or nail matrix. Any severe OM defined as 3 or more affected toes on one foot.
4 Estimated target toenail thickness >3mm.
5 Presence of dermatophytoma (defined as thick masses of fungal hyphae and necrotic keratin between the nail plate and nail bed) on the target nail.
6 History of dermatophyte infections unresponsive to systemic or topical anti-fungal drugs (other than OM).
7 Presence of toenail infection that does not involve a dermatophyte.
8 Presence of toenail infection that involves a non-dermatophyte fungus or yeast in combination with a dermatophyte where the non-dermatophyte is, in the opinion of the Investigator, considered to be
causative of OM based on clinical appearance, medical history or lifestyle risk.
9 Topical treatment with an antifungal medication within 12 weeks before Randomisation/Visit 2 (with the exception of up to 2 weeks’ treatment during the screening period with a non-terbinafine topical antifungal to treat clinically active TP).
Other exclusion criteria
10 Systemic use of anti-fungal treatment within 12 months before Randomisation/Visit 2.
11 Past use within the last 6 months before Randomisation/Visit 2 or planned use of laser therapy, photodynamic therapy, chemical, surgical, relevant mechanical removal for OM or debridement.
12 Concomitant clinically suspected active TP at Randomisation/Visit 2.
13 Known allergy or known intolerabilities to any of the tested treatment products.
14 Subjects with diabetes, immune suppression, peripheral vascular disease, lymphatic insufficiency, recurrent cellulitis, or other compromised states of health whether due to underlying medical disorders or to long-term immunosuppressive treatments (including >4 weeks systemic corticoids or >4 weeks topical corticoids on the feet). Topical immunosuppressive treatment if not on the target nail is allowed.
15 Females of childbearing potential with a positive serum pregnancy test at Screening/Visit 1 and/or a positive urine pregnancy test at Randomisation/Visit 2 are excluded.
16 Women of childbearing potential who are pregnant or breast feeding or who plan to become pregnant after enrolment until 28 days after the last dose of IMP.
17 Subjects previously randomised in this trial or received BB2603 previously.
18 Use of any investigational agent during the study or within 28 days or 5 half-lives prior to Randomisation/Visit 2, whichever is longer.
19 Close affiliation with the Investigator (eg, a close relative) or persons working at a trial site, or subject who is an employee of the Sponsor’s company.
20 Subjects who are institutionalised because of legal or regulatory order.
21 Hepatic impairment with AST or ALT >5 x Upper Limit of Normal.
22 Estimated creatinine clearance using Cockcroft-Gault formula and actual body weight <30 mL/min.
23 Presence of any other condition or infection of the foot or nail or other disease process that might affect the safety and well-being of the subject or confound the treatment evaluation (eg, psoriasis, lichen planus, or other medical conditions known to induce nail changes, trauma, previous toenail surgery with any residual disfigurement or any dermatological or nail condition that could mimic the signs and symptoms of OM, signs of severe peripheral circulatory insufficiency, use of chronic immunosuppressive medication or radiation therapy within 2 months prior to trial entry or planned during the trial period, immunocompromised).
24 Subjects deemed to be at risk of re-infection or recurrence of OM due to occupational, environmental or behavioural lifestyle in the opinion of the Investigator.
25 Any other significant disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in this trial, or may influence the result of the trial, or the subject’s availability to participate in the trial.
26 Any known or suspected hypersensitivity to, or known allergy to, or other intolerability to BB2603 or its active ingredient or excipients. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The dual primary endpoints are clear nail growth (clinical response) and/or negative dermatophyte culture (mycological response), 4 weeks after having completed a 12 week course of BB2603-10 versus vehicle. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The following binary endpoints at Week 52:
1.Completely Clear nail
2.Negative KOH
3.Negative dermatophyte culture
4.Complete Cure defined as completely clear nail, negative KOH and negative dermatophyte culture
5.Almost Complete Cure defined as complete or almost clear nail (minimal evidence of OM on target toenail plate of ≤10% of the distal aspect based on clinimetric assessment of digital photographs), negative KOH and negative dermatophyte culture will be summarised and analysed as per the primary endpoints to compare BB2603-10 with vehicle. They will be analysed using a CMH test and the CI for the difference in proportions will be computed using the unstratified method of Miettinen and Nurminen (Miettinen and Nurminen 1985). Any treatment switching prior to Week 52 will be treated as treatment failure. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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) | 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 | 4 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 18 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 18 |
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