A Trial Involving Treatment of BB2603 in Subjects With Distal Subungual Onychomycosis of the Toenail
A Trial Involving Treatment of BB2603 in Subjects With Distal Subungual Onychomycosis of the Toenail
This study will be a multicenter, international, randomized, vehicle-controlled,
 parallel-group, double-blinded study. Subjects who are eligible to participate with a
 confirmed diagnosis of Distal Subungual onychomycosis (DSO) of the toenail will be randomized
 and participate in one of the following treatment groups: BB2603-1: 0.01% terbinafine/0.03%
 polyhexanide formulation, or BB2603-3: 0.03% terbinafine/0.09% polyhexanide formulation, or
 BB2603-10: 0.1% terbinafine/0.3% polyhexanide formulation, or Vehicle: 0.3% polyhexanide/20%
 ethanol/water formulation. The subject in each treatment group will be treated twice daily
 (BID) for 12 weeks and then complete a 28-day post-treatment visit.
Onychomycosis (OM; fungal nail infection) is a common and contagious fungal infection of the
 nail plate or nail bed, leading to the gradual destruction of the nail plate. OM is
 considered the most prevalent of the nail ailments, accounting for about 50% of all diseased
 nails and about 30% of cutaneous fungal infections. The prevalence of OM is reported to be
 23% across Europe, 13.8% in North America and approximately 10% in Japan, with the prevalence
 increasing in Western countries, presumably due to lifestyle changes and the ageing of the
 population.

 Distal subungual onychomycosis (DSO) is the most common form of OM, characterised by invasion
 of the nail bed and underside of the nail plate beginning at the hyponychium. This infection
 is visualised as nails with normal surface texture and thickness but variable "bays" of white
 nail that extend from the distal nail tip proximally into the area of the nail bed. The vast
 majority of cases of OM are caused by dermatophyte fungi. In 80% to 98% of affected
 individuals, Trichophyton rubrum with additional infections caused by Trichophyton
 mentagrophytes var interdigitale (commonly referred to as Trichophyton mentagrophytes) or
 Epidermophyton floccosum. The dermatophyte Trichophyton rubrum is the major cause of tinea
 pedis (TP; athlete's foot) and OM. OM is a progressive disease; if left untreated, OM can
 lead to permanent nail damage and associated discomfort.

 Onychomycosis is currently treated with surgery, medical devices (eg laser therapy), oral or
 topical anti-fungal agents or a combination of both. Oral terbinafine, when used for a
 minimum of 3 months, can achieve an efficacy of 38% or higher if treatment is extended but
 has a significant drug-interaction and side effect profile, including liver failure, and
 periodic monitoring (after 4-6 weeks of treatment) of liver function test is recommended.
 Topical agents are used for up to 18 months but have significantly lower efficacy rates of
 less than 20%.

 Terbinafine is a well-established synthetic allylamine anti-fungal developed by Sandoz (now
 Novartis) and commercially available worldwide for more than 25 years in different oral and
 topical formulations as a dermal cream (1%), emulsion gel (1%), solution/spray (1%), as well
 as oral tablets (250 mg and 125 mg). It is highly hydrophobic in nature and tends to
 accumulate in skin, nails, and fatty tissues. Terbinafine's anti-fungal mechanism of action
 is by inhibition of squalene epoxidase in the fungal cell membrane. This leads to a
 deficiency in ergosterol and an intracellular accumulation of squalene, resulting in fungal
 cell rupture/lysis (fungicidal activity).

 Dermatophytoses of nails, in contrast to those at other body sites, are particularly
 difficult to eradicate with drug treatment. This is the consequence of factors intrinsic to
 the nail (the hard, protective nail plate, sequestration of pathogens between the nail bed
 and plate, and slow growth of the nail). The unique barrier properties of the nail plate,
 which hampers the passage of anti-fungal drugs in a concentration required to eradicate the
 deeply-seated causative fungi in the nail bed, is a specific challenge.

 As such, there is a recognized need for a simple, effective and curative topical treatment
 for OM. Furthermore, topical treatment may result in minimal adverse systemic events and
 possibly improved adherence.
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 Clinical Study Protocol

 -  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 interrupted in case of pregnancy.

 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.

 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, either
 alone or in combination with a dermatophyte, or any other infection (eg bacterial).

 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.