The objective of this open label phase IIa trial is to evaluate the efficacy and tolerability of a once a week dose of 200 mg R126638, for a maximum of 12 weeks, for the treatment of toenail onychomycosis.
ID
Source
Brief title
Condition
- Skin and subcutaneous tissue disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Therapeutic cure i.e. mycological and clinical cure
Secondary outcome
Scoring of individual signs and symptoms
Measuring length of unaffected nail
Mycological evaluation
Background summary
R126638 is a synthetic triazole antifungal agent, with excellent potential for
oral and topical treatment of fungal infections of skin, hair, nails, oral and
genital mucosa. It is clear from in vitro data that R126638 is active against
infections caused by dermatophytes (Trichophyton spp., Microsporum canis,
Epidermophyton floccosum), yeasts (including C. albicans and Malassezia spp.)
and many other fungi (Odds et al., 2004). The strong activity of R126638 is
ascribed to its prominent affinity to fungal cytochrome P450, which is involved
in the biosynthesis of ergosterol from lanosterol (Vanden Bossche et al.,
2004). Ergosterol is a vital component of cellular membranes in fungi and its
specific inhibition by R126638 results in altered fungal growth and impaired
viability. In vivo experiments in mice and guinea-pigs provided further
evidence for a potent antifungal activity of R126638. A superior efficacy of
R126638 over itraconazole (factor 4-8) has been found in experimental models of
superficial fungal infections (Odds et al., 2004).
Experiments in human liver microsomes revealed that CYP3A4 was the cytochrome
P450 form which was the most sensitive to inhibition by R126638. The drug shows
a much lower interaction potential with CYP 3A4 compared to ketoconazole and
itraconazole and does not significantly inhibit the human cytochromes P450 1A2,
2D6, 2C9, 2A6 and 2E1 (Vanden Bossche et al., 2004).
Onychomycosis is the most frequent nail disease and represents 30% of all
mycotic infections of the skin. It is often caused by dermatophyte, yeasts or
moulds. Fungal nail infections are chronic and recalcitrant to treatment.
Currently available topical antifungals are generally ineffective; therefore
oral antimycotics have become the treatment of choice. Itraconazole and
terbinafine have been developed for pulse-therapy. The disadvantage of both
drugs is the use for a complete week every month for several months.
Fluconazole and the new azole, R126638, might require shorter treatment
durations. For fluconazole a treatment schedule of a single weekly dosing has
been tested in explorative trials. Since the MIC values for fluconazole are
higher than those for R126638 (Jessup et al., 2000; Odds et al., 2004), it is
expected that R126638 might show a high activity in onychomycosis by similar
treatment schedules.
Recent pharmacokinetic studies have shown that R126638 has a high affinity for
the nail (Van de Velde et al., in prep). In volunteers who received 100 or 200
mg o.d. for 1 week nail plate kinetics indicated that the drug could be
detected in the nail at the first sampling point at 2 weeks after start of
therapy, indicating that R126638 penetrates the nail via the nail bed. The
identification of R126638 in fingernails by a second concentration peak,
reflects that penetration via the nail matrix. Itraconazole penetrates the nail
in a similar way. The Cmax in toenails seen at 4 to 8 weeks amounted to
179.3±144.1 ng/g. In part of the subject a secondary peak was seen at 12 to 24
weeks. Clearance from the nails was shown to be slow since the mean residence
times were 27.8±15.4 weeks for the 200 mg dose group.
R126638 will be administered p.o. as oral solution at a dose of 200 mg once a
week for a maximum of 3 months. Exposure levels after administration of this
single weekly oral dose of 200 mg are expected to lead to an effective
treatment of onychomycosis by clearing the dermatophyte, yeast or mould
infection.
The expected exposure levels are also lower than those observed at the no-toxic
effect dose levels in rats and dogs. To obtain a high bioavailability, R126638
should be administered as an oral solution after overnight fasting. The plasma
level after intake of a single dose of 200 mg R126638, given as an oral
solution, produced a Cmax of 755 ng/ml and an AUC0-24h of 7672 ng.h/ml
(Bruynseels et al., 2004). Slight clinical changes such as vomiting and soft
faeces were observed in dogs from the dose of 40 mg/kg body weight onwards.
Both symptoms were slight and disappeared shortly thereafter. At a dose of 40
mg/kg the Cmax amounted to 1595 ng/ml and the AUC0-24h was 26500 ng.h/ml in
these dogs.
Cardiovascular safety, clinical laboratory safety and tolerability of single
oral doses of 12.5 up to 1200 mg were studied in three phase I cross-over
trials each with 18 volunteers (Van der Geest et al., 2000; Tritsmans et al.,
2000; Leempoels et al., 2000). A fourth phase I study was a multiple dose
trial with R126638 dosed for 1 week at 100 mg and 200 mg compared to placebo
(Bruynseels et al., 2004). In these four phase I studies, the number of
adverse events with R126638 was limited and comparable with placebo.
Furthermore, in all four phase I studies, no consistent or relevant changes in
vital signs, electrocardiogram, and clinical laboratory tests were reported.
From these studies it was concluded that R126638 administered as a single dose
(dose ranging from 12.5 to 1200 mg) and as a multiple dose for 1 week at
(dosages of 100 and 200 mg) is safe and well tolerated. (Van der Geest et al.,
2000; Tritsmans et al., 2000; Leempoels et al., 2000; Bruynseels et al., 2004).
Study objective
The objective of this open label phase IIa trial is to evaluate the efficacy
and tolerability of a once a week dose of 200 mg R126638, for a maximum of 12
weeks, for the treatment of toenail onychomycosis.
Study design
Open label phase IIa trial
Intervention
Blood sampling: On maximum 7 of the 8 visits. This for a safety evaluation.
ECG recording: Three times, once pre-treatment and twice post-treatment. This
for a safety evaluation with special attention for the QT/QTc interval.
Study burden and risks
The number of adverse events reported in clinical trials with R126638 was very
limited and relatedness with the product considered absent or doubtful. Adverse
experiences reported in association with the use of R126638 are expected to be
similar with those reported for other azoles:
1) headache
2) gastro-intestinal disturbances (nausea, diarrhoea)
3) skin reactions (such as itch, erythema)
4) reversible changes in liver enzymes.
Cipalstraat 3
2440 Geel
Belgie
Cipalstraat 3
2440 Geel
Belgie
Listed location countries
Age
Inclusion criteria
1. Male and female subjects of 18 to 70 years old including extremes.
2. Clinical diagnosis of disto-lateral onychomycosis of the toenails.
3. Diagnosis confirmed by microscopic examination and culture
4. If the subject is of childbearing potential, she must have a negative urine pregnancy test at inclusion and agree to use effective forms of birth control (double barrier method) during the duration of the clinical trial or until the first menses after 60 days following the last dose of study medication, whichever is longer. She must be on a stable regimen, for at least one month, of oral contraceptives, contraceptive implant or depot injection, contraceptive patch, IUD, condom and spermicidal agent or diaphragm and spermicidal agent.
5. Availability of a signed informed consent prior to beginning protocol-specific procedures, indicating an understanding of the purpose of this trial and a willingness to adhere to the treatment regimen and trial procedures described in this protocol.
6. The subject is in good health and free of any disease or physical condition which, in the investigator*s opinion, might impair evaluation of onychomycosis of the toenail(s).
Exclusion criteria
1. More than 50% involvement of the most severely affected toenail.
2. An involvement of the nail matrix.
3. Lateral onychomycosis involving > 50% of the length of the most severely affected toenail.
4. Extensive hyperkeratosis (>3mm nail thickness) on the most severely affected toenail.
5. An involvement nail of the little toes only
6. Psoriasis or diabetics.
7. History of significant sensitivity, or significant allergy to azoles or related drugs or any ingredient in the study medication.
8. Severe coexisting hepatic, renal, or bone marrow disease, hyperlipidemia, chronic pancreatitis, or a history indicating adrenal cortex dysfunction or any other serious disease (including cancer and subjects known to be HIV positive).
9. History of heart-failure, myocardial infarction within the past six months, cardiac arrhythmia, or under treatment for heart disorders.
10. Clinical significant abnormal ECG-intervals or morphology of the ECG, QT or QTc>450 ms.
11. Use of any local or systemic anti-mycotic therapy two weeks (local) or three months (systemic) before treatment.
12. Current use of prohibited medication. CYP3A4 metabolized substrates such as triazolam, oral midazolam, alprazolam, buspirone, Ca-channel blockers such as dihydropyridines and verapamil, tiralazad, fentanyl, alfentanyl, coumarins; CYP3A4 metabolized HMG-CoA reductase inhibitors such as lovastatin, simvastatin, atorvastatin, pravastatin; potent enzyme inducers of CYP3A4, e.g. phenytoin phenobarbital, carbamazepine, isoniazid, rifampin, rifabutin; potent inhibitors of CYP3A4, e.g. ritonavir, indinavir and saquinavir; drugs known to prolong QT-interval such as class Ia and III antiarrythmics, sotalol, terenadine, astemizole, cisapride, levacetylmethadol (levomethadyl), misolastine, azolastine, antimalarials such as chloroquine, quinidine and halofantrine, macrolides, quinolones, antipsychotics; systemic immunosuppressants e.g. cyclosporine and tacrolimus, rapamycin (sirolimus), methotrexate, 6-mercaptopurine; systemic corticosteroids.
13. Out of range laboratory values that the investigators considers as pathologic.
14. History or suspicion of alcohol abuse or drug abuse, or psychological or other emotional problems which, in the investigator*s opinion, are likely to invalidate informed consent, or limit the ability of the subject to comply with the protocol requirements.
15. Breasting-feeding women and pregnant women.
16. Participation in an investigational study within 30 days prior to study entry.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
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Other (possibly less up-to-date) registrations in this register
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2005-004611-30-NL |
| CCMO | NL13110.060.06 |