Trial document




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  DRKS00009547

Trial Description

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Title

A randomized, double-blind, vehicle-controlled, parallel-group trial to assess the efficacy, safety and tolerability of P-3073 for topical treatment of nail psoriasis

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Trial Acronym

PM1434

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URL of the Trial

http:///

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Brief Summary in Lay Language

Psoriasis is a noninfectious inflammatory skin disease. Psoriasis can occur anywhere on the skin and its appendages, including the nails. When psoriasis involves the nails, it is often the cause of unpleasant appearance, nail fragility, pain and other discomforts.

Nail involvement in psoriasis is common and the main psoriatic features in the nails are punctuate small, funnel-shaped depressions (pitting), discoloration of the nails, detachment of the nail plate from the bed, as well as thickening of the tissue below the nail plate.

Nail psoriasis is not a dangerous condition: it is not life threatening, but can be a very bothersome condition and it takes a long time to heal. There are no approved topical treatments on the market specifically indicated for nail psoriasis. Usually a fingernail takes six months to completely re-grow. Therefore any treatment of this condition will take considerable time, (at least six months), to produce a clearly visible result.

The purpose of this trial is to provide the sponsor, physicians and patients with more information regarding the efficacy and safety of the study medication. The investigational product (called P-3073) is a new nail solution with Calcipotriol as the active substance for the treatment of mild to moderate psoriatic fingernail(s). P-3073 is under development by the Company Polichem S.A., Lugano (Switzerland).

The active ingredient of the nail solution, Calcipotriol, a well-known active substance against psoriasis, is though, only available on the market as a medication for the local treatment of psoriasis of the skin. Medication for the local treatment of nails affected by psoriasis is not available. There is a medical need for a local treatment of mild to moderate signs and symptoms of nail psoriasis, where the use of other systemic (= affecting the whole body or many organs) products such as those containing cortisone, for example, (= medication reacting oninflammatory reactions, pain, hyperactivity of the immune system) are not recommended.

The investigational product P-3073 contains a carrier substance (also known as “vehicle”), that through the local application of the investigational product, enables the active substance Calcipotriol to penetrate easier into the nail and directly reach the area where it combats the cause of nail psoriasis.

In this study the investigational product P-3073 will be compared with an identical nail solution called placebo that does not contain a substance against psoriasis, but has the same carrier substance and is therefore known as a “vehicle”.
P-3073 nail solution containing either calcipotriol as active drug (named P-3073) at a concentration of 0.005% or vehicle (placebo), identical to the study medication in appearance but without any antipsoriatic activity.

The patient will be requested to apply P-3073 or Vehicle (=placebo) once a day for 24 weeks of treatment. The patient will apply P-3073 or Vehicle (Placebo) on dry nail/s, after shower or bath, before bedtime. A single thin layer of the product shall be applied, by means of the applicator in the cap of the glass bottle, over the entire nail plate and 5 mm of surrounding skin and under the free edge of the nail.

The solution dries in approximately 30 seconds. After nail solution application, the nails should not be washed for at least 6 hours because the product is easily removed by water. After 6 hours, normal hygienic measures can be followed.
P-3073 or Vehicle (Placebo) shall be applied to all affected fingernails, maximum 10 fingernails.

The patients will be randomly allocated to one treatment group (randomization).
The probability to be assigned to the active treatment regimen is 50%, like flipping a coin. The study is double- blind, this means that neither the patient nor the investigator will know the treatment the patient are applying.



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Brief Summary in Scientific Language

Psoriasis is a genetically predetermined hyper-proliferative skin disease characterized by increased cell proliferation, glycogen accumulation and incomplete differentiation in cells of the epidermis.

The diagnosis of psoriasis can be determined clinically and histologically, if needed. Before treatment for psoriasis can be initiated, the grading and severity must be determined and the treatment (topical or systemic) should be chosen according to the “Psoriasis Area and Severity Index” (PASI) and/or the “Body Surface Area” (BSA). Patients with PASI values ≤ 10 are not indicated for systemic treatment.

Nail involvement in psoriasis is common and has been reported in about 50% of cases with a lifetime incidence estimated to be between 80 and 90%. The main psoriatic features in the nails are: pitting, discoloration of the nail, onycholysis, subungual hyperkeratosis, nail plate abnormalities and splinter hemorrhages.

Nail psoriasis is difficult to treat because of the location of the disease, the recurring nature of its symptoms, and treatment non-compliance. There are important adverse consequences on patients’ quality-of-life and treatments are often not effective.

There is an unsatisfied medical need for the treatment of mild-to-moderate prescriptive topical treatment of the signs and symptoms of nail localization of psoriatic lesions, where the use of systemic products, such as biologics or corticosteroids, is not recommended and no topical product is available. Unfortunately, no standard of care therapeutic regimen exists.

The Medical Board of the National Psoriasis Foundation recommends four different treatment scenarios: the use of topical or systemic treatment, including biologics is based on the severity of the pathology.

Calcipotriol is commonly used for the topical treatment of skin psoriasis.
To date, there is in the international literature a number of clinical trials done with no specific nail formulation containing 0.005% calcipotriol (i.e., cream or ointment) in patients with nail psoriasis. Overall, 244 patients with nail localization of psoriasis have been included in 9 clinical studies and treated with 0.005% calcipotriol cream or ointment twice daily for 3-6 months, alone or in combination with other products. The rate of efficacy, in terms of improvement of signs and symptoms of nail psoriasis, ranged between 50% and 80% of treated patients. Calcipotriol 0.005% cream was effective in potentiating the efficacy of oral cyclosporine and, applied once daily on the affected nails in combination with corticosteroids, it showed similar efficacy as calcipotriol alone applied twice daily.

The most frequent adverse experiences reported were irritation and burning at the application site in approximately 1.2% of treated patients for both events. Erythema and diffuse urticaria were also observed in 0.41% of patients treated for nail psoriasis.

Since no standard of care exists for the treatment of nail psoriasis, Polichem S.A. developed a novel product (P-3073), a water based solution containing calcipotriol 0.005% in hydroxypropyl-chitosan (HPCH) as a film forming agent. The formulation is designed to maintain the active ingredient in contact with the nail plate for up to 24 hours, thereby achieving drug concentrations in the nail plate and nail bed sufficient to mitigate the signs and symptoms of psoriatic nails.
After application on dry nails P-3073 evaporates quickly and the active ingredient (calcipotriol) permeates the nail lamina. The application is permeable to moisture and air; it is easily removed with water, thereby avoiding any nail damage induced by the use of nail polish and organic solvents.

HPCH vehicle is currently used worldwide by Polichem S.A. in several products indicated for treatment of onychomycosis and onychodystrophy.
Nonclinical toxicology studies with P-3073 calcipotriol nail solution evidenced lack of irritation potential on skin or eyes and no skin sensitization at a drug concentrations 10 times higher than those expected for human use. On the basis of data generated in 28-day dermal toxicity studies performed in rabbits and minipigs, it can be concluded that P-3073 calcipotriol 0.005% medicated nail solution demonstrated no relevant signs of toxicity when dermally applied.

To evaluate the hypothesis of the efficacy of P-3073 nail solution in the treatment of nail psoriasis, a phase II study to compare P 3073 versus placebo and versus another active compound, P-3072 containing cyclosporine 5%, was performed. Eighty-three patients (34 in the P-3073 group, 30 in the P-3072 group and 14 in the vehicle) affected by nail psoriasis in at least one fingernail were enrolled in a randomised, double-blind, placebo-controlled, parallel-group trial and treated once daily for 24 weeks. Patients were also evaluated after a follow-up period of 12 weeks. The changes in clinical signs of the nail bed (salmon patch, onycholysis, hyperkeratosis and splinter hemorrhage) and of the nail matrix (pitting, leukonychia, red spots in lunula, nail plate crumbling) were evaluated by means of NAPSI score at the end of treatment and at the follow-up visit.

The results showed that the change of NAPSI score, of the QoL and of the other clinical outcomes such as discomfort indicated a strong and statistical trend for P-3073 efficacy and no effects of P-3072.

P-3073, used in clinical trials, was safe and did not affect calcium metabolism. From Polichem data on file, the average amount of nail solution applied in adults per week, if ten nails are involved, is 700 mg, containing 35 mcg of calcipotriol, much lower than the approved weekly dose of 100 g of cream, corresponding to 5 mg of calcipotriol, in calcipotriol products for skin psoriasis.

Based on results of the phase II clinical study, Polichem planned this randomized clinical trial (RCT) phase III study versus vehicle to confirm the clinical efficacy and safety of P-3073 in patients affected by isolated psoriatic nail(s) and/or those with psoriatic nails and concomitant mild-to-moderate plaque psoriasis.

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Organizational Data

  •   DRKS00009547
  •   2015/11/05
  •   2015/10/08
  •   no
  •   Approved
  •   AFmu-426/2015, Ethik-Kommission I der Medizinischen Fakultät Heidelberg
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Secondary IDs

  •   2015-002365-34 
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Health Condition or Problem studied

  •   L40.0 -  Psoriasis vulgaris
  •   Nail Psoriasis
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Interventions/Observational Groups

  •   P-3073 (calcipotriol 0.005%) nail solution o.d. over 24 weeks
  •   Placebo (=Vehicle) nail solution o.d. over 24 weeks
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Characteristics

  •   Interventional
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  •   Randomized controlled trial
  •   Blinded
  •   patient/subject, investigator/therapist, data analyst
  •   Placebo
  •   Treatment
  •   Parallel
  •   III
  •   No
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Primary Outcome

Primary Objective:
To assess the efficacy of topical P-3073 in the treatment of mild to moderate psoriatic fingernail/s (defined as fingernail/s with matrix psoriasis NAPSI score and/or bed psoriasis NAPSI score greater or equal to 1 and less than or equal to 3 at baseline).

Primary endpoint:
The primary endpoint is the change from baseline in total NAPSI to Week 24 (end of treatment).

NAPSI:
To assign a score to each nail for nail bed and nail matrix psoriasis, the Nail Psoriasis Severity Index (NAPSI) will be used. The nail plate is divided into four quadrants by imaginary longitudinal and horizontal lines. Nail matrix psoriasis is assessed by the presence of any feature of nail matrix psoriasis, including nail pitting, leukonychia, red spots in the lunula, and crumbling in each quadrant of the nail.

Nail bed psoriasis is assessed by the presence of any features of nail bed psoriasis, including onycholysis, oil drop (salmon patch) dyschromia, splinter haemorrhages, and nail bed hyperkeratosis in each quadrant of the nail. The score is 0 if the findings are not present, 1 if they are present in 1 quadrant of the nail, 2 if present in 2 quadrants of a nail, 3 if present in 3 quadrants of a nail, and 4 if present in 4 quadrants of a nail. Thus each nail has a matrix score (0-4) and a nail bed score (0-4), and the total nail score is the sum of those two (0-8). The sum of the scores from all involved fingernails is 0-80 (total NAPSI score for that patient at that time) and represents the total score.

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Secondary Outcome

Secondary Objectives:
• To assess if the topical treatment with P-3073 is able to improve the quality of life and the discomfort in patients with psoriatic fingernail.
• To assess the safety and tolerability of topical P-3073 in the treatment of psoriatic fingernail.

Secondary endpoints:
• Nail PGA response rate at week 24.

• Change from baseline in NAPSI matrix and NAPSI bed at week 24.

• Change from baseline in patient’s quality-of-life at week 24.

• Change in discomfort due to fingernail psoriasis at week 24.

• Proportions of nails with improvement in total NAPSI, NAPSI matrix and NAPSI bed at week 24.

• Overall safety by recording any AE during the entire study duration and the tolerability after the nail solution application, by means of severity scores for skin irritation.

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Countries of Recruitment

  •   Germany
  •   Latvia
  •   Czech Republic
  •   Russian Federation
  •   Poland
  •   Bulgaria
  •   Greece
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Locations of Recruitment

  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • Doctor's Practice 
  • Medical Center 
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Recruitment

  •   Actual
  •   2015/12/22
  •   330
  •   Multicenter trial
  •   International
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   80   Years
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Additional Inclusion Criteria

• Written informed consent before starting any study-related procedure.

• Patients aged greater or equal to 18 and less than or equal to 80 years old.

• Men or women.

• Outpatients.

• Patients with mild to moderate psoriastic fingernail(s) defined as fingernail/s with matrix psoriasis NAPSI score and/or bed psoriasis NAPSI score greater or equal to 1 and less than or equal to 3 at baseline. The sum of the scores for each nail should range between 1 and 6.

• In case of skin involvement, patients with established clinical diagnosis of mild-to-moderate psoriasis (BSA involvement less than or equal to 8% or PASI less than or equal to 10).

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Exclusion Criteria

• Use of any systemic treatment for psoriasis during the last six months before the screening visit until the end of the study.

• Use of photochemotherapy (phototherapy is allowed) or other forms of radiotherapy during the last four weeks before the screening visit until the end of the study.

• Positive mycology findings (KOH evaluation or culture) obtained in the three months before the screening visit or positive KOH evaluated at the screening visit).

• Patients using nail polish or other nail cosmetic products during last 72 hours prior to study drug application until the end of the study.

• Systemic use of the following therapies for any reason during last three months before the screening visit until the end of the study: immunosuppressives, chemotherapy and corticosteroids (topical use for plaque psoriasis is allowed).

• Consumption of Vitamin D or its analogues for any reason during the last three months before the screening visit.

• Patients with a clinically significant history of cardiovascular, renal, neurologic, liver, immunologic or endocrine dysfunction. A clinically significant disease is defined as one that in the opinion of the investigator may either put the patient at risk because of participation in the study or is a disease that 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.

• History of hypercalcaemia or hypercalciuria.

• History of previous or current malignancy; in particular lymphoma, melanoma and/or basal cell carcinoma.

• History of allergic reactions to Calcipotriol or P-3073 excipients.

• Patients unable to understand the procedures and purposes of the study.

• Patients unable or unwilling to accept and meet study requirements.

• Use of an investigational drug or participation in an investigational study within 30 days prior to application of study medication.

• Alcohol or substance abuse.

• AIDS symptoms or any other immunodeficiency.

Additional exclusion criteria for females only:
• Breast-feeding patients.

• Positive urine pregnancy test at screening (performed for all females of child bearing potential (not surgically sterile) or for those in non- surgical post-menopause for less than 1 year).

• Female of childbearing potential having unprotected sexual intercourse with any non-sterile male partner (i.e., a male who has not been sterilized by vasectomy at least 6 months prior to drug application) within 14 days prior to study drug application.
Acceptable methods of contraception are the following:

Methods that can achieve a failure rate of less than 1% per year:

- combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, transdermal

- progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, implantable

- intrauterine device (IUD) (placed at least 4 weeks prior to study drug application)

- intrauterine hormone-releasing system (IUS)

- bilateral tubal occlusion

- sexual abstinence

Methods that can achieve a failure rate of more than 1% per year:

- 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.

Exclusion criteria during the study:

• Any systemic treatment for psoriasis.

• Any topical product on nails (cosmetic or local treatment for nail psoriasis).

• Systemic use of the following therapies: immunosuppressives, chemotherapy, corticosteroids (topical use on plaque psoriasis is allowed).

• Consumption of Vitamin D or its analogues for any reason during the last three months before the screening visit.

• Evidence of pregnancy will lead the treatment to be stopped and pregnancy outcome followed up until delivery.

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Addresses

  • start of 1:1-Block address primary-sponsor
    • Polichem SA
    • Ms.  Dr.  Renata  Palmieri 
    • Via Senago 42 D
    • 6912  Lugano- Pazzallo
    • Switzerland
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    • Psoriasis-Zentrum Klinik für Dermatologie, Venerologie und Allergologie Universitätsklinikum Schleswig-Holstein, Campus Kiel
    • Mr.  Priv.-Doz. Dr. med.  Sascha  Gerdes 
    • Schittenhelmstr. 7
    • 24105  Kiel
    • Germany
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    • Universitätsklinikum Heidelberg Hautklinik Psoriasiszentrum
    • Mr.  Prof. Dr. med.  Knut  Schäkel 
    • Im Neuenheimer Feld 440
    • 69120  Heidelberg
    • Germany
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    • Psoriasis-Zentrum Klinik für Dermatologie, Venerologie und Allergologie Universitätsklinikum Schleswig-Holstein, Campus Kiel
    • Mr.  Priv.-Doz. Dr. med.  Sascha  Gerdes 
    • Schittenhelmstr. 7
    • 24105  Kiel
    • Germany
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Sources of Monetary or Material Support

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    • Polichem SA
    • Ms.  Dr.  Renata  Palmieri 
    • Via Senago 42 D
    • 6912  Lugano- Pazzallo
    • Switzerland
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Status

  •   Recruiting complete, follow-up complete
  •   2017/02/08
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Trial Publications, Results and other Documents

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* This entry means the parameter is not applicable or has not been set.