A Phase I Study to Assess the Safety and Tolerability of Topical CRx-197 Formulations in Healthy Volunteers

Study Overview
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Brief Summary
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This will be a phase I, single center, randomized, vehicle-controlled, blinded study comparing two dosage strengths of CRx-197 cream, nortriptyline, an active comparator (0.1% mometasone) and placebo (the active ingredient free vehicle cream of CRx-197)in healthy volunteers.

Official Title
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A Phase I, Single-Center, Randomized, Vehicle-Controlled Study to Assess the Safety and Tolerability of Topical CRx-197 Formulations in Healthy Volunteers

Conditions
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Atopic Dermatitis

Intervention / Treatment
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* Drug: nortriptyline HCl + loratadine
* Drug: nortriptyline HCl + loratadine
* Drug: nortriptyline HCl
* Drug: mometasone furoate
* Drug: Active ingredient free vehicle cream of CRx-197


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must voluntarily sign and date the written Informed Consent prior to any study specific procedures Subject must be 18 to 60 years of age Subject must have healthy skin on which reddening can be easily recognized in the area where they will place the test fields Subject must be free from a condition/disease that the investigator feels interferes with the interpretation of the study results. Females of childbearing potential should either be surgically sterile (hysterectomy or tubal ligation), or should use a highly effective medically accepted contraceptive regimen. A highly effective method of birth control is defined as those which result in a lower failure rate (i.e., less than 1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence or vasectomised partner. Exclusion Criteria: Suntan, hyper- or hypo-pigmentation, or tattoos in the area where they will place the test fields Dark skinned persons whose skin color prevents ready assessment of skin reactions Cardiac disease, including recent myocardial infarction, any degree of heart block or other cardiac arrhythmias and valvular heart disease Mania Narrow angle glaucoma Hyperthyroidism by medical history, TSH less than LLN, or subject receiving any thyroid medication Severe liver disease - ALT laboratory value that exceeds 1.5x ULN Inflammatory dermatoses (e.g., atopic dermatoses/eczema, psoriasis) Any skin condition involving the test fields including but not limited to bacterial, viral, or fungal skin infections, acne, rosacea Active varicella, tuberculosis, syphilis or post-vaccine reactions Autoimmune disease (e.g., lupus erythematosis) Known allergic reactions or hypersensitivity to any of the components of the study treatments Allergy to adhesives on the patches used for occlusion in the study UV therapy or significant UV exposure in the four weeks before treatment application History of malignancy (except for treated or excised basal cell carcinoma) Surgery within the previous 3 months (except for minor cosmetic or dental procedures) History of drug or alcohol abuse (as defined by the Investigator) Symptoms of a clinically significant illness in the four weeks before treatment application that may influence the outcome of the study Positive for HIV antibody Systemic treatments in the four weeks prior to treatment application that may interact with any of the study drugs, such as: Glucocorticoids, MAO inhibitors, anti-depressants, anti-seizure medications, anti-psychotics and anti-histamines Subjects who require medications that inhibit the CYP450 2D6 pathway such as:Quinidine, Cimetidine, Type 1 anti-arrhythmic, Phenothiazines, Selective serotonin reuptake inhibitors, Reserpine, other anticholinergic drugs, and sympathomimetic drugs Treatment with any investigational agent within one month before treatment application for this trial Female subject who is pregnant , lactating, or with a positive pregnancy test Unwilling or unable to comply with the requirements of this protocol, including the presence of any condition (physical, mental, or social) that is likely to affect the subject's return for follow-up visits on schedule Other unspecified reasons that, in the opinion of the Investigator, make the subject unsuitable for enrollment Subject is institutionalized because of legal or regulatory order

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CRx-197 high dose (0.1% nortriptyline HCl + 0.3% loratadine)<br> | Drug: nortriptyline HCl + loratadine<br>* Topical<br>|
| Experimental: CRx-197 low dose (0.1% nortriptyline HCl + 0.1% loratadine)<br> | Drug: nortriptyline HCl + loratadine<br>* Topical<br>|
| Experimental: 0.1% nortriptyline HCl<br> | Drug: nortriptyline HCl<br>* Topical<br>|
| Active Comparator: 0.1% mometasone furoate<br> | Drug: mometasone furoate<br>* Topical<br>|
| Placebo Comparator: Active ingredient free vehicle cream of CRx-197<br> | Drug: Active ingredient free vehicle cream of CRx-197<br>* Topical<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of CRx-197 as assessed by treatment emergent adverse events, physical exams, vital signs, concomitant medications/procedures and subject assessment of pruritus. |  | 2 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in change from baseline in psoriatic infiltrate measured by ultrasound between CRx-197, nortriptyline, active comparator as well as vehicle of CRx-197 and untreated test field(s) |  | Days 8, 15, 22, 29 and 43 | 
| Difference in change from baseline in erythema measured by chronometry between CRx-197, nortriptyline, active comparator, vehicle of CRx-197, untreated test field(s) and normal skin |  | Days 8, 15, 22, 29 and 43 | 
| Modified PASI between CRx-197, nortriptyline, active comparator, vehicle of CRx-197, untreated test field(s) |  | Baseline, and Days 8, 15, 22, 29 and 43 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CombinatoRx, Atopic, Dermatitis, Topical, CRx-197, Normal Healthy Volunteers