Study of the Clinical Activity, Safety, and Tolerability of SRT2104 in Subjects With Moderate to Severe Plaque-Type Psoriasis

Sirtris, a GSK Company40 enrolled

Overview

This double-blind, placebo-controlled study will be conducted at 5 study centers in the United States. Approximately 30 subjects with moderate to severe plaque-type psoriasis will take part. The study will consist of a screening period of up to 21 days, a 12-week treatment period with 7 on-treatment clinic visits (approximately one every 2 weeks) and a post-dosing follow-up clinic visit approximately 30 days after the last dose of study drug is taken. Subjects will be randomized to receive either 250mg, 500mg or 1000mg of study drug or placebo. Study drug will be taken by mouth on a full stomach, every day for 84 days. Vital signs, clinical laboratory results (hematology, chemistry, and urinalysis), ECGs and physical examinations will be assessed at periodic intervals from Day 1 through Day 84. A skin biopsy will be taken at the beginning and the end of the dosing period to evaluate any effects of the study drug on psoriasis. Investigators will perform other psoriasis evaluations (including the Psoriasis Area and Severity Index \[PASI\] and the Physician's Global Assessment \[PGA\] at 5 different times throughout the study to quantify the effects of SRT2104 on psoriasis activity. Subjects will complete questionnaires throughout the study, to document their sense of well-being and mood at 4 different times during the study. Five blood samples will be obtained at different timepoints during the study, to measure the amount of SRT2104 in the body.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

Conditions

Psoriasis

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Able and willing to provide written informed consent to participate in the study * Be male or female aged 18 to 80 years (inclusive) * Have a diagnosis of clinically confirmed, stable (without recent documented flare within 30 days prior to the Screening Visit), plaque-type psoriasis for at least 6 months involving ≥10% of body surface area * Have a baseline PASI of ≥10 * Be a candidate for systemic psoriasis therapy, in the opinion of the investigator * If a female subject of child-bearing potential, be willing to use reliable contraception for the duration of the study, through the 30 day safety follow up telephone call * Be willing and able to comply with the protocol for the duration of the study Exclusion Criteria: * Has received systemic non-biologic psoriasis therapy or PUVA phototherapy within 4 weeks prior to the Screening Visit, or had topical psoriasis treatment or UVB phototherapy within 2 weeks prior to the Screening Visit * Has received previous treatment with biologic agents within 5 drug half-lives (or within 3 months if half-life is unknown) prior to the first dose of SRT2104 * Has received a live vaccination within 4 weeks prior to the Screening Visit or intends to have a live vaccination during the course of the study * Use of any other non-psoriatic prescription drug therapy, with the exception of any prescription medication administered at a stable dose for at least 6 weeks prior to the Screening Visit; however, the administration of proton pump inhibitors during the study dosing period is prohibited * Use of any dietary or herbal supplements, with the exception of those administered at a stable dose for at least 6 weeks prior to the Screening Visit * Has received any investigational drug or experimental procedure within 30 days prior to the first dose of SRT2104 * Has an active infection (e.g., sepsis, pneumonia, abscess, etc.) or be at high risk of developing an infection, in the opinion of the investigator, prior to the first dose of SRT2104 * Has a history of a positive tuberculosis test or a positive tuberculosis test at the Screening Visit that cannot be attributed to a prior BCG inoculation * Has a positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of the Screening Visit * Has a positive test for HIV antibody * Has an abnormal chest x-ray at the Screening Visit which, in the opinion of the investigator, would preclude entry into the trial * Has a 12-lead electrocardiogram (ECG) with changes considered to be clinically significant on medical review including prolonged QTc intervals as defined below: * QTcB ≥450 msec (based on single or average QTc value of triplicate ECGs obtained over a brief period) * QTcB ≥480 msec in subjects with Bundle Branch Block * Has renal or liver impairment, defined as: * Serum creatinine level of ≥ 1.4 mg/dL for females and ≥ 1.5 mg/dL for males * AST and ALT ≥ 2xULN or * Alkaline phosphatase and bilirubin \> 1.5xULN (an isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin is \<35%) * Has active neoplastic disease or history of neoplastic disease within 5 years of study entry (except for basal or squamous cell carcinoma of the skin, or carcinoma in situ which have been definitively treated with standard of care approaches) * Is pregnant or breast-feeding. Confirmation that a female subject is not pregnant must be established by negative pregnancy tests at Screening and Day 1 * Has a significant history of alcoholism or drug/chemical abuse, or consumes more than 3 standard units/day of alcohol. A standard unit of alcohol is defined as 250 mL of beer, 25 mL of spirit, or 125 mL of wine * History of sensitivity to any of the study medications, or components thereof, or a history of drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates their participation * Has an acute or chronic illness which, in the opinion of the investigator, could pose a threat or harm to the subject

Outcomes

Primary Outcomes

Assessment of Clinical Activity by Improvement Score (Using Krueger Criteria): Number of Participants With Good or Excellent Improvement Score Based on Histological Assessments of Skin Biopsies After 12 Weeks of Exposure

According to the Krueger criteria, improvement score is classified as Good improvement defined as reduction in epidermal thickness by at least 30% normalized keratinocyte differentiation but most keratinocytes still express K16. Excellent improvement defined as reduction in epidermal thickness to normal or almost normal normalized keratinocyte differentiation and absent keratinocyte expression of K16. No improvement defined as no improvement in epidermal thickness keratinocyte differentiation or K16 expression on keratinocytes. A binomial response was defined for each participant according to whether the participant had an improvement score of "good or excellent improvement" (response=1) or not (response=0). Number of participants with good or excellent improvement score are presented.

Time frame: 12 weeks

Number of Participants With Any Adverse Events (AE) and Serious Adverse Events (SAE)

An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse. SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant. The AE category in the data table includes participants who experienced serious or non-serious adverse events or both.