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

NCT01154101 | Completed Phase 2 Results DMC

• 1 other identifier: 114296
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 8

Brief Summary

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.

Conditions

Psoriasis

Outcome Measures

Primary Outcomes (6)

• 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.

  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.

  Up to Follow-up (Day 114)

• Number of Participants With Hematology and Coagulation Abnormalities of Potential Clinical Concern

  Hematology parameters included hemoglobin, hematocrit, red blood cell count, red cell distribution width, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelets, white blood cell count and complete white blood cell count differential. Coagulation parameters included activated partial thromboplastin time and prothrombin time/international normalized ratio. The potential clinical concern range for hematology parameters were: white blood cell count (low: \<0.67x10\^9/Liter x lower limit of normal \[LLN\] and high: \>1.82x10\^9/L x upper limit of normal \[ULN\]), neutrophil count: (low: \<0.83x10\^9/Liter x LLN), hemoglobin (low: \<0.85 gram/Liter x LLN and high: \>1.03 gram/Liter x ULN for males and \>1.13 gram/Liter x ULN for females), hematocrit with units ratio (high: \>1.02 x ULN for males and \>1.17 x ULN for females), platelet count (low: \<0.67x10\^9/Liter x LLN and high \>1.57x10\^9/Liter x ULN) and lymphocytes (low: \<0.81x10\^9/Liter x LLN).

  Up to Follow-up (Day 114)

• Number of Participants With Clinical Chemistry Abnormalities of Potential Clinical Importance

  The potential clinical concern range for clinical chemistry parameters were: Albumin:(low: \<0.86 gram/Liter x LLN), Calcium:(low: \<0.91 millimol/Liter \[mmol/L\] x LLN and high: \>1.06 mmol/L x ULN), Creatinine: (high: \>1.3 mmol /L x ULN), Glucose: (low: \<0.71 mmol/L x LLN, high: \>1.41 mmol/L x ULN), Magnesium: (low: \<0.63 mmol/L x LLN, high: \>1.03 mmol/L x ULN), Phosphorus: (low: \<0.8 mmol/L x LLN, high: \>1.14 mmol/L x ULN), Sodium: (low: \<0.96 mmol/L x LLN, high: \>1.03 mmol/L x ULN), Urea: (high: \>1.5 mmol/L x ULN), Gamma glutamyl transferase: (high: \>2 International units per L x ULN), Total bilirubin (high: 1.5 x ULN), both alanine amino transferase and aspartate amino transferase (high:≥ 2x ULN Units/L) and Bicarbonate: (low: \<18 mmol/L and high: \>32 mmol/L). Number of participants with clinical chemistry abnormalities of potential clinical importance are presented.

  Up to Follow-up (Day 114)

• Number of Participants With Abnormal Electrocardiogram (ECG) Values

  12-lead ECG was performed in the rested state with the participant in the supine position with ECG leads on for at least 5 minutes prior to ECG recording. ECGs included PR (PQ), QRS, QT and QT corrected by Bazett's formula (QTcB), QT corrected by Fridericia's formula (QTcF) intervals. Identification of any conduction abnormalities were recorded in the eCRF. If a participant's QTc intervals were prolonged, then the ECG was done in triplicate with results reported as an average of the three ECGs. Number of participants with abnormal electrocardiogram (ECG) values are presented.

  Up to Follow-up (Day 114)

• Number of Participants With Vital Signs of Potential Clinical Importance

  Vital sign assessments included measurements of resting heart rate and blood pressure. Potential clinical concern range for systolic blood pressure: \<85 and \>160 millimeter of mercury (mmHg), for diastolic: \<45 and \>100 mmHg and heart rate: \<40 and \>110 beats per minute. Number of participants with vital signs of potential clinical importance are presented.

  Up to Follow-up (Day 114)

Secondary Outcomes (6)

• Number of Participants With Clinical Activity in Psoriasis Area and Severity Index (PASI) Score After 4, 8, and 12 Weeks of Exposure

  Weeks 4, 8 and 12

• Summary of Physician's Global Assessment (PGA) Score After 4, 8 and 12 Weeks of Exposure

  Weeks 4, 8 and 12

• Area Under Curve (AUC) of 12 Weeks of Dosing With 0.25 g, 0.5 g and 1.0 g SRT2104 in the Fed State in Participants

  Pre-dose (30 minutes or less before dosing: 1 sample), 0.5 to 2 hours and 3 to 6 hours post-dose (1 sample), 6 to 22 hours post-dose (2 samples) up to Week 12

• Maximum Plasma Concentration (Cmax) of 12 Weeks of Dosing With 250 Milligrams (mg), 500 mg and 1000 mg SRT2104 in the Fed State in Participants

  One sample: Pre-dose (30 minutes or less before dosing), One sample: 0.5 to 2 hours post-dose and 3 to 6 hours post-dose and 2 samples 6 to 22 hours post dose, at any Visit 4 (Day 28 or Week 4), Visit 6 (Day 56 or Week 8) or Visit 8 (Day 84 or Week 12)

• Change From Baseline in Fibroblast Growth Factor 21 (FGF21) as an Indicator of the Pharmacodynamic Effects of SRT2104

  Baseline (Day 1) and Days 28, 56 and 84

Study Arms (3)

Cohort 2 - 500mg SRT2104/placebo dose group

ACTIVE COMPARATOR

10 subjects will be randomized 4:1 (SRT2104: placebo) in each of 3 treatment arms (250mg, 500mg, or 1000mg). Cohort 2 will commence after Cohort 1 has completed 28 consecutive days of dosing, followed by the completion of a safety review by an Independent Safety Review Committee. Cohort 2 will be administered at approximately the same time every day, approximately 15 minutes following the consumption of food. Subjects must wait at least 1 hour after dosing before consuming additional calories. Dietary recommendations for the meal that precedes dosing will be provided to the study subjects by the clinical site staff.

Drug: Placebo; Drug: SRT2104

Cohort 3 - 1000mg SRT2104/placebo dose group

ACTIVE COMPARATOR

10 subjects will be randomized 4:1 (SRT2104: placebo) in each of 3 treatment arms (250mg, 500mg, or 1000mg). Cohort 3 will commence after Cohort 2 has completed 28 consecutive days of dosing, followed by the completion of a safety review by an Independent Safety Review Committee. Cohort 3 will be administered four SRT2104 capsules at approximately the same time every day, approximately 15 minutes following the consumption of food. Subjects must wait at least 1 hour after dosing before consuming additional calories. Dietary recommendations for the meal that precedes dosing will be provided to the study subjects by the clinical site staff.

Drug: Placebo; Drug: SRT2104

Cohort 1 - 250mg SRT2104/placebo dose group

ACTIVE COMPARATOR

10 subjects will be randomized 4:1 (SRT2104: placebo) in each of 3 treatment arms (250mg, 500mg, or 1000mg). Cohort 1 will be administered at approximately the same time every day, approximately 15 minutes following the consumption of food. Subjects must wait at least 1 hour after dosing before consuming additional calories. Dietary recommendations for the meal that precedes dosing will be provided to the study subjects by the clinical site staff. Dosing for Cohort 2 will not commence until Cohort 1 has completed 28 consecutive days of dosing, followed by the completion of a safety review by an Independent Safety Review Committee.

Drug: Placebo; Drug: SRT2104

Interventions

Placebo DRUG

For the placebo product, the SRT2104 drug substance will be replaced by microcrystalline cellulose (Avicel® PH 105) to match the SRT2104 investigational product.

Cohort 1 - 250mg SRT2104/placebo dose group; Cohort 2 - 500mg SRT2104/placebo dose group; Cohort 3 - 1000mg SRT2104/placebo dose group

SRT2104 DRUG

SRT2104 drug substance is a new chemical entity which is supplied as a fine, yellowish/amber powder. The SRT2104 investigational product is prepared by packing 250 mg of micronized SRT2104 powder with no additional additives into a size 00 opaque, hard gelatin capsule, packaged in dosing bottles containing a single daily dose.

Cohort 1 - 250mg SRT2104/placebo dose group; Cohort 2 - 500mg SRT2104/placebo dose group; Cohort 3 - 1000mg SRT2104/placebo dose group

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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:

Sponsors & Collaborators

• Sirtris, a GSK Company: lead
• GlaxoSmithKline: collaborator

Study Sites (8)

GSK Investigational Site

St Louis, Missouri, 63117, United States

Location

GSK Investigational Site

New York, New York, 10016, United States

Location

GSK Investigational Site

New York, New York, 10065, United States

Location

GSK Investigational Site

Portland, Oregon, 97223, United States

Location

GSK Investigational Site

Philadelphia, Pennsylvania, 19103, United States

Location

GSK Investigational Site

Johnston, Rhode Island, 02919, United States

Location

GSK Investigational Site

Dallas, Texas, 75246, United States

Location

GSK Investigational Site

Seattle, Washington, 98101, United States

Location

Related Publications (1)

• Krueger JG, Suarez-Farinas M, Cueto I, Khacherian A, Matheson R, Parish LC, Leonardi C, Shortino D, Gupta A, Haddad J, Vlasuk GP, Jacobson EW. A Randomized, Placebo-Controlled Study of SRT2104, a SIRT1 Activator, in Patients with Moderate to Severe Psoriasis. PLoS One. 2015 Nov 10;10(11):e0142081. doi: 10.1371/journal.pone.0142081. eCollection 2015.

  PMID: 26556603 DERIVED

Related Links

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

MeSH Terms

Conditions

Psoriasis

Interventions

SRT2104

Condition Hierarchy (Ancestors)

Skin Diseases, Papulosquamous; Skin Diseases; Skin and Connective Tissue Diseases

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 22, 2010
• First Posted: June 30, 2010
• Study Start: June 7, 2010
• Primary Completion: November 9, 2011
• Study Completion: November 9, 2011
• Last Updated: October 13, 2017
• Results First Posted: October 13, 2017

Record last verified: 2017-09

Data Sharing

• IPD Sharing: Will share

Locations

US (8)