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

• ClinicalTrials.gov Identifier: NCT01154101
• Recruitment Status: Completed
• First Posted: June 30, 2010
• Results First Posted: October 13, 2017
• Last Update Posted: October 13, 2017
• Sponsor: Sirtris, a GSK Company
• Collaborator: GlaxoSmithKline
• Information provided by (Responsible Party): GlaxoSmithKline ( Sirtris, a GSK Company )

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Psoriasis
• Interventions: Drug: Placebo; Drug: SRT2104
• Enrollment: 40

Participant Flow

Recruitment Details	A total of 40 participants with moderate to severe plaque-type psoriasis were enrolled. This study was conducted at eight centers in the United States: New York (2); Missouri (1); Oregon (1); Pennsylvania (1); Rhode Island (1); Texas (1); Washington (1), from 07 June 2010 to 09 November 2011.
Pre-assignment Details	Participants were asked to sign the informed consent form (ICF) at the Screening Visit, which was conducted within 21 days prior to administration of the first dose of study drug on Day 1.

Arm/Group Title	Placebo	SRT2104 0.25 g	SRT2104 0.5 g	SRT2104 1.0 g	No Treatment
Arm/Group Description	Eligible participants received SRT2104 matching placebo capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants received SRT2104 0.25 gram (g) capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants received SRT2104 0.5 g capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants received SRT2104 1.0 g capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants in this arm received no treatment. No treatment arm was used when participants were randomized but discontinued prior to dosing.
Period Title: Overall Study
Started	7	9	12	11	1
Completed	7	5	9	9	0
Not Completed	0	4	3	2	1
Reason Not Completed
Adverse Event	0	2	1	1	0
Lost to Follow-up	0	1	0	1	0
Withdrawal by Subject	0	1	2	0	1

Baseline Characteristics

Arm/Group Title		Placebo	SRT2104 0.25 g	SRT2104 0.5 g	SRT2104 1.0 g	No Treatment	Total
Arm/Group Description		Eligible participants received SRT2104 matching placebo capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants received SRT2104 0.25 gram (g) capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants received SRT2104 0.5 g capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants received SRT2104 1.0 g capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants in this arm received no treatment. No treatment arm was used when participants were randomized but discontinued prior to dosing.	Total of all reporting groups
Overall Number of Baseline Participants		7	9	12	11	1	40
Baseline Analysis Population Description		Sex and Race assessments were performed for the entire population (40 participants). However, for Age only 39 participants were available (1 participant withdrew from the study from the 'No Treatment group') and hence data was not collected for that participant.
Age, Continuous [1]; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	7 participants	9 participants	12 participants	11 participants	0 participants	39 participants
		51.4 (14.88)	40.6 (16.05)	49.3 (14.41)	44.6 (13.58)		46.4 (14.63)
		[1] Measure Analysis Population Description: For the "no treatment" group: the single participant in this arm had withdrawn from the study, therefore the age data was not collected for this single participant in this arm.
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	7 participants	9 participants	12 participants	11 participants	1 participants	40 participants
	Female	1 14.3%	3 33.3%	0 0.0%	5 45.5%	1 100.0%	10 25.0%
	Male	6 85.7%	6 66.7%	12 100.0%	6 54.5%	0 0.0%	30 75.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	7 participants	9 participants	12 participants	11 participants	1 participants	40 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	0 0.0%	1 8.3%	0 0.0%	0 0.0%	1 2.5%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Black or African American	1 14.3%	2 22.2%	0 0.0%	1 9.1%	0 0.0%	4 10.0%
	White	6 85.7%	7 77.8%	10 83.3%	10 90.9%	1 100.0%	34 85.0%
	More than one race	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	1 8.3%	0 0.0%	0 0.0%	1 2.5%

Outcome Measures

1. Primary Outcome

Title	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
Description	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

Outcome Measure Data

Analysis Population Description

The Efficacy Analysis Set (EAS) population comprised of all randomized participants who took at least one dose of study medication, had at least one activity measurement at Baseline, at least one post-Baseline study visit. Only those participants available at the specified time points were analyzed.

Arm/Group Title	Placebo	SRT2104 0.25 g	SRT2104 0.5 g	SRT2104 1.0 g
Arm/Group Description:	Eligible participants received SRT2104 matching placebo capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants received SRT2104 0.25 g capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants received SRT2104 0.5 g capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants received SRT2104 1.0 g capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.
Overall Number of Participants Analyzed	7	6	9	11
Measure Type: Count of Participants; Unit of Measure: Participants
	1 14.3%	3 50.0%	4 44.4%	2 18.2%

2. Primary Outcome

Title	Number of Participants With Any Adverse Events (AE) and Serious Adverse Events (SAE)
Description	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.
Time Frame	Up to Follow-up (Day 114)

Outcome Measure Data

Analysis Population Description

Safety Analysis Set (SAF) population which comprised of all participants who received at least one dose of study medication.

Arm/Group Title	Placebo	SRT2104 0.25 g	SRT2104 0.5 g	SRT2104 1.0 g
Arm/Group Description:	Eligible participants received SRT2104 matching placebo capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants received SRT2104 0.25 g capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants received SRT2104 0.5 g capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants received SRT2104 1.0 g capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.
Overall Number of Participants Analyzed	7	9	12	11
Measure Type: Count of Participants; Unit of Measure: Participants
AE	3 42.9%	4 44.4%	9 75.0%	11 100.0%
SAE	0 0.0%	2 22.2%	0 0.0%	1 9.1%

3. Primary Outcome

Title	Number of Participants With Hematology and Coagulation Abnormalities of Potential Clinical Concern
Description	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).
Time Frame	Up to Follow-up (Day 114)

Outcome Measure Data

Analysis Population Description

SAF Population.

Arm/Group Title	Placebo	SRT2104 0.25 g	SRT2104 0.5 g	SRT2104 1.0 g
Arm/Group Description:	Eligible participants received SRT2104 matching placebo capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants received SRT2104 0.25 g capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants received SRT2104 0.5 g capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants received SRT2104 1.0 g capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.
Overall Number of Participants Analyzed	7	9	12	11
Measure Type: Count of Participants; Unit of Measure: Participants
	0 0.0%	0 0.0%	1 8.3%	2 18.2%

4. Primary Outcome

Title	Number of Participants With Clinical Chemistry Abnormalities of Potential Clinical Importance
Description	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.
Time Frame	Up to Follow-up (Day 114)

Outcome Measure Data

Analysis Population Description

SAF Population. Only those participants available at the specified time points were analyzed.

Arm/Group Title	Placebo	SRT2104 0.25 g	SRT2104 0.5 g	SRT2104 1.0 g
Arm/Group Description:	Eligible participants received SRT2104 matching placebo capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants received SRT2104 0.25 g capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants received SRT2104 0.5 g capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants received SRT2104 1.0 g capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.
Overall Number of Participants Analyzed	7	9	12	11
Measure Type: Count of Participants; Unit of Measure: Participants
	4 57.1%	3 33.3%	5 41.7%	5 45.5%

5. Primary Outcome

Title	Number of Participants With Abnormal Electrocardiogram (ECG) Values
Description	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.
Time Frame	Up to Follow-up (Day 114)

Outcome Measure Data

Analysis Population Description

SAF Population.

Arm/Group Title	Placebo	SRT2104 0.25 g	SRT2104 0.5 g	SRT2104 1.0 g
Arm/Group Description:	Eligible participants received SRT2104 matching placebo capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants received SRT2104 0.25 g capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants received SRT2104 0.5 g capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants received SRT2104 1.0 g capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.
Overall Number of Participants Analyzed	7	9	12	11
Measure Type: Count of Participants; Unit of Measure: Participants
	3 42.9%	1 11.1%	4 33.3%	6 54.5%

6. Primary Outcome

Title	Number of Participants With Vital Signs of Potential Clinical Importance
Description	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.
Time Frame	Up to Follow-up (Day 114)

Outcome Measure Data

Analysis Population Description

SAF Population.

Arm/Group Title	Placebo	SRT2104 0.25 g	SRT2104 0.5 g	SRT2104 1.0 g
Arm/Group Description:	Eligible participants received SRT2104 matching placebo capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants received SRT2104 0.25 g capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants received SRT2104 0.5 g capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants received SRT2104 1.0 g capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.
Overall Number of Participants Analyzed	7	9	12	11
Measure Type: Count of Participants; Unit of Measure: Participants
	0 0.0%	0 0.0%	0 0.0%	2 18.2%

7. Secondary Outcome

Title	Number of Participants With Clinical Activity in Psoriasis Area and Severity Index (PASI) Score After 4, 8, and 12 Weeks of Exposure
Description	PASI score was determined by evaluation of body surface area (BSA) covered by plaque psoriasis in 4 areas (head/neck, arms, trunk and legs with area score of 0.1, 0.2, 0.3 and 0.4 respectively). This test included combination of both degree of involvement (assessed as per the % of affected body area using a 7-point scale such that 0=0% involvement, 1=1-9%, 2=10-29%, 3=30-49%, 4=50-69%, 5=70-89% and 6=90-100%) and severity (evaluated individually using a 5-point scale that ranged as 0=No evidence of sign, 1=slight evidence, 2=moderate evidence, 3=marked evidence and 4=very marked, most severe evidence of sign) of erythema, induration and desquamation in each of the same 4 areas. PASI score ranges from 0 (no psoriasis) to 72 (worse psoriasis). Final PASI=(sum of severity score for each area)x(% body affected score x area score).
Time Frame	Weeks 4, 8 and 12

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set (EAS) population. Only those participants available at the specified time points were analyzed.

Arm/Group Title		Placebo	SRT2104 0.25 g	SRT2104 0.5 g	SRT2104 1.0 g
Arm/Group Description:		Eligible participants received SRT2104 matching placebo capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants received SRT2104 0.25 g capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants received SRT2104 0.5 g capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants received SRT2104 1.0 g capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.
Overall Number of Participants Analyzed		7	9	12	11
Measure Type: Count of Participants; Unit of Measure: Participants
Week 4: 25% Improvement in PASI score from Day 1	Number Analyzed	7 participants	9 participants	12 participants	11 participants
		2 28.6%	1 11.1%	3 25.0%	7 63.6%
Week 4: 50% Improvement in PASI score from Day 1	Number Analyzed	7 participants	9 participants	12 participants	11 participants
		0 0.0%	0 0.0%	1 8.3%	0 0.0%
Week 4: 75% Improvement in PASI score from Day 1	Number Analyzed	7 participants	9 participants	12 participants	11 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
Week 8: 25% Improvement in PASI score from Day 1	Number Analyzed	7 participants	7 participants	11 participants	11 participants
		2 28.6%	2 28.6%	5 45.5%	8 72.7%
Week 8: 50% Improvement in PASI score from Day 1	Number Analyzed	7 participants	7 participants	11 participants	11 participants
		1 14.3%	2 28.6%	4 36.4%	4 36.4%
Week 8: 75% Improvement in PASI score from Day 1	Number Analyzed	7 participants	7 participants	11 participants	11 participants
		0 0.0%	1 14.3%	2 18.2%	0 0.0%
Week 12: 25% Improvement in PASI score from Day 1	Number Analyzed	7 participants	6 participants	9 participants	11 participants
		2 28.6%	2 33.3%	6 66.7%	8 72.7%
Week 12: 50% Improvement in PASI score from Day 1	Number Analyzed	7 participants	6 participants	9 participants	11 participants
		2 28.6%	2 33.3%	3 33.3%	4 36.4%
Week 12: 75% Improvement in PASI score from Day 1	Number Analyzed	7 participants	6 participants	9 participants	11 participants
		1 14.3%	2 33.3%	2 22.2%	1 9.1%

8. Secondary Outcome

Title	Summary of Physician's Global Assessment (PGA) Score After 4, 8 and 12 Weeks of Exposure
Description	The severity of psoriatic lesions over the whole body were assessed by the investigator using the PGA scoring system. A 0 to 6 point rating scale was used, as follows: 0 = Clear (no signs of psoriasis), 1 = Almost clear (slight elevation, scale and/or erythema), 2 = Mild (mild plaque elevation, scale and/or erythema), 3 = Mild to moderate (mild plaque elevation with moderate erythema and/or scale), 4 = Moderate (moderate plaque elevation, scale and/or erythema), 5 = Moderate to severe (marked plaque elevation, scale and/or erythema), 6 = Severe (very marked plaque elevation, scale and/or erythema). Higher scores indicated worse psoriasis. Participants in the SRT2104 0.25 g dose group inadvertently used an incorrect version of the PGA scale and thus do not have PGA data available. Participants in the SRT2104 0.25 g dose group inadvertently used an incorrect version of the PGA scale and thus do not have PGA data available.
Time Frame	Weeks 4, 8 and 12

Outcome Measure Data

Analysis Population Description

EAS Population. Only those participants available at the specified time points were analyzed.

Arm/Group Title		Placebo	SRT2104 0.25 g	SRT2104 0.5 g	SRT2104 1.0 g
Arm/Group Description:		Eligible participants received SRT2104 matching placebo capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants received SRT2104 0.25 g capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants received SRT2104 0.5 g capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants received SRT2104 1.0 g capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.
Overall Number of Participants Analyzed		7	0	12	11
Measure Type: Count of Participants; Unit of Measure: Participants
Week 4: Very Severe	Number Analyzed	5 participants	0 participants	12 participants	11 participants
		1 20.0%		0 0.0%	0 0.0%
Week 4: Severe	Number Analyzed	5 participants	0 participants	12 participants	11 participants
		1 20.0%		2 16.7%	1 9.1%
Week 4: Moderate	Number Analyzed	5 participants	0 participants	12 participants	11 participants
		2 40.0%		9 75.0%	4 36.4%
Week 4: Mild	Number Analyzed	5 participants	0 participants	12 participants	11 participants
		1 20.0%		1 8.3%	6 54.5%
Week 4: Minimal	Number Analyzed	5 participants	0 participants	12 participants	11 participants
		0 0.0%		0 0.0%	0 0.0%
Week 4: Clear	Number Analyzed	5 participants	0 participants	12 participants	11 participants
		0 0.0%		0 0.0%	0 0.0%
Week 8: Very Severe	Number Analyzed	5 participants	0 participants	11 participants	11 participants
		1 20.0%		0 0.0%	0 0.0%
Week 8: Severe	Number Analyzed	5 participants	0 participants	11 participants	11 participants
		1 20.0%		1 9.1%	0 0.0%
Week 8: Moderate	Number Analyzed	5 participants	0 participants	11 participants	11 participants
		2 40.0%		6 54.5%	3 27.3%
Week 8: Mild	Number Analyzed	5 participants	0 participants	11 participants	11 participants
		1 20.0%		3 27.3%	7 63.6%
Week 8: Minimal	Number Analyzed	5 participants	0 participants	11 participants	11 participants
		0 0.0%		1 9.1%	1 9.1%
Week 8: Clear	Number Analyzed	5 participants	0 participants	11 participants	11 participants
		0 0.0%		0 0.0%	0 0.0%
Week 12: Very Severe	Number Analyzed	5 participants	0 participants	9 participants	11 participants
		1 20.0%		0 0.0%	0 0.0%
Week 12: Severe	Number Analyzed	5 participants	0 participants	9 participants	11 participants
		1 20.0%		2 22.2%	0 0.0%
Week 12: Moderate	Number Analyzed	5 participants	0 participants	9 participants	11 participants
		2 40.0%		2 22.2%	5 45.5%
Week 12: Mild	Number Analyzed	5 participants	0 participants	9 participants	11 participants
		1 20.0%		3 33.3%	3 27.3%
Week 12: Minimal	Number Analyzed	5 participants	0 participants	9 participants	11 participants
		0 0.0%		2 22.2%	3 27.3%
Week 12: Clear	Number Analyzed	5 participants	0 participants	9 participants	11 participants
		0 0.0%		0 0.0%	0 0.0%

9. Secondary Outcome

Title	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
Description	A total of five blood samples (6 milliliter [mL] each) were obtained from each participant up to Week 12, for determination of SRT2104 plasma concentrations. No two samples were separated by less than an hour. One pre-dose sample was collected prior to taking study medication (30 minutes or less before dosing) at any Visit 4 (Week 4), Visit 6 (Week 8) or Visit 8 (Week 12). A single pharmacokinetic (PK) sample was collected in the time interval of 0.5 to 2 hours post-dose and also 3 to 6 hours post-dose at any Visit 4 (Week 4), Visit 6 (Week 8) or Visit 8 (Week 12). Two PK samples were collected in the time interval of 6 to 22 hours post dose at any Visit 4 (Week 4), Visit 6 (Week 8) or Visit 8 (Week 12).
Time Frame	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

Outcome Measure Data

Analysis Population Description

PK population which comprised of all participants who received at least one dose of SRT2104 for whom a PK sample was obtained and analyzed.

Arm/Group Title	SRT2104 0.25 g	SRT2104 0.5 g	SRT2104 1.0 g
Arm/Group Description:	Eligible participants received SRT2104 0.25 g capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants received SRT2104 0.5 g capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants received SRT2104 1.0 g capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.
Overall Number of Participants Analyzed	9	11	11
Mean (Standard Deviation); Unit of Measure: Nanogram x hour/milliliter (ng*h/mL)
	2148.08 (1247.182)	4189.46 (2143.021)	8358.45 (7466.966)

10. Secondary Outcome

Title	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
Description	A total of five blood samples (6 mL each) were obtained from each participant at any Visit 4 (Day 28 or Week 4), Visit 6 (Day 56 or Week 8) or Visit 8 (Day 84 or Week 12), for determination of SRT2104 plasma concentrations. No two samples were separated by less than an hour. One pre-dose sample was collected prior to taking study medication (30 minutes or less before dosing) at any Visit 4 (Day 28 or Week 4), Visit 6 (Day 56 or Week 8) or Visit 8 (Day 84 or Week 12). A single pharmacokinetic (PK) sample was collected in the time interval of 0.5 to 2 hours post-dose and also 3 to 6 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). Two PK samples were collected in the time interval of 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).
Time Frame	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)

Outcome Measure Data

Analysis Population Description

PK population.

Arm/Group Title	SRT2104 0.25 g	SRT2104 0.5 g	SRT2104 1.0 g
Arm/Group Description:	Eligible participants received SRT2104 0.25 g capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants received SRT2104 0.5 g capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants received SRT2104 1.0 g capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.
Overall Number of Participants Analyzed	9	11	11
Mean (Standard Deviation); Unit of Measure: ng/mL
	261.64 (134.403)	406.67 (237.787)	1005.89 (813.346)

11. Secondary Outcome

Title	Change From Baseline in Fibroblast Growth Factor 21 (FGF21) as an Indicator of the Pharmacodynamic Effects of SRT2104
Description	The pharmacodynamic effects of SRT2104 was measured by biomarkers of psoriatic disease activity and/or sirtuin pathway activation (hsCRP and FGF21) in blood samples. Baseline was Day 1. Change from Baseline was calculated by subtracting Baseline values from post-Baseline values.
Time Frame	Baseline (Day 1) and Days 28, 56 and 84

Outcome Measure Data

Analysis Population Description

EAS population. Only those participants available at the specified time points were analyzed.

Arm/Group Title		Placebo	SRT2104 0.25 g	SRT2104 0.5 g	SRT2104 1.0 g
Arm/Group Description:		Eligible participants received SRT2104 matching placebo capsules, orally, once daily after meal (at the same time every dosing day) for 84 days.	Eligible participants received SRT2104 0.25 g capsules, orally, once daily after meal (at the same time every dosing day) for 84 days.	Eligible participants received SRT2104 0.5 g capsules, orally, once daily after meal (at the same time every dosing day) for 84 days.	Eligible participants received SRT2104 1.0 g capsules, orally, once daily after meal (at the same time every dosing day) for 84 days.
Overall Number of Participants Analyzed		7	9	12	11
Mean (Standard Deviation); Unit of Measure: Picogram per milliliter
Day 28	Number Analyzed	6 participants	6 participants	11 participants	9 participants
		-61.67 (269.031)	-94.53 (154.104)	56.93 (177.244)	329.82 (930.329)
Day 56	Number Analyzed	5 participants	5 participants	9 participants	9 participants
		-67.04 (276.937)	-72.72 (366.774)	148.93 (305.634)	268.39 (961.010)
Day 84	Number Analyzed	5 participants	4 participants	9 participants	9 participants
		-86.12 (300.144)	-189.60 (364.475)	58.31 (223.237)	-673.32 (1590.594)

12. Secondary Outcome

Title	Change From Baseline in High-sensitivity C-reactive Protein (hsCRP) as an Indicator of the Pharmacodynamic Effects of SRT2104
Description	The pharmacodynamic effects of SRT2104 was measured by biomarkers of psoriatic disease activity and/or sirtuin pathway activation (hsCRP and FGF21) in blood samples. Baseline was Day 1. Change from Baseline was calculated by subtracting Baseline values from post-Baseline values.
Time Frame	Baseline (Day 1) and Days 28, 56 and 84

Outcome Measure Data

Analysis Population Description

EAS population. Only those participants available at the specified time points were analyzed.

Arm/Group Title		Placebo	SRT2104 0.25 g	SRT2104 0.5 g	SRT2104 1.0 g
Arm/Group Description:		Eligible participants received SRT2104 matching placebo capsules, orally, once daily after meal (at the same time every dosing day) for 84 days.	Eligible participants received SRT2104 0.25 g capsules, orally, once daily after meal (at the same time every dosing day) for 84 days.	Eligible participants received SRT2104 0.5 g capsules, orally, once daily after meal (at the same time every dosing day) for 84 days.	Eligible participants received SRT2104 1.0 g capsules, orally, once daily after meal (at the same time every dosing day) for 84 days.
Overall Number of Participants Analyzed		7	9	12	11
Mean (Standard Deviation); Unit of Measure: mg per Liter
Day 28	Number Analyzed	7 participants	8 participants	10 participants	10 participants
		0.11 (2.330)	-0.14 (1.148)	1.18 (1.954)	-0.96 (2.211)
Day 56	Number Analyzed	7 participants	6 participants	7 participants	10 participants
		0.59 (3.552)	-0.18 (1.897)	-1.31 (3.261)	-0.48 (2.640)
Day 84	Number Analyzed	7 participants	5 participants	8 participants	10 participants
		0.66 (3.895)	-0.16 (1.055)	-0.75 (3.159)	0.27 (1.351)

Adverse Events

Time Frame	Up to Follow-up (Day 114)
Adverse Event Reporting Description	SAF Population was used.
Arm/Group Title	Placebo	SRT2104 0.25 g	SRT2104 0.5 g	SRT2104 1.0 g
Arm/Group Description	Eligible participants received SRT2104 matching placebo capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants received SRT2104 0.25 g capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants received SRT2104 0.5 g capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.	Eligible participants received SRT2104 1.0 g capsules, orally, once daily after meal (at the same time every dosing day) for 12 weeks.
All-Cause Mortality
	Placebo	SRT2104 0.25 g	SRT2104 0.5 g	SRT2104 1.0 g
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/7 (0.00%)	0/9 (0.00%)	0/12 (0.00%)	0/11 (0.00%)
Serious Adverse Events
	Placebo	SRT2104 0.25 g	SRT2104 0.5 g	SRT2104 1.0 g
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/7 (0.00%)	2/9 (22.22%)	0/12 (0.00%)	1/11 (9.09%)
Gastrointestinal disorders
Pancreatitis † 1	0/7 (0.00%)	1/9 (11.11%)	0/12 (0.00%)	0/11 (0.00%)
Investigations
Alanine aminotransferase increased † 1	0/7 (0.00%)	0/9 (0.00%)	0/12 (0.00%)	1/11 (9.09%)
Blood bilirubin increased † 1	0/7 (0.00%)	0/9 (0.00%)	0/12 (0.00%)	1/11 (9.09%)
Respiratory, thoracic and mediastinal disorders
Pneumonitis † 1	0/7 (0.00%)	1/9 (11.11%)	0/12 (0.00%)	0/11 (0.00%)
1 Term from vocabulary, MedDRA 12.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Placebo	SRT2104 0.25 g	SRT2104 0.5 g	SRT2104 1.0 g
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	3/7 (42.86%)	3/9 (33.33%)	9/12 (75.00%)	11/11 (100.00%)
Eye disorders
Eye pain † 1	0/7 (0.00%)	0/9 (0.00%)	0/12 (0.00%)	1/11 (9.09%)
Gastrointestinal disorders
Nausea † 1	0/7 (0.00%)	1/9 (11.11%)	0/12 (0.00%)	1/11 (9.09%)
Vomiting † 1	0/7 (0.00%)	1/9 (11.11%)	0/12 (0.00%)	1/11 (9.09%)
Abdominal pain upper † 1	0/7 (0.00%)	0/9 (0.00%)	1/12 (8.33%)	0/11 (0.00%)
Constipation † 1	1/7 (14.29%)	0/9 (0.00%)	0/12 (0.00%)	0/11 (0.00%)
Diarrhoea † 1	0/7 (0.00%)	0/9 (0.00%)	0/12 (0.00%)	1/11 (9.09%)
Dyspepsia † 1	0/7 (0.00%)	0/9 (0.00%)	1/12 (8.33%)	0/11 (0.00%)
Flatulence † 1	0/7 (0.00%)	0/9 (0.00%)	0/12 (0.00%)	1/11 (9.09%)
Food poisoning † 1	0/7 (0.00%)	0/9 (0.00%)	0/12 (0.00%)	1/11 (9.09%)
Toothache † 1	0/7 (0.00%)	1/9 (11.11%)	0/12 (0.00%)	0/11 (0.00%)
General disorders
Fatigue † 1	0/7 (0.00%)	0/9 (0.00%)	0/12 (0.00%)	2/11 (18.18%)
Pyrexia † 1	1/7 (14.29%)	0/9 (0.00%)	0/12 (0.00%)	1/11 (9.09%)
Malaise † 1	0/7 (0.00%)	0/9 (0.00%)	0/12 (0.00%)	1/11 (9.09%)
Oedema peripheral † 1	0/7 (0.00%)	0/9 (0.00%)	1/12 (8.33%)	0/11 (0.00%)
Infections and infestations
Upper respiratory tract infection * 1	1/7 (14.29%)	0/9 (0.00%)	1/12 (8.33%)	1/11 (9.09%)
Furuncle † 1	0/7 (0.00%)	0/9 (0.00%)	0/12 (0.00%)	1/11 (9.09%)
Influenza † 1	0/7 (0.00%)	0/9 (0.00%)	1/12 (8.33%)	0/11 (0.00%)
Nasal abscess † 1	0/7 (0.00%)	0/9 (0.00%)	0/12 (0.00%)	1/11 (9.09%)
Pharyngitis † 1	1/7 (14.29%)	0/9 (0.00%)	0/12 (0.00%)	0/11 (0.00%)
Sinusitis † 1	0/7 (0.00%)	0/9 (0.00%)	1/12 (8.33%)	0/11 (0.00%)
Skin infection † 1	0/7 (0.00%)	0/9 (0.00%)	1/12 (8.33%)	0/11 (0.00%)
Urinary tract infection † 1	0/7 (0.00%)	0/9 (0.00%)	0/12 (0.00%)	1/11 (9.09%)
Viral infection † 1	0/7 (0.00%)	0/9 (0.00%)	0/12 (0.00%)	1/11 (9.09%)
Injury, poisoning and procedural complications
Contusion † 1	0/7 (0.00%)	0/9 (0.00%)	0/12 (0.00%)	1/11 (9.09%)
Injury † 1	0/7 (0.00%)	0/9 (0.00%)	0/12 (0.00%)	1/11 (9.09%)
Joint sprain † 1	0/7 (0.00%)	0/9 (0.00%)	1/12 (8.33%)	0/11 (0.00%)
Investigations
Alanine aminotransferase increased † 1	0/7 (0.00%)	0/9 (0.00%)	0/12 (0.00%)	2/11 (18.18%)
Aspartate aminotransferase increased † 1	0/7 (0.00%)	0/9 (0.00%)	0/12 (0.00%)	2/11 (18.18%)
Hepatic enzyme increased † 1	0/7 (0.00%)	0/9 (0.00%)	1/12 (8.33%)	1/11 (9.09%)
Blood phosphorus decreased † 1	0/7 (0.00%)	0/9 (0.00%)	0/12 (0.00%)	1/11 (9.09%)
Blood potassium increased † 1	0/7 (0.00%)	0/9 (0.00%)	0/12 (0.00%)	1/11 (9.09%)
Metabolism and nutrition disorders
Dehydration † 1	0/7 (0.00%)	1/9 (11.11%)	0/12 (0.00%)	0/11 (0.00%)
Diabetes mellitus † 1	0/7 (0.00%)	1/9 (11.11%)	0/12 (0.00%)	0/11 (0.00%)
Hypokalaemia † 1	0/7 (0.00%)	1/9 (11.11%)	0/12 (0.00%)	0/11 (0.00%)
Hyponatraemia † 1	0/7 (0.00%)	1/9 (11.11%)	0/12 (0.00%)	0/11 (0.00%)
Musculoskeletal and connective tissue disorders
Psoriatic arthropathy † 1	0/7 (0.00%)	0/9 (0.00%)	1/12 (8.33%)	2/11 (18.18%)
Pain in extremity † 1	0/7 (0.00%)	0/9 (0.00%)	1/12 (8.33%)	1/11 (9.09%)
Arthralgia † 1	0/7 (0.00%)	0/9 (0.00%)	0/12 (0.00%)	1/11 (9.09%)
Back pain † 1	0/7 (0.00%)	0/9 (0.00%)	0/12 (0.00%)	1/11 (9.09%)
Flank pain † 1	1/7 (14.29%)	0/9 (0.00%)	0/12 (0.00%)	0/11 (0.00%)
Myalgia † 1	0/7 (0.00%)	0/9 (0.00%)	0/12 (0.00%)	1/11 (9.09%)
Osteoarthritis † 1	0/7 (0.00%)	0/9 (0.00%)	0/12 (0.00%)	1/11 (9.09%)
Nervous system disorders
Dizziness † 1	0/7 (0.00%)	0/9 (0.00%)	0/12 (0.00%)	3/11 (27.27%)
Headache † 1	0/7 (0.00%)	0/9 (0.00%)	2/12 (16.67%)	1/11 (9.09%)
Disturbance in attention † 1	0/7 (0.00%)	0/9 (0.00%)	0/12 (0.00%)	1/11 (9.09%)
Paraesthesia † 1	0/7 (0.00%)	0/9 (0.00%)	0/12 (0.00%)	1/11 (9.09%)
Psychiatric disorders
Depression † 1	0/7 (0.00%)	0/9 (0.00%)	0/12 (0.00%)	1/11 (9.09%)
Skin and subcutaneous tissue disorders
Pruritus † 1	1/7 (14.29%)	0/9 (0.00%)	0/12 (0.00%)	1/11 (9.09%)
Actinic keratosis † 1	0/7 (0.00%)	0/9 (0.00%)	0/12 (0.00%)	1/11 (9.09%)
Erythema annulare † 1	1/7 (14.29%)	0/9 (0.00%)	0/12 (0.00%)	0/11 (0.00%)
Ingrowing nail † 1	1/7 (14.29%)	0/9 (0.00%)	0/12 (0.00%)	0/11 (0.00%)
1 Term from vocabulary, MedDRA 12.0; † Indicates events were collected by systematic assessment; * Indicates events were collected by non-systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.

Results Point of Contact

• Name/Title: GSK Response Center
• Organization: GlaxoSmithKline
• Phone: 866-435-7343

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Krueger JG, Suárez-Fariñas 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.

• Responsible Party: GlaxoSmithKline ( Sirtris, a GSK Company )
• ClinicalTrials.gov Identifier: NCT01154101
• Other Study ID Numbers: 114296
• First Submitted: April 22, 2010
• First Posted: June 30, 2010
• Results First Submitted: August 7, 2017
• Results First Posted: October 13, 2017
• Last Update Posted: October 13, 2017