Clinical trial NCT01018017: A Clinical Study to Assess the Safety, Tolerability, and Activity of Oral SRT2104 Capsules Administered for 28 Days to Subjects With Type 2 Diabetes Mellitus
Official title: A Phase IIa, Randomized, Placebo-Controlled, Double-Blind Clinical Study to Assess the Safety, Tolerability, and Activity of Oral SRT2104 Capsules Administered for 28 Days to Subjects With Type 2 Diabetes Mellitus
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Diabetes Mellitus, Type 2
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2009-11-23
Enrollment: 86
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: Randomized, placebo-controlled, parallel-group, double-blind, multiple-dose, activity and safety clinical study of SRT2104 administered orally once daily for 28 consecutive days. This will be an inpatient/outpatient study to assess the safety and pharmacokinetics of SRT2104 in type 2 diabetic male and female subjects on an existing, stable, background metformin therapy. Approximately 80 subjects will be enrolled. Subjects will be evenly randomized to receive SRT2104 2.0 g/day or placebo in the fed state.

Subjects will be required to stay overnight at the study center on Days -2, -1, 0, 1 (optional discharge at investigator's discretion), 27, 28, 41, and 42. During these admissions, pharmacokinetic, biomarker and glycated albumin samples will be collected, and glucose profiling, OGTT, glucose stabilization, hyperinsulinemc euglycemic clamp (HEGC) studies with indirect calorimetry and various other safety and activity procedures will be performed. On Day 1 of the study, subjects will be randomized to receive SRT2104 or placebo. Day 43 will be the last day of the study and subjects will be released. In addition, subjects will be asked to return to the study center on Day 14 for interim safety assessments.

During the dosing period, study personnel will contact subjects by telephone on Days 7 and 21 to conduct a safety assessment. Subjects will be required to monitor their fasting blood glucose and complete a daily diary for the outpatient portion of the study between Days 1 and 28. A follow-up, safety phone call will occur 30 days following their final dose of SRT2104 or placebo (Day 58 of the study) to identify any possible additional adverse events or concomitant medications.

Detailed description: Randomized, placebo-controlled, parallel-group, double-blind, multiple-dose, activity and safety clinical study of SRT2104 administered orally once daily for 28 consecutive days. This will be an inpatient/outpatient study to assess the safety and pharmacokinetics (PK) of SRT2104 in type 2 diabetic (T2D) male and female subjects on an existing, stable, background metformin therapy. Approximately 112 subjects aged 18-65 years, who fulfill the inclusion/exclusion criteria, will be screened for this study to enroll approximately 80 subjects. Subjects will be evenly randomized to receive SRT2104 2.0 g/day or placebo approximately 15 minutes following consumption of a standardized morning meal. Subjects will remain on a fixed dose of test material for all dosing days in the study.

Subjects will sign the informed consent form at the Screening Visit, and will undergo screening assessments to verify eligibility for the study. If eligible and willing to participate, subjects will return to the clinic within 21 days of the Screening Visit to participate in the pre-dosing phase of the study. On Day 1 of the study, subjects will be randomized to receive SRT2104 or placebo. Subjects will be required to stay overnight at the study center on Days -2, -1, 0, 1 (optional discharge at investigator's discretion), 27, 28, 41, and 42 for testing, to assess safety, and to gather required biomarker samples. In addition, subjects will be asked to return to the study center on Day 14 for interim safety assessments. The subject will be telephoned on Days 7 and 21 to assess safety. Subjects will be required to monitor their fasting blood glucose and complete a daily diary for the outpatient portion of the study between Days 1 and 28. A follow-up, safety phone call will occur 30 days following their final dose of SRT2104 or placebo (Day 58 of the study) to identify any possible additional adverse events (AEs) or concomitant medications.

Eligibility criteria: Inclusion Criteria:

* Able and willing to provide written informed consent to participate in the study
* Ambulatory male and female subjects (of any race) with T2D within the age range of 18-65 years (inclusive) at the time of screening
* All female subjects must be of non-childbearing potential. All male subjects must agree with their partners to use double-barrier birth control or abstinence while participating in the study and for 12 weeks following the last dose of investigational product. For the purposes of this study, non-childbearing is defined as:

  * Amenorrheic for at least 12 consecutive months; menopausal status in amenorrheic females will be confirmed by demonstrating levels of follicle stimulating hormone (FSH) \>40-138 mIU/mL and estradiol \< 30 pg/mL at entry. In the event a subject's menopause status has been clearly established (for example, the subject indicates she has been amenorrheic for 10 years), but FSH and/or estradiol levels are not consistent with a post-menopausal condition, determination of subject eligibility will be at the discretion of the principal investigator with agreement of the independent medical monitor
  * At least 6 weeks post-surgical bilateral oophorectomy (with or without hysterectomy) or post tubal ligation
* The subject must be on stable metformin monotherapy for a minimum of 3 months prior to the Screening visit.
* HbA1c of 6.5%-9.5% (inclusive)
* Body Mass Index (BMI) of 22-38 kg/m\^2 (inclusive)
* Resting supine blood pressure (BP) \< 160/90 mmHg
* Have a normal 12-lead electrocardiogram (ECG) or one with changes considered to be clinically insignificant on medical review and QTc intervals as defined below:

  * QTcB must be \<450 msec for males and \<470 msec for females (based on single or average QTc value of triplicate ECGs obtained over a brief period)
  * QTcB must be \<480 msec in subjects with Bundle Branch Block
* Comprehension of the nature and purpose of the study and able to comply with the protocol requirements
* Able to communicate in person and by telephone in a manner that allows all protocol procedures to be carried out safely and reliably in the opinion of the investigative site staff

Exclusion Criteria:

* Any major illness in the 3 months prior to study entry or any significant ongoing chronic medical illness not related to diabetes (e.g., recent myocardial infarction, unstable angina, stroke, or transient ischemic attack) which in the opinion of the principal investigator or medical monitor could risk subject safety or interpretation of the results
* 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
  * alkaline phosphatase and bilirubin \> 1.5xULN (an isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin is \<35%)
* A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of Screening
* A positive test for HIV antibody
* History of or current gastrointestinal diseases influencing drug absorption as judged by the investigator
* Significant history of alcoholism or drug/chemical abuse, or a positive result of the urine drug/alcohol screen at the Screening Visit, or consuming more than 28 units of alcohol per week (one unit of alcohol equals about 250 mL of beer or lager, one glass of wine, or 20 mL spirits)
* Participation in any clinical trial within 3 months prior to the first dose of investigational product in the current study
* History of difficulty in donating blood or accessibility of veins in left or right arm
* Donation or loss of blood (more than 500 mL) within 3 months prior to receiving the first dose of investigational product
* Use of any prescription drug therapy, with the exception of any prescription medication administered at a stable dose for at least 6 weeks prior to Screening, provided the medication is not contraindicated by the metformin label (see Appendix A for Glucophage® Summary of Product Characteristics)
* Use of any anti-diabetic therapy other than metformin, within 3 months of the first dose of investigational product
* Use of any dietary or herbal supplements within 3 weeks prior to the first dose of investigational product
* 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
* Active neoplastic disease or history of neoplastic disease within 5 years of study entry (except for basal cell carcinoma of the skin or carcinoma in situ)
* Increased risk of thrombosis, e.g., subjects with a history of deep leg vein thrombosis or family history of deep leg vein thrombosis, as judged by the investigator

Primary outcomes:
measure: The areas under the glucose concentration time curve from time 0 (dosing) to 2 hours post-dose (AUC 0-2h, glucose) obtained during an oral glucose tolerance test (OGTT) on days 28 and 42.
timeFrame: Day 28 and Day 42
measure: The areas under the serum insulin concentration time curve from time 0 (dosing) to 2 hours post-dose (AUC 0-2h, insulin) obtained during OGTT, on days 28 and 42.
timeFrame: Day 28 and 42
measure: Measurement of insulin sensitivity consisting of the insulin sensitivity index (ISIest) obtained during OGTT.
timeFrame: Up to Day 42
measure: Measurement of insulin sensitivity consisting of the composite whole body sensitivity index (ISIcomposite) obtained during OGTT
timeFrame: Up to Day 42
measure: Measurement of insulin sensitivity consisting of the hepatic insulin sensitivity (HIRI) obtained during OGTT
timeFrame: Up to Day 42
measure: Measurement of insulin sensitivity consisting of the muscular insulin sensitivity (MISI) obtained during OGTT.
timeFrame: Up to Day 42
measure: Measurement of insulin sensitivity consisting of the insulin resistance index obtained during OGTT
timeFrame: Up to Da y 42
measure: Measurement of insulin sensitivity consisting of the beta cell function based on homeostasis model assessment :HOMA-IR, obtained during OGTT
timeFrame: Up to Day 42
measure: Measurement of insulin sensitivity consisting of the beta cell function based on homeostasis model assessment : HOMA-%B, obtained during OGTT.
timeFrame: Up to Day 42
measure: Measurement of insulin sensitivity consisting of the quantitative insulin sensitivity check index (QUICKI) obtained during OGTT.
timeFrame: Up to Day 42
measure: Determination of sensitivity and metabolic clearance consisting of the insulin sensitive index (SI), Obtained during an hyperinsulinemic euglycemic glucose clamp (HEGC)
timeFrame: Up to Day 43
measure: Determination of insulin sensitivity during first (M1) and second (M2) insulin infusion step.
timeFrame: Up to Day 43
measure: Insulin sensitivity in relation to mean insulin infusion concentration (M/I1 and M/I2) ,Obtained during HEGC
timeFrame: Up to Day 43
measure: Metabolic clearance rate during first and second insulin infusion step (MCR1, MCR2) on Day 29, and 43
timeFrame: Up to Day 43
measure: Variables of metabolic clearance rate including M1ree and M2ree.
timeFrame: Up to Day 43
measure: Variables of metabolic clearance rate including MCR1ree and MCR2ree .
timeFrame: Up to Day 43
measure: Variables of metabolic clearance rate including M/I1ree and M/I2ree.
timeFrame: Up to Day 43
measure: Mean steady state concentration Free fatty acids (FFA), and glycerols
timeFrame: Up to Day 43
measure: Mean C-peptide concentration (mean C-peptideSS1 and C-peptideSS2) obtained during HEGC
timeFrame: Up to Day 43
measure: Number of participants with all adverse events (AEs) and serious adverse events (SAEs)
timeFrame: Up to 28 days
measure: Number of participants with hypoglycemic events
timeFrame: Up to Day 28
measure: Number of participants with abnormal Physical examination findings
timeFrame: Up to Day 41
measure: Change from baseline in Vital signs-systolic blood pressure (SBP) and diastolic blood pressure (DBP).
timeFrame: Up to Day 43
measure: Change from baseline in Vital signs-Heart rate
timeFrame: Up to Day 43
measure: Change from baseline in Vital signs-Respiratory rate
timeFrame: Up to Day 43
measure: Change from baseline in Vital signs-Temperature.
timeFrame: Up to Day 43
measure: Number of participants with abnormal electrocardiogram (ECG) recordings
timeFrame: Up to Day 43
measure: Mean hematology parameters including white blood cell (WBC) and platelets count
timeFrame: Up to Day 42
measure: Mean hematology parameters including WBC Differential count and Red cell distribution width (RDW)
timeFrame: Up to Day 42
measure: Mean hematology parameters including Hemoglobin (Hb) and Mean corpuscular hemoglobin concentration (MCHC)
timeFrame: Up to Day 42
measure: Mean hematology parameters including: hematocrit count
timeFrame: Up to Day 42
measure: Mean hematology parameters including corpuscular volume (MCV)
timeFrame: Up to Day 42
measure: Mean hematology parameters including corpuscular hemoglobin (MCH)
timeFrame: Up to Day 42
measure: Mean hematology parameters including Red Blood Cells (RBCs) count
timeFrame: Up to Day 42
measure: Summary of urinalysis data: PH
timeFrame: Up to Day 42
measure: Number of participants with urinalysis
timeFrame: Up to Day 42
measure: Mean clinical chemistry parameters including calcium, chloride, magnesium, potassium, sodium, bicarbonate, phosphate, glucose, urea and blood urea
timeFrame: Up to Day 42
measure: Mean clinical chemistry parameters including direct bilirubin, indirect bilirubin, total bilirubin ,uric acid
timeFrame: Up to Day 42
measure: Mean clinical chemistry parameters including alkaline phosphatase (ALP), Alanine aminotransferase (ALT), Aspartate aminotransaminase (AST), Lactate dehydrogenase (LDH), Creatine kinase
timeFrame: Up to Day 42
measure: Mean clinical chemistry parameters including albumin
timeFrame: Up to Day 42
measure: Mean clinical chemistry parameters including serum creatinine
timeFrame: Up to Day 42
Secondary outcomes:
measure: The area under the plasma concentration time curve of SRT2104 from time 0 (dosing) to 24 hours post-dose (AUC 0-24h)
timeFrame: Day 1 and 28 at pre-dose, and at 15, 30 minutes,1, 2, 3, 4, 8, 12 and 24 hours
measure: The area under the plasma concentration time curve of SRT2104 from time 0 to infinity (AUC 0-∞)
timeFrame: Day 1 and 28 at pre-dose, and at 15, 30 minutes,1, 2, 3, 4, 8, 12 and 24 hours
measure: Mean maximum plasma concentration of SRT2104 (Cmax)
timeFrame: Day 1 and 28 at pre-dose, and at 15, 30 minutes,1, 2, 3, 4, 8, 12 and 24 hours
measure: Mean time to maximum plasma SRT2104 concentration (tmax)
timeFrame: Day 1 and 28 at pre-dose, and at 15, 30 minutes,1, 2, 3, 4, 8, 12 and 24 hoursDay 1, 2, 28, and 29
measure: Mean Terminal elimination rate constant of SRT2104 (ƛz)
timeFrame: Day 1 and 28 at pre-dose, and at 15, 30 minutes,1, 2, 3, 4, 8, 12 and 24 hours
measure: Mean terminal plasma elimination half time (t1/2) of SRT2104.
timeFrame: Day 1 and 28 at pre-dose, and at 15, 30 minutes,1, 2, 3, 4, 8, 12 and 24 hours
measure: Energy expenditure (indirect calorimetry) parameters-Oxygen consumption (% O2) at ss1 and ss2
timeFrame: Up to Day 43
measure: Energy expenditure (indirect calorimetry) parameters- Carbon dioxide production(CO2) at ss1 and ss2
timeFrame: Up to Day 43
measure: Energy expenditure (indirect calorimetry) parameters-Resting energy expenditure (ree) at ss1 and ss2
timeFrame: Up to Day 43
measure: Energy expenditure (indirect calorimetry) parameters Carbohydrate/glucose oxidation rate (c) at ss1 and ss2
timeFrame: Up to Week 43
measure: Energy expenditure (indirect calorimetry) parameters- Fat oxidation rate (f) at ss1 and ss2
timeFrame: up to Day 43
measure: Energy expenditure (indirect calorimetry) parameters-Urinary urea excretion rate (n)
timeFrame: Up to Day 43
measure: Energy expenditure (indirect calorimetry) parameters-Oxidative and non- oxidative glucose disposal (VO2 and VCO2) at ss1 and ss2
timeFrame: Up to Day 43
measure: Energy expenditure (indirect calorimetry )parameters-Respiratory exchange ratio (RER)
timeFrame: Up to Day 43
measure: Mean 7-point-blood glucose-AUC
timeFrame: Up to Day 42
measure: Muscle histology and biomarkers of oxidative capacity -mitochondrial deoxyribonucleic acid (DNA).
timeFrame: Up to Day 28
measure: Muscle histology and biomarkers of oxidative capacity-Citrase synthase activity (Complex I)
timeFrame: Up to Days 28
measure: Muscle histology and biomarkers of oxidative capacity-Citrase synthase activity (Complex II/III and IV)
timeFrame: Up to Day 28
measure: Muscle histology and biomarkers of oxidative capacity-succinate dehydrogenase content Complex I, Complex II/III, complex IV.
timeFrame: Day 0, 29, and 43
Other outcomes:
Locations:
city: Neuss
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: