Clinical trial NCT00937326: Clinical Study to Assess the Safety and Pharmacokinetics of SRT2104 in Type 2 Diabetic Human Subjects
Official title: A Phase II, Randomized, Placebo-Controlled, Double-Blind, Multiple-Dose Clinical Study to Assess the Safety and Pharmacokinetics of SRT2104 in Type 2 Diabetic Human Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Diabetes Mellitus, Type 2
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
Collaborators: name: GlaxoSmithKline
First posted: 2009-07-13
Enrollment: 227
Sex: ALL
Minimum age (years): 30
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary purpose of this study is to determine the safety and tolerability of SRT2104 (0.25, 0.5, 1.0, and 2.0 g/day) in type 2 diabetic subjects when administered once daily for 28 consecutive days, and to characterize the pharmacokinetic profile of SRT2104 after a single dose and multiple administrations in type 2 diabetic subjects.

The secondary purpose of this study is to determine the effect of SRT2104 (0.25, 0.5, 1.0, and 2.0 g/day) when administered once daily for 28 consecutive days on fasting blood glucose and insulin and post-prandial blood glucose and insulin in type 2 diabetic subjects.

Detailed description: Study Objectives

Primary:

1. To determine the safety and tolerability of SRT2104 (0.25, 0.5, 1.0, and 2.0 g/day) in type 2 diabetic subjects when administered once daily for 28 consecutive days.
2. To characterize the pharmacokinetic profile of SRT2104 (0.25, 0.5, 1.0, and 2.0 g/day) after a single dose and multiple administrations in type 2 diabetic subjects.

Secondary:

1. To determine the effect of SRT2104 (0.25, 0.5, 1.0, and 2.0 g/day) when administered once daily for 28 consecutive days on fasting blood glucose and insulin and post-prandial blood glucose and insulin in type 2 diabetic subjects.

Study Design:

Prospective, multi-center, clinical study of SRT2104 administered orally once daily for 28 consecutive days; randomized, placebo-controlled, double-blind, multiple-dose, inpatient/outpatient study to assess the safety and pharmacokinetics (PK) of SRT2104 in type 2 diabetic male and female subjects on an existing, stable, background metformin therapy. Approximately 225 subjects aged 30-70, who fulfill the inclusion/exclusion criteria, will be enrolled in this study to ensure completion of forty (40) evaluable subjects within each of five dosing groups. Subjects will be evenly randomized to receive SRT2104 at one of five doses, placebo (A), 0.25 g/day (B), 0.5 g/day (C), 1.0 g/day (D), or 2.0 g/day (E), once a day for 28 consecutive days, approximately 15 minutes following consumption of a standardized 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 over a 2-day period 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 dosing phase of the study. Subjects will be randomized to receive SRT2104 or placebo, and will be required to stay overnight at the study center on Day -1 and Day 27 to gather required PK samples and to assess safety on Day 1 and Day 28 respectively. In addition, subjects will be asked to return to the study center on Days 2 and 29; for three interim weekly safety assessments (on Days 8, 15, 22); and for an End of Study safety assessment 7 days after they complete the 28-day dosing period. A follow-up safety call will be made to each subject 30 days following their final dose of SRT2104 or placebo.

Eligibility criteria: Inclusion Criteria:

1. Subjects of any race and gender within the age range of 30 to 70 years.
2. All female subjects must be of non-child-bearing potential. For the purposes of this study, this is defined as the subject being amenorrheic for at least 12 consecutive months, or at least 6 weeks post-surgical bilateral oophorectomy with or without hysterectomy, or women who underwent tubal ligation. Menopausal status will be confirmed by demonstrating levels of follicle stimulating hormone (FSH) 40 - 138 mIU/ml and oestradiol \< 20 pg/ml at entry, unless this information is available in the subject's medical record. 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 oestradiol levels are not consistent with a post-menopausal condition, determination of subject eligibility will be at the discretion of the principal investigator following consultation with the sponsor and medical monitor
3. 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 study drug.
4. Willingness to provide written informed consent to participate in the study
5. HbA1c ≥ 7.5 and ≤ 10.5
6. Fasting glucose ≥ 160 and ≤ 240 mg/dL
7. Body Mass Index (BMI) ≥ 25.0 kg/m\^2 and ≤ 40.0 kg/m\^2
8. On stable metformin medication for at least 3 months (≥ 1.0 g/day) prior to Screening
9. No prior history of HIV 1 or 2
10. Absence of disease markers for hepatitis B \& C virus
11. Absence of significant disease or clinically significant abnormal laboratory values on the laboratory evaluations, medical history or physical examination during the screening; normal end organ function
12. Have a normal 12-lead ECG or one with abnormality considered to be clinically insignificant
13. Have a normal chest X-ray (P. A. View) or one with abnormality considered to be clinically insignificant
14. Comprehension of the nature and purpose of the study and compliance with the requirement of the entire protocol

Exclusion Criteria:

1. Any major illness in the past three months or any significant ongoing chronic medical illness not related to diabetes
2. Renal or liver impairment, defined as serum creatinine level of ≥ 1.4 mg/dL for females and ≥ 1.5 mg/dL for males, and greater than two times the upper limit of normal for liver enzymes, respectively.
3. History of or current gastro-intestinal diseases influencing drug absorption, except for appendectomy
4. History, within 3 years, of drug abuse (including Benzodiazepines, opioids, amphetamine, cocaine, and THC)
5. History of alcoholism (more than two years), moderate drinkers (more than three drinks per day) or having consumed alcohol within 48 hrs prior to dosing \[one drink is equal to one unit of alcohol (one glass wine, half pint beer, one measure of spirit)\]
6. Participation in any clinical trial within the past three months
7. History of difficulty in donating blood or accessibility of veins in left or right arm
8. Donation of blood (one unit or 350 ml) within three months prior to receiving the first dose of test material
9. Use of any prescription drug therapy, with 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
10. Use of any alternate anti-diabetic therapy, except metformin, within three months of enrollment

Primary outcomes:
measure: Number of Participants With Any Adverse Event (AE), Serious Adverse Event (SAE), AE Related to Study Medication, AE Leading to Discontinuation and Fatal AE of Death
timeFrame: Up to Follow-up (58 days)
measure: Number of Participants With AE by Intensity of Mild, Moderate and Severe
timeFrame: Up to Follow-up (58 days)
measure: Mean Change From Baseline in Weight Over Time
timeFrame: Baseline (Day 1) and up to Day 35
measure: Change From Baseline in Vital Sign Parameter of Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Over Time
timeFrame: Baseline (Day 1, pre-dose) and up to Day 35
measure: Change From Baseline in Vital Sign Parameter of Heart Rate (HR) Over Time
timeFrame: Baseline (Day 1, pre-dose) and up to Day 35
measure: Change From Baseline in Vital Sign Parameter of Respiratory Rate (RR) Over Time
timeFrame: Baseline (Day 1, pre-dose) and up to Day 35
measure: Change From Baseline in Vital Sign Parameter of Temperature Over Time
timeFrame: Baseline (Day 1, pre-dose) and up to Day 35
measure: Change From Baseline in Electrocardiogram (ECG) Values Over Time
timeFrame: Baseline (Day 1, pre-dose) and up to Day 35
measure: Change From Baseline in Hematology Parameters of Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelet and White Blood Cell (WBC) Count Over Time
timeFrame: Baseline (Day 1) and up to Day 35
measure: Change From Baseline in Hematology Parameter of Red Blood Cell (RBC) Count Over Time
timeFrame: Baseline (Day 1) and up to Day 35
measure: Change From Baseline in Hematology Parameter of Hematocrit Over Time
timeFrame: Baseline (Day 1) and up to Day 35
measure: Change From Baseline in Hematology Parameter of Hemoglobin Over Time
timeFrame: Baseline (Day 1) and up to Day 35
measure: Change From Baseline in Hematology Parameter of Mean Corpuscular Hemoglobin Over Time
timeFrame: Baseline (Day 1) and up to Day 35
measure: Change From Baseline in Hematology Parameter of Mean Corpuscular Hemoglobin Concentration Over Time
timeFrame: Baseline (Day 1) and up to Day 35
measure: Change From Baseline in Hematology Parameter of Mean Corpuscular Volume Over Time
timeFrame: Baseline (Day 1) and up to Day 35
measure: Change From Baseline in Coagulation Parameters of Activated Partial Thromplastin Time (aPTT) and Prothrombin Time (PT) Over Time
timeFrame: Baseline (Day 1), Day 28 and Day 35
measure: Change From Baseline in Coagulation Parameter of International Normalized Ratio Over Time
timeFrame: Baseline (Day 1), Day 28 and Day 35
measure: Change From Baseline in Chemistry Parameters of Alanine Aminotransferase (ALT), Aspartate Aminotrasferase (AST), Alkaline Phosphatase (ALP), Creatinine Phosphokinase and Lactate Dehydrogenase (LDH) Over Time
timeFrame: Baseline (Day 1) and up to Day 35
measure: Change From Baseline in Chemistry Parameter of Bicarbonate, Blood Urea Nitrogen (BUN), Calcium, Chloride, Magnesium, Phosphate, Potassium and Sodium Over Time
timeFrame: Baseline (Day 1) and up to Day 35
measure: Change From Baseline in Chemistry Parameter of Direct Bilirubin, Indirect Bilirubin, Serum Creatinine, Total Bilirubin and Uric Acid Over Time
timeFrame: Baseline (Day 1) and up to Day 35
measure: Change From Baseline in Chemistry Parameter of Lipid Profile Over Time
timeFrame: Baseline (Day 1) and up to Day 35
measure: Change From Baseline in Chemistry Parameter of Albumin and Total Protein Over Time
timeFrame: Baseline (Day 1) and up to Day 35
measure: Change From Baseline in Urinalysis Parameter of Specific Gravity Over Time
timeFrame: Baseline (Day 1) and up to Day 35
measure: Change From Baseline in Urinalysis Parameter of pH Over Time
timeFrame: Baseline (Day 1) and up to Day 35
measure: Area Under Plasma Concentration Curve From Time 0 to Last Measurable Time Point (AUC 0-t), From Time 0 to Infinity (AUC 0-infinity) and From Time 0 to Trough Concentration (AUC 0-τ) of SRT2104 on Day 1 and Day 28
timeFrame: Day 1 (pre-dose, 15 and 30 minutes, 1, 2, 3, 4, 8 and 12 hour post-dose), Day 2 (24 hour post-Day 1 dose), Day 8, 15 and 22 (pre-dose), Day 28 (pre-dose, and 15 and 30 minutes, 1, 2, 3, 4, 8 and 12 hour post-dose) and Day 29 (24 hour post-Day 28)
measure: Observed Maximum Plasma Concentration (Cmax) of SRT2104 at Day 1 and Day 28
timeFrame: Day 1 (pre-dose, 15 and 30 minutes, 1, 2, 3, 4, 8 and 12 hour post-dose), Day 2 (24 hour post-Day 1 dose), Day 8, 15 and 22 (pre-dose), Day 28 (pre-dose, and 15 and 30 minutes, 1, 2, 3, 4, 8 and 12 hour post-dose) and Day 29 (24 hour post-Day 28 dose)
measure: Time to Cmax (Tmax) at Day 1 and Day 28
timeFrame: Day 1 (pre-dose, 15 and 30 minutes, 1, 2, 3, 4, 8 and 12 hour post-dose), Day 2 (24 hour post-Day 1 dose), Day 8, 15 and 22 (pre-dose), Day 28 (pre-dose, and 15 and 30 minutes, 1, 2, 3, 4, 8 and 12 hour post-dose) and Day 29 (24 hour post-Day 28 dose)
measure: Terminal Elimination Half Life (T1/2) of SRT2104 at Day 1 and Day 28
timeFrame: Day 1 (pre-dose, 15 and 30 minutes, 1, 2, 3, 4, 8 and 12 hour post-dose), Day 2 (24 hour post-Day 1 dose), Day 8, 15 and 22 (pre-dose), Day 28 (pre-dose, and 15 and 30 minutes, 1, 2, 3, 4, 8 and 12 hour post-dose) and Day 29 (24 hour post-Day 28 dose)
measure: Apparent Total Clearance of SRT2104 From Plasma After Oral Administration (CL/F) on Day 1 and Day 28
timeFrame: Day 1 (pre-dose, 15 and 30 minutes, 1, 2, 3, 4, 8 and 12 hour post-dose), Day 2 (24 hour post-Day 1 dose), Day 8, 15 and 22 (pre-dose), Day 28 (pre-dose, and 15 and 30 minutes, 1, 2, 3, 4, 8 and 12 hour post-dose) and Day 29 (24 hour post-Day 28 dose)
measure: Apparent Volume of Distribution After Oral Administration (Vd/F) at Day 1 and Day 28
timeFrame: Day 1 (pre-dose, 15 and 30 minutes, 1, 2, 3, 4, 8 and 12 hour post-dose), Day 2 (24 hour post-Day 1 dose), Day 8, 15 and 22 (pre-dose), Day 28 (pre-dose, and 15 and 30 minutes, 1, 2, 3, 4, 8 and 12 hour post-dose) and Day 29 (24 hour post-Day 28 dose)
Secondary outcomes:
measure: Mean Fasting Plasma Glucose (FPG) Levels Over Time
timeFrame: Up to Day 35
measure: Change From Baseline in FPG Levels Over Time
timeFrame: Baseline (Day 1) and up to Day 35
measure: Mean Fasting Plasma Insulin (FPI) Levels Over Time
timeFrame: Up to Day 35
measure: Change From Baseline in FPI Over Time
timeFrame: Baseline (Day 1) and up to Day 35
measure: Mean Post-prandial Glucose (PPG) and Post-prandial Insulin (PPI) Levels at Day 28
timeFrame: Day 28
measure: Change From Baseline in PPG and PPI Levels at Day 28
timeFrame: Baseline (Day 1) and Day 28
measure: Mean Glycosylated Hemoglobin A (HbA1c) Levels on Day 28
timeFrame: Day 28
measure: Change From Baseline in HbA1c Levels at Day 28
timeFrame: Baseline (Day 1) and Day 28
measure: AUC From Time 0 to 1 h (AUC 0-1) and AUC From Time 0 to 2 h (AUC 0-2) for PPG and PPI at Day 1 and Day 28
timeFrame: Day 1 (30 minutes, 60 minutes and 2 hour) and Day 28 (30 minutes, 60 minutes and 2 hour)
measure: Mean Fructosamine Levels at Day 1 and Day 28
timeFrame: Day 1 and Day 28
measure: Change From Baseline in Fructosamine Levels at Day 28
timeFrame: Baseline (Day 1) and Day 28
measure: Mean Homeostatic Model Assessment-insulin Resistance (HOMA-IR) at Day 1 and Day 28
timeFrame: Day 1 and Day 28
measure: Change From Baseline in HOMA-IR at Day 28
timeFrame: Baseline (Day 1) and Day 28
measure: Mean HOMA-percentage Cell Beta Function at Day 1 and Day 28
timeFrame: Day 1 and Day 28
measure: Change From Baseline in HOMA-percentage of Beta Cell Function at Day 28
timeFrame: Baseline (Day 1) and Day 28
Other outcomes:
Locations:
city: Byala
country: Bulgaria
facility: GSK Investigational Site
city: Dimitrovgrad
country: Bulgaria
facility: GSK Investigational Site
city: Haskovo
country: Bulgaria
facility: GSK Investigational Site
city: Pleven
country: Bulgaria
facility: GSK Investigational Site
city: Plovdiv
country: Bulgaria
facility: GSK Investigational Site
city: Plovdiv
country: Bulgaria
facility: GSK Investigational Site
city: Ruse
country: Bulgaria
facility: GSK Investigational Site
city: Sofia
country: Bulgaria
facility: GSK Investigational Site
city: Sofia
country: Bulgaria
facility: GSK Investigational Site
city: Tallinn
country: Estonia
facility: GSK Investigational Site
city: Tallinn
country: Estonia
facility: GSK Investigational Site
city: Tallinn
country: Estonia
facility: GSK Investigational Site
city: Balantonfured
country: Hungary
facility: GSK Investigational Site
city: Eger
country: Hungary
facility: GSK Investigational Site
city: Gyula
country: Hungary
facility: GSK Investigational Site
city: Kecskemet
country: Hungary
facility: GSK Investigational Site
city: Sopron
country: Hungary
facility: GSK Investigational Site
city: Szekszard
country: Hungary
facility: GSK Investigational Site
city: Zalaegerszeg
country: Hungary
facility: GSK Investigational Site
city: Cieszyn
country: Poland
facility: GSK Investigational Site
city: Lubin
country: Poland
facility: GSK Investigational Site
city: Lubin
country: Poland
facility: GSK Investigational Site
city: Pulawy
country: Poland
facility: GSK Investigational Site
city: Radzymin
country: Poland
facility: GSK Investigational Site
city: Ruda Slaska
country: Poland
facility: GSK Investigational Site
city: Slupsk
country: Poland
facility: GSK Investigational Site
city: Tychy
country: Poland
facility: GSK Investigational Site
city: Warszawa
country: Poland
facility: GSK Investigational Site
city: Bacau
country: Romania
facility: GSK Investigational Site
city: Braila
country: Romania
facility: GSK Investigational Site
city: Buzau
country: Romania
facility: GSK Investigational Site
city: Constanta
country: Romania
facility: GSK Investigational Site
city: Oradea
country: Romania
facility: GSK Investigational Site
city: Ploiesti
country: Romania
facility: GSK Investigational Site
city: Timisoara
country: Romania
facility: GSK Investigational Site
city: Barnaul
country: Russian Federation
facility: GSK Investigational Site
city: Kemerovo
country: Russian Federation
facility: GSK Investigational Site
city: Kemerovo
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Novosibirsk
country: Russian Federation
facility: GSK Investigational Site
city: Novosibirsk
country: Russian Federation
facility: GSK Investigational Site
city: Rostov-on-Don
country: Russian Federation
facility: GSK Investigational Site
city: St. Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: St.-Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Tumen
country: Russian Federation
facility: GSK Investigational Site
city: Ufa
country: Russian Federation
facility: GSK Investigational Site
city: Yaroslavl
country: Russian Federation
facility: GSK Investigational Site
city: Kharkiv
country: Ukraine
facility: GSK Investigational Site
city: Mykolaiv
country: Ukraine
facility: GSK Investigational Site
city: Simferopol
country: Ukraine
facility: GSK Investigational Site
city: Ternopil
country: Ukraine
facility: GSK Investigational Site
city: Vinnitsa
country: Ukraine
facility: GSK Investigational Site
city: Zaporizhzhya
country: Ukraine
facility: GSK Investigational Site
city: Zaporizhzhya
country: Ukraine
facility: GSK Investigational Site
city: Birmingham
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: Newport
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: