Investigate the Efficacy and Safety of GSK1070806 in Obese Subjects With T2DM

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01648153
First received: July 12, 2012
Last updated: April 24, 2014
Last verified: April 2014

July 12, 2012
April 24, 2014
August 2012
September 2013   (final data collection date for primary outcome measure)
Change from baseline in fasting plasma glucose and weighted mean glucose AUC (0-4hrs) post-Mixed Meal Test (MMT) [ Time Frame: Up to 85 days after the first does ] [ Designated as safety issue: No ]
To evaluate the efficacy of two repeat intravenous dose administrations of GSK1070806 in subjects with T2DM
Same as current
Complete list of historical versions of study NCT01648153 on ClinicalTrials.gov Archive Site
  • Safety and tolerability parameters include: adverse events, clinical laboratory tests, electrocardiograms (ECGs), and vital signs [ Time Frame: Up to 210 days after the first dose ] [ Designated as safety issue: Yes ]
    To evaluate the safety and tolerability of two repeat intravenous dose administrations of GSK1070806 in obese subjects with T2DM
  • Change from baseline in % HbA1c, fasting blood insulin, and C-peptide levels; change from baseline in weighted mean insulin, and C-peptide levels [AUC (0-4hrs)] post-MMT and derived measures of insulin sensitive [ Time Frame: Up to 85 days after the first dose ] [ Designated as safety issue: No ]
    To evaluate the effect of two repeat intravenous dose administrations of GSK1070806 on additional markers of efficacy, in obese subjects with T2DM
  • AUC(0-τ) [ Time Frame: Up to 210 days after the first dose ] [ Designated as safety issue: No ]
    To evaluate the plasma PK of repeat intravenous doses of GSK1070806 in obese subjects with T2DM
  • Serum levels of free IL-18 and drug bound IL 18 [ Time Frame: Up to 210 days after the first dose ] [ Designated as safety issue: Yes ]
    To investigate the effect of repeat intravenous doses of GSK1070806 on free and drug bound IL 18 levels (if measurable) in obese subjects with T2DM.
  • Change from baseline in serum and/or plasma levels of biomarkers of inflammation (e.g. hs-CRP, and IL-6) and metabolic disease (e.g. adiponectin, fructosamine, total cholesterol, high-density lipoprotein (HDL)/low-density lipoprotein (LDL), triglycerides [ Time Frame: Up to 85 days after the first dose ] [ Designated as safety issue: No ]
    To explore the pharmacodynamic (PD) effect of repeat intravenous doses of GSK1070806 on biomarkers of inflammation and metabolic disease
  • Change from baseline in waist circumference and BMI [ Time Frame: Up to 85 days after the first dose ] [ Designated as safety issue: No ]
    To investigate the effect of repeat intravenous doses of GSK1070806 on body composition in obese subjects with T2DM
  • Cmax [ Time Frame: Up to 210 days after the first dose ] [ Designated as safety issue: No ]
    To evaluate the plasma PK of repeat intravenous doses of GSK1070806 in obese subjects with T2DM
  • Tmax [ Time Frame: Up to 210 days after the first dose ] [ Designated as safety issue: No ]
    To evaluate the plasma PK of repeat intravenous doses of GSK1070806 in obese subjects with T2DM
  • after the second dose λz [ Time Frame: Up to 210 days after the first dose ] [ Designated as safety issue: No ]
    To evaluate the plasma PK of repeat intravenous doses of GSK1070806 in obese subjects with T2DM
  • t1/2 [ Time Frame: Up to 210 days after the first dose ] [ Designated as safety issue: No ]
    To evaluate the plasma PK of repeat intravenous doses of GSK1070806 in obese subjects with T2DM
  • Safety and tolerability parameters include: adverse events, clinical laboratory tests, electrocardiograms (ECGs), and vital signs [ Time Frame: Up to 210 days after the first dose ] [ Designated as safety issue: Yes ]
    To evaluate the safety and tolerability of two repeat intravenous dose administrations of GSK1070806 in obese subjects with T2DM
  • Change from baseline in % HbA1c, fasting blood insulin, and C-peptide levels; change from baseline in weighted mean insulin, and C-peptide levels [AUC (0-4hrs)] post-MMT and derived measures of insulin sensitiv [ Time Frame: Up to 85 days after the first dose ] [ Designated as safety issue: No ]
    To evaluate the effect of two repeat intravenous dose administrations of GSK1070806 on additional markers of efficacy, in obese subjects with T2DM
  • AUC(0-τ) [ Time Frame: Up to 210 days after the first dose ] [ Designated as safety issue: No ]
    To evaluate the plasma PK of repeat intravenous doses of GSK1070806 in obese subjects with T2DM
  • Serum levels of free IL-18 and drug bound IL 18 [ Time Frame: Up to 210 days after the first dose ] [ Designated as safety issue: Yes ]
    To investigate the effect of repeat intravenous doses of GSK1070806 on free and drug bound IL 18 levels (if measurable) in obese subjects with T2DM.
  • Change from baseline in serum and/or plasma levels of biomarkers of inflammation (e.g. hs-CRP, and IL-6) and metabolic disease (e.g. adiponectin, frucosamine, total cholesterol, high-density lipoprotein (HDL)/low-density lipoprotein (LDL), triglycerides) [ Time Frame: Up to 85 days after the first dose ] [ Designated as safety issue: No ]
    To explore the pharmacodynamic (PD) effect of repeat intravenous doses of GSK1070806 on biomarkers of inflammation and metabolic disease
  • Change from baseline in waist circumference and BMI [ Time Frame: Up to 85 days after the first dose ] [ Designated as safety issue: No ]
    To investigate the effect of repeat intravenous doses of GSK1070806 on body composition in obese subjects with T2DM
  • Cmax [ Time Frame: Up to 210 days after the first dose ] [ Designated as safety issue: No ]
    To evaluate the plasma PK of repeat intravenous doses of GSK1070806 in obese subjects with T2DM
  • Tmax [ Time Frame: Up to 210 days after the first dose ] [ Designated as safety issue: No ]
    To evaluate the plasma PK of repeat intravenous doses of GSK1070806 in obese subjects with T2DM
  • after the second dose λz [ Time Frame: Up to 210 days after the first dose ] [ Designated as safety issue: No ]
    To evaluate the plasma PK of repeat intravenous doses of GSK1070806 in obese subjects with T2DM
  • t1/2 [ Time Frame: Up to 210 days after the first dose ] [ Designated as safety issue: No ]
    To evaluate the plasma PK of repeat intravenous doses of GSK1070806 in obese subjects with T2DM
Not Provided
Not Provided
 
Investigate the Efficacy and Safety of GSK1070806 in Obese Subjects With T2DM
A Single Blind (Sponsor-unblinded), Placebo-controlled, Parallel-group Study to Investigate the Efficacy and Safety of GSK1070806 in the Treatment of Obese Subjects With T2DM.

GSK1070806 is a humanised IgG1/kappa antibody which is directed against the soluble cytokine interleukin-18 (IL-18). The aims of this placebo controlled study are to evaluate the efficacy, safety, tolerability, pharmacokinetics and pharmacodynamics of GSK1070806 in obese subjects with Type 2 diabetes mellitus (T2DM), and to gain a better understanding of the mechanism by which GSK1070806 exerts its therapeutic effects.

The study will be a randomised, single-blind (sponsor-unblinded), placebo-controlled, study to investigate the efficacy, safety, tolerability, pharmacokinetics and pharmacodynamics of repeat intravenous infusions (2 doses 4-weeks apart) of GSK1070806 in obese patients with T2DM. The primary objective of the study will be to assess improvements in fasting and postprandial glucose control. This will be a parallel-group study in 30 obese subjects with T2DM who are poorly controlled on metformin monotherapy (HbA1C>7% but <9.5%), and who have levels of microalbuminuria indicative of progressive kidney disease i.e. 30-300mg/L albumin in urine or ACR ≥3.5 mg/mmol (female) or ≥2.5 mg/mmol (male) and ≤30mg/mmol. There will be three treatment groups comprising two active and one placebo arm with 10 subjects per dose group. The study contains a broad range of biomarker assessments, the purpose of which is to evaluate the mechanistic basis by which GSK1070806 exerts its therapeutic benefit in subjects with T2DM.

Subjects will be randomised into one of the three treatment groups where they will receive two intravenous infusions of GSK1070806 or placebo twenty-eight days apart. A MMT challenge will be conducted on Day 1, Day 29, Day 57 and Day 85 for evaluation of the primary endpoints.

Interventional
Phase 2
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Investigator)
Primary Purpose: Basic Science
Diabetes Mellitus
  • Biological: GSK1070806
    To investigate the efficacy and biomarker changes of GSK1070806 after 0.25mg/kg IV administration
  • Other: Placebo (saline)
    To compare the efficacy and biomarker changes between placebo and active groups
  • Biological: GSK1070806
    To investigate the efficacy and biomarker changes of GSK1070806 after 5mg/kg IV administration
  • Active Comparator: GSK1070806 0.25mg/kg
    TwoIV administrations of 0.25mg/kg GSK1070806 4weeks apart
    Intervention: Biological: GSK1070806
  • Active Comparator: GSK1070806 5mg/kg
    Two IV administrations of 5mg/kg of GSK1070806 4 weeks apart
    Intervention: Biological: GSK1070806
  • Placebo Comparator: Placebo (Saline)
    Two IV administrations of saline 4 weeks apart
    Intervention: Other: Placebo (saline)
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
37
January 2014
September 2013   (final data collection date for primary outcome measure)

Inclusion Criteria:

  1. A diagnosis of T2DM as determined by a responsible physician based on a medical evaluation including medical history, physical examination, and laboratory tests, with onset at least 6 months prior to Screening.
  2. Male or female between 18 and 70 years of age inclusive, at the time of signing the informed consent.
  3. HbA1c levels ≥ 7.0 % and ≤ 9.5%; at Screening.
  4. On a stable dose of monotherapy with metformin for three months prior to screening, and at a total daily dose greater than or equal to 1000 mg for at least 2 months prior to dosing.
  5. Fasting plasma glucose level < 13.3 mmol/L (240 mg/dL) at screening.
  6. Obese with BMI ≥ 30 kg/m2, and < 40 kg/m2.
  7. Presence of microalbuminuria: 30-300mg/L albumin in urine or Albumin Creatinine Ratio (ACR) ≥ 3.5 mg/mmol (female) or ≥2.5 mg/mmol (male) and ≤ 30 mg/mmol (female and male)..
  8. The subject is capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
  9. A female subject is eligible to participate if she is of:

    • Non-childbearing potential
    • Child-bearing potential and agrees to use an acceptable form of contraception.
  10. Male subjects must agree to use one of the contraception methods listed
  11. ALT < 2xULN; alkaline phosphatase and bilirubin ≤ 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
  12. Single or Average QTc, QTcB or QTcF < 450 msec; or QTc < 480 msec in subjects with Bundle Branch Block.

Exclusion Criteria:

  1. Current evidence, or history within the last 7 days, of an influenza-like illness as defined by fever (>38°C) and two or more of the following symptoms: cough, sore throat, runny nose, sneezing, limb / joint pain, headache, vomiting / diarrhoea in the absence of a known cause, other than influenza.
  2. Use of anti-inflammatory drugs including corticosteroids, chronic maintenance therapy with NSAIDs, anti-Tumor Necrosis Factor (anti-TNF) or anti-Interleukin-1 (anti-IL1) within 60 days prior to dosing.
  3. Current evidence of ongoing or acute infection, history of repeated, chronic or opportunistic infections (e.g. recurrent folliculitis, other cutaneous infections or repeated pneumonia) or history of a serious bacterial infection within 6 months of randomisation.
  4. History of malignancy or significant cardiac, pulmonary, metabolic, renal, hepatic, or gastrointestinal conditions.
  5. History chronic granulomatous infections, such as of Mycobacterium tuberculosis or any other previous Mycobacterium infection.
  6. Creatinine clearance less than 60ml/min
  7. Screens positive of Hepatitis B surface antigen, Hepatitis C antibody or Human Immunodeficiency Virus (HIV)
  8. History of a severe allergic reaction, anaphylaxis or immunodeficiency.
  9. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
  10. A positive pre-study drug/alcohol screen.
  11. History of regular alcohol consumption within 6 months of the study
  12. The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
  13. Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
  14. Unable to refrain from the use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication.
  15. History of sensitivity to any of the study medications, or components thereof
  16. Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
  17. Pregnant females as determined by positive serum or urine hCG test at screening.
  18. Lactating females.
  19. Unwillingness or inability to follow the procedures outlined in the protocol.
  20. Subject is mentally or legally incapacitated.
  21. Subject has received a live attenuated vaccine(s) within 30 days of randomisation or will require vaccination with a live attenuated vaccine prior to the end of the study.
Both
18 Years to 70 Years
No
Contact information is only displayed when the study is recruiting subjects
Spain,   United Kingdom
 
NCT01648153
116378
No
GlaxoSmithKline
GlaxoSmithKline
Not Provided
Study Director: GSK Clinical Trials GlaxoSmithKline
GlaxoSmithKline
April 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP