Dose-Ranging Study in Treatment Naive Type 2 Diabetes Mellitus(T2DM)
Condition: Diabetes Mellitus, Type 2
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Intervention: GSK189075; pioglitazone; Placebo
Intervention description: Experimental Drug; Active Control; Placebo Comparator
Intervention MeSH terms: Pioglitazone
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 334.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: Pioglitazone; HbA1c; Diabetes mellitus

Summary:

      This is a dose-ranging study that will evaluate the efficacy, safety and tolerability of a
      range of doses of investigational product and pioglitazone, compared to placebo, administered
      as monotherapy over 12 weeks in treatment naive patients with T2DM
    

Eligibility criteria:

        Inclusion criteria:

          -  Subjects with a documented diagnosis of T2DM and have an HbA1c level at Visit 1 of
             ≥7.0% and ≤9.5% as measured by a central laboratory. Subjects with HbA1c <7.5% must
             have a fasting fingerstick glucose ≥7 mmol/L (126 mg/dL) at Week 0 prior to
             randomization.

          -  Subjects who are treatment-naïve and have not taken insulin, or any oral or injectable
             anti-diabetic medication in the past 3 months and have not taken a glucose lowering
             agent for ≥4 weeks at any time in the past, or Subjects who are newly diagnosed and
             treated with diet and exercise for a minimum of 6 weeks

          -  Subjects who are 18 to 70 years of age inclusive at the time of Screening.

          -  Females of non-childbearing and childbearing potential are eligible to participate as
             follows:

               -  Women of childbearing potential must be willing to use one of the following
                  contraception methods: intrauterine device, condom or occlusive cap (diaphragm or
                  cervical/vault caps) plus spermicidal agent for at least 30 days prior to the
                  start of study medication, throughout the study and the follow-up visit. Note:
                  use of oral contraceptives is not permitted.

               -  Women of non-child bearing potential are defined as follows: females regardless
                  of age, with functioning ovaries and who have a current documented tubal ligation
                  [Hatcher, 2004] bilateral oophorectomy or total hysterectomy, or females who are
                  post-menopausal).

        (Post-menopausal is defined as after one year without menses with an appropriate clinical
        profile, e.g. age appropriate, >45 years, in the absence of hormone replacement therapy. In
        addition to the above criteria, if the post-menopausal status is still questionable, a
        blood sample should be drawn for simultaneous measurement of follicle stimulating hormone
        and estradiol; values considered to confirm the post-menopausal state are respectively: FSH
        >40 MIU/mL and estradiol <40pg/mL (<140 pmol/L)).

          -  Informed Consent: a signed and dated written consent must be obtained from the subject
             before any procedures are performed.

        Exclusion Criteria:

          -  Metabolic Disease

               -  Diagnosis of Type 1 diabetes mellitus.

               -  History of ketoacidosis which has required hospitalization.

               -  Thyroid disorder [TSH below the lower limit of the reference range (LLRR) of
                  0.4mIU/L or above the upper limit of the reference range (ULRR) of >5.5 mIU/L at
                  Screening]. Hypothyroidism treated with the same dose and regimen of thyroid
                  hormone replacement for at least 3 months prior to Screening is allowed.

               -  BMI of <22 or >43 kg/m2.

               -  Significant weight gain or loss (as defined as >5% of total body weight) in the 3
                  months prior to Screening.

          -  Diabetic Medication

               -  Has taken insulin or any oral or injectable anti-diabetic medication ≥4 weeks at
                  any time prior to screening.

               -  Has taken insulin or any oral or injectable anti-diabetic medication within 3
                  months of screening.

          -  Cardiovascular Disease

               -  Recent history or presence of clinically significant acute cardiovascular disease
                  including:

                    1. Documented myocardial infarction in the 6 months prior to Screening.

                    2. Coronary revascularization including percutaneous transluminal coronary
                       angioplasty (PTCA) or coronary artery bypass graft (CABG) surgery either
                       planned and/or occurred in the 6 months prior to Screening.

                    3. Unstable angina in the 6 months prior to Screening.

                    4. Clinically significant supraventricular arrhythmias requiring medical
                       therapy, or history of nonsustained or sustained ventricular tachycardia.
                       Symptomatic valvular heart disease or valvular heart disease requiring
                       therapy other than endocarditis prophylaxis.

                    5. Congestive heart failure (CHF, New York Heart Association (NYHA) Class II to
                       IV) requiring pharmacologic treatment. NYHA Class I may be included in
                       accordance with the local prescribing information for pioglitazone.

                    6. Blood pressure (BP) >150/100mmHg. If a subject is receiving permitted
                       antihypertensive therapy, then they must be on stable dose(s) of therapy for
                       at least 4 weeks prior to Screening.

                    7. Has a QTc interval (Bazett's) ≥450msec at Screening on a single ECG or an
                       average value from 3 ECGs taken 5 minutes apart (on local reading of ECG).

                    8. Other clinically significant ECG abnormalities which, in the opinion of the
                       investigator, may affect the interpretation of efficacy and safety data, or
                       which otherwise contraindicates participation in a clinical trial with a new
                       chemical entity.

               -  Fasting triglycerides ≥400mg/dL (4.56mmol/L) at Screening. If a subject is
                  receiving permitted lipid-lowering therapy, then they must be on a stable dose(s)
                  of therapy for at least 6 weeks prior to Screening. Niacin and bile acid
                  sequestrants are prohibited.

          -  Hepatic Disease

        Has a diagnosis of active hepatitis (hepatitis B surface antigen or hepatitis C antibody),
        or clinically significant hepatic enzyme elevation including:

        Any one of the following enzymes greater than 2 times the upper limit of the reference
        range (ULRR) value at Screening.

          -  alanine transaminase (ALT).

          -  aspartate transaminase (AST).

          -  alkaline phosphatase (AP). Has a total bilirubin level that is >1.5 times the ULRR at
             Screening with the exception of suspected or confirmed Gilbert's disease.

               -  Pancreatic Disease

          -  Secondary causes of diabetes:

          -  history of chronic or acute pancreatitis

               -  Renal Disease

          -  Significant renal disease at Screening as manifested by:

        Glomerular filtration rate (GFR) <60mL/min (as estimated from serum creatinine at Visit 1
        and demographic data using the MDRD equation).For the MDRD equation, please refer to the
        study procedures manual.

        Proteinuria of ≥1+ by urinary dipstick

          -  Recurrent genitourinary tract infections defined as ≥2 episodes of complicated or
             uncomplicated cystitis or pyelonephritis in the 6 months prior to Screening

          -  A positive qualitative urinary dipstick for leukocytes, red blood cells (RBC) or
             nitrites at Screening.

               -  Concurrent Disease

          -  Has any concurrent condition or any clinically significant abnormality identified on
             the screening physical examination, laboratory tests (including blood electrolytes),
             electrocardiogram, including pulmonary, neurological or inflammatory diseases, which,
             in the opinion of the investigator, may affect the interpretation of efficacy and
             safety data, or which otherwise contraindicates participation in a clinical trial with
             a new chemical entity

          -  History of significant co-morbid diseases active in the 6 months prior to Screening
             (e.g., cholecystitis, acute pancreatitis, gastrointestinal disease, chronic diarrhea,
             etc.)

          -  Has a history of malignancy within the past five years [other than superficial
             squamous cell carcinoma which is non-invasive on pathology or basal cell carcinoma
             which is successfully treated with local excision] and cervical cancer in situ treated
             definitively at least 6 months prior to Screening

               -  Concurrent Medication

          -  Is currently taking or has taken any of the following medications in the 8 weeks prior
             to Screening:

               1. Digoxin

               2. Warfarin and other oral anticoagulants (aspirin and non-steroidal
                  anti-inflammatory drugs are permitted)

               3. Bile acid sequestrants

               4. Niacin (excluding routine vitamin supplementation)

               5. Antiobesity agents (including fat absorption blocking agents)

               6. Oral or injectable corticosteroids (inhaled and intranasal corticosteroids are
                  permitted)

               7. Loop diuretics

               8. Monoamine oxidase inhibitors and tricyclic amines

               9. Antiretroviral drugs

              10. St John's Wort

              11. Oral chromium

                    -  Pregnancy & Breast Feeding

          -  Is currently lactating or pregnant

               -  Other

          -  Current smoker who is unable to abstain from smoking while in the clinic at each visit

          -  Has a history of alcohol or substance abuse within the past year at Screening or
             alcohol or substance abuse during treatment, as determined by the investigator:

          -  Unwilling to refrain from the use of illicit drugs and adhere to other protocol-stated
             restrictions while participating in the study.

          -  Has an average weekly intake of greater than 21 units or an average daily intake of
             greater than 3 units (males) or an average weekly intake of greater than 14 units or
             an average daily intake of greater than 2 units (females). One unit is equivalent to a
             half-pint of beer or 1 measure of spirits or 1 glass of wine

          -  Has participated in any study with an investigational or marketed drug in the 3 months
             prior to Screening

          -  In the opinion of the investigator has a risk of non-compliance with study procedures,
             or cannot read, understand, or complete study related materials, particularly the
             informed consent

          -  Known allergy to any of the tablet excipients, or history of drug or other allergy,
             which, in the opinion of the responsible study physician