Clinical trial NCT00500331: Dose-Ranging Study in Treatment Naive Type 2 Diabetes Mellitus(T2DM)
Official title: A Double-blind, Randomized 12-week Study to Evaluate the Safety and Efficacy of GSK189075 Tablets vs Pioglitazone in Treatment Naive Subjects With Type 2 Diabetes Mellitus
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Diabetes Mellitus, Type 2
Keywords: Pioglitazone
HbA1c
Diabetes mellitus
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2007-07-12
Enrollment: 334
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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

Primary outcomes:
measure: Change From Baseline (Week 0) in Glycosylated Hemoglobin (HbA1c) (%) at Week 12
timeFrame: Baseline (Week 0) and Week 12
Secondary outcomes:
measure: Change From Baseline in HbA1c (%) at Weeks 4 and 8
timeFrame: Baseline (Week 0) and Week 4 and Week 8
measure: Change From Baseline to Week 12 in Fasting Plasma Glucose (FPG) at Weeks 4, 8 and 12
timeFrame: Baseline (Week 0) and Week 4, Week 8 and Week 12
measure: Change From Baseline to Week 12 in Fructosamine
timeFrame: Baseline (Week 0) to Week 12
measure: Change From Baseline to Week 12 in Fasting Insulin
timeFrame: Baseline (Week 0) to Week 12
measure: Number of Participants at Week 12 With: HbA1c <= 6.5%, HbA1c <7.0%; FPG <7 Mmo/L, FPG <7.8 mmol/L; FPG <5.5 mmol/L; a Decrease From Baseline of HbA1c >= 0.7%; a Decrease From Baseline of FPG ≥1.7 mmol/L
timeFrame: Week 12
measure: Percent Change From Baseline in Lipid Parameters at Weeks 4, 8 and 12(Triglycerides [TG], Total Cholesterol [TC], Low-density Lipoprotein Cholesterol [LDL-C] and High-density Lipoprotein Cholesterol [HDL-C])
timeFrame: Baseline (Week 0) and Week 4, Week 8 and Week 12
measure: Change From Baseline to Week 12 in Body Weight
timeFrame: Baseline (Week 0) to Week 12
measure: Change From Baseline to Week 12 in Waist Circumference
timeFrame: Baseline (Week 0) to Week 12
measure: Change From Baseline in 24-hour Percent of Filtered Glucose Excreted in Urine
timeFrame: Baseline (Week 0) and Week 12 (24-hour urine collection)
measure: Change From Baseline in Plasma Glucose Area Under the Curve (AUC) During a 2-hour Oral Glucose Tolerance Test (OGTT)
timeFrame: Baseline (Week 0) and Week 12 (0 to 2 hour OGTT)
measure: Change From Baseline in Insulin AUC During a 2-hour OGTT
timeFrame: Baseline (Week 0) and Week 12 (0 to 2-hour OGTT)
measure: Change From Baseline in C-peptide AUC During a 2-hr OGTT
timeFrame: Baseline (Week 0) and Week 12 (0 to 2 hour OGTT)
measure: Number of Participants With On-therapy Adverse Events (AE) and Serious Adverse Events (SAE)
timeFrame: Up to 12 weeks
measure: Number of Participants With On-therapy Hypoglycemia
timeFrame: Up to 14 weeks
measure: Number of Participants With Change From Baseline Vital Signs of Potential Clinical Concern
timeFrame: Up to 14 weeks
measure: Number of Participants With Electrocardiogram (ECG) Values of Potential Clinical Concern
timeFrame: Up to Early withdrawal (Between Week 12 and Week 14)
measure: Number of Participants With Change From Baseline in Standard Laboratory Parameters of Potential Clinical Concern
timeFrame: Up to 14 weeks
Other outcomes:
Locations:
city: Mesa
country: United States
facility: GSK Investigational Site
state: Arizona
city: Hollywood
country: United States
facility: GSK Investigational Site
state: Florida
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Saint Cloud
country: United States
facility: GSK Investigational Site
state: Florida
city: Sunset
country: United States
facility: GSK Investigational Site
state: Louisiana
city: Oxon Hill
country: United States
facility: GSK Investigational Site
state: Maryland
city: Las Vegas
country: United States
facility: GSK Investigational Site
state: Nevada
city: Las Vegas
country: United States
facility: GSK Investigational Site
state: Nevada
city: Las Vegas
country: United States
facility: GSK Investigational Site
state: Nevada
city: Albuquerque
country: United States
facility: GSK Investigational Site
state: New Mexico
city: Canal Fulton
country: United States
facility: GSK Investigational Site
state: Ohio
city: Simpsonville
country: United States
facility: GSK Investigational Site
state: South Carolina
city: San Antonio
country: United States
facility: GSK Investigational Site
state: Texas
city: Burke
country: United States
facility: GSK Investigational Site
state: Virginia
city: Buenos Aries
country: Argentina
facility: GSK Investigational Site
state: Buenos Aires
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: GSK Investigational Site
state: Buenos Aires
city: Ciudad Autónoma de Buenos Aires
country: Argentina
facility: GSK Investigational Site
state: Buenos Aires
city: Cordoba
country: Argentina
facility: GSK Investigational Site
state: Córdova
city: Buenos Aires
country: Argentina
facility: GSK Investigational Site
city: Cordoba
country: Argentina
facility: GSK Investigational Site
city: Mendoza
country: Argentina
facility: GSK Investigational Site
city: Quilmes
country: Argentina
facility: GSK Investigational Site
city: Tucuman
country: Argentina
facility: GSK Investigational Site
city: Pleven
country: Bulgaria
facility: GSK Investigational Site
city: Plovdiv
country: Bulgaria
facility: GSK Investigational Site
city: Sofia
country: Bulgaria
facility: GSK Investigational Site
city: Sofia
country: Bulgaria
facility: GSK Investigational Site
city: Varna
country: Bulgaria
facility: GSK Investigational Site
city: Santiago
country: Chile
facility: GSK Investigational Site
state: Región Metro De Santiago
city: Santiago
country: Chile
facility: GSK Investigational Site
state: Región Metro De Santiago
city: San José
country: Costa Rica
facility: GSK Investigational Site
city: Brno
country: Czechia
facility: GSK Investigational Site
city: Brno
country: Czechia
facility: GSK Investigational Site
city: Brno
country: Czechia
facility: GSK Investigational Site
city: Ceske Budejovice
country: Czechia
facility: GSK Investigational Site
city: Cheb
country: Czechia
facility: GSK Investigational Site
city: Havirov - Soumbrak
country: Czechia
facility: GSK Investigational Site
city: Olomouc
country: Czechia
facility: GSK Investigational Site
city: Prague
country: Czechia
facility: GSK Investigational Site
city: Praha 5
country: Czechia
facility: GSK Investigational Site
city: Praha 5
country: Czechia
facility: GSK Investigational Site
city: Praha 5
country: Czechia
facility: GSK Investigational Site
city: Semily
country: Czechia
facility: GSK Investigational Site
city: Sumperk
country: Czechia
facility: GSK Investigational Site
city: Usti nad Labem
country: Czechia
facility: GSK Investigational Site
city: Znojmo
country: Czechia
facility: GSK Investigational Site
city: Bammental
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Kippenheim
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Mannheim
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Weinheim
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Haag
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Hoehenkirchen-Siegertsbrunn
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Lampertheim
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Damme
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Hannover
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Hildesheim
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Bergkamen
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Mainz
country: Germany
facility: GSK Investigational Site
state: Rheinland-Pfalz
city: Rhaunen
country: Germany
facility: GSK Investigational Site
state: Rheinland-Pfalz
city: Speyer
country: Germany
facility: GSK Investigational Site
state: Rheinland-Pfalz
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Budapest
country: Hungary
facility: GSK Investigational Site
city: Budapest
country: Hungary
facility: GSK Investigational Site
city: Budapest
country: Hungary
facility: GSK Investigational Site
city: Budapest
country: Hungary
facility: GSK Investigational Site
city: Debrecen
country: Hungary
facility: GSK Investigational Site
city: Erd
country: Hungary
facility: GSK Investigational Site
city: Győr
country: Hungary
facility: GSK Investigational Site
city: Miskolc
country: Hungary
facility: GSK Investigational Site
city: Miskolc
country: Hungary
facility: GSK Investigational Site
city: Mosonmagyaróvár
country: Hungary
facility: GSK Investigational Site
city: Nyirtegyhaza
country: Hungary
facility: GSK Investigational Site
city: Pécs
country: Hungary
facility: GSK Investigational Site
city: Szentes
country: Hungary
facility: GSK Investigational Site
city: Szigetvar
country: Hungary
facility: GSK Investigational Site
city: Szombathely
country: Hungary
facility: GSK Investigational Site
city: Veszprem
country: Hungary
facility: GSK Investigational Site
city: Zalaegerszeg
country: Hungary
facility: GSK Investigational Site
city: Bangalore
country: India
facility: GSK Investigational Site
city: Bangalore
country: India
facility: GSK Investigational Site
city: Bangalore
country: India
facility: GSK Investigational Site
city: Kochi
country: India
facility: GSK Investigational Site
city: Mumbai
country: India
facility: GSK Investigational Site
city: New Delhi
country: India
facility: GSK Investigational Site
city: Pune
country: India
facility: GSK Investigational Site
city: Jelgava
country: Latvia
facility: GSK Investigational Site
city: Limbazi
country: Latvia
facility: GSK Investigational Site
city: Riga
country: Latvia
facility: GSK Investigational Site
city: Riga
country: Latvia
facility: GSK Investigational Site
city: Riga
country: Latvia
facility: GSK Investigational Site
city: Riga
country: Latvia
facility: GSK Investigational Site
city: Riga
country: Latvia
facility: GSK Investigational Site
city: Talsi
country: Latvia
facility: GSK Investigational Site
city: Tukums
country: Latvia
facility: GSK Investigational Site
city: Kaunas
country: Lithuania
facility: GSK Investigational Site
city: Kaunas
country: Lithuania
facility: GSK Investigational Site
city: Kaunas
country: Lithuania
facility: GSK Investigational Site
city: Vilnius
country: Lithuania
facility: GSK Investigational Site
city: Vilnius
country: Lithuania
facility: GSK Investigational Site
city: Tijuana
country: Mexico
facility: GSK Investigational Site
state: Baja California Norte
city: Mexico City
country: Mexico
facility: GSK Investigational Site
state: Estado De México
city: Monterrey
country: Mexico
facility: GSK Investigational Site
state: Nuevo León
city: Durango
country: Mexico
facility: GSK Investigational Site
city: Mexico
country: Mexico
facility: GSK Investigational Site
city: Mexico
country: Mexico
facility: GSK Investigational Site
city: Auckland
country: New Zealand
facility: GSK Investigational Site
city: Auckland
country: New Zealand
facility: GSK Investigational Site
city: Hamilton
country: New Zealand
facility: GSK Investigational Site
city: Rotorua
country: New Zealand
facility: GSK Investigational Site
city: Lima
country: Peru
facility: GSK Investigational Site
city: Lima
country: Peru
facility: GSK Investigational Site
city: Bydgoszcz
country: Poland
facility: GSK Investigational Site
city: Grudziadz
country: Poland
facility: GSK Investigational Site
city: Lodz
country: Poland
facility: GSK Investigational Site
city: Porabka
country: Poland
facility: GSK Investigational Site
city: Siemianowice Slaskie
country: Poland
facility: GSK Investigational Site
city: Wroclaw
country: Poland
facility: GSK Investigational Site
city: Ponce
country: Puerto Rico
facility: GSK Investigational Site
city: Brasov
country: Romania
facility: GSK Investigational Site
city: Bucharest
country: Romania
facility: GSK Investigational Site
city: Deva
country: Romania
facility: GSK Investigational Site
city: Iasi
country: Romania
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: St. Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: St.-Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Tomsk
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: Bellville
country: South Africa
facility: GSK Investigational Site
city: Gauteng
country: South Africa
facility: GSK Investigational Site
city: Orangegrove, Linksfield West
country: South Africa
facility: GSK Investigational Site
city: Parow
country: South Africa
facility: GSK Investigational Site
city: Roodepoort
country: South Africa
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Sykes AP, O'Connor-Semmes R, Dobbins R, Dorey DJ, Lorimer JD, Walker S, Wilkison WO, Kler L. Randomized trial showing efficacy and safety of twice-daily remogliflozin etabonate for the treatment of type 2 diabetes. Diabetes Obes Metab. 2015 Jan;17(1):94-7. doi: 10.1111/dom.12391. Epub 2014 Nov 3.