Clinical trial NCT00495469: Dose-Ranging Study In Subjects With Type 2 Diabetes Mellitus Who Are Treatment-Naive
Official title: A Once-Daily Dose-Ranging Study of GSK189075 Versus Placebo In The Treatment of Type 2 Diabetes Mellitus in Treatment-Naïve Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Diabetes Mellitus, Type 2
Keywords: Diabetes mellitus HbA1c
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2007-07-03
Enrollment: 250
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 to evaluate the efficacy, safety and tolerability of a range of doses of GSK189075 (an SGLT2 inhibitor) compared to placebo, administered over 12 weeks in treatment-naive subjects with type 2 diabetes mellitus


Eligibility criteria: Inclusion Criteria:

* Subjects with a documented diagnosis of T2DM and HbA1c ≥7.0% and ≤9.5% measured by the central laboratory at Visit 1.

  * Note: Subjects with HbA1c \<7.5% must have a fasting fingerstick glucose ≥7 mmol/L (126 mg/dL) at Week 0, prior to randomization.
  * Note: The proportion of subjects who are randomized with an HbA1c \<7.5% will be limited to be no more than 20% (approximately 51 subjects)
* 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 childbearing and non-childbearing and 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 who have a current documented tubal ligation, or who are surgically sterile (i.e. documented total hysterectomy or bilateral oophorectomy), or females who are post-menopausal.

All females must have a negative urine pregnancy test on the day of, and prior to randomization.

* 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 \<0.4 MIU/L (\<0.4 MCIU/mL) or \>5.5 mIU/L (\>5.5 MCIU/mL) at Screening
  * BMI of \<22 kg/m2 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 within 3 months of screening
  * Has taken insulin or any oral or injectable anti-diabetic medication ≥4 weeks at any time in the past
* Cardiovascular Disease

Recent history or presence of clinically significant acute cardiovascular disease including:

* Documented myocardial infarction in the 6 months prior to Screening.
* 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.
* Unstable angina in the 6 months prior to Screening.
* 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.
* Congestive heart failure (CHF, New York Heart Association (NYHA) Class II to IV) requiring pharmacologic treatment or the NYHA Class criteria in accordance with the local prescribing information for pioglitazone.
* 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.
* Based on local readings, the subject has an initial QTc interval (Bazett's)≥450msec at Screening, and after two additional ECGs taken 5 minutes apart, the average of the QTC interval from the three ECGs is ≥450msec.
* Other clinically significant ECG abnormalities which, in the opinion of the Investigator, may affect the interpretation of efficacy or 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 aminotransferase (ALT)
* aspartate aminotransferase (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 calculated by Quest at Visit using the Modification of Diet in Renal Disease (MDRD) equation

  •≥1+ protein on urine dipstick
* Trace or ≥1+ leukocyte esterase on urine dipstick
* Trace or ≥1+ blood on urine dipstick
* Positive nitrite on urine dipstick
* Recurrent genitourinary tract infections defined as ≥2 episodes of complicated or uncomplicated cystitis or pyelonephritis in the 6 months prior to Screening.

  * Concurrent Disease
* Has any concurrent condition or any clinically significant abnormality identified on the screening physical examination, laboratory tests (including blood electrolytes), ECG, 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.).
* History of malignancy within the past 5 years other than superficial squamous cell carcinoma (non-invasive on pathology) or basal cell carcinoma (successfully treated with local excision).
* History of 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:

* Digoxin
* Warfarin and other oral anticoagulants (aspirin and non-steroidal anti-inflammatory drugs are permitted)
* Bile acid sequestrants
* Niacin (excluding routine vitamin supplementation)
* Antiobesity agents (including fat absorption blocking agents)
* Oral or injectable corticosteroids (inhaled, topical and intranasal corticosteroids are permitted)
* Loop diuretics
* Monoamine oxidase inhibitors and tricyclic amines
* Antiretroviral drugs
* St John's Wort
* Oral chromium 9.Breast Feeding 10.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 alcohol of \>21 units or an average daily intake of \>3 units (males) or an average weekly intake of \>14 units or an average daily intake of \>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 or capsule excipients, or history of drug or other allergy, which, in the opinion of the responsible study physician, contraindicates participation.

Primary outcomes:
measure: Mean Change From Baseline in Hemoglobin A1c (Glycosylated Hemoglobin) (HbA1c) at Week 12
timeFrame: Baseline (Week 0) and at Week 12
Secondary outcomes:
measure: Mean Change From Baseline in HbA1c at Weeks 4 and 8
timeFrame: Baseline (Week 0) and at Week 4 nad 8
measure: Mean Change From Baseline to Week 12 in Fasting Plasma Glucose (FPG)
timeFrame: Baseline (Week 0) and at Week 12
measure: Mean Change From Baseline to Week 12 in Fructosamine (Corrected)
timeFrame: Baseline (Week 0) and at Week 12
measure: Number of Participants Who Were HbA1c Responders at Week 12
timeFrame: Week 12
measure: Number of Participants Who Were Fasting Plasma Glucose (FPG) Responders at Week 12
timeFrame: Week 12
measure: Mean Change From Baseline to Week 12 in Triglycerides
timeFrame: Baseline (Week 0) and at Week 12
measure: Mean Change From Baseline to Week 12 in Total Cholesterol
timeFrame: Baseline (Week 0) and at Week 12
measure: Mean Change From Baseline to Week 12 in Low Density Lipoprotein Cholesterol (LDL-c)
timeFrame: Baseline (Week 0) and Week 12
measure: Mean Change From Baseline to Week 12 in High Density Lipoprotein Cholesterol (HDL-c)
timeFrame: Baseline (Week 0) and Week 12
measure: Mean Change From Baseline to Week 12 in LDL-c/HDL-c Ratio
timeFrame: Baseline (Week 0) and Week 12
measure: Mean Change From Baseline to Week 12 in Total Cholesterol/HDL-c Ratio
timeFrame: Baseline (Week 0) and Week 12
measure: Mean Change From Baseline to Week 12 in Body Weight
timeFrame: Baseline (Week 0) and Week 12
measure: Number of Participants With Any On-therapy Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to Week 12
measure: Number of Participants With On-therapy Hypoglycemia
timeFrame: Up to Week 12
measure: Number of Participants With Vital Signs of Potential Clinical Importance (PCI) at Any Time on Therapy
timeFrame: Up to Week 12
measure: Number of Participants With Abnormal Electrocardiogram (ECG) Findings at Any Time Post-Baseline
timeFrame: Up to Week 12
measure: Number of Participants With Abnormal Chemistry Value of PCI at Any Time on Therapy
timeFrame: Up to Week 12
measure: Number of Participants With Abnormal Hematology Value of PCI at Any Time on Therapy
timeFrame: Up to Week 12
Other outcomes:
Locations:
city: Mesa
country: United States
facility: GSK Investigational Site
state: Arizona
city: Artesia
country: United States
facility: GSK Investigational Site
state: California
city: Buena Park
country: United States
facility: GSK Investigational Site
state: California
city: Fresno
country: United States
facility: GSK Investigational Site
state: California
city: Greenbrae
country: United States
facility: GSK Investigational Site
state: California
city: La Jolla
country: United States
facility: GSK Investigational Site
state: California
city: Norwalk
country: United States
facility: GSK Investigational Site
state: California
city: Petaluma
country: United States
facility: GSK Investigational Site
state: California
city: Sacramento
country: United States
facility: GSK Investigational Site
state: California
city: San Mateo
country: United States
facility: GSK Investigational Site
state: California
city: Santa Ana
country: United States
facility: GSK Investigational Site
state: California
city: Tarzana
country: United States
facility: GSK Investigational Site
state: California
city: Torrance
country: United States
facility: GSK Investigational Site
state: California
city: Deland/Florida
country: United States
facility: GSK Investigational Site
state: Florida
city: Hollywood
country: United States
facility: GSK Investigational Site
state: Florida
city: Jacksonville/Florida
country: United States
facility: GSK Investigational Site
state: Florida
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Ocoee/Florida
country: United States
facility: GSK Investigational Site
state: Florida
city: Saint Cloud
country: United States
facility: GSK Investigational Site
state: Florida
city: Atlanta
country: United States
facility: GSK Investigational Site
state: Georgia
city: Atlanta
country: United States
facility: GSK Investigational Site
state: Georgia
city: Bloomingdale
country: United States
facility: GSK Investigational Site
state: Illinois
city: Chicago
country: United States
facility: GSK Investigational Site
state: Illinois
city: Oak Brook
country: United States
facility: GSK Investigational Site
state: Illinois
city: South Bend
country: United States
facility: GSK Investigational Site
state: Indiana
city: Lafayette
country: United States
facility: GSK Investigational Site
state: Louisiana
city: Lake Charles
country: United States
facility: GSK Investigational Site
state: Louisiana
city: Oxon Hill
country: United States
facility: GSK Investigational Site
state: Maryland
city: Boston
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Gulfport
country: United States
facility: GSK Investigational Site
state: Mississippi
city: Jackson
country: United States
facility: GSK Investigational Site
state: Mississippi
city: Kosciusko
country: United States
facility: GSK Investigational Site
state: Mississippi
city: Rolling Fork
country: United States
facility: GSK Investigational Site
state: Mississippi
city: Chesterfield
country: United States
facility: GSK Investigational Site
state: Missouri
city: St. Louis/Missouri
country: United States
facility: GSK Investigational Site
state: Missouri
city: Henderson
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: Las Vegas
country: United States
facility: GSK Investigational Site
state: Nevada
city: Las Vegas
country: United States
facility: GSK Investigational Site
state: Nevada
city: Clifton
country: United States
facility: GSK Investigational Site
state: New Jersey
city: Albuquerque
country: United States
facility: GSK Investigational Site
state: New Mexico
city: Commack
country: United States
facility: GSK Investigational Site
state: New York
city: Ithaca
country: United States
facility: GSK Investigational Site
state: New York
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: Asheboro/North Carolina
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Canal Fulton
country: United States
facility: GSK Investigational Site
state: Ohio
city: Bensalem/Pennsylvania
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: West Chester
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Manning
country: United States
facility: GSK Investigational Site
state: South Carolina
city: Simpsonville
country: United States
facility: GSK Investigational Site
state: South Carolina
city: Athens/Tennessee
country: United States
facility: GSK Investigational Site
state: Tennessee
city: Corpus Christi
country: United States
facility: GSK Investigational Site
state: Texas
city: Dallas
country: United States
facility: GSK Investigational Site
state: Texas
city: Dallas
country: United States
facility: GSK Investigational Site
state: Texas
city: Harlingen/Texas
country: United States
facility: GSK Investigational Site
state: Texas
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: Midland
country: United States
facility: GSK Investigational Site
state: Texas
city: San Anonio
country: United States
facility: GSK Investigational Site
state: Texas
city: San Antonio
country: United States
facility: GSK Investigational Site
state: Texas
city: Burke
country: United States
facility: GSK Investigational Site
state: Virginia
city: Bellevue
country: United States
facility: GSK Investigational Site
state: Washington
city: Langley
country: Canada
facility: GSK Investigational Site
state: British Columbia
city: Bathurst
country: Canada
facility: GSK Investigational Site
state: New Brunswick
city: Bay Roberts
country: Canada
facility: GSK Investigational Site
state: Newfoundland and Labrador
city: Brampton
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Mississauga
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Oakville
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Ottawa
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Thornhill
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: L'ancienne-Lorette
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Québec
country: Canada
facility: GSK Investigational Site
city: Brno
country: Czechia
facility: GSK Investigational Site
city: Brno
country: Czechia
facility: GSK Investigational Site
city: Praha 10
country: Czechia
facility: GSK Investigational Site
city: Praha 5
country: Czechia
facility: GSK Investigational Site
city: Parnu
country: Estonia
facility: GSK Investigational Site
city: Tallinn
country: Estonia
facility: GSK Investigational Site
city: Tallin
country: Estonia
facility: GSK Investigational Site
city: Tartu
country: Estonia
facility: GSK Investigational Site
city: Allmendingen
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Wangen
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Grossheirath
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Hohenau
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Kuenzing
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Muenchen
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Muenchen
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Parsberg
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Ruhmannsfelden
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Sulzbach-Rosenberg
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Falkensee
country: Germany
facility: GSK Investigational Site
state: Brandenburg
city: Brinkum/Stuhr
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Einbeck
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Hannover
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Lueneburg
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Tostedt
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Hassloch
country: Germany
facility: GSK Investigational Site
state: Rheinland-Pfalz
city: Ingelheim
country: Germany
facility: GSK Investigational Site
state: Rheinland-Pfalz
city: Wolmirstedt
country: Germany
facility: GSK Investigational Site
state: Sachsen-Anhalt
city: Dresden
country: Germany
facility: GSK Investigational Site
state: Sachsen
city: Freital
country: Germany
facility: GSK Investigational Site
state: Sachsen
city: Schmiedeberg
country: Germany
facility: GSK Investigational Site
state: Sachsen
city: Luebeck
country: Germany
facility: GSK Investigational Site
state: Schleswig-Holstein
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Athens
country: Greece
facility: GSK Investigational Site
city: Athens
country: Greece
facility: GSK Investigational Site
city: Thessaloniki,
country: Greece
facility: GSK Investigational Site
city: Thessaloniki
country: Greece
facility: GSK Investigational Site
city: Bangalore
country: India
facility: GSK Investigational Site
city: Bangalore
country: India
facility: GSK Investigational Site
city: Chennai
country: India
facility: GSK Investigational Site
city: Mumbai
country: India
facility: GSK Investigational Site
city: Pune
country: India
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: Guadalajara
country: Mexico
facility: GSK Investigational Site
state: Jalisco
city: Cuernavaca
country: Mexico
facility: GSK Investigational Site
state: Morelos
city: Mérida
country: Mexico
facility: GSK Investigational Site
state: Yucatán
city: Durango
country: Mexico
facility: GSK Investigational Site
city: Rotorua
country: New Zealand
facility: GSK Investigational Site
city: Bydgoszcz
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: Aibonito/Puerto Rico
country: Puerto Rico
facility: GSK Investigational Site
city: Caguas
country: Puerto Rico
facility: GSK Investigational Site
city: Carolina
country: Puerto Rico
facility: GSK Investigational Site
city: Ponce
country: Puerto Rico
facility: GSK Investigational Site
city: Rio Piedras
country: Puerto Rico
facility: GSK Investigational Site
city: Trujillo Alto/Puerto Rico
country: Puerto Rico
facility: GSK Investigational Site
city: Arad
country: Romania
facility: GSK Investigational Site
city: Brasov
country: Romania
facility: GSK Investigational Site
city: Sfantu Gheorghe
country: Romania
facility: GSK Investigational Site
city: Timisoara
country: Romania
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Saint-Peterburgh
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: Lenasia South
country: South Africa
facility: GSK Investigational Site
state: Gauteng
city: Bellville
country: South Africa
facility: GSK Investigational Site
city: Gauteng
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
city: Dnipropetrovsk
country: Ukraine
facility: GSK Investigational Site
city: Kyiv
country: Ukraine
facility: GSK Investigational Site
city: Vinnitsa
country: Ukraine
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Sykes AP, Kemp GL, Dobbins R, O'Connor-Semmes R, Almond SR, Wilkison WO, Walker S, Kler L. Randomized efficacy and safety trial of once-daily remogliflozin etabonate for the treatment of type 2 diabetes. Diabetes Obes Metab. 2015 Jan;17(1):98-101. doi: 10.1111/dom.12393. Epub 2014 Nov 3.