Clinical trial NCT00353587: Safety and Efficacy Study of Metaglidasen in Type 2 Diabetes in Patients Suboptimally Controlled on Insulin
Official title: Phase 2/3, Randomized, Double-blind, Placebo- and Active Comparator-controlled, Parallel, Multicenter Study to Determine Safety and Efficacy of Metaglidasen in Treatment of Type 2 Diabetes Suboptimally Controlled on Insulin
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Type 2 Diabetes
Keywords: insulin sensitizer
type 2 diabetes
diabetes
glucose control
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2006-07-18
Enrollment: 396
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a multicenter, randomized, double-blind, placebo- and active comparator-controlled phase 2/3 study of three dose levels of MBX-102 (200, 400, 600 mg) given orally to patients with type 2 diabetes receiving concomitant therapy with insulin. Eligible patients will be adults with type 2 diabetes who are taking intermediate- and/or long-acting insulin or pre-mixed (e.g., "70/30") insulin, or a combination of insulin and one or two non-TZD hypoglycemic agents including sulfonylurea, metformin, acrabose or Byetta, but who are poorly controlled on their existing therapy. Preference for enrollment will be given to patients on insulin monotherapy. Patients treated with a combination of insulin and other hypoglycemic agent(s) must be willing and able to discontinue and washout of the hypoglycemic agent(s) for the entire duration of the study (in toto, approximately 28 weeks). Patients who are taking fixed doses of a short-acting insulin (e.g., not a "sliding scale") in combination with intermediate-acting insulin may qualify for the study if both the patient and investigator are willing to either change to pre-mixed insulin (e.g., 70/30) or discontinue use of the short acting insulin for at least 26 weeks. Patients treated with a sliding scale of short-acting insulin will not be eligible for enrollment.

Detailed description: This is a multicenter, randomized, double-blind, placebo- and active comparator-controlled phase 2/3 study of three dose levels of MBX-102 (200, 400, 600 mg) given orally to patients with type 2 diabetes receiving concomitant therapy with insulin. Eligible patients will be adults with type 2 diabetes who are taking intermediate- and/or long-acting insulin or pre-mixed (e.g., "70/30") insulin, or a combination of insulin and one or two non-TZD hypoglycemic agents including sulfonylurea, metformin, acrabose or Byetta, but who are poorly controlled on their existing therapy. Preference for enrollment will be given to patients on insulin monotherapy. Patients treated with a combination of insulin and other hypoglycemic agent(s) must be willing and able to discontinue and washout of the hypoglycemic agent(s) for the entire duration of the study (in toto, approximately 28 weeks). Patients who are taking fixed doses of a short-acting insulin (e.g., not a "sliding scale") in combination with intermediate-acting insulin may qualify for the study if both the patient and investigator are willing to either change to pre-mixed insulin (e.g., 70/30) or discontinue use of the short acting insulin for at least 26 weeks. Patients treated with a sliding scale of short-acting insulin will not be eligible for enrollment.

Following any insulin dose adjustment during the first few weeks of the study, insulin dose and regimen should remain constant for the duration of the study.

No stand alone (e.g., other than pre-mixed) short- or ultrashort-acting insulin and/or sliding scale will be allowed for the entire duration of the study.

A minimum of 400 patients will be randomized in this study (approximately 80 to each of the five treatment arms). Additional patients may be enrolled as appropriate to replace screen failures and drop-outs during the initial period of the study.

Eligibility criteria: Inclusion Criteria:

* Type 2 diabetes (as described by the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus24) treated with insulin alone (a stable dose of long and/or intermediate-acting insulin or pre-mixed insulin e.g., "70/30") ≥ 30 units/day for at least 3 months, but poorly controlled on their existing therapy
* Or, patients treated with insulin (as above) in combination with non-TZD hypoglycemic agents (e.g., a sulfonylurea, metformin, acrabose, or Byetta for at least 3 months, but poorly controlled on their existing therapy
* Or, patients treated with fixed doses of short-acting insulin in combination with intermediate-acting insulin for at least 3 months, but poorly controlled on their existing therapy
* Patients in last 2 categories must be willing to discontinue the use of OHA and/or short-acting insulin (or change to pre-mixed insulin) for at least 26 weeks.
* Male or female, 18-75 years of age
* Provide informed consent and agree to comply with study requirements
* Current monotherapy insulin dose regimen ≥ 30 units/day (stable for 8-week Run-in/stabilization Period); or patients who need insulin dose adjustment must have a stabilized dose ≥ 30 units/day. Patients must not have taken TZDs within 5 months of screening
* All female patients must be surgically sterile, post-menopausal (at least 40 years of age with no history of menses for at least 2 years) or agree to use adequate contraception(s) that must include a barrier method (other methods may include oral contraceptives, double barrier methods, intra-uterine devices, or abstinence). Depo contraceptives are excluded
* Female patients must not be pregnant or lactating
* BMI 26-44 kg/m2
* Hemoglobin A1c must be ≥7.5%, ≤11.5% at both Screening and Visit 4
* Patients must have a FPG ≤ 220 mg/dl
* Patients must have liver function tests ≤ 2X the upper limits of normal for AST, ALT, and bilirubin, and ≤ 2.5X the upper limits of normal for ALP and GGT
* Patients must have serum creatinine ≤ 1.8 mg/dl for males and ≤ 1.5 mg/dl for females and BUN ≤ 40 mg/dl
* Fecal occult blood test must be negative
* All other clinical laboratory parameters must be within normal limits or considered not clinically significant for participation in this study, including: hematology, coagulation, other serum chemistry, and other urinalysis parameters
* TSH must be ≤ 3x ULN and patient clinically euthyroid in opinion of investigator. If TSH is \> ULN but ≤ 3x ULN, and patient is clinically euthyroid, FT4 should be drawn and must be WNL
* Electrocardiogram (ECG) must be normal, or considered not clinically significant, for participation in this study
* Patients must have a blood pressure ≤ 160/90 mm/hg including hypertensive patients controlled with medication

Exclusion Criteria:

Patients will be excluded from study participation if any of the following applies:

* History of diabetes secondary to pancreatitis or pancreatectomy
* Requirement for short-acting insulin during the study
* Weight loss \> 10 pounds in the three months prior to study
* History of TZD use (Actos or Avandia) within 5 months of Screening Visit
* History of TZD discontinuation due to side effect or lack of efficacy
* Prior history of endoscopically or radiographically documented peptic ulcer disease within last 5 years (unless patient had documented H. pylori infection with subsequent treatment and no recurrence)
* Prior history of GI bleeding within last 5 years (except for hemorrhoids or perianal disease)
* Known infection with the human immunodeficiency virus (HIV) or history of viral hepatitis type B or C
* History of congestive heart failure within last 5 years (NYHA Class III-IV)
* History of significant pulmonary disease, myocardial infarction, cerebrovascular accident, or nephrotic syndrome within last 1 year
* Elevated creatine phosphokinase (\> 2X the upper limits of normal)
* Malignancy within the last 5 years (except resected basal cell carcinoma)
* Ongoing active infection, as evidenced by symptoms such as temperature \> 38.5° C and/or clinically significant elevation in WBC count (i.e., not asymptomatic colonization)
* Change in treatment with lipid-lowering agent after screening visit
* Current or expected requirement for anticoagulant therapy \[except for low- dose (≤ 325 mg/d) aspirin\]
* Current or expected treatment with phenytoin
* Current or anticipated treatment with non-steroidal anti-inflammatory drugs (i.e., naproxen, ibuprofen, Vioxx, Celebrex, indomethacin, etc.). However, patients may take aspirin \< 325 mg/day for cardiovascular prophylaxis
* Known hypersensitivity to NSAIDs
* Treatment with any other investigational therapy within the 30 days prior to Screening Visit
* History of illicit drug or alcohol abuse within last 1 year
* Current or expected treatment with systemic corticosteroids (except topical, ophthalmic, intra-articular, or inhaled at a dose \< 1600 μg/day)
* Any other condition that compromises the ability of the patient to provide informed consent or to comply with the objectives and procedures of this protocol, as judged by the investigator.

Primary outcomes:
measure: Evaluate effects of MBX-102 administered orally at doses of 200, 400 and 600 mg daily for 16 weeks, on glucose control, as measured by HbA1c
measure: Evaluate safety of MBX-102 with particular emphasis on endpoints of weight gain and edema
Secondary outcomes:
Other outcomes:
Locations:
city: Jonesboro
country: United States
facility: NEA Clinic
state: Arkansas
city: Buena Park
country: United States
facility: Associated Pharmaceutical Research Center, Inc.
state: California
city: Los Angeles
country: United States
facility: The Intermed Group
state: California
city: Los Angeles
country: United States
facility: LAC/USC Medical Center
state: California
city: Miami
country: United States
facility: International Research Associates, LLC
state: Florida
city: Palm Harbor
country: United States
facility: Suncoast Clinical Research, Inc.
state: Florida
city: Pembroke Pines
country: United States
facility: Andres Patron DO PA
state: Florida
city: Chicago
country: United States
facility: Cedar-Crosse Research Center
state: Illinois
city: Gurnee
country: United States
facility: Clinical Investigation Specialists, Inc.
state: Illinois
city: Olive Branch
country: United States
facility: Olive Branch Research
state: Mississippi
city: Columbus
country: United States
facility: Optimed Research, LLC
state: Ohio
city: Greer
country: United States
facility: Radiant Research - Greer
state: South Carolina
city: Dallas
country: United States
facility: Dallas Diabetes & Endocrine Center
state: Texas
city: Houston
country: United States
facility: Mercury Pharma Services
state: Texas
city: Midland
country: United States
facility: Diabetes Center of the Southwest
state: Texas
city: San Antonio
country: United States
facility: Diabetes & Glandular Disease Research Associates, P.A.
state: Texas
city: Richmond
country: United States
facility: McGuire VA Medical Center
state: Virginia
city: Richmond
country: United States
facility: National Clinical Research
state: Virginia
city: Buenos Aires
country: Argentina
facility: Consultorio Integral de Atencion al Diabetico (CIAD)
city: Buenos Aires
country: Argentina
facility: CIMEL
city: Buenos Aires
country: Argentina
facility: Centro de Atencion Integral en Diabetes, Endocrinologica y Metabolismo
city: Buenos Aires
country: Argentina
facility: Fundacion CIDEA
city: Buenos Aires
country: Argentina
facility: Sanatorio Municipal Dr. Julio Mendez
city: Buenos Aires
country: Argentina
facility: Instituto Medico Especializado
city: Buenos Aires
country: Argentina
facility: Hospital Thompson
city: Buenos Aires
country: Argentina
facility: Clinica Dleta Zarate
city: Buenos Aires
country: Argentina
facility: Hospital Privado de Comunidad
city: Capital Federal
country: Argentina
facility: Consultorios Asociados de Endocrinologia
city: Cordoba
country: Argentina
facility: Instituto Latinoamericano de Investigaciones Clinicas
city: Cordoba
country: Argentina
facility: Sanatorio Parque
city: Cordoba
country: Argentina
facility: Fundacion Marcelino Rusculleda Batlle
city: Mendoza
country: Argentina
facility: Instituto de Clinica Medica y Diabetes
city: Rio Negro
country: Argentina
facility: Policlio Modelo de Cipoletti
city: Salta
country: Argentina
facility: Hospital San Bernardo
city: San Juan Capital
country: Argentina
facility: CER San Juan Centro Polivalente de Asistencia e Investigacion Clinica
city: Panjagutta, Hyderabad
country: India
facility: Nizam's Institute of Medical Sciences
state: Andhra Pradesh
city: Karnal
country: India
facility: Bharti Research Institute of Diabetes & Endocrinology
state: Haryana
city: Cochin
country: India
facility: Amrita Institute of Medical Sciences
state: Kerala
city: Attavar
country: India
facility: Kasturba Medical College Hospital
state: Mangalore
city: Ahmedabad
country: India
facility: Sterling Hospital
city: Bangalore
country: India
facility: St. John's Medical College Hospital
city: Bangalore
country: India
facility: M.S. Ramaih Medical College & Hospital
city: Bangalore
country: India
facility: Diacon Hospital
city: Chennai
country: India
facility: Sri Ramachandra Medical Centre
city: Chennai
country: India
facility: Dr. V. Seshiah Diabetes Care & Research Institute
city: Kolkata
country: India
facility: Apollo Gleneages/Dept. of Endocrinology
city: Maharashtra
country: India
facility: Diabetes Care and Research Center
city: Manipal
country: India
facility: Kasturba Hospital
city: Mumbai
country: India
facility: Chowpatty Medical Center
city: Mumbai
country: India
facility: Mediheights Healthcare Pvt. Ltd.
city: Pune
country: India
facility: KEM Hospital
city: Trivandrum
country: India
facility: Kerala Institute of Medical Sciences
city: Vellore
country: India
facility: Christian Medical College Hospital
city: Afula
country: Israel
facility: Endocrinology Institute, Haemek Medical Center
city: Ashkelon
country: Israel
facility: Barzilai Medical Center
city: BeEr-Sheva
country: Israel
facility: Soroka Medical Center
city: Haifa
country: Israel
facility: Rambam Medical Center
city: Haifa
country: Israel
facility: Linn Medical Center
city: Holon
country: Israel
facility: Wolfson Medical Center
city: Jerusalem
country: Israel
facility: Hadassah University Hospital
city: Jerusalem
country: Israel
facility: Clalit Health Services
city: Nahariya
country: Israel
facility: Institution of Diabetes and Metabolism
city: Petach Tikva
country: Israel
facility: Endocrinology & Diabetes Institute
city: Safed
country: Israel
facility: Department of Endocrinology, Ziv Medical Center
city: Tel Aviv
country: Israel
facility: Institute of Metabolic Diseases
city: Tel-Aviv
country: Israel
facility: Zamenhoff Medical Center
city: Zrifin
country: Israel
facility: Assaf Haroffe Medical Center
Study officials:
References: