Safety and Efficacy Study of Metaglidasen in Type 2 Diabetes in Patients Suboptimally Controlled on Insulin

Type 2 Diabetes Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00353587
• Other study ID #: M102-20509
• Status: Completed
• Phase: Phase 2/Phase 3
• First received: July 14, 2006
• Last updated: April 29, 2015
• Start date: May 2006
• Est. completion date: November 2007

Study information

• Verified date: April 2015
• Source: CymaBay Therapeutics, Inc.
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 396
• Est. completion date: November 2007
• Est. primary completion date: November 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Type 2 Diabetes

Intervention

Drug:
• MBX-102
MBX-102 200 mg once daily for 16 weeks
• MBX-102
MBX-102 400 mg once daily for 16 weeks
• MBX-102
MBX-102 600 mg once daily for 16 weeks
• Placebo
MBX-102 Placebo once daily for 16 weeks
• Actos
Actos 30 mg once daily for 16 weeks

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
CymaBay Therapeutics, Inc.

Countries where clinical trial is conducted

United States,  Argentina,  India,  Israel, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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			No
Primary	Evaluate safety of MBX-102 with particular emphasis on endpoints of weight gain and edema			Yes