| Outcome Measures: |
Primary: Number of Participants With Adverse Events (AEs), Serious Adverse Events, Death and Clinical Significant AEs During 4 Months (Period II), Adverse events are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards., 4 months (Period II)|Change From Baseline in Hemoglobin A1c (HbA1c) at Month 4 During Dose-finding Period of the Study (Period II), HbA1c was measured by National glycohemoglobin standardization program (NGSP) certified methodology. HbA1c is an integrated measure of average glucose concentration in plasma in the last 2-3 months. The analysis of covariance (ANCOVA) included treatment and metformin dose group as main effects and baseline HbA1c as a covariate., Baseline, Month 4|Change From Baseline in Dynamic Phase Secreted Insulin Per Unit of Glucose Concentration (Φd) Over 4 Months (Period III), This was planned as interim analysis and was not conducted because the study was terminated in period III., Baseline, Over Month 4 | Secondary: Change From Baseline in C-peptide Area Under Curve (AUC 0-4 Hours ) Following Meal Test (Period II), A standard liquid mixed-meal challenge was done at baseline and Month 4. Patients completed each standard meal challenge with measurement of C-peptide prior to and after a liquid mixed meal. Sampling times were -20, -10, and -1, 10, 20, 30, 60, 90, 120, 150, 180 and 240 minutes relative to start of meal. C-peptide levels over 4 hrs were shown as Area Under the Curve,(AUC). AUC was calculated as: x=1 AUC ΣAx n Where Ax = AUC for the 240 min.interval, and X = 1 for the 1st interval. The analysis of covariance included baseline C-peptide AUC 0-4 hours as a covariate., Baseline, Month 4|Change From Baseline in Prandial Plasma Glucose Area Under Curve (AUC0-4 Hours ) Following Meal Test (Period II), A standard liquid mixed-meal challenge was done at baseline and Month 4. Patients completed each standard meal challenge with measurement of glucose prior to and after a liquid mixed meal. Sampling times were -20, -10, and -1, 10, 20, 30, 60, 90, 120, 150, 180 and 240 minutes relative to the start of meal. Glucose levels over 4 hrs were shown as Area Under the Curve,(AUC). AUC was calculated as: x=1 AUC ΣAx n Where Ax = AUC for the 240 min.interval, and X = 1 for the 1st interval. The model of analysis of covariance included baseline plasma glucose AUC 0-4 hours as a covariate., Baseline, Month 4|Change From Baseline in Insulin Area Under Curve (AUC 0-4 Hours ) Following Meal Test (Period II), A standard liquid mixed-meal challenge was done at baseline and Month 4. Patients completed each standard meal challenge with measurement of insulin prior to and after a liquid mixed meal. Sampling times were -20, -10, and -1, 10, 20, 30, 60, 90, 120, 150, 180 and 240 minutes relative to the start of meal. Insulin levels over 4 hrs were shown as Area Under the Curve,(AUC). AUC was calculated as: x=1 AUC ΣAx n Where Ax = AUC for the 240 min.interval, and X = 1 for the 1st interval. Model of analysis of covariance included baseline insulin AUC 0-4 hours as covariate., Baseline, Month 4|Change From Baseline in 2-hour Glucose Level Following Meal Test (Period II), A standard liquid mixed-meal challenge was done at baseline and Month 4. Patients fasted overnight after 10 pm on day prior to scheduled visit. Study visits should occur before 10 am. Patients completed each standard meal challenge with measurement of glucose prior to and after a liquid mixed meal. The sampling times were -20, -10, and -1, 10, 20, 30, 60, 90, 120, 150, 180 and 240 minutes relative to the start of meal. The analysis of covariance included treatment and metformin dose group as main effects and baseline 2-hour glucose level as covariate., Baseline, Month 4|Change From Baseline in Peak Glucose Level Following Meal Test (Period II), A standard liquid mixed-meal challenge was done at baseline and Month 4. Patients fasted overnight after 10 pm on day prior to scheduled visit. Study visits should occur before 10 am. Patients completed each standard meal challenge with measurement of glucose prior to and after a liquid mixed meal. The sampling times were -20, -10, and -1, 10, 20, 30, 60, 90, 120, 150, 180 and 240 minutes relative to the start of meal. The analysis of covariance included treatment and metformin dose group as main effects and baseline peak glucose level as covariate., Baseline, Month 4|Change From Baseline in Peak C-peptide Following Meal Test (Period II), A standard liquid mixed-meal challenge was done at baseline and Month 4. Patients fasted overnight after 10 pm on the day prior to scheduled visit. Study visits should occur before 10 am. Patients completed each standard meal challenge with measurement of C-peptide prior to and after a liquid mixed meal. Sampling times were -20, -10, and -1, 10, 20, 30, 60, 90, 120, 150, 180 and 240 minutes relative to the start of meal. The analysis of covariance included treatment and metformin dose group as main effects and baseline peak C-peptide level as a covariate., Baseline, Month 4|Change From Baseline in Peak Insulin Level Following Meal Test (Period II), A standard liquid mixed-meal challenge was done at baseline and Month 4. Patients fasted overnight after 10 pm on day prior to scheduled visit. Study visits should occur before 10 am. Patients completed each standard meal challenge with measurement of insulin prior to and after a liquid mixed meal. The sampling times were -20, -10, and -1, 10, 20, 30, 60, 90, 120, 150, 180 and 240 minutes relative to the start of meal. The analysis of covariance included treatment and metformin dose group as main effects and baseline 2-hour insulin level as covariate., Baseline, Month 4|Change From Baseline in Insulin Secretion Rates Relative to Glucose AUC (0-2 Hours) at Month 4 Following Meal Test (Period II), Change in Insulin Secretion Rate stimulated by Liquid mixed-meal challenge. A standard liquid mixed-meal challenge was done at baseline and Month 4. Blood samples were taken prior to and after meal for glucose and insulin at sample times: -20, -10, -1 and 10, 20, 30, 60, 90, 120, 180, and 240 minutes relative to the start of the meal. The model of analysis of covariance included baseline Insulin secretion rate relative to glucose AUC at 0-2 hours as a covariate., Baseline, Month 4|Change From Baseline in 2 Hour Insulin Secretion Rate Derived Based on Glucose and C-peptide Following at Month 4 Following Meal Test (Period II), A standard liquid mixed-meal challenge was done at baseline and Month 4. A 2 hour insulin secretion rate using deconvolution was performed. The deconvolution was an algorithm that analyzed the insulin secretion rate relative to glucose and C-peptide combined. Blood samples were taken prior to and after meal at sample times: -20, -10, -1 and 10, 20, 30, 60, 90, 120, 180, and 240 minutes relative to the start of the meal. The analysis of covariance included treatment and metformin dose group as main effects and baseline 2 hour Insulin secretion rate as a covariate., Baseline, Month 4|Change From Baseline in Peak Plasma Glucose Level (7-point Glucose Testing) at Month 4(Period II), Patients were asked to check their glucose level (7 times) using their glucose meter on one of the seven days prior to the Meal Challenge Visits (Period II: baseline, Month 4. Patient was instructed to test at following timepoints: fasting before breakfast, 2 hours after starting breakfast, before lunch, 2 hours after starting lunch, before dinner, 2 hours after dinner and at bedtime. The patient documented the results in their Study Diary. The analysis of covariance included treatment and metformin dose group as main effects and baseline peak plasma glucose level as a covariate., Baseline, Month 4|Change From Baseline in Average Plasma Glucose Level (7-point Glucose Testing) at Month 4 (Period II), Patients were asked to check their glucose level (7 times) using their glucose meter on one of the seven days prior to the Meal Challenge Visits (Period II: Month 0 (Baseline), Month 4. Patient was instructed to test at following timepoints: fasting before breakfast, 2 hours after starting breakfast, before lunch, 2 hours after starting lunch, before dinner, 2 hours after dinner and at bedtime. Patient documented the results in their Study Diary. The analysis of covariance included treatment and metformin dose group as main effects and baseline average plasma glucose level as a covariate., Baseline, Month 4|Change From Baseline in Fasting Plasma Glucose at Month 4 (Period II), Change in Fasting Glucose Level measured from plasma taken at Baseline and at Month 4. The analysis of covariance included treatment and metformin dose group as main effects and baseline fasting plasma glucose level as a covariate., Baseline, Month 4|Change From Baseline in Fasting Insulin at Month 4 (Period II), Change in fasting insulin Level measured from blood samples taken at Baseline and at Month 4. The analysis of covariance included treatment and metformin dose group as main effects and baseline fasting insulin level as a covariate., Baseline, Month 4|Change From Baseline in Homeostatic Model Assessment B (HOMA2 B) Beta Cell Function (%B) at Month 4 (Period II), The homeostatic model assessment (HOMA) is a method used to quantify insulin resistance and beta (β)-cell function. HOMA2-B is a computer model that uses fasting plasma insulin and glucose concentrations to estimate steady state beta cell function (%B) as a percentage of a normal reference population (normal young adults). Time profile of postprandial glucose, insulin and C-peptide were assessed as measures of β-cell response to stimulation. The analysis of covariance included treatment and metformin dose group as main effects and baseline HOMA-B as a covariate., Baseline, Month 4|Change From Baseline in Homeostatic Model Assessment Insulin Resistance (HOMA2 IR) at Month 4 (Period II), The homeostatic model assessment (HOMA) is a method used to quantify insulin resistance and beta (β)-cell function. HOMA2-IR is a computer model that uses fasting plasma insulin and glucose concentrations to estimate insulin resistance which is the reciprocal of insulin sensitivity (%S)(100/%S)as a percentage of a normal reference population (normal young adults). The analysis of covariance included treatment and metformin dose group as main effects and baseline HOMA2 IR as a covariate., Baseline, Month 4|Change From Baseline in Quantitative Insulin Sensitivity Check Index (QUICKI) at Month 4 (Period II), The Quantitative Insulin Sensitivity Check Index (QUICKI) score, measures insulin sensitivity which is the inverse of insulin resistance. The score is calculated by the equation: 1 /(log(fasting insulin µU/mL) + log(fasting glucose mg/dL)). In normal subjects, the mean score ± SE is 0.366 ± 0.029. The analysis of covariance included treatment and metformin dose group as main effects and baseline QUICKI as a covariate., Baseline, Month 4|Change From Baseline in High-sensitivity C-reactive Protein (hsCRP) at Month 4 (Period II), The change from baseline in hsCRP (on the logarithmic scale) at Month 4 was measured for this analysis. The analysis of covariance included treatment and metformin dose group as main effects and baseline hsCRP as a covariate., Baseline, Month 4|Percentage Change From Baseline in Fasting Lipids Profile at Month 4 (Period II), The fasting lipid profiles included triglycerides, total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), calculated very low-density lipoprotein (VLDL), non-HDL cholesterol. Percentage change was measured as \[(value at month 4 - baseline value)/baseline value\]\*100%. The analysis of covariance model included treatment and metformin dose group as main effects and baseline triglycerides, total cholesterol, LDL, HDL, VLDL and non-HDL as covariates., Baseline, Month 4
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| Locations: |
Anasazi Internal Medicine, Phoenix, Arizona, United States|Whittier Institute of Diabetes, La Jolla, California, United States|Novartis Investigative Site, Los Gatos, California, United States|Novartis Investigative Site, Santa Monica, California, 90404, United States|Orange County Research Center, Tustin, California, United States|Novartis Investigative Site, Atlanta, Georgia, United States|Deaconess Clinic, Evansville, Indiana, United States|Novartis Investigative Site, Jackson, Mississippi, United States|Novartis Investigative Site, Picayune, Mississippi, United States|Novartis Investigative Site, Trenton, New Jersey, United States|Diabetes Research Center, Columbus, Ohio, United States|Tri-State Medical Group, Beaver, Pennsylvania, United States|Preferred Primary Care Physicians, Pittsburgh, Pennsylvania, United States|Novartis Investigative Site, Columbia, South Carolina, United States|R/D Clinical Research, Lake Jackson, Texas, United States|Novartis Investigative Site, Pasadena, Texas, United States|Novartis Investigative Site, San Antonio, Texas, United States|Medical Research Initiatives Inc, Virginia Beach, Virginia, United States|Clinica de Fracturas y Ortopedia, Mar del Plata, Buenos Aires, C1100ABB, Argentina|DIM Clinica Privada, Buenos Aires, B1704ETD, Argentina|Centro Medico Viamonte, Buenos Aires, C1120AAC, Argentina|Consultorios Asociados de Endocrinologia, Buenos Aires, C1425AGC, Argentina|Hospital Juan Ramon Vidal, Corrientes, W3410AVV, Argentina|Novartis Investigative Site, Rosario Santa Fe, S2000AII, Argentina|Instituto de Investigaciones Biomedicas, Santa Fe, S3000FNF, Argentina|Centro de Investigaciones Clinicas del Litoral, Santa Fe, S3000FWO, Argentina|Private Practice - DEMEULEMEESTER, Gozée, Belgium|Novartis Investigative Site, Heist-op-den-berg, Belgium|UZ Brussel, Jette, Belgium|Novartis Investigative Site, Hong Kong, China|Praxis F. Franzmann, Bad Oeynhausen, 32549, Germany|emovis GmbH, Berlin, 10629, Germany|Praxis Dr. Stütz, Bretten, 75015, Germany|GWT-TUB GmbH, Dresden, 01307, Germany|Gemeinschaftspraxis und Dialysezentrum Karlstraße, Düsseldorf, Germany|Asklepios Klinik St. Georg, Hamburg, 20099, Germany|Städt. Kankenhaus Nordstadt, Hannover, 30167, Germany|Diabeteszentrum Hohenmölsen, Hohenmölsen, 06679, Germany|Johannes Gutenberg-Universität Mainz, Mainz, 55101, Germany|Zentrum für Klinische Forschung Neuwied (ZKSN), Neuwied, 56564, Germany|Praxis Dr. Wunderer, Nürnberg, 90489, Germany|Praxis Dr. Kosch, Pirna, 01796, Germany|Praxis Dr. Alawi, Saarlouis, 66740, Germany|Praxis Dr. Klein, Schenklengsfeld, 36277, Germany|Forschungszentrum Ruhr, KliFoCenter GmbH, Witten, 58455, Germany|Fővárosi Önkormányzat Péterfy Sándor Utcai Kórház - Rendelőintézet és Baleseti Központ, Budapest, Hungary|Sandor Karolyi Hospital, Budapest, Hungary|Semmelweiss Medical University, Budapest, Hungary|Kenezy Gyula Korhaz, Debrecen, Hungary|Szegedi Egyetem, Szeged, Hungary|Zala Megyei Korhaz, Zalaegerszeg, Hungary|Gokula Metropolis Clinical Research Centre, Bangalore-, India|Bangalore Diabetes Hospital, Bangalore, India|Jnana Sanjeevini Medical Center, Bangalore, India|SAMATVAM, Bangalore, India|Madras Diabetes Reasearch Foundation, Chennai, India|Amrita Institute of Medical Sciences and Research Center, Cochin, India|Nizam's Institute of Medical Sciences, Hyderabaad, India|Diabetes Thyroid Hormone Research Institute Pvt. Ltd., Indore, India|S R Kalla Memorial Gastro & General Hospital, Jaipur, India|Pitale Diabetes & Hormone Centre, Nagpur, India|Health and Research Centre, Trivandrum, India|King George Hospital, Visakhapatnam, India|National Hospital Organization Nagoya Medical Center, Nagoya, Aichi, 460-0001, Japan|Kyushu Rosai Hospital, Kitakyushu, Fukuoka, 800-0296, Japan|NHO Yokohama Medical Center, Yokohama, Kanagawa, 245-8575, Japan|Musashikoganei Clinic, Koganei-city, Tokyo, 184-0004, Japan|Novartis Investigative Site, Minato-ku, Tokyo, Japan|Fujikoshi Hospital, Toyama-city, Toyama, 930-0964, Japan|Saiseikai Fukuoka General Hospital, Fukuoka, 810-0001, Japan|Kokura Medical Center, Kitakyusyu, Japan|Seino Internal Medicine Clinic, Koriyama, Japan|Geriatrics Research Institute Hospital, Maebashi, Japan|Takagi Hospital, Ohkawa, Japan|Sakai Hospital Kinki University School of Medicine, Sakai, Japan|Novartis Investigative Site, Pusan, 614-735, Korea, Republic of|Novartis Investigative Site, Seoul, 135-710, Korea, Republic of|Novartis Investigative Site, Seoul, 135-720, Korea, Republic of|Novartis Investigative Site, Seoul, 139-872, Korea, Republic of|Novartis Investigative Site, Suwon, 442-721, Korea, Republic of|Instituto Delgado de Investigacion Medica, Arequipa, Peru|Clinica Chiclayo, Chiclayo, Peru|Hospital Nacional Cayetano Heredia, San Martin de Porres, Peru|Centro de Investigacion Clinica Trujillo, Trujillo, Peru|Ambulatory of Institute of Nutrition Diseases and Diabetes, Bucharest, Romania|Medical Centre "Sanatatea ta", Bucuresti, Romania|Novartis Investigative Site, Bucuresti, Romania|Policlinica Dr. Citu Timisoara, Timisoara, Romania|203 Maxwell Centre, Durban, South Africa|Parklands Medical Centre, Durban, South Africa|St Augustines Medical Centre, Durban, South Africa|Synapta Clinical Research Centre, Durban, South Africa|Drs Essack and Mitha, Johannesburg, South Africa|PE Greenacres Hospital, Port Elizabeth, South Africa|26 Daffodil Street, Stanger, South Africa|Ankara Ataturk Training and Research Hospital, Ankara, Turkey|Gulhane Askeri Tip Akademisi, Ankara, Turkey|Hacettepe University Medical Faculty, Ankara, Turkey|S.B. Yildirim Beyazit Training and Research Hospital, Ankara, Turkey|Istanbul University Cardiology Institute, Istanbul, Turkey|Ege University Medical Faculty, Izmir, Turkey|Hayat Tip Merkezi (Hayat Medical Center) Deapartment of Internal Diseases, Karabuk, Turkey|Morriston Hospital, Swansea, England, SA6 6NL, United Kingdom|Birmingham Heartlands Hospital, Birmingham, United Kingdom|Royal Bournemouth Hospital, Bournemouth, United Kingdom|Rowden Medical Partnership, Wiltshire, United Kingdom
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