Dose Finding, Safety and Efficacy of Monthly Subcutaneous Canakinumab Administration in Metformin Monotherapy Treated Type 2 Diabetic Patients
- Conditions
- Diabetes Mellitus, Type 2
- Interventions
- Registration Number
- NCT00900146
- Lead Sponsor
- Novartis
- Brief Summary
This was a four month dose ranging study followed by a 24 to 48 month extension at the selected dose to characterize the safety and efficacy of the injectable IL-1B (interleukin 1, beta) antagonist canakinumab in the treatment of patients with Type 2 diabetes mellitus (T2DM) already treated on maximum dose metformin.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 556
-
Patients must have a documented diagnosis of Type 2 diabetes confirmed by World Health Organization (WHO) criteria either a FPG≥ 7.0 mmol/l (126 mg/dl) or an Oral glucose tolerance test (OGTT) test 2-hour PG ≥ 11.1 mmol/l (200 mg/dl).
-
Patients must:
- be naïve to anti-diabetes drug therapy (except for short term treatment courses with insulin in connection with hospitalization, etc.)
- meet protocol specified Glycosylated hemoglobin / hemoglobin A1c (HbA1c) criteria
- be eligible for metformin monotherapy OR
- be on stable metformin monotherapy treatment for at least three months at Screening
- meet protocol specified HbA1c criteria
- take metformin as their first and only treatment with anti-diabetes drug therapy OR
- be taking an AGI as their first and only anti-diabetes drug therapy (except short term treatment courses with insulin in connection with hospitalizations, etc)
- meet protocol specified HbA1c criteria
- be eligible for metformin monotherapy
-
Patients must have a morning fasting plasma glucose result < 180 mg/dl at Visit 3 (Month -1) analyzed by the Central Laboratory.
-
Were on a daily dose of metformin ≥ 1000 mg (or less according to local regulations)
-
Type 1 diabetes, diabetes resulting from pancreatic injury or secondary forms of diabetes.
-
Any of the following significant laboratory abnormalities:
- Serum Glutamic acid decarboxylase (GAD)-antibody positivity
- Clinically significant Thyroid stimulating hormone (TSH) outside of normal range at Screening
- Renal function indicating high risk metformin use, including serum creatinine concentrations (≥1.5 mg/dL for males, ≥1.4 mg/dL for females) or other evidence of abnormal creatinine clearance.
- Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 2 x upper limit of normal (ULN), or total bilirubin > 2 x ULN and/or direct bilirubin > ULN at Screening, confirmed with repeat measure within one week.
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History or current findings of active pulmonary disease as evidenced by a history of positive purified protein derivative (PPD), QuantiFERON-TB Gold (QFT-G), AFB sputum or positive PPD followed by positive chest x-ray or QFT-G, or ongoing antibiotic treatment for latent TB.
-
Risk factors for TB as defined in protocol
-
Known presence or suspicion of active or recurrent bacterial, fungal or viral infection at the time of enrollment proven or suspected to be related to immunocompromise including HIV or active or recurrent Hepatitis B and Hepatitis C.
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Systemic or local treatment of any immune modulating agent in doses with systemic effects or live vaccinations within 3 months
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Stroke, myocardial infarction, acute coronary syndrome, revascularization procedure or recurrent TIA within the last 6 months.
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Unwillingness to use insulin glargine as the additional medication should glycemic control deteriorate.
Other protocol-defined inclusion/exclusion criteria may apply
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo + Metformin Placebo In 4 month dose finding period as well as during intermediate period, patients received one injection of canakinumab matching placebo monthly and continued on a stable dose of metformin ≥ 1000 mg daily (or lower dose if required by local regulations). Canakinumab 5 mg + Metformin Canakinumab In 4-Month Dose-finding period, patients visited the clinic monthly and had 5 mg Canakinumab injected in the clinic at each visit and continued on a stable dose of metformin ≥ 1000 mg daily (or lower dose if required by local regulations). During this period, patients with consecutive morning fasting glucose \>200 mg/dL were treated with a daily injection of insulin glargine as add-on therapy. The intermediate period began after patients completed their 4-month visit and lasted until the primary analysis was completed and the optimal dose was selected. Patients continued on their randomized treatment and made brief visits to the clinic every month. From this point onward, patients with consecutive HbA1c \>7.5% were treated with a daily injection of insulin glargine as add-on therapy. Canakinumab 5 mg + Metformin Metformin In 4-Month Dose-finding period, patients visited the clinic monthly and had 5 mg Canakinumab injected in the clinic at each visit and continued on a stable dose of metformin ≥ 1000 mg daily (or lower dose if required by local regulations). During this period, patients with consecutive morning fasting glucose \>200 mg/dL were treated with a daily injection of insulin glargine as add-on therapy. The intermediate period began after patients completed their 4-month visit and lasted until the primary analysis was completed and the optimal dose was selected. Patients continued on their randomized treatment and made brief visits to the clinic every month. From this point onward, patients with consecutive HbA1c \>7.5% were treated with a daily injection of insulin glargine as add-on therapy. Canakinumab 15 mg + Metformin Canakinumab In 4-Month Dose-finding period, patients visited the clinic monthly and had 15 mg Canakinumab injected in the clinic at each visit and continued on a stable dose of metformin ≥ 1000 mg daily (or lower dose if required by local regulations). During this period, patients with consecutive morning fasting glucose \>200 mg/dL were treated with a daily injection of insulin glargine as add-on therapy. The intermediate period began after patients completed their 4-month visit and lasted until the primary analysis was completed and the optimal dose was selected. Patients continued on their randomized treatment and made brief visits to the clinic every month. From this point onward, patients with consecutive HbA1c \>7.5% were treated with a daily injection of insulin glargine as add-on therapy. Canakinumab 15 mg + Metformin Metformin In 4-Month Dose-finding period, patients visited the clinic monthly and had 15 mg Canakinumab injected in the clinic at each visit and continued on a stable dose of metformin ≥ 1000 mg daily (or lower dose if required by local regulations). During this period, patients with consecutive morning fasting glucose \>200 mg/dL were treated with a daily injection of insulin glargine as add-on therapy. The intermediate period began after patients completed their 4-month visit and lasted until the primary analysis was completed and the optimal dose was selected. Patients continued on their randomized treatment and made brief visits to the clinic every month. From this point onward, patients with consecutive HbA1c \>7.5% were treated with a daily injection of insulin glargine as add-on therapy. Canakinumab 50 mg + Metformin Canakinumab In 4-Month Dose-finding period, patients visited the clinic monthly and had 50 mg Canakinumab injected in the clinic at each visit and continued on a stable dose of metformin ≥ 1000 mg daily (or lower dose if required by local regulations). During this period, patients with consecutive morning fasting glucose \>200 mg/dL were treated with a daily injection of insulin glargine as add-on therapy. The intermediate period began after patients completed their 4-month visit and lasted until the primary analysis was completed and the optimal dose was selected. Patients continued on their randomized treatment and made brief visits to the clinic every month. From this point onward, patients with consecutive HbA1c \>7.5% were treated with a daily injection of insulin glargine as add-on therapy. Canakinumab 50 mg + Metformin Metformin In 4-Month Dose-finding period, patients visited the clinic monthly and had 50 mg Canakinumab injected in the clinic at each visit and continued on a stable dose of metformin ≥ 1000 mg daily (or lower dose if required by local regulations). During this period, patients with consecutive morning fasting glucose \>200 mg/dL were treated with a daily injection of insulin glargine as add-on therapy. The intermediate period began after patients completed their 4-month visit and lasted until the primary analysis was completed and the optimal dose was selected. Patients continued on their randomized treatment and made brief visits to the clinic every month. From this point onward, patients with consecutive HbA1c \>7.5% were treated with a daily injection of insulin glargine as add-on therapy. Canakinumab 150 mg + Metformin Canakinumab In 4-Month Dose-finding period, patients visited the clinic monthly and had 150 mg Canakinumab injected in the clinic at each visit and continued on a stable dose of metformin ≥ 1000 mg daily (or lower dose if required by local regulations). During this period, patients with consecutive morning fasting glucose \>200 mg/dL were treated with a daily injection of insulin glargine as add-on therapy. The intermediate period began after patients completed their 4-month visit and lasted until the primary analysis was completed and the optimal dose was selected. Patients continued on their randomized treatment and made brief visits to the clinic every month. From this point onward, patients with consecutive HbA1c \>7.5% were treated with a daily injection of insulin glargine as add-on therapy. Canakinumab 150 mg + Metformin Metformin In 4-Month Dose-finding period, patients visited the clinic monthly and had 150 mg Canakinumab injected in the clinic at each visit and continued on a stable dose of metformin ≥ 1000 mg daily (or lower dose if required by local regulations). During this period, patients with consecutive morning fasting glucose \>200 mg/dL were treated with a daily injection of insulin glargine as add-on therapy. The intermediate period began after patients completed their 4-month visit and lasted until the primary analysis was completed and the optimal dose was selected. Patients continued on their randomized treatment and made brief visits to the clinic every month. From this point onward, patients with consecutive HbA1c \>7.5% were treated with a daily injection of insulin glargine as add-on therapy. Placebo + Metformin Metformin In 4 month dose finding period as well as during intermediate period, patients received one injection of canakinumab matching placebo monthly and continued on a stable dose of metformin ≥ 1000 mg daily (or lower dose if required by local regulations).
- Primary Outcome Measures
Name Time Method Number of Participants With Adverse Events (AEs), Serious Adverse Events, Death and Clinical Significant AEs During 4 Months (Period II) 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.
Change From Baseline in Hemoglobin A1c (HbA1c) at Month 4 During Dose-finding Period of the Study (Period II) Baseline, Month 4 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.
Change From Baseline in Dynamic Phase Secreted Insulin Per Unit of Glucose Concentration (Φd) Over 4 Months (Period III) Baseline, Over Month 4 This was planned as interim analysis and was not conducted because the study was terminated in period III.
- Secondary Outcome Measures
Name Time Method Change From Baseline in C-peptide Area Under Curve (AUC 0-4 Hours ) Following Meal Test (Period II) Baseline, Month 4 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.
Change From Baseline in Prandial Plasma Glucose Area Under Curve (AUC0-4 Hours ) Following Meal Test (Period II) Baseline, Month 4 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.
Change From Baseline in Insulin Area Under Curve (AUC 0-4 Hours ) Following Meal Test (Period II) Baseline, Month 4 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.
Change From Baseline in 2-hour Glucose Level Following Meal Test (Period II) Baseline, Month 4 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.
Change From Baseline in Peak Glucose Level Following Meal Test (Period II) Baseline, Month 4 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.
Change From Baseline in Peak C-peptide Following Meal Test (Period II) Baseline, Month 4 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.
Change From Baseline in Peak Insulin Level Following Meal Test (Period II) Baseline, Month 4 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.
Change From Baseline in Insulin Secretion Rates Relative to Glucose AUC (0-2 Hours) at Month 4 Following Meal Test (Period II) Baseline, Month 4 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.
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) Baseline, Month 4 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.
Change From Baseline in Peak Plasma Glucose Level (7-point Glucose Testing) at Month 4(Period II) Baseline, Month 4 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.
Change From Baseline in Average Plasma Glucose Level (7-point Glucose Testing) at Month 4 (Period II) Baseline, Month 4 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.
Change From Baseline in Fasting Plasma Glucose at Month 4 (Period II) Baseline, Month 4 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.
Change From Baseline in Fasting Insulin at Month 4 (Period II) Baseline, Month 4 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.
Change From Baseline in Homeostatic Model Assessment B (HOMA2 B) Beta Cell Function (%B) at Month 4 (Period II) Baseline, Month 4 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.
Change From Baseline in Homeostatic Model Assessment Insulin Resistance (HOMA2 IR) at Month 4 (Period II) Baseline, Month 4 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.
Change From Baseline in Quantitative Insulin Sensitivity Check Index (QUICKI) at Month 4 (Period II) Baseline, Month 4 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.
Change From Baseline in High-sensitivity C-reactive Protein (hsCRP) at Month 4 (Period II) Baseline, Month 4 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.
Percentage Change From Baseline in Fasting Lipids Profile at Month 4 (Period II) Baseline, Month 4 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.
Trial Locations
- Locations (88)
Centro de Investigaciones Clinicas del Litoral
🇦🇷Santa Fe, Argentina
Clinica Chiclayo
🇵🇪Chiclayo, Peru
King George Hospital
🇮🇳Visakhapatnam, India
Hospital Nacional Cayetano Heredia
🇵🇪San Martin de Porres, Peru
Fővárosi Önkormányzat Péterfy Sándor Utcai Kórház - Rendelőintézet és Baleseti Központ
🇭🇺Budapest, Hungary
Amrita Institute of Medical Sciences and Research Center
🇮🇳Cochin, India
Nizam's Institute of Medical Sciences
🇮🇳Hyderabaad, India
Praxis Dr. Wunderer
🇩🇪Nürnberg, Germany
DIM Clinica Privada
🇦🇷Buenos Aires, Argentina
St Augustines Medical Centre
🇿🇦Durban, South Africa
Seino Internal Medicine Clinic
🇯🇵Koriyama, Japan
Takagi Hospital
🇯🇵Ohkawa, Japan
Birmingham Heartlands Hospital
🇬🇧Birmingham, United Kingdom
Royal Bournemouth Hospital
🇬🇧Bournemouth, United Kingdom
Gulhane Askeri Tip Akademisi
🇹🇷Ankara, Turkey
Hacettepe University Medical Faculty
🇹🇷Ankara, Turkey
S.B. Yildirim Beyazit Training and Research Hospital
🇹🇷Ankara, Turkey
Hayat Tip Merkezi (Hayat Medical Center) Deapartment of Internal Diseases
🇹🇷Karabuk, Turkey
Policlinica Dr. Citu Timisoara
🇷🇴Timisoara, Romania
Ankara Ataturk Training and Research Hospital
🇹🇷Ankara, Turkey
Istanbul University Cardiology Institute
🇹🇷Istanbul, Turkey
Ege University Medical Faculty
🇹🇷Izmir, Turkey
26 Daffodil Street
🇿🇦Stanger, South Africa
Drs Essack and Mitha
🇿🇦Johannesburg, South Africa
203 Maxwell Centre
🇿🇦Durban, South Africa
Parklands Medical Centre
🇿🇦Durban, South Africa
Synapta Clinical Research Centre
🇿🇦Durban, South Africa
PE Greenacres Hospital
🇿🇦Port Elizabeth, South Africa
Morriston Hospital
🇬🇧Swansea, England, United Kingdom
Anasazi Internal Medicine
🇺🇸Phoenix, Arizona, United States
Novartis Investigative Site
🇷🇴Bucuresti, Romania
Tri-State Medical Group
🇺🇸Beaver, Pennsylvania, United States
Clinica de Fracturas y Ortopedia
🇦🇷Mar del Plata, Buenos Aires, Argentina
Centro Medico Viamonte
🇦🇷Buenos Aires, Argentina
Consultorios Asociados de Endocrinologia
🇦🇷Buenos Aires, Argentina
Instituto de Investigaciones Biomedicas
🇦🇷Santa Fe, Argentina
Hospital Juan Ramon Vidal
🇦🇷Corrientes, Argentina
Private Practice - DEMEULEMEESTER
🇧🇪Gozée, Belgium
Praxis F. Franzmann
🇩🇪Bad Oeynhausen, Germany
UZ Brussel
🇧🇪Jette, Belgium
emovis GmbH
🇩🇪Berlin, Germany
Städt. Kankenhaus Nordstadt
🇩🇪Hannover, Germany
Praxis Dr. Alawi
🇩🇪Saarlouis, Germany
Asklepios Klinik St. Georg
🇩🇪Hamburg, Germany
Praxis Dr. Kosch
🇩🇪Pirna, Germany
Praxis Dr. Klein
🇩🇪Schenklengsfeld, Germany
Semmelweiss Medical University
🇭🇺Budapest, Hungary
Kenezy Gyula Korhaz
🇭🇺Debrecen, Hungary
Zala Megyei Korhaz
🇭🇺Zalaegerszeg, Hungary
Szegedi Egyetem
🇭🇺Szeged, Hungary
Sandor Karolyi Hospital
🇭🇺Budapest, Hungary
Gokula Metropolis Clinical Research Centre
🇮🇳Bangalore-, India
Bangalore Diabetes Hospital
🇮🇳Bangalore, India
SAMATVAM
🇮🇳Bangalore, India
Jnana Sanjeevini Medical Center
🇮🇳Bangalore, India
Madras Diabetes Reasearch Foundation
🇮🇳Chennai, India
Health and Research Centre
🇮🇳Trivandrum, India
Diabetes Thyroid Hormone Research Institute Pvt. Ltd.
🇮🇳Indore, India
National Hospital Organization Nagoya Medical Center
🇯🇵Nagoya, Aichi, Japan
S R Kalla Memorial Gastro & General Hospital
🇮🇳Jaipur, India
Pitale Diabetes & Hormone Centre
🇮🇳Nagpur, India
Kyushu Rosai Hospital
🇯🇵Kitakyushu, Fukuoka, Japan
Musashikoganei Clinic
🇯🇵Koganei-city, Tokyo, Japan
NHO Yokohama Medical Center
🇯🇵Yokohama, Kanagawa, Japan
Saiseikai Fukuoka General Hospital
🇯🇵Fukuoka, Japan
Fujikoshi Hospital
🇯🇵Toyama-city, Toyama, Japan
Kokura Medical Center
🇯🇵Kitakyusyu, Japan
Instituto Delgado de Investigacion Medica
🇵🇪Arequipa, Peru
Geriatrics Research Institute Hospital
🇯🇵Maebashi, Japan
Sakai Hospital Kinki University School of Medicine
🇯🇵Sakai, Japan
Centro de Investigacion Clinica Trujillo
🇵🇪Trujillo, Peru
Rowden Medical Partnership
🇬🇧Wiltshire, United Kingdom
Ambulatory of Institute of Nutrition Diseases and Diabetes
🇷🇴Bucharest, Romania
Medical Centre "Sanatatea ta"
🇷🇴Bucuresti, Romania
Preferred Primary Care Physicians
🇺🇸Pittsburgh, Pennsylvania, United States
Johannes Gutenberg-Universität Mainz
🇩🇪Mainz, Germany
Whittier Institute of Diabetes
🇺🇸La Jolla, California, United States
R/D Clinical Research
🇺🇸Lake Jackson, Texas, United States
Orange County Research Center
🇺🇸Tustin, California, United States
Deaconess Clinic
🇺🇸Evansville, Indiana, United States
GWT-TUB GmbH
🇩🇪Dresden, Germany
Gemeinschaftspraxis und Dialysezentrum Karlstraße
🇩🇪Düsseldorf, Germany
Diabetes Research Center
🇺🇸Columbus, Ohio, United States
Zentrum für Klinische Forschung Neuwied (ZKSN)
🇩🇪Neuwied, Germany
Forschungszentrum Ruhr, KliFoCenter GmbH
🇩🇪Witten, Germany
Praxis Dr. Stütz
🇩🇪Bretten, Germany
Diabeteszentrum Hohenmölsen
🇩🇪Hohenmölsen, Germany
Medical Research Initiatives Inc
🇺🇸Virginia Beach, Virginia, United States