Dose Finding, Safety and Efficacy of Monthly Subcutaneous Canakinumab Administration in Metformin Monotherapy Treated Type 2 Diabetic Patients

Overview[ - collapse ][ - ]

Purpose 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.
ConditionDiabetes Mellitus, Type 2
InterventionDrug: Canakinumab
Drug: Metformin
Drug: Placebo
PhasePhase 2/Phase 3
SponsorNovartis
Responsible PartyNovartis
ClinicalTrials.gov IdentifierNCT00900146
First ReceivedMay 6, 2009
Last UpdatedJanuary 17, 2012
Last verifiedJanuary 2012

Tracking Information[ + expand ][ + ]

First Received DateMay 6, 2009
Last Updated DateJanuary 17, 2012
Start DateApril 2009
Estimated Primary Completion DateNovember 2010
Current Primary Outcome Measures
  • Number of Participants With Adverse Events (AEs), Serious Adverse Events, Death and Clinical Significant AEs During 4 Months (Period II) [Time Frame: 4 months (Period II)] [Designated as safety issue: Yes]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) [Time Frame: Baseline, Month 4] [Designated as safety issue: No]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) [Time Frame: Baseline, Over Month 4] [Designated as safety issue: No]This was planned as interim analysis and was not conducted because the study was terminated in period III.
Current Secondary Outcome Measures
  • Change From Baseline in C-peptide Area Under Curve (AUC 0-4 Hours ) Following Meal Test (Period II) [Time Frame: Baseline, Month 4] [Designated as safety issue: No]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) [Time Frame: Baseline, Month 4] [Designated as safety issue: No]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) [Time Frame: Baseline, Month 4] [Designated as safety issue: No]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) [Time Frame: Baseline, Month 4] [Designated as safety issue: No]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) [Time Frame: Baseline, Month 4] [Designated as safety issue: No]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) [Time Frame: Baseline, Month 4] [Designated as safety issue: No]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) [Time Frame: Baseline, Month 4] [Designated as safety issue: No]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) [Time Frame: Baseline, Month 4] [Designated as safety issue: No]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) [Time Frame: Baseline, Month 4] [Designated as safety issue: No]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) [Time Frame: Baseline, Month 4] [Designated as safety issue: No]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) [Time Frame: Baseline, Month 4] [Designated as safety issue: No]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) [Time Frame: Baseline, Month 4] [Designated as safety issue: No]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) [Time Frame: Baseline, Month 4] [Designated as safety issue: No]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) [Time Frame: Baseline, Month 4] [Designated as safety issue: No]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) [Time Frame: Baseline, Month 4] [Designated as safety issue: No]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) [Time Frame: Baseline, Month 4] [Designated as safety issue: No]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) [Time Frame: Baseline, Month 4] [Designated as safety issue: No]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) [Time Frame: Baseline, Month 4] [Designated as safety issue: No]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.

Descriptive Information[ + expand ][ + ]

Brief TitleDose Finding, Safety and Efficacy of Monthly Subcutaneous Canakinumab Administration in Metformin Monotherapy Treated Type 2 Diabetic Patients
Official TitleDose Finding, Safety and Efficacy of Monthly Subcutaneous Canakinumab Administration for the Treatment of Hyperglycemia in Metformin Monotherapy Treated Type 2 Diabetic Patients: a Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study
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 DescriptionNot Provided
Study TypeInterventional
Study PhasePhase 2/Phase 3
Study DesignAllocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
ConditionDiabetes Mellitus, Type 2
InterventionDrug: Canakinumab
Canakinumab lyophilized cake (25 mg and 150 mg in individual 6 mL glass vials ) was reconstituted and then used to dilute the 25mg or 150mg solutions to make 5mg, 15mg and 50mg injections.
Drug: Metformin
Before randomization, in drug naïve patients at a dose of 1000 mg with the evening meal or 500 mg b.i.d. (twice daily) with two main meals. At the randomization visit, patients were prescribed with no less than 1,000mg/day.
Drug: Placebo
Placebo lyophilized cake will be reconstituted and then used to dilute the 25mg or 150mg solutions to make 5mg, 15mg and 50mg injections.
Study Arm (s)
  • Experimental: Canakinumab 5 mg + 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.
  • Experimental: Canakinumab 15 mg + 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.
  • Experimental: Canakinumab 50 mg + 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.
  • Experimental: Canakinumab 150 mg + 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 Comparator: Placebo + 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).

Recruitment Information[ + expand ][ + ]

Recruitment StatusTerminated
Estimated Enrollment556
Estimated Completion DateNovember 2010
Estimated Primary Completion DateNovember 2010
Eligibility Criteria
Inclusion Criteria:

1. 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).

2. 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

3. Patients must have a morning fasting plasma glucose result < 180 mg/dl at Visit 3
(Month -1) analyzed by the Central Laboratory.

4. Were on a daily dose of metformin ≥ 1000 mg (or less according to local regulations)

Exclusion Criteria:

1. Type 1 diabetes, diabetes resulting from pancreatic injury or secondary forms of
diabetes.

2. 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.

3. 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.

4. Risk factors for TB as defined in protocol

5. 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.

6. Systemic or local treatment of any immune modulating agent in doses with systemic
effects or live vaccinations within 3 months

7. Stroke, myocardial infarction, acute coronary syndrome, revascularization procedure
or recurrent TIA within the last 6 months.

8. Unwillingness to use insulin glargine as the additional medication should glycemic
control deteriorate.

Other protocol-defined inclusion/exclusion criteria may apply
GenderBoth
Ages18 Years
Accepts Healthy VolunteersNo
ContactsNot Provided
Location CountriesUnited States, Argentina, Belgium, China, Germany, Hungary, India, Japan, Korea, Republic of, Peru, Romania, South Africa, Turkey, United Kingdom

Administrative Information[ + expand ][ + ]

NCT Number NCT00900146
Other Study ID NumbersCACZ885I2202
Has Data Monitoring CommitteeNot Provided
Information Provided ByNovartis
Study SponsorNovartis
CollaboratorsNot Provided
Investigators Study Director: Novartis Pharmaceuticals Corporation Sponsor GmbH
Verification DateJanuary 2012

Locations[ + expand ][ + ]

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, United States, 90404
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, Argentina, C1100ABB
DIM Clinica Privada
Buenos Aires, Argentina, B1704ETD
Centro Medico Viamonte
Buenos Aires, Argentina, C1120AAC
Consultorios Asociados de Endocrinologia
Buenos Aires, Argentina, C1425AGC
Hospital Juan Ramon Vidal
Corrientes, Argentina, W3410AVV
Novartis Investigative Site
Rosario Santa Fe, Argentina, S2000AII
Instituto de Investigaciones Biomedicas
Santa Fe, Argentina, S3000FNF
Centro de Investigaciones Clinicas del Litoral
Santa Fe, Argentina, S3000FWO
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, Germany, 32549
emovis GmbH
Berlin, Germany, 10629
Praxis Dr. Stütz
Bretten, Germany, 75015
GWT-TUB GmbH
Dresden, Germany, 01307
Gemeinschaftspraxis und Dialysezentrum Karlstraße
Düsseldorf, Germany
Asklepios Klinik St. Georg
Hamburg, Germany, 20099
Städt. Kankenhaus Nordstadt
Hannover, Germany, 30167
Diabeteszentrum Hohenmölsen
Hohenmölsen, Germany, 06679
Johannes Gutenberg-Universität Mainz
Mainz, Germany, 55101
Zentrum für Klinische Forschung Neuwied (ZKSN)
Neuwied, Germany, 56564
Praxis Dr. Wunderer
Nürnberg, Germany, 90489
Praxis Dr. Kosch
Pirna, Germany, 01796
Praxis Dr. Alawi
Saarlouis, Germany, 66740
Praxis Dr. Klein
Schenklengsfeld, Germany, 36277
Forschungszentrum Ruhr, KliFoCenter GmbH
Witten, Germany, 58455
Sandor Karolyi Hospital
Budapest, Hungary
Semmelweiss Medical University
Budapest, Hungary
Fővárosi Önkormányzat Péterfy Sándor Utcai Kórház - Rendelőintézet és Baleseti Központ
Budapest, Hungary
Kenezy Gyula Korhaz
Debrecen, Hungary
Szegedi Egyetem
Szeged, Hungary
Zala Megyei Korhaz
Zalaegerszeg, Hungary
Bangalore Diabetes Hospital
Bangalore, India
Jnana Sanjeevini Medical Center
Bangalore, India
SAMATVAM
Bangalore, India
Gokula Metropolis Clinical Research Centre
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, Japan, 460-0001
Kyushu Rosai Hospital
Kitakyushu, Fukuoka, Japan, 800-0296
NHO Yokohama Medical Center
Yokohama, Kanagawa, Japan, 245-8575
Musashikoganei Clinic
Koganei-city, Tokyo, Japan, 184-0004
Novartis Investigative Site
Minato-ku, Tokyo, Japan
Fujikoshi Hospital
Toyama-city, Toyama, Japan, 930-0964
Saiseikai Fukuoka General Hospital
Fukuoka, Japan, 810-0001
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, Korea, Republic of, 614-735
Novartis Investigative Site
Seoul, Korea, Republic of, 135-720
Novartis Investigative Site
Seoul, Korea, Republic of, 139-872
Novartis Investigative Site
Seoul, Korea, Republic of, 135-710
Novartis Investigative Site
Suwon, Korea, Republic of, 442-721
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
Hacettepe University Medical Faculty
Ankara, Turkey
S.B. Yildirim Beyazit Training and Research Hospital
Ankara, Turkey
Gulhane Askeri Tip Akademisi
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, United Kingdom, SA6 6NL
Birmingham Heartlands Hospital
Birmingham, United Kingdom
Royal Bournemouth Hospital
Bournemouth, United Kingdom
Rowden Medical Partnership
Wiltshire, United Kingdom