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

Diabetes Mellitus, Type 2 Clinical Trial

Official title:

Dose 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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00900146
• Other study ID #: CACZ885I2202
• Status: Terminated
• Phase: Phase 2/Phase 3
• First received: May 6, 2009
• Last updated: January 17, 2012
• Start date: April 2009
• Est. completion date: November 2010

Study information

• Verified date: January 2012
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Health authority: Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia MedicaBelgium: Federal Agency for Medicinal Products and Health ProductsGermany: Paul-Ehrlich-InstitutHungary: National Institute of PharmacyIndia: Drugs Controller General of IndiaJapan: Ministry of Health, Labor and WelfarePeru: General Directorate of Pharmaceuticals, Devices, and DrugsRomania: National Medicines AgencySouth Africa: National Health Research Ethics CouncilTurkey: Ministry of HealthUnited Kingdom: Medicines and Healthcare Products Regulatory AgencyUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 556
• Est. completion date: November 2010
• Est. primary completion date: November 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 74 Years

Eligibility

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

Study Design

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2

Intervention

Drug:
• 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.
• 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.
• Placebo
Placebo lyophilized cake will be reconstituted and then used to dilute the 25mg or 150mg solutions to make 5mg, 15mg and 50mg injections.

Locations

Country	Name	City	State
Argentina	Centro Medico Viamonte	Buenos Aires
Argentina	Consultorios Asociados de Endocrinologia	Buenos Aires
Argentina	DIM Clinica Privada	Buenos Aires
Argentina	Hospital Juan Ramon Vidal	Corrientes
Argentina	Clinica de Fracturas y Ortopedia	Mar del Plata	Buenos Aires
Argentina	Novartis Investigative Site	Rosario Santa Fe
Argentina	Centro de Investigaciones Clinicas del Litoral	Santa Fe
Argentina	Instituto de Investigaciones Biomedicas	Santa Fe
Belgium	Private Practice - DEMEULEMEESTER	Gozée
Belgium	Novartis Investigative Site	Heist-op-den-berg
Belgium	UZ Brussel	Jette
China	Novartis Investigative Site	Hong Kong
Germany	Praxis F. Franzmann	Bad Oeynhausen
Germany	emovis GmbH	Berlin
Germany	Praxis Dr. Stütz	Bretten
Germany	GWT-TUB GmbH	Dresden
Germany	Gemeinschaftspraxis und Dialysezentrum Karlstraße	Düsseldorf
Germany	Asklepios Klinik St. Georg	Hamburg
Germany	Städt. Kankenhaus Nordstadt	Hannover
Germany	Diabeteszentrum Hohenmölsen	Hohenmölsen
Germany	Johannes Gutenberg-Universität Mainz	Mainz
Germany	Zentrum für Klinische Forschung Neuwied (ZKSN)	Neuwied
Germany	Praxis Dr. Wunderer	Nürnberg
Germany	Praxis Dr. Kosch	Pirna
Germany	Praxis Dr. Alawi	Saarlouis
Germany	Praxis Dr. Klein	Schenklengsfeld
Germany	Forschungszentrum Ruhr, KliFoCenter GmbH	Witten
Hungary	Fovárosi Önkormányzat Péterfy Sándor Utcai Kórház - Rendelointézet 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
India	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
Japan	Saiseikai Fukuoka General Hospital	Fukuoka
Japan	Kyushu Rosai Hospital	Kitakyushu	Fukuoka
Japan	Kokura Medical Center	Kitakyusyu
Japan	Musashikoganei Clinic	Koganei-city	Tokyo
Japan	Seino Internal Medicine Clinic	Koriyama
Japan	Geriatrics Research Institute Hospital	Maebashi
Japan	Novartis Investigative Site	Minato-ku	Tokyo
Japan	National Hospital Organization Nagoya Medical Center	Nagoya	Aichi
Japan	Takagi Hospital	Ohkawa
Japan	Sakai Hospital Kinki University School of Medicine	Sakai
Japan	Fujikoshi Hospital	Toyama-city	Toyama
Japan	NHO Yokohama Medical Center	Yokohama	Kanagawa
Korea, Republic of	Novartis Investigative Site	Pusan
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Suwon
Peru	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
Romania	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
South Africa	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
Turkey	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
United Kingdom	Birmingham Heartlands Hospital	Birmingham
United Kingdom	Royal Bournemouth Hospital	Bournemouth
United Kingdom	Morriston Hospital	Swansea	England
United Kingdom	Rowden Medical Partnership	Wiltshire
United States	Novartis Investigative Site	Atlanta	Georgia
United States	Tri-State Medical Group	Beaver	Pennsylvania
United States	Novartis Investigative Site	Columbia	South Carolina
United States	Diabetes Research Center	Columbus	Ohio
United States	Deaconess Clinic	Evansville	Indiana
United States	Novartis Investigative Site	Jackson	Mississippi
United States	Whittier Institute of Diabetes	La Jolla	California
United States	R/D Clinical Research	Lake Jackson	Texas
United States	Novartis Investigative Site	Los Gatos	California
United States	Novartis Investigative Site	Pasadena	Texas
United States	Anasazi Internal Medicine	Phoenix	Arizona
United States	Novartis Investigative Site	Picayune	Mississippi
United States	Preferred Primary Care Physicians	Pittsburgh	Pennsylvania
United States	Novartis Investigative Site	San Antonio	Texas
United States	Novartis Investigative Site	Santa Monica	California
United States	Novartis Investigative Site	Trenton	New Jersey
United States	Orange County Research Center	Tustin	California
United States	Medical Research Initiatives Inc	Virginia Beach	Virginia

Sponsors (1)

Lead Sponsor	Collaborator
Novartis

Countries where clinical trial is conducted

United States,  Argentina,  Belgium,  China,  Germany,  Hungary,  India,  Japan,  Korea, Republic of,  Peru,  Romania,  South Africa,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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)	Yes
Primary	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	No
Primary	Change From Baseline in Dynamic Phase Secreted Insulin Per Unit of Glucose Concentration (Fd) 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	No
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 SAx 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	No
Secondary	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 SAx 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	No
Secondary	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 SAx 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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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 (ß)-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 ß-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	No
Secondary	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 (ß)-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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No