Clinical trial NCT00900146: Dose Finding, Safety and Efficacy of Monthly Subcutaneous Canakinumab Administration in Metformin Monotherapy Treated Type 2 Diabetic Patients
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Diabetes Mellitus, Type 2
Keywords: type 2 diabetes
canakinumab
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2009-05-12
Enrollment: 556
Sex: ALL
Minimum age (years): 18
Maximum age (years): 74
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Number of Participants With Adverse Events (AEs), Serious Adverse Events, Death and Clinical Significant AEs During 4 Months (Period II)
timeFrame: 4 months (Period II)
measure: Change From Baseline in Hemoglobin A1c (HbA1c) at Month 4 During Dose-finding Period of the Study (Period II)
timeFrame: Baseline, Month 4
measure: Change From Baseline in Dynamic Phase Secreted Insulin Per Unit of Glucose Concentration (Φd) Over 4 Months (Period III)
timeFrame: Baseline, Over Month 4
Secondary outcomes:
measure: Change From Baseline in C-peptide Area Under Curve (AUC 0-4 Hours ) Following Meal Test (Period II)
timeFrame: Baseline, Month 4
measure: Change From Baseline in Prandial Plasma Glucose Area Under Curve (AUC0-4 Hours ) Following Meal Test (Period II)
timeFrame: Baseline, Month 4
measure: Change From Baseline in Insulin Area Under Curve (AUC 0-4 Hours ) Following Meal Test (Period II)
timeFrame: Baseline, Month 4
measure: Change From Baseline in 2-hour Glucose Level Following Meal Test (Period II)
timeFrame: Baseline, Month 4
measure: Change From Baseline in Peak Glucose Level Following Meal Test (Period II)
timeFrame: Baseline, Month 4
measure: Change From Baseline in Peak C-peptide Following Meal Test (Period II)
timeFrame: Baseline, Month 4
measure: Change From Baseline in Peak Insulin Level Following Meal Test (Period II)
timeFrame: Baseline, Month 4
measure: Change From Baseline in Insulin Secretion Rates Relative to Glucose AUC (0-2 Hours) at Month 4 Following Meal Test (Period II)
timeFrame: Baseline, Month 4
measure: 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)
timeFrame: Baseline, Month 4
measure: Change From Baseline in Peak Plasma Glucose Level (7-point Glucose Testing) at Month 4(Period II)
timeFrame: Baseline, Month 4
measure: Change From Baseline in Average Plasma Glucose Level (7-point Glucose Testing) at Month 4 (Period II)
timeFrame: Baseline, Month 4
measure: Change From Baseline in Fasting Plasma Glucose at Month 4 (Period II)
timeFrame: Baseline, Month 4
measure: Change From Baseline in Fasting Insulin at Month 4 (Period II)
timeFrame: Baseline, Month 4
measure: Change From Baseline in Homeostatic Model Assessment B (HOMA2 B) Beta Cell Function (%B) at Month 4 (Period II)
timeFrame: Baseline, Month 4
measure: Change From Baseline in Homeostatic Model Assessment Insulin Resistance (HOMA2 IR) at Month 4 (Period II)
timeFrame: Baseline, Month 4
measure: Change From Baseline in Quantitative Insulin Sensitivity Check Index (QUICKI) at Month 4 (Period II)
timeFrame: Baseline, Month 4
measure: Change From Baseline in High-sensitivity C-reactive Protein (hsCRP) at Month 4 (Period II)
timeFrame: Baseline, Month 4
measure: Percentage Change From Baseline in Fasting Lipids Profile at Month 4 (Period II)
timeFrame: Baseline, Month 4
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Anasazi Internal Medicine
state: Arizona
city: La Jolla
country: United States
facility: Whittier Institute of Diabetes
state: California
city: Los Gatos
country: United States
facility: Novartis Investigative Site
state: California
city: Santa Monica
country: United States
facility: Novartis Investigative Site
state: California
city: Tustin
country: United States
facility: Orange County Research Center
state: California
city: Atlanta
country: United States
facility: Novartis Investigative Site
state: Georgia
city: Evansville
country: United States
facility: Deaconess Clinic
state: Indiana
city: Jackson
country: United States
facility: Novartis Investigative Site
state: Mississippi
city: Picayune
country: United States
facility: Novartis Investigative Site
state: Mississippi
city: Trenton
country: United States
facility: Novartis Investigative Site
state: New Jersey
city: Columbus
country: United States
facility: Diabetes Research Center
state: Ohio
city: Beaver
country: United States
facility: Tri-State Medical Group
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Preferred Primary Care Physicians
state: Pennsylvania
city: Columbia
country: United States
facility: Novartis Investigative Site
state: South Carolina
city: Lake Jackson
country: United States
facility: R/D Clinical Research
state: Texas
city: Pasadena
country: United States
facility: Novartis Investigative Site
state: Texas
city: San Antonio
country: United States
facility: Novartis Investigative Site
state: Texas
city: Virginia Beach
country: United States
facility: Medical Research Initiatives Inc
state: Virginia
city: Mar del Plata
country: Argentina
facility: Clinica de Fracturas y Ortopedia
state: Buenos Aires
city: Buenos Aires
country: Argentina
facility: DIM Clinica Privada
city: Buenos Aires
country: Argentina
facility: Centro Medico Viamonte
city: Buenos Aires
country: Argentina
facility: Consultorios Asociados de Endocrinologia
city: Corrientes
country: Argentina
facility: Hospital Juan Ramon Vidal
city: Rosario Santa Fe
country: Argentina
facility: Novartis Investigative Site
city: Santa Fe
country: Argentina
facility: Instituto de Investigaciones Biomedicas
city: Santa Fe
country: Argentina
facility: Centro de Investigaciones Clinicas del Litoral
city: Gozée
country: Belgium
facility: Private Practice - DEMEULEMEESTER
city: Heist-op-den-berg
country: Belgium
facility: Novartis Investigative Site
city: Jette
country: Belgium
facility: UZ Brussel
city: Hong Kong
country: China
facility: Novartis Investigative Site
city: Bad Oeynhausen
country: Germany
facility: Praxis F. Franzmann
city: Berlin
country: Germany
facility: emovis GmbH
city: Bretten
country: Germany
facility: Praxis Dr. Stütz
city: Dresden
country: Germany
facility: GWT-TUB GmbH
city: Düsseldorf
country: Germany
facility: Gemeinschaftspraxis und Dialysezentrum Karlstraße
city: Hamburg
country: Germany
facility: Asklepios Klinik St. Georg
city: Hannover
country: Germany
facility: Städt. Kankenhaus Nordstadt
city: Hohenmölsen
country: Germany
facility: Diabeteszentrum Hohenmölsen
city: Mainz
country: Germany
facility: Johannes Gutenberg-Universität Mainz
city: Neuwied
country: Germany
facility: Zentrum für Klinische Forschung Neuwied (ZKSN)
city: Nürnberg
country: Germany
facility: Praxis Dr. Wunderer
city: Pirna
country: Germany
facility: Praxis Dr. Kosch
city: Saarlouis
country: Germany
facility: Praxis Dr. Alawi
city: Schenklengsfeld
country: Germany
facility: Praxis Dr. Klein
city: Witten
country: Germany
facility: Forschungszentrum Ruhr, KliFoCenter GmbH
city: Budapest
country: Hungary
facility: Fővárosi Önkormányzat Péterfy Sándor Utcai Kórház - Rendelőintézet és Baleseti Központ
city: Budapest
country: Hungary
facility: Sandor Karolyi Hospital
city: Budapest
country: Hungary
facility: Semmelweiss Medical University
city: Debrecen
country: Hungary
facility: Kenezy Gyula Korhaz
city: Szeged
country: Hungary
facility: Szegedi Egyetem
city: Zalaegerszeg
country: Hungary
facility: Zala Megyei Korhaz
city: Bangalore-
country: India
facility: Gokula Metropolis Clinical Research Centre
city: Bangalore
country: India
facility: Bangalore Diabetes Hospital
city: Bangalore
country: India
facility: Jnana Sanjeevini Medical Center
city: Bangalore
country: India
facility: SAMATVAM
city: Chennai
country: India
facility: Madras Diabetes Reasearch Foundation
city: Cochin
country: India
facility: Amrita Institute of Medical Sciences and Research Center
city: Hyderabaad
country: India
facility: Nizam's Institute of Medical Sciences
city: Indore
country: India
facility: Diabetes Thyroid Hormone Research Institute Pvt. Ltd.
city: Jaipur
country: India
facility: S R Kalla Memorial Gastro & General Hospital
city: Nagpur
country: India
facility: Pitale Diabetes & Hormone Centre
city: Trivandrum
country: India
facility: Health and Research Centre
city: Visakhapatnam
country: India
facility: King George Hospital
city: Nagoya
country: Japan
facility: National Hospital Organization Nagoya Medical Center
state: Aichi
city: Kitakyushu
country: Japan
facility: Kyushu Rosai Hospital
state: Fukuoka
city: Yokohama
country: Japan
facility: NHO Yokohama Medical Center
state: Kanagawa
city: Koganei-city
country: Japan
facility: Musashikoganei Clinic
state: Tokyo
city: Minato-ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Toyama-city
country: Japan
facility: Fujikoshi Hospital
state: Toyama
city: Fukuoka
country: Japan
facility: Saiseikai Fukuoka General Hospital
city: Kitakyusyu
country: Japan
facility: Kokura Medical Center
city: Koriyama
country: Japan
facility: Seino Internal Medicine Clinic
city: Maebashi
country: Japan
facility: Geriatrics Research Institute Hospital
city: Ohkawa
country: Japan
facility: Takagi Hospital
city: Sakai
country: Japan
facility: Sakai Hospital Kinki University School of Medicine
city: Pusan
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Suwon
country: Korea, Republic of
facility: Novartis Investigative Site
city: Arequipa
country: Peru
facility: Instituto Delgado de Investigacion Medica
city: Chiclayo
country: Peru
facility: Clinica Chiclayo
city: San Martin de Porres
country: Peru
facility: Hospital Nacional Cayetano Heredia
city: Trujillo
country: Peru
facility: Centro de Investigacion Clinica Trujillo
city: Bucharest
country: Romania
facility: Ambulatory of Institute of Nutrition Diseases and Diabetes
city: Bucuresti
country: Romania
facility: Medical Centre "Sanatatea ta"
city: Bucuresti
country: Romania
facility: Novartis Investigative Site
city: Timisoara
country: Romania
facility: Policlinica Dr. Citu Timisoara
city: Durban
country: South Africa
facility: 203 Maxwell Centre
city: Durban
country: South Africa
facility: Parklands Medical Centre
city: Durban
country: South Africa
facility: St Augustines Medical Centre
city: Durban
country: South Africa
facility: Synapta Clinical Research Centre
city: Johannesburg
country: South Africa
facility: Drs Essack and Mitha
city: Port Elizabeth
country: South Africa
facility: PE Greenacres Hospital
city: Stanger
country: South Africa
facility: 26 Daffodil Street
city: Ankara
country: Turkey
facility: Ankara Ataturk Training and Research Hospital
city: Ankara
country: Turkey
facility: Gulhane Askeri Tip Akademisi
city: Ankara
country: Turkey
facility: Hacettepe University Medical Faculty
city: Ankara
country: Turkey
facility: S.B. Yildirim Beyazit Training and Research Hospital
city: Istanbul
country: Turkey
facility: Istanbul University Cardiology Institute
city: Izmir
country: Turkey
facility: Ege University Medical Faculty
city: Karabuk
country: Turkey
facility: Hayat Tip Merkezi (Hayat Medical Center) Deapartment of Internal Diseases
city: Swansea
country: United Kingdom
facility: Morriston Hospital
state: England
city: Birmingham
country: United Kingdom
facility: Birmingham Heartlands Hospital
city: Bournemouth
country: United Kingdom
facility: Royal Bournemouth Hospital
city: Wiltshire
country: United Kingdom
facility: Rowden Medical Partnership
Study officials:
affiliation: Sponsor GmbH
name: Novartis Pharmaceuticals Corporation
role: STUDY_DIRECTOR
References:
citation: Noe A, Howard C, Thuren T, Taylor A, Skerjanec A. Pharmacokinetic and pharmacodynamic characteristics of single-dose Canakinumab in patients with type 2 diabetes mellitus. Clin Ther. 2014 Nov 1;36(11):1625-37. doi: 10.1016/j.clinthera.2014.08.004. Epub 2014 Sep 18.
citation: Hensen J, Howard CP, Walter V, Thuren T. Impact of interleukin-1beta antibody (canakinumab) on glycaemic indicators in patients with type 2 diabetes mellitus: results of secondary endpoints from a randomized, placebo-controlled trial. Diabetes Metab. 2013 Dec;39(6):524-31. doi: 10.1016/j.diabet.2013.07.003. Epub 2013 Sep 25.
citation: Ridker PM, Howard CP, Walter V, Everett B, Libby P, Hensen J, Thuren T; CANTOS Pilot Investigative Group. Effects of interleukin-1beta inhibition with canakinumab on hemoglobin A1c, lipids, C-reactive protein, interleukin-6, and fibrinogen: a phase IIb randomized, placebo-controlled trial. Circulation. 2012 Dec 4;126(23):2739-48. doi: 10.1161/CIRCULATIONAHA.112.122556. Epub 2012 Nov 5.