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

NCT00900146 | Terminated Phase 2 Results

• 1 other identifier: CACZ885I2202
• Study Type: interventional
• Target: 556
• Locations: 14 countries
• Sites: 106

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.

Conditions

Diabetes Mellitus, Type 2

Keywords

type 2 diabetes; canakinumab

Outcome Measures

Primary Outcomes (3)

• Number of Participants With Adverse Events (AEs), Serious Adverse Events, Death and Clinical Significant AEs During 4 Months (Period II)

  Adverse events are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards.

  4 months (Period II)

• Change From Baseline in Hemoglobin A1c (HbA1c) at Month 4 During Dose-finding Period of the Study (Period II)

  HbA1c was measured by National glycohemoglobin standardization program (NGSP) certified methodology. HbA1c is an integrated measure of average glucose concentration in plasma in the last 2-3 months. The analysis of covariance (ANCOVA) included treatment and metformin dose group as main effects and baseline HbA1c as a covariate.

  Baseline, Month 4

• Change From Baseline in Dynamic Phase Secreted Insulin Per Unit of Glucose Concentration (Φd) Over 4 Months (Period III)

  This was planned as interim analysis and was not conducted because the study was terminated in period III.

  Baseline, Over Month 4

Secondary Outcomes (18)

• Change From Baseline in C-peptide Area Under Curve (AUC 0-4 Hours ) Following Meal Test (Period II)

  Baseline, Month 4

• Change From Baseline in Prandial Plasma Glucose Area Under Curve (AUC0-4 Hours ) Following Meal Test (Period II)

  Baseline, Month 4

• Change From Baseline in Insulin Area Under Curve (AUC 0-4 Hours ) Following Meal Test (Period II)

  Baseline, Month 4

• Change From Baseline in 2-hour Glucose Level Following Meal Test (Period II)

  Baseline, Month 4

• Change From Baseline in Peak Glucose Level Following Meal Test (Period II)

  Baseline, Month 4

Study Arms (5)

Canakinumab 5 mg + Metformin

EXPERIMENTAL

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.

Drug: Canakinumab; Drug: Metformin

Canakinumab 15 mg + Metformin

EXPERIMENTAL

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.

Drug: Canakinumab; Drug: Metformin

Canakinumab 50 mg + Metformin

EXPERIMENTAL

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.

Drug: Canakinumab; Drug: Metformin

Canakinumab 150 mg + Metformin

EXPERIMENTAL

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.

Drug: Canakinumab; Drug: Metformin

Placebo + Metformin

PLACEBO COMPARATOR

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).

Drug: Metformin; Drug: Placebo

Interventions

Canakinumab DRUG

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.

Canakinumab 15 mg + Metformin; Canakinumab 150 mg + Metformin; Canakinumab 5 mg + Metformin; Canakinumab 50 mg + Metformin

Metformin DRUG

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.

Canakinumab 15 mg + Metformin; Canakinumab 150 mg + Metformin; Canakinumab 5 mg + Metformin; Canakinumab 50 mg + Metformin; Placebo + Metformin

Placebo DRUG

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

Placebo + Metformin

Eligibility Criteria

• Age: 18 Years - 74 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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.
• 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.
• Systemic or local treatment of any immune modulating agent in doses with systemic effects or live vaccinations within 3 months
• Stroke, myocardial infarction, acute coronary syndrome, revascularization procedure or recurrent TIA within the last 6 months.
• Unwillingness to use insulin glargine as the additional medication should glycemic control deteriorate.

Sponsors & Collaborators

• Novartis: lead

Study Sites (106)

Anasazi Internal Medicine

Phoenix, Arizona, United States

Location

Whittier Institute of Diabetes

La Jolla, California, United States

Location

Novartis Investigative Site

Los Gatos, California, United States

Location

Novartis Investigative Site

Santa Monica, California, 90404, United States

Location

Orange County Research Center

Tustin, California, United States

Location

Novartis Investigative Site

Atlanta, Georgia, United States

Location

Deaconess Clinic

Evansville, Indiana, United States

Location

Novartis Investigative Site

Jackson, Mississippi, United States

Location

Novartis Investigative Site

Picayune, Mississippi, United States

Location

Novartis Investigative Site

Trenton, New Jersey, United States

Location

Diabetes Research Center

Columbus, Ohio, United States

Location

Tri-State Medical Group

Beaver, Pennsylvania, United States

Location

Preferred Primary Care Physicians

Pittsburgh, Pennsylvania, United States

Location

Novartis Investigative Site

Columbia, South Carolina, United States

Location

R/D Clinical Research

Lake Jackson, Texas, United States

Location

Novartis Investigative Site

Pasadena, Texas, United States

Location

Novartis Investigative Site

San Antonio, Texas, United States

Location

Medical Research Initiatives Inc

Virginia Beach, Virginia, United States

Location

DIM Clinica Privada

Buenos Aires, Buenos Aires, B1704ETD, Argentina

Location

Centro Medico Viamonte

Buenos Aires, Buenos Aires, C1120AAC, Argentina

Location

Consultorios Asociados de Endocrinologia

Buenos Aires, Buenos Aires, C1425AGC, Argentina

Location

Clinica de Fracturas y Ortopedia

Mar del Plata, Buenos Aires, C1100ABB, Argentina

Location

Hospital Juan Ramon Vidal

Corrientes, Corrientes Province, W3410AVV, Argentina

Location

Instituto de Investigaciones Biomedicas

Santa Fe, Santa Fe Province, S3000FNF, Argentina

Location

Centro de Investigaciones Clinicas del Litoral

Santa Fe, Santa Fe Province, S3000FWO, Argentina

Location

Novartis Investigative Site

Rosario Santa Fe, S2000AII, Argentina

Location

Private Practice - DEMEULEMEESTER

Gozée, Belgium

Location

Novartis Investigative Site

Heist-op-den-Berg, Belgium

Location

UZ Brussel

Jette, Belgium

Location

Novartis Investigative Site

Hong Kong, China

Location

Praxis F. Franzmann

Bad Oeynhausen, 32549, Germany

Location

emovis GmbH

Berlin, 10629, Germany

Location

Praxis Dr. Stütz

Bretten, 75015, Germany

Location

GWT-TUB GmbH

Dresden, 01307, Germany

Location

Gemeinschaftspraxis und Dialysezentrum Karlstraße

Düsseldorf, Germany

Location

Asklepios Klinik St. Georg

Hamburg, 20099, Germany

Location

Städt. Kankenhaus Nordstadt

Hanover, 30167, Germany

Location

Diabeteszentrum Hohenmölsen

Hohenmölsen, 06679, Germany

Location

Johannes Gutenberg-Universität Mainz

Mainz, 55101, Germany

Location

Zentrum für Klinische Forschung Neuwied (ZKSN)

Neuwied, 56564, Germany

Location

Praxis Dr. Wunderer

Nuremberg, 90489, Germany

Location

Praxis Dr. Kosch

Pirna, 01796, Germany

Location

Praxis Dr. Alawi

Saarlouis, 66740, Germany

Location

Praxis Dr. Klein

Schenklengsfeld, 36277, Germany

Location

Forschungszentrum Ruhr, KliFoCenter GmbH

Witten, 58455, Germany

Location

Fővárosi Önkormányzat Péterfy Sándor Utcai Kórház - Rendelőintézet és Baleseti Központ

Budapest, Hungary

Location

Sandor Karolyi Hospital

Budapest, Hungary

Location

Semmelweiss Medical University

Budapest, Hungary

Location

Kenezy Gyula Korhaz

Debrecen, Hungary

Location

Szegedi Egyetem

Szeged, Hungary

Location

Zala Megyei Korhaz

Zalaegerszeg, Hungary

Location

Bangalore Diabetes Hospital

Bangalore, India

Location

Gokula Metropolis Clinical Research Centre

Bangalore, India

Location

Jnana Sanjeevini Medical Center

Bangalore, India

Location

SAMATVAM

Bangalore, India

Location

Madras Diabetes Reasearch Foundation

Chennai, India

Location

Nizam's Institute of Medical Sciences

Hyderabaad, India

Location

Diabetes Thyroid Hormone Research Institute Pvt. Ltd.

Indore, India

Location

S R Kalla Memorial Gastro & General Hospital

Jaipur, India

Location

Amrita Institute of Medical Sciences and Research Center

Kochi, India

Location

Pitale Diabetes & Hormone Centre

Nagpur, India

Location

Health and Research Centre

Trivandrum, India

Location

King George Hospital

Visakhapatnam, India

Location

National Hospital Organization Nagoya Medical Center

Nagoya, Aichi-ken, 460-0001, Japan

Location

Saiseikai Fukuoka General Hospital

Fukuoka, Fukuoka, 810-0001, Japan

Location

Kyushu Rosai Hospital

Kitakyushu, Fukuoka, 800-0296, Japan

Location

NHO Yokohama Medical Center

Yokohama, Kanagawa, 245-8575, Japan

Location

Musashikoganei Clinic

Koganei, Tokyo, 184-0004, Japan

Location

Novartis Investigative Site

Minato-ku, Tokyo, Japan

Location

Fujikoshi Hospital

Toyama, Toyama, 930-0964, Japan

Location

Kokura Medical Center

Kitakyushu, Japan

Location

Seino Internal Medicine Clinic

Kōriyama, Japan

Location

Geriatrics Research Institute Hospital

Maebashi, Japan

Location

Takagi Hospital

Ohkawa, Japan

Location

Sakai Hospital Kinki University School of Medicine

Sakai, Japan

Location

Instituto Delgado de Investigacion Medica

Arequipa, Peru

Location

Clinica Chiclayo

Chiclayo, Peru

Location

Hospital Nacional Cayetano Heredia

San Martín de Porres, Peru

Location

Centro de Investigacion Clinica Trujillo

Trujillo, Peru

Location

Ambulatory of Institute of Nutrition Diseases and Diabetes

Bucharest, Romania

Location

Medical Centre "Sanatatea ta"

Bucharest, Romania

Location

Novartis Investigative Site

Bucharest, Romania

Location

Policlinica Dr. Citu Timisoara

Timișoara, Romania

Location

203 Maxwell Centre

Durban, South Africa

Location

Parklands Medical Centre

Durban, South Africa

Location

St Augustines Medical Centre

Durban, South Africa

Location

Synapta Clinical Research Centre

Durban, South Africa

Location

Drs Essack and Mitha

Johannesburg, South Africa

Location

26 Daffodil Street

KwaDukuza, South Africa

Location

PE Greenacres Hospital

Port Elizabeth, South Africa

Location

Novartis Investigative Site

Pusan, 614-735, South Korea

Location

Novartis Investigative Site

Seoul, 135-710, South Korea

Location

Novartis Investigative Site

Seoul, 135-720, South Korea

Location

Novartis Investigative Site

Seoul, 139-872, South Korea

Location

Novartis Investigative Site

Suwon, 442-721, South Korea

Location

Ankara Ataturk Training and Research Hospital

Ankara, Turkey (Türkiye)

Location

Gulhane Askeri Tip Akademisi

Ankara, Turkey (Türkiye)

Location

Hacettepe University Medical Faculty

Ankara, Turkey (Türkiye)

Location

S.B. Yildirim Beyazit Training and Research Hospital

Ankara, Turkey (Türkiye)

Location

Istanbul University Cardiology Institute

Istanbul, Turkey (Türkiye)

Location

Ege University Medical Faculty

Izmir, Turkey (Türkiye)

Location

Hayat Tip Merkezi (Hayat Medical Center) Deapartment of Internal Diseases

Karabük, Turkey (Türkiye)

Location

Morriston Hospital

Swansea, England, SA6 6NL, United Kingdom

Location

Birmingham Heartlands Hospital

Birmingham, United Kingdom

Location

Royal Bournemouth Hospital

Bournemouth, United Kingdom

Location

Rowden Medical Partnership

Wiltshire, United Kingdom

Location

Related Publications (3)

• 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.

  PMID: 25240532 DERIVED

• 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.

  PMID: 24075453 DERIVED

• 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.

  PMID: 23129601 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

canakinumab; Metformin

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

862-778-8300

Study Officials

• Novartis Pharmaceuticals Corporation

  Sponsor GmbH

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 6, 2009
• First Posted: May 12, 2009
• Study Start: April 1, 2009
• Primary Completion: November 1, 2010
• Study Completion: November 1, 2010
• Last Updated: February 20, 2012
• Results First Posted: February 20, 2012

Record last verified: 2012-01

Locations

ZA (7); PE (4); IN (12); US (18); AR (8); CN (1); HU (6); TU (7); KR (5); RO (4); GB (4); BE (3); DE (15); JP (12)