Diabetes Mellitus, Type 2Phase 2/3NCT00900146
Dose Finding, Safety and Efficacy of Monthly Subcutaneous Canakinumab Administration in Metformin Monotherapy Treated Type 2 Diabetic Patients
A Phase 2/3 study testing Canakinumab and Metformin in people with Diabetes Mellitus, Type 2, run by Novartis at 106 sites in 14 countries.
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. Read more about this study
- Who is it for?
- Ages 18 to 74 years
- Conditions the study is for
- Diabetes Mellitus, Type 2
- What is being tested?
- Canakinumab and Metformin
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 556 participants
- Where
- 106 sitesin 14 countries
- Study dates
- Apr 2009to Nov 2010
- Phase
- Phase 2/3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 74 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Show all 13Show fewer
- 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)
Who cannot join
- 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.
Show all 13Show fewer
- 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.
- Other protocol-defined inclusion/exclusion criteria may apply
Trial locations and contacts
106 sites in 14 countries.
106 sites in 14 countries
United States18 sites
Novartis Investigative Site
Atlanta, Georgia
Tri-State Medical Group
Beaver, Pennsylvania
Novartis Investigative Site
Columbia, South Carolina
Diabetes Research Center
Columbus, Ohio
Deaconess Clinic
Evansville, Indiana
Novartis Investigative Site
Jackson, Mississippi
Whittier Institute of Diabetes
La Jolla, California
R/D Clinical Research
Lake Jackson, Texas
Novartis Investigative Site
Los Gatos, California
Novartis Investigative Site
Pasadena, Texas
Anasazi Internal Medicine
Phoenix, Arizona
Novartis Investigative Site
Picayune, Mississippi
Preferred Primary Care Physicians
Pittsburgh, Pennsylvania
Novartis Investigative Site
San Antonio, Texas
Novartis Investigative Site
Santa Monica, California, 90404
Novartis Investigative Site
Trenton, New Jersey
Orange County Research Center
Tustin, California
Medical Research Initiatives Inc
Virginia Beach, Virginia
Germany15 sites
Praxis F. Franzmann
Bad Oeynhausen, 32549
emovis GmbH
Berlin, 10629
Praxis Dr. Stütz
Bretten, 75015
GWT-TUB GmbH
Dresden, 01307
Gemeinschaftspraxis und Dialysezentrum Karlstraße
Düsseldorf
Asklepios Klinik St. Georg
Hamburg, 20099
Städt. Kankenhaus Nordstadt
Hanover, 30167
Diabeteszentrum Hohenmölsen
Hohenmölsen, 06679
Johannes Gutenberg-Universität Mainz
Mainz, 55101
Zentrum für Klinische Forschung Neuwied (ZKSN)
Neuwied, 56564
Praxis Dr. Wunderer
Nuremberg, 90489
Praxis Dr. Kosch
Pirna, 01796
Praxis Dr. Alawi
Saarlouis, 66740
Praxis Dr. Klein
Schenklengsfeld, 36277
Forschungszentrum Ruhr, KliFoCenter GmbH
Witten, 58455
India12 sites
Bangalore Diabetes Hospital
Bangalore
Gokula Metropolis Clinical Research Centre
Bangalore
Jnana Sanjeevini Medical Center
Bangalore
SAMATVAM
Bangalore
Madras Diabetes Reasearch Foundation
Chennai
Nizam's Institute of Medical Sciences
Hyderabaad
Diabetes Thyroid Hormone Research Institute Pvt. Ltd.
Indore
S R Kalla Memorial Gastro & General Hospital
Jaipur
Amrita Institute of Medical Sciences and Research Center
Kochi
Pitale Diabetes & Hormone Centre
Nagpur
Health and Research Centre
Trivandrum
King George Hospital
Visakhapatnam
Japan12 sites
Saiseikai Fukuoka General Hospital
Fukuoka, Fukuoka, 810-0001
Kyushu Rosai Hospital
Kitakyushu, Fukuoka, 800-0296
Kokura Medical Center
Kitakyushu
Musashikoganei Clinic
Koganei, Tokyo, 184-0004
Seino Internal Medicine Clinic
Kōriyama
Geriatrics Research Institute Hospital
Maebashi
Novartis Investigative Site
Minato-ku, Tokyo
National Hospital Organization Nagoya Medical Center
Nagoya, Aichi-ken, 460-0001
Takagi Hospital
Ohkawa
Sakai Hospital Kinki University School of Medicine
Sakai
Fujikoshi Hospital
Toyama, Toyama, 930-0964
NHO Yokohama Medical Center
Yokohama, Kanagawa, 245-8575
Argentina8 sites
DIM Clinica Privada
Buenos Aires, Buenos Aires, B1704ETD
Centro Medico Viamonte
Buenos Aires, Buenos Aires, C1120AAC
Consultorios Asociados de Endocrinologia
Buenos Aires, Buenos Aires, C1425AGC
Hospital Juan Ramon Vidal
Corrientes, Corrientes Province, W3410AVV
Clinica de Fracturas y Ortopedia
Mar del Plata, Buenos Aires, C1100ABB
Novartis Investigative Site
Rosario Santa Fe, S2000AII
Instituto de Investigaciones Biomedicas
Santa Fe, Santa Fe Province, S3000FNF
Centro de Investigaciones Clinicas del Litoral
Santa Fe, Santa Fe Province, S3000FWO
South Africa7 sites
203 Maxwell Centre
Durban
Parklands Medical Centre
Durban
St Augustines Medical Centre
Durban
Synapta Clinical Research Centre
Durban
Drs Essack and Mitha
Johannesburg
26 Daffodil Street
KwaDukuza
PE Greenacres Hospital
Port Elizabeth
Turkey (Türkiye)7 sites
Ankara Ataturk Training and Research Hospital
Ankara
Gulhane Askeri Tip Akademisi
Ankara
Hacettepe University Medical Faculty
Ankara
S.B. Yildirim Beyazit Training and Research Hospital
Ankara
Istanbul University Cardiology Institute
Istanbul
Ege University Medical Faculty
Izmir
Hayat Tip Merkezi (Hayat Medical Center) Deapartment of Internal Diseases
Karabük
Hungary6 sites
Fővárosi Önkormányzat Péterfy Sándor Utcai Kórház - Rendelőintézet és Baleseti Központ
Budapest
Sandor Karolyi Hospital
Budapest
Semmelweiss Medical University
Budapest
Kenezy Gyula Korhaz
Debrecen
Szegedi Egyetem
Szeged
Zala Megyei Korhaz
Zalaegerszeg
South Korea5 sites
Novartis Investigative Site
Pusan, 614-735
Novartis Investigative Site
Seoul, 135-710
Novartis Investigative Site
Seoul, 135-720
Novartis Investigative Site
Seoul, 139-872
Novartis Investigative Site
Suwon, 442-721
Peru4 sites
Instituto Delgado de Investigacion Medica
Arequipa
Clinica Chiclayo
Chiclayo
Hospital Nacional Cayetano Heredia
San Martín de Porres
Centro de Investigacion Clinica Trujillo
Trujillo
Romania4 sites
Ambulatory of Institute of Nutrition Diseases and Diabetes
Bucharest
Medical Centre "Sanatatea ta"
Bucharest
Novartis Investigative Site
Bucharest
Policlinica Dr. Citu Timisoara
Timișoara
United Kingdom4 sites
Birmingham Heartlands Hospital
Birmingham
Royal Bournemouth Hospital
Bournemouth
Morriston Hospital
Swansea, England, SA6 6NL
Rowden Medical Partnership
Wiltshire
Belgium3 sites
Private Practice - DEMEULEMEESTER
Gozée
Novartis Investigative Site
Heist-op-den-Berg
UZ Brussel
Jette
About this study
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
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
- Being tested
- Canakinumab, Metformin, Placebo
- Keywords
- type 2 diabetes, canakinumab
- Medical subject headings
- Diabetes Mellitus, Type 2
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CanakinumabDrug
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.
MetforminDrug
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.
PlaceboDrug
Placebo lyophilized cake will be reconstituted and then used to dilute the 25mg or 150mg solutions to make 5mg, 15mg and 50mg injections.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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). Receives: Drug: Metformin; Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 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)
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.
Measured: Baseline, Month 4
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 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.
Measured: Baseline, Month 4
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 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.
Measured: Baseline, Month 4
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.
Measured: Baseline, Month 4
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.
Measured: Baseline, Month 4
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.
Measured: Baseline, Month 4
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.
Measured: Baseline, Month 4
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.
Measured: Baseline, Month 4
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.
Measured: Baseline, Month 4
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.
Measured: Baseline, Month 4
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.
Measured: Baseline, Month 4
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.
Measured: Baseline, Month 4
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.
Measured: Baseline, Month 4
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 (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.
Measured: Baseline, Month 4
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 (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.
Measured: Baseline, Month 4
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.
Measured: Baseline, Month 4
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.
Measured: Baseline, Month 4
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.
Measured: Baseline, Month 4
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 May 2009 (estimated)
- Study startApr 2009
- Primary completionNov 2010
- Study completionNov 2010
Why it stopped: Numerically modest lowering of HbA1c with canakinumab in combination with metformin was inadequate to continue patients with T2DM into Period IV of this study.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Diabetes Mellitus, Type 2Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 556 participants (actual)
Sponsor and investigators
- Lead sponsor
- Novartis
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Novartis Pharmaceuticals Corporation, Study director, Sponsor GmbH
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00900146
- Sponsor's protocol ID
- CACZ885I2202
- Status last verified
- Jan 2012
- First submitted
- 6 May 2009
- Last updated
- 20 Feb 2012
- Results posted
- Yes, on ClinicalTrials.gov
Publications
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.
PubMed 25240532Hensen 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.
PubMed 24075453Ridker 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.
PubMed 23129601
Study at a glance
From the registry record, last updated by the sponsor on 20 Feb 2012. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT00900146
- Acronym / sponsor ID
- CACZ885I2202
- Conditions
- Diabetes Mellitus, Type 2
- Keywords
- type 2 diabetes, canakinumab
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Numerically modest lowering of HbA1c with canakinumab in combination with metformin was inadequate to continue patients with T2DM into Period IV of this study.
- Enrolment
- 556 participants (actual)
- Lead sponsor
- NovartisIndustry (pharma, biotech, devices)
- Study start
- Apr 2009
- Primary completion
- Nov 2010 (actual)
- Study completion
- Nov 2010 (actual)
- First posted
- 12 May 2009 (estimated)
- Results
- Posted 20 Feb 2012
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 5
| Arm | Type | Receives |
|---|---|---|
| Canakinumab 5 mg + Metformin | Experimental | Drug: Canakinumab, Drug: MetforminIn 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 | Experimental | Drug: Canakinumab, Drug: MetforminIn 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 | Experimental | Drug: Canakinumab, Drug: MetforminIn 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 | Experimental | Drug: Canakinumab, Drug: MetforminIn 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 | Placebo comparator | Drug: Metformin, Drug: PlaceboIn 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). |
Who may qualify
- Ages
- 18 to 74 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (13 listed)
- 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:
- 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)
Key exclusion criteria (13 listed)
- Type 1 diabetes, diabetes resulting from pancreatic injury or secondary forms of diabetes.
- Any of the following significant laboratory abnormalities:
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| CanakinumabCanakinumab 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 | Canakinumab 15 mg + Metformin, Canakinumab 150 mg + Metformin, Canakinumab 5 mg + Metformin, Canakinumab 50 mg + Metformin |
| MetforminBefore 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 | Canakinumab 15 mg + Metformin, Canakinumab 150 mg + Metformin, Canakinumab 5 mg + Metformin, Canakinumab 50 mg + Metformin, Placebo + Metformin |
| PlaceboPlacebo lyophilized cake will be reconstituted and then used to dilute the 25mg or 150mg solutions to make 5mg, 15mg and 50mg injections. | Drug | Placebo + Metformin |
Primary outcome
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)
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
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
This was planned as interim analysis and was not conducted because the study was terminated in period III.
18 secondary outcomes
Change From Baseline in C-peptide Area Under Curve (AUC 0-4 Hours ) Following Meal Test (Period II)
Time frame: Baseline, Month 4
Change From Baseline in Prandial Plasma Glucose Area Under Curve (AUC0-4 Hours ) Following Meal Test (Period II)
Time frame: Baseline, Month 4
Change From Baseline in Insulin Area Under Curve (AUC 0-4 Hours ) Following Meal Test (Period II)
Time frame: Baseline, Month 4
Change From Baseline in 2-hour Glucose Level Following Meal Test (Period II)
Time frame: Baseline, Month 4
Change From Baseline in Peak Glucose Level Following Meal Test (Period II)
Time frame: Baseline, Month 4
Change From Baseline in Peak C-peptide Following Meal Test (Period II)
Time frame: Baseline, Month 4
Change From Baseline in Peak Insulin Level Following Meal Test (Period II)
Time frame: Baseline, Month 4
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
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
Change From Baseline in Peak Plasma Glucose Level (7-point Glucose Testing) at Month 4(Period II)
Time frame: Baseline, Month 4
Change From Baseline in Average Plasma Glucose Level (7-point Glucose Testing) at Month 4 (Period II)
Time frame: Baseline, Month 4
Change From Baseline in Fasting Plasma Glucose at Month 4 (Period II)
Time frame: Baseline, Month 4
Change From Baseline in Fasting Insulin at Month 4 (Period II)
Time frame: Baseline, Month 4
Change From Baseline in Homeostatic Model Assessment B (HOMA2 B) Beta Cell Function (%B) at Month 4 (Period II)
Time frame: Baseline, Month 4
Change From Baseline in Homeostatic Model Assessment Insulin Resistance (HOMA2 IR) at Month 4 (Period II)
Time frame: Baseline, Month 4
Change From Baseline in Quantitative Insulin Sensitivity Check Index (QUICKI) at Month 4 (Period II)
Time frame: Baseline, Month 4
Change From Baseline in High-sensitivity C-reactive Protein (hsCRP) at Month 4 (Period II)
Time frame: Baseline, Month 4
Percentage Change From Baseline in Fasting Lipids Profile at Month 4 (Period II)
Time frame: Baseline, Month 4
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Feb 2012.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 25240532Noe 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.
- Derived from this study: PubMed 24075453Hensen 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.
- Derived from this study: PubMed 23129601Ridker 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.
Related trials for Diabetes Mellitus, Type 2
Not yet recruitingPhase 3
Efficacy and Safety of Once-Weekly SHR-3167 Compared With Once-Daily Insulin Glargine in Adults With Insulin-Naive Type 2 Diabetes
Type 2 Diabetes
Active, not recruiting
Digital Reinforcement of Motivational Interviewing Micro-Skills Among Primary Care Healthcare Professionals
Hypertension (Without Type 2 Diabetes Mellitus)
Recruiting
Investigating Vascular Properties of HEMI and SPG Signals in Individuals With or at Risk for Chronic Kidney Disease
Chronic Kidney Disease, Hypertension (HTN)
Not yet recruitingPhase 3
A Study to Evaluate the Effectiveness and Safety of the Drug AZD6234 for Managing Weight in Adults Who Are Obese or Overweight. These Participants May or May Not Also Have Type 2 Diabetes
Obesity, Overweight
Not yet recruiting
Impact of Endoscopic Sleeve Gastroplasty (ESG) in Obese Adults With Type 2 Diabetes (T2D)
Type 2 Diabetes Mellitus (T2D), Obesity (BMI>30)
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Novartis Pharmaceuticals Corporation study director
Sponsor GmbH
106 sites in 14 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Canakinumab and Metformin in people with Diabetes Mellitus, Type 2, run by Novartis at 106 sites in 14 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 20 Feb 2012. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 106 sites in United States, Germany, India, Japan, Argentina and 9 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 20 Feb 2012). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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)). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00900146, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Feb 2012.