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

Novartis

Status and phase: Terminated; Phase 3; Phase 2

Conditions: Diabetes Mellitus, Type 2

Treatments: Drug: Canakinumab; Drug: Placebo; Drug: Metformin

Study type: Interventional

Funder types: Industry

Identifiers

NCT00900146

CACZ885I2202

Details and patient eligibility

About

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.

Enrollment: 556 patients

Sex: All

Ages: 18 to 74 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

---

556 participants in 5 patient groups, including a placebo group

Canakinumab 5 mg + Metformin

Experimental group

Description:

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.

Treatment:

Drug: Canakinumab

Drug: Metformin

Canakinumab 15 mg + Metformin

Experimental group

Description:

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.

Treatment:

Drug: Canakinumab

Drug: Metformin

Canakinumab 50 mg + Metformin

Experimental group

Description:

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.

Treatment:

Drug: Canakinumab

Drug: Metformin

Canakinumab 150 mg + Metformin

Experimental group

Description:

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.

Treatment:

Drug: Canakinumab

Drug: Metformin

Placebo + Metformin

Placebo Comparator group

Description:

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).

Treatment:

Drug: Placebo

Drug: Metformin