| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Type II Diabetes Mellitus |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10012601 |
| E.1.2 | Term | Diabetes mellitus |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
For Period II
• To assess safety and tolerability of four doses of ACZ885 (5 mg, 15 mg, 50 mg, and
150 mg) vs. placebo as an add-on regimen over 4 months in patients with T2DM pretreated
and continuing on a stable dose of metformin ≥ 1000 mg daily (or lower dose if
required by local regulations).
• To assess the effect on HbA1c of four doses of ACZ885 (5 mg, 15 mg, 50 mg, and 150 mg) vs. placebo as an add-on regimen over 4 months in patients with T2DM pretreated and continuing on a stable dose of metformin ≥ 1000 mg daily (or lower dose if required by local regulations).
• To assess the anti-apoptotic effect of ACZ885 vs. placebo on the meal challenge
derived dynamic phase secreted insulin per unit of glucose concentration (Φd) in
patients with T2DM who have been on study drug for 4 months, an interim analysis
will be performed when 150 patients complete the Meal Challenge Test at Visit 8.
For Period III
see full protocol
For Period IV
see full protocol |
|
| E.2.2 | Secondary objectives of the trial |
For Period II:
• To evaluate the effect of 4-month treatment of ACZ885 at doses 5 mg, 15 mg, 50 mg, and 150 mg vs. placebo on the following variables:
- Area under the curve (AUC) and peak values of C-peptide following meal test
- Area under the curve (AUC), 2-hour value and peak value of glucose and insulin following meal test
- Insulin secretion rate derived based on glucose and C-peptide following meal test
- Average and peak values based on 7-point glucose meter data
For Period IV:
• To evaluate the effect of long-term treatment of ACZ885 at the dose selected based on the efficacy and safety data from the 4-month treatment period vs. placebo on the following variables:
- Duration of insulin use and insulin dose
- Area under the curve (AUC) and peak values of C-peptide following meal test
- Area under the curve (AUC), 2-hour value and peak value of glucose and insulin following meal test
For detailed list see full protocol |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patients must give written informed consent before any study related procedures are
performed.
2. Patients must have a documented diagnosis of Type 2 diabetes confirmed by WHO criteria
either a FPG≥ 7.0 mmol/l (126 mg/dl) or an OGTT test 2-hour PG ≥ 11.1 mmol/l (200
mg/dl). This documented diagnosis must be available prior to screening of the patient.
3. Patients must:
• be naïve to anti-diabetes drug therapy (except for short term treatment courses with
insulin in connection with hospitalization)
• have an HbA1c between 7.5% and 11% (inclusive) at Screening analyzed by the
Central Laboratory
• be eligible for metformin monotherapy
OR
• be on stable metformin monotherapy treatment for at least three months at
Screening
• have an HbA1c between 7.0% and 9% (inclusive) at Screening analyzed by the
Central Laboratory
• take metformin as their first and only treatment with anti-diabetes drug therapy
(except for short term treatment courses with insulin in connection with
hospitalization, etc.)
OR
• be taking an α-glucosidase inhibitor as their first and only treatment with antidiabetes
drug therapy (except for short term treatment courses with insulin in
connection with hospitalization, etc.)
• have the α-glucosidase inhibitor stopped and be washed out from the α-glucosidase
inhibitor for at least a week prior to Run-in
• have an HbA1c between 7.0% and 9.0% (inclusive) at Screening analyzed by the
Central Laboratory
• be eligible for metformin monotherapy
4. Patients must have a morning fasting plasma glucose result < 180 mg/dl (< 10.0 mmol/l )
at Visit 3 (Month -1) analyzed by the Central Laboratory.
5. At the Randomization Visit (Month 0), patients must be on a daily dose of metformin ≥
1000 mg (or less if local regulation does not permit 1000 mg/day).
6. Age from 18-74 years, inclusive, and of either sex. |
|
| E.4 | Principal exclusion criteria |
1. Type 1 diabetes, diabetes that is a result of pancreatic injury or secondary forms of
diabetes, e.g. Cushing’s syndrome and acromegaly.
2. Any of the following significant laboratory abnormalities:
• Serum GAD-antibody positivity analyzed by the Central Laboratory.
• Clinically significant TSH outside of normal range at Screening analyzed by the
Central Laboratory.
• 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) at Screening, confirmed with repeat measure within one week.
• Total bilirubin >2 times ULN and/or direct bilirubin greater than the ULN at
Screening, confirmed by a repeat measurement within one week.
3. Known chronic liver disease of any aetiology.
4. History or current findings of active pulmonary disease (e.g. tuberculosis, fungal
diseases) as evidenced by any of the following:
• History of positive PPD skin test result followed by positive chest x-ray/positive
QFT-G test and no completion of treatment.
• A positive PPD skin test followed by a positive chest x-ray or positive QFT(-G) test
(with or without positive chest x-ray) during the screening period.
• History of a positive QFT(-G) test and no completion of treatment.
• History of a positive AFB sputum sample and no completion of treatment.
• Requirement for administration of antibiotics against latent tuberculosis (e.g.,
isoniazide). Courses of antibiotic therapy started prior to entering the study should not
be prematurely terminated to allow inclusion into the study.
5. One of the risk factors for TB such as:
• History of any of the following: residence in a congregate setting (e.g. jail or prison,
homeless shelter, or chronic care facility), substance abuse (e.g. injection or non
injection); health-care workers with unprotected exposure to patients who are at high risk of TB or patients with TB disease before the identification and correct airborne precautions of the patient, or
• Close contact (i.e. share the same air space in a household or other enclosed
environment for a prolonged period (days or weeks, not minutes or hours)) with a
person with active pulmonary TB disease.
6. 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 immunocompromisation,
including patients with evidence of Human Immunodeficiency Virus (HIV) infection.
7. Known presence or suspicion of active or recurrent Hepatitis B and Hepatitis C infections
(based on history and/or findings from the Central Lab).
8. Any surgical or underlying hepatic, hematologic, pulmonary, infectious, autoimmune or
gastrointestinal conditions which in the opinion of the investigator immunocompromises
the patient and/or places the patient at unacceptable risk for participation in
immunodulatory therapy.
9. Any systemic treatment or local treatment of any immune modulating agent in doses with
systemic effects. Topical, inhaled or local steroid use in doses that are not considered to
cause systemic effects are permitted.
10. Live vaccinations within 3 months prior to the Randomization Visit or live vaccinations
planned during the trial and up to three months following the last dose.
11. Stroke, myocardial infarction, acute coronary syndrome, revascularization procedure or
recurrent TIA within the last 6 months.
12. Unwillingness to use insulin glargine as the additional medication should glycemic control
deteriorate.
13. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 halflives
of enrollment, whichever is longer.
14. History of hypersensitivity to any of the study drugs or to drugs of similar chemical
classes.
15. History of malignancy of any organ system (other than localized basal cell carcinoma of
the skin), treated or untreated, within the past 5 years, regardless of whether there is
evidence of local recurrence or metastases.
16. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female
after conception and until the termination of gestation, confirmed by a positive hCG
laboratory test (> 5 mIU/mL).
see full list in Protocol |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy variable for the dose finding period (Period II) is the change from baseline in HbA1c at Month 4. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 18 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 44 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 15 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 15 |
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