| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
- Incidence of CV outcomes compared to placebo for the TZD class as a whole, rosiglitazone (RSG), and pioglitazone (PIO) when added to the therapeutic regimen of a person with type 2 diabetes who has additional risk factors for CV events.
- Determine whether adding vitamin D in such individuals is superior to adding placebo with respect to reducing the incidence of death or serious cancers requiring hospitalization, chemotherapy or surgery compared to placebo. |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10012601 |
| E.1.2 | Term | Diabetes mellitus |
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| 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 |
This trial will determine the relative incidence of CV outcomes compared to placebo for the TZD class as a whole, rosiglitazone (RSG), and pioglitazone (PIO) when added to the therapeutic regimen of a person with type 2 diabetes who has additional risk factors for CV events.
The trial will also separately determine whether adding vitamin D in such individuals is superior to adding placebo with respect to reducing the incidence of death or serious cancers requiring hospitalization, chemotherapy or surgery compared to placebo. This will be assessed both at the end of the TZD follow-up phase and then after up to 10 years of total follow-up.
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| E.2.2 | Secondary objectives of the trial |
Secondary objectives (TZDs): assess at 4.5 years if rosiglitazone is non-inferior to pioglitazone with respect to the primary outcome and if pioglitazone is non-inferior to placebo with respect to the primary outcome. Assess if the addition of a TZD versus placebo for up to 5.5 years will reduce total mortality. We also aim to answer the questions: does the addition of rosiglitazone versus placebo for up to 5.5 years reduce: a) the primary outcome; b) total mortality; or c) microvascular outcomes?Does the addition of pioglitazone versus placebo for up to 5.5 years reduce a) the primary outcome; b) total mortality; or c) microvascular outcomes?
Secondary questions (Vitamin D): a) does the addition of vitamin D for up to 10 years versus placebo reduce total mortality? b) does the addition of vitamin D versus placebo for up to 10 years reduce total fractures?
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Men or women with:
a) newly detected type 2 diabetes based on a fasting plasma glucose higher than 7.0 mmol/l (126 mg/dL) or a 2 hour plasma glucose higher than 11.1 mmol/l (200 mg/dL) on an oral glucose tolerance test, or b) a history of type 2 diabetes
2. A1C 6.5-9.5% inclusive
3. A) Age ≥ 50 years and evidence of vascular disease(at least 1):
a) prior myocardial infarction
b) prior stroke
c) coronary, carotid or peripheral artery revascularization ≥4 years earlier
d) previous documented myocardial ischemia on either an exercise stress test or on any cardiac imaging, or previous unstable angina with ECG changes or cardiac enzyme elevation
OR
B) Age ≥ 55 years and evidence of subclinical vascular disease (at least 1):
a) microalbuminuria or proteinuria
b) history of treated or untreated hypertension with left ventricular hypertrophy by ECG or echocardiogram
c) >50% stenosis on any imaging of coronary, carotid or lower extremity arteries
d) ankle/brachial index <0.9
OR
C) Age ≥ 60 years and at least 2 of the following CVD risk factors:
a) current tobacco use
b) LDL-C ≥3.4 mmol/L (130 mg/dL)
c) HDL-C < 1.0 mmol/L (40 mg/dL) for men and < 1.3 mmol/L (50 mg/dL) for women or triglycerides ≥ 2.3 mmol/L (200 mg/dL)
d) BP lowering medication use or untreated SBP ≥ 140 mmHg or DBP ≥ 95 mmHg
e) Waist to hip ratio > 1.0 for men and > 0.8 for women
4. On no insulin and on less or equal than 2 anti-diabetes drugs (OAD) where at least one drug is at or below the half-maximal dose (as indicated in the MOP) with stable dosing for 10 weeks prior to screening
5. A negative pregnancy test for all females of childbearing potential (i.e., ovulating, pre-menopausal, and not surgically sterile) and agreement to use adequate birth control (according to local regulations) throughout the study
6. Adherence ≥80% and tolerability to single-blind study medication during the run-in phase
7.Provision of signed and dated informed consent prior to any study procedures |
|
| E.4 | Principal exclusion criteria |
1. Type 1 diabetes
2. Current need for insulin treatment
3. Symptomatic hyperglycemia requiring immediate therapy in the judgment of the physician
4. An acute cardiovascular event within 30 days prior to randomization
5. Symptomatic heart failure (i.e. New York Heart Association class II or higher) or any episode of previous pulmonary edema or known ejection fraction < 0.4 or current use of loop diuretics
6. Any fracture within the past 1 year
7. Currently planned coronary, carotid or peripheral artery revascularization or cardiac valve surgery
8. Coronary, carotid or peripheral artery revascularization within the 4 years prior to screening in the absence of angina, MI, or stroke in the intervening period
9. End stage renal disease requiring renal replacement therapy
10. Receiving drug therapy to treat liver disease
11. A diagnosis of cancer (other than superficial squamous, basal cell skin cancer, or adequately treated cervical carcinoma in situ) in the past 3 years of current treatment for the active cancer (other than prophylactic)
12. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level > 2.5 times the upper limit of normal
13. A prior heart transplant or awaiting a heart transplant
14. Previous or current hypercalcemia, hyperparathyroidism, osteomalacia or other indication or contraindication for vitamin D therapy
15. Clinically or medically unstable with expected survival < 1 year
16. Unwillingness to permit sites to contact their primary physicians to communicate information about the study and the participant’s data
17. Any other factor likely to limit protocol compliance or reporting of adverse events
18. Inability to discontinue a TZD (if taking one) in the judgement of the physician/investigator
19. Contraindications to or history of hypersensitivity to the investigational products
20. History of renal stones within the past 2 years
21. Participation in another clinical trial of an investigational agent
22. Previous randomization in this study
French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The composite cardiovascular primary outcome for the TZD research questions is the first occurrence of either: a) cardiovascular (CV) death; b) nonfatal myocardial infarction (MI); or c) nonfatal stroke.
The composite primary outcome for the vitamin D research question is death or serious cancer requiring hospitalization, chemotherapy or surgery. |
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| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| 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) | No |
| 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) | Yes |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 240 |
| 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 |
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| 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
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| The follow-up time planned in the protocol is a maximum of 5.5 years (i.e. 5.5 years after randomization of the first subject). This is the anticipated duration of follow-up required to accumulate a sufficient number of events to assess the primary outcomes. The end of trial is defined as when all patients have completed the final visit or have been contacted to ascertain their health status. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 10 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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