Primary objective : Under conditions of first-line drug treatment in antidiabetic drug naïve/drug free patients (no antidiabetic drug treatment in the last 6 months), with type 2 diabetes mellitus and dyslipidemia, to show that : - the efficacy of a…
ID
Source
Brief title
Condition
- Diabetic complications
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary criteria: HbA1c, TG
Secondary outcome
Secondary criteria:
Efficacy parameters:
• FPG,
• TC, HDL-C, LDL-C, Non-HDL-C, LDL particle size, Apo AI, Apo B, Apo CIII,
• Body weight.
Safety parameters:
• Adverse events,
• Clinical examination including presence of peripheral edema and vital signs,
• Hematology: RBC, hemoglobin, hematocrit, platelets, WBC and differential
count,
• Biochemistry: CPK, AST, ALT, Gamma GT, alkaline phosphatase, total bilirubin,
creatinine, uric acid.
Background summary
Optimal management of individuals with type 2 diabetes mellitus (T2DM) to
prevent both the macrovascular and microvascular complications requires a
multifactorial approach and includes management of hyperglycemia, hypertension,
body weight and the associated abnormal lipid profile. While the management of
hyperglycemia and of hypertension have received considerable attention over the
years, it is only recently that the importance of dyslipidemia - as a major
risk factor for coronary heart disease (CHD) in diabetes - has been recognized
as a key therapeutic target. The American Diabetes Association (ADA) guidelines
[1] suggest that improved glycemic control alone will not be likely to
completely eliminate excess risk of CHD in T2DM patients: clearly a
multifactorial approach is necessary.
The dyslipidemia of T2DM typically includes hypertriglyceridemia (both in the
fasting and
post prandial state), reduced HDL-C, normal total and LDL-C but with a
preponderance ofsmall atherogenic dense LDL particles [2].
Cardiovascular disease, in particular CHD accounts for up to 80% of the
morbidity
observed in patients with T2DM. In comparison to those without diabetes the
risk of CHD is increased 2 - 4 times in patients with diabetes [3]. In a
publication derived from
NHANES III, the age-adjusted prevalence of CHD in Americans over 50 years of
age with
both metabolic syndrome and diabetes was 19.2% which was three fold higher than
that observed in the diabetic patients without the features of metabolic
syndrome [4]. TG elevation in T2DM clearly independently predicts
cardiovascular events [5].
Specific drug treatments (oral antidiabetic drugs or insulin) which improve the
glycemic
control have only a small lipid improving effect, and therefore drug treatments
directed at the specific dyslipidemia of T2DM are now considered key therapies
to reduce the high cardiovascular events in these patients.
The importance of tight glycemic control as demonstrated in the United Kingdom
Prospective Diabetes Study (UKPDS) [6] was confirmed with the use of metformin
therapy in obese patients. Analysis of the results for overweight T2DM patients
in the UKPDS [7] treated with metformin after failure of diet alone showed
significant reductions of diabetesrelated deaths by 42%, of all cause mortality
by 36%, and of risk of myocardial infarction by 39%.
Rosiglitazone, a member of the thiazolidinedione class of antidiabetic agents,
improves
glycemic control by improving insulin sensitivity [8]. Rosiglitazone is a
highly selective
and potent agonist for the peroxisome proliferator-activated receptor-gamma
(PPAR
(gamma)). In humans, PPAR receptors are found in key target tissues for insulin
action
such as adipose tissue, skeletal muscle, and liver. Activation of PPAR (gamma)
nuclear
receptors regulates the transcription of insulin-responsive genes involved in
the control of glucose production, transport, and utilization. In addition,
PPAR (gamma)-responsive genes also participate in the regulation of fatty acid
metabolism.
Metformin is a biguanide widely used as an oral antidiabetic agent for the
first line
treatment of T2DM. It is marketed worldwide, and has been used for more than 40
years. Metformin does not increase pancreatic insulin secretion and, in
contrast to sulphonylureas, does not produce hypoglycemia in either patients
with T2DM or normal subjects. It has beneficial effects on body weight, fasting
plasma insulin levels, fasting blood glucose levels in subjects with visceral
obesity at risk of T2DM and in patient with T2DM [9] [10] [11].
The fibric acid derivatives, which are PPARα agonists, are important
therapeutic drugs
targeting the dyslipidemia of T2DM, in particular the reduction of TG and
increase in
HDL-C. The St Mary*s Ealing Northwick Park Diabetes Cardiovascular Disease
Prevention
(SENDCAP) [12] Study and the Veterans* Affairs High Density Lipoprotein
Cholesterol
Intervention Trial (VA-HIT) [13] both reported significant reductions in
coronary events in patients with T2DM with effective TG lowering with fibrate
therapy.
In the Diabetes Atherosclerosis Intervention Study (DAIS) [14] significantly
lower
progression of angiographic coronary disease was shown on fenofibrate.
Currently both the ADA [1] and NICE Guidance (UK) [15] recommend the addition
of fibrate therapy, either as monotherapy or in combination with statins for
diabetic patients with low HDL-C (< 40mg/dL) and LDL-C between 100 and 129
mg/dl or patients needing treatment for all three lipid fractions.
The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study [
16], the
largest intervention study ever conducted for the prevention of cardiovascular
events in
patients with T2DM, showed that in the subset of patients without prior CVD,
the majority of the FIELD study population, fenofibrate significantly reduced
the first occurrence of non-fatal MI or CHD death and total cardiovascular
events.
Fenofibrate has been shown to be effective in improving lipid abnormalities in
diabetic
patients receiving oral hypoglycemic agents or insulin without any change in
glycemic
control [ 17]. Changes in the lipid profile, which are maintained during
long-term treatment with fenofibrate, are believed to be consistent with a
reduction in the cardiovascular risk.
As of now, no fixed combination of fenofibrate and metformin is registered.
Therefore, coprescription of fenofibrate and metformin is common in diabetic
patients. In France,
approximatively 9% of patients treated with metformin are also treated with
fenofibrate, a total of more than 300,000 prescriptions per year. In the US, 3%
of all prescriptions of products containing metformin (including other fixed
combinations) are in co-prescription with fenofibrate.
Based on the complementary effects of fenofibrate and metformin and their
individual
safety, a single combination tablet of these 2 compounds is being developed by
FOURNIER S.A. achieve additive clinical benefits as well as improvement of
medication
compliance by a reduced number of tablets to be administered. This fixed
combination
(FC), LF23-0121, combines fenofibrate 160 mg and different strengths of
metformin. The overall objective of the clinical development plan is to
evaluate the efficacy and safety of the fenofibrate and metformin FC in
patients with mixed T2DM and dyslipidemia (type IIb/IV).
This study, C LF23-0121 05 01, is part of the clinical development plan of
LF23-0121 and will be conducted in such patients. The trial will be conducted
in compliance with the
protocol, GCP and the applicable local regulatory requirement(s).
Study objective
Primary objective : Under conditions of first-line drug treatment in
antidiabetic drug naïve/drug free patients (no antidiabetic drug treatment in
the last 6 months), with type 2 diabetes mellitus and dyslipidemia, to show
that :
- the efficacy of a fixed combination of fenofibrate and metformin on glycemic
control is not inferior to that of rosiglitazone
- the efficacy of a fixed combination (FC) of fenofibrate and metformin on
triglyceride control is superior to that of rosiglitazone
Study design
Methodology : This study is a double-blind, randomized, controlled, multicenter
study comparing 2 treatments administered through forced titration over 2
periods of 12 weeks each, defined as Period 1 and Period 2. Study drug will
consist of concomitant administration of active fenofibrate and metformin FC +
placebo rosiglitazone or active rosiglitazone + placebo fenofibrate and
metformin FC.
Double-blind on the product (not on the dose), double-placebo.
In Period 1, patients will take daily 2 tablets (1 active and 1 placebo) in the
morning and 1 tablet (active or placebo) in the evening, i.e. a total of 3
tablets per day.
In Period 2, patients will take daily 2 tablets (1 active and 1 placebo) in the
morning and in the evening and 1 tablet (active or placebo) at noon., i.e. a
total of 5 tablets per day.
Active treatments and doses are the following:
Fenofibrate and metformin FC
Fenofibrate and metformin FC (study group)
Period 1 80 mg fenofibrate + 500 mg metformin bid (2 weeks)
80 mg fenofibrate + 850 mg metformin bid* (4 weeks)
Period 2 54 mg fenofibrate + 850 mg metformin tid (6 weeks)
Rosiglitazon (control group)
Period 1 4 mg rosiglitazon od (6 weeks)
Period 2 4 mg rosiglitazon bid (6weeks)
*In order to improve gastrointestinal tolerance to metformin, the FC dose of 80
mg fenofibrate + 850 mg metformin bid will be reached in Period 1 after 2 weeks
of treatment at a lower dose of metformin (500 mg bid).
After a 4 to 6 week run-in period, with standard diet and exercise
recommendations only, the patients will be randomized on the day of V1 to one
of the 2 arms. A balanced stratification between arms will be made based on sex
(male/female), concomitant use of statin (yes/no), and according to HbA1c
value: 6.5% <= HbA1c <= 8% and 8% < HbA1c <= 9.5%.
A Lipid Data Safety Monitoring Board will be setup in order to monitor lipid
values throughout the study. This Lipid Data Safety Monitoring Board will be
constituted of at least two experienced physicians, independent from study
participants.
Intervention
After a 4 to 6 week run-in period, with standard diet and exercise
recommendations only, the patients will be randomized on the day of V1 to one
of the 2 arms. A balanced stratification between arms will be made based on sex
(male/female), concomitant use of statin (yes/no), and according to HbA1c
value: 6.5% <= HbA1c <= 8% and 8% < HbA1c <= 9.5%.
Active treatments and doses are the following:
Fenofibrate and metformin FC (study group)
Period 1 80 mg fenofibrate + 500 mg metformin bid (2 weeks)
80 mg fenofibrate + 850 mg metformin bid* (4 weeks)
Period 2 54 mg fenofibrate + 850 mg metformin tid (6 weeks)
Rosiglitazon (control group)
Period 1 4 mg rosiglitazon od (6 weeks)
Period 2 4 mg rosiglitazon bid (6weeks)
*In order to improve gastrointestinal tolerance to metformin, the FC dose of 80
mg fenofibrate + 850 mg metformin bid will be reached in Period 1 after 2 weeks
of treatment at a lower dose of metformin (500 mg bid).
Study burden and risks
Burden: 5 visits to the trial center.
The screening visit should last 1,5 hour ans the other visits 1 hour.
During these visits there will be taken a blood sample.
The risks of fenofibrate, metformin and roziglitazone are well known, see the
SmPCs of these separate registered drugs.
Anngrove, Carrigtwohill
Co. Cork
Ierland
Anngrove, Carrigtwohill
Co. Cork
Ierland
Listed location countries
Age
Inclusion criteria
At inclusion (V0):
1. Male or female aged from 18 to 75 years old,
2. With type 2 diabetes mellitus and dyslipidemia inadequately controlled with lifestyle modifications (diet and exercise),
3. With antidiabetic drug status as follows:
• Antidiabetic drug naive patients: who have never been on prior antidiabetic drug treatment,
or,
• Antidiabetic drug free patients: who have not received antidiabetic drug treatment in the last 6 months,
4. Having signed a written informed consent.
At randomization (V1):
5. FPG >= 126 mg/dL dL (>= 7.0 mmol/L) and < 300 mg/dL (< 16.7 mmol/L). Glycemic status of the patients will be confirmed based on two FPG assays, BV0 and BV1,
6. HbA1c >= 6.5% and <= 9.5%,
7. Hypertriglyceridemia with or without hypercholesterolemia, defined by TG >= 150 mg/dL and <= 400 mg/dL (TG >= 1.69 mmol/L and <= 4.52 mmol/L), assayed at BV1.
Exclusion criteria
Patient with any of the following conditions will not be included in the trial:
1. Known Type 1 diabetes,
2. With LDL-C > 130mg/dL (3.35 mmol/L),
3. In cardiovascular secondary prevention,
4. Body mass index > 40 kg/m2,
5. Women who are not postmenopausal if they are not surgically sterilized (i.e. bilateral tubal ligation, bilateral or two unilateral oophorectomies, hysterectomy), or not using adequate contraceptive precautions,
6. Pregnant or lactating women,
7. Known hypersensitivity to fibrates, metformin, rosiglitazone or any of their components or known photoallergic or phototoxic reactions under treatment with fibrates or ketoprofen,
8. Known allergy to peanut or arachis oil or soya lecithin or related products due to the risk of hypersensitivity reactions,
9. Having received an investigational drug in the last 30 days before date of inclusion,
10. Unable or unwilling to comply with the protocol and the standard diet and exercise recommendations,
11. Likely to withdraw from the study before its completion.;Concomitant medications:
12. Treated within the last 6 months before randomization with any antidiabetic drug treatment,
13. Treated within the last 2 months before randomization with a lipid-lowering drug (except statins). Patients who were on a statin before inclusion may be included provided the dose does not exceed the maximum daily dose authorized in the study ) and is kept constant throughout the study.
14. Treated within the last 2 months before randomization with cyclosporin A, and any other immunosuppressive agent, with protease inhibitors (indinavir, ritonavir, saquinavir, *), for obesity by medical treatment (orlistat, sibutramine*) and/or surgery (gastroplasty, bypass,*), with rifampin (inducer of CYP2C8)
15. Change within the last 2 months before randomization, and during the course of the study, in the medications that could interfere with the lipid or glycemic profile.;Associated diseases or conditions:
16. Diabetic ketoacidosis, diabetic pre-coma,
17. Current chronic pancreatitis, or identified risk or known history of acute pancreatitis,
18. Known cholelithiasis without cholecystectomy,
19. Significant hepatic disease: AST and/or ALT > 2 times the upper limit of normal (ULN),
20. Musculoskeletal disease with increased creatine phosphokinase (CPK) > 3 times ULN,
21. Renal failure or renal dysfunction defined by a creatinine clearance < 60 mL/min as calculated with the Cockroft-Gault algorithm: creatinine clearance = [(140 - age) x weight (kg) / 7.2 x serum creatinine (mg/L)] for males and [x 0.85] in females,
22. Acute conditions with the potential to alter renal function (such as dehydration, severe infection, shock, intravascular administration of iodinated contrast agents),
23. Acute or chronic disease which may cause tissue hypoxia such as respiratory failure,
24. Known congestive heart failure or past medical history of congestive heart failure (class I to IV),
25. Known abnormal thyroid hormone levels, or high thyroid stimulating hormone (TSH) level. (clinically euthyroid subjects on stable replacement doses of thyroid hormone are eligible for inclusion),
26. Other uncontrolled endocrine or metabolic disease known to influence serum lipids or lipoproteins,
27. Patients particularly susceptible to hypoglycemic effects, such as debilitated, or malnourished patients, acute alcohol intoxication, excessive alcohol intake,
28. Known gastric or peptic ulcer or intestinal disease within the previous 3 months of randomization capable of modifying the intestinal absorption of the drugs,
29. Any other severe pathology such as cancer or mental illness or degenerative disease that would limit study evaluation or participation.;In addition in patients aged under 35 years the following exclusion criteria will apply:
30. Body mass index < 25 kg/m2,
31. Ever been treated by Insulin,
32. Family history of type 1 diabetes.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2005-006060-63-NL |
| CCMO | NL12150.003.06 |