The primary objective of this study is to demonstrate the superiority of insulin glargine over liraglutide in termsof percentage of patients reaching a HbA1c < 7% at the end of the comparative period in Type 2 diabetic patientsfailing…
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Brief title
Condition
- Glucose metabolism disorders (incl diabetes mellitus)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The main criterion will be the percentage of patients reaching a HbA1c < 7% at
the end of the comparative period
(week 24).
Secondary outcome
To assess the effect of insulin glargine in comparison with liraglutide on:
* HbA1c level
* Percentage of patients whose HbA1c has decreased but remains >= 7% at the end
of the comparative period
* Percentage of patients whose HbA1c has increased at the end of the
comparative period
* Fasting Plasma Glucose (FPG)
* 7-point Plasma Glucose (PG) profiles
* Hypoglycemia occurrence
* Body weight
* Adverse events
* Patient reported outcome measures (PROMs): DTSQs, DTSQc and ADDQoL
* Diabetes specific treatment costs
Background summary
Diabetes treatment and management is evolving. New classes of drugs are being
tested and introduced to the market. One of the most promising field of
research is constituted by the incretin therapies that include both DiPeptidyl
Peptidase IV (DPP-IV) inhibitors and
Glucagon Like Peptide-1 (GLP-1) analogues.
The GLP-1 analogues are injectable drugs that aim at maintaining glucose
homeostasis through various mechanisms that include insulin secretion
stimulation, glucagon secretion inhibition, gastric emptying delay and central
enhancement of satiety (1). The main clinical outcomes of these actions are a
glucose-dependent regulation of blood glucose levels with a very limited risk
of hypoglycemia and a decrease in body weight (1). These are very desirable
outcomes as many other hypoglycemic agents are associated with either a risk of
hypoglycemia or a body weight increase or both. Exenatide, an Eli Lilly
compound, was the first GLP-1 analogue to be marketed (in 2006-2007); exenatide
is an
injectable drug to be administered twice daily. Liraglutide, a Novo Nordisk
compound, represents a step forward as it is a once daily drug and seems to
have a better efficacy than exenatide (2). It has been approved in Europe by
the EMEA in 2009 and is already
launched in a few European countries. It has also been recently approved by the
FDA and is about to be launched in the US.
Despite these promises, GLP-1 analogues are currently considered by the
ADA/EASD recommendations as tier 2 options due to the relatively limited
knowledge and the lack of long term experience. Indeed, the current ADA/EASD
guidelines recommend as tier 1 option well validated drugs such as metformin,
sulfonylureas and basal insulin. It is interesting to note that in case of non
response with GLP-1 analogues, the ADA/EASD societies recommend stopping the
GLP-1 analogue and switching to another drug including the introduction of
basal insulin (3).
Insulin glargine is a once daily insulin analogue that covers the
patients*needs in terms of basal insulin supplementation. It is a well studied
drug that allows patients insufficiently controlled with oral agents to reach a
HbA1c close to or below 7% in the majority of the
cases provided an adequate and tight titration of the insulin glargine dose
(4). As for many drugs, the response rate to insulin glargine depends on the
initial HbA1c level (the lower the HbA1c level, the higher the response rate),
but even for high baseline HbA1c levels,
insulin glargine is able to provide decent response rates (5). Compared with
the traditional NPH insulin, it has been demonstrated that insulin glargine
reduces the risk of hypoglycemia especially at night (6).
Liraglutide is a once daily GLP-1 analogue that has been carefully evaluated
through the LEAD programme, a programme comprising 6 randomized controlled
trials implemented in Type 2 Diabetes (T2D) patients failing oral agents (2,
7-11). In these studies, liraglutide
was associated with a HbA1c decrease ranging 1-1.5%. In the LEAD 5 trial (7)
that compared liraglutide and insulin glargine, liraglutide was found slightly
more efficient than insulin glargine but the way the insulin glargine dose was
titrated was questionable: indeed, the final insulin glargine dose was
surprisingly low and the final fasting blood glucose higher than in other
treat-to-target trials (4). In all the LEAD trials the mean baseline HbA1c was
around 8-8.5% and little is known about the effects of the drug in patients
with high HbA1c levels.
The current study will mainly compare the introduction of insulin glargine and
liraglutide in a population of T2D patients uncontrolled by their oral
treatment. Compared with the LEAD 5 study, the current study design aims at a
broader population allowing patients
with higher baseline HbA1c levels to enter the study. It will also try to
achieve a better insulin dose titration thanks to a carefully designed
titration algorithm and to the implementation of an independent Titration
Committee that will advise the investigators in
case of difficulties. The maintenance dose of liraglutide used in the study
will be the one recommended by the Summary of Product Characteristics (SmPC)
(i.e. 1.8mg/day with the option of decreasing to 1.2mg/day in case of poor
tolerance).
Study objective
The primary objective of this study is to demonstrate the superiority of
insulin glargine over liraglutide in terms
of percentage of patients reaching a HbA1c < 7% at the end of the comparative
period in Type 2 diabetic patients
failing lifestyle management and oral agents.
Study design
Phase IIIb/IV, multicenter, international, 24-week, randomized (1:1),
parallelgroup,open-label, comparative study followed by a 24-week extension
period with insulin glargine for patients not adequately controlled with
liraglutide.
Intervention
Not applicable
Study burden and risks
During the screening visit (week -2) a blood sample (8 mL of blood) will be
taken in fasting conditions for laboratory testing including HbA1c, lipids
analysis and biochemistry. For non-menopausal women, a blood pregnancy test
will also be performed.
At Visit 2 (week 0), If patient is eligilible, he/she will be treated either
with insulin glargine or with liraglutide (once daily injection) in combination
with an oral antidiabetes drugs.
Patients in the insuline glargine arm will need to measure their blood glucose
level every morning (before breakfast). These values are needed for the dose
adjustments of insulin (increase or decrease).
The starting dose for the group treated with Liraglutide is 0.6 mg once a day,
during one week. The physian can decide to increase/decrease the liraglutide
dose with the use of the blood glucose level. Patients in the liraglutide arm
will be asked to measure their blood glucose level every morning (before
breakfast) in the week prior to Visits 2, 7, 10, 11 and 12.
All The patients also need to measure their blood glucose level 7 times daily
on 3 consecutive days in the week prior to Visits 2,10 and 12.
At Visit 12 (week 24), patients in the liraglutide group with a HbA1c superior
or equal to 7%, will stop liraglutide and will start treatment with insulin
glargine. For all other patients, the study will be ended and the study.
Kampenringweg 45 D-E
2803 PE GOUDA
NL
Kampenringweg 45 D-E
2803 PE GOUDA
NL
Listed location countries
Age
Inclusion criteria
Inclusion criteria for the comparative period:;- Patients aged from 35 to 75 years inclusively,
- With Type 2 Diabetes diagnosed for at least 1 year,
- Treated with lifestyle interventions and metformin at the maximum tolerated dosage (with a minimum daily dosage of 1g), either alone or in combination with an oral insulin secretagogue (sulfonylurea, glinide or DPP-IV inhibitor), for more than 3 months,
- 7.5% < HbA1c <= 12%,
- BMI between 25 and 40 kg/m2 inclusively ,
- Ability and willingness to perform PG self monitoring using the sponsor-provided glucose meter and to complete the patient diary,
- Willingness and ability to comply with the study protocol,
- Signed informed consent obtained prior to any study procedure.;Inclusion criteria for the extension period:;- Patients treated with liraglutide (at the maximum tolerated dosage), having a mean FPG >= 250 mg/dL at Visit 10 or Visit 11, or a HbA1c >= 7% at Visit 12
- Dosage of metformin compliant with the inclusion criterion of Visit 1 (i.e. maximum tolerated dosage, with a minimum daily dosage of 1g), and maintained stable during the comparative period.
Exclusion criteria
Exclusion criteria for the comparative period:;- Previous treatment with GLP-1 analogues or insulin (for in the past year (except in case of temporary treatment for gestational diabetes, surgery,
hospitalization*),
- Treatment with thiazolidinediones or α-Glucosidases inhibitors within 3 months prior to study entry,
- Diabetes other than Type 2 diabetes (e.g. secondary to pancreatic disorders, drug or chemical agents intake*),
- Pregnant women (women of childbearing potential must have a negative pregnancy test at study entry and a medically approved contraceptive method),
- Lactating women,
- Hospitalized patients (except hospitalization for routine diabetes check-up),
- Active proliferative retinopathy, as defined by a photocoagulation or vitrectomy occurrence in the 6 months prior to study entry, or any other unstable (rapidly progressing) retinopathy that may require photocoagulation or surgical treatment during the study, documented by a retina examination within 2 years prior to study entry,
- Impaired renal function (creatinine clearance < 60 mL/mn),
- Impaired hepatic function (ALT, AST >= 2.5 times the upper limit of normal range),
- Personal or family history of medullary thyroid carcinoma,
- Multiple endocrine neoplasia syndrome type 2,
- Severe gastro-intestinal disease (including inflammatory bowel disease or diabetic gastroparesis),
- Congestive heart failure,
- History of acute pancreatitis,
- Treatment with corticosteroids with potential systemic action for more than 10 days within 3 months prior to study entry,
- Alcohol or drug abuse in the past 5 years,
- History of sensitivity to the study drugs or to drugs with a similar chemical structure.
- Night shift worker,
- Presence of any condition (medical, psychological, social or geographical), current or anticipated that would compromise the patient*s safety or limit the patient successful participation in the study.;Exclusion criteria for the extension period:;- Treatment with oral antidiabetic drugs other than metformin and patient*s usual sulfonylurea if any, or with insulin during the comparative period (except in case of an emergency, for a period of time less than 7 days),
- Treatment with corticosteroids with potential systemic action within the last 3 months of the comparative period,
- Pregnant women (women of childbearing potential must have a negative pregnancy test at extension period entry and a medically approved contraception method),
- Lactating women,
- Hospitalized patients (except hospitalization for routine diabetes check-up),
- Active proliferative retinopathy, as defined by a photocoagulation or vitrectomy occurrence during the comparative period, or any other unstable (rapidly progressing) retinopathy that may require photocoagulation or surgical treatment during the extension period,
- Impaired renal function (creatinine clearance < 60 mL/mn),
- Impaired hepatic function (ALT, AST >= 2.5 times the upper limit of normal range),
- History of sensitivity to insulin glargine.
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 | EUCTR2010-018437-21-NL |
ClinicalTrials.gov | NCT01117350 |
CCMO | NL32454.060.10 |