Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02113332 |
| Other study ID # |
MDILiraglutide |
| Secondary ID |
2012-001941-42 |
| Status |
Completed |
| Phase |
Phase 2
|
| First received |
April 10, 2014 |
| Last updated |
February 1, 2015 |
| Start date |
January 2013 |
| Est. completion date |
August 2014 |
Study information
| Verified date |
December 2014 |
| Source |
Vastra Gotaland Region |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Sweden: Regional Ethical Review Board |
| Study type |
Interventional
|
Clinical Trial Summary
Liraglutide, a GLP-1-analogue has been shown to be an effective treatment option in patients
on oral anti-diabetes therapy with beneficial effects on both glycaemic control and weight.
However, to date there are no clinical trials of liraglutide added to insulin therapy, a
population of patients generally having worse glycaemic control and weight gain. In clinical
guidelines, use of multiple daily insulin injections (MDI) is usually the final therapeutic
option for type 2 diabetic patients.
The primary study aim is to evaluate whether the addition of liraglutide, compared to
placebo, reduces the HbA1c level for overweight and obese type 2 diabetes patients with
inadequate glycaemic control treated with multiple daily insulin injections (MDI). MDI is
defined as treatment with any basal insulin combined with separate meal time insulin
injections before the main meals, i.e. an insulin regimen with premixed insulin is not
considered as MDI.
The planned study duration is 24 weeks and includes 120 patients at 15 centers in Sweden.
Description:
Background
Patients with type 2 diabetes are generally treated with metformin and diet as first-line
therapy (1). In Sweden sulphonylureas are generally recommended as the next treatment option
due to their low cost and evidence for reducing diabetes complications (2). The next line of
therapy includes adding basal or premixed insulin. As a final step multiple daily insulin
injections with basal and prandial insulin have become the standard if glycaemic control
does not meet targets. Obesity is another co-morbid condition in this population (3). The
United Kingdom Prospective Diabetes Study (UKPDS) published 1998, the seminal trial
demonstrating the importance of glycaemic control in type 2 diabetes, illustrated that
insulin therapy (mostly basal insulin alone) is accompanied by significant weight gain in
patients with type 2 diabetes (4). MDI generally results in even greater weight gain. Today
there are few treatment options in patients with type 2 diabetes on MDI with poor glycaemic
control.
In patients with basal, intermediate or premixed insulin, addition of sitagliptin has shown
further reduction in HbA1c of 0.6 percentage units (6 mmol/mol) with no change in weight
(5). However, the effect in patients with the most severe disease, namely those requiring
MDI, was not evaluated. In combination with metformin or sulphonylurea, adding the
GLP-1-analogue liraglutide, compared with adding sitagliptin, has shown greater reductions
in HbA1c and significant weight reductions (6). In an uncontrolled study in clinical
practice, the addition of exanatide (n=22) or liraglutide (n=43) to patients on insulin
therapy, the majority using MDI, was associated with a mean reduction in HbA1c by 1.0
percentage units (10 mmol/mol), reduction in weight of 7.1 kg and, simultaneously, a mean
reduction in insulin dose by 37 units (7). At baseline patients were generally obese (mean
BMI 36kg/m2), had poor glycaemic control, mean HbA1c of 8.9% (74 mmol/mol) and insulin doses
of 92 units. The number of hypoglycaemic events was low, treatment satisfaction was high and
patients rated hypoglycaemic episodes to be fewer than with insulin therapy alone. From
these results it seems that there may be a beneficial effect associated with liraglutide
when added to type 2 diabetic patients on MDI; however, this requires confirmation in a
randomised clinical trial. This question is of particular concern since currently there are
no treatment options for reducing weight and insulin doses while simultaneously improving
glycaemic control for this patient group having most advanced disease. Further, many
clinicians today use a therapeutic strategy consisting of MDI as a final treatment option,
but many patients do still not reach target HbA1c and some even continue to have very poor
glycaemic control (7). Therefore, the aim of this study is to study the effect on HbA1c when
adding liraglutide to MDI in overweight and obese patients with impaired glycaemic control.
The proposed study is a randomised double-blind trial for 24 weeks including patients with
type 2 diabetes and poor glycaemic control despite being treated with MDI for at least 6
months.
The aim is to study the effect on HbA1c when adding liraglutide to MDI in overweight or
obese patients with impaired glycaemic control.
Study drug preparation
Novo Nordisk will provide study medication and treatment codes. Apoteket AB, Sweden, will
handle study treatment logistics.
Site monitoring
Gothia Forum, Gothenburg, Sweden
Data management
Gothia Forum will provide the eCRF system to be used in the study. Data Management
(including the randomisation system) and statistical analysis will be performed by
Statistiska Konsultgruppen, Gothenburg, Sweden.
Lab and continuous glucose monitoring
All laboratory tests will be measured at the Research Centre for Laboratory Medicine at
Karolinska University Hospital, Stockholm, Sweden.
The DexCom G4 CGM device will be used for 21 days (7 days during the run-in period, 7 days
during week 12 ± 7 days and 7 days during the last 2 weeks of the trial) for blinded
monitoring of glucose values.
Risk-benefit assessment
Previously published observations from clinical practice (7) have shown that patients
treated with multiple daily insulin injections (MDI) with concomitant addition of
liraglutide (off-label) decreases the HbA1c by approximately 10 mmol/mo (1 percentage unit),
reduces the weight by 7 kg and decreases the insulin dose with 37 units (7). These patients
were prior to treatment overweight (BMI around 36), had HbA1c on average 74 mmol /mol and
insulin doses were at 92 units. Patients also rated hypoglycaemias to be fewer when insulin
was combined with liraglutide than when used alone. In general, patients reported an
improved quality of life.
There is always a risk of hypoglycaemia during insulin therapy irrespective of any
additional glucose-lowering therapy. However, previous findings from clinical practice (7)
and that the effect of GLP-1 on insulin release is only observed under hyperglycaemic
conditions (8) indicate that liraglutide does probably not lead to major increased risks of
hypoglycaemias. Since, liraglutide has been associated with a reduction in body weight in
previous clinical trials (8) it is likely that such an effect exists also in individuals
treated with insulin.
In summary, the risk of side effects or adverse reactions with the combination of insulin
and liraglutide is probably small in relation to the improved hyperglycaemic control and
weight reduction that may exist when adding liraglutide in type 2 diabetic patients with
basal and prandial insulin.
Rational
Multiple daily insulin injections (MDI) are regarded as the most advanced treatment regimen
in patients with type 2 diabetes. At study start all patients have been treated with MDI for
at least 6 months but are still suffering from poor glycaemic control. The patients included
are also overweight or obese. It is therefore of importance to evaluate whether this patient
group have a beneficial effect, on the glycaemic control and weight reduction, by adding
liraglutide, since liraglutide has shown such beneficial effects in combination with oral
glucose lowering drugs.
Moreover, beneficial effects by liraglutide have been observed when used off-label in
combination with insulin in clinical practice (7).
Design
This is a double-blind, placebo-controlled clinical trial with parallel-group design. The
study involves 120 patients at 15 health centres in Sweden and includes 10 visits over 26
weeks.
Treatments
The study drug will be liraglutide which includes 3 different dosages: 0.6 mg, 1.2 mg and
1.8 mg. Liraglutide will be titrated to 1.8 mg by increasing the dose every week. Since
subjects will have inappropriate glycaemic control (greater than or equal to 7.5%=58
mmol/mol HbA1c) no general reduction in insulin doses will be made, but if glucose curves
during the run-in period show clearly lower mean glucose levels than those corresponding to
HbA1c 7.5%=58 mmol/mol or are well-controlled before certain meals, insulin adjustments will
temporarily be considered during the titration phase of liraglutide/placebo.
Liraglutide will be available at a concentration of 6.0 mg/ml and supplied in a 3 ml
disposable pen-injector. Placebo is supplied in an identical disposable pen-injector.
Randomization
After a run-in period of maximally 60 days, patients will be randomised to receive either
0.6 mg liraglutide or 0.6 mg placebo. Novo Nordisk will provide (coded) medication pens and
the associated code-list. No study personnel other than a designated data manager
responsible for setting-up randomisation will have access to the complete code-list until
the study blind is broken. Apoteket AB/farmaci will handle study treatment logistics.
Minimisation (optimal allocation) using a centralised web system (handled by Statistiska
Konsultgruppen) will be used for randomisation. At randomisation each subject will be
assigned a randomisation code that (blindly) represents the treatment (liraglutide or
placebo) that the patient is randomised to. The patient will also be assigned a unique and
anonymous Subject ID.
Breaking blind
The study is double-blinded. The randomisation codes will not be broken until last subject's
last visit and when all study data are collected, the study database is cleaned and declared
locked. Apoteket AB/farmaci will be responsible for keeping the complete randomisation list.
The code for a particular subject may be broken in a medical emergency situation.
Apoteket/farmaci is equipped with 24 hour emergency telephone service in case of need for
breaking blind in an individual patient.
Telephone number:
Weekdays 08.30-16.00: 040-33 26 74. Any other time: 040-331000 - ask for emergency telephone
service.
The subject should be withdrawn from the study in case of a code break but be included in
the safety population in the statistical analyses.
Duration
The expected duration of subject participation is approximately 32 weeks (maximally 60 days
run-in, and 24 weeks follow-up after randomisation).
Study population
The study will include 120 patients at 15 centres in Sweden. Patients requiring MDI and who
are on no other diabetes drugs except metformin will be recruited and included in the study
after receiving oral and written information about the study and given informed consent and
fulfilling all the inclusion criteria and none of the exclusion criteria. The study
population will be identified among diabetic outpatient clinics at hospitals and will be
recruited on a community-wide basis and in communication with primary care physicians.
The written information will include objects and purpose of the study, risks and benefits,
and a detailed description of the events during the study. The patient will have the
opportunity to ask additional questions at the first clinic visit The patients will be
randomised 1:1 to liraglutide or placebo Randomisation codes will be assigned strictly
sequentially as subjects are eligible for randomisation. If a subject discontinues
participation in the study, his/her enrolment/subject number cannot be reused. Drop-outs
(expected to be ~5%) will not be replaced.
Study Stop Criteria
The Sponsor/Investigator may decide to stop the trial or part of the trial at any time for
medical reasons. Furthermore, the manufacturers of the study drugs may revoke their
products, which may lead to the entire study may be interrupted.
If a trial is prematurely terminated or suspended, the Investigator should promptly inform
the patients and ensure appropriate therapy and follow-up. Furthermore, the Investigator
should promptly inform the Ethics committee and provide a detailed written explanation. The
regulatory authority should be informed according to national regulations.
Drop-outs
Patients who drop-out from the study or receive rescue therapy shall be requested for
follow-up on an additional visit. HbA1c, FPG, C-peptide, pro-insulin, amylase, lipase, liver
transaminases, creatinine, calcitonin, fasting blood lipids, adiponectin, sensitive CRP,
apolipoproteins, weight, blood pressure, insulin dose, waist-hip ratio, abdominal sagittal
diameter, concomitant medications and treatment satisfaction shall be checked. Blood samples
for biobank will be taken. Insulin doses and other medications recorded. If drop-out exists
the reason shall be recorded. Regarding rescue therapy the variables above shall be checked
if possible before rescue therapy is given.
Investigational product and treatment of subjects
The trial product will be dispensed to each subject as required according to treatment
group. The centralized web randomisation system will allocate trial product Dispensing Unit
Number (DUN) to the subject at the randomisation visit. The correct DUN must be dispensed to
the subject.
The Investigator must ensure availability of proper storage conditions and record and
evaluate the temperature (at least every working day). Storage facilities should be checked
frequently. A log to document the temperature must be kept.
The study is planned for 24 weeks and in addition a run-in period of maximally 60 days.
Capillary glucose values will be measured before each meal and 1.5-2 hours after meals at 2
days during the 60-day run-in period, 2 days per week during the first 3 weeks of the trial
and 2 days during the last 2 weeks of the trial. Capillary glucose curves performed during
the run-in period and the last two weeks of the study will always be measured after the week
with CGM to not disturb the interpretation of CGM data. The Contour XT SMBG meter (Bayer)
shall be used for capillary glucose measurements during the study. The SMBG meter shall be
checked at eash visit before initiating CGM, i.e. during the run-in period, week 12 (+- 7
days) and week 23-24. Calibration will be performed according to the manufacturer's
standards. The SMBG meter shall be introduced at visit 4. During 7 days of the run-in
period, 7 days of week 12 ± 7 days and 7 days of the 2 last weeks in the study, CGM with
DexCom 4G will be used. CGM should be taken for 7 days, but a minimum of 5 days is
acceptable. If a shorter period exists, a new sensor shall be set to get data for a total of
7 days (A total period of 5 days is acceptable). Investigators will recommend patients
measure 3-4 glucose values per day before meals and at bedtime daily according to clinical
guidelines for potentially adjusting insulin doses, diet or physical activity.
Liraglutide/placebo will be administered at 0.6 mg the first week, 1.2 mg the second week
and 1.8 mg the third week and onward. Dose increase periods can be extended based on
subject's tolerance to the trial product. If the subject does not tolerate 1.8 mg
liraglutide/placebo due to side effects, the dose shall be reduced to 1.2 mg
liraglutide/placebo. Correspondingly, if 1.2 mg liraglutide/placebo is not tolerated 0.6 mg
liraglutide/placebo shall be used.
Since subjects will have inappropriate glycaemic control (greater than or equal to 7.5%=58
mmol/mol in HbA1c) no general reduction in insulin doses will be made. However, glucose
profiles during the run-in period shall be judged by the clinician. In the following cases
the clinician will consider to take the following actions when liraglutide is added:
A) If the patient has a mean glucose level lower than 8.5 mmol/l the clinician should
consider reducing the total insulin dose by 10%-20% when adding liraglutide 0.6 mg B) If
glucose levels before a certain meal are well-controlled (less than 7 mmol/l) the clinician
should consider reducing the meal-time insulin dose administered at the previous meal by
10%-20% when adding liraglutide 0.6 mg. If daytime hypoglycaemia has occurred a larger than
20% reduction in the insulin dose at the previous meal shall be considered when adding
liraglutide 0.6 mg.
C) If fasting glucose is 5.0-7.0 mmol/l the basal insulin shall be reduced by 20%-30% when
adding liraglutide 0.6 mg.
D) If fasting glucose is less than 5 mmol/l or nocturnal hypoglycaemia has occurred during
the run-in period basal insulin shall be reduced by 20%-40%. Novel evaluations with glucose
measurements during 4-5 days shall be performed to confirm that FPG is greater than 5 mmol/l
and no new nocturnal hypoglycaemia exists before adding liraglutide. A novel evaluation
according to point A)-D) shall then be performed from the new glucose values when adding
liraglutide.
When increasing liraglutide from 0.6 mg to 1.2 mg as well as from 1.2 mg to 1.8 mg the
corresponding actions as points A-D above shall be considered based on glucose values and
hypoglycaemias during the previous week.
After titrating liraglutide/placebo to 1.8 mg in patients where insulin doses at any stage
have been reduced, the insulin doses will be increased until the original doses are reached.
However, the titration will be stopped, i.e., the insulin doses will not be titrated to the
original doses, if glucose levels at any stage in the phase of increasing doses are already
on target. For example, if the mean glucose level before a certain meal is less than 7
mmol/l after adding liraglutide/placebo 1.8 mg, the insulin dose before the previous meal
will not be increased although the dose has been reduced. Correspondingly, if mean FPG is
less than 7.0 mmol/l the basal insulin dose will not be increased although it has been
reduced.
The total insulin dose shall not be titrated higher than the original total insulin dose at
any point during the study, except if rescue therapy is required. The diabetes educator or
physician will have regular telephone contact with the patient during the initial period
when liraglutide is titrated and for possibly adjusting insulin doses. At the 6, 12 and 18
week follow-up visits and other contacts with the patient, e.g. telephone contacts, the
insulin doses can be increased in patients with a lower insulin dose than the original
insulin dose before randomisation so long as glucose levels then not are on target (less
than 7.0 mmol/l fasting or before meal). However, the insulin doses shall not be increased
higher than the original doses, except if rescue therapy is undertaken In daily activity,
the patient will continue to adjust meal-time insulin doses in the same way as previously
performed in clinical practice.
Rescue Criteria
If the fasting self-measured plasma glucose (fasting SMPG) values taken on three separate
days or if any of the FPG samples analysed by the central laboratory exceeds the limit of
15.5 mmol/l from baseline to week 12 or 13.5 mmol/l from week 12 to week 24, the subject
should be called for an unscheduled visit as soon as possible. The next scheduled visit
should not be awaited. A confirmatory FPG should be obtained and analysed by the central
laboratory. If this FPG exceeds the above described values, and no treatable intercurrent
cause for the hyperglycaemia has been diagnosed (e.g. compliance to liraglutide/placebo,
missing of insulin dose in the evening, infection), the subject should receive rescue
therapy.
Rescue therapy is defined as an increase of the total insulin dose above the original total
insulin dose (i.e. total insulin dose at baseline, at randomisation).
It should be noticed that rescue therapy is NOT given if the total insulin dose was
initially reduced in the trial and the total insulin dose is increased by the physician due
to FPG above thresholds but not higher than the total original insulin dose. Rescue therapy
will not exist either if a patient increases the total insulin dose at any point in time
above the total original insulin dose by, e.g., self-adjustments of meal-time insulin doses
in daily activity.
Other medication, which is considered necessary for the subject's safety and well-being, may
be given at the discretion of the investigator. Medications prescribed before study entry
should preferably remain unchanged during the study period unless changes are made for
safety reasons.
Procedures for Monitoring Subject Compliance
Compliance and adherence to protocol will be checked at each contact with the patient.
Subject compliance will be assessed by DMG monitoring accountability. The unused amount of
trial product will be assessed against the dispensed amount and, in case of discrepancies,
the subjects must be asked about compliance.
The individual delegated by the Investigator must keep track of all received, used, partly
used and unused trial products and, if possible, all empty packaging. This shall be properly
documented. Used, partly used and unused trial products and empty packaging must be stored
separately from non-allocated trial products. Used, partly used and unused trial products
must be stored until the monitor has performed drug accountability.
Destruction of trial products will be performed in accordance with local legislation and
recorded on a destruction form.
Liraglutide/Placebo
Not in use: The liraglutide/placebo pen-injector must be stored in a refrigerator at a
temperature between +2°C and +8°C. Keep away from the cooling element. Do not freeze and do
not use if it has been frozen.
In use: After first opening the liraglutide/placebo pen-injector can be stored for one month
at temperatures below +30°C or in a refrigerator between +2°C and +8°C.
The liraglutide/placebo pen-injector must be protected from all sources of light, and the
pen cap should be kept on when the pen is not in use. The liraglutide/placebo should not be
used if it does not appear clear and colorless.
In case of incorrect storage the Investigator or site staff must contact Novo Nordisk
without delay. Trial product(s) must be set on-hold and not dispensed to subjects until
notified by Novo Nordisk.
The individual delegated by the Investigator must keep track of all received, used, partly
used and unused trial products and, if possible, all empty packaging, by using the drug
accountability module in the centralised web system. No trial product should be dispensed to
any person not enrolled in the trial.
Returned trial product(s) (used, partly used or unused and if possible, empty packaging
material) must be stored separately from non-allocated trial product(s). Destruction of
trial products will be done according to local laws and will be recorded on a destruction
form, which must be signed by the individual responsible for destruction.
Standardised procedures for administration of questionnaires
The questionnaires will be filled in at the study site. The patients should be allowed to
sit alone in a reasonable quiet environment to answer the questions. It will be emphasized
that patients complete the questionnaires prior to clinical measurements and before meeting
a doctor. Questionnaires should be answered by the patient herself alone, however, the
nurse/assistant will be informed about helping the patients to complete the questionnaires
if necessary, however without influencing the patients' responses. Ensure the patient
confidentiality. Study nurse/assistant should check the questionnaires for completeness. The
principal investigator will assure that appropriate training relevant to the study is given
Trial Procedures
Run-in period
The purpose of the run-in period is to check glucose values as a basis for possible insulin
adjustments and to perform CGM before randomisation. Blinded CGM will be performed during 1
week of the 60-day run-in period. Capillary glucose values before meals and 1.5 hours after
meals will be measured during at least 2 days, after the CGM-period. Treatment satisfaction
(DTSQs) will be checked, preferentially before initiating CGM, since CGM may influence
treatment satisfaction.
Randomization visit
Glucose profiles and hypoglycaemias during the run-in period will be checked to judge
whether insulin reductions shall be performed (See section 8.2 Titration Algorithm).
At the randomisation visit the following variables will be measured before randomisation and
blood samples will be sent to the Research Centre for Laboratory Medicine at Karolinska
University Hospital. All blood samples are recommended to be fasting to facilitate logistics
since several tests require fasting conditions.
- Systolic and diastolic blood pressure after at least 5 minutes rest in sitting position
with appropriate cuff-size
- HbA1c and fasting glucose
- Amylase, lipase, creatinine, liver transaminases
- Fasting Blood Lipids (Triglycerides, Total-, HDL- and LDL-Cholesterol), fasting
apolipoproteins
- Weight
- Waist-hip ratio and abdominal sagittal diameter
- Type of insulin and doses of insulin and metformin
- AE, SAE and hypoglycaemia
- Adiponectin, sensitive CRP
- GAD-antibodies, calcitonin, amylase, lipase
- Fasting C-peptide and fasting pro-insulin
- Biobank samples
- Type of insulin, doses of insulin and doses of metformin recorded.
- Other types of medications recorded
- A morning urin sample of Albuminuria/Creatinine ratio will be measured with local
laboratory analysis either at inclusion/exclusion visit or at randomisation visit.
Web randomisation will be performed with minimisation (optimal allocation) to liraglutide or
placebo in 1:1 proportion.
Telephone contacts
The diabetes educator or the physician will have telephone contact with the patient as
follows:
- The day after starting liraglutide/placebo
- One of the 2 days before increasing liraglutide/placebo to 1.2 mg
- The day after the increase to 1.2 mg
- One of the two days before increasing liraglutide/placebo to 1.8 mg
- The day after increasing liraglutide to 1.8 mg
- One week after the increase of liraglutide/placebo to 1.8 mg
More frequent telephone contacts during the initial weeks or later in the study will be made
depending on the decision of the diabetic educator or physician if needed for the individual
patient.
At each telephone contact, insulin adjustments will be considered according to specified
algorithms, i.e.:
- if hypoglycaemia exists
- If glucose values are well-controlled before titrating liraglutide/placebo
In patients where insulin doses are reduced at any stage during the titration of
liraglutide, regular telephone contacts every 3-4 day after titrating liraglutide/placebo to
1.8 mg shall be performed. Insulin doses will then be increased until the original insulin
doses are reached. The increase of insulin doses will be stopped at a lower level earlier
before original doses are reached if glucose levels already are on target.
Clinical Visits
Clinical visits will be performed at weeks 6, 12, 18 and 24. Visit at Week 6, 12 and 18
At the 6 weeks follow-up visit (± 7 days), 12 weeks follow-up visit (± 7 days) and 18 weeks
(± 7 days) follow-up visit the following variables will be measured:
- Systolic and diastolic blood pressure after at least 5 minutes rest in sitting position
with appropriate cuff-size
- HbA1c, Fasting plasma glucose sent to central laboratory
- Weight
- Type of insulin and doses of insulin and doses of metformin
- AE, SAE and hypoglycaemia
- Changes to concomitant medication
- Trial product dispensing
- At week 12: blood lipids, lipase, amylase, liver transaminases, creatinine, calcitonin
and biobank samples sent to central laboratory. Waist-hip ratio and abdominal sagittal
diameter shall be measured.
Week 12 ± 7 days
- Blinded CGM will be performed during 1 week.
- Treatment satisfaction (DTSQs) will be evaluated, preferentially before CGM since CGM
may influence the treatment satisfaction.
Two last weeks (week 23-24)
- Blinded CGM will be performed during 7 days. Capillary glucose values measured before
and 1.5 hours after meals during 2 days.
- Treatment satisfaction (DTSQs and DTSQc) will be performed, preferentially before CGM
since CGM may influence treatment satisfaction.
Week 24
At the final 24 weeks follow-up visit (± 7 days) the following variables will be measured
(all blood samples sent to central laboratory):
- Physical investigation
- Systolic and diastolic blood pressure after at least 5 minutes rest in sitting position
- HbA1c and fasting plasma glucose
- Fasting blood lipids (Triglycerides, Total-, HDL- and LDL-Cholesterol) and
apolipoproteins
- Weight
- Waist-hip ratio and abdominal sagittal diameter
- Sensitive CRP, adiponectin, liver transaminases, creatinine, calcitonin, lipase and
amylase
- Type of insulin and doses of insulin and metformin
- AE, SAE and hypoglycaemia
- Changes to concomitant medication
- Fasting C-peptide and fasting pro-insulin
- Biobank samples
- A morning urin sample of Albuminuria/Creatinine ratio will be measured with local
laboratory analysis.
Hypoglycaemias
Hypoglycaemias will be defined according to the general guidelines from the American
Diabetes Association of definitions of hypoglycaemias in study settings (9). Hypoglycaemias
will be divided into documented symptomatic hypoglycaemias, documented asymptomatic
hypoglycaemias and severe hypoglycaemias. Patients will be counselled of typical symptoms of
hypoglycaemia and given a diabetes diary for recordings of glucose values, signs of
hypoglycaemias and recovery from symptoms after intake of carbohydrates. The frequency of
hypoglycaemia with glucose values below 3.0 mmol/l and 4.0 mmol/l will both be used as
endpoints. Severe hypoglycaemias will also be recorded in the diabetes diary. If a severe
hypoglycaemia appears the responsible physician for the patient should be informed as soon
as possible. The following parameters of hypoglycaemia will be recorded in accordance with
guidelines for study design of the American Diabetes Association:
- Number of documented symptomatic hypoglycaemias (PG less than 4.0 mmol/l).
- Number of documented asymptomatic hypoglycaemia (PG less than 4.0 mmol/l).
- The number of symptomatic and asymptomatic documented hypoglycaemia with PG less than
3.0 mmol/l will also be recorded.
- Number of glucose values recorded by CGM below 3.0 mmol/l and 4.0 mmol/l respectively.
- Number of severe hypoglycaemias.
Patients shall be informed regarding the symptoms of hypoglycaemia and requested to
immediately perform a finger stick glucose measurement if symptoms occur that may be related
to hypoglycaemia, but to avoid delay in treating these symptoms.
Full analysis set (ITT-population) The full analysis set (ITT-population) consists of all
randomised patients who received at least one dose of study medication and has at least one
follow-up measurement.
Primary Efficacy Analysis Primary efficacy analysis will be change in HbA1c from baseline to
24 weeks follow-up between the two treatment groups using analysis of covariance (ANCOVA)
with HbA1c at baseline as covariate on the full analysis set (ITT-population), two-sided
test on significance level 0.05. If HbA1c from 24 weeks follow-up is missing the last
observation carry forward (LOCF) principle from 6, 12 and 18 weeks will be applied. All
measurements obtained after rescue therapy should be excluded in all efficacy analyses.
