Patent Application
20130040878
Subject of the present invention is a pharmaceutical combination for use in the treatment of a diabetes type 2 patient, said combination comprising (a) desPro36Exendin-4(1-39)-Lys6-NH2 (AVE0010, lixisenatide) or/and a pharmaceutically acceptable salt thereof, and (b) metformin or/and a pharmaceutically acceptable salt thereof, wherein the compound (a) is administered once daily before an evening meal. Yet another aspect is a method for treatment of diabetes type 2 patients, said method comprising administering desPro36Exendin-4(1-39)-Lys6-NH2 or/and a pharmaceutically acceptable salt thereof, in combination with metformin to a subject in need thereof, wherein compound (a) is administered once daily before an evening meal.
In a healthy person the release of insulin by the pancreas is strictly coupled to the concentration of blood glucose. An increased level of blood glucose, as appears after meals, is rapidly counterbalanced by a respective increase in insulin secretion. In fasting condition the plasma insulin level drops to a basal value which is sufficient to ensure the continuous supply of glucose to insulin-sensitive organs and tissues and to keep the hepatic glucose production at a low level at night.
In contrast to diabetes type 1, there is not generally a lack of insulin in diabetes type 2 but in many cases, particularly in progressive cases, the treatment with insulin is regarded as the most suitable therapy, if required in combination with orally administered anti-diabetic drugs.
An increased glucose level in the blood over several years without initial symptoms represents a significant health risk. It could clearly be shown by the large-scale DCCT study in the USA (The Diabetes Control and Complications Trial Research Group (1993) N. Engl. J. Med. 329, 977-986) that chronically increased levels of blood glucose are a main reason for the development of diabetes complications. Examples for diabetes complications are micro and macrovascular damages that possibly manifest themselves in retinopathies, nephropathies or neuropathies and lead to blindness, renal failure and the loss of extremities and are accompanied by an increased risk of cardiovascular diseases. It can thus be concluded that an improved therapy of diabetes primarily has to aim keeping blood glucose in the physiological range as closely as possible.
A particular risk exists for overweight patients suffering from diabetes type 2, e.g. patients with a body mass index (BMI)≧30. In these patients the risks of diabetes overlap with the risks of overweight, leading e.g. to an increase of cardiovascular diseases compared to diabetes type 2 patients being of a normal weight. Thus, it is particularly necessary to treat diabetes in these patients while reducing the overweight.
Metformin is a biguanide hypoglycemic agent used in the treatment of non-insulin-dependent diabetes mellitus (diabetes mellitus type 2) not responding to dietary modification. Metformin improves glycemic control by improving insulin sensitivity and decreasing intestinal absorption of glucose. Metformin is usually administered orally. However, control diabetes mellitus type 2 in obese patients by metformin may be insufficient. Thus, in these patients, additional measures for controlling diabetes mellitus type 2 may be required.
The compound desPro36Exendin-4(1-39)-Lys6-NH2 (AVE0010, lixisenatide) is a derivative of Exendin-4. AVE0010 is disclosed as SEQ ID NO:93 in WO 01/04156:
Exendins are a group of peptides which can lower blood glucose concentration. The Exendin analogue AVE0010 is characterised by C-terminal truncation of the native Exendin-4 sequence. AVE0010 comprises six C-terminal lysine residues not present in Exendin-4.
In the context of the present invention, AVE0010 includes pharmaceutically acceptable salts thereof. The person skilled in the art knows pharmaceutically acceptable salts of AVE0010. A preferred pharmaceutically acceptable salt of AVE0010 employed in the present invention is acetate.
In the Example of the present invention, it was demonstrated that AVE0010 (Lixisenatide) in an add-on therapy to metformin can be effectively administered 1 hour before an evening meal or 1 hour before a morning meal. Significantly improved glycemic control and decreased weight were observed:
A first aspect of the present invention is a pharmaceutical combination for use in the treatment of a diabetes type 2 patient, said combination comprising
In the context of the present invention, “administration before an evening meal” in particular refers to administration in a range from about 4 h, from about 3 h, from about 2 h, from about 1 h 30 min to about 15 min, to about 30 min, or to about 40 min before the evening meal, or about 1 hour before the evening meal.
Preferred is an administration in a range from about 2 h or from about 1 h 30 min, to about 30 min before the evening meal. More preferred is administration about 1 hour before the evening meal.
A further aspect of the present invention is a pharmaceutical combination for use in the treatment of a diabetes type 2 patient, said combination comprising
n the context of the present invention, “administration before a morning meal” in particular refers to administration in a range from about 4 h, from about 3 h, from about 2 h, from about 1 h 30 min to about 15 min, to about 30 min, or to about 40 min before the morning meal, or about 1 hour before the morning meal.
Preferred is an administration in a range from about 2 h or from about 1 h 30 min, to about 30 min before the morning meal. More preferred is administration about 1 hour before the morning meal.
In the present invention, metformin can be administered according to commonly known administration protocols of metformin. For example, metformin can be administrated once daily or twice daily.
Metformin is the international nonproprietary name of 1,1-dimethylbiguanide (CAS Number 657-24-9). In the present invention, the term “metformin” includes any pharmaceutically acceptable salt thereof.
In the present invention, metformin may be administered orally. The skilled person knows formulations of metformin suitable for treatment of diabetes type 2 by oral administration. Metformin may be administered to a subject in need thereof, in an amount sufficient to induce a therapeutic effect. Metformin may be administered in a dose of at least 1.0 g/day or at least 1.5 g/day. For oral administration, metformin may be formulated in a solid dosage form, such as a tablet or pill. Metformin may be formulated with suitable pharmaceutically acceptable carriers, adjuvants, or/and auxiliary substances.
In the present invention, desPro36Exendin-4(1-39)-Lys6-NH2 or/and a pharmaceutically acceptable salt may be administered in an add-on therapy to administration of metformin.
In the present invention, the terms “add-on”, “add-on treatment” and “add-on therapy” relate to treatment of diabetes mellitus type 2 with metformin and AVE0010. Metformin and AVE0010 may be administered within a time interval of 24 h. Metformin and AVE0010 each may be administered in a once-a-day-dosage. Metformin and AVE0010 may be administered by different administration routes. Metformin may be administered orally, and AVE0010 may be administered parenterally.
The subject to be treated by the medicament of the present invention suffering from diabetes type 2 may be a subject suffering from diabetes type 2, wherein diabetes type 2 is not adequately controlled by treatment with metformin alone, for instance with a dose of at least 1.0 g/day metformin or at least 1.5 g/day metformin for 3 months. In the present invention, a subject the diabetes type 2 of which is not adequately controlled may have a HbA1c value in the range of 7% to 10%.
The subject to be treated by the medicament of the present invention suffering from diabetes type 2 may be an obese subject. In the present invention, an obese subject may have a body mass index of at least 30 kg/m2.
The subject to be treated by the medicament of the present invention suffering from diabetes type 2 may have a normal body weight. In the present invention, a subject having normal body weight may have a body mass index in the range of 17 kg/m2 to 25 kg/m2, or 17 kg/m2 to <30 kg/m2.
The subject to be treated by the medicament of the present invention may be an adult subject. The subject may have an age of at least 18 years of may have an age in the range of 18 to 80 years, of 18 to 50 years, or 40 to 80 years, or 50 to 60 years. The subject may be younger than 50 years.
The subject to be treated by the medicament of the present invention preferably does not receive an antidiabetic treatment, for instance by insulin or/and related compounds.
The subject to be treated by the medicament of the present invention may suffer from diabetes mellitus type 2 for at least 1 year or at least 2 years. In particular, in the subject to be treated, diabetes mellitus type 2 has been diagnosed at least 1 year or at least 2 years before onset of therapy by the medicament of the present invention.
The subject to be treated may have a HbA1c value of at least about 8% or at least about 7.5%. The subject may also have a HbA1c value of about 7 to about 10%. The example of the present invention demonstrates that treatment by AVE0010 results in a reduction of the HbA1c value in diabetes type 2 patients.
In yet another aspect of the present invention, the combination as described herein can be used for improving glycemic control. In the present invention, improvement of glycemic control in particular refers to improvement of postprandial plasma glucose concentration, improvement of fasting plasma glucose concentration, or/and improvement of the HbA1c value.
In yet another aspect of the present invention, the combination as described herein can be used for improving the HbA1c value in a patient suffering from diabetes type 2. Improving the HbA1c value means that the HbA1c value is reduced below 6.5% or 7%, for example after treatment for at least one month, at least two months, or at least three months.
In yet another aspect of the present invention, the combination as described herein can be used for improving glucose tolerance in a patient suffering from diabetes type 2. Improving glucose tolerance means that the postprandial plasma glucose concentration is reduced by the active agent of the present invention. Reduction means in particular that the plasma glucose concentration reaches normoglycemic values or at least approaches these values.
In the present invention, normoglycemic values are blood glucose concentrations of in particular 60-140 mg/dl (corresponding to 3,3 bis 7.8 mM/L). This range refers in particular to blood glucose concentrations under fasting conditions and postprandial conditions.
The subject to be treated may have a 2 hours postprandial plasma glucose concentration of at least 10 mmol/L, at least 12 mmol/L, or at least 14 mmol/L. These plasma glucose concentrations exceed normoglycemic concentrations.
The subject to be treated may have a glucose excursion of at least 2 mmol/L, at least 3 mmol/L, at least 4 mmol/L or at least 5 mmol/L. In the present invention, the glucose excursion is in particular the difference of the 2 hours postprandial plasma glucose concentration and the plasma glucose concentration 30 minutes prior to a meal test.
“Postprandial” is a term that is well known to a person skilled in the art of diabetology. The term “postprandial” describes in particular the phase after a meal or/and exposure to glucose under experimental conditions. In a healthy person this phase is characterised by an increase and subsequent decrease in blood glucose concentration. The term “postprandial” or “postprandial phase” typically ends up to 2 h after a meal or/and exposure to glucose.
The subject to be treated as disclosed herein may have a fasting plasma glucose concentration of at least 8 mmol/L, at least 8.5 mmol/L or at least 9 mmol/L. These plasma glucose concentrations exceed normoglycemic concentrations.
In another aspect of the present invention, the combination as described herein can be used for improving (i.e. reducing) fasting plasma glucose in a patient suffering from diabetes type 2. Reduction means in particular that the plasma glucose concentration reaches normoglycemic values or at least approaches these values.
The combination of the present invention can be used in the treatment of one or more of the medical indications described herein, for example in treatment of diabetes type 2 patients, as described herein, or for conditions associated with diabetes type 2, such as improvement of glycemic control, reduction of the fasting plasma glucose concentration, for the improvement of glucose excursion, reduction of the postprandial plasma glucose concentration, improvement of glucose tolerance, improving the HbA1c value, weight loss or/and prevention of weight gain.
In the present invention, desPro36Exendin-4(1-39)-Lys6-NH2 or/and the pharmaceutically acceptable salt thereof may be administered to a subject in need thereof, in an amount sufficient to induce a therapeutic effect.
In the present invention, desPro36Exendin-4(1-39)-Lys6-NH2 or/and the pharmaceutically acceptable salt thereof may be formulated with suitable pharmaceutically acceptable carriers, adjuvants, or/and auxiliary substances.
The compound desPro36Exendin-4(1-39)-Lys6-NH2 or/and a pharmaceutically acceptable salt thereof may be administered parenterally, e.g. by injection (such as by intramuscular or by subcutaneous injection). Suitable injection devices, for instance the so-called “pens” comprising a cartridge comprising the active ingredient, and an injection needle, are known. The compound desPro36Exendin-4(1-39)-Lys6-NH2 or/and a pharmaceutically acceptable salt thereof may be administered in a suitable amount, for instance in an amount in the range of 10 to 15 μg per dose or 15 to 20 μg per dose.
In the present invention, desPro36Exendin-4(1-39)-Lys6-NH2 or/and a pharmaceutically acceptable salt thereof may be administered in a daily dose in the range of 10 to 20 μg, in the range of 10 to 15 μg, or in the range of 15 to 20 μg. DesPro36Exendin-4(1-39)-Lys6-NH2 or/and a pharmaceutically acceptable salt thereof may be administered by one injection per day.
In the present invention, desPro36Exendin-4(1-39)-Lys6-NH2 or/and a pharmaceutically acceptable salt thereof may be provided in a liquid composition. The skilled person knows liquid compositions of AVE0010 suitable for parenteral administration. A liquid composition of the present invention may have an acidic or a physiologic pH. An acidic pH preferably is in the range of pH 1-6.8, pH 3.5-6.8, or pH 3.5-5. A physiologic pH preferably is in the range of pH 2.5-8.5, pH 4.0-8.5, or pH 6.0-8.5. The pH may be adjusted by a pharmaceutically acceptable diluted acid (typically HCl) or pharmaceutically acceptable diluted base (typically NaOH).
The liquid composition comprising desPro36Exendin-4(1-39)-Lys6-NH2 or/and a pharmaceutically acceptable salt thereof may comprise a suitable preservative. A suitable preservative may be selected from phenol, m-cresol, benzyl alcohol and p-hydroxybenzoic acid ester. A preferred preservative is m-cresol.
The liquid composition comprising desPro36Exendin-4(1-39)-Lys6-NH2 or/and a pharmaceutically acceptable salt thereof may comprise a tonicity agent. A suitable tonicity agent may be selected from glycerol, lactose, sorbitol, mannitol, glucose, NaCl, calcium or magnesium containing compounds such as CaCl2. The concentration of glycerol, lactose, sorbitol, mannitol and glucose may be in the range of 100-250 mM. The concentration of NaCl may be up to 150 mM. A preferred tonicity agent is glycerol.
The liquid composition comprising desPro36Exendin-4(1-39)-Lys6-NH2 or/and a pharmaceutically acceptable salt thereof may comprise methionine from 0.5 μg/mL to 20 μg/mL, preferably from 1 μg/ml to 5 μg/ml. Preferably, the liquid composition comprises L-methionine.
A further aspect of the present invention is a pharmaceutical combination as disclosed herein for use in inducing weight loss in diabetes type 2 patients or/and for preventing weight gain in diabetes type 2 patients.
A further aspect of the present invention is a method for inducing weight loss in diabetes type 2 patients or/and for preventing weight gain in diabetes type 2 patients, said method comprising administering desPro36Exendin-4(1-39)-Lys6-NH2 or/and a pharmaceutically acceptable salt thereof, in combination with metformin to a subject in need thereof. In particular, the combination as described herein may be administered. In the method of the present invention, the subject may be the subject defined herein.
A further aspect of the present invention is a method for treatment of diabetes type 2 patients, said method comprising administering desPro36Exendin-4(1-39)-Lys6-NH2 or/and a pharmaceutically acceptable salt thereof, in combination with metformin to a subject in need thereof, wherein desPro36Exendin-4(1-39)-Lys6-NH2 or/and a pharmaceutically acceptable salt thereof is administered once daily before an evening meal. In particular, the combination as described herein may be administered. In the method of the present invention, the subject may be the subject defined herein.
A further aspect of the present invention is a method for treatment of diabetes type 2 patients, said method comprising administering desPro36Exendin-4(1-39)-Lys6-NH2 or/and a pharmaceutically acceptable salt thereof, in combination with metformin to a subject in need thereof wherein desPro36Exendin-4(1-39)-Lys6-NH2 or/and a pharmaceutically acceptable salt thereof is administered once daily before a morning meal. In particular, the combination as described herein may be administered. In the method of the present invention, the subject may be the subject defined herein.
Yet another aspect of the present invention refers to the use of the combination as described herein for the manufacture of a medicament for the treatment of a medical indication, as described herein. For example, the combination as described herein can be used for the manufacture of a medicament for the treatment of a diabetes type 2 patient, wherein the compound (a), as described herein, is administered once daily before an evening meal. In another example, the combination as described herein can be used for the manufacture of a medicament for the treatment of a diabetes type 2 patient, wherein the compound (a), as described herein, is administered once daily before a morning meal. In another example, the combination as described herein can be used for the manufacture of a medicament for inducing weight loss in diabetes type 2 patients or/and for preventing weight gain in diabetes type 2 patients. The combination of the present invention can also be used for the manufacture of a medicament for the treatment of diabetes type 2 patients, or for the treatment of conditions associated with diabetes type 2, such as improvement of glycemic control, reduction of the fasting plasma glucose concentration, for the improvement of glucose excursion, reduction of the postprandial plasma glucose concentration, improving the HbA1c value, or/and improvement of glucose tolerance. The medicament can be formulated as described herein. For example the medicament can comprise a parenteral formulation of AVE0010 or/and a pharmaceutically acceptable salt thereof, and an oral formulation of metformin or/and a pharmaceutically acceptable salt thereof.
The invention is further illustrated by the following example and figures.
FIG. 1—Study design
FIG. 2—Step-down testing procedure
FIG. 3—Kaplan-Meier plot of time to treatment discontinuation due to any reason—Randomized population
FIG. 4—Plot of mean change in HbA1c (%) from baseline by visit up to Week 24—mITT population
FIG. 5—Plot of mean change in fasting plasma glucose (mmol/L) from baseline by visit up to Week 24—mITT population
FIG. 6—Plot of mean change in body weight (kg) from baseline by visit up to Week 24—mITT population
FIG. 7—Plot of mean change in HbA1c (%) from baseline by visit—mITT population
FIG. 8—Plot of mean change in fasting plasma glucose (mmol/L) from baseline by visit—mITT population
FIG. 9—Plot of mean change in body weight (kg) from baseline by visit—mITT population
A Randomized, Double-Blind, Placebo-Controlled, 4-Arm, Unbalanced Design, Parallel-Group, Multicenter, Multinational Study Assessing the Efficacy and Safety of Lixisenatide on Top of Metformin in Patients with Type 2 Diabetes, not Adequately Controlled with Metformin
A randomized, double-blind, placebo-controlled, 4-arm, unbalanced design, parallel-group, multicenter, multinational study assessing the efficacy and safety of lixisenatide on top of metformin in patients with type 2 diabetes, not adequately controlled with metformin. The approximate minimum study duration per patient was 79 weeks (up to 2 weeks screening+1 week run-in +24-week main double-blind treatment+variable extension+3 days follow-up). A 4-week post-treatment follow-up was performed in patients from the morning injection arms. The extension period ended for all patients approximately at the scheduled date of week 76 visit (V25) for the last randomized patient.
The study was conducted in 133 centers in 16 countries. The primary objective of the study was to assess the efficacy of lixisenatide injected in the morning within 1 hour prior to breakfast on glycemic control in comparison to placebo in terms of HbA1c reduction (absolute change) over a period of 24 weeks.
A total of 680 patients were randomized to one of four treatment arms (255 in each lixisenatide morning and evening injection arm and 85 in each placebo morning and evening injection arm). All randomized patients were exposed to the study treatment and included in the modified intent-to-treat (mITT) population. The placebo morning and evening injection arms were combined in the analyses. Demographics and baseline characteristics were generally similar across the treatment aims with fewer Hispanic and female patients in the combined placebo group. During the whole study treatment period, 169 (24.9%) patients prematurely discontinued the study treatment with a higher percentage in the lixisenatide evening injection arm (27.5%) and a lower percentage in the lixisenatide morning injection arm (22.4%) compared to the combined placebo group (24.7%). In lixisenatide-treated patients, the main reason for treatment discontinuation was “adverse events” (10.2% for evening injection and 8.2% for morning injection versus 3.5% for combined placebo) followed by “other reasons” (8.6% for each lixisenatide arm versus 11.2% for combined placebo).
Efficacy analyses are based on 24-week treatment. The least squared (LS) mean changes from baseline to Week 24 in HbA1c were −0.87% in the lixisenatide morning injection aim. (LS mean difference vs. combined placebo=−0.48%, p-value=<0.0001), and −0.75% in the lixisenatide evening injection arm (LS mean difference vs. combined placebo=−0.37%, p-value=<0.0001), in comparison to −0.38% in the combined placebo group. The percentages of patients reaching HbA1c≦6.5 or <7% at week 24 were significantly higher in both lixisenatide arms than in the combined placebo group (for HbA1c≦6.5%, 23.8% in the lixisenatide morning injection arm and 19.2% in the lixisenatide evening injection arm, versus 10.4% in the combined placebo group; for HbA1c<7%, 43% in the lixisenatide morning injection arm and 40.6% in the lixisenatide evening injection arm, versus 22% in the combined placebo group).
Treatment with lixisenatide also improved post-prandial glycemic control as shown by the results for 2-hour Post-Prandial Glucose (PPG) and for glucose excursion in the morning injection arms (meal test was not performed in the evening injection arms). 2-hour PPG was significantly decreased from baseline to Week 24 in the lixisenatide arm, compared to the placebo arm with a LS mean difference of −4.51 mmol/L (p-value<0.0001). Both lixisenatide arms demonstrated a statistically significant reduction from baseline to Week 24 in Fasting Plasma Glucose (FPG) compared to the combined placebo group (for lixisenatide morning injection, LS mean difference=−0.94 mmol/L, p-value=<0.0001; for lixisenatide evening injection, LS mean difference=−0.56 mmol/L, p-value=0.0046). The LS mean decrease in body weight was 2.01 kg in the lixisenatide morning injection arm and 2.02 kg in the lixisenatide evening injection arm, compared to 1.64 kg in the combined placebo group, with no significant difference observed. Per the testing strategy for multiplicity adjustment, the inferential testing for the subsequent efficacy variables was exploratory since the body weight analysis failed to show a statistically significant difference. A noticeable improvement in β-cell function assessed by HOMA-β was observed in both lixisenatide arms. The LS mean difference was 12.12 (p-value=0.0002 without adjustment for multiplicity) in the lixisenatide morning injection arm and 8.96 (p-value=0.0071 without adjustment for multiplicity) in the lixisenatide evening injection arm, when compared to the combined placebo group. In addition, both lixisenatide arms had substantially lower rates of patients requiring rescue therapy during the main 24-week double-blind treatment period (2.7% for morning injection and 3.9% for evening injection), compared to the combined placebo group (10.6%). No clinically relevant difference in Fasting Plasma Insulin (FPI) was observed between each lixisenatide arm and the combined placebo group.
Safety analyses are based on whole study treatment. Lixisenatide was well tolerated. The incidence of treatment emergent adverse events (TEAEs) was higher in lixisenatide arms (84.7% for morning injection and 83.5% for evening injection), compared to the combined placebo group (75.3%). One patient in the lixisenatide morning injection arm had a TEAE of pancreatic carcinoma leading to death. Two patients in the lixisenatide evening arm died due to post-treatment AEs (haemothorax and lymphoma respectively). A total of 58 patients had at least one serious TEAE, with higher rate in the lixisenatide evening injection arm (10.2%), followed by the lixisenatide morning injection arm (8.2%) and the combined placebo group (6.5%). The most commonly reported TEAE for lixisenatide-treated patients was nausea (64 [25.1%] patients for morning injection and 63 [24.7%] for evening injection, versus 16 [9.4%] for the combined placebo) followed by headache (49 [19.2%] patients for morning injection and 42 [16.5%] for evening injection, versus 28 [16.5%] for the combined placebo). Diarrhoea was reported in 39 (15.3%) patients for morning injection and 36 (14.1%) for evening injection, versus 20 (11.8%) for the combined placebo; and vomiting in 35 (13.7%) patients for morning injection and 40 (15.7%) for evening injection, versus 9 (5.3%) for the combined placebo. Eighteen (7.1%) patients in the lixisenatide morning injection arm and 22 (8.6%) in the lixisenatide evening injection arm had symptomatic hypoglycemia events per protocol definition, compared to 4 (2.4%) placebo-treated patients. None of the symptomatic hypoglycemia events were severe in intensity. A total of 10 patients (3 [1.2%] for lixisenatide morning injection, 4 [1.6%] for lixisenatide evening injection, and 3 [1.8%] for combined placebo) had reported 12 TEAEs that were adjudicated as allergic reactions by ARAC. Of these, 3 events (anaphylactic reaction and angioedema in one patient in the lixisenatide morning injection arm and urticaria in one patient in the lixisenatide evening injection arm) were adjudicated as possibly related to IP. No case of acute pancreatitis was reported in the study. There was no clinically relevant difference in terms of safety and tolerability between morning and evening injection regimen for lixisenatide.
1.1 Primary Objective
The primary objective of this study was to assess the efficacy of lixisenatide on glycemic control when it was used in the morning within 1 hour prior to the meal in comparison to placebo as an add-on treatment to metformin in term's of HbA1c reduction (absolute change) over a period of 24 weeks in patients with type 2 diabetes, not adequately controlled with metformin.
1.2 Key Secondary Objective(s)
The secondary objectives of this study were:
This was a randomized, double-blind, placebo-controlled, 4-arm, unbalanced design (3:1:3:1), parallel-group, multicenter, multinational study: morning injection (255 lixisenatide treated vs. 85 placebo treated patients) and evening injection (255 lixisenatide vs. 85 placebo treated patients). The study was double-blind with regard to active and placebo treatments. The study drug volume (i.e. dose of active drug or matching placebo) and the time of injection (morning vs. evening) were not blinded. The patients were stratified by screening values of HbA1c (<8%, ≧8%) and body mass index (BMI) (<30 kg/m2, ≧30 kg/m2).
The approximate minimum double-blind study duration per patient was 79 weeks (up to 2 weeks screening+1 week run-in +24 weeks main double-blind treatment+variable extension+3 days follow-up). A 4-week follow-up was performed in patients from the morning injection arms only. Patients who completed the 24-week main double-blind period underwent a variable double-blind extension period, which ended for all patients approximately at the scheduled date of week 76 visit (V25) for the last randomized patient.
The standardized meal challenge test was performed in patients in the morning injection arms only.
3.1 Primary Endpoint
The primary efficacy variable was the absolute change in HbA1c from baseline to Week 24, which is defined as: HbA1c value at Week 24—HbA1c value at baseline.
If a patient permanently discontinued the treatment, or received rescue therapy during the main 24-week double-blind treatment period, or did not have HbA1c value at Week 24, the last post-baseline on-treatment HbA1c measurement during the main 24-week double-blind on-treatment period was used as HbA1c value at Week 24 (last observation carried forward [LOCF] procedure).
3.2 Secondary Endpoints
3.2.1 Key Efficacy Endpoints
For secondary efficacy variables, the same procedure for handling missing assessments/early discontinuation was applied as for the primary efficacy variable.
3.2.2 Safety Endpoints
The safety analysis was based on the reported TEAEs and other safety information including symptomatic hypoglycemia and severe symptomatic hypoglycemia, local tolerability at injection site, allergic events (as adjudicated by ARAC), suspected pancreatitis, increased calcitonin, vital signs, 12-lead ECG and laboratory tests.
Major cardiovascular events were also collected and adjudicated by a Cardiovascular events Adjudication Committee (CAC). The adjudicated and confirmed events by CAC from this study and other lixisenatide phase 3 studies will be pooled for analyses and summarized in a separate report based on the statistical analysis plan for the overall cardiovascular assessment of lixisenatide. The KRM/CSR will not present the summary of the adjudicated and confirmed CV events from this study.
The sample size/power calculations were performed based on the primary efficacy variable, absolute change from baseline to week 24 in HbA1c.
A total of 680 patients (255 in each lixisenatide morning or evening injection arm and 85 in each placebo morning or evening injection arm) provided a power of 97% (or 87%) to detect a difference of 0.5% (or 0.4%) in the absolute change in HbA1c from baseline to Week 24 between lixisenatide and placebo. This calculation assumed a common standard deviation of 1.3% with a 2-sided test at the 5% significance level. The sample size calculations were based upon the 2-sample t test and made using nQuery® Advisor 5.0. Standard deviation was estimated in a conservative manner from previously conducted diabetes studies (based on published data of similarly designed study and on internal data, not published), taking into account early dropout.
5.1 Analysis Populations
The modified intent-to-treat (mITT) population consisted of all randomized patients who received at least one dose of double-blind investigational product (IP), and had both a baseline assessment and at least one post-baseline assessment of efficacy variables.
The safety population was defined as all randomized patients who took at least one dose of the double-blind IP.
5.2 Primary Efficacy Analysis
The primary efficacy variable (change in HbA1c from baseline to Week 24) was analyzed using an analysis of covariance (ANCOVA) model with treatment arms (morning injection lixisenatide and placebo arms, evening injection lixisenatide and placebo arms), randomization strata of screening HbA1c (<8.0, ≧8.0%), randomization strata of screening BMI (<30, ≧30 kg/m2) values, and country as fixed effects and using the baseline HbA1c values as a covariate. Differences between each lixisenatide arm and the placebo combined group and its two-sided 95% confidence intervals as well as p-value were estimated within the framework of ANCOVA. In the ANCOVA model, the morning and evening injection placebo arms were included as separate treatments, but combined as one group when presenting results and making comparisons using appropriate contrast (e.g., [−0.5, −0.5, 1, 0] in the order of placebo morning injection, placebo evening injection, lixisenatide morning injection and lixisenatide evening injection when comparing the lixisenatide morning injection arm with the placebo combined group).
A stepwise testing procedure was applied in order to ensure type I error control. First, morning injection lixisenatide arm was compared to the combined placebo group (primary objective). If the test was statistically significant, the evening injection lixisenatide arm would be compared to the combined placebo group (secondary objective).
The primary analysis of the primary efficacy variable was performed based on the mITT population and the measurements obtained during the main 24-week double-blind on-treatment period for efficacy variables. The main 24-week double-blind on-treatment period for efficacy variables except those from the standardized meal test was defined as the time from the first dose of the double-blind IP up to 3 days (except for FPG, FPI, and HOMA-β by central laboratory, which was up to 1 day) after the last dose of the double-blind IP injection on or before Visit 12/Week 24 visit (or Day 169 if Visit 12/Week 24 visit was missing), or up to the introduction of the rescue therapy, whichever the earliest. The main 24-week double-blind on-treatment period for efficacy variables from the meal challenge test including PPG and glucose excursion was defined as the time from the first dose of the double-blind IP up to the date of the last dose of the double-blind IP injection on or before Visit 12/Week 24 visit (or Day 169 if Visit 12/Week 24 visit was missing), or up to the introduction of the rescue therapy, whichever the earliest. The LOCF procedure was used by taking the last available post-baseline on-treatment HbA1c measurement (before the initiation of the new medication in the event of rescue therapy) as the HbA1c value at week 24.
5.3 Secondary Efficacy Analysis
Once the primary efficacy variable was statistically significant at α=0.05 for both comparisons, the testing procedure was performed to test the change in 2-hour PPG (mmol/L) after a standardized meal test from baseline to Week 24 in the morning injection arms, then to test the remaining secondary efficacy variables by the following prioritized order in 2 separate branches: the morning injection arm versus the combined placebo and the evening injection arm versus the combined placebo. The tests stopped as soon as an endpoint was found not statistically significant at α=0.05 (
All continuous secondary efficacy variables at week 24 as described in Section 3.2.1 were analyzed using the similar approach and ANCOVA model as described in Section 5.2 for the primary analysis of the primary efficacy endpoint. The adjusted estimates of the treatment mean difference between lixisenatide and placebo and two-sided 95% confidence intervals were provided.
The following categorical secondary efficacy variables at Week 24 were analyzed using a Cochran-Mantel-Haenszel (CMH) method stratified on randomization strata (screening HbA1c [<8.0, ≧8%] and screening BMI [<30, ≧30 kg/m2]):
Number and percentage of patients with ≧5% weight loss from baseline at week 24 were presented by treatment groups.
All secondary endpoints at the end of treatment were only evaluated by descriptive statistics (mean, standard deviation, median and ranges provided in CSR).
5.4 Safety Analysis
The safety analyses were primarily based on the on-treatment period of the whole study. The on-treatment period of the whole study was defined as the time from the first dose of double-blind IP up to 3 days after the last dose of IP administration during the whole study period regardless of rescue status. The 3-day interval was chosen based on the half-life of the IP (approximately 5 times the half-life).
In addition, the safety analyses for the 24-week double-blind treatment period will be summarized in CSR.
The summary of safety results (descriptive statistics or frequency tables) is presented by treatment groups.
6.1 Study Patients
6.1.1 Patient Accountability
The study was conducted in 133 centers in 16 countries (Australia, Canada, Chile, Czech Republic, Germany, Croatia, Mexico, Morocco, Philippines, Romania, Russian Federation, South Africa, Spain, Ukraine, United States and Venezuela). A total of 1374 patients were screened and 680 were randomized to one of the four treatment arms. The most common reason for non-randomization was HbA1c value out of ranges at the screening visit as defined per protocol (483 [35.2%] out of 1374 screened patients).
All 680 randomized patients were exposed to the study treatment and included in mITT population. Table 1 provides the number of patients included in each analysis population.
6.1.2 Study Disposition
Table 2 provides the summary of patient disposition for each treatment group. During the overall treatment period, 169 (24.9%) patients prematurely discontinued the study treatment with a higher percentage in the lixisenatide evening injection arm (27.5%) and a lower percentage in the lixisenatide morning injection arm (22.4%) compared to the combined placebo group (24.7%). In lixisenatide treated patients, the main reason for treatment discontinuation was “adverse events” (10.2% for evening injection and 8.2% for morning injection versus 3.5% for combined placebo) followed by “other reasons” (8.6% for each lixisenatide arm versus 11.2% for combined placebo). Similar results were observed for the main 24-week treatment period, where a total of 65 (9.6%) patients prematurely discontinued the study treatment (12.2% in the lixisenatide evening injection arm, 8.6% in the lixisenatide morning injection arm versus 7.1% in the combined placebo group) with the main reason also being “adverse events” for lixisenatide arms (5.1% for evening injection and 4.7% for morning injection, versus 1.2% for the combined placebo). The time-to-onset of treatment discontinuation due to any reason for the overall treatment period is depicted in
Two patients in the lixisenatide evening injection arm were not counted in Table 22 because their treatments were discontinued due to AEs that occurred during the post-treatment period.
6.1.3 Demographics and Baseline Characteristics
The demographic and patient baseline characteristics were generally similar across treatment arms for the safety population (Table 3), with however fewer Hispanic and female patients in the combined placebo group. The median age was 55 years and 56.9% were female. The study population was primarily Caucasian (88.8%). The majority of the patients (65.1%) were obese.
Disease characteristics including diabetic history were generally comparable across treatment arms (Table 4). Across all treatment arms, the median duration of diabetes was 4.74 years and the median age at onset of diabetes was 48 years. On average patients were on metformin for 3.61 years and the median daily metformin dose was 2000 mg.
HbA1c, 2-hour PPG, FPG, body weight, HOMA-β at baseline were generally comparable across treatment arms for the safety population (Table 5). The average HbA1c at baseline was 8.06%.
6.1.4 Dosage and Duration
The average treatment exposure was similar across treatment groups: 549.9 days (78.6 weeks) in the combined placebo, 543.9 days (77.7 weeks) in the lixisenatide morning injection arm, and 515.6 days (73.7 weeks) in the lixisenatide evening injection arm (Table 6). Of the 510 lixisenatide-treated patients, 450 (90.2% for morning injection and 86.3% for evening injection) were exposed to IP for 24 weeks (169 days) or longer, and 310 (62.4% and 59.2%, respectively) were exposed for 18 months (547 days) or longer. Five patients did not record the last administration date on CRF page “End of treatment” and hence their durations of exposure were set to missing following the SAP data handling convention.
At the end of double-blind treatment, the proportion of patients who reached the target daily dose of 20 μg was lower in lixisenatide arms (91.4% for morning injection and 91.8% for evening injection), compared to the combined placebo group (97.6%) (Table 7). Similar result was observed at the end of 24-week double-blind treatment period, with 92.2% in each lixisenatide arm versus 97.1% in the combined placebo group (Table 8). The dose at the end of titration is presented in Table 30.
6.2 Efficacy
6.2.1 Primary Efficacy Endpoint
Table 9 summarizes the results of the primary efficacy parameter, change from baseline to Week 24 (LOCF) in HbA1c using an ANCOVA analysis.
According to the pre-specified primary analysis, a statistically significant reduction of HbA1c, was demonstrated from baseline to Week 24 in both lixisenatide arms, compared to the combined placebo group (for lixisenatide morning injection, LS mean difference=−0.48%; p-value=<0.0001; for lixisenatide evening injection, LS mean difference=−0.37%; p-value=<0.0001).
(a)Analysis of covariance (ANCOVA) model with treatment groups (morning injection lixisenatide and placebo arms, evening injection lixisenatide and placebo arms), randomization strata of screening HbA1c (<8.0, ≧8.0%), randomization strata of screening BMI (<30, ≧30 kg/m2), and country as fixed effects and baseline HbA1c value as a covariate.
Table 10 summarizes the proportion of patients with treatment response HbA1c≦6.5% or ≦7% at Week 24, respectively. Treatment responses were similar in lixisenatide arms. The analysis of HbA1c responders using the CMH method showed a statistically significant treatment difference between each lixisenatide arm versus the combined placebo (for HbA1c≦6.5% at Week 24, p-value=0.0003 for lixisenatide morning injection and p-value=0.0120 for lixisenatide evening injection; for HbA1c<7% at Week 24, p-value=<0.0001 for both lixisenatide arms).
(a)Cochran-Mantel-Haenszel (CMH) method stratified by randomization strata of screening HbA1c (<8.0 or ≧8.0%) and randomization strata of screening body mass index (<30 or ≧30 kg/m2).
6.2.2 Key Secondary Efficacy Endpoints
The ANCOVA analyses of 2-hour PPG, FPG, body weight, HOMA-β, FPI and glucose excursion are presented in this section. Error! Reference source not found. and Error! Reference source not found. illustrate the mean (±SE) change from baseline in FPG and body weight over time during the main 24-week double-blind treatment period. Mean (±SE) changes from baseline in FPG and body weight over time up to Week 76 are depicted in Error! Reference source not found. and Error! Reference source not found. in the appendix respectively. The percentage of patients who were rescued during the main 24 week double-blind treatment period is presented in Table 16.
A statistically significant improvement in 2-hour PPG was demonstrated in the lixisenatide morning injection arm, compared to the placebo morning injection arm with a LS mean difference of −4.51 mmol/L (p-value<0.0001) (Table 11). Treatment with lixisenatide substantially decreased glucose excursion after a standardized meal from baseline to Week 24 compared to the combined placebo group (LS mean difference=−3.88 mmol/L with a 95% CI (−4.818 to −2.939) (Table 18).
For FPG, both lixisenatide arms showed a statistically significant decrease from baseline to Week 24 compared to the combined placebo group (in the lixisenatide morning injection arm, LS mean difference=−0.94 mmol/L and p-value=<0.0001; in the lixisenatide evening injection arm, LS mean difference=−0.56 mmol/L and p-value=0.0046) (Table 12).
The LS mean decrease in body weight was 2.01 kg in the lixisenatide morning injection arm and 2.02 kg in the lixisenatide evening injection arm, compared to 1.64 kg in the combined placebo group, with no significant difference observed (Table 13). The percentage of patients who had ≧5% weight loss from baseline to Week 24 was higher in both lixisenatide arms (14.9% for morning injection and 19.3% for evening injection) than in the combined placebo group (11.3%) (Table 14).
Per the testing strategy for multiplicity adjustment, the inferential testing for the subsequent efficacy variables was exploratory, since the body weight analysis failed to show a statistically significant difference (Error! Reference source not found).
A noticeable improvement in β-cell function assessed by HOMA-β was observed in both lixisenatide arms. LS mean difference was 12.12 (p-value=0.0002 without adjustment for multiplicity) in the lixisenatide morning injection arm and 8.96 (p-value=0.0071 without adjustment for multiplicity) in the evening injection arm, compared to the combined placebo group (Table 15).
Both lixisenatide arms had substantially lower rates of patients requiring rescue therapy during the main 24-week double-blind treatment period (2.7% for morning injection and 3.9% for evening injection), compared to the combined placebo group (10.6%) (Table 16).
No clinically relevant difference in FPI was observed between each lixisenatide arm and the combined placebo group (Table 17).
(a)Analysis of covariance (ANCOVA) with treatment groups (morning injection lixisenatide and placebo arms), randomization strata of screening HbA1c (<8.0, ≧8.0%), randomization strata of screening body mass index (<30, ≧30 kg/m2), and country as fixed effects and 2-hour post-prandial plasma glucose value at baseline as a covariate.
(a)Analysis of covariance (ANCOVA) with treatment groups (morning injection lixisenatide and placebo arms, evening injection lixisenatide and placebo arms), randomization strata of screening HbA1c (<8.0, ≧8.0%), randomization strata of screening body mass index (<30, ≧30 kg/m2), and country as fixed effects and fasting plasma glucose value at baseline as a covariate.
(a)Analysis of covariance (ANCOVA) with treatment groups (morning injection lixisenatide and placebo arms, evening injection lixisenatide and placebo arms), randomization strata of screening HbA1c (<8.0, ≧8.0%), randomization strata of screening body mass index (<30, ≧30 kg/m2), and country as fixed effects and body weight at baseline as a covariate.
(a)Analysis of covariance (ANCOVA) model with treatment groups (morning injection lixisenatide and placebo arms, evening injection lixisenatide and placebo arms), randomization strata of screening HbA1c (<8.0, ≧8.0%), randomization strata of screening body mass index (<30, ≧30 kg/m2), and country as fixed effects and baseline HOMA-β value as a covariate.
(a)Cochran-Mantel-Haenszel (CMH) method stratified by randomization strata of screening HbA1c (<8.0 or ≧8.0%) and randomization strata of screening body mass index (<30 or ≧30 kg/m2).
(a)Analysis of covariance (ANCOVA) with treatment groups (morning injection lixisenatide and placebo arms, evening injection lixisenatide and placebo arms), randomization strata of screening HbA1c (<8.0, ≧8.0%), randomization strata of screening body mass index (<30, ≧30 kg/m2), and country as fixed effects and fasting plasma insulin value at baseline as a covariate.
(a)Analysis of covariance (ANCOVA) model with treatment groups (morning injection lixisenatide and placebo arms), randomization strata of screening HbA1c (<8.0, ≧8.0%), randomization strata of screening body mass index (<30, ≧30 kg/m2), and country as fixed effects and baseline glucose excursion value as a covariate.
6.3 Safety
An overview of the adverse events observed during the on-treatment period of the whole study is provided in Table 19. The proportion of patients who experienced TEAEs was higher in the lixisenatide-treated patients (84.7% for morning injection and 83.5% for evening injection), compared to the combined placebo group (75.3%). One patient in the lixisenatide evening arm had a TEAE of pancreatic carcinoma leading to death. Two patients in the lixisenatide evening arm died due to post-treatment AEs (haemothorax and lymphoma respectively). The lixisenatide evening injection arm had higher rate of serious TEAEs (10.2%), followed by the lixisenatide morning injection arm (8.2%) and the combined placebo group (6.5%). Similar pattern was also observed in TEAEs leading to treatment discontinuation with 9.4% in the lixisenatide evening injection arm, 8.2% in the lixisenatide morning injection arm, compared to 3.5% in the combined placebo group. Table 20, Table 21, and Table 22 summarize TEAEs leading to death, serious TEAEs, and TEAEs leading to treatment discontinuation by primary SOC, HLGT, HLT and PT, respectively. The most common TEAE leading to treatment discontinuation was nausea in both lixisenatide-treated groups (6 [2.4%] patients for morning injection and 7 [2.7%] for evening injection), while no patients discontinued treatment due to nausea in the combined placebo group.
Table 32 in the appendix presents the incidences of TEAEs during the on-treatment period of the whole study occurring in at least 1% of patients in the combined placebo group or any individual lixisenatide group. Nausea was the most frequently reported TEAE in both lixisenatide-treated groups (64 [25.1%] patients for morning injection and 63 [24.7%] for evening injection). Sixteen placebo-treated patients (9.4%) reported nausea. The second most frequently reported TEAE in the lixisenatide-treated patients was headache (49 [19.2%] patients for morning injection and 42 [16.5%] for evening injection), followed by diarrhoea (39 [15.3%] patients for morning injection and 36 [14.1%] for evening injection) and vomiting (35 [13.7%] patients for morning injection and 40 [15.7%] for evening injection). In the combined placebo group, 28 [16.5%] patients reported headache, 20 [11.8%] diarrhoea, and 9 [5.3%] vomiting.
Escherichia urinary tract infection
During the on-treatment period of the whole study, 18 (7.1%) patients in the lixisenatide morning injection arm, 22 (8.6%) in the lixisenatide evening injection arm reported at least one symptomatic hypoglycemia event per protocol definition, compared to 4 (2.4%) in the combined placebo group (Table 23). None of the symptomatic hypoglycemia events were severe in intensity. Twelve additional patients (5 in the lixisenatide morning injection arm, 6 in the lixisenatide morning injection arm and 1 in the combined placebo group) reported hypoglycemia (Table 32), but these events did not meet the protocol-specified definition (for all cases but 2 the associated glucose values≧60 mg/dL, 1 with no glucose value recovered without counter measurements, and 1 with symptoms recorded only).
Seventeen (6.7%) patients in each lixisenatide arm and 6 (3.5%) in the combined placebo group experienced injection site reaction AEs (Table 24). The injection site reaction AEs were identified by searching the term “injection site” in either the PTs coded from the investigator reported terms or the PTs from the ARAC diagnosis after the allergic reaction adjudication. None of these reactions was serious or severe in intensity. Only 1 event (reported as “allergic exanthema” and coded to PT “dermatitis allergic” from the investigator reported term) in the lixisenatide evening injection arm led to IP discontinuation. The event was sent to ARAC but was not adjudicated as an allergic reaction; the coded term from ARAC diagnosis was local reaction at injection site.
A total of 41 events were reported for 36 patients as possible allergic events by investigators and sent to ARAC for adjudication during the on-treatment period of the whole study. Of these, 12 events in 10 patients (3 [1.2%] patients in the lixisenatide morning injection arm, 4 [1.6%] in the lixisenatide evening injection arm, and 3 [1.8%] in the combined placebo group) were adjudicated as allergic reactions by ARAC including 3 events in 2 patients (1 with anaphylactic reaction and angioedema in the lixisenatide morning injection arm and 1 with urticaria in the lixisenatide evening injection arm) adjudicated as possibly related to IP (Table 25).
Per protocol, any increase in amylase and/or lipase above twice the upper limit of normal range (ULN) that had been confirmed by a repeat measurement was to be monitored and documented on a pre-specified AE form for “suspected pancreatitis”. During the on-treatment period of the whole study, 3 (1.2%) patients in the lixisenatide morning injection arm, 9 (3.5%) in the lixisenatide evening injection arm, and 1 (0.6%) in the combined placebo group reported 15 TEAEs with the pre-specified AE form (Table 26). Among them, one patient in the lixisenatide evening injection arm reported suspected pancreatitis.
Patients who had at least one value of lipase or amylase≧3 ULN during the on-treatment period are summarized in (Table 27). A total of 15 patients experienced elevated lipase (≧3 ULN): 2 [0.8%] in the lixisenatide morning injection atm, 9 [3.5%] in the lixisenatide evening injection arm, and 4 [2.4%] in the combined placebo group. Four (1.6%) patients in the lixisenatide evening injection arm and 1 patient (0.6%) in the combined placebo group had elevated amylase≧3 ULN whereas none in the lixisenatide morning injection arm did. No one had both lipase and amylase≧3 ULN during the whole study.
Per protocol, any calcitonin value≧20 pg/mL confirmed by a repeat measurement was to be monitored and reported on the pre-specified AE form for “increased calcitonin≧20 pg/mL”. During the on-treatment period of the whole study, 5 (2%) patients in the lixisenatide morning injection arm, 4 (1.6%) in the lixisenatide evening injection arm and 3 (1.8%) in the combined placebo group reported TEAEs with the pre-specified AE form (Table 28). Among the 8 lixisenatide-treated who experienced increased blood calcitonin, 1 patient in the evening arm had calcitonin value≧50 ng/L, 3 in each morning and evening injection arm had calcitonin values≧20 but <50 ng/L, and 1 in the morning arm had calcitonin value≦20 ng/L. In the combined placebo group, 1 patient had had calcitonin<20 ng/L and 2 patients had calcitonin value≧20 but<50 ng/L. In addition, 1 patient in the lixisenatide evening injection arm was diagnosed with node in left lobe of thyroid gland coded to PT “thyroid neoplasm”. Her calcitonin level was reported <20 ng/L and the event was assessed as not related to the IP by the investigator.
A total of 4 patients (0.6%) in the lixisenatide combined group reported a TEAEs of thyroid neoplasm during the study versus none in the placebo combined group.
There was no AE reported on the pre-specified adverse event form for “increased calcitonin≧20 pg/mL” after the discontinuation of IP in the study.
Patients with at least one serum calcitonin measurement during the on-treatment period of the whole study are summarized in Table 29 according to the 4 pre-defined categories of calcitonin level at baseline. A total of 17 patients had calcitonin values≧20 ng/L: 4 (1.7%) patients in the lixisenatide morning injection arm, 8 (3.5%) patient in the lixisenatide evening arm and 5 (3.1%) patients in the combined placebo group. Amongst them, 10 patients (3 for lixisenatide morning injection, 4 for lixisenatide evening injection and 3 for combined placebo) reported a TEAE with the pre-specified AE form (Table 28). Five out of the 12 lixisenatide-treated patients and 3 out of the 5 placebo-treated patients had a calcitonin value≧20 ng/L but did not report a TEAE with the pre-specified AE form because of an unconfirmed elevation. In the lixisenatide-treated patients, 1 in each morning and evening injection arm had a single value≧50 ng/L and 3 in the lixisenatide evening injection arm had a single value≧20 but <50 ng/L. In the combined placebo group, 2 patients had single value≧20 but <50 ng/L and the third patient had 2 measurements≧20 but <50 ng/L but both repeated tests were <20 ng/L. It should be pointed out that calcitonin measurements were implemented in a protocol amendment after most patients were already randomized in this study. Therefore, baseline calcitonin values are not available for most patients.
aCalculated as (number of patients with events * 100 divided by total exposure + 3 days in patient years).
| Number | Date | Country | Kind |
|---|---|---|---|
| EP 11 166 052.8 | May 2011 | EP | regional |
