Patent Application
20190054146
Subject of the present invention is a method for treatment of diabetes mellitus type 2 with AVE0010 (lixisenatide) as add-on therapy to administration of metformin.
Metformin is a biguanide hypoglycemic agent used in the treatment of Type 2 diabetes mellitus not responding to dietary modification. Metformin improves glycemic control by improving insulin sensitivity. 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.
Hypoglycaemia is the critical limiting factor in the glycaemic management of diabetes in both the short and long term. Despite steady improvements in the glycaemic management of diabetes, population-based data indicate that hypoglycaemia continues to be a major problem for people with both type 1 and type 2 diabetes (American diabetes association, workgroup on hypoglycemia: Defining and Reporting Hypoglycemia in Diabetes. Diabetes Care 28(5), 2005, 1245-1249).
A first aspect of the present invention is a method for the treatment of diabetes mellitus type 2 comprising administering
In particular, the method is a method for the prevention of hypoglycaemia in a diabetes mellitus type 2 patient. More particular, the method is a method for the prevention of symptomatic hypoglycaemia or severe symptomatic hypoglycaemia in a diabetes mellitus type 2 patient.
More particular, the method of the present invention is a method for the prevention of hypoglycaemia in a diabetes type 2 patient having an increased risk of hypoglycaemia, in particular a diabetes type 2 patient having experienced at least one hypoglycaemic event. The hypoglycaemic event can be a symptomatic hypoglycaemic event or a severe symptomatic hypoglycaemic event.
In the present invention, hypoglycaemia is a condition wherein a diabetes mellitus type 2 patient experiences a plasma glucose concentration of below 60 mg/dL (or below 3.3 mmol/L), below 50 mg/dL, below 40 mg/dL, or below 36 mg/dL.
By the method of the present invention, hypoglycaemia can be reduced to below 12%, below 11%, below 10%, below 9%, below 8%, below 7%, below 6% or below 5% of diabetes type 2 patients receiving the combination of lixisenatide and metformin, as described herein.
In the present invention, “symptomatic hypoglycaemia” or “symptomatic hypoglycaemic event” is a condition associated with a clinical symptom that results from the hypoglycaemia, wherein the plasma glucose concentration is below 60 mg/dL (or below 3.3 mmol/L), below 50 mg/dL, or below 40 mg/dL. A clinical symptoms can be, for example, sweating, palpitations, hunger, restlessness, anxiety, fatigue, irritability, headache, loss of concentration, somnolence, psychiatric disorders, visual disorders, transient sensory defects, transient motor defects, confusion, convulsions, and coma. In the method of the present invention, one or more clinical symptoms of symptomatic hypoglycaemia, as indicated herein, can be selected. Symptomatic hypoglycaemia may be associated with prompt recovery after oral carbohydrate administration.
In the present invention, “severe symptomatic hypoglycaemia” or “severe symptomatic hypoglycaemic event” is a condition with a clinical symptom, as indicated herein, that results from hypoglycaemia, wherein the plasma glucose concentration is below 36 mg/dL (or below 2.0 mmol/L). Severe symptomatic hypoglycaemia can be associated with acute neurological impairment resulting from the hypoglycaemic event. In a severe symptomatic hypoglycaemia, the patient may require the assistance of another person, if, for example, the patient could not treat or help him/herself due to the acute neurological impairment. The definition of severe symptomatic hypoglycaemia may include all episodes in which neurological impairment is severe enough to prevent self-treatment and which were thus thought to place patients at risk for injury to themselves or others. The acute neurological impairment may be at least one selected from somnolence, psychiatric disorders, visual disorders, transient sensory defects, transient motor defects, confusion, convulsions, and coma.
Severe symptomatic hypoglycaemia may be associated with prompt recovery after oral carbohydrate, intravenous glucose, or/and glucagon administration.
Normoglycaemia may relate to a blood plasma concentration of glucose of from 60 mg/dL to 140 mg/dL (corresponding to 3.3 mmol/L to 7.8 mmol/L).
It has surprisingly been found in a clinical trial that during treatment of diabetes mellitus type 2 patients with lixisenatide combined with metformin, only 5% of patients had symptomatic hypoglycaemic events, whereas in a comparative trial, 14.6% of diabetes mellitus type 2 patients treated with a combination of exenatide and metformin reported symptomatic hypoglycaemia during the same period. This results indicate that the combination of lixisenatide and metformin can be used for the prevention of hypoglycaemia.
The combination of lixisenatide and metformin, as described herein, can also be used for the reduction or/and prevention of side effects of anti-diabetic treatment in diabetes mellitus type 2 patients.
In the present invention, side effects of the combination of lixisenatide and metformin are investigated in a clinical trail of treatment of diabetes mellitus type 2 patients with lixisenatide combined with metformin (Example 2). In this trial, side effects are described by treatment emergent adverse events (TEAEs).
The side effect may be a gastrointestinal motility and defaecation condition, for example diarrhoea, non-infective diarrhoea, a gastrointestinal atonic and hypomotility disorder NEC, constipation, gastrooesophageal reflux disease. The side effect may also by a gastrointestinal sign and symptom, for example a dyspeptic sign and symptom, dyspepsia, flatulence, bloating, distension, abdominal distension, gastrointestinal and abdominal pain (for example, excluding oral and throat pain), abdominal pain, pain of the upper abdomen, abdominal discomfort, a nausea or/and vomiting symptom, nausea or vomiting. In particular, the side effect is nausea or vomiting. More particular, the side effect is nausea.
It has surprisingly been found that in the clincal trial, side effects were reduced, for example nausea (see, for example, Table 29 of Example 2), compared with a comparative trial of treatment of diabetes mellitus type 2 patients with a combination of exenatide and metformin.
The side effect may also be pancreatitis. During the on-treatment period of the clinical trial, 5 (1.6%) lixisenatide-treated patients and 9 (2.8%) exenatide-treated patients reported events of changes in pancreatic enzymes or lipase or amylase for “suspected pancreatitis” (Tables 23 and 24 of Example 2). However, no case of acute pancreatitis was observed.
The side effect may also be an increased blood calcitonin concentration. In the clinical trial, eight patients (4 [1.3%] in each group) reported a calcitonin value ≥20 ng/L (Table 25). No value ≥50 ng/L was reported. Five (1.8%) patients in the lixisenatide group and 8 (3.0%) patients in the exenatide group had a value of calcitonin ≥20 ng/L during the on treatment period (Table 26).
These results indicate that the combination of lixisenatide and metformin can be used for the reduction or/and prevention of side effects of anti-diabetic treatment in diabetes mellitus type 2 patients. In particular, these results indicate that the combination of lixisenatide and metformin can be used for the reduction or/and prevention of nausea, pancreatitis or/and increased blood calcitonin concentration.
The compounds of (a) and (b) may be administered to a subject in need thereof, in an amount sufficient to induce a therapeutic effect.
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.
AVE0010 (desPro36Exendin-4(1-39)-Lys6-NH2) or/and a pharmaceutically acceptable salt thereof may be administered 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. AVE0010 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 once a day (progressive titration from 10 to 15 and to 20 μg/day. 20 μg is the effective maintenance dose).
In the present invention, AVE0010 or/and a pharmaceutically acceptable salt thereof may be administered in a daily dose in the range of 10 to 15 μg or in the range of 15 to 20 μg once a day (progressive titration from 10 to 15 and to 20 μg/day. 20 μg is the effective maintenance dose). AVE0010 or/and a pharmaceutically acceptable salt thereof may be administered by one injection per day.
In the present invention, a liquid composition comprising desPro36Exendin-4(1-39)-Lys6-NH2 or/and a pharmaceutically acceptable salt thereof may be employed. 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 to 8.5, or pH 6.0 to 8.5. The pH may be adjusted by a pharmaceutically acceptable diluted acid (typically HCl) or pharmaceutically acceptable diluted base (typically NaOH).
The preferred pH is in the range of pH 3.5 to 5.0.
The liquid composition may contain a buffer, such as a phosphate, a citrate, an acetate.
Preferably, it can contain an acetate buffer, in quantities up to 5 μg/mL, up to 4 μg/mL or up to 2 μg/mL.
The liquid composition of the present invention 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 of the present invention 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.
In addition, the liquid composition may contain L-methionin from 0.5 μg/mL to 20 μg/mL, preferably from 1 μg/mL to 5 μg/mL. Preferably, it contains L-methionin.
Metformin is the international non proprietary 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 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.
In the present invention, desPro36Exendin-4(1-39)-Lys6-NH2 or/and a pharmaceutically acceptable salt is 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 subcutaneously.
The subject to be treated by the method 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.
The subject to be treated by the method of the present invention may have a HbA1c value in the range of 7% to 10%.
The subject to be treated by the method of the present invention may have a HbA1c value of at least 8%, In particular, the subject to be treated by the method of the present invention may have a HbA1c value in the range of 8% to 10%.
The subject to be treated by the method of the present invention may have a HbA1c value of below 8%, In particular, the subject to be treated by the method of the present invention may have a HbA1c value in the range of 7% to 8%.
The subject to be treated by the method of the present invention may be an adult subject. The subject may have an age in the range of 18 to 50 years.
The method of the present invention preferably is a method of treatment of 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%.
Another aspect of the present invention is a pharmaceutical combination comprising
Preferably, the combination of the present invention is for use in the treatment of diabetes mellitus type 2.
Preferably, the combination of the present invention is for use in the prevention of hypoglycaemia, as described herein, in diabetes mellitus type 2 patients.
More preferably the combination of the present invention is for use in the prevention of hypoglycaemia in a diabetes type 2 patient having an increased risk of hypoglycaemia, in particular a diabetes type 2 patient having experienced at least one hypoglycaemic event. The hypoglycaemic event can be a symptomatic hypoglycaemic event or a severe symptomatic hypoglycaemic event.
Preferably, the combination of the present invention is for use in the prevention of side effects of anti-diabetic treatment, as described herein, in diabetes mellitus type 2 patients. In particular, the side effect is nausea, pancreatitis or/and increased blood calcitonin concentration.
The combination of the present invention may be administered as described herein in the context of the method of the present invention. The compounds (a) and (b) of the combination of the present invention may be formulated as described herein in the context of the method of the present invention.
Yet another aspect of the present invention is the use of a combination comprising
The medicament comprises desPro36Exendin-4(1-39)-Lys6-NH2 and metformin in separate formulations, as described herein.
The combination of the present invention can be used for production of a medicament for the prevention of hypoglycaemia, as described herein, in diabetes mellitus type 2 patients.
The combination of the present invention can be used for production of a medicament for the prevention of side effects of anti-diabetic treatment in diabetes mellitus type 2 patients, as described herein. In particular, the side effect is nausea, pancreatitis or/and increased blood calcitonin concentration.
The invention is further illustrated by the following Examples and Figures.
24-week study comparing lixisenatide (AVE0010) to sitagliptin as add-on to metformin in obese type 2 diabetic patients younger than 50
Subject of the example is a randomized, double-blind, double-dummy, 2-arm parallel-group, multicenter, 24-week study comparing the efficacy and safety of lixisenatide (AVE0010) to sitagliptin (CAS Number 486460-32-6) as add-on to metformin in obese type 2 diabetic patients younger than 50 years and not adequately controlled with metformin. Sitagliptin is an antidiabetic drug, acting as an inhibitor of dipeptidyl peptidase 4 (DPP4) resulting in enhanced level of Glucagon-Like Peptide 1, thereby reducing blood glucose levels in diabetic patients.
Study Primary Objectives
The primary objective of this study is to assess the efficacy of lixisenatide on a composite endpoint of glycemic control (HbA1c) and body weight in comparison to sitagliptin as an add-on treatment to metformin over a period of 24 weeks in obese type 2 diabetic patients younger than 50.
Study Secondary Objectives are assessment of the effects of lixisenatide on:
Specific Vulnerable Populations:
Women of child-bearing potential using contraception.
Inclusion Criteria
Patients (male and female) with type 2 diabetes mellitus, as defined by WHO (21), diagnosed for at least 1 year at the time of screening visit, insufficiently controlled with metformin at a stable dose of at least 1.5 g/day, for at least 3 months prior to the screening visit. Patients with obesity (BMI≥30 kg/m2) and aged from 18 years to less than 50 years.
Exclusion Criteria
Duration of Study Period Per Subject
Maximum duration of 27 weeks±7 days (3-week screening+24-week double-blind, double-dummy, active-controlled treatment+3-day follow-up)
A randomized, open-label, active-controlled, 2-arm parallel-group, multicenter 24 week study followed by an extension assessing the efficacy and safety of AVE0010 versus exenatide on top of metformin in patients with type 2 diabetes not adequately controlled with metformin
Summary
A randomized, open-label, active-controlled, 2-arm, parallel-group, multicenter, multinational study assessing the efficacy and safety of lixisenatide in comparison to exenatide as an add-on treatment to metformin in patients with type 2 diabetes was performed. The approximate minimum study duration per patient was 78 weeks (up to 2 weeks screening+24-week main treatment+variable extension+3 days follow-up). The study was conducted in 122 centers in 18 countries. The primary objective of the study was to assess the efficacy of lixisenatide on glycemic control in comparison to exenatide in terms of HbA1c reduction (absolute change) over a period of 24 weeks.
A total of 634 patients were randomized to one of the two treatment groups (318 in the lixisenatide group and 316 in the exenatide group). All randomized patients were exposed to the study treatment. Demographics and baseline characteristics were generally similar across the treatment groups. Eighteen patients (7 patients in lixisenatide and 11 patients in exenatide) were excluded from the mITT population for efficacy analyses due to lack of post-baseline efficacy data. During the overall study treatment period, 198 (31.2%) patients prematurely discontinued the study treatment. The percentages of patients who discontinued the treatment were similar between treatment groups (32.1% for lixisenatide and 30.4% for exenatide). The main reason for treatment discontinuation was “adverse events” (14.2% in each group) followed by “other reasons” (9.1% for lixisenatide and 9.8% for exenatide), “lack of efficacy” (6.0% for lixisenatide and 1.9% for exenatide) and “poor compliance to protocol” (2.2% for lixisenatide and 4.1% for exenatide).
The least squared (LS) mean changes from baseline to Week 24 in HbA1c were −0.79% for the lixisenatide group and −0.96% for the exenatide group (LS mean difference vs. exenatide=0.17%). The non-inferiority of lixisenatide compared to exenatide was demonstrated, as the upper bound of the two-sided 95% CI of the LS mean difference was less than the predefined non-inferiority margin of 0.4%. Superiority of lixisenatide over exenatide was not demonstrated.
Lixisenatide was well tolerated. Overall incidence of treatment emergent adverse events (TEAEs) was comparable between the two treatment groups. Six patients (3 patients in each treatment) had SAEs on-treatment leading to death. Forty-eight serious TEAEs occurred during the on-treatment period of the whole study with a similar incidence rate in each treatment group (8.2% for lixisenatide and 7.0% for exenatide). The most commonly reported TEAE was nausea (28.6% for lixisenatide-treated patients, 37.7% exenatide treated patients). Sixteen (5.0%) lixisenatide-treated patients had symptomatic hypoglycemia events as defined in the protocol during the on-treatment period whereas 46 (14.6%) exenatide-treated patients reported symptomatic hypoglycemia during the same period. None of symptomatic hypoglycemia events were severe. A total of 9 patients (6 [1.9%] lixisenatide-treated patients and 3 [0.9%] exenatide-treated patients) reported events adjudicated as an allergic reaction by the Allergic Reaction Assessment Committee (ARAC) but none of them were adjudicated as possibly related to the investigational product.
1. Objectives
Primary Objective
The primary objective of this study was to assess the efficacy of lixisenatide on glycemic control in comparison to exenatide as an add-on treatment to metformin in terms of HbA1c reduction over a period of 24 weeks in patients with type 2 diabetes.
Secondary Objective(S)
Trial Design
This was a randomized, open-label, active-controlled, 2-arm, parallel-group, multicenter, multinational study planned in 300 lixisenatide treated and 300 exenatide treated patients.
The patients were stratified by screening values of HbA1c (<8.0%, ≥8.0%) and Body Mass Index (BMI<30, ≥30 kg/m2).
Per the protocol amendment 4 (dated on 18 Jan. 2010), the approximate minimum study duration per patient was 78 weeks (up to 2 weeks screening+24 weeks main open-label treatment+variable extension+3 days follow-up). Patients who completed the 24-week main open-label period underwent a variable open label extension period, which ended for all patients approximately at the scheduled date of week 76 visit (V24) for the last randomized patient.
The primary efficacy variable was the absolute change in HbA1c from baseline to week 24, which was defined as: HbA1c at week 24-HbA1c at baseline.
If a patient discontinued the treatment prematurely or received rescue therapy during the main 24-week open-label treatment period or did not have HbA1c value at week 24 visit, the last post-baseline on-treatment HbA1c measurement during the main 24-week on-treatment period was used as HbA1c value at week 24 (Last Observation Carry Forward [LOCF] procedure).
Secondary Endpoints
Efficacy Endpoints
The same procedure for handling missing assessment/early discontinuation was applied as for the primary endpoint.
The secondary efficacy variables were:
All secondary endpoints at the end of treatment were to be evaluated by descriptive statistics only (presented in CSR)
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 Adjudication Committee (CAC). The adjudicated and confirmed events by CAC from this study and other lixisenatide phase 2-3 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.
Health Related Quality-of-Life Variables (PAGI-QOL Questionnaire)
The same procedure for handling missing assessment/early discontinuation was applied as for the primary endpoint. The consequence of the gastrointestinal tolerability on health related quality of life was evaluated by the PAGI-QOL questionnaire, which consisted of 30 questions and covered five dimensions including daily activities, clothing, diet and food habits, relationship and psychological well-being and distress. The total score was calculated by taking the mean of the five dimension scores (subscale scores) and ranged from 0 to 5 with lower scores indicating better quality of life. Change in PAGI-QOL total score from baseline to week 24 is analyzed.
Sample Size Calculation Assumptions
The sample size/power calculations were performed based on the primary variable, change from baseline to week 24 in HbA1c.
A sample size of 600 (300 patients in each group) ensured that the upper confidence limit of the two-side 95% confidence interval for the adjusted mean difference between lixisenatide and exenatide would not exceed 0.4% HbA1c with 96% power assuming that the standard deviation was 1.3 and the true difference between lixisenatide and exenatide was zero in HbA1c. 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.
Statistical Methods
Analysis Populations
The modified intent-to-treat (mITT) population consisted of all randomized patients who received at least one dose of open-label 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 study medication.
Primary Efficacy Analysis
The primary endpoint (change in HbA1c from baseline to week 24) was analyzed using an analysis of covariance (ANCOVA) model with treatment, randomization strata of screening HbA1c (<8.0, ≥8.0%), randomization strata of screening BMI (<30, ≥30 kg/m2) and country as fixed effects and using the baseline value as a covariate.
Differences between lixisenatide and exenatide and two-sided 95% confidence intervals were estimated within the framework of ANCOVA. To assess non-inferiority, the upper bound of the two-sided 95% CI for the difference of the adjusted mean change in HbA1c from baseline to week 24 between lixisenatide and exenatide was compared with the predefined non-inferiority margin of 0.4% HbA1c. Non-inferiority was demonstrated if the upper bound of the two-sided 95% CI of the difference between lixisenatide and exenatide on mITT population was ≤0.4%. If non-inferiority was established, a corresponding check of statistical superiority was to be performed for the primary endpoint.
The primary analysis of the primary efficacy variable was performed based on the mITT population and the measurements obtained during the main 24-week on-treatment period for efficacy variables. The main 24-week on-treatment period was defined as the time from the first dose of the IP up to 3 days (except for FPG by central laboratory, which was up to 1 day) after the last dose of the IP injection on or before V11/week 24 visit (or D169 if V11/week 24 visit was missing), or up to the introduction of rescue therapy, whichever was the earliest. In case of discontinuation of IP before week 24, HbA1c was assessed at the time of discontinuation. The LOCF procedure was used by taking this 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.
Secondary Efficacy Analysis
No formal statistical test was performed for any secondary efficacy endpoints.
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 above for the primary analysis of the primary efficacy endpoint. The adjusted estimates of the treatment mean difference between lixisenatide and exenatide and two-sided 95% confidence intervals were provided.
The following categorical secondary efficacy variables at the week 24 were analyzed:
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)
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 open-label IP injection up to 3 days after the last dose of open-label 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 treatment period will be summarized in CSR. The summary of safety results (descriptive statistics or frequency tables) is presented by treatment groups.
Health Related Quality-of-Life Analysis No formal statistical test was performed for the PAGI-QOL total score.
The PAGI-QOL total score at week 24 was analyzed using the similar approach and ANCOVA model as described above for the primary analysis of the primary efficacy endpoint.
Results
Study Patients
Patient Accountability
The study was conducted in 122 centers in 18 countries (Argentina, Austria, Brazil, Colombia, Denmark, Finland, Germany, Greece, Hungary, Italy, Netherlands, Norway, Poland, Puerto Rico, Russian Federation, Spain, Sweden and United States). A total of 1243 patients were screened and 639 were randomized to one of the two treatment groups. One site in Germany (#276905) who randomized 5 patients (out of 8 screened patients) was found to have a significant non-compliance to the protocol. Prior to the database lock, it was decided to exclude these patients from all efficacy and safety analyses and subsequently this had been communicated to US FDA. Safety data from this site will be separately reported in the CSR. The main reason for screening failure was HbA1c value at the screening visit out of the defined protocol ranges (426 [34.5%] out of 1235 screened patients excluding the German site mentioned above).
Six hundred thirty-four randomized patients were included in the analysis (318 in the lixisenatide group and 316 in the exenatide group) and all patients were exposed to the study treatment. Eighteen patients (7 patients in the lixisenatide group and 11 patients in the exenatide group) were excluded from mITT population for efficacy analyses due to lack of post-baseline efficacy data. Table 1 provides the number of patients included in each analysis population.
Study Disposition
Table 2 provides the summary of patient disposition for each treatment group. During the overall treatment period, 198 (31.2%) patients prematurely discontinued the study treatment. The percentages of patients who discontinued the treatment were similar between treatment groups (32.1% for lixisenatide and 30.4% for exenatide). The main reason for treatment discontinuation was “adverse events” (14.2% in each group) followed by “other reasons” (9.1% for lixisenatide and 9.8% for exenatide), “lack of efficacy” (6.0% for lixisenatide and 1.9% for exenatide) and “poor compliance to protocol” (2.2% for lixisenatide and 4.1% for exenatide). The time-to-onset of treatment discontinuation due to any reason for the overall treatment period is depicted in
Demographics and Baseline Characteristics
The demographic and patient baseline characteristics were generally similar between the two treatment groups for the safety population (Table 3). The median age of the study population was 57.5 years. The majority of the patients were Caucasian (92.7%). The percentage of male patients (59.2%) in the exenatide group was higher than the percentage in the lixisenatide group (47.5%).
Disease characteristics including diabetic history were generally comparable between the two treatment groups (Table 4). The mean duration of metformin treatment was slightly longer in the exenatide group (4.21 years) than in the lixisenatide group (3.79 years).
HbA1c and FPG at baseline were comparable between two treatment groups for the safety population (Table 5). A higher mean body weight at baseline was observed in the exenatide group (96.09 kg) compared with the lixisenatide group (94.01 kg).
The patient assessment of upper gastrointestinal disorders—Quality of life (PAGI-QOL) total score at baseline was similar between the two treatment groups (Table 6).
Dosage and Duration
The average treatment exposure was similar between the two treatment groups (494.8 days (70.6 weeks) for the lixisenatide group and 483.0 days (69 weeks) for the exenatide group) [Table 7]. Out of 634 patients, 536 (85.2% in the lixisenatide group and 83.9% in the exenatide group) had at least 169 days (24 weeks) of treatment and 345 (55.0% in the lixisenatide group and 53.8% in the exenatide group) had at least 547 days (18 months) of treatment. Note that the treatment duration of 5 patients (4 patients in the lixisenatide group and 1 patient in the exenatide group) was not summarized due to their missing end of treatment dates.
For the lixisenatide group, 295 (92.8%) patients and 293 (92.1%) patients were at the target total daily dose of 20 μg at the end of the 24-week treatment period and at the end of treatment, respectively (Tables 8 and 9). For the exenatide group, 263 (83.2%) patients and 217 (68.7%) patients were at the target total daily dose 20 μg at the end of 24-week treatment period and at the end of treatment, respectively (Tables 8 and 9).
Efficacy
Primary Efficacy Endpoint
Main Analysis
Table 10 summarizes the results of the primary efficacy parameter, change from baseline to Week 24 (LOCF) in HbA1c using an ANCOVA analysis.
The LS mean changes from baseline to Week 24 in HbA1c was −0.79% for the lixisenatide group and −0.96% for the exenatide group (LS mean difference versus exenatide=0.17%). Based on the pre-specified primary analysis, non-inferiority of lixisenatide versus exenatide was demonstrated as the upper bound of the two-sided 95% CI of the LS mean difference was less than the predefined non-inferiority margin 0.4%. Superiority of lixisenatide over exenatide was not demonstrated.
a Analysis of covariance (ANCOVA) model with treatment groups (Exenatide and Lixisenatide), 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.
Secondary Analysis
Table 11 summarizes the proportion of patients with treatment response HbA1c≤6.5% or <7% at Week 24, respectively. At Week 24, 28.5% of lixisenatide-treated patients and 35.4% of exenatide-treated patients had achieved HbA1c values ≤6.5%; 48.5% of patients in the lixisenatide group and 49.8% of patients in the exenatide group had achieved HbA1c values <7%.
Other Efficacy Endpoints
Table 12 and Table 13 summarize the ANCOVA analyses of FPG and body weight, respectively.
For FPG, the LS mean changes from baseline to Week 24 was −1.22 mmol/L for the lixisenatide group and −1.45 mmol/L for the exenatide group (LS mean difference versus exenatide=0.23 mmol/L).
The LS mean body weight loss from baseline at Week 24 was 2.96 kg for the lixisenatide-treated patients and 3.98 kg for the exenatide-treated patients (LS mean difference versus exenatide=1.02 kg). Body weight continued to decrease after the 24 week main treatment period in both treatments (
The percentages of patients requiring rescue therapy at Week 24 were small in the two groups (Table 15).
a Analysis of covariance (ANCOVA) model with treatment groups (Exenatide and Lixisenatide), randomization strata of screening HbA1c (<8.0, ≥8.0%), BMI (<30, ≥30 kg/m2) at screening, and country as fixed effects and baseline FPG as a covariate.
a Analysis of covariance (ANCOVA) model with treatment groups (Exenatide and Lixisenatide), 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 body weight as a covariate.
Safety
An overview of the adverse events observed during the on-treatment period of the whole study is provided in Table 16. The proportion of patients who experienced TEAEs was generally comparable between the lixisenatide-treated and exenatide-treated groups. Six patients (3 patients in each treatment group) had SAEs during the on-treatment period leading to death. Forty-eight serious TEAEs occurred during the on-treatment period of the whole study with a similar incidence rate in each treatment group (8.2% for lixisenatide and 7.0% for exenatide). The percentage of patients with TEAEs leading to treatment discontinuation was the same in both groups (14.2%). Tables 17, 18, and 19 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 treatment groups (15 [4.7%] patients in lixisenatide and 19 [6.0%] patients in exenatide).
Table 29 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 any treatment group. Nausea was the most frequently reported TEAE in the lixisenatide group (91 patients [28.6%]). A higher percentage of exenatide-treated patients (119 [37.7%] patients) reported nausea. The second most frequently reported TEAE in the lixisenatide-treated patients was diarrhea (48 patients [15.1%]) followed by headache (46 patients [14.5%]). The corresponding number of patients (%) in the exenatide group was 54 (17.1%) for diarrhea and 31 (9.8%) for headache.
Hypoglycemia
Sixteen (5.0%) lixisenatide-treated patients had symptomatic hypoglycemia events per protocol definition during the on-treatment period for the whole study, whereas 46 (14.6%) exenatide-treated patients reported symptomatic hypoglycemia during the same period (Table 20). None of the symptomatic hypoglycemia events was severe in intensity.
Symptomatic Hypoglycemia
Symptomatic hypoglycemia is defined as an event with clinical symptoms that are considered to result from a hypoglycemic episode (e.g., sweating, palpitations, hunger, restlessness, anxiety, fatigue, irritability, headache, loss of concentration, somnolence, psychiatric or visual disorders, transient sensory or motor defects, confusion, convulsions, or coma) with an accompanying plasma glucose ≤60 mg/dL (3.3 mmol/L) or associated with prompt recovery after oral carbohydrate administration if no plasma glucose value is available. Symptoms with an associated plasma glucose ≥60 mg/dL (3.3 mmol/L) should not be reported as a hypoglycemia.
Symptomatic hypoglycemia is to be reported as an adverse event. Additional information should be collected on a specific symptomatic hypoglycemic event complementary form.
Severe Symptomatic Hypoglycemia
Severe symptomatic hypoglycemia is defined as an event with clinical symptoms that are considered to result from hypoglycemia in which the patient required the assistance of another person, because the patient could not treat him/herself due to acute neurological impairment directly resulting from the hypoglycemic event, and one of the following:
The definition of severe symptomatic hypoglycemia includes all episodes in which neurological impairment was severe enough to prevent self-treatment and which were thus thought to place patients at risk for injury to themselves or others. Note that “requires assistance” means that the patient could not help himself or herself. Someone being kind that assists spontaneously the patient when not necessary does not qualify as “requires assistance.”
Severe symptomatic hypoglycemia will be qualified as an SAE only if it fulfills SAE criteria.
aPercents are calculated using the number of safety patients as the denominator.
bCalculated as (number of patients with events * 100 divided by total exposure + 3 days in patient years).
Thirty-six patients (9.1% for lixisenatide and 2.2% for exenatide) experienced injection site reaction AEs (Table 21). The injection site reaction AEs were identified by searching the term “injection site” in either the investigator reported AE PTs or PTs from the ARAC diagnosis during the allergic reaction adjudication. None of the reactions was serious or severe.
A total of 42 cases were reported as a suspected allergic event by investigators during the on-treatment period of the whole study and sent to ARAC for adjudication. Thirteen of them (in 6 (1.9%) lixisenatide-treated patients and 3 (0.9%) exenatide-treated patients) were adjudicated as an allergic reaction by the ARAC, but none of the events was adjudicated as possibly related to IP.
During the on-treatment period of the whole study, 5 (1.6%) lixisenatide-treated patients and 9 (2.8%) exenatide-treated patients reported events of changes in pancreatic enzymes or lipase or amylase on a specific AE page for “suspected pancreatitis” following the protocol recommendation (Table 23). Patients with at least one value of lipase or amylase ≥3 ULN are summarized in Table 24. One lixisenatide-treated patient, who reported one increase of lipase and one pancreatic enzymes increased event on the specific AE page, had a lipase value >3ULN as well as amylase value >3ULN during the treatment period. No case of acute pancreatitis was observed in the study.
The same number of patients (11 [3.5%] patients in lixisenatide and 11 [3.6%] in exenatide) with elevated lipase (≥3 ULN) was observed in each treatment group [Table 24]. Three (1.0%) patients in the lixisenatide group had elevated amylase (≥3 ULN), and none in the exenatide group.
Eight patients (4 [1.3%] in each group) reported a calcitonin value ≥20 ng/L on a specific AE page for “increased calcitonin” (Table 25). No value ≥50 ng/L was reported.
Five (1.8%) patients in the lixisenatide group and 8 (3.0%) patients in the exenatide group had a value of calcitonin ≥20 ng/L during the on treatment period (Table 26). It should be pointed out that calcitonin measurements were added in a protocol amendment after all patients were already randomized. Therefore baseline values are missing for all patients.
Health Related Quality-of-Life (PAGI-QOL Questionnaire)
Table 27 summarizes the ANCOVA analysis result of PAGI-QOL total score. The LS mean changes in PAGI-QOL total score from baseline to Week 24 was −0.09 for the lixisenatide group and −0.06 for the exenatide group (LS mean difference versus exenatide=−0.03).
aAnalysis of covariance (ANCOVA) model with treatment groups (Exenatide and Lixisenatide), 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 PAGI-QOL total score as a covariate.
For Week 24 (LOCF), the analysis included measurements obtained up to 3 days after the last dose of the investigational product inj
Day 169 if Visit 11 (Week 24) is not available.
indicates data missing or illegible when filed
| Number | Date | Country | Kind |
|---|---|---|---|
| 11153106.7 | Feb 2011 | EP | regional |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 15144270 | May 2016 | US |
| Child | 15952776 | US | |
| Parent | 13363956 | Feb 2012 | US |
| Child | 15144270 | US |
