Efficacy and Safety of a Biosimilar Liraglutide (Melitide®) Versus the Reference Liraglutide (Victoza®) in People with Type 2 Diabetes Mellitus: A Randomized, Double-Blind, Noninferiority Clinical Trial
Liraglutide effectively controls blood glucose level and reduces body weight. The aim of this study was to compare the efficacy and safety of a biosimilar liraglutide (Melitide®; CinnaGen, Tehran, Iran) to the reference liraglutide (Victoza®; Novo Nordisk, Bagsvaerd, Denmark) in people with type 2 diabetes mellitus (T2DM).
Methods
In this phase 3 clinical noninferiority trial, adult patients with inadequately controlled T2DM and with hemoglobin A1C (HbA1C) levels of 7–10.5% on at least two oral glucose-lowering drugs with stable doses for at least 3 months were randomized to receive Melitide® (n = 150) or Victoza® (n = 150) 1.8 mg/day for 26 weeks. The primary outcome was assessment of the noninferiority of Melitide® to Victoza® in terms of change in HbA1C level with a prespecified margin of 0.4%. The secondary outcomes were the assessment of additional efficacy parameters (including the proportion of patients achieving HbA1C levels of < 7%), the incidence of adverse events, and immunogenicity.
Results
Of the 300 participants enrolled in this study, 235 were included in the per-protocol analysis (112 in the Melitide® group and 123 in the Victoza® group). The mean (standard deviation) changes in HbA1C were − 1.76% (1.22) in the Melitide® group and − 1.59% (1.31) in the Victoza® group. The upper limit of the 95% one-sided confidence interval (CI) of the mean difference between Melitide® and Victoza® in lowering HbA1C was lower than the predefined margin (mean difference − 0.18, 95% CI − 0.5 to 0.15). Similar findings were obtained with the intention-to-treat analysis. No statistically significant differences were observed between the two study arms regarding the proportion of patients achieving HbA1C < 7% (p = 0.210), other efficacy parameters (p > 0.05), and reported adverse events (p = 0.916). Furthermore, none of the patients developed anti-liraglutide antibodies.
Conclusion
The biosimilar liraglutide (Melitide®) was noninferior in efficacy and comparable in safety when compared with the reference liraglutide.
Trial Registration
NCT03421119.
Key Summary Points
Why carry out this study?
Liraglutide is a glucagon-like peptide 1 receptor agonist used to treat type 2 diabetes mellitus (T2DM).
Liraglutide has also been shown to positively affect body weight and cardiovascular parameters.
Using biosimilar products for diabetic patients is associated with potentially lower treatment costs and better availability of effective medications.
This phase 3 clinical trial compared the efficacy, safety, and immunogenicity of a biosimilar liraglutide candidate (Melitide®) with the reference product (Victoza®) in adults with T2DM.
What was learned from the study?
Compared to Victoza®, Melitide® showed noninferior efficacy in lowering HbA1C in 26 weeks of treatment.
Other efficacy outcomes, adverse events, and immunogenicity were comparable between the two study arms.
The results of this study indicate that Melitide® is effective and safe for use in T2DM patients.
Introduction
Glucagon-like peptide 1 (GLP-1) receptor agonists are a class of antidiabetic agents commonly added to oral glucose-lowering drugs (OGLDs) to regulate blood glucose levels [1]. These agents are considered to be appropriate initial therapy for individuals with type 2 diabetes mellitus (T2DM) with or at high risk for atherosclerotic cardiovascular disease (ASCVD) [2].
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Liraglutide, a human GLP-1 analog, was first approved by the U.S. Food and Drug Administration (FDA) in January 2010 for glycemic control in adult patients with T2DM [3]. The efficacy of liraglutide as monotherapy or in combination with OGLDs in the management of T2DM has been evaluated in the Liraglutide Effect and Action in Diabetes (LEAD) studies [4‐9]. Liraglutide exhibits its pharmacologic effects by enhancing glucose-dependent insulin secretion, slowing gastric emptying, and reducing postprandial glucagon and food intake [10]. In addition to its hypoglycemic effects, liraglutide induces weight loss and improves beta cell function as well as several cardiovascular risk markers [11, 12].
The increasing incidence of diabetes worldwide and its tremendous burden on healthcare systems necessitates that effective medications are provided at an affordable cost, particularly in countries with lower incomes. Compared with the original products, biosimilars lower health care costs and increase access to essential medications. In preclinical studies of a biosimilar liraglutide (Melitide®; CinnaGen, Tehran, Iran), no meaningful differences were observed from the reference liraglutide (Victoza®; Novo Nordisk, Bagsvaerd, Denmark). The aim of the present study was to assess the noninferiority of Melitide® to Victoza® in terms of reducing hemoglobin A1C (HbA1C), as well as to compare other efficacy parameters and safety after 26 weeks of treatment.
Methods
Study Design and Intervention
This was a 26-week, randomized, double-blind, active-controlled, parallel-group, and noninferiority phase 3 clinical trial conducted from July 2019 to December 2021 in 17 study centers in Iran. Subjects were randomly assigned (1:1) to receive either Melitide® or Victoza® subcutaneously once daily. We followed the standard dose titration protocol: 0.6 mg daily during the first week, 1.2 mg daily during the second week up to the end of the fourth week, and 1.8 mg daily until the end of the trial. The first dose was administered by a trained nurse; thereafter and following instructions, patients injected themselves. Prior to enrollment, all participants signed written informed consent forms.
This study was performed in accordance with the principles of the 1964 Declaration of Helsinki and its later amendments, and with Good Clinical Practice guidelines. The study was approved by the ethics committees of Iran University of Medical Sciences (IR.IUMS.REC.1396.31731) and Alborz University of Medical Sciences (IR.ABZUMS.REC.1398.052). These ethical approvals covered all the necessary approvals for 17 study centers. Consent for publication was not applicable in this study. The study is registered at ClinicalTrials.gov (NCT03421119).
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Participants
Adult patients with T2DM aged between 18 and 80 years were eligible to enroll in this study.
Inclusion criteria were: receiving a stable dose of at least 1500 mg metformin while taking at least half of the maximum dose of a sulfonylurea or a non-sulfonylurea medication for 3 months or longer; HbA1C levels ≥ 7% and ≤ 10.5%; and body-mass index (BMI) of 20–45 kg/m2.
Exclusion criteria were: (1) insulin treatment within the last 3 months (except for intercurrent disease); (2) liver dysfunction (alanine aminotransferase ≥ 2.5-fold higher than the upper limit of normal); (3) kidney impairment (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m2); (4) uncontrolled hypertension (≥ 160/100 mmHg); (5) active malignancy; (6) systemic corticosteroid treatment within the last 3 months; (7) using any medications other than OGLDs affecting blood glucose (androgens, monoamine oxidase inhibitors, quinolone antibiotics and salicylate with the anti-inflammatory dose); (8) current use of dipeptidyl peptidase-4 (DPP-4) inhibitors; (9) previous exposure to exenatide or liraglutide; (10) personal or family history of medullary thyroid cancer; (11) history of multiple endocrine neoplasia type 2; (12) history of pancreas cancer or pancreatitis; (13) previous documented myocardial infarction, uncontrolled congestive heart failure, or unstable angina within the last 3 months; (14) history or known case of proliferative or severe non-proliferative diabetic retinopathy; (15) pregnancy and lactation, or planning to become pregnant; (16) hypersensitivity to liraglutide or any component of the study medication; (17) failure to provide informed consent; and (18) non-compliance with the study protocol.
Randomization and Blinding
After screening and confirmation of eligibility, patients were randomly assigned to receive the biosimilar (Melitide®) or the reference liraglutide (Victoza®) in a 1:1 ratio. Using R software version 3.2.3 (Foundation for Statistical Computing, Vienna, Austria), randomization was conducted centrally in permuted blocks of two or four. The investigators, patients, and outcome assessors were masked to treatment arms.
Assessments and Outcomes
The primary outcome was to assess the noninferiority of Melitide® to the Victoza® in terms of change in HbA1C from baseline to week 26. The secondary outcomes were the percentage of patients achieving HbA1C targets (HbA1C < 7%, HbA1C ≤ 6.5%); and changes in body weight, fasting plasma glucose (FPG), blood pressure, pulse rate, and lipid profile (including low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], and triglycerides [TG]), and eGFR from baseline to week 26. In addition, immunogenicity and safety parameters were compared between the two treatment groups.
All laboratory tests were performed by a central laboratory at baseline and at weeks 12 and 26 of the study. Blood pressure, pulse rate, body weight, and waist circumference were also assessed at the same time points by trained nurses. In addition, serum levels of anti-liraglutide antibodies were measured at baseline and week 26 for immunogenicity assessment.
A “Patient Diary” was designed to record daily adverse events (AEs) by patients. The incidence, severity (graded based on Common Terminology Criteria for Adverse Events [CTCAE] v5.0) [13], and casual relationship (assessed based on World Health Organization [WHO] guideline [14]) of the AEs were documented and reported. The AEs were reported based on the Medical Dictionary for Regulatory Activities (MedDRA) terms as the preferred term (PT) and system organ class (SOC). Serious adverse events (SAEs) were defined according to International Conference on Harmonization (ICH) guideline (E2B) [15]. Gastrointestinal disorders (such as nausea, vomiting, dyspepsia, diarrhea, and constipation) and hypoglycemia were assessed as AEs of special interest.
In this study, minor hypoglycemia was defined as grade 1 or 2, and major hypoglycemia was defined as grade 3 and 4. Gastrointestinal disorders were categorized as transient and non-transient; an AE was transient if it did not persist after week 8.
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Sample Size and Statistical Analysis
A sample sizes of 120 patients per group was required to achieve an 80% power to detect the noninferiority of Melitide® against Victoza® with a noninferiority margin of 0.4% using a one-sided, two-sample t-test at a significance level of 0.025 [16]. A true difference between means of 0 and a population standard deviation (SD) of 1.1% was assumed. Considering a drop-out rate of 20%, a total sample size of 300 patients was required. The efficacy of Melitide® would be judged to be noninferior to Victoza® if the upper limit of the one-sided 95% confidence interval (95% CI) of difference in mean HbA1C change from baseline to week 26, calculated by the two-sample t-test, was less than the prespecified noninferiority margin (0.4%).
Summary statistics included the number of subjects, mean, and SD for continuous variables, and frequencies and percentages for categorical variables. To conduct the sensitivity analysis for the primary outcome, we performed an analysis of covariance (ANCOVA) model, considering baseline HbA1C values and treatment groups as covariates. The least squares means and 95% CIs were calculated based on the ANCOVA model. Primary efficacy analysis was performed on a per-protocol (PP) basis. The PP population included all randomized patients who completed the 26-week study period without major protocol violations. An intention-to-treat (ITT) analysis was also used as the sensitivity analysis. The ITT population included all randomized patients who had at least one HbA1C measurement after baseline; the missing HbA1C values at the week 26 time point were imputed by the last observation carried forward (LOCF) method in the ITT analysis for the primary outcome. Logistic regression was applied to compare proportions of subjects achieving HbA1C targets and to generate odds ratios (ORs). Treatment was a fixed effect and baseline HbA1C was a covariate. Secondary endpoints were assessed by the ANCOVA model. Safety analyses were performed using descriptive statistics. The safety population included all patients who received at least one dose of study medications. Between-group differences in the incidence rates were assessed by the Chi-squared test. The significance level for all tests was 0.05. All statistical analyses were conducted using STATA version 14.0 (StataCorp, College Station, TX, USA) and R version 3.2.3 (Foundation for Statistical Computing).
Results
Among the 521 patients screened, 221 did not meet the eligibility criteria; the remaining 300 patients were randomly assigned to each study arm (n = 150 per study arm) (Fig. 1). The demographics and baseline characteristics of the study participants are shown in Table 1.
Fig. 1
Flow diagram of patient enrollment. ITT intention-to-Treat, PP per protocol
Table 1
Demographics and baseline characteristics of the participants
Variable
Melitide® (N = 150)a
Victoza® (N = 150)a
p valueb
Gender (male), n (%)
51 (34%)
58 (38.67%)
0.401
Age (years)
52.64 (8.75)
52.89 (8.52)
0.799
Body weight (kg)
84.98 (14.28)
85.57 (13.92)
0.718
Body-mass index (kg/m2)
31.78 (4.90)
31.77 (4.83)
0.991
Diabetes duration (years)
8.99 (6.02)
8.32 (5.83)
0.334
HbA1C (%)
8.97 (0.93)
9.01 (0.92)
0.686
FPG (mmol/L)
10.01 (2.49)
9.62 (2.40)
0.164
MDRD eGFR (mL/min/1.73 m2)
94.79 ± 21.24
94.16 ± 18.55
0.784
Systolic blood pressure (mmHg)
122.33 (11.06)
122.81 (12.06)
0.719
Diastolic blood pressure (mmHg)
78.49 (7.07)
77.27 (7.88)
0.159
Cardiovascular diseases, n (%)
42 (28.00%)
39 (26.00%)
0.696
Nephrology/urology diseases, n (%)
6 (4.00%)
9 (6.00%)
0.427
Data are presented as the number of participants with the percentage of total participants in the treatment group given in parentheses, or as the mean with the standard deviation (SD) in parentheses
eGFR Estimated glomerular filtration rate, FPG fasting plasma glucose, HbA1C hemoglobin A1C, MDRD Modification of Diet in Renal Disease (Study)
aFull analysis set
bBased on t-test or Chi-squared test
×
Primary Outcome Measure
The PP population included 235 patients (112 in the Melitide® group and 123 in the Victoza® group), and the ITT population included 250 patients (121 in the Melitide® group and 129 in the Victoza® group). In both study arms, HbA1C levels decreased over the first 12 weeks of treatment and remained stable until week 26 (Fig. 2). In the PP population, the mean changes in HbA1C from baseline to week 26 were − 1.76% (SD 1.22) in the Melitide® group and − 1.59% (SD 1.31) in the Victoza® group (difference − 0.18; 95% CI − 0.50 to 0.15; p = 0.288). The least squares mean changes in HbA1C were − 1.77% (95% CI − 1.99 to − 1.55) in the Melitide® group and − 1.58% (95% CI − 1.79 to − 1.37) in the Victoza® group (difference − 0.19; 95% CI − 0.49 to 0.12; p = 0.224). Similarly, in the ITT population, the mean changes in HbA1C from baseline to week 26 were − 1.71% (SD 1.25) in the Melitide® group and − 1.60% (SD 1.29) in the Victoza® group (difference − 0.11; 95% CI − 0.42 to 0.21; p = 0.503). The least squares mean changes in HbA1C were − 1.72% (95% CI − 1.93 to − 1.51) in the Melitide® group and − 1.59% (95% CI − 1.80 to − 1.39) in the Victoza® group (difference − 0.13; 95% CI − 0.42 to 0.17; p = 0.390). The upper limit of the one-sided 95% CIs for the difference between the two study arms was below the prespecified noninferiority margin of 0.4%, which showed the noninferiority of Melitide® compared with Victoza® in terms of lowering HbA1C in both the PP and ITT populations using both the t-test and ANCOVA models (Fig. 3).
Fig. 2
Changes in hemoglobin A1C (HbA1C) from baseline to week 26. Data are presented as the mean with 95% confidence intervals (error bars)
Fig. 3
Forest plot comparing Melitide® with Victoza® in terms of mean difference in changes in HbA1C levels from baseline to week 26. The t-test analysis and analysis of covariance (ANCOVA) model were applied for the per-protocol and intention-to-treat populations. CI Confidence interval
×
×
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Secondary Outcome Measures
A total of 112 patients in the Melitide® group and 125 patients in the Victoza® group were analyzed for the secondary outcomes. At week 26, the proportion of patients with HbA1C < 7% (45.54% in the Melitide® group and 37.60% in the Victoza® group; OR 1.42; 95% CI 0.82–2.46; p = 0.210) and HbA1C ≤ 6.5% (27.68% in the Melitide® group and 27.20% in the Victoza® group; OR 1.01; 95% CI 0.56–1.83; p = 0.968) were comparable in both study arms. Both study arms showed decreased FPG levels (least squares mean changes of − 2.19 mmol/L [95% CI − 2.65 to − 1.74] in the Melitide® group and − 1.88 mmol/L [95% CI − 2.31 to − 1.44] in the Victoza® group) and decreased body weight (least squares mean − 3.45 kg [95% CI− 4.20 to − 2.71] in the Melitide® group and − 3.75 kg [95% CI − 4.46 to − 3.05] in the Victoza® group) at week 26. Moreover, comparable reduction in waist circumference and blood pressure and an improvement in lipid profiles were observed in both groups. None of the secondary outcomes differed significantly between the two study arms (Table 2).
bBased on analysis of covariance (ANCOVA) model with adjusted baseline measures
Safety
Overall, 126/151 (83.44%) patients in the Melitide® group and 125/149 (83.89%) patients in the Victoza® group experienced at least one AE. The most common system organ class (SOC) of the reported AEs was gastrointestinal disorders, followed by investigations, and nervous system disorders. A summary of key safety results of the study is demonstrated in Table 3.
Table 3
Adverse events profile
Melitide® (N = 151)
Victoza® (N = 149)
Any adverse event
126 (83.44%)
125 (83.89%)
Severe adverse eventsa
At least one severe adverse event
10 (6.62%)
4 (2.68%)
Corona virus infection
3 (1.99%)
0
Papillary thyroid cancer
2 (1.32%)
0
Abdominal pain
1 (0.66%)
0
Blood pressure increased
1 (0.66%)
0
Constipation
1 (0.66%)
0
Hernia
1 (0.66%)
0
Influenza
1 (0.66%)
0
Lipase increased
1 (0.66%)
2 (1.34%)
Cholelithiasis
0
1 (0.67%)
Hypoglycemia
0
1 (0.67%)
Common adverse eventsb
Gastrointestinal disorders
93 (61.59%)
101 (67.79%)
Nausea
58 (38.41%)
59 (39.60%)
Dyspepsia
29 (19.21%)
29 (19.46%)
Constipation
26 (17.22%)
20 (13.42%)
Diarrhoea
23 (15.23%)
31 (20.81%)
Vomiting
8 (5.30%)
12 (8.05%)
Investigations
65 (43.05%)
49 (32.89%)
Nervous system disorders
45 (29.80%)
55 (36.91%)
General disorders and administration site conditions
33 (21.85%)
24 (16.11%)
Metabolism and nutrition disorders
33 (21.85%)
26 (17.45%)
Infections and infestations
24 (15.89%)
15 (10.07%)
Endocrine disorders
22 (14.57%)
17 (11.41%)
Musculoskeletal and connective tissue disorders
13 (8.61%)
13 (8.72%)
Data are presented as the number of patients with the percentage of total participants in safety analysis set given in parentheses
aA severe adverse event was defined as grade 3 or higher based on CTCAE (Common Terminology Criteria for Adverse Events) v 5.0
bCommon adverse events were events reported in > 5% of patients in each group
The most common preferred terms (PT) of the reported AEs were nausea, increased lipase, and headache in both groups, with nausea, dyspepsia, diarrhea, and constipation transient in most patients in both groups. A total of 82.76% of patients (48/58) in the Melitide® group and 71.19% of patients (42/59) in the Victoza® group experienced transient nausea (p = 0.102). Among all the patients reporting hypoglycemic events, 22/22 (100%) patients in the Melitide® group and 16/17 (94.12%) patients in the Victoza® group experienced minor hypoglycemia events. Only one patient in the Victoza® group experienced major hypoglycemia (Table 3). Blood calcitonin levels were comparable between the two groups during the study.
Altogether, 11 SAEs were reported (10 in the Melitide® group and 1 in the Victoza® group). However, only one SAE in each group was possibly related to the medication (gastrointestinal complications in Melitide® group and cholelithiasis in the Victoza® group). All AEs were graded based on severity, and there were no significant differences between the number of patients experiencing at least one grade 3 or higher AE in the study groups (10/151 [6.62%] patients in the Melitide® group and 4/149 [2.68%] patients in the Victoza® group; p = 0.106). Two cases of papillary thyroid cancer were reported in the Melitide® group, both of which happened during the study and were evaluated as unlikely to be related to the study medication by the investigator and could be attributed to patients’ familial history and related risk factors.
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Immunogenicity
Serum samples were obtained from 134 patients in each study arm, and all were negative for anti-liraglutide antibodies.
Discussion
In this study, the biosimilar liraglutide (Melitide®) was noninferior to Victoza® in terms of lowering HbA1C levels. Furthermore, both Melitide® and Victoza® showed comparable effects on body weight, lipid profile, blood pressure, and incidence of AEs.
The latest guidelines of the American Diabetes Association and the European Association for the Study of Diabetes (ADA-EASD) recommend the use of GLP-1 receptor agonists, such as liraglutide, semaglutide, and exenatide, as initial injectable therapy in most T2DM cases, including patients with HbA1C < 11%. Compared with insulin, GLP-1 receptor agonists promote weight loss and are associated with a lower risk of hypoglycemia risk as well as cardiovascular benefits [17, 18]. As excess body weight negatively affects glycemic control, blood pressure, and lipid profile, GLP-1 analogs are of great interest in diabetes management due to their weight loss properties and cardioprotective effects [19‐21].
The decrease in HbA1C level over 26 weeks of treatment with either Melitide® (1.76%) or Victoza® (1.59%) observed in the present study is consistent with the results of other trials. In a study comparing liraglutide with sitagliptin, patients with a mean baseline HbA1C level of 8.4% showed a decrease in HbA1C of 1.5% at week 26 of treatment with 1.8 mg liraglutide [16]. In the LEAD trials evaluating the efficacy of liraglutide combined with OGLDs, HbA1C levels in patients with baseline levels of 8.2–8.6% fell by 1–1.5% after treatment with 1.8 mg liraglutide [4, 5, 7‐9]. In the studies by Vilsbøll et al. [22, 23], daily injections of 1.9 mg of liraglutide decreased HbA1C by around 1.5% after 14 weeks of treatment. Similarly, a study evaluating the effects of liraglutide versus insulin glargine in subjects with poorly controlled T2DM showed a 1.79% reduction in HbA1C level after 24 weeks of treatment with liraglutide [24]. According to previous studies, HbA1C reduction is positively correlated to baseline levels [25, 26]. In our study, both the t-test analysis and the ANCOVA model, when adjusted for the baseline values, showed that the changes in HbA1C were similar between groups in both the PP and ITT populations. In addition, the proportion of patients achieving HbA1C levels of < 7% and ≤ 6.5% with both Melitide® (45.54% and 27.68%, respectively) and Victoza® (37.6% and 27.2%, respectively) in this study were comparable to those reported in previous studies with liraglutide [4, 5].
Melitide® and (Victoza®) both promote weight reduction, with results similar to those of previous studies on liraglutide that showed a weight reduction of about 3 kg [9, 16]. As with previous studies, liraglutide treatment was associated with a slight decrease in both systolic and diastolic blood pressure and a slight increase in pulse rate [9, 27]. Moreover, in the present study, liraglutide was associated with decreased LDL-C, HDL-C, and TG levels in both study arms, also similar to previously reported results [7, 16]. The effects of GLP-1 analog treatment on waist circumference and its association with cardiovascular risks have also been investigated in earlier studies [28, 29]. A reduction of approximately 4 cm in waist circumference in the present study is in accordance with the results from these earlier studies on liraglutide [28, 30].
Considering that T2DM is a chronic condition, an acceptable safety profile is essential for successful treatment. Both Melitide® and Victoza® were well tolerated. Most AEs were mild or moderate. The majority of SAEs were unlikely to be related to the study medications, and only one SAE was perhaps possibly related to treatment in each group. The overall safety profiles of Melitide® and Victoza® were not different from those reported in other studies on liraglutide [7, 9]. Although gastrointestinal AEs were reported more frequently, they were mainly mild to moderate and transient, and reported in similar proportions across the groups. The most common AE with both Melitide® and Victoza® was nausea (38.41% and 39.60%, respectively), similar to that found in the LEAD-4 study (40%) [7]. Additionally, vomiting reported in the Melitide® and Victoza® groups (5.30% and 8.05%, respectively) was comparable to the incidence of vomiting in the LEAD-6 study (6.0%) [9].
This study has a number of limitations. A longer treatment duration and a relatively larger sample size might have enabled us to detect differences between the two medications in terms of rare AEs. In addition, the COVID-19 outbreak during the implementation of the study resulted in a higher drop-out rate than was expected, although all efforts were made to encourage the participants to comply with the scheduled visits.
Conclusion
In this 26-week study, Melitide® was noninferior to Victoza® in terms of glycemic control. Moreover, both products were comparable in terms of weight reduction effect and safety profile.
Acknowledgements
The authors gratefully acknowledge the individuals who participated in this trial.
Medical Writing/Editorial Assistance
The drafting and editing of the manuscript were assisted by the medical writing team at Orchid Pharmed Company under the supervision of Dr. Hamidreza Kafi and funded by Cinnagen.
Declarations
Conflict of Interest
Mohammad Ebrahim Khamseh received research grants/honorarium from Novo Nordisk Pars, Sanofi, Abidi, and Cinnagen pharmaceuticals. Alireza Esteghamati received research grants/honorarium from Novo Nordisk Pars, Sanofi, Abidi, and Cinnagen pharmaceuticals. Mojtaba Malek received research grants/honorarium from Novo Nordisk Pars, Sanofi, Abidi. Farhad Hosseinpanah received honorarium from Novo Nordisk Pars, Sanofi, Abidi, and Cinnagen pharmaceuticals. Hamidreza Kafi is the head of the Medical Department of Orchid Pharmed Company, which is the CinnaGen Company partner in conducting clinical trials. Mehran Zamanzadeh, Mohammad Khaledi, Arezoo Monavari, Laily Najafi, Zahra Banazadeh, Ramin Malboosbaf, Rokhsareh Aghili, Sedigheh Mahdikhah, and Hasan Ganjizadeh-Zavereh have nothing to disclose.
Ethical Approval
This study was performed in accordance with the principles of the 1964 Declaration of Helsinki and its later amendments, and with Good Clinical Practice guidelines. The study was approved by the ethics committees of Iran University of Medical Sciences (IR.IUMS.REC.1396.31731) and Alborz University of Medical Sciences (IR.ABZUMS.REC.1398.052). These ethical approvals covered all the necessary approvals for 17 study centers. Consent for publication was not applicable in this study. The study is registered at ClinicalTrials.gov (NCT03421119).
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Efficacy and Safety of a Biosimilar Liraglutide (Melitide®) Versus the Reference Liraglutide (Victoza®) in People with Type 2 Diabetes Mellitus: A Randomized, Double-Blind, Noninferiority Clinical Trial
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