Saxagliptin in Combination With Dapagliflozin - Effects on Islet Cell Function
Information source: Profil Mainz GmbH & Co KG
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Type2 Diabetes Mellitus
Intervention: Saxagliptin (Drug)
Phase: Phase 4
Status: Not yet recruiting
Sponsored by: Prof. Dr. Thomas Forst Official(s) and/or principal investigator(s): Thomas Forst, Prof. Dr., Principal Investigator, Affiliation: Profil Mainz GmbH & Co KG, Rheinstraße 4c, 55116 Mainz
Overall contact: Thomas Forst, Prof. Dr., Phone: +49 (0) 6131 2162 701, Email: thomas.forst@profil.com
Summary
The purpose of this study is to evaluate alpha- and beta-cell function during combination
treatment with saxagliptin in addition to dapagliflozin and metformin compared to placebo in
addition to dapagliflozin and metformin in subjects with T2DM on stable metformin background
therapy.
Clinical Details
Official title: Effect of Saxagliptin in Addition to Dapagliflozin and Metformin on Insulin Resistance, Islet Cell Dysfunction, and Metabolic Control in Subjects With Type 2 Diabetes Mellitus on Previous Metformin Treatment
Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
Primary outcome: Glucagon / insulin ratio during hyperglycaemic clamp phase (AUCGluc270-390min / AUCIns270-390min)
Secondary outcome: Glucagon release during hyperglycaemic clamp phase (AUCGluc270-390min; pg/ml*min)First phase glucagon release during hyperglycaemic clamp phase (AUCGluc270-290min; pg/ml*min) First phase insulin release during hyperglycaemic clamp phase (AUCIns270-290min; pmol/l*min) Second phase insulin release during hyperglycaemic clamp phase (AUCIns290-390min; pmol/l*min) First Phase glucagon / insulin ratio during hyperglycaemic clamp phase (AUCGluc270-290min / AUCIns270-290min) Second Phase glucagon / insulin ratio during hyperglycaemic clamp phase (AUCGluc290-390min / AUCIns290-390min) Intact proinsulin release during hyperglycaemic clamp (AUCIP270-390min ; pmol/l*min) Insulin / proinsulin ratio during hyperglycaemic clamp (AUCIns270-390min / AUCIP270-390min) C-Peptide release during hyperglycaemic clamp (AUCC-Pep270-390min ; pmol/l*min) C-Peptide/Insulin ratio during hyperglycaemic clamp (AUCC-Pep270-390min / AUCIP270-390min) M-Value during euglycaemic-hyperinsulinaemic clamp phase (mg/kg*min) HOMAIR Index Body Weight (kg) Fasting Adiponectin (µg/ml) Fasting Plasma Glucose (mg/dl) HbA1C (mmol/mol; %) QuantoseTM Score Blood Lipids (Triglycerides [mg/dl]; total, HDL, LDL cholesterol [mg/dl])
Detailed description:
List of Abbreviations AE Adverse event ALT Alanine aminotransferase ANOVA Analysis of
variance APTT Activated partial thromboplastin time AST Aspartate aminotransferase AUCins
Area under the serum insulin concentration time curve BMI Body mass index CRF Case report
form CTA Clinical trial application ECG Electrocardiogram FSFV First subject first visit
GCP Good clinical practice GIR Glucose infusion rate GIRmax Maximum glucose infusion rate
HbA1C N-(1-deoxy)-fructosyl-haemoglobin HBsAg Hepatitis B surface antigen HIV Human
immunodeficiency virus ICH International conference on harmonisation IEC Independent ethics
committee INR International normalised ratio IRB Institutional review board IU International
unit i. v. Intravenous(ly) LSFV Last subject first visit LSLV Last subject last visit MedDRA
Medical Dictionary of Regulatory Activities OAD Oral antidiabetic drug q. d. daily SAE
Serious adverse event SAP Statistical analysis plan s. c. Subcutaneous(ly) SMPG self-measured
plasma glucose SOP Standard operating procedure WHO-DDE World Health Organization Drug
Dictionary Enhanced
Under physiological conditions blood glucose is kept within a narrow range by complex
interactions of several signalling pathways. In this context, fine-tuning of alpha- and beta
cell activity is fundamental to avoid excessive metabolic excursions. The pathogenesis of
type 2 diabetes mellitus (T2DM) is driven by insulin resistance, followed by an increasing
imbalance between alpha and beta cell activity which is characterised by relative insulin
deficiency and increased glucagon secretion especially in the postprandial state.
Individual arrangement of complementary antidiabetic drugs in the escalation of
pharmacological intervention in T2DM is a major challenge. There is substantial need to
provide a scientific rationale for the best effective combination of antidiabetic drugs with
regard to their potency to address different aspects in the pathophysiology of T2DM.
Therefore, studies evaluating potential synergistic and/or complementary effects of
pharmacological interventions in T2DM deem imperative.
This study aims to evaluate the effect of the DPP-IV inhibitor saxagliptin (as compared to
placebo) in addition to the SGLT-2 inhibitor dapagliflozin on insulin resistance, pancreatic
alpha and beta cell function.
Triple therapy with metformin, SGLT-2 inhibitors, and DPP-IV inhibitors was shown to be
efficacious and safe in several studies and has been approved for the treatment of T2DM by
the European Medical Agency. Therefore, subjects with T2DM on a stable metformin background
therapy will be enrolled in this trial.
This is a single center, phase IV, prospective, placebo-controlled, exploratory,
proof-of-mechanism study.
This is a two-step treatment trial with a first open label and a second randomised,
double-blinded, placebo controlled treatment phase. In treatment phase 1 (TP1, 30±4 days),
26 subjects will receive dapagliflozin 10 mg once daily as add on to their pre-existing
metformin monotherapy. Thereafter, in treatment phase 2 (TP2, 30±4 days), subjects will be
randomised to additional saxagliptin 5 mg or corresponding placebo treatment in a 1: 1 ratio.
Trial subjects will subsequently undergo both treatment phases, and endpoint assessments
will be performed at the beginning and end of each treatment phase on Visits 2, 3, and
4Assignment of treatment allocation will take place at the investigational site. The total
study duration for a subject will be between 64 to 84 days.
The use of a combined euglycaemic-hyperinsulinaemic and hyperglycaemic glucose clamp
protocol is chosen in order to assess parameters of insulin resistance as well as alpha- and
beta-cell function under highly standardised conditions within a small study population.
Trained members of staff will perform all administrations of the IMP at the clinical site.
Drug accountability will be performed from Visit 2 to Visit 4 based on subject diaries and
returned study medication.
Whenever a deviation is noted by the Investigator, the Sponsor and/or monitor should be
informed and the implications of the deviation must be reviewed and discussed. The deviation
must be documented, explaining the reason for the deviation (root cause analysis), actions
taken and the impact of the deviation on the subject(s) and/or the trial. The safety
laboratory will perform a first check on their values for safety parameters and flag any
values outside the reference range. The Investigator must evaluate all results outside the
reference range. Before the Investigator starts the trial, the laboratory reference ranges
must be available in the Investigator's Trial File. The results provided by the safety
laboratory will be part of the trial database. Data Management is the responsibility of
Profil Institut für Stoffwechselforschung GmbH, Neuss Germany.
The objectives of the monitoring procedures are to ensure that (i) the safety and rights of
the trial subjects are respected, (ii) that accurate, valid and complete data are collected,
and (iii) that the trial is conducted in accordance with the trial protocol, the principles
of GCP and local legislation.
The monitor must be given direct access to the Trial Investigator File and source documents
(original documents, data and records). Direct access includes permission to examine,
analyse, verify and reproduce any record(s) and report(s) that are important to evaluation
of the clinical trial.
Key tasks of the monitor include verifying the presence of informed consent, the adherence
to the inclusion/exclusion criteria, the documentation of SAEs, and the recording of all
safety and efficacy variables. The monitor will also confirm the completeness of patient
records, the adherence to the protocol and the progress in subject enrolment.
Profil Institut für Stoffwechselforschung GmbH, Neuss, Germany, will be responsible for the
statistical analysis. The statistical planning and conduct of analyses of the data from this
study will follow the principles defined in relevant ICH guidelines and the Sponsor's
biostatistical standard operating procedures (SOPs). All statistical analyses will be
performed using SAS® (SAS Institute Inc., Cary, North Carolina, United States of America
[USA]), version 9. 3 or later.
For the lack of existing data for confirmatory sample size calculation, the study is
designed as an exploratory proof-of-mechanism study with an experimental assessment set-up.
All obtained results will be handled with equal emphasis in a strictly exploratory sense.
The data obtained from the trial will serve for the purpose of thesis generation and the
design of potential confirmatory studies.
Dapagliflozin as well as Saxagliptin have been approved for treatment of T2DM in adult male
and female patients. Because it is moreover not expected that the effects of either drug on
the endpoint measures will differ between male and female subjects with T2DM, a specific
gender distribution is not planned for this study.
Based on a previous study in twelve patients with T2DM treatment with dapagliflozin, a group
size of 12 patients in each group has a power of 80% to detect a difference at a
significance level of 0,05 (two-tailed).
Before data are released for statistical analysis, a blinded review of all data will take
place to identify protocol deviations that may potentially affect the results. This review
will be performed without revealing which trial product the subjects are assigned to. The
blinding of the trial products will be maintained for everyone involved in allocating
subjects to the analysis sets until data are released for statistical analysis. Furthermore,
outliers will be identified by data review according to ICH-E9, using a fake randomisation.
In addition, protocol deviations, which may potentially affect the results, will be
identified and it will be evaluated if subjects and/or data should be excluded from the
analysis.
The subjects and observations excluded from analysis sets, and the reason for this, will be
described in the clinical trial report.
All available data will be included in data listings and tabulations. In general no
imputation of values for missing data will be performed.
In general, metric variables and derived parameters will be presented using descriptive
summary statistics including arithmetic means, median, minimum, maximum and standard
deviations. Categorical variables will be presented using descriptive summary statistics
including number of patients and percentages. Percentages of patients will be based on
non-missing values.
In addition, for all efficacy variables as well as the derived parameters the geometric
means and coefficients of variation will be presented as well.
Descriptive summaries will also be presented. Unless otherwise stated, all formal tests will
be conducted at the two-sided 5% level of significance. No alpha adjustment will be done.
All analyses on primary and secondary efficacy endpoints will be interpreted in an
exploratory manner.
To investigate the dapagliflozin-corrected treatment effect, the evaluation of the change
from Visit 3 to Visit 4 in incremental AUCGluc270-390min / AUCIns270-390min will be
performed using analysis of covariance (ANOVA) with change in incremental AUCGluc270-390min
/ AUCIns270-390min as response, treatment as fixed effect and baseline (Visit 2) value as
covariate. From this model, least square means of change from Visit 3 to Visit 4 and 95%
confidence intervals for these changes will be calculated. In addition, estimate of the
placebo-corrected treatment effect (difference of least square mean of Visit 3 to Visit 4
changes between saxagliptin and placebo) and corresponding 95% confidence interval will be
calculated.
If the data are homogeneous or not normally distributed and cannot be successfully
transformed, the analysis will be performed by non-parametric technique using Wilcoxon
Signed Rank Test for within treatment comparisons and Wilcoxon Rank-Sum Test for between
treatment comparisons based on a two-sided alpha level of 0. 05. In addition, the estimate of
Hodges and Lehmann and the corresponding 95% non-parametric confidence interval will be
shown.
The secondary efficacy endpoints derived from the hyperglycaemic clamp phase based on
incremental AUCs will be calculated as described for the primary endpoint.
All AEs that will be entered into the CRF (all AEs since first dosing) will be coded. All
AEs will be presented by individual listings and frequency tables broken down by body system
and preferred terms as assigned by the Medical Dictionary for Regulatory Activity, as
appropriate. Separate tables for serious adverse events, by severity, as well as by
relationship to trial medication, will be provided.
Eligibility
Minimum age: 30 Years.
Maximum age: 75 Years.
Gender(s): Both.
Criteria:
Inclusion Criteria:
1. Diabetes mellitus type 2 for at least three months prior to Screening
2. HbA1c 7. 0%-9. 9%, both inclusive
3. Treatment with metformin (daily dose 1500 - 3000 mg)
4. Age 30-75 years, both inclusive
5. BMI 25-35 kg/m^2, both inclusive
Exclusion Criteria:
1. Use of any oral antidiabetic treatment except for metformin (i. e., sulphonylureas,
DPP-IV inhibitors, thiazolidinediones, SGLT-2 inhibitors) within the last three
months prior to Screening
2. Use of insulin or GLP-1 analogues within three months prior to Screening
3. Treatment with any other investigational drug within three months before screening
4. History of diabetes mellitus type 1
5. Acute infections within the last two weeks prior to Screening
6. Anamnestic history of hypersensitivity to the study drugs or to drugs with similar
chemical structures
7. History of severe or multiple allergies
8. GFR (as calculated by the Cockroft-Gault equation) < 60 ml/min at Screening
9. State after kidney transplantation
10. Laboratory safety value(s) outside the reference range and deemed clinically relevant
by the Investigator
11. Sexually active woman of childbearing age not practicing a highly effective method of
birth control as defined as those which result in a low failure rate (i. e., less than
1% per year) when used consistently and correctly such as implants, injectables,
combined oral contraceptives, hormonal IUDs, sexual abstinence or vasectomised
partner
12. Pregnancy or breast feeding
13. Systolic blood pressure outside the range of 100-160 mmHg or diastolic blood pressure
above 90 mmHg at Screening
14. Acute myocardial infarction or cerebral event (stroke/TIA) within six months prior to
Screening
15. Uncontrolled unstable angina pectoris or history of pericarditis, myocarditis,
endocarditis
16. Increased risk of thromboembolism, e. g. subjects with a history of deep leg vein
thrombosis or family history of deep leg vein thrombosis, as judged by the
Investigator
17. Hemodynamic relevant aortic stenosis, Aortic aneurysm
18. Repeated episodes of severe hypoglycaemia within six months prior to Screening
19. History of diabetic ketoacidosis, praecoma diabeticum, or diabetic coma
20. Recurrent urogenital infections
21. Haematuria
22. History of pancreatitis
23. Progressive fatal disease
24. Elective surgery planned during study participation
25. Acute or scheduled investigation with iodine containing radiopaque material
26. History of drug or alcohol abuse in the past two years
27. Donation of blood, major blood loss (>=500 ml), or major surgery within the last
three months prior to Screening
28. Active hepatitis B, measured by positive tests of surface antigen HBsAg and/or active
hepatitis C, measured by positive hepatitis C virus antibody tests (HCV) at Screening
29. Positive human immunodeficiency virus (HIV) antibodies or HIV 1 Ag at Screening
Locations and Contacts
Thomas Forst, Prof. Dr., Phone: +49 (0) 6131 2162 701, Email: thomas.forst@profil.com Additional Information
Starting date: December 2014
Last updated: December 1, 2014
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