A clinical trial to compare the glycaemic control and safety of insulin degludec/liraglutide (IDegLira) with insulin glargine (IGlar) as add-on therapy to SGLT2i in subjects with type 2 diabetes mellitus
Scientific Title of Study
A clinical trial comparing glycaemic control and safety of insulin degludec/liraglutide (IDegLira) versus insulin glargine (IGlar) as add-on therapy to SGLT2i in subjects with type 2 diabetes mellitus
Starting dose of 10 dose steps (10 Units Insulindegludec+ 0.36 mg Liraglutide) / 26 weeks/ Once daily Injection / Subcutaneous
Comparator Agent
Insulin glargine
Starting dose of 10 Units (10 Units Insulin Glargine) / 26 weeks/ Once daily Injection / Subcutaneous
Inclusion Criteria
Age From
18.00 Year(s)
Age To
70.00 Year(s)
Gender
Both
Details
1. Informed consent obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial.
2. Male or female, age greater than or equal to 18 years at the time of signing informed consent.
3. Subjects diagnosed (clinically) with type 2 diabetes mellitus.
4. HbA1c 7.0-11.0% (53-97 mmol/mol) (both inclusive) by central laboratory analysis.
5. BMI greater than or equal to 20 kg/m2 and lesser than 40 kg/m2.
6. Insulin naïve subjects; however short term insulin treatment for a maximum of 14 days prior to the day of screening is allowed, as well as prior insulin treatment for gestational diabetes.
7. Oral antidiabetic treatment:
a. SGLT2i: Subjects must have been on a stable daily dose of any SGLT2i (greater than or equal to half of the maximum approved dose according to current local label or maximum tolerated dose as documented in subject medical record, or minimum recommended maintenance dose according to current local label) for at least 90 days prior to the day of screening.
b. Combination therapy: Stable daily dose of SGLT2i as outlined above in combination with stable daily dose(s) of metformin with/without DPP4i is allowed:
i. Metformin (greater than or equal to 1500 mg or maximum tolerated dose as documented in the subject medical record) for at least 90 days prior to the day of screening.
ii. DPP4i (greater than or equal to half of the maximum approved dose according to local label or maximum tolerated dose as documented in subject medical record) for at least 90 days prior to the day of screening.
iii. Stable daily doses, as outlined above, of fixed dose combination products combining either SGLT2i and metformin or SGLT2i and DPP4i, according to locally approved label for at least 90 days prior to the day of screening are also allowed
ExclusionCriteria
Details
" 1. Known or suspected hypersensitivity to trial product(s) or related products.
2. Previous participation in this trial. Participation is defined as signed informed consent.
3. Receipt of any investigational medicinal product within 90 days prior to screening.
4. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using adequate contraceptive methods (adequate contraceptive measures as required by local regulation or practice).
5. Use of any OADs (other than SGLT2i in monotherapy or in combination with metformin or DPP4i or pioglitazone as described in the inclusion criteria) within 90 days prior to the day of screening.
6. Use of GLP-1 receptor agonist (e.g., exenatide or liraglutide) within 90 days prior to the day of screening.
7. Acute decompensation of glycaemic control requiring immediate intensification of treatment to
prevent severe metabolic dysregulation (e.g., diabetes ketoacidosis) in the previous 90 days prior to the day of the screening.
8. Family or personal history of multiple endocrine neoplasia type 2 or medullary thyroids carcinoma.
9. Screening calcitonin ≥ 50 ng/L.
10. History of pancreatitis (acute or chronic).
11. Any of the following: myocardial infarction, stroke or hospitalisation for unstable angina and/or
transient ischaemic attack within the past 180 days prior to the day of screening.
12. Subjects presently classified as being in NYHA Class III or IV.
13. Planned coronary, carotid or peripheral artery revascularisation at the day of screening.
14. Renal impairment eGFR 60 mL/min/1.73 m2 as per CKD-EPI.
15. Impaired liver function, defined as ALT ≥ 2.5 times upper normal limit at screening.
16. Inadequately treated blood pressure as defined as Class 2 hypertension or higher (systolic ≥ 160
mmHg or diastolic ≥ 100 mmHg) at screening.
17. Anticipated initiation or change in concomitant medications for more than 14 consecutive days or on a frequent basis known to affect weight or glucose metabolism (e.g., orlistat, thyroid hormones, corticosteroids).
18. Proliferative retinopathy or maculopathy requiring acute treatment. Verified by fundus photography or dilated fundoscopy performed within 90 days prior to randomisation.
19. History or presence of malignant neoplasms within the last 5 years (except basal and squamous
cell skin cancer and in-situ carcinomas).
20. History of diabetic ketoacidosis.
21. Any disorder, except for conditions associated with diabetes, which in the investigator’s opinion
might jeopardise subject’s safety or compliance with the protocol.
"
Method of Generating Random Sequence
Computer generated randomization
Method of Concealment
Centralized
Blinding/Masking
Open Label
Primary Outcome
Outcome
TimePoints
Change from baseline in HbA1c
Week 0 to week 26
Secondary Outcome
Outcome
TimePoints
1. Change from baseline in body weight after 26 weeks
2. Number of treatment-emergent severe or BG confirmed symptomatic hypoglycaemic episodes during 26 weeks
3. Insulin dose, total daily dose (U)
Week 0 to week 26
Target Sample Size
Total Sample Size="416" Sample Size from India="50"
This is a 26-week randomised, active-controlled, multicentre, multinational, two-arm parallel, openlabel, TTT trial in subjects with T2DM. Subjects inadequately controlled on treatment with SGLT2i ± OAD will be eligible for the trial. The trial will compare IDegLira to IGlar as an add-on to treatment with SGLT2i ± OAD. Inadequately controlled T2DM is defined as an HbA1c level of 7.0-11.0 % (53-97 mmol/mol) (both inclusive).A total of 416 subjects will be randomized using IWRS in a 1:1 manner to either of the two trial arms, IDegLira (OD) or IGlar (OD). The total trial duration will be approximately 32 weeks, consisting of a 2 week screening period, a 26-week treatment period, and two follow-up contacts (FU1 and FU2).
CTRI Number
CTRI/2017/07/008990 [Registered on: 06/07/2017] Trial Registered Prospectively
This trial will study if it is beneficial in terms of blood sugar control, and safe, to add liraglutide to anti-diabetes medication like sodium-glucose co- transporter 2 (SGLT2) inhibitor with or without metformin.
Scientific Title of Study
"This is a 26-week, confirmatory, randomised, double-blind, placebo-controlled, multicentre,
multinational, two-arm, parallel-group trial, investigating the effect and safety of adding liraglutide
1.8 mg/day to pre-trial treatment with any SGLT2 inhibitor (as monotherapy or in combination withmetformin) in subjects with T2DM who have not achieved adequate glycaemic control despite
stable treatment with SGLT2 inhibitor ± metformin for at least 90 days prior to trial participation.
"
Secondary IDs if Any
Secondary ID
Registry
NN2211-4315 version 2.0 dated 26 Oct 2016
Protocol Number
U1111-1184-8086
UTN
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Department of Endocrinology, 3rd Floor, Main Building,
Musheerabad, Secunderabad,
Telangana 500003
Hyderabad
9849172161 04027504441 drdvsreddyendo@yahoo.com
Dr Leena Ashwin Dabhi
AMC MET Medical College Sheth L. G. General Hospital
Research Room
Opp. (Old) X-Ray Room and Radiology Department, Near Medicine Department OPD, Ground Floor, Old Building, Rambag, Maninagar,
Ahmedabad
Gujurat 380008
Ahmadabad
9879144653 917925464653 leenadabhilg@gmail.com
Dr Vaishali Deshmukh
Deenanath Mangeshkar Hospital and research centre
Near Mhatre Bridge, Erandawne
Pune
Maharastra 411004
Pune
Liraglutide will be initiated with a starting dose of 0.6 mg/day, with subsequent weekly
dose escalations of 0.6 mg/day in accordance with the approved dose escalation for liraglutide until
the maintenance dose of 1.8 mg/day in this trial is reached. Escalation from 0.6 to 1.2 then 1.8
mg/day can be extended by 7 days in total if subjects do not tolerate an increase in dose during dose
escalation, at the discretion of the investigator.
duration : 29 weeks
route of administration: subcutaneous
Comparator Agent
Placebo
Placebo will be initiated with a starting dose of 0.6 mg/day, with subsequent weekly
dose escalations of 0.6 mg/day in accordance with the approved dose escalation for liraglutide until
the maintenance dose of 1.8 mg/day in this trial is reached. Escalation from 0.6 to 1.2 then 1.8
mg/day can be extended by 7 days in total if subjects do not tolerate an increase in dose during dose
escalation, at the discretion of the investigator.
duration : 29 weeks
route of administration: subcutaneous
1. Informed consent obtained before any trial-related activities. Trial-related activities are any
procedures that are carried out as part of the trial, including activities to determine suitability
for the trial.
2. Male or female, age ≥ 18 years at the time of signing informed consent.
3. Diagnosed with type 2 diabetes mellitus.
4. HbA1c of 7.0-9.5% (53-80 mmol/mol) (both inclusive).
5. Stable dose of an SGLT-2 inhibitor as monotherapy or in combination (including fixed-dose
drug combination) with a stable dose of metformin (≥ 1500 mg or maximum tolerated dose)
for at least 90 days prior to the day of screening. All medications in compliance with current
local label.
6. Body mass index greater than 20 kg/m2."
ExclusionCriteria
Details
1. Known or suspected hypersensitivity to trial product(s) or related products.
2. Previous participation in this trial. Participation is defined as signed informed consent.
3. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing
potential and not using an adequate contraceptive method (adequate contraceptive measure
as required by local regulation or practice).Brazil: According to resolution 466/12: Regarding exclusion criterion: Female who is
pregnant, breast-feeding or intends to become pregnant or is of childbearing potential and not
using adequate contraceptive methods (adequate contraceptive measures as required by local
regulation or practice). For women who expressly declare free of the risk of pregnancy, either
by not engaging in sexual activity or by having sexual activity with no birth potential risk, use of
contraceptive method will not be mandatory.
4. Receipt of any investigational medicinal product within 90 days before screening.
5. Treatment with any medication for the indication of diabetes or obesity other than stated in
the inclusion criteria within the past 90 days prior to the day of screening. However, short
term insulin treatment for a maximum of 14 days during the 90 days prior to the day of
screening is allowed.
6. Any disorder which in the investigator’s opinion might jeopardise subject’s safety or
compliance with the protocol.
7. History of diabetic ketoacidosis while being treated with SGLT2 inhibitors.
8. Family or personal history of multiple endocrine neoplasia type 2 or medullary thyroid
carcinoma. Family is defined as a first degree relative.
9. History or presence of pancreatitis (acute or chronic).
10. Renal impairment measured as estimated Glomerular Filtration Rate (eGFR) value of < 60
mL/min/1.73m2 as defined by KDIGO1 classification using isotope dilution mass
spectrometry (IDMS) for serum creatinine measured at screening.
11. Impaired liver function, defined as ALT ≥2.5 times upper normal limit at screening.
12. Subjects presently classified as being in New York Heart Association (NYHA) Class IV.
13. Planned coronary, carotid or peripheral artery revascularisation known on the day of
screening.
14. Any of the following: myocardial infarction, stroke, hospitalization for unstable angina or
transient ischaemic attack within the past 180 days prior to the day of screening.
15. Inadequately treated blood pressure defined as Grade 3 hypertension or higher (systolic
≥180 mmHg or diastolic ≥110 mmHg) at screening.
Method of Generating Random Sequence
Computer generated randomization
Method of Concealment
Centralized
Blinding/Masking
Double Blind Double Dummy
Primary Outcome
Outcome
TimePoints
To compare the effect of liraglutide 1.8 mg/day versus placebo as add-on to an SGLT2 inhibitor ± metformin on glycaemic control in subjects with type 2 diabetes mellitus.
To compare the effect of liraglutide 1.8 mg/day versus placebo as add-on to an SGLT2 inhibitor ±
metformin in subjects with type 2 diabetes mellitus with regards to:
Body weight related parameters
Selected cardiovascular risk factors
Safety
Change from baseline to week 26 in body weight
To compare the effect of liraglutide 1.8 mg/day versus placebo as add-on to an SGLT2 inhibitor ±
metformin in subjects with type 2 diabetes mellitus with regards to:
selected glucose metabolism parameters
Change from baseline to week 26 in body weight
Target Sample Size
Total Sample Size="303" Sample Size from India="50"
Is SGLT2 inhibitors(diabetes drug) effective?:Test on exfoliated human kidney cell.
Scientific Title of Study
SGLT2 EXPRESSION IN HUMAN RENAL PROXIMAL TUBULAR CELLS FOR PREDICTING EFFICACY OF SGLT2 INHIBITORS
Secondary IDs if Any
Secondary ID
Registry
NIL
NIL
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Name
Dr Sujoy Ghosh
Address
Institute of post graduate medical education and research and SSKM hospital
244 AJC Bose road kolkata 700020
Ronald Ross Building 4th floor room no 8 Department of Endocrinology and Metabolism
Kolkata WEST BENGAL 700020 India
Phone
9674625823
Fax
03322236558
Email
drsujoyghosh2000@gmail.com
Details Contact Person Scientific Query
Name
Dr Sujoy Ghosh
Address
Institute of post graduate medical education and research and SSKM hospital
244 AJC Bose road kolkata 700020
Ronald Ross Building 4th floor room no 8 Department of Endocrinology and Metabolism
WEST BENGAL 700020 India
Phone
9674625823
Fax
03322236558
Email
drsujoyghosh2000@gmail.com
Details Contact Person Public Query
Name
Dr Sujoy Ghosh
Address
Institute of post graduate medical education and research and SSKM hospital
244 AJC Bose road kolkata 700020
Ronald Ross Building 4th floor room no 8 Department of Endocrinology and Metabolism
Canagliflozin 100mg once daily orally will be given in both groups of type 2 diabetes patients (both with glucose levels between 180-250 mg/dl). Group 1: with Glycosuria at baseline. Group 2: without Gylcosuria at baseline. Glycaemic response in both groups will be compared and also corroborated with expression of SGLT2 receptor at baseline and after intervention.
Healthy subjects- normoglycaemic (Fasting glucose <100mg/dl) and 2hr Post 75gm glucose, plasma venous glucose <140 mg/dl.
Individuals with prediabetes: (Fasting glucose <100mg/dl but <126 mg/dl) and/or 2hr Post 75gm glucose, plasma venous glucose >140 mg/dl but < 200 mg/dlType2 Diabetes as per ADA criteria, on lifestyle modification and drugs (other than SGLT2 inhibitors) but with current venous plasma glucose levels (fasting, 2 hour post prandial and/or random) greater than 180mg/dl but less than 250mg/dl
ExclusionCriteria
Details
• Prior SGLT2 inhibitor therapy in last 6 months
• Individuals on insulin therapy
• Contraindications to SGLT2 inhibitor therapy
• Comorbidities requiring hospital admission including CVA, CAD, CKD, dialysis, surgery, pregnancy, lactation, or complications arising thereof.
Method of Generating Random Sequence
Not Applicable
Method of Concealment
Not Applicable
Blinding/Masking
Not Applicable
Primary Outcome
Outcome
TimePoints
This study will be first of its kind to help us to define If SGLT2/GLUT2 is overexpressed in Indians with Type 2 Diabetes and/or individuals with pre-diabetes.
This will provide pathophysiological basis for prediction of treatment benefit with SGLT2 inhibitors in Indians.
This study is likely to provide clinical insights into patient characteristics which help predict response to SGLT2 inhibitors (example presence or absence of glycosuria.
1year
Secondary Outcome
Outcome
TimePoints
This will provide pathophysiological basis for prediction of treatment benefit with SGLT2 inhibitors in Indians.
This study is likely to provide clinical insights into patient characteristics which help predict response to SGLT2 inhibitors (example presence or absence of glycosuria.
1year
Target Sample Size
Total Sample Size="80" Sample Size from India="80"
Diabetes mellitus is estimated to affect nearly 350million of the global population and predicted to affect over 550million by 2035.In healthy (ie, glucose-tolerant) individuals, approximately 160–180 grams of glucose from plasma is filtered by the kidneys daily. Renal glucose homeostatsis includes gluconeogenesis, glucose uptake from circulation for metabolism by kidney and renal glucose filtration followed by reabsorption. Bulk of filtered glucose i.e.90% is reabsorbed by the low-affinity/high-capacity sodium glucose co-transporter (SGLT2) located in the S1 segments of proximal tubule and residual glucose is then absorbed by the high-affinity/low-capacity SGLT1 in the S3 segment. Transcellular glucose transport is facilitated by two basolateral membrane glucose transporters: the low-affinity GLUT2 in the S1 segment and the high-affinity GLUT1 in the S3 segment. Hence almost no glucose is excreted into the urine in normoglycaemic individuals. In a healthy adult, the maximum glucose transport capacity known as the renal threshold for glucose equates to a filtration rate of 260–350 mg/min/1.73 m2, which is equivalent to a plasma glucose concentration of approximately 180 mg/dL. Once this threshold is exceeded extra glucose cannot be reabsorbed and is excreted into the urine, resulting in glycosuria.In previous studies it has been suggested that the renal threshold in patient with uncontrolled diabetes may increase upto 250mg/dl,presumably due to upregulation of SGLT2. The filtered glucose load at glomerulus or glomerular filtration rate (GFR)is increased with hyperglycemia and diabetes is associated with glomerular hyperfiltration. A study in humans with type 1 diabetes showed a significant increase in the renal transport maximum (Tmax) of glucose , implying possible upregulation in tubular glucose carriers.Different studies have demonstrated that SGLT2 and tubular GLUT2 expressions were increased in alloxan induced and streptozotocin induced diabetic rats respectively. Human data regarding renal expression of SGLT2 and GLUT in diabetes is limited. Studies have demonstrated increased expression ofintestinal glucose carriers in patients with type 2 diabetes. No studies have been conducted in individuals with pre-diabetes regarding expression of SGLT2 and GLUT2 in pre-diabetes in human renal proximal tubular cells.
In our study we would isolate and subculture highly differentiated proximal tubular epithelial cells from human urine. This technique, with its variations, is a significant new tool in understanding the expression and activity of renal glucose transporters in human proximal tubular epithelial cells from subjects with prediabetes, type 2 diabetes as compared to healthy volunteers. SGLT2 might be pathologically and demonstrably upregulated in PCT of prediabetics and diabetics as compared to normal subjects. It will also try to prove that glycosuria in diabetic and prediabetic subjects occurs due to upregulation of SGLT2, which may have variability (quantitative or qualitative) in expression due to differences with possible genetic polymorphism. Hence these subgroup of diabetics and prediabetics are much less likely to respond to SGLT2 inhibition than non glycosuric subjects. Thus, this study might ultimately have a huge impact in future in lowering the burden of medical expenditure regarding indiscriminate use of these costly group of drugs (SGLT2inhibitors) in clinical practice.
