Clinical Trials List
Protocol NumberCLIK066B2204
2017-07-28 - 2018-12-31
Phase II
Terminated3
ICD-10E11.59
Type 2 diabetes mellitus with other circulatory complications
ICD-9250.00
Diabetes mellitus without mention of complication, Type II [non-insulin dependent type][NIDDM type] [ adult-onset type] or unspecified type, not stated as uncontrolled
A multi-center, randomized, double-blind, parallel-group dose-finding study to assess the effect of 3 doses of LIK066 compared to placebo or empagliflozin in type 2 diabetes mellitus patients with heart failure
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Trial Applicant
NOVARTIS (TAIWAN) CO., LTD.
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Sponsor
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Trial scale
Multi-Regional Multi-Center
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Update
2025/08/20
Investigators and Locations
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- Wen-Chung Yu 無
- Kang-Ling Wang 無
- Hao-min Cheng 無
- 李慶威 無
- 許百豐 無
- Shih-Hsien Sung 無
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
Audit
None
Co-Principal Investigator
- Pei-Ying Pai 無
- 王宇澄 無
- 林晏年 無
- Lien-Cheng Hsiao 無
- 吳宏彬 無
- 陳科維 無
- 陳恬恩 無
- Shih-Sheng Chang 無
The Actual Total Number of Participants Enrolled
0 Terminated
Condition/Disease
type 2 diabetes mellitus patients with heart failure
Objectives
To determine the dose-response signal and assess the dose-response relationship of LIK066 2.5mg, 10mg, and 50mg qd as measured by the change from baseline (BL) in NT-proBNP relative to placebo after 12 weeks of treatment in T2DM patients with HF.
Secondary objectives
1. To evaluate the effect of all LIK066 doses vs placebo at 12 weeks and 36 weeks on:
Change from BL in glycated haemoglobin (HbA1c), see Section 6.4.6.
Change from BL in fasting plasma glucose (FPG), see Section 6.4.7.
Change from BL in weight, see Section 6.4.1.
Change from BL in body composition (bio-impedance in all patients where appropriate
and dual-energy x-ray absorptiometry (DXA) in a subset of patients, see Section 6.4.3)
Change from BL in sitting systolic blood pressure (SBP) and diastolic blood pressure
(DBP), see Section 6.4.8.
Change from BL in the fasting lipid profile and hsCRP, see Section 6.4.9.
Change from BL in 24h urinary glucose and sodium excretion, in a subset of patients, see Section 6.4.10.
Change from BL in left atrial size and volume assessed by echocardiography, see
Section 6.4.5.
Change from BL in NYHA class, see Section 6.4.4.
2. To evaluate the effect of all LIK066 doses vs empagliflozin at 12 weeks and 36 weeks on:
Change from BL in HbA1c, see Section 6.4.6.
Change from BL in FPG, see Section 6.4.7.
Change from BL in weight, see Section 6.4.1.
Change from BL in body composition (bio-impedance in all patients where appropriate
and DXA in a subset of patients, see Section 6.4.3)
Change from BL in sitting SBP and diastolic blood pressure (DBP), see Section 6.4.8.
Change from BL in the fasting lipid profile and hsCRP, see Section 6.4.9.
Change from BL in 24h urinary glucose and sodium excretion, in a subset of patients
(see Section 6.4.10).
3. To evaluate the change from BL to 36 weeks in all LIK066 doses vs placebo on NT-proBNP.
4. To evaluate safety (adverse events (AEs) and lab parameters) and tolerability of LIK066
over 12 weeks and over 36 weeks for all patients (see Section 6.5)
5. To evaluate 24h urinary calcium and phosphate excretion after 12 weeks and after 36 weeks
in a subset of patients (see Section 6.4.10).
6. To evaluate bone mineral density in a subset of patients (see Section 6.5.5)
Test Drug
LIK066
Active Ingredient
LIK066
Dosage Form
Film-coated tablets
Dosage
2.5mg/10mg/50mg
Endpoints
To determine the dose-response signal and assess the dose-response relationship of three dose regimens of LIK066 as measured by the change from baseline (BL) in NT-proBNP relative to placebo after 12 weeks of treatment in T2DM patients with HF
Inclution Criteria
Inclusion criteria
Patients eligible for inclusion in this study must fulfill all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. Male or female outpatients, ≥ 18 years of age at Visit 1.
3. BMI ≥ 22kg/m2
at Visit 1.
4. Type 2 diabetes with HbA1c between 7.0% and 10.0% at Visit 1.
5. Documented symptomatic chronic heart failure (NYHA II-IV) with at least one of the
following symptoms at the time of Visit 1:
Dyspnea on exertion
Orthopnea
Paroxysmal nocturnal dyspnea
Peripheral edema
6. Plasma NT-proBNP > 400pg/ml at Visit 1.
7. Patients receiving ACEi, ARBs, MRAs, ARNi and/or β-blockers must be on a stable dose
of these medications during the 1 month period prior to Visit 1.
8. Patients must be on diuretic therapy prior to Visit 1 (flexible dosing is permitted).
9. Controlled systolic BP defined as a target systolic BP less than 140mmHg; systolic BP up
to and including 160mmHg if patient is on three or more medications to control BP, at
randomization (Visit 201).
10. eGFR ≥ 45ml/min/1.73m2
at Visit 1 (calculated by the Modification of Diet in Renal
Disease formula (MDRD)).
11. Serum potassium ≤ 5.2mM at Visit 1.
Patients eligible for inclusion in this study must fulfill all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. Male or female outpatients, ≥ 18 years of age at Visit 1.
3. BMI ≥ 22kg/m2
at Visit 1.
4. Type 2 diabetes with HbA1c between 7.0% and 10.0% at Visit 1.
5. Documented symptomatic chronic heart failure (NYHA II-IV) with at least one of the
following symptoms at the time of Visit 1:
Dyspnea on exertion
Orthopnea
Paroxysmal nocturnal dyspnea
Peripheral edema
6. Plasma NT-proBNP > 400pg/ml at Visit 1.
7. Patients receiving ACEi, ARBs, MRAs, ARNi and/or β-blockers must be on a stable dose
of these medications during the 1 month period prior to Visit 1.
8. Patients must be on diuretic therapy prior to Visit 1 (flexible dosing is permitted).
9. Controlled systolic BP defined as a target systolic BP less than 140mmHg; systolic BP up
to and including 160mmHg if patient is on three or more medications to control BP, at
randomization (Visit 201).
10. eGFR ≥ 45ml/min/1.73m2
at Visit 1 (calculated by the Modification of Diet in Renal
Disease formula (MDRD)).
11. Serum potassium ≤ 5.2mM at Visit 1.
Exclusion Criteria
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No
additional exclusions may be applied by the investigator, in order to ensure that the study
population will be representative of all eligible patients.
1. Use of other investigational drugs within 5 half-lives of Visit 1, or within 30 days,
whichever is longer.
2. History of hypersensitivity to any of the study drugs or their excipients or to drugs of similar chemical classes.
3. History or current diagnosis of electrocardiogram (ECG) abnormalities indicating
significant risk of safety for patients participating in the study such as:
Concomitant clinically significant cardiac arrhythmias, e.g., sustained ventricular
tachycardia, and clinically significant second or third degree AV -block without a
pacemaker.
History of familial long QT syndrome or known family history of torsades de pointes.
Atrial fibrillation with a resting heart rate >100 beats per minute (bpm).
4. Patients taking medications prohibited by the protocol (see Section 5.5.8)
5. History of malignancy of any organ system (other than localized basal cell carcinoma of
the skin or in situ cervical cancer), treated or untreated, within the past 5 years,
regardless of whether there is evidence of local recurrence or metastases.
6. Pregnant or nursing (lactating) women.
7. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using basic methods of contraception during dosing of
investigational drug. Basic contraception methods include:
Total abstinence (when this is in line with the preferred and usual lifestyle of the
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation
methods) and withdrawal are not acceptable methods of contraception.
Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking
investigational drug. In case of oophorectomy alone, only when the reproductive
status of the woman has been confirmed by follow up hormone level assessment.
Male sterilization (at least 6 months prior to screening). For female patients on the
study, the vasectomized male partner should be the sole partner for that patient.
Barrier methods of contraception: condom or occlusive cap (diaphragm or
cervical/vault caps). For UK: with spermicidal foam/gel/film/cream/vaginal
suppository.
Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of
contraception or other forms of hormonal contraception that have comparable efficacy
(failure rate <1%), for example hormone vaginal ring or transdermal hormone
contraception or placement of an intrauterine device (IUD) or intrauterine system
(IUS).
In case of use of oral contraception women should have been stable on the same pill for a
minimum of 3 months before taking investigational drug.
Women are considered post-menopausal and not of child bearing potential if they have had 12
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with
or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In the case
of oophorectomy alone, only when the reproductive status of the woman has been confirmed
by follow up hormone level assessment is she considered not of child bearing potential.
If the above wording is not in line with specific country regulations, exclusion criteria for
women of child-bearing potential will be managed locally and in line with those regulations.
8. Type 1 diabetes, monogenic diabetes, diabetes resulting from pancreatic injury, or
secondary forms of diabetes (e.g. Cushing’s syndrome or acromegaly-associated diabetes).
9. Use of SGLT2 inhibitors within 2 months of Visit 1, or between Visit 1 and Visit 201
(randomization).
10. Self-measured FPG > 12.2mM (220mg/dL) on two occasions in the week prior to
randomization (Visit 201).
11. Ketoacidosis, lactic acidosis, or hyperosmolar coma within 6 months of Visit 1, or between
Visit 1 and Visit 201 (randomization).
12. Symptomatic genital infection or UTI in the 4 weeks prior to Visit 1, or between Visit 1 and
Visit 201 (randomization).
13. GI disorders associated with chronic diarrhea.
14. Myocardial infarction (MI), stroke, surgery for heart disease, percutaneous coronary
intervention (PCI) in the 3 months prior to Visit 201 (randomization).
15. Unstable angina within 3 months of Visit 1, or between Visit 1 and Visit 201
(randomization).
16. Isolated right HF due to pulmonary disease.
17. Dyspnea and/or edema from non-cardiac causes, such as lung disease, anemia, or severe
obesity.
18. Hemodynamically significant mitral and /or aortic valve disease.
19. Hemodynamically significant obstructive lesions of left ventricular outflow tract, including
aortic stenosis.
20. Hypertrophic obstructive cardiomyopathy.
21. Secondary forms of cardiomyopathy such as restrictive cardiomyopathy or infiltrative
cardiomyopathy (e.g., amyloid disease).
22. Patients with a history of any organ transplant or who were on a transplant list (life
expectancy < 6 months at time of entry into the study).
23. Patients with a mean sitting systolic blood pressure ≤ 100mmHg, at randomization (Visit
201).
24. Patients with an implantable medical device (e.g. cardioverter defibrillator (ICD)) that has
discharged in the month prior to Visit 1.
25. Episode(s) of malignant ventricular tachycardia or any other types of severe arrhythmia
producing significant hemodynamic consequences or considered life-threatening within 3
months of Visit 1.
26. Acute or chronic liver disease (except liver steatosis), such as hepatitis, cirrhosis or portal
hypertension at Visit 1 or Visit 201 (randomization).
27. History of hepatitis B or C, or Hepatitis A or B vaccination in the last 3 months pri or to
Visit 1, or between Visit 1 and Visit 201 (randomization).
28. Active substance abuse, alcohol abuse (as defined by consumption of more than 24 alcohol
units per week) and alcohol related history of disease within the past 2 years.
29. Chronic treatment with medication which has a hepatotoxic potential.
30. Chronic use of anti-retroviral therapies.
31. Chronic use of strong CYP3A4 inhibitors (e.g. clarithromycin, telithromycin, itraconazole,
ketoconazole, voriconazole or posaconazole) or chronic use of strong uridine-5’-
diphosphoglucoronosyltransferase (UGT) inhibitors (e.g. probenecid, valproic acid or
mefenamic acid).
32. Concurrent medical condition that may interfere with the interpretation of efficacy and
safety data.
33. Clinically significant thyroid stimulation hormone (TSH) level outside of the normal range
at Visit 1.
34. Alanine aminotransferase (ALT), or aspartate aminotransferase (AST) more than three-fold
above upper limit of normal (>3 x ULN), or total bilirubin/direct bilirubin > 1.5 x ULN) at
Visit 1, confirmed by repeat measurement within 5 working days of the respective visit.
35. Hemoglobin < 11g/L in men, < 10g/L in women at Visit 1 (screening).
36. Platelet count < 100,000/μl and/or white blood cell (WBC) count < 4000/μl at Visit 1
(screening).
37. Hematuria determined by dipstick measurement at Visit 1 (screening).
38. Elevated fasting triglycerides (TG) > 5.6mM (500mg/dl), at Visit 1 (screening), confirmed
by repeat measurement within 3 working days of the respective visit.
39. Clinically significant laboratory abnormalities which, in the opinion of the investigator,
cause the patient to be considered inappropriate for inclusion in the study.
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No
additional exclusions may be applied by the investigator, in order to ensure that the study
population will be representative of all eligible patients.
1. Use of other investigational drugs within 5 half-lives of Visit 1, or within 30 days,
whichever is longer.
2. History of hypersensitivity to any of the study drugs or their excipients or to drugs of similar chemical classes.
3. History or current diagnosis of electrocardiogram (ECG) abnormalities indicating
significant risk of safety for patients participating in the study such as:
Concomitant clinically significant cardiac arrhythmias, e.g., sustained ventricular
tachycardia, and clinically significant second or third degree AV -block without a
pacemaker.
History of familial long QT syndrome or known family history of torsades de pointes.
Atrial fibrillation with a resting heart rate >100 beats per minute (bpm).
4. Patients taking medications prohibited by the protocol (see Section 5.5.8)
5. History of malignancy of any organ system (other than localized basal cell carcinoma of
the skin or in situ cervical cancer), treated or untreated, within the past 5 years,
regardless of whether there is evidence of local recurrence or metastases.
6. Pregnant or nursing (lactating) women.
7. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using basic methods of contraception during dosing of
investigational drug. Basic contraception methods include:
Total abstinence (when this is in line with the preferred and usual lifestyle of the
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation
methods) and withdrawal are not acceptable methods of contraception.
Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking
investigational drug. In case of oophorectomy alone, only when the reproductive
status of the woman has been confirmed by follow up hormone level assessment.
Male sterilization (at least 6 months prior to screening). For female patients on the
study, the vasectomized male partner should be the sole partner for that patient.
Barrier methods of contraception: condom or occlusive cap (diaphragm or
cervical/vault caps). For UK: with spermicidal foam/gel/film/cream/vaginal
suppository.
Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of
contraception or other forms of hormonal contraception that have comparable efficacy
(failure rate <1%), for example hormone vaginal ring or transdermal hormone
contraception or placement of an intrauterine device (IUD) or intrauterine system
(IUS).
In case of use of oral contraception women should have been stable on the same pill for a
minimum of 3 months before taking investigational drug.
Women are considered post-menopausal and not of child bearing potential if they have had 12
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with
or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In the case
of oophorectomy alone, only when the reproductive status of the woman has been confirmed
by follow up hormone level assessment is she considered not of child bearing potential.
If the above wording is not in line with specific country regulations, exclusion criteria for
women of child-bearing potential will be managed locally and in line with those regulations.
8. Type 1 diabetes, monogenic diabetes, diabetes resulting from pancreatic injury, or
secondary forms of diabetes (e.g. Cushing’s syndrome or acromegaly-associated diabetes).
9. Use of SGLT2 inhibitors within 2 months of Visit 1, or between Visit 1 and Visit 201
(randomization).
10. Self-measured FPG > 12.2mM (220mg/dL) on two occasions in the week prior to
randomization (Visit 201).
11. Ketoacidosis, lactic acidosis, or hyperosmolar coma within 6 months of Visit 1, or between
Visit 1 and Visit 201 (randomization).
12. Symptomatic genital infection or UTI in the 4 weeks prior to Visit 1, or between Visit 1 and
Visit 201 (randomization).
13. GI disorders associated with chronic diarrhea.
14. Myocardial infarction (MI), stroke, surgery for heart disease, percutaneous coronary
intervention (PCI) in the 3 months prior to Visit 201 (randomization).
15. Unstable angina within 3 months of Visit 1, or between Visit 1 and Visit 201
(randomization).
16. Isolated right HF due to pulmonary disease.
17. Dyspnea and/or edema from non-cardiac causes, such as lung disease, anemia, or severe
obesity.
18. Hemodynamically significant mitral and /or aortic valve disease.
19. Hemodynamically significant obstructive lesions of left ventricular outflow tract, including
aortic stenosis.
20. Hypertrophic obstructive cardiomyopathy.
21. Secondary forms of cardiomyopathy such as restrictive cardiomyopathy or infiltrative
cardiomyopathy (e.g., amyloid disease).
22. Patients with a history of any organ transplant or who were on a transplant list (life
expectancy < 6 months at time of entry into the study).
23. Patients with a mean sitting systolic blood pressure ≤ 100mmHg, at randomization (Visit
201).
24. Patients with an implantable medical device (e.g. cardioverter defibrillator (ICD)) that has
discharged in the month prior to Visit 1.
25. Episode(s) of malignant ventricular tachycardia or any other types of severe arrhythmia
producing significant hemodynamic consequences or considered life-threatening within 3
months of Visit 1.
26. Acute or chronic liver disease (except liver steatosis), such as hepatitis, cirrhosis or portal
hypertension at Visit 1 or Visit 201 (randomization).
27. History of hepatitis B or C, or Hepatitis A or B vaccination in the last 3 months pri or to
Visit 1, or between Visit 1 and Visit 201 (randomization).
28. Active substance abuse, alcohol abuse (as defined by consumption of more than 24 alcohol
units per week) and alcohol related history of disease within the past 2 years.
29. Chronic treatment with medication which has a hepatotoxic potential.
30. Chronic use of anti-retroviral therapies.
31. Chronic use of strong CYP3A4 inhibitors (e.g. clarithromycin, telithromycin, itraconazole,
ketoconazole, voriconazole or posaconazole) or chronic use of strong uridine-5’-
diphosphoglucoronosyltransferase (UGT) inhibitors (e.g. probenecid, valproic acid or
mefenamic acid).
32. Concurrent medical condition that may interfere with the interpretation of efficacy and
safety data.
33. Clinically significant thyroid stimulation hormone (TSH) level outside of the normal range
at Visit 1.
34. Alanine aminotransferase (ALT), or aspartate aminotransferase (AST) more than three-fold
above upper limit of normal (>3 x ULN), or total bilirubin/direct bilirubin > 1.5 x ULN) at
Visit 1, confirmed by repeat measurement within 5 working days of the respective visit.
35. Hemoglobin < 11g/L in men, < 10g/L in women at Visit 1 (screening).
36. Platelet count < 100,000/μl and/or white blood cell (WBC) count < 4000/μl at Visit 1
(screening).
37. Hematuria determined by dipstick measurement at Visit 1 (screening).
38. Elevated fasting triglycerides (TG) > 5.6mM (500mg/dl), at Visit 1 (screening), confirmed
by repeat measurement within 3 working days of the respective visit.
39. Clinically significant laboratory abnormalities which, in the opinion of the investigator,
cause the patient to be considered inappropriate for inclusion in the study.
The Estimated Number of Participants
-
Taiwan
24 participants
-
Global
992 participants
