Hepatic Steatosis in type 2 diabetes (T2DM) MedDRA version: 20.0 Level: PT Classification code 10067585 Term: Type 2 diabetes mellitus System Organ Class: 10027433 - Metabolism and nutrition disorders MedDRA version: 20.0 Level: PT Classification code 10019708 Term: Hepatic steatosis System Organ Class: 10019805 - Hepatobiliary disorders
Conditions
Interventions
Product Name: ISIS 484137
Product Code: 484137
Pharmaceutical Form: Solution for injection
INN or Proposed INN: ISIS 484137
CAS Number: N/A
Current Sponsor code: ISIS 484137
Concentration unit: mg/ml
Sponsors
Ionis Pharmaceuticals, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Must have given written informed consent (signed and dated) and any authorizations required by local law and be able to comply with all study requirements 2. Males or females. Aged 18 to 75, inclusive, at the time of informed consent 3. Females must be non-pregnant and non-lactating, and either surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or post-menopausal (defined as 12 months of spontaneous amenorrhea without an alternative medical cause and FSH levels in the postmenopausal range for the laboratory involved Males must be surgically sterile, abstinent*or, if engaged in sexual relations with a female of child-bearing potential, the subject must be using an acceptable contraceptive method (as per protocol) from the time of signing the informed consent form until at least 13 weeks after the last dose of Study Drug (ISIS 484137 or placebo) * Abstinence is only acceptable as true abstinence, i.e., when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of a trial and withdrawal are not acceptable methods of contraception. 4. Body Mass Index (BMI) = 27.0 - = 39.0 kg/m2 5. Diagnosis of T2DM with an HbA1c = 7.3% and = 9.5% at Screening 6. Subjects must have been on a stable dose of the following oral antidiabetic therapy: metformin, sulfonylurea (SU), dipeptidyl peptidase-IV (DPPIV inhibitor) or sodium glucose like transport protein 2 (SGLT2) inhibitor for a minimum of 3 months prior to screening evaluation and will be required to continue their stable dose of oral antidiabetic therapy throughout the study. The use of thiazolidinediones (e.g., pioglitazone, rosiglitazone) and injectable antidiabetic therapy is not permitted (e.g., insulin, glucagon like peptide [GLP1 analogs]) 7. = 10% liver fat as assessed by MRI-PDFF prior to randomization 8. Stable body weight (BW) (i.e., not varying by > 5% for at least 3 months) before Screening 9. Agree to maintain current diet and exercise regimen 10. Agree to abstain from alcoholic beverages for at least 48 hours prior to clinic visits and not increase alcohol consumption during the study Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 40 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 5
Exclusion criteria
Exclusion criteria: 1. Clinically-significant abnormalities in medical history or physical examination 2. Central Laboratory results prior to randomization (Screening and/or Run-In) as follows, or any other clinically-significant abnormalities in screening laboratory values that would render a subject unsuitable for inclusion: a. Urine protein/creatinine (P/C) ratio > 0.2 mg/mg. In the event of P/C ratio above this threshold eligibility may be confirmed by a quantitative total urine protein measurement of upper limit of normal (ULN) d. Estimated glomerular filtration rate (GFR) 1.5 ULN f. Total bilirubin > ULN g. Have a current or previous diagnosis of Gilbert’s disease h. Platelet count 12, established fibrosis = Stage 3 fibrosis (Scale 0-4) or any cirrhosis 8. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated. Subjects with a history of other malignancies that have been treated with curative intent and which have no recurrence within 5 years may also be eligible if approved by the Sponsor Medical Monitor 9. Treatment with another investigational drug, biological agent, or device within 1 month of Screening, or 5 half-lives of investigational agent, whichever is longer 10. Treatment with any non- ION- or ISIS-oligonucleotide (including small interfering ribonucleic acid [siRNA]) at any time or prior treatment with an ION- or ISIS oligonucleotide within 9 months of Screening. Subjects who have previously received only a single-dose of an ISIS-oligonucleotide as part o
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objectives are: 1. To evaluate the safety and tolerability of ISIS 484137 250 mg per week subcutaneous (SC) injection in adult subjects with type 2 diabetes mellitus (T2DM) 2. To evaluate the pharmacodynamic effects of ISIS 484137 250 mg per week SC injection on the absolute reduction of liver fat (assessed by magnetic resonance imaging [MRI] proton density fat fraction [PDFF]) in adult subjects with T2DM;Secondary Objective: The secondary objectives are: 1. To evaluate the pharmacodynamic effects of ISIS 484137 250 mg per week SC injection on liver fat (percent relative reduction and percent of subjects with = 30% relative reduction) assessed by MRI-PDFF 2. To evaluate the pharmacodynamic effects of ISIS 484137 250 mg per week SC injection on liver volume assessed by MRI-PDFF 3. To evaluate the pharmacodynamic effects of ISIS 484137 250 mg per week SC injection on plasma lipoprotein profile (triglycerides [TG], total cholesterol, low density lipoprotein cholesterol [LDL-C], apolipoprotein B [apoB], very low density lipoproteins [VLDL], high density lipoprotein [HDL] and Non-HDL) 4. To evaluate the pharmacodynamic effects of ISIS 484137 250 mg per week SC injection on insulin resistance (IR) and glucose control (insulin, glucose, homeostatic model assessment-insulin resistance [HOMA-IR], hemoglobin A1c [HbA1c]);Primary end point(s): Safety Endpoint: The safety and tolerability of ISIS 484137 will be accessed by determining the incidence and severity of AEs and will be evaluated by reviewing: • AEs (including bleeding events) • Vital signs and weight • Physical examination • Clinical laboratory tests • Coagulation parameters • Use of concomitant medications Primary Pharmacodynamic Endpoint: The primary PD endpoint is the absolute change in liver fat percentage as quantified by MRI PDFF from Baseline MRI to Post-Treatment MRI. ;Timepoint(s) of evaluation of this end point: Safety Assessments: Weekly laboratory assessments will be obta | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary endpoints include: • Relative percent change in liver fat percentage from Baseline MRI to Post-Treatment MRI • Proportion of subjects with = 30% relative reduction in liver fat percentage from Baseline MRI to Post-Treatment MRI • Percent change in liver volume from Baseline MRI to Post-Treatment MRI • Percent change in plasma lipoprotein profile (triglycerides, total cholesterol, LDL-C, apoB, VLDL, HDL, and Non-HDL) from Baseline to the average of the Post-Treatment values assessed 1 and 2 weeks after the last dose (PT1 and PT2 Visits) • Percent change in parameters of hepatic IR (FPG, insulin, and HOMA-IR) from Baseline to the first Post-Treatment value assessed 1 week after the last dose (PT1 Visit) • Absolute change in HbA1c from Baseline to the first Post-Treatment value assessed 1 week after the last dose (PT1 Visit) ;Timepoint(s) of evaluation of this end point: Safety Assessments: Weekly laboratory assessments will be obtained throughout the Treatment Period Week 1-Week 13. Laboratory assessments will be obtained at regular intervals throughout the 13-week Post-Treatment Period. | — |
Countries
Canada, France, Hungary, Poland, United Kingdom
Contacts
Public ContactSeung Chun Manager Reg Affairs
Ionis Pharmaceuticals, Inc.
Outcome results
None listed