A controlled study to assess the safety, tolerability and effect of the study drug, ISIS 484137, on hepatic steatosis (fatty liver) in adult patients with Type 2 diabetes
- Conditions
- Hepatic Steatosis in type 2 diabetes (T2DM)MedDRA version: 20.0Level: PTClassification code 10067585Term: Type 2 diabetes mellitusSystem Organ Class: 10027433 - Metabolism and nutrition disordersMedDRA version: 20.0Level: PTClassification code 10019708Term: Hepatic steatosisSystem Organ Class: 10019805 - Hepatobiliary disordersTherapeutic area: Diseases [C] - Nutritional and Metabolic Diseases [C18]
- Registration Number
- EUCTR2017-003197-13-HU
- Lead Sponsor
- Ionis Pharmaceuticals, Inc.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 45
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
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 < 300 mg/24-hr
b. Persistently positive test (including trace) for blood on urinalysis. In the event of a positive test eligibility may be confirmed with urine microscopy showing < 5 red blood cells (RBC) per high power field (Persistently positive defined as 2 out of 3)
c. Serum creatinine > upper limit of normal (ULN)
d. Estimated glomerular filtration rate (GFR) < 60 mL/min (as determined by the Cockcroft-Gault Equation for creatinine clearance)
e. Alanine aminotransferase (ALT) ALT or aspartate aminotransferase (AST) > 1.5 ULN
f. Total bilirubin > ULN
g. Have a current or previous diagnosis of Gilbert’s disease
h. Platelet count < 170,000/mm3 (< 170 x 109/L)
3. Show evidence of uncorrected hypothyroidism or hyperthyroidism hormone results at Screening. Subjects receiving dose-stable thyroid replacement therapy for at least 3 months prior to Screening will be allowed to participate as long as thyroid tests (TSH/T3/T4) show that subject is euthyroid
4. History of solid organ transplantation or renal dialysis
5. Clinically-significant complications of diabetes (e.g., history of painful neuropathy, nephropathy, proliferative retinopathy and/or foot ulcers)
6. Subjects on lipid lowering medications must be on a stable dose and regimen for = 3 months prior to Screening. Subjects receiving treatment with statins should be within the dose levels listed below. Other statin regimens should be discussed and approved with the Sponsor Medical Monitor or designee:
• Simvastatin, pravastatin, atorvastatin and fluvastatin at = 40 mg/day
• Lovastatin or rosuvastatin at = 20 mg/day
• Pitavastatin up to 4 mg/day
7. Known history of or evidence of liver disease with a positive test for human immunodeficiency virus (HIV), hepatitis C (HCV) or chronic hepatitis B (HBV) or chronic liver disease other than NASH including alcoholic liver disease, Wilson’s disease, hemochromatosis, or iron overload, Alpha-1-antitrypsin (A1AT) deficiency, prior known drug-induced liver injury, known or suspected hepatocellular carcinoma (HCC), current placement on a liver transplant list, or MELD score > 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
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method