| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hepatic Steatosis in type 2 diabetes (T2DM) |
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| E.1.1.1 | Medical condition in easily understood language |
| Fatty liver in type 2 diabetes. Diabetes is characterised by the body being unable to metabolise glucose (a simple sugar). This leads to high levels of blood glucose which may damage the organs. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10067585 |
| E.1.2 | Term | Type 2 diabetes mellitus |
| E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10019708 |
| E.1.2 | Term | Hepatic steatosis |
| E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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 |
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| E.2.2 | Secondary objectives of the trial |
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]) |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 |
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| E.4 | Principal 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 < 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 of a clinical study may be included as long as a duration of ≥ 4 months has elapsed since dosing
11. Recent history of, or current drug or alcohol abuse. Regular and excessive use of alcohol within 6 months prior to Screening (> 7 drinks/week for females, > 14 drinks/week for males (1 drink = 5 ounces (150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of hard liquor), or use of soft drugs (such as marijuana) within 3 months prior to Screening, or hard drugs (such as cocaine and phencyclidine [PCP]) within 1-year prior to screening, or positive urine drug screen at Screening
12. Concomitant medication restrictions:
a. Use of agents or medications known to significantly impact BW within 3 months prior
b. chronic use of systemic corticosteroids
c. other antidiabetic medications not outlined in Inclusion Criteria #6,
d. other medications, per Investigator, known to cause liver toxicity or steatosis
e. Use of anticoagulant/antiplatelet agents unless the dose has been stable for 4 weeks prior to the first dose of Study Drug and regular clinical monitoring is performed, use of the non steroidal anti-inflammatory drug (NSAID) nimesulide or any other drug influencing coagulation (except low dose aspirin < 160 mg/day and other short acting NSAIDS with a half-life < 20 hours)
f. obeticholic acid or ursodeoxycholic acid
Full list of exclusion criteria included in protocol |
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| E.5 End points |
| E.5.1 | 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.
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| E.5.1.1 | 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. |
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| E.5.2 | 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)
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| E.5.2.1 | 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. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 17 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| France |
| Hungary |
| Poland |
| United Kingdom |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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