Hyperlipoproteinemia(a) and Established Cardiovascular Disease (CVD) MedDRA version: 20.1 Level: LLT Classification code 10020668 Term: Hyperlipoproteinemia System Organ Class: 100000004861 MedDRA version: 20.1 Level: LLT Classification code 10007648 Term: Cardiovascular disease, unspecified System Organ Class: 100000004849
Conditions
Interventions
Product Name: ISIS 681257
Product Code: ISIS 681257
Pharmaceutical Form: Solution for injection
INN or Proposed INN: ISIS 681257
CAS Number: N/A
Current Sponsor code: ISIS 681257
Other descriptive nam
Sponsors
Akcea Therapeutics, 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 and = 80 years old at the time of informed consent 3. Clinical diagnosis of CVD defined as documented coronary artery disease, stroke, or peripheral artery disease 4. Lp(a) plasma level = 60 mg/dL 5. Must be on standard-of-care preventative therapy for other than elevated Lp(a) CVD risk factors 6. Patients on the following medications must be on a stable regimen for at least 4 weeks prior to Screening and expected to remain on a stable regimen through the end of the post-treatment follow-up period: a. Lipid lowering drugs (statins, ezetimibe, PCSK9 inhibitors, niacin, fibrates, fish oil or other products containing omega-3 fatty acids (including OTC preparations) b. Antiplatelet drugs c. Testosterone, estrogens, progesterone, growth hormone or progestins 7. Females: must be non-pregnant and non-lactating and either; a. surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy); b. post-menopausal (defined as 12 months of spontaneous amenorrhea in females > 55 years of age or, in females = 55 years, 12 months of spontaneous amenorrhea without an alternative medical cause and FSH levels in the postmenopausal range for the laboratory involved); c. Abstinent* or, d. if engaged in sexual relations of child-bearing potential, agree to use 2 highly effective contraceptive methods (refer to Section 6.3.1) from the time of signing the informed consent form until at least 16 weeks after the last dose of Study Drug (ISIS 681257 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 8. Males must be surgically sterile or, if engaged in sexual relations with a female of child-bearing potential, the patient must be using an acceptable contraceptive method (refer to Section 6.3.1) from the time of signing the informed consent form until at least 16 weeks after the last dose of ISIS 681257 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 175 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 95
Exclusion criteria
Exclusion criteria: 1. Within 6 months of Screening: acute coronary syndrome, major cardiac surgery, or stroke/transient ischemic attack 2. Within 3 months of Screening: coronary, carotid, or peripheral arterial revascularization, major non-cardiac surgery, or lipoprotein apheresis 3. Heart failure NYHA class IV 4. Uncontrolled hypertension (systolic > 160 or diastolic > 100 mm Hg) 5. History of acute kidney injury within 12 months of Screening 6. Uncontrolled hyper or hypothyroidism 7. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1 8. Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C or chronic hepatitis B 9. 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 10. Patients with a history of major bleed or high-risk of bleeding diathesis 11. Recent history of, or current drug or alcohol abuse 12. Known history or presence of systemic allergic or pseudoallergic (drug) reactions 13. Hypersensitivity to the active substance or to any of the excipients 14. Clinically-significant abnormalities in screening laboratory values that would render a patient unsuitable for inclusion, including the following: a. Urine protein/creatinine ratio (UPCR) = 0.25 mg/mg. In the event of a UPCR above this threshold, eligibility may be confirmed by a quantitative total urine protein measurement of less than 300 mg/24-hr b. Urine albumin/creatinine ratio (UACR) = 100 mg/g. In the event of a UACR above this threshold, eligibility may be confirmed by a quantitative total urine albumin measurement of less than 150 mg/24-hr c. Estimated GFR less than 60 mL/min as determined by the Chronic Kidney Disease-Epidemiological Collaboration (CKD-EPI) Equation for creatinine clearance d. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.0 x ULN e. Bilirubin > ULN, unless prior diagnosis and documentation of Gilbert’s syndrome in which case total bilirubin must be = 3 mg/dL f. Alkaline phosphatase (ALP) > ULN g. Platelet count less than LLN 15. Use of warfarin, direct thrombin inhibitors or factor Xa inhibitors 16. Treatment with another investigational drug, biological agent, or device within 1 month of Screening, or 5 half-lives of investigational agent, whichever is longer 17. Treatment with any non-Ionis oligonucleotide (including small interfering ribonucleic acid [siRNA]) at any time or prior treatment with an Ionis oligonucleotide or siRNA within 9 months of screening. Patients that have previously received only 1 dose of an Ionis oligonucleotide as part of a clinical study may be included as long as = 4 months has elapsed since dosing 18. BMI > 40 kg/m2 19. Blood donation of 50-499 mL within 30 days of Screening or of > 499 mL within 8 weeks of screening 20. Unwillingness to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator 21. Have any other conditions, which, in the opinion of the Investigator or Sponsor would make the patient unsuitable for inclusion, or could interfere with the patient participating in or completing the Study
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the safety, including tolerability, of ISIS 681257 and to assess the efficacy of different doses and dosing regimens of ISIS 681257 for reduction of plasma Lp(a) levels in patients with hyperlipoproteinemia(a) and established CVD.;Secondary Objective: To evaluate the efficacy of ISIS 681257 on plasma levels of low density lipoprotein cholesterol (LDL-C), apolipoprotein B100 (apoB), oxidized phospholipids (OxPL) on apo(a) [OxPL-apo(a)], and OxPL on apoB (OxPL-apoB). To evaluate pharmacokinetics (PK) of ISIS 681257 across different doses and dose regimens in patients with hyperlipoproteinemia(a) and established CVD.;Primary end point(s): The primary endpoint is the percent change in plasma Lp(a) from baseline at the primary analysis time point for ISIS 681257 treatment groups compared to placebo.;Timepoint(s) of evaluation of this end point: The primary analysis time point is at Week 25 for patients who received every 4-week dosing (Cohorts A-C) and at Week 27 for patients who received every 2-week or weekly dosing (Cohorts D and E). | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): The secondary endpoints comprise the effect of ISIS 681257 as compared to placebo at the primary analysis time point on the following: - Percent change from baseline in LDL-C - Proportion of patients who achieve plasma Lp(a) = 50mg/dL (= 125 nmol/L) - Proportion of patients who achieve plasma Lp(a) = 30 mg/dL (= 75 nmol/L) - Percent change from baseline in apoB - Percent change from baseline in OxPL-apo(a) - Percent change from baseline in OxPL-apoB;Timepoint(s) of evaluation of this end point: See primary analysis time point (E.5.1.1) | — |
Countries
Canada, Denmark, Germany, Netherlands, United States
Contacts
Public ContactChief Development
Akcea Therapeutics- A Subsidiary of Ionis Pharmaceuticals, Inc.
Outcome results
None listed