A controlled study to assess the safety, tolerability, and activity of the study drug, ISIS 494372, given subcutaneously in patients with high Lipoprotein(a)

Phase 1

Conditions: High Lipoprotein(a)
MedDRA version: 18.0Level: PTClassification code 10054009Term: Lipoprotein (a) increasedSystem Organ Class: 10022891 - Investigations
Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

Registration Number: EUCTR2014-000701-13-GB

Lead Sponsor: Isis Pharmaceuticals, Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 64

Inclusion Criteria

• Males or females aged 18-75 inclusive

• Females non-pregnant and non-lactating, surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy) 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), abstinent, or if engaged in sexual relations of child-bearing potential, subject is 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 Study Drug

• Males must be surgically sterile, abstinent or if engaged in sexual relations with a female of child-bearing potential, the patient must be using an acceptable contraceptive method from the time of signing the informed consent form until at least 16 weeks after the last dose of Study Drug

• BMI =40 kg/m2

• Lipoprotein(a) =125 and < 438 nmol/L ( = 50 and < 175 mg/dL at time of screening (Cohort A)

• Lipoprotein(a) = 438 nmol/L (=175 mg/dL ) at time of screening (Cohort B)
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 30

Exclusion Criteria

• Clinically significant abnormalities in medical history (e.g., documented previous myocardial infarction, PCI, or major surgery within 3 months of screening, planned surgery that would occur during the study) or physical examination at screening

• Clinically significant abnormalities in screening laboratory values that would render a patient unsuitable for inclusion, including the following:
a. Urine protein/creatinine (P/C) ratio = 0.2 mg/mg. In the event of a P/C ratio above this threshold, eligibility may be confirmed by a quantitative total urine protein measurement of < 150 mg/24 hr
b. Positive test (including trace) for blood upon urinalysis. In the event of a positive test, eligibility may be confirmed with a urine microscopy showing <= 5 red blood cells (RBCs) per high power field
c. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1.5 x ULN
d. Bilirubin, > ULN. Patients with Gilbert’s syndrome (elevated indirect bilirubin with normal direct bilirubin and normal ALT and AST) may be eligible after discussion with the Medical Monitor
e. Alkaline phosphatase, serum creatinine or BUN > ULN
f. Platelet count < LLN

• Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1

• Known history or positive test for human immunodeficiency virus (HIV), hepatitis C, or chronic hepatitis B

• 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

• History of bleeding diathesis or coagulopathy

• Recent history of, or current drug or alcohol abuse

• Use of statins, ezetimibe niacin, fish oil or other products containing omega-3 fatty acids (including OTC preparations), or fibrates unless on a stable regimen for at least 8 weeks prior to dosing and will remain on a stable regimen for the duration of the study

• Use of testosterone, estrogens, progesterone or (progestins unless on a stable regimen for at least 8 weeks prior to Screening and will remain on a stable regimen through the end of the Post-Treatment Evaluation Period
• Patients who are currently receiving apheresis to reduce elevated levels of lipids

• Use of concomitant drugs (including herbal or OTC medications other than ibuprofen, paracetamol, topical aspirin-based analgesics, antihistamine, or topical steroids, = 1% hydrocortisone) unless authorized by the Sponsor Medical Monitor

• Blood donation of 50-499 mL within 30 days of screening or of >499 mL within 8 weeks of screening

• Have any other conditions, which, in the opinion of the Investigator would make the patient unsuitable for inclusion, or could interfere with the patient participating in or completing the study

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To characterize the safety and tolerability of ISIS 494372 in individual patients at escalating doses of 100, 200, and 300 mg/week<br><br>To characterize the efficacy of ISIS 494372 in lowering Lp(a) using a dose titration study design<br>;Secondary Objective: None;Primary end point(s): To characterize the safety and tolerability of ISIS 494372 in individual patients at doses of 100, 200, and 300 mg/week<br><br>To characterize the efficacy of ISIS 494372 in lowering Lp(a) using a dose titration study design;Timepoint(s) of evaluation of this end point: LPLV - Day 190

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): none;Timepoint(s) of evaluation of this end point: none

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