Clinical Trials Register

Summary
EudraCT Number:	2016-003373-18
Sponsor's Protocol Code Number:	ISIS681257-CS6
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-02-17
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Denmark - DHMA

A.2

EudraCT number

2016-003373-18

A.3

Full title of the trial

A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging Phase 2 Study of ISIS 681257 Administered Subcutaneously to
Patients with Hyperlipoproteinemia(a) and Established Cardiovascular Disease (CVD)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A controlled study to evaluate the safety and the effectiveness of different doses and dosing regimens of ISIS 681257 for the reduction of plasma Lp(a) levels in patients with hyperlipoproteinemia(a) and established Cardio Vascular Disease.

A.3.2

Name or abbreviated title of the trial where available

Phase 2 Study of ISIS 681257 in Patients With Hyperlipoproteinemia(a) and Established Cardiovascular

A.4.1

Sponsor's protocol code number

ISIS681257-CS6

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Akcea Therapeutics, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Akcea Therapeutics, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Akcea Therapeutics- A Subsidiary of Ionis Pharmaceuticals, Inc.
B.5.2	Functional name of contact point	Chief Development
B.5.3	Address:
B.5.3.1	Street Address	55 Cambridge Parkway, Suite 100
B.5.3.2	Town/ city	Cambridge
B.5.3.3	Post code	MA 02142
B.5.3.4	Country	United States
B.5.4	Telephone number	+16712070282
B.5.6	E-mail	Lodea@akceatx.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	ISIS 681257
D.3.2	Product code	ISIS 681257
D.3.4	Pharmaceutical form	Injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ISIS 681257
D.3.9.1	CAS number	N/A
D.3.9.2	Current sponsor code	ISIS 681257
D.3.9.3	Other descriptive name	ISIS 681257
D.3.9.4	EV Substance Code	SUB185194
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	Yes
D.3.11.13.1	Other medicinal product type	2'-MOE antisense oligonucleotide

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Injection
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Hyperlipoproteinemia(a) and Established Cardiovascular Disease (CVD)

E.1.1.1

Medical condition in easily understood language

Hyperlipoproteinemia(a) and Established Cardiovascular Disease (CVD)

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10020668
E.1.2	Term	Hyperlipoproteinemia
E.1.2	System Organ Class	100000004861

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10007648
E.1.2	Term	Cardiovascular disease, unspecified
E.1.2	System Organ Class	100000004849

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

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.

E.2.2

Secondary objectives of the trial

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.

E.2.3

Trial contains a sub-study

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 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

E.4

Principal 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

E.5 End points

E.5.1

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.

E.5.1.1

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).

E.5.2

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) ≤ 50 mg/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

E.5.2.1

Timepoint(s) of evaluation of this end point

See primary analysis time point (E.5.1.1)

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

dose-ranging (5 cohorts)

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

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

Denmark

Germany

Netherlands

United States

E.8.7

Trial has a data monitoring committee

Yes

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

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

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:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

270

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2017-06-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-05-22

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-11-13

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