This study has been transitioned to CTIS with ID 2024-510696-38-00 check the CTIS register for the current data. Primary objective: To evaluate the efficacy of olezarsen as compared to placebo on the percent change in fasting triglycerides from…
ID
Source
Brief title
Condition
- Metabolic and nutritional disorders congenital
- Lipid metabolism disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is the percent change in fasting triglycerides (TG) from
Baseline at month 6 (average of Weeks 25 and 27) compared to placebo
Secondary outcome
Secondary endpoints include the following:
• Percent change in fasting TG from Baseline at Month 12 (average of Week 51
and Week 53) compared to placebo
• Proportion of patients who achieve fasting TG < 500 mg/dL (5.65 mmol/L) at
Month 6 and proportion of patients who achieve fasting TG < 500 mg/dL at Month
12 compared to placebo
• Proportion of patients who achieve fasting TG < 880 mg/dL (10 mmol/L) at
Month 6 and proportion of patients who achieve fasting TG < 880 mg/dL at Month
12 compared to placebo in the subgroup of patients with baseline TG >= 880 mg/dL
• Proportion of patients who achieve fasting TG < 1000 mg/dL (11.29 mmol/L) at
Month 6 and proportion of patients who achieve fasting TG < 1000 mg/dL at Month
12 compared to placebo in the subgroup of patients with baseline TG >= 1000 mg
• Percent change from Baseline at Month 6 and at Month 12 compared to placebo
in fasting:
o apoC-III
o VLDL-C
o Non-HDL-C
o HDL-C
• Adjudicated acute pancreatitis event rate during the Treatment Period
compared to placebo in patients with >= 2 events of adjudicated acute
pancreatitis in 5 years prior to enrollment. This endpoint will be evaluated in
the combined data from this study and ISIS 678354-CS6 (another Phase 3 study in
patients with severe hypertriglyceridemia) as the individual studies may not
have sufficient sample size to support meaningful conclusions.
• Adjudicated acute pancreatitis event rate from Week 13 to Week 53 compared to
placebo in patients with >= 2 events of adjudicated acute pancreatitis in 5
years prior to enrollment. This endpoint will be evaluated in the combined data
from this study and ISIS 678354-CS6 for the same reason as above
• Adjudicated acute pancreatitis event rate during the Treatment Period
compared to placebo. This endpoint will be evaluated in the combined data from
this study and ISIS 678354-CS6 for the same reason as above.
• Adjudicated acute pancreatitis event rate from Week 13 to Week 53 compared to
placebo. This endpoint will be evaluated in the combined data from this study
and ISIS 678354-CS6 for the same reason as above
Additional/Exploratory endpoints:
Change or percent change from Baseline compared to placebo in the following:
• Proportion of patients who achieve various % reductions in fasting TG from
Baseline at Month 6 and proportion of patients who achieve various % reductions
in fasting TG from Baseline at Month 12 compared to placebo
• Proportion of patients who achieve various thresholds in fasting TG at Month
6 and proportion of patients who achieve various thresholds in fasting TG at
Month 12 compared to placebo
• Proportion of patients who develop fasting TG > 2000 mg/dL (22.6 mmol/L) at
Month 6 and proportion of patients who develop fasting TG > 2000 mg/dL at Month
12 compared to placebo in the subgroup of patients with baseline TG <= 2000 mg/dL
• Percent change from Baseline at Month 6 and at Month 12 compared to placebo
in fasting remnant cholesterol, TC, LDL-C, apoB, apoB-48, apo E, and apoA-1
• Lipoprotein particle size/number (select sites*)
• Homeostatic Model Assessment of Insulin Resistance (HOMA--IR), Homeostatic
Model Assessment of Beta Cell Function (HOMA-B), hemoglobin A1c (HbA1c)
• Fibrosis-4 index (FIB-4 index)
• Inflammatory and exploratory biomarkers in blood related to cardiometabolic
diseases
• Patient-reported abdominal pain and other symptoms as measured by the FCS
Symptoms module of the FCS Symptoms and Impacts Scale and health-related
quality of life (HRQoL) as measured by the PROMIS 29+2 measure, the EQ-5D-5L,
the Patient Global Impression of Health and Patient Global Impression of Change
in Health measures
• Change in hepatic fat fraction (HFF) from Baseline to Month 12, as measured
by MRI, (select sites*)
*To be conducted at a limited number of selected sites
Safety endpoints:
• Event rates of independently adjudicated MACE and the composite of CV death,
non-fatal MI, non-fatal ischemic stroke, and arterial revascularization
(coronary and non-coronary), and the triple composite of CV death, non-fatal
MI, and non-fatal ischemic stroke
• Relationship of triglyceride polygenic risk score with triglyceride lowering
and pancreatitis event rate
• Incidence of all-cause ER visits, incidence of all-cause hospitalizations,
incidence of ER visits for abdominal pain or hospitalizations for abdominal
pain,
and total inpatient days compared to placebo
• PK: Plasma peak and trough exposure; half-life for subjects who will not
rollover to the OLE study.
• exposure/response relationship for apoliprotein C-III and triglyceride, and
factors affecting pharmacokinetics and -dynamics may be evaluated in this
study, or in the future, as part of the population PK/PD and covariate
analysis, if deemed appropriate, and results will be reported separately
Background summary
High levels of fats (triglycerides) in the blood (Severe Hypertriglyceridemia)
causes reduced blood flow in the microcirculation. This may affect many organ
systems including the central nervous system, the cardiovascular system, the
musculoskeletal system, and the gastrointestinal system. This may also affect a
person*s health-related quality of life. People often experience frequent and
severe abdominal pain (stomach area), lack of energy and strength, anxiety
about potential pain attacks and overall health, difficulty concentrating and
are at a higher risk of developing acute inflammation of the pancreas. The
pancreas is an organ in the stomach area that helps with digestion and
regulates blood sugar. Inflammation of the pancreas causes severe pain in the
stomach area, often requires long stays in the hospital, and may result in
pancreatic damage and critical illness. Standard therapeutic fat-lowering
agents such as statin, ezetimibe, fibrates, fish oils and niacin, may be
insufficient in reducing triglycerides in people with severe
hypertriglyceridemia.
Apolipoprotein C-III (apoC-III) is found in blood and increases the fat levels
in the blood. The study drug, olezarsen, reduces the amount of apoC-III in the
blood. This may help people lower the amount of fat in the blood. The study
drug could hopefully reduce some of the symptoms you may experience with high
fat levels (e.g. inflammation of the pancreas). Health authorities have not
approved the study drug for the treatment of severe hypertriglyceridemia and as
such can only be used for research. The study drug has previously been tested
in humans.
Study objective
This study has been transitioned to CTIS with ID 2024-510696-38-00 check the CTIS register for the current data.
Primary objective: To evaluate the efficacy of olezarsen as compared to placebo
on the percent change in fasting triglycerides from Baseline
Secondary objectives:
• Proportion of patients who achieve fasting triglycerides < 500 mg/dL (5.65
mmol/L)
• Proportion of patients who achieve fasting triglycerides < 880 mg/dL (10
mmol/L)
• Proportion of patients who achieve fasting TG < 1000 mg/dL (11.29 mmol/L)
• Percent change from Baseline in fasting apolipoprotein C-III, very-low
density lipoprotein cholesterol (VLDL-C), non-high-density lipoprotein
cholesterol (HDL-C), and high-density lipoprotein cholesterol (HDL-C)
• Adjudicated acute pancreatitis event rate in patients with >= 2 events of
adjudicated acute pancreatitis in 5 years prior to enrollment.
• Adjudicated acute pancreatitis event rate
Other/Exploratory Objectives:
• Proportion of patients with various % reduction in fasting TG from Baseline
• Proportion of patients achieving thresholds in reduction in fasting TG
• Proportion of patients who develop fasting TG > 2000 mg/dL (22.6 mmol/L)
• Percent change from Baseline in fasting remnant cholesterol, total
cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein
B (apoB), apolipoprotein 48 (apoB48), apolipoprotein E (apoE), and
apolipoprotein A-1 (apoA-1)
• Lipoprotein particle size/number (select sites*)
• Measures of glycemia
• Fibrosis-4 index (FIB-4 index)
• Inflammatory and exploratory biomarkers in blood, related to cardiometabolic
diseases
• Patient-reported abdominal pain, other symptoms and health-related quality of
life (HRQoL)
• Change in hepatic fat fraction (HFF) (select sites*)
• Major adverse cardiovascular events (MACE)
• Relationship of TG polygenic risk score with TG lowering and pancreatitis
event rate
• Incidence of all-cause ER visits, incidence of all-cause hospitalizations,
incidence of ER visits for abdominal pain or hospitalizations for
abdominal pain, and total inpatient days compared to placebo
• Pharmacokinetics (PK): exposure/response analysis using relevant exposure
parameters and biomarkers
* To be conducted at a limited number of selected sites
Study design
This is a multi-center, randomized, double-blind, placebo-controlled study.
Eligible patients will enter an approximately 4 to 8-weeks, but no more than 12
weeks, Screening Period that includes an at least 2-week Diet/Life-style
Stabilization/Run-in Period and an approximately 2-week Qualification Period.
Following qualification, approximately 540 eligible patients will be randomized
1:1 to Cohort A (50 mg) or Cohort B (80 mg) and each cohort further randomized
2:1 to receive olezarsen or placebo in a 53-week Treatment Period. Patients in
Cohort A will receive 50 mg of olezarsen once every 4 weeks (Q4W) or matching
volume of placebo (0.5 mL) during Weeks 1-49 of the Treatment Period. Patients
in Cohort B will receive 80 mg olezarsen once Q4W or matching volume of placebo
(0.8 mL) during Weeks 1-49 of the Treatment Period. The 80-mg dose (blinded
olezarsen or placebo) may be adjusted to 50 mg Q4W due to tolerability or
safety reasons at any point during the study following consultation with the
Sponsor Medical Monitor or designee. Randomization will be stratified by (1) TG
>= 880 mg/dL (10 mmol) vs. < 880 mg/dL and (2) prior history of pancreatitis
(within 10 years prior to Screening). Diet and life-style counseling should
commence at the start of the Screening Period and continue to be reinforced
throughout the trial. Following the Week 53 visit eligible patients may elect
to enroll in an OLE study, pending study approval by the Independent Ethics
Committee/Institutional Review Board (IEC/IRB) and the appropriate regulatory
authority. Patients not participating in the OLE will enter the 13-week
Post-Treatment Evaluation Period. All endpoints will be evaluated after the
last patient has completed the Week 53/ET Visit.
Intervention
Olezarsen (ISIS 678354, an antisense oligonucleotide inhibitor of
Apolipoprotein C-III production) or placebo will be administered as
subcutaneous (SC) injections. Doses of 50 and 80 mg olezarsen administered once
every 4 weeks were chosen based on the pre-clinical data and the
pharmacodynamic and safety analysis of the Phase 1 study in healthy volunteers
with hypertriglyceridemia and the Phase 2 study in patients with
hypertriglyceridemia and established cardiovascular disease (CVD) or at high
risk for CVD. Patients who will receive the placebo will be administered a
matching volume of placebo (0.5 or 0.8 ml).
Study burden and risks
Burden:
The study will take about 70-78 weeks and will include 21 visits.
Procedures: Subjects will undergo physical exams (body weight and height),
vital signs examination (blood pressure, body temperature, respiratory and
pulse rate), several blood draws, urine assessments, MRI and
electrocardiography. The medical and medication history will be reviewed. The
subject has to fill in questionnaires. Patients are asked to be on a stable
diet and should limit their alcohol consumption, for optimal control of
triglycerides; diet counseling will be provided for this. Furthermore, male
patients and women of childbearing potential must refrain from sperm/egg
donation and either be abstinent or practice effective contraception from the
time of signing the informed consent form until at least 17weeks after their
last dose of Study Drug. Before collecting fasting blood samples, the subject
must fast for at least 10 hours
The study drug (side effects) and procedure (e.g. skin irritation from ecg,
feeling faint due to fasting, bruise from collecting blood) are associated with
some risks.
Benefits: If the subject participates in this research, it does not mean that
the subject's disease will be cured or he/she will suffer less from his/her
disease. But if the subject takes part he/she will help the investigators to
get more insight into the treatment of Severe Hypertriglyceridemia.
Gazelle Court 2855
Carlsbad CA 92010
US
Gazelle Court 2855
Carlsbad CA 92010
US
Listed location countries
Age
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. Aged >= 18 years at the time of informed consent
3. Fasting Triglycerides (TG) >= 500 mg/dL (5.65 mmol/L) at both the Run-in
period and the Qualification Period as follows:
a. Fasting TG >= 500 mg/dL (5.65 mmol/L) at Screening run-in visit. If the
fasting TG is < 500 mg/dL and >= 350 mg/dL (3.95 mmol/L) up to 2 additional
tests may be performed with the average of the tests used to be considered
eligible
b. Fasting TG >= 500 mg/dL (5.65 mmol/L) at Screening Qualification visit.
If the fasting TG is < 500 mg/dL and >= 350 mg/dL (3.95 mmol/L) up to 2
additional tests may be performed with the average of the tests used for
qualification
4. Patients must be on lipid-lowering therapy that should adhere to standard of
care (SOC) per local guidelines. Lipid-lowering medications should be optimized
and stabilized for at least 4 weeks prior to Screening to minimize changes in
these medications during the study. Patients taking over-the-counter (OTC)
omega-3 fatty acids should make every effort to remain on the same brand
through the end of the study
5. Satisfy the following:
a. 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 follicle-stimulating
hormone (FSH) levels in the postmenopausal range for the laboratory involved)
c. abstinent* or
d. if engaged in sexual relations of childbearing potential, agree to use
a highly effective contraceptive method from the time of signing the informed
consent form until at least 17 weeks after the last dose of Study Drug
(olezarsen or placebo)
b. Males: Surgically sterile, abstinent* or if engaged in sexual relations
with a female of childbearing potential, patient is utilizing a highly
effective contraceptive method from the time of signing the informed consent
form until at least 17weeks after the last dose of Study Drug (olezarsen 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
6. Patients must be willing to comply with diet and lifestyle recommendations
as able.
Exclusion criteria
1. Diabetes mellitus with any of the following:
a. Newly diagnosed within 12 weeks prior to Screening or during the screening
period
b. HbA1c >= 9.5% at Screening
c. Change in basal insulin regimen > 20% within 3 months prior to Screening or
during the Screening period.
d. For patients with type 1 diabetes: episode of diabetic ketoacidosis, or >= 3
episodes of severe hypoglycemia within the 6 months prior to Screening or
during the Screening period.
2. Acute coronary syndrome or stroke/TIA within 6 months prior to Screening or
during the screening period. Major surgery, peripheral revascularization, or
non-urgent percutaneous coronary intervention within 3 months prior to, or
during Screening, or upcoming planned major surgery or major procedure (e.g.,
arterial revascularization) during the course of the study
3. Active pancreatitis within 4 weeks prior to Screening or during the
screening period.
4. Screening laboratory results as follows, or any other clinically significant
abnormalities in screening laboratory values that would render a patient
unsuitable for inclusion:
a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3.0 ×
ULN
b. Total bilirubin > 1.5 ULN unless due to Gilbert*s syndrome
c. Estimated GFR (eGFR) < 30 mL/min/1.73 m2 [as determined by the CKD EPI
formula for creatinine clearance; (Levey et al. 2009)]
d. Urine protein/creatinine ratio (UPCR) >= 500 mg/g (56.5 mg/mmol)
5. Uncontrolled arterial hypertension (BP > 180/ /100 mmHg) despite
antihypertensive therapy
6. Uncontrolled hypothyroidism such as those with thyroid-stimulating hormone
(TSH) > 1.5 × ULN and free thyroxine (T4) < LLN, clinical evidence of
hypothyroidism, or thyroid hormone therapy that has not been stable for >= 4
weeks prior to, or during Screening
7. Active infection requiring systemic antiviral or antimicrobial therapy that
will not be completed prior to Study Day 1 or active Covid-19 infection with or
without therapy that will not be resolved by Study Day 1
8. Active infection with human immunodeficiency virus (HIV), hepatitis C or
hepatitis B diagnosed by initial serological testing and confirmed with RNA
testing (HIV, Hepatitis C), or positive HBsAg (hepatitis B), respectively, or
treatment for hepatitis C within 6 months prior to Screening. Patients at
Screening who test positive by serology (for example, positive for Hepatitis C
antibody), but negative by RNA may be allowed in consultation with the Sponsor
Medical Monitor or designee
9. Malignancy diagnosed or treated within 5 years prior to Screening or during
the Screening period, except for non-melanoma skin cancers, cervical in situ
carcinoma, breast ductal carcinoma in situ, or stage 1 prostate carcinoma that
has been successfully treated. Patients 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 or
designee
10. A diagnosis of FCS (type 1 Hyperlipoproteinemia) by documentation of
confirmed homozygote, compound heterozygote or double heterozygote for
loss-of-function mutations in type 1-causing genes (such as LPL, GPIHBP1,
APOA5, APOC2, GPD1, or LMF1). Patients with suspected FCS and no prior such
diagnosis should be genetically tested prior to randomization (Patients should
be genetically tested if the score is >= 9).
11. Hypersensitivity to the active substance or to any of the excipients
(olezarsen or placebo)
12. Treatment with another investigational drug (non-oligonucleotide),
biological agent, or device within 1 month of Screening, or 5 half-lives of
investigational agent, whichever is longer
13. Previous treatment with an oligonucleotide (including small interfering
ribonucleic acid [siRNA]) within 4 months, or 5 half-lives, whichever is
longer, of Screening or during the Screening Period. This exclusion does not
apply to vaccines
14. Concomitant medication/procedure restrictions:
a. Systemic corticosteroids or anabolic steroids within 6 weeks prior to
Screening or during the study unless approved by the Sponsor Medical Monitor or
designee. This exclusion does not apply to local injections with no expected
systemic effect.
b. Use of bile acid resins such as colestipol, cholestyramine, or colesevelam
within 4 weeks prior to or during Screening or planned during the study
c. Plasma apheresis within 4 weeks prior to or during Screening or planned
during the study
d. Change or expected need for significant change in titration of medications
known to exacerbate hypertriglyceridemia such as non-selective beta blockers
(e.g.,propranolol, nadolol, timolol, penbutolol, sotalol, pindolol), thiazides,
isotretinoin, oral antidiabetic medications, tamoxifen, estrogens or progestins
within 4 weeks prior to Screening or throughout the duration of the trial.
e. Change or expected need for significant change in titration of therapies
known to significantly reduce triglycerides (such as GLP-1 agonists, other
incretin mimetics, phentermine/topiramate, naltrexone/bupropion, xenical, or
bariatric surgery) within 3 months prior to screening or throughout the
duration of the trial.
f. Change or expected need for significant change in atypical antipsychotic
medications (e.g., olanzapine and clozapine) within 3 months prior to Screening
or throughout the duration of the trial.
15. Blood or plasma donation of 50 to 499 mL within 30 days prior to Screening
or of > 499 mL within 60 days prior to Screening or planned during the study.
16. Unwillingness to comply with study procedures, including follow-up, as
specified by this protocol, or unwillingness to cooperate fully with the
Investigator
17. Have any other conditions, including current or recent (< 1 year) alcohol
abuse or other substance abuse, which, in the opinion of the Investigator would
make the patient unsuitable for inclusion, or could interfere with the patient
participating in or complete the study
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-510696-38-00 |
| EudraCT | EUCTR2021-002192-19-NL |
| ClinicalTrials.gov | NCT05079919 |
| CCMO | NL78070.000.22 |