Primary objectiveTo evaluate the efficacy of ISIS 678354 as compared to placebo on the percent change in fasting triglycerides (TG) from BaselineSecondary objectives• Proportion of patients who achieve >= 40% reduction in fasting TG from Baseline…
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 TG from Baseline at 6
months (average of Weeks 23, 25 and 27) compared to placebo
Secondary outcome
Secondary endpoints include the following:
• Percent change in fasting TG from Baseline at 12 months (average of Week 51
and Week 53) compared to placebo
• Proportion of patients who achieve >= 40% reduction in fasting TG from
baseline at 6 months compared to placebo
• Percent change in fasting apoB-48 from Baseline at 6 months compared to
placebo
• Proportion of patients who achieve fasting TG <= 750 mg/dL at 6 months
compared to placebo
• Proportion of patients who achieve fasting TG <= 500 mg/dL at 6 months
compared to placebo
• Adjudicated acute pancreatitis event rate during the Treatment Period (Week 1
through Week 53) compared to placebo, in patients with >= 2 events of
adjudicated acute pancreatitis in 5 years prior to enrollment
• Adjudicated acute pancreatitis event rate during the Treatment Period (Week 1
through Week 53) compared to placebo
• 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
• Adjudicated acute pancreatitis event rate from Week 13 to Week 53
compared to placebo
• Proportion of patients who achieve >= 70% reduction in fasting TG from
Baseline at 6 months compared to placebo
• Proportion of patients who achieve fasting TG <= 500 mg/dL at 6 months
compared to placebo
Additional/Exploratory Endpoints
Frequency and severity of patient-reported abdominal pain and other FCS-related
symptoms, diet, and impacts, HRQoL, and ER visits, incidence of all-cause
hospitalizations and total inpatient days, compared to placebo
Safety Endpoints
Safety and tolerability assessments include adverse events, clinical laboratory
tests, ECGs, use of concomitant medications, and independently adjudicated
events rates of Major Adverse Cardiovascular Events (MACE) for ISIS 678354 as
compared to placebo
Background summary
Familial Chylomicronemia Syndrome (FCS) is an inherited disease characterized
by severe hypertriglyceridemia and chylomicronemia. It is a rare autosomal
recessive disease that can be diagnosed either in childhood or adulthood. FCS
is characterized by frequent and severe abdominal pain, repetitive colicky
pain, repeated episodes of potentially fatal acute pancreatitis, and in
children, can result in a failure to thrive. Fasting plasma triglycerides (TG)
levels in FCS patients are typically 10-fold to 100-fold above normal (1,500 to
15,000 mg/dL), despite extreme dietary fat restriction (20 g or approximately
15-20% of daily calorie intake). The etiology of extreme hypertriglyceridemia
in FCS is considered to be ineffective TG clearance. ApoC-III is a major
regulator of lipoprotein metabolism and plays a pivotal role in regulating
plasma TG levels. The study drug, ISIS 678354, is designed to reduce the amount
of apoC-III in the blood. Reducing the amount of apoC-III in the blood may help
lower the amount of TG and chylomicrons. These results hopefully alleviate some
of the symptoms of FCS patients which are related to high TG levels.
Study objective
Primary objective
To evaluate the efficacy of ISIS 678354 as compared to placebo on the percent
change in fasting triglycerides (TG) from Baseline
Secondary objectives
• Proportion of patients who achieve >= 40% reduction in fasting TG from Baseline
• Percent change in fasting apoB-48 from Baseline
• Proportion of patients who achieve fasting TG <= 750 mg/dL (8.4 mmol/L)
• 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
• Proportion of patients who achieve >= 70% reduction in fasting TG from Baseline
• Proportion of patients who achieve fasting TG <= 500 mg/dL (5.7 mmol/L)
Additional / Exploratory Objectives
Patient reported abdominal pain, other FCS-related symptoms, diet, and impacts,
health-related quality of life (HRQoL), cognitive function, and emergency room
(ER) visits, incidence of all-cause hospitalizations and total inpatient days
Safety Objective
To evaluate the safety and tolerability of ISIS 678354
Study design
This is a multi-center, randomized, double-blind, placebo-controlled study.
Eligible patients will enter an approximately 4-week, but no more than 8-week,
Screening Period that includes an at least 2-week diet stabilization/run-in
period for patients not already on a stable diet, and an approximately 2-week
qualification period. Following qualification, approximately 60 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 ISIS 678354 or placebo in a 53
week Treatment Period. Patients in Cohort A will receive 50 mg of ISIS 678354
once every 4 weeks or matching volume of placebo (0.5 mL) Weeks 1-49, of the
Treatment Period. Patients in Cohort B will receive 80-mg ISIS 678354 once
every 4 weeks or matching volume of placebo (0.8 mL) Weeks 1-49 of the
Treatment Period. Randomization will be stratified by (1) prior history of
pancreatitis (within 10 years prior to Screening) and (2) previous treatment
with volanesorsen. Dietary counseling will commence at the start of the diet
stabilization period and will be reinforced at intervals throughout the
Treatment and Follow-up Period. Following the Week 53 visit, eligible patients
may elect to enroll in an open-label extension (OLE) study pending study
approval by the institutional review board/independent ethics committee
(IRB/IEC) and the appropriate regulatory authority. Patients not participating
in the OLE will enter the 13-week Post-Treatment Evaluation Period. The
primary endpoint for the study will be evaluated after the last patient has
completed the Week 53/ET Visit and will be based on the percent change in
fasting TG from Baseline at the primary analysis time point (Month 6).
Intervention
ISIS 678354 or placebo will be administered as subcutaneous (SC) injections.
Doses of 50 mg or 80 mg 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.
Study burden and risks
Burden: During the study, the patients will be asked to come to the hospital
for 22 visits.
Subjects will be treated with ISIS 678354 or placebo every 4 weeks during the
treatment period, they will receive the treatment via subcutaneous injection in
their abdomen, thigh, or upper arm 13 times in total. A physical examination
and heart tracing (ECG) will be done and weight, height, and vital signs will
be measured. Urine and blood tests will be done to check general health,
pregnancy, post-menopausal status, for genetic testing, and to test for HIV and
hepatitis B and C. Information about adverse events will be collected during
the study visits. On a daily basis, subjects will complete the FCS Symptoms and
Diet daily dairy to record FCS symptoms and changes in their diet. A
demographic questionnaire, health, and medication questionnaire, and quality of
life questionnaire will be conducted. The patient will be asked not to consume
alcohol and is encouraged to follow a low-fat diet of not more than 20 gram of
fat per day during the study.
Risk: Possible side effects of the study drug and study procedures.
Gazelle Court 2855
Carlsbad CA 92010
US
Gazelle Court 2855
Carlsbad CA 92010
US
Listed location countries
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. A diagnosis of Familial Chylomicronemia Syndrome (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)
4. Fasting TG >= 880 mg/dL (10 mmol/L) at Screening. If the fasting TG is < 880
mg/dL up to 2 additional tests may be performed with any single test used to
qualify
5. History of pancreatitis (defined as a recorded diagnosis of acute
pancreatitis or hospitalization or emergency room (ER) visit for severe
abdominal pain consistent with acute pancreatitis and for which no alternate
diagnosis was made) within 10 years prior to Screening. Patients without a
recorded history of pancreatitis, or no recorded history within 10 years prior
to Screening, are also eligible but their enrollment will be capped at 35%
(i.e., <= 21 of the 60 planned patients)
6. Willing to follow a diet comprising <= 20 g fat per day during the study
7. Willing to complete all Patient Reported Outcome assessments throughout the
study as described in Section 6.2.5
8. Satisfy the following:
a. Females: must be non-pregnant and non-lactating and either:
i. surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral
salpingectomy, bilateral oophorectomy)
ii. 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)
iii. abstinent* or
iv. if engaged in sexual relations of child-bearing 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 (ISIS
678354 or placebo)
b. Males: Surgically sterile, abstinent*, or if engaged in sexual relations
with a female of child-bearing potential, patient is utilizing 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 (ISIS 678354 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
9. Atypical antipsychotic medications (e.g., olanzapine and clozapine) will be
allowed if on a stable dose for at least 3 months prior to Screening and dose
and regimen expected to remain constant through the end of their participation
in this study
10. The following concomitant medications will be allowed if on a stable dose
for at least 4 weeks prior to Screening and dose and regimen expected to remain
constant through the end of their participation in this study (occasional or
intermittent use of over-the-counter (OTC) medications will be allowed at
Investigator*s discretion):
a. Statins, omega-3 fatty acids (prescription and OTC), fibrates, or other
lipid-lowering medications. Patients taking OTC omega-3 fatty acids should
make every effort to remain on the same brand through the end of the study
b. Antidiabetic medications
c. Antihypertensive medications
d. Oral anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, and apixaban)
and regular clinical monitoring is performed
e. Tamoxifen, estrogens or progestins
Exclusion criteria
1. Clinically significant abnormalities in medical history (e.g., previous
acute coronary syndrome within 6 months of Screening, major surgery within 3
months of Screening) or physical examination
2. Active pancreatitis within 4 weeks prior to Screening
3. Screening laboratory results as follows, or any other clinically significant
abnormalities in screening laboratory values that would render a patient
unsuitable for inclusion:
a. Platelet count < 100K/mm3 at Screening or Qualification. If the platelet
count is < 100K/mm3 up to 2 additional tests may be performed to qualify at
both Screening and Qualification
b. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3.0 ×
upper limit of normal (ULN)
c. Total bilirubin > ULN unless due to Gilbert*s syndrome
d. Estimated GFR< 45 mL/min/1.73 m2 [as determined by the CKD-EPI formula for
creatinine clearance; (Levey et al. 2009)]
e. Urine protein/creatinine ratio (UPCR) >= 500 mg/g or urine albumin/creatinine
ratio (UACR) >= 300 mg/g
4. Uncontrolled arterial hypertension (blood pressure [BP] > 160/100 mmHg)
5. History of bleeding diathesis or coagulopathy or clinically significant
abnormality in coagulation parameters at Screening
6. 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.
7. Active infection with human immunodeficiency virus (HIV), hepatitis C or
hepatitis B diagnosed by initial serological testing and confirmed with RNA
testing, or prior treatment for hepatitis C. Patients at Screening who test
positive by serology, but negative by RNA may be allowed in consultation with
the Sponsor Medical Monitor
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. 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
9. Blood donation of 50 to 499 mL within 30 days of Screening or of > 499 mL
within 60 days of Screening
10. 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
11. Previous treatment with an oligonucleotide (including small interfering
ribonucleic acid [siRNA]) within 4 months of Screening, or 5 half-lives,
whichever is longer. This exclusion does not apply to vaccines.
12. Concomitant medication/procedure restrictions:
a. Systemic corticosteroids or anabolic steroids within 6 weeks prior to
Screening and during the study unless approved by the Sponsor Medical Monitor
b. Plasma apheresis within 4 weeks prior to Screening or planned during the
study
13. Unwillingness to comply with study procedures, including follow-up, as
specified by this protocol, or unwillingness to cooperate fully with the
Investigator
14. 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
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 |
|---|---|
| EudraCT | EUCTR2020-002536-67-NL |
| ClinicalTrials.gov | NCT04568434 |
| CCMO | NL75086.000.20 |