Primary objectives: To evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of ISIS 416858 (200, 250, and 300 mg once weekly) as compared to placebo.Exploratory Objectives: Incidence of myocardial infarction (MI), stroke, systemic…
ID
Source
Brief title
Condition
- Other condition
- Coagulopathies and bleeding diatheses (excl thrombocytopenic)
Synonym
Health condition
End-Stage Renal Disease
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety and Tolerability Evaluations
The safety and tolerability of ISIS 416858 will be assessed by determining the
incidence and severity of adverse events (including bleeding events) and
changes in laboratory evaluations.
The primary safety outcome is the combination of major bleeding (MB) and
clinically-relevant non-major bleeding (CRNMB) during the treatment period (or
early study termination).
Secondary outcome
Other safety parameters including (S)AEs, deaths, vital signs, ECG and
laboratory parameters will also be recorded. This may include additional
information regarding events of interest (i.e. bleeding events, thrombotic
events).
Pharmacokinetic Evaluations
Plasma pharmacokinetics will be assessed following the first and last dose in
the PK subgroup, whenever possible. Additionally, plasma trough and
post-treatment samples will be collected during treatment and post-treatment
evaluation period, respectively, for the measurement of ISIS 416858
concentrations.
Pharmacodynamic Evaluations
Coagulation parameters such as FXI activity and antigen, aPTT, PT and INR will
be monitored throughout the treatment and post-treatment evaluation period
visits.
The rate/frequency of clotting on the dialysis filters and circuit will be
measured as an exploratory analysis.
Background summary
ISIS 416858 is a 2*-methoxyethyl chimeric antisense inhibitor of the molecular
target Factor XI (FXI). FXI is a plasma glycoprotein that is synthesized
primarily in the liver. Preclinical studies suggest that FXI inhibitors can
prevent venous and arterial thrombosis without affecting hemostasis, and
congenital FXI-deficient patients have a low incidence of ischemic stroke and
venous thromboembolism (VTE) (Schumacher et al. 2010). Thus, selective
inhibition of FXI may represent a novel approach for the prevention of
undesired thrombotic events such as VTE and ischemic stroke as well as clotting
of hemodialysis circuits which limits the effectiveness of hemodialysis.
Study objective
Primary objectives: To evaluate the safety, pharmacokinetics (PK), and
pharmacodynamics (PD) of ISIS 416858 (200, 250, and 300 mg once weekly) as
compared to placebo.
Exploratory Objectives: Incidence of myocardial infarction (MI), stroke,
systemic embolism, and cardiovascular (CV) mortality.
Study design
This is a Phase 2, multi-center, stratified, randomized, double-blind,
placebo-controlled study of ISIS 416858 (IONIS-FXIRX an Antisense Inhibitor of
Factor XI) treatment for up to 26 weeks in ESRD patients receiving hemodialysis
at least 3 times a week.
Subjects included in this study will maintain all of their standard of care
dialysis treatments (including heparins) as determined by their treating
practitioners.
Subjects will be stratified based on the diagnosis of documented atrial
fibrillation at Screening, and then subjects will be randomized to 1 of 3 dose
cohorts in a 1:1:1 ratio (Cohort A, Cohort B, and Cohort C). Within each dose
cohort, subjects will be randomized in a 3:1 ratio to receive subcutaneous
treatment with either ISIS 416858 or placebo.
Cohorts A, B, and C
Patients in Cohort A will be randomized to receive once weekly either 200 mg
ISIS 416858 or placebo, subjects in Cohort B will be randomized to receive
either 250 mg ISIS 416858 or placebo, and Cohort C will be randomized to
receive either 300 mg ISIS 416858 or placebo.
The study will include a 4-week screening period and a 26-week treatment period
followed by a 12-week post-treatment evaluation period.
Upon completion of screening evaluations, including SC tolerability assessments
with 0.9% sterile saline injections, eligible subjects will receive Study Drug
(ISIS 416858 or placebo) once weekly for the 26-week treatment period. All
doses of Study Drug will be administered subcutaneously (SC) after completion
of the hemodialysis treatment and within 2 hours (preferably within 15
minutes).
Intervention
on the diagnosis of documented atrial fibrillation and then randomized to 1 of
3 dose cohorts in a 1:1:1 ratio (Cohort A, Cohort B, and Cohort C). Within each
dose cohort, subjects will be randomized in a 3:1 ratio to receive subcutaneous
treatment with either ISIS 416858 or placebo that is added to standard of care
hemodialysis therapies as prescribed by their providers, including heparin.
Cohort A: Approximately 68 dialysis subjects will be randomized 3:1 to either
200 mg ISIS 416858 or placebo
Cohort B: Approximately 68 dialysis subjects will be randomized 3:1 to either
250 mg ISIS 416858 or placebo
Cohort C: Approximately 68 dialysis subjects will be randomized 3:1 to either
300 mg ISIS 416858 or placebo
The SC Tolerability assessments using 0.9% sterile saline will be administered
as two 0.75 mL noncontiguous injections on Study Days S-14 (± 3) and S-7 (± 3).
For Cohort A, B and C, the Sponsor will provide ISIS 416858 (200 mg/mL, 1.0 mL)
and Placebo (1.0 mL). All doses are given by SC injection.
ISIS 416858 or placebo will be administered SC post-dialysis session within 2
hours (preferably within 15 minutes) once each week for a total of 26
consecutive weeks of treatment in all cohorts.
The injection volume will be 1.0 mL for Cohort A (200 mg), 1.25 mL for Cohort B
(250 mg) and 1.5 mL for Cohort C (300 mg). Cohorts B and C will be administered
Study Drug (ISIS 416858 or placebo) as two noncontiguous SC injections.
Study burden and risks
ISIS 416858 has been evaluated in 4 clinical studies: (1) A study in 66 healthy
volunteers in which treatment was given up to 6 weeks (ISIS 416858-CS1 study);
(2) A combination study in healthy volunteers with another blood thinner drug
that is made from heparin called enoxaparin (a blood thinner also known as
Lovenox) in 14 healthy volunteers for up to 5 weeks (ISIS 416858-CS2 study);
(3) A study in which treatment was administered for up to 6 weeks in 232
subjects that had total knee replacement surgery (ISIS 416858-CS3 study); (4) a
study in which 36 subjects with end-stage renal disease on hemodialysis were
administered treatment for up to 12 weeks (ISIS 416858-CS4 study).
ISIS 416858 at doses from 50 mg to 300 mg was well tolerated in the healthy
volunteers and did not cause any bleeding events. For subjects in the ISIS
416858-CS3 study, treatment with the 300 mg dose of the study drug
significantly reduced blood clotting without any increase in bleeding events
after the major surgery on the knee as compared to standard treatment with
enoxaparin. In subjects with end-stage renal disease on hemodialysis in the
ISIS 416858-CS4 study, treatment with 200 and 300 mg doses of the study drug
was generally safe and well-tolerated and the results suggested a reduction in
severe dialysis circuit clotting. To date, only one serious side effect
(allergic reaction) has been reported as related to ISIS 416858, and the person
quickly and completely recovered within 2 days and required no further
treatment.
Oligonucleotide compounds, the same type of compounds as ISIS 416858 are known
to reach their highest concentrations in the liver and kidney. Therefore, your
liver function will be monitored thoroughly throughout the study. Based on the
results of the previous clinical trials in over 336 subjects, ISIS 416858 at
the multiple dose range of 50-300 mg did not affect liver and kidney function.
Thus, it is expected that ISIS 416858 at dose levels used in this study will
not affect your liver and kidney function.
The most common side effects in the previous studies were mild adverse events
at the subcutaneous injection site. Typically, this includes mild redness that
may be accompanied by pain, bruising, discoloration, itching, and/or swelling
at the injection site. These events at the injection site are typically mild
and normally disappear spontaneously within a week on their own. In general,
the reactions do not appear to worsen with repeated dosing or result in any
generalized effects in the body.
The potential for bleeding to happen due to this blood thinner that decreases
factor XI levels is a risk. However, in subjects with congenital (existing at
or before birth) factor XI deficiency, no spontaneous bleeding has been
reported. Bleeding symptoms in surgical settings have been investigated in
subjects with congenital factor XI deficiency. Mild bleeding typically can
occur after surgery or injuries to areas such as the mouth, nose and
genitourinary (genital and urinary) system. Additionally, there is a risk that
ISIS 416858 treatment may not prevent the formation of blood clots in the
dialysis circuit that may occur during hemodialysis. However, in this study,
you will be checked for potential clots by the study staff so that if needed,
you can be treated immediately. You will also be continued on your regular
medications that are prescribed by your dialysis providers, such as heparin
during hemodialysis so that blood clots do not occur.
Decreasing factor XI levels with ISIS 416858 has not been associated with
increased bleeding risk in any of the studies completed to date. For example,
no bleeding without a known cause (spontaneous) has been observed in the
previous clinical studies even in subjects in whom factor XI levels were
reduced by more than 80% to almost undetectable levels for several weeks.
Subjects receiving hemodialysis can be at a high risk of blood clotting as well
as bleeding events. You will be observed carefully for all possible side
effects.
In previously conducted animal studies, ISIS 416858 was given at similar or
higher doses to what you will receive. The only serious side effect observed in
these animal studies was a low occurrence of severe platelet decrease (reduced
amount of blood cells that help blood clot) for which ISIS 416858 treatment had
to be stopped or treatment with corticosteroids (a treatment that increases
platelet levels) had to be initiated. Due to low platelet counts 2 out of the
16 animals in the highest dose group did not continue the study and were put to
sleep. These platelet reductions were not associated with any major bleeding.
Minor bleeding events have reported in subjects treated with ISIS 416858 and
with placebo. Most of the minor bleeding events involved bleeding at the
indwelling catheter site, the administration and blood sampling site or on the
skin, and most subjects did not have symptoms and did not require treatment.
The minor bleeding events were not associated with a reduction in FXI levels.
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. Males or females aged 18 to 85 years old at the time of informed consent.
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); or,
iii. if engaged in sexual relations and of child-bearing potential, agree to use 2 highly effective contraceptive methods from the time of signing the informed consent form until at least 84 days (approximately 5 half-lives of ISIS 416858) after the last dose of Study Drug (ISIS 416858 or placebo).
b Males: Surgically sterile or if engaged in sexual relations with a female of child-bearing potential, subject is utilizing an acceptable contraceptive method from the time of signing the informed consent form until at least 84 days (approximately 5 half-lives of ISIS 416858) after the last dose of Study Drug (ISIS 416858 or placebo).
3. End stage renal disease maintained on outpatient hemodialysis at a healthcare center for > 3 months from screening with hemodialysis at least 3-times per week for a minimum of 9 hours per week of prescribed treatment time and plan to continue this throughout the study.
Exclusion criteria
1. Subjects with a history of a major medical event (e.g., previous acute coronary syndrome, stroke or transient ischemic attack, or systemic thromboembolic event) within 3 months of screening, major surgery within 3 months of screening, or new major physical examination finding (not accounted for by past medical history), except for documented atrial fibrillation.
2. Active bleeding (as judged clinically significant by the Investigator) within the past 3 months from screening or documented bleeding diathesis (excluding uremia), coagulopathy, or recent history of prolonged compression time at arteriovenous fistula.
3. Screening laboratory results as follows:
* Platelet count < 150,000 cells/mm3
* < 180,000 cells/mm3 for platelet function/activation subgroup
* INR > 1.4
* aPTT > upper limit of normal (ULN)
* FXI activity < 0,3 U/ml
* ALT or AST > 2 x ULN
* Total bilirubin > ULN
4. Subject is not willing to have weekly subcutaneous injections over the study period as assessed during screening.
5. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1 (first dose) or IV antibiotic use at the time of Screening.
6. Unwillingness to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator.
7. Known history of or positive test at Screening for human immunodeficiency virus (HIV), hepatitis C or chronic hepatitis B.
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. Subjects 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).
9. Treatment with another investigational drug, biological agent, or device within 1 month of screening, or 5 half-lives of investigational agent, whichever is longer.
10. Any history of previous treatment with an oligonucleotide (including siRNA). Subjects that have previously received only a single-dose of an ISIS-oligonucleotide as part of a clinical study may be included as long as a duration * 4 months has elapsed since dosing.
11. Attending nephrologist answers "no" to the question, "Would you be surprised if this patient died in the next year?"
12. Within 6 months prior to screening, have any of the following:
* More than 3 episodes of severe hypoglycemia requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions
* One (1) event of hypoglycemia in which the patient required hospitalization
* Recurrent syncope and recurrent hypotension in the inter-dialytic period requiring intervention
13. Planned major surgery in the next 6 months, including subjects receiving a kidney transplant or subjects that anticipate changing dialysis modality (i.e. hemodialysis to peritoneal dialysis).
14. Recent history of, or current drug or alcohol abuse as determined by the Investigator.
15. Concomitant use of anticoagulant/antiplatelet agents (e.g., warfarin, dabigatran, rivaroxaban, clopidogrel) that may affect coagulation (except low dose aspirin (* 100 mg/day)) during Treatment and Post-treatment Evaluation Periods is not allowed. Stable doses of heparins during dialysis are permitted.
16. Uncontrolled hypertension as judged by the Investigator. For example, subjects with a pre- or post-dialysis blood pressure (BP) that is > 180 mmHg on at least 3 of the last 5 dialysis treatments.
17. Have any other conditions, which, in the opinion of the Investigator or Sponsor would make the subject unsuitable for inclusion, or could interfere with the subject 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 | EUCTR2017-002165-21-NL |
| CCMO | NL62709.000.17 |