This study has been transitioned to CTIS with ID 2024-518318-25-00 check the CTIS register for the current data. Primary: • To evaluate the efficacy of vutrisiran compared to placebo on reducing all-cause mortality and cardiovascular (CV)-related…
ID
Source
Brief title
Condition
- Cardiac disorders, signs and symptoms NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary outcome is a composite outcome of all-cause mortality and recurrent CV
events (CV hospitalizations and urgent HF visits) in both the overall
population and the vutrisiran monotherapy subgroup (defined as patients not on
tafamidis at study baseline).
Secondary outcome
The following secondary endpoints will be defined in both the overall
population and the vutrisiran monotherapy subgroup:
• Change from baseline in 6-minute walk test (6-MWT)
• Change from baseline in the Kansas City Cardiomyopathy Questionnaire Overall
Summary (KCCQ-OS)
• All-cause mortality
• Change from baseline in NYHA class
Background summary
(also see research protocol section 1.5)
ATTR amyloidosis is a rare, serious, life-threatening, multisystemic disease
encompassing hereditary ATTR (hATTR) amyloidosis and wild-type ATTR (wtATTR)
amyloidosis, which result from either hereditary (genetic mutation) or
nonhereditary (aging) causes, respectively.
TTR, also known as prealbumin, is a tetrameric protein produced by hepatocytes,
the choroid plexus, and retina.[Liz 2010] More than 95% of TTR in the
circulation is derived from the liver. The primary physiological role of TTR
is to serve as a carrier of retinol (also known as vitamin A), which involves
TTR binding to the retinol binding protein (RBP): vitamin A complex. However,
there is evidence to suggest that vitamin A transport and tissue uptake can
occur in the absence of circulating RBP.
Previously, the sponsor developed patisiran. Patisiran is a siRNA targeting
hepatic TTR mRNA developed by the Sponsor. Patisiran, which is formulated as a
lipid nanoparticle (LNP), is administered every 3 weeks (q3w) by intravenous
(IV) infusion, and requires use of premedications in order to prevent
infusion-related reactions. It is approved for use in patients with hATTR
amyloidosis with polyneuropathy in a number of regions, including Canada, the
EU, Japan, and the US. These approvals were based on the results of a large,
randomized, double-blind, placebo-controlled, Phase 3, Study ALN-TTR02-004
(APOLLO).[Adams 2018] This study demonstrated that patisiran treatment
significantly improved neuropathy, quality of life, and a range of disease
manifestations relative to placebo in hATTR amyloidosis patients with
polyneuropathy across a broad range of disease severity and TTR genotypes.
Presently, the sponsor is developing vutrisiran for SC administration for the
treatment of ATTR amyloidosis, inlcuding the treatment of patients with ATTR
amyloidosis with cardiomyopathy. Vutrisiran utilizes a mechanism similar to
patisiran in that RNAi is used to selectively target and degrade TTR mRNA, thus
preventing the synthesis of both wt and mutant TTR in the liver, the primary
source of circulating TTR.
Study objective
This study has been transitioned to CTIS with ID 2024-518318-25-00 check the CTIS register for the current data.
Primary: • To evaluate the efficacy of vutrisiran compared to placebo on
reducing all-cause mortality and cardiovascular (CV)-related hospitalizations
Secondary: To evaluate the efficacy of vutrisiran compared with placebo
treatment on:
• Functional capacity
• Patient-reported health status and health-related quality of life
• All-cause mortality
• Severity of clinical heart failure symptoms
Exploratory: To evaluate the efficacy of vutrisiran compared with placebo
treatment on:
• Severity of clinical heart failure symptoms
• Additional cardiac biomarkers and biomarker-based risk assessments
• Nutritional Status
• Assessments of quality of life
PD and PK:
• To characterize the PD effect of vutrisiran on transthyretin (TTR)
• To characterize plasma pharmacokinetics (PK) of vutrisiran
• To assess presence of antidrug antibodies (ADA) against vutrisiran
Safety:
• To evaluate the safety and tolerability of vutrisiran in patients with ATTR
amyloidosis with cardiomyopathy
Study design
This is a Phase 3, randomized (1:1), double-blind, placebo-controlled,
multicenter study to evaluate the efficacy and safety of vutrisiran in
approximately 600 patients with ATTR amyloidosis with cardiomyopathy.
Approximately 20% of the study population is anticipated to have hereditary
ATTR (hATTR) and 80% wild-type ATTR (wtATTR) amyloidosis with cardiomyopathy.
At baseline, patients are either:
• Tafamidis-naïve (see inclusion criterion #3 for definition); or
• Currently receiving tafamidis (Note: must be on-label use of commercial
tafamidis per an approved cardiomyopathy indication in the country of use).
This group will be capped at 30% of total enrollment in the study.
The study consists of 3 periods (Figure 1):
1. Screening Period: Up to 45 days during which patients will undergo screening
assessments to determine eligibility.
2. Double-Blind Period (DB Period):
• At the start of the DB Period, eligible patients will be randomized in a 1:1
ratio to receive 25 mg of vutrisiran or placebo administered as a subcutaneous
(SC) injection once every 3 months (q3M; every 12 weeks ±7 days) for up to 36
months. Study drug will be administered at the clinic during scheduled study
assessment visits.
* In addition to study drug, all patients will take the recommended daily
allowance of vitamin A during their DB Period and Follow-up Period (see below).
• An individual patient*s DB Period will end after they complete their Month 36
Visit, or 30 months after the last patient is randomized, whichever comes
first. As such, the length of each patient*s intended treatment during the DB
Period may vary from 30 to 36 months.
• The primary analysis will be conducted after the last patient has completed
the Month 30 Visit or otherwise discontinued.
3. Follow-Up Period after the last dose of vutrisiran on study:
• Following their last dose of vutrisiran in the DB Period, patients will
commence safety follow-up visits every 12 weeks for the durations outlined
below.
• Prior to unblinding, the duration of the Follow-up Period for a patient will
be 1 year from their last dose of study drug. For women of child-bearing
potential, the duration of the Follow-up Period will be 18 months from their
last dose of study drug. Patients will continue vitamin A supplementation
during their Follow-up Period.
• After unblinding, all patients who were on placebo, and patients who received
vutrisiran whose serum TTR level has returned to >=80% of baseline or who have
completed the Follow-up Period, whichever comes first, may discontinue further
follow-up and stop taking vitamin A; all patients will be followed for a
minimum of 3 months.
• For any patient who starts a TTR lowering treatment as part of clinical care,
and has completed a minimum of 3 months of safety follow-up, further follow-up
will be discontinued.
Intervention
Vutrisiran is a subcutaneously (SC) administered N-acetylgalactosamine
(GalNAc)-conjugated small interfering RNA (siRNA), which targets
liver-expressed messenger RNA (mRNA) for transthyretin (TTR).
Study drug (vutrisiran or placebo) will be administered using a pre-filled
syringe and a needle safety device. The outside of the pre-filled syringe
barrel will be masked in such a way as to hide the identity of the study drug
contained within.
Starting on Day 1, patients will receive 25 mg of vutrisiran or placebo
administered as a SC injection once every 3 months (q3M; every 12 weeks; ±7
days) for up to 36 months. Study drug will be administered under the
supervision of the Investigator or designee.
Reference Treatment, Dose, and Mode of Administration
The control drug for this study will be a placebo (sodium chloride 0.9% w/v for
SC administration), which will be administered at the same dosing interval and
volume as the study drug.
Duration of Treatment and Study Participation
The planned duration of treatment for each patient is up to 36 months
(approximately 3 years).
The estimated total time on study for each patient is up to approximately 4
years, including a Screening Period of up to 45 days, a DB Period of up to 36
months, and a Follow-up Period of up to 1 year (18 months for women of
child-bearing potential).
Study burden and risks
These adverse effects/discomforts/side effects are common (may affect up to 1
in 10 people):
• Injection site reactions
• Pain in joints (arthralgia)
• Shortness of breath (dyspnea)
• Blood draw: Drawing blood may be painful or cause some bruising. We will take
at each visit, 3 - 40.7 mL blood each time from the subject. This amount does
not cause any problems in adults. To compare: a blood donation involves 500 ml
of blood being taken each time.
• Echocardiogram (ECHO): the subject will have gel applied to the chest (this
could feel cold) to help sound waves sent to the heart from a probe passed over
the chest *echo* back to the probe. The sound waves create a picture of the
heart. the subject may be asked to move or hold his/her breath briefly to get
better pictures.
• Electrocardiogram (ECG): the subject will have small sticky pads placed on
different areas of the body. Wires connected to the pads will send information
on the electrical activity back to a machine for recording and measuring. Minor
skin irritation could develop from the adhesive used on the pads.
Injection Site Reactions
Vutrisiran will be given under your skin (subcutaneous) in your abdomen, arm,
or thigh, and you could develop a reaction at the site of the injection, known
as injection site reaction (ISR). It is possible that you could develop pain,
tenderness, redness, swelling, itching, formation of sores, skin color changes,
or other reactions around an injection site. These reactions usually resolve by
themselves. In the phase 1 study, mild and transient ISRs were seen in 4 out of
60 (7%) healthy volunteers given vutrisiran; in the phase 3 study, ISRs were
reported in 5 out of 122 (4.1%) patients given vutrisiran and in 5 out of 629
(0.8%) doses of vutrisiran administered.
During the study, the study staff will check the site of injection for any
reactions. If you have a reaction, a dermatologist (skin doctor) may examine
you. This examination may include taking photographs, collecting a skin sample
(biopsy) or other laboratory testing. The photographs will, whenever possible,
be taken in such a way as to prevent disclosure of your identity. The Sponsor
may want to have the biopsy sample evaluated by a pathologist who is
specialized in skin reactions. If you agree, the Sponsor may perform additional
testing on the biopsy tissue to increase the understanding of vutrisiran and
the reactions at the injection site.
Low Vitamin A
Treatment with vutrisiran lowers vitamin A levels in your blood. Decreases in
Vitamin A levels in the blood are not expected to have medical consequences
based on studies in animals and in people (healthy volunteers and patients) who
received similar siRNA drugs that lowered vitamin A. Your vitamin A levels will
be followed with blood tests during the study and, as a precautionary measure,
you will be asked to take a daily Vitamin A supplement during the study and for
up to 12-18 months after your final dose of study treatment. Tell your doctor
if you experience eye symptoms such as decrease in night vision, dry eyes, poor
vision, hazy or cloudy vision, which could be related to low vitamin A levels.
Reproductive Health
It is not known if the use of vutrisiran in pregnant women might harm an unborn
child. Data from animal studies are insufficient to determine the risk to the
unborn child. It is unknown if breastfeeding while taking vutrisiran may cause
harm to the child.
Vitamin A is needed for the normal development of an unborn child. Levels of
vitamin A that are too high or too low can harm the normal development of an
unborn child. The effects of reduction in a mother*s TTR protein and vitamin A
caused by vutrisiran and the effects of vitamin A supplementation on an unborn
child are unknown.
Are there any risks with using vutrisiran in combination with other drugs?
The side effects of using vutrisiran in combination with other drugs are not
known at this time, but vutrisiran may increase or decrease the level of other
drugs that the subject takes. It is very important to tell the study doctor or
his/her study staff about any drugs the subject is taking, discuss any dose
changes before they happen, any drugs the subject has taken in the past, and
any drugs the subject may start taking while in the study, including drugs
obtained without a prescription. Drugs that the subject takes that require
their levels to be followed may need to have their levels checked more
frequently.
Third Street 300
Cambridge 02142
US
Third Street 300
Cambridge 02142
US
Listed location countries
Age
Inclusion criteria
1. Age 18 (or age of legal consent per local regulations, whichever is
older) to 85 years, inclusive.
2. Documented diagnosis of ATTR amyloidosis with cardiomyopathy,
classified as either hATTR amyloidosis with cardiomyopathy or wtATTR
amyloidosis with cardiomyopathy
3. Medical history of HF with at least 1 prior hospitalization for HF (not
due to arrhythmia or a conduction system disturbance treated with a
permanent pacemaker) OR clinical evidence of HF (with or without
hospitalization) manifested by signs and symptoms of volume overload
or elevated intracardiac pressures (eg, elevated jugular venous
pressure, shortness of breath or signs of pulmonary congestion on x-ray
or auscultation, peripheral edema) that currently requires treatment
with a diuretic.
4. Patient meets one of the following criteria: a. Tafamidis-naïve and not
actively planning to commence treatment
with tafamidis during the first 12 months following randomization (per
exclusion criterion #7); or
b. On tafamidis (Note: must be on-label use of commercial tafamidis
per an approved cardiomyopathy indication and dose in the country of use)
5. Patient is clinically stable, with no CV-related hospitalizations within 6
weeks prior to randomization, as assessed by the Investigator.
6. Screening NT-proBNP >300 ng/L and <8500 ng/L; in patients with permanent or
persistent atrial fibrillation, screening NT-proBNP >600 ng/L and <8500ng/L.
7. Able to complete >=150 meters on the 6-MWT at Screening.
8. Have a Karnofsky performance status of >=60%.
Exclusion criteria
1. Has known primary amyloidosis (AL amyloidosis) or leptomeningeal amyloidosis.
2. NYHA Class IV heart failure; or NYHA Class III heart failure AND ATTR
Amyloidosis Disease Stage 3 (defined as NT-proBNP >3000 ng/L and
eGFR <45 ml/min)
3. Has a polyneuropathy disability (PND) Score IIIa, IIIb, or IV (requires
cane or stick to walk due to polyneuropathy, or is wheelchair bound) at
the Screening visit.
4. Has any of the following laboratory parameter assessments at
Screening:
a. AST or ALT levels >2.0 × ULN,
b. Total bilirubin >2.0 × ULN. Patients with elevated total bilirubin that
is secondary to documented Gilbert's syndrome are eligible if the total
bilirubin is <2 × ULN)
c. International normalized ratio (INR) >1.5 (unless patients were on
anticoagulant therapy in which case excluded if INR >3.5)
5. Has eGFR <30 mL/min/1.73 m2 (using the modification of diet in
renal disease [MDRD] formula) at Screening.
6. Has known human immunodeficiency virus infection; or evidence of
current or chronic hepatitis C virus or hepatitis B virus infection.
7. Tafamidis-naïve patients (per inclusion criteria #4a) for whom the
Investigator
actively plans or anticipates commencing treatment with tafamidis either during
the screening period or the first 12 months following randomization, taking into
consideration clinical status, patient preference and/or commercial
availability of tafamidis.
8. Received prior TTR-lowering treatment (including revusiran, patisiran
or inotersen) or participated in a gene therapy trial for hATTR
amyloidosis.
9. Is currently taking diflunisal; if previously on this agent, must have at
least a 30-day wash-out prior to dosing (Day 1).
10. Is currently taking doxycycline or tauroursodeoxycholic acid or
ursodeoxycholic acid; if
previously on any of these agents, must have completed a 30-day washout
prior to dosing (Day 1).
11. Unwilling to avoid any concurrent treatment with diflunisal,
ursodeoxycholic acid/tauroursodeoxycholate/doxycycline, or TTR lowering agents
(eg,
patisiran, inotersen)
12. Current or future participation in another investigational device or
drug study, scheduled to occur during this study, or has received an
investigational agent or device within 30 days (or 5 half-lives of the
investigational drug, whichever is longer) prior to dosing (Day 1). In the
case of investigational TTR stabilizer drugs, washout for 3 months prior
to dosing (Day 1) is required; this does not apply to patients who are on
tafamidis at baseline (per inclusion criterion #4).
13. Requires treatment with or is unwilling to avoid any concurrent
treatment with nondihydropyridine calcium channel blockers (eg,
verapamil, diltiazem).
14. Other non-TTR cardiomyopathy, hypertensive cardiomyopathy,
cardiomyopathy due to valvular heart disease, or cardiomyopathy due to
ischemic heart disease (eg, prior myocardial infarction with documented
history of cardiac enzymes and ECG changes) that the Investigator feels
is a significant contributor or the predominant cause of the patient's
heart failure.
15. Unstable congestive heart failure (CHF) (including patients who
require adjustment of existing diuretics or addition of new diuretics at
time of screening for purposes of achieving optimal management of
CHF).
16. Had acute coronary syndrome or unstable angina within the past 3
months.
17. Has history of sustained ventricular tachycardia or aborted
ventricular fibrillation.
18. Has history of atrioventricular nodal or sinoatrial nodal dysfunction
for which a pacemaker is indicated but will not be placed.
19. Has persistent elevation of systolic (>170 mmHg) or diastolic (>100
mmHg) blood pressure that is considered uncontrolled by physician.
20. Has untreated hypo- or hyperthyroidism.
21. Has an active infection requiring systemic antiviral, antiparasitic or
antimicrobial therapy that will not be completed prior to dosing (Day 1).
22. Prior or anticipated (during the first 12 months after randomization)
heart, liver or other organ transplant or implantation of left-ventricular
assist device.
23. History of multiple drug allergies; or history of allergic reaction to any
component of or excipient in the study drug.
24. History of intolerance to SC injection(s) or significant abdominal
scarring that could potentially hinder study drug administration or
evaluation of local tolerability.
25. Has other medical conditions or comorbidities which, in the opinion
of the Investigator, would interfere with study compliance or data
interpretation.
26. Is not willing to comply with the contraceptive requirements during
the study period.
27. Female patient is pregnant, planning a pregnancy, or breast-feeding.
28. Unwilling or unable to limit alcohol consumption throughout the
course of the study.
29. History of alcohol abuse, within the last 12 months before screening,
in the opinion of the Investigator.
30. History of illicit drug abuse within the past 5 years that in the
opinion of the Investigator would interfere with compliance with study
procedures or follow-up visits.
Design
Recruitment
Medical products/devices used
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 | CTIS2024-518318-25-00 |
| EudraCT | EUCTR2019-003153-28-NL |
| CCMO | NL71235.000.20 |