This study has been transitioned to CTIS with ID 2023-508365-33-00 check the CTIS register for the current data. To determine the efficacy of ALNTTRSC02 in patients with hATTR amyloidosis by evaluating the effect on neurologic impairment. To…
ID
Source
Brief title
Condition
- Heart failures
- Neurological disorders congenital
- Gastrointestinal signs and symptoms
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To determine the efficacy of ALNTTRSC02 in patients with hATTR amyloidosis by
evaluating the effect on neurologic impairment.
Secondary outcome
To determine the efficacy of ALN-TTRSC02 on quality of life, gait speed,
neurological impairment, nutritional status, and disability
To demonstrate the noninferiority of ALNTTRSC02 compared to patisiran with
respect to serum TTR-levels.
Background summary
Hereditary transthyretin amyloidosis (hATTR) is a rare genetic disease that
tends to run in some families. hATTR amyloidosis is caused by certain
variations in the gene for a protein called transthyretin, or TTR. The liver
is the main organ that produces TTR protein, and TTR then circulates in the
blood stream. Abnormal TTR protein can gradually deposit in many tissues and
organs of the body, in collections of proteins called amyloid fibrils. These
amyloid fibril collections can often affect the function of important organs
such as the nerves, the heart, and the gut. This leads to the symptoms of
amyloidosis, including weakness, numbness, shortness of breath,
lightheadedness, and diarrhea.
ALN-TTRSC02 is an investigational drug, which means it is not approved by the
Health Authority in the Netherlands, or Health Authorities of any other
country, for the treatment of hATTR amyloidosis at this time.
ALN-TTRSC02 consists of a small interfering ribonucleic acid (siRNA) molecule
attached to a sugar molecule which helps deliver the siRNA to the liver, where
the TTR protein is made. The siRNA in ALN-TTRSC02 works by interfering with the
ability of RNA (ribonucleic acid), a molecule that the cells use to produce
proteins, to make TTR proteins in the liver. ALN-TTRSC02 therefore reduces the
body*s TTR protein levels, which may in turn reduce the number of amyloid
fibrils in the organs of patients with hATTR amyloidosis.
Study objective
This study has been transitioned to CTIS with ID 2023-508365-33-00 check the CTIS register for the current data.
To determine the efficacy of ALNTTRSC02 in patients with hATTR amyloidosis by
evaluating the effect on neurologic impairment. To determine the efficacy of
ALN-TTRSC02 on quality of life, gait speed, neurologic impairment, nutritional
status, and disability. To demonstrate the noninferiority of ALNTTRSC02
compared to patisiran with respect to serum TTR-levels.
To determine the effect of ALN- TTRSC02 on:
* disability and nutritional status
* Manifestations of cardiac amyloid involvement
* Other assessment of neurologic impairment
* Other assessments of quality of life
* Disease stage
* Performance of daily activities
* To characterize the pharmacodynamic (PD) effect of ALN-TTRSC02 and patisiran
on serum TTR and vitamin A levels
* To characterize plasma pharmacokinetics (PK) of ALN-TTRSC02 and patisiran
* To assess presence of antidrug antibodies (ADA) to ALN-TTRSC02 and patisiran
To determine the safety and tolerability of ALN-TTRSC02 in patients with hATTR
amyloidosis
Study design
This is a global, Phase 3 randomized, open-label study designed to evaluate
efficacy, safety, and PK/PD of ALN-TTRSC02 in adult patients with hATTR
amyloidosis. Patients will be randomized 3:1 to ALN-TTRSC02 or patisiran, a
reference comparator. Randomization will be stratified by TTR genotype (V30M
vs. non-V30M) and baseline NIS score (<50 vs >=50).
The study will consist of a Screening Period of up to 42 days, an 18-month
Treatment Period, and an 42-month Randomized Treatment Extension Period (RTE)
as of Amendment 4, in lieu of the 18-month Treatment Extension Period
(hereafter referred to as the Legacy Treatment Extension Period). A Follow-up
Period of up to 1 year will occur after the last dose of study drug.
Intervention
Eligible patients will be randomized 3:1 on Day 1 to receive 25 mg of
ALN-TTRSC02 administered as a subcutaneous (SC) injection once every 3 months
or patisiran administered as an intravenous (IV) infusion once every 3 weeks.
After approximately 18 months of treatment, patients will stop receiving
patisiran and begin receiving ALN-TTRSC02 for the remainder of the study as
part of the Randomized Treatment Extension period (approximately another 42
months). Patients who are given patisiran will have to receive required
medications listed below prior to each dose of patisiran:
• Intravenous corticosteroid (dexamethasone 10 mg, or equivalent)
• Oral paracetamol (500 mg, or equivalent)
• Intravenous H1 blocker (diphenhydramine 50 mg, or equivalent)
• Intravenous H2 blocker (ranitidine 50 mg, or equivalent)
Study burden and risks
As ALN-TTRSC02 is designed to go to the liver, there is a potential for changes
in liver function. Alcohol intake of >2 drinks/day is not allowed during the
study
Treatment with ALN-TTRSC02 lowers vitamin A levels in your blood. As a
precautionary measure, you will be asked to take a daily Vitamin A supplement
during the study.
It is not known if the use of ALN-TTRSC02 in pregnant women might harm an
unborn child. Women of child-bearing age should not be pregnant when starting
treatment with ALN-TTRSC02 and must agree to use effective contraception during
their participation in this study.
The comparator, patisiran may also cause side effects. The most common ones are
infusion-related signs such as:
• Stomach pain
• Feeling sick (nausea)
• Body aches or pain, including pain in the back, neck, or joints
• Headache
• Feeling tired (fatigue)
• Chills
• Dizziness
• Cough, feeling short of breath, or other breathing problems
• Reddening of the face or body (flushing), skin warm, or rash
• Chest discomfort or chest pain
• Rapid heart rate
• Low or high blood pressure
• Pain, redness, burning sensation, or swelling at or near the infusion site
Other side effects of Patisiran or the pre-medication can occur. However, there
may be side-effects that are still unknown.
It is not yet known whether the long-term reduction of blood TTR protein levels
with ALN-TTRSC02 in patients with hATTR amyloidosis will favorably affect the
course of the disease. Therefore, it is not known whether you will benefit from
this treatment. Your participation may contribute to increased knowledge that
may help in the future development of a new therapy for patients with hATTR
amyloidosis.
In a phase 3 clinical study, patisiran was shown to improve neuropathy and
quality of life in patients with hATTR amyloidosis and polyneuropathy, and on
this basis has been approved for use as a treatment for patients with hATTR
amyloidosis and polyneuropathy in the United States and Europe.
Participation in the study also means:
- Additional time
- Additional tests
- Instructions you need to follow
Third Street 300
Cambridge 02142 MA
US
Third Street 300
Cambridge 02142 MA
US
Listed location countries
Age
Inclusion criteria
This study will include adults age 18 (or age of legal consent, whichever is
older) to 85 years of age, with a documented TTR mutation, and a confirmed
diagnosis of symptomatic hATTR amyloidosis with an NIS of 5 to 130 (inclusive),
a PND score of <=3b, and KPS >=60%.
Exclusion criteria
Patients are excluded from the study if any of the following criteria apply:
Disease-specific Conditions
1. Has had a liver transplant or is likely, in the opinion of the Investigator,
to undergo liver transplantation during the 18-month Treatment Period of the
study
2. Has known other (non-hATTR) forms of amyloidosis or clinical evidence of
leptomeningeal amyloidosis
3. Has a New York Heart Association heart failure classification >2
Laboratory Assessments
4. Has any of the following laboratory parameter assessments:
a. ALT and/or AST >1.5× upper limit of normal reference range (ULN)
b. Total bilirubin >ULN (>1.5 ULN in patients with Gilbert's Syndrome)
c. International normalized ratio (INR) >1.2 (patients on anticoagulant therapy
with an INR of <=3.5 will be allowed)
(Note: ALT, AST, and total bilirubin laboratory criteria must be met at both
Screening Visit 1 and Screening Visit 2)
5. Platelet count <50,000/µL
6. Absolute neutrophil count (ANC) <1500 cells/mm³
7. Estimated glomerular filtration rate (eGFR) <=30 mL/min/1.73m2 (using the
Modification of Diet in Renal Disease [MDRD] formula)
8. Has vitamin B12 levels below the lower limit of normal (LLN)
9. Has known human immunodeficiency virus (HIV) infection; or evidence of acute
or chronic hepatitis C virus (HCV) or hepatitis B virus (HBV) infection
Prior/Concomitant Therapy
10. 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)
11. Received prior TTR-lowering treatment or participated in a gene therapy
trial for hATTR amyloidosis
12. Is currently taking tafamidis, doxycycline, or tauroursodeoxycholic acid;
if previously on any of these agents, must have completed a 14-day wash-out
prior to dosing (Day 1)
13. Is currently taking diflunisal; if previously on this agent, must have at
least a 3-day wash-out prior to dosing (Day 1)
Medical Conditions
14. Has other known causes of sensorimotor or autonomic neuropathy (eg,
autoimmune disease, monoclonal gammopathy) that the treating physician believes
to be contributing to the neuropathy
15. Had acute coronary syndrome within the past 3 months
16. Has uncontrolled clinically significant cardiac arrhythmia or unstable
angina
17. Has known type 1 diabetes
18. Has had type 2 diabetes mellitus for >=5 years
19. Has untreated hypo- or hyperthyroidism
20. Has had a major surgery within the past 3 months or has a major surgery
planned during the study through Month 18
21. Has an active infection requiring systemic antiviral, antiparasitic or
antimicrobial therapy that will not be completed prior dosing (Day 1)
22. Had a malignancy within 2 years, except for basal or squamous cell
carcinoma of the skin or carcinoma in situ of the cervix that has been
successfully treated
23. Anticipated survival is less than 2 years, in the opinion of the
Investigator
24. History of multiple drug allergies; or history of allergic reaction to an
oligonucleotide or GalNAc; or had a prior severe reaction to a liposomal
product or any component of patisiran (ALN-TTR02)
25. Is unable to take the required premedications (see Section 5.2.2.2)
26. History of intolerance to subcutaneous (SC) injection(s) or significant
abdominal scarring that could potentially hinder study drug administration or
evaluation of local tolerability
27. Any condition (eg, medical concern), which in the opinion of the
Investigator, would make the patient unsuitable for dosing or which could
interfere with the study compliance, the patient*s safety and/or the patient*s
participation through the Month 18 visit of the study. This includes
significant active and poorly controlled (unstable) cardiovascular, neurologic,
gastrointestinal, endocrine, renal or psychiatric disorders unrelated to hATTR
identified by key laboratory abnormalities or medical history
Contraception, Pregnancy, and Breastfeeding
28. Is not willing to comply with the contraceptive requirements during the
study period, as described in Section 5.5.1.
29. Female patient is pregnant or breastfeeding
Alcohol Use
30. Unwilling or unable to limit alcohol consumption throughout the course of
the study. Alcohol intake of >2 units/day is excluded during the study (unit: 1
glass of wine [approximately 125 mL] = 1 measure of spirits [approximately 1
fluid ounce] = * pint of beer [approximately 284 mL])
31. History of alcohol abuse, within the last 12 months before screening, in
the opinion of the Investigator
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 | CTIS2023-508365-33-00 |
| EudraCT | EUCTR2018-002098-23-NL |
| CCMO | NL67887.000.19 |