Primary objective:To evaluate the efficacy of ION-682884, based on the change from Baseline in serum Transthyretin (TTR) concentration, modified Neuropathy Impairment Score +7 (mNIS+7), and Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (…
ID
Source
Brief title
Condition
- Peripheral neuropathies
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Week 35 Interim Analysis: Change from Baseline in serum TTR concentration and
the mNIS+7;
Week 66 Final Analysis: Change from Baseline in serum TTR concentration,
mNIS+7 and Norfolk QOL-DN
Secondary outcome
Secondary endpoints:
Week 35 Interim Analysis:
* Change from Baseline in Norfolk QOL-DN
Week 66 Final Analysis:
* Change from Baseline in the NSC score at Weeks 35 and 66
* Change from Baseline in the PCS score of SF-36 at Week 65
* Change from Baseline in PND score at Week 65
* Change from Baseline in mBMI at Week 65
Additional/Exploratory endpoints:
Change from Baseline in mNIS+7 at Week 85
Change from Baseline in Norfolk QOL-DN at Week 85
Change from Baseline in 10MWT at Weeks 37 and 81
Change from Baseline in R-ODS at Weeks 37 and 81
Change from Baseline in COMPASS-31 at Weeks 37 and 81
Change from Baseline in EQ-5D-5L at Weeks 37 and 81
Change from Baseline in the SF-36 at Week 35
Frequency of all cause hospitalizations in all patients by Week 66
Frequency of all cause hospitalizations in patients with cardiac involvement by
Week 66
Change from Baseline in ECHO parameters, including LV mass, LV wall thickness,
IVS thickness, and GLS, at Week 65 in patients with cardiac involvement
Change from Baseline in NT-proBNP at Week 65 in patients with cardiac
involvement
Change from Baseline in PGIS at Weeks 37 and 85
PGIC at Weeks 37 and 85
Plasma trough and post-treatment concentrations of ION-682884 or inotersen in
all patients, area under the curve (AUC), Cmax, and tmax in a subset of
patients, and t**z for patients who do not roll over to the OLE study.
Safety endpoints:
Change from Baseline in platelet count per Common Terminology Criteria for
Adverse Events (CTCAE) grade.
Change from Baseline in renal function.
Additional safety endpoints include: adverse events, vital signs and weight,
physical examination, clinical laboratory tests, ECG, use of concomitant
medication, ophthalmology examination, thyroid panel, inflammatory panel,
coagulation, and immunogenicity
Background summary
See section 2 of the enclosed protocol
Study objective
Primary objective:
To evaluate the efficacy of ION-682884, based on the change from Baseline in
serum Transthyretin (TTR) concentration, modified Neuropathy Impairment Score
+7 (mNIS+7), and Norfolk Quality of Life Questionnaire-Diabetic Neuropathy
(Norfolk QOL-DN) as compared to the historical control of placebo arm in the
ISIS 420915-CS2 NEURO-TTR (inotersen) trial
Secondary objectives:
To evaluate the efficacy of ION-682884, as compared to the placebo cohort in
the NEURO-TTR trial, based on the change from Baseline in:
* Neuropathy Symptom and Change (NCS) score
* Physical Component Summary (PCS) score of 36-Item Short Form Survey (SF-36)
* Polyneuropathy disability (PND) score
* Modified body mass index (mBMI)
Additional/Exploratory objectives:
To evaluate the efficacy of ION-682884 in mNIS+7 at Week 85, compared to
Baseline.
To evaluate the efficacy of ION-682884 in the Change from Baseline in the
Patient Global Impression of Severity (PGIS) and Patient Global Impression of
Change (PGIC) at Weeks 37 and 85.
To evaluate the efficacy of ION-682884, as compared to the historical control
of the placebo arm in the ALN-TTR02-004 trial (APOLLO trial, ClinicalTrials.gov
Identifier: NCT01960348) in:
* Change from Baseline in Norfolk QOL-DN at Week 85
* Change from Baseline in 10-Meter Walk Test (10MWT)
* Change from Baseline in Rasch-built Overall Disability Score (R ODS)
* Change from Baseline in Composite Autonomic Symptom Score-31 (COMPASS-31)
* Change from Baseline in 5 Level EQ-5D (EQ-5D-5L)
To evaluate the efficacy of ION-682884, as compared to the placebo cohort in
the NEURO-TTR trial, in:
* Change from Baseline in the SF-36
* Frequency of all-cause hospitalizations (in all patients and in patients with
cardiac involvement)
* Change from Baseline in transthoracic echocardiogram (ECHO) parameters
including left ventricular (LV) mass, LV wall thickness, intraventricular
septum (IVS) thickness, global longitudinal strain (GLS), in patients with
cardiac involvement
* Change from Baseline in N-terminal pro b-type natriuretic peptide (NT-proBNP)
in patients with cardiac involvement
To evaluate the plasma trough and post-treatment concentrations of ION 682884
or inotersen in all patients, and to evaluate plasma pharmacokinetic (PK)
parameters in a subset of patients.
Safety objectives:
To evaluate safety and tolerability of ION-682884 in hATTR-PN patients, in the
following measures: change from Baseline in platelet count and renal function,
adverse events, vital signs and weight, physical examination findings, clinical
laboratory tests, electrocardiogram (ECG) parameters, use of concomitant
medication, ophthalmology examination, thyroid panel tests, inflammatory panel
tests, coagulation tests, and immunogenicity tests.
Study design
This is a multicenter, open-label study with historical controls and an active
reference arm (inotersen). Approximately 140 patients will be randomized 6:1
to receive subcutaneous (SC) injections of either ION-682884 (n = 120) once
every 4 weeks or inotersen (n = 20) once a week. Patients will also take daily
supplemental doses of the recommended daily allowance of vitamin A.
An interim analysis will be conducted at Week 35. Primary endpoint (PEP)
analysis will be performed at Week 66.
Patients included in the inotersen reference arm will be crossed over to
ION-682884 at Week 37 after completing the Week 35 assessments.
All patients will continue dosing with ION-682884 until Week 81 with end
of-treatment (EOT) assessments at Week 85, 4 weeks after the last dose.
At Week 35, an interim analysis will be performed in hierarchical order for the
following 3 efficacy endpoints: 1) serum TTR reduction; 2) mNIS+7; 3) Norfolk
QOL-DN.
At Week 66, co-primary endpoints will be: 1) serum TTR reduction; 2) mNIS+7;
3) Norfolk QOL-DN.
Following treatment and the EOT assessments, 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 authorities. All participating patients in the OLE study
will continue to receive ION-682884 once every 4 weeks. Patients not
participating in the OLE will enter the 20-week post treatment evaluation
portion of this study after completing the EOT assessments.
A Data and Safety Monitoring Board (DSMB) will be established to review safety,
tolerability and efficacy data (as needed) collected during this study, both
individual events and aggregate data.
Intervention
Please refer to section E6 of the protocol.
Study burden and risks
Inotersen was administered to over 100 patients with polyneuropathy in a
medical-scientific trial comparing to placebo. The most common side effects
(may affect more than 20% of people) of inotersen treatment were:
* Injection site reactions (may include pain, redness, swelling, itching, rash,
bruising, and change in color at the injection site)
* Nausea and/or vomiting
* Headache
* Tiredness
* Low amount of platelet in the blood
* Diarrhea and/or constipation
* Feeling faint or dizzy, especially on standing up (low blood pressure,
hypotension)
* Fever
Serious side effects of inotersen and how this may relate to ION-682884
Severely reduced platelet count (<3% patients taking inotersen)
Low platelet count is a common side effect of inotersen (occurring in <3% of
patients in the study).
ION-682884 is very similar drug to inotersen although at much lower dose,
reduction of platelets is therefore considered a potential risk for ION-682884.
Kidney inflammation (glomerulonephritis) (<3% in patients taking inotersen)
Both kidney inflammation and a decrease in kidney function have been observed
in patients taking inotersen in a medical-scientific trial. In one of these
patients, the kidney inflammation led to the need for dialysis.
ION-682884 and inotersen are similar to each other and are known to accumulate
in the kidney. Side effects of the kidney have not been observed in the ongoing
healthy volunteer study with ION-682884. ION-682884 has not yet been tested in
polyneuropathy patients. Thus, kidney side effects are considered as a
potential risk for ION-682884.
Full list of risks can be found in the enclosed informed consent form
Patient's participation in this study may involve known or unknown risks for
pregnant women, unborn children, or breastfed babies. This is why pregnant or
breastfeeding women may not participate in this study and every effort to avoid
pregnancy is important during the participation in this study
Because the study drug may be transferred in seminal fluid, every effort to
avoid pregnancy is important for partners of male patients. In addition, males
must either be abstinent which means they will not have sexual relations with a
woman who is already pregnant or able to get pregnant or use a highly effective
contraceptive method during the study and for at least 24 weeks after taking
the last dose of study drug. Male patients whose female partner becomes
pregnant or is pregnant must use a condom to protect the fetus.
Gazelle Court 2855
Carlsbad CA92010
US
Gazelle Court 2855
Carlsbad CA92010
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 to 82 years at the time of informed consent
3. 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
highly effective contraceptive methods (refer to Section 6.3.1) from the time
of signing the informed consent form until at least 24 weeks after the last
dose of ION*682884 or inotersen and agree to receive a monthly pregnancy test
b. Males: Surgically sterile (i.e., bilateral orchidectomy) or, if engaged in
sexual relations with a woman of child bearing potential (WOCBP), the patient
or the patient*s non-pregnant female partner must use a highly effective
contraceptive method (refer to Section 6.3.1) from the time of signing the
informed consent form until at least 24 weeks after the last dose of ION*682884
or inotersen.
* Abstinence (i.e., refraining from heterosexual intercourse throughout the
duration of study participation) 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.
4. hATTR-PN as defined by meeting all 3 of the following criteria:
a. Stage 1 (ambulatory without assistance) or Stage 2 (ambulatory with
assistance) according to the Familial Amyloid Polyneuropathy (FAP) or Coutinho
Stage
b. Documented genetic mutation in the TTR gene
c. Symptoms and signs consistent with neuropathy associated with transthyretin
amyloidosis, including NIS * 10 and * 130
5. Willingness to adhere to vitamin A supplementation per protocol
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. Screening laboratory results as follows, or any other clinically significant
abnormalities in screening laboratory values that would render a patient
unsuitable for inclusion:
a. Urine protein/creatinine ratio (UPCR) * 1000 mg/g. In the event of UPCR
above this threshold, eligibility may be confirmed by a repeat random urine
test with UPCR < 1000 mg/g or a quantitative total urine protein measurement of
< 1000 mg/24 hr
b. Renal insufficiency as defined by estimated glomerular filtration rate
(eGFRcreat-cys) < 45 mL/min/1.73 m2 at Screening (eGFRcreat-cys is calculated
using the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]
creatinine-cystatin C equation from 2012) (Inker et al. 2012)
c. Positive test (including trace) for blood on urinalysis. In the event of a
positive test, eligibility may be confirmed with urine microscopy showing * 5
red blood cells per high power field
d. Alanine aminotransferase/ aspartate aminotransferase (ALT/AST) > 2 × upper
limit of normal (ULN)
e. Bilirubin * 1.5 × ULN (patients with bilirubin * 1.5 × ULN may be allowed on
study if indirect bilirubin only is elevated, ALT/AST is not greater than the
ULN and genetic testing confirming Gilbert*s disease)
f. Platelets < 125 × 109/L
g. HbA1C * 7%
h. Abnormal thyroid function tests with clinical significance per Investigator
judgement in consultation with the Sponsor Medical Monitor
i. Serum vitamin A (or retinol) level at Screening < lower limit of normal
(LLN). For patients with a TTR mutation at position 84 (e.g., Ile84Ser or
Ile84Asn) and vitamin A < LLN the exclusion criterion is signs or symptoms of
vitamin A deficiency (such as dry eye, Bitots* spot observed in the
ophthalmology exam, that in the opinion of the ophthalmologist is consistent
with vitamin A deficiency)
1. Active infection requiring systemic antiviral or antimicrobial therapy that
will not be completed prior to Study Day 1
2. Unwillingness to comply with study procedures, including follow up, as
specified by this protocol, or unwillingness to cooperate fully with the
Investigator
3. Known history of or positive test for human immunodeficiency virus (HIV),
hepatitis C (patients confirmed as cured from previous hepatitis C can be
included) or chronic hepatitis B
4. Uncontrolled hypertension (BP > 160/100 mm Hg)
5. 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
6. Current treatment with any approved drug for hereditary TTR amyloidosis such
as Vyndaqel® / Vyndamax* (tafamidis), Tegsedi* (inotersen), Onpattro*
(patisiran), off-label use of diflunisal, doxycycline or tauroursodeoxycholic
acid (TUDCA). If previously treated with Vyndaqel® / Vyndamax*, diflunisal or
doxycycline, and TUDCA, must have discontinued treatment at least 2 weeks prior
to Study Day 1
7. Previous treatment with Tegsedi* (inotersen) or Onpattro* (patisiran) or
other oligonucleotide or RNA therapeutic (including siRNA)
8. Treatment with another investigational drug, biological agent, or device
within 3 months of screening, or 5 half-lives of study agent, whichever is
longer
9. History of bleeding, diathesis or coagulopathy
10. Recent history of, or current drug or alcohol abuse
11. Use of oral anticoagulants, unless the dose has been stable for 4 weeks
prior to the first dose of ION*682884 or inotersen and regular clinical
monitoring is performed
12. Karnofsky performance status * 50%
13. Other causes of sensorimotor or autonomic neuropathy (e.g., autoimmune
disease, diabetic neuropathy)
14. Prior liver transplant or anticipated liver transplant within 1 year of
Screening
15. New York Heart Association (NYHA) functional classification of * 3
16. Known immunoglobulin light chain amyloidosis (AL amyloidosis)
17. Known leptomeningeal amyloidosis
18. Known multiple myeloma
19. Monoclonal gammopathy of undetermined significance (MGUS) and/or
immunoglobulin free light chain ratio < 0.26 and > 1.65 unless fat, bone
marrow, or heart biopsy confirming the absence of light chain by mass
spectrometry or immunoelectron microscopy
20. Presence of known type 1 or type 2 diabetes mellitus
21. Anticipated survival less than 2 years
22. 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 | EUCTR2019-001698-10-NL |
| ClinicalTrials.gov | NCT04136184 |
| CCMO | NL73848.000.21 |