This study has been transitioned to CTIS with ID 2024-512163-31-00 check the CTIS register for the current data. Primary objective: To evaluate the clinical efficacy of ION363 in clinical functioning and survival in FUS-ALS patients. Secondary…
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Brief title
Condition
- Neurological disorders congenital
- Neuromuscular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is to evaluate the effects of ION363 vs. placebo on change
from Baseline to Study Day 505 in Part 1 Cohorts A and B on functional
impairment, measured by joint rank analysis of the combined assessment of the
following:
• In-clinic ALSFRS-R total score
• Time of rescue. (Rescue takes place if there is a deterioration to an
ALSFRS-R total score of < 15 points AND a decrease of >= 10 points from Baseline
at Study Day 253, or later, that is confirmed after an interval of at least 4
weeks. Rescue means the patient may discontinue Part 1 and enter Part 2 of the
study.)
• Ventilation assistance-free survival (VAFS), defined as the time to the
earliest occurrence of one of the following events:
o Death
o Permanent ventilation (> 22 hours of mechanical ventilation [invasive or
noninvasive] per day for > 21 consecutive days in the absence of an acute
reversible event)
Secondary outcome
Secondary endpoints:
Evaluate the effects of ION363 vs. placebo on change (or geometric mean ratio,
as appropriate) from Baseline to Study Day 505 in Part 1 Cohorts A and B*on
clinical assessments and biomarkers of disease severity, specifically the
following endpoints:
• Geometric mean ratio from Baseline in serum neurofilament light chain (NfL)
• Change from Baseline in the in-clinic ALSFRS-R
• Change from Baseline in the in-clinic SVC
• Change from Baseline in handheld dynamometry (HHD)
• Change from Baseline in Amyotrophic Lateral Sclerosis Specific Quality of
Life-Revised (ALSSQOL-R)
• Overall survival
• VAFS
• Geometric mean ratio from Baseline in CSF NfL
• Geometric mean ratio from Baseline in CSF FUS protein
Exploratory endpoints:
Evaluate the effects of ION363 vs. placebo on change from Baseline to Study Day
505 in Part 1 Cohorts A and B on the following endpoints:
• At-home ALSFRS-R total score
• At-home vital capacity
• King*s ALS Clinical Staging (King*s)
• Clinical Global Impression-Improvement (CGI-I) and Severity (CGI-S)
• Patient Global Impression-Improvement (PGI-I) and Severity (PGI-S)
• Center for Neurologic Study-Bulbar Function Scale (CNS-BFS)
• Speech-based analytics (Aural Analytics)
• Ventilation use
• Rate of *rescue* from Part 1
• Health-related quality of life (HRQoL) as measured by:
o Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS)
o ALS Assessment Questionnaire, 5-item (ALSAQ-5)
o Fatigue Severity Scale (FSS)
o Zarit Burden Interview, 12-item (ZBI-12)
o EuroQol 5-Dimension 5-Level (EQ-5D-5L)
o Amyotrophic Lateral Sclerosis-Health Index (ALS-HI)
• Cognitive and behavioral functioning
o Edinburgh Cognitive and Behavioural ALS Screen (ECAS)
• Patient exit interview
• Disease biomarkers may include but are not limited to:
o CSF and serum neurofilament heavy chain (NfH)
o CSF YKL40 (also known as chitinase-3-like protein 1 [CHI3L1]), tau,
neurogranin, glial fibrillary acidic protein (GFAP), and pentraxins
o Plasma C-reactive protein
• Volumetric MRI, including whole brain and ventricles
Safety endpoints:
Safety and tolerability of ION363 will be assessed by determining the incidence
and severity of the following parameters:
• Treatment-emergent AEs, serious AEs and changes in concomitant medications
• Physical examination and neurological assessment
• Vital signs (body temperature, heart rate [HR], BP, weight, respiration)
• Electrocardiograms (ECGs)
• CSF safety labs (cell counts, protein, albumin, glucose)
• Laboratory tests (clinical chemistry, hematology, coagulation, urinalysis)
• Columbia - Suicide Severity Rating Scale (C-SSRS)
• Plasma anti-ION363 antibodies
• Worsening of disease biomarkers and clinical efficacy assessments that
exceeds what is expected from worsening of the underlying disease
• CSF and serum oligoclonal bands or free kappa index and immunoglobulin G
(IgG) collected at Baseline (and during study as indicated)
Clinical and CSF measures will be used to monitor for unexpected deterioration
Background summary
Amyotrophic lateral sclerosis is a fatal neurodegenerative disease
pathologically characterized by aggressive deterioration of frontotemporal
neurons, corticospinal tract, brainstem neurons, and anterior horn neurons
(Statland et al. 2015). Patients suffer with loss of muscle mass, strength,
and function in bulbar, respiratory, and voluntary muscle. Decline is
inevitable, with death from respiratory failure following 2 to 5 years after
diagnosis for most patients. Amyotrophic lateral sclerosis (ALS) associated FUS
mutations are often associated with a more severe course compared to ALS
patients associated with other genetic mutations.
Unfortunately, there is no effective treatment available for this form of ALS.
This study involves providing an investigational drug called ION363. ION363 is
designed to reduce the body*s production of the FUS protein that may contribute
to the ALS caused by a mutation in the FUS gene.
Study objective
This study has been transitioned to CTIS with ID 2024-512163-31-00 check the CTIS register for the current data.
Primary objective: To evaluate the clinical efficacy of ION363 in clinical
functioning and survival in FUS-ALS patients.
Secondary objective: To further evaluate the effects of ION363 in halting,
reversing, or slowing the deterioration of clinical functioning and biomarkers
of disease severity in FUS-ALS patients.
Exploratory objective: To further evaluate the effects of ION363 in halting,
reversing, or slowing the deterioration of clinical functioning and global
health in FUS-ALS patients.
Safety objective: To evaluate the safety and tolerability of ION363 in FUS-ALS
patients.
Study design
ION363-CS1 is a global, multicenter study of ION363 delivered by intrathecal
(IT) bolus injection in adolescent and adult patients with, or developing,
FUS-ALS.
The study consists of 3 parts: Part 1, a randomized, double-blind,
placebo-controlled treatment period; Part 2, a treatment extension period; and
Part 3, an additional open-label Treatment Period.
Part 1, Randomized, Double-blind, Placebo-controlled Treatment Period:
Part 1 is a multicenter, parallel-group, double-blind study of a single-dose
regimen of 100 mg ION363 vs. placebo (randomized in a 2:1 ratio) delivered by
lumbar IT bolus injection in adolescent and adult FUS mutation carriers with
signs or symptoms of ALS who are >= 10 years of age. Part 1 consists of a
Screening Period of up to 4 weeks, a Treatment Period of 60 weeks, and a
Post-Treatment Follow-up Period of 12 or 40 weeks. After completing the
Treatment Period a 12-week Post-Treatment Follow-up Period in Part 1, patients
can enter Part 2. Patients who do not enter Part 2 will complete a 40-week
Post-Treatment Follow-up Period in Part 1.
In Part 1, eligible patients will be assigned to either Cohort A, B, or C
depending on their slow vital capacity (SVC), age, and ALS Functioncal Rating
(ALSFRS-R) pre-study slope.
- Cohort A will enroll FUS-ALS patients who have SVC >= 50% of predicted value
and are 10 to 65 years of age (inclusive) at the time of informed consent. All
eligible patients 10 to 29 years of age (inclusive) will enroll into Cohort A
without regard to ALSFRS-R pre-study slope. Patients in Cohort A who are 30 to
65 years of age (inclusive) must have an ALSFRS-R pre-study slope >= 0.4 points
per month. Cohort A will be stratified by age of onset of ALS symptoms: < 25
years (Strata 1; juvenile amyotrophic lateral sclerosis [JALS]) and >= 25 years
(Strata 2; non-JALS).
- Cohort B will enroll FUS-ALS patients who have SVC >= 50% of predicted value
and are >= 30 years of age at the time of informed consent. All eligible
patients > 65 years of age will enroll into Cohort B without regard to ALSFRS-R
pre-study slope. Patients in Cohort B who are 30 to 65 years of age (inclusive)
must have an ALSFRS-R pre-study slope < 0.4 points per month.
- Cohort C will enroll up to 12 FUS-ALS patients who have SVC < 50% of
predicted value, are 10 to 30 years of age (inclusive) at the time of informed
consent, and had ALS symptom onset within 12 months before the time of informed
consent. Patients in Cohort C have no ALSFRS-R pre-study slope criterion.
Enrollment in Part 1 will stop when the total number of patients in Cohorts A
and B reaches 73, regardless of whether enrollment in Cohort C has reached 12
patients. Eligibility criteria thresholds are specified below for respiratory
function and cognitive impairment symptom burden. Patients on a stable dose of
riluzole, edaravone, and/or Relyvrio (sodium phenylbutyrate/taurursodiol
combination, called Albrioza in Canada) will be permitted in the study.
Patients enrolled in Part 1 will receive 7 doses of Study Drug (ION363 or
placebo). Study Drug will be administered every 12 weeks over the 60-week
Treatment Period with an additional loading dose administered 4 weeks after the
first dose. Doses will be administered via lumbar IT bolus on Study Days 1, 29,
85, 169, 253, 337, and 421.
Patients in Part 1 who experience a deterioration in total ALSFRS-R score to
<15 points AND a decrease of >= 10 points from Baseline at Study Day 253, or
later, that is confirmed, after an interval of at least 4 weeks may discontinue
Part 1 and enter Part 2 of the study (refer to Section 3.8).
Part 2: Treatment Extension Period
Part 2 is a multicenter, 96 or 124-week period for patients from Part 1,and for
patients from the Investigator-initiated study (IIS) that consists of an
84-week Treatment Period and a 12- or 40-week Post-treatment Follow-up Period.
All patients entering Part 2 will receive open-label ION363 on Day 1 of Part 2.
Patients coming from Part 1 may have received either ION363 or placebo in Part
1; ; those who received placebo in Part 1 would thus require a loading dose of
ION363 at 4 weeks after their initial dose in Part 2. To maintain the blinding
of Study Drug assignment in Part 1, patients from Part 1 will first enter a
4-week Loading Period in which they receive their second dose in Part 2 as
follows, in a double-blind manner: patients who received placebo in Part 1 will
receive ION363 on Study Day 29 of Part 2 and patients who received ION363 in
Part 1 will receive placebo on Study Day 29 of Part 2. Except for the loading
dose on Study Day 29, ION363 will be administered open-label every 12 weeks
during the 84-week Treatment Period (for a total of 9 doses of Study Drug
during Part 2 for patients coming from Part 1).
For patients completing the 12-week Part 1 Post-treatment Follow-up Period,
their first visit of Part 2 will align with Part 1 Study Day 505 to maintain a
12-week dosing interval. Patients who have been rescued (refer to Section 3.8)
in Part 1 may enter Part 2 after confirmation of *rescue* status, with their
initial administration of Study Drug in the Part 2 Treatment Period occurring
12 weeks after their last administration of Study Drug in Part 1.
Patients coming from the IIS all received ION363 in the IIS and will thus enter
directly into the 84-week Open-Label Treatment Period in Part 2 and receive
open-label ION363 every 12 weeks with no loading dose (for a total of 8 doses
of ION363 during Part 2 for patients
coming from the IIS).
After the 84-week Part 2 Treatment Period, patients who are continuing to Part
3 will complete a 12-week Post-Treatment Follow-up Period, with the Part 3 Day
1 visit aligning with the Part 2 Day 673 visit, and patients who are not
continuing to Part 3 will complete a 40-week Posttreatment
Follow-up Period (approximately 5 half-lives of the drug).
Part 3: Additional Open-Label Extension Period
Patients who complete the Part 2 Treatment Period are eligible to participate
in Part 3 if ION363 is not commercially available in the patient*s country at
that time. Patients may continue to receive open-label treatment in Part 3 for
up to 3 additional years or until ION363 becomes commercially available in the
patient*s country or until the Sponsor discontinues the development program,
whichever occurs earlier. ION363 dosing in Part 3 will continue at clinic
visits at 12-week intervals. For patients who terminate early from Part 3,
there will be a Post-Treatment Follow-up Period of 40 weeks.
Intervention
Throughout the study, each dose of ION363 or placebo will be administered as a
single 20 mL IT bolus injection.
Study Drug will be administered as a slow IT bolus injection (taking 1 to 3
minutes) using a *spinal anesthesia* needle and syringe. The target site for
needle insertion is the L3/L4 space but may be 1 space above or 1 to 2 spaces
below this level, if needed. Prior to the injection, an equal volume of CSF
will be collected for analyses. Spinal ultrasound (or another imaging technique
according to site practices) may be used for the LP procedure, if deemed
necessary, but is not required. Local anesthesia may be used for the LP
procedure, following institutional procedures.
Part 1: Patients will receive a total of 7 doses of Study Drug (ION363 or
placebo). Study Drug will be administered every 12 weeks over the 60-week
Treatment Period aside from a loading dose administered 4 weeks after the first
dose.
Part 2: Patients entering Part 2 after completing or being rescued in Part 1
will receive open-label ION363 every 12 weeks and an additional blinded loading
dose of Study Drug on Day 29 (ION363 for patients who had received placebo in
Part 1, placebo for patients who had received ION363 in Part 1). Patients
entering Part 2 from the IIS will receive open-label ION363 every 12 weeks
without the additional loading dose.
Part 3: All patients for whom ION363 is not commercially available after Part 2
completion will receive ION363 at dosing intervals of 12 weeks for up to 3
years.
Study burden and risks
Based on preclinical data, there are currently no identified risks associated
with ION363. Risks associated with the lumbar puncture (LP) procedure will be
minimized by the use of atraumatic needles, aseptic procedures, exclusion of
patients at increased risk of infection, herniation and loss of coagulation,
and close patient monitoring after study drug administration. Patients will be
closely monitored for signs and symptoms of neurologic effects.
Gazelle Court 2855
Carlsbad CA 92010
US
Gazelle Court 2855
Carlsbad CA 92010
US
Listed location countries
Age
Inclusion criteria
Inclusion Criteria for Part 1
1. Must provide written informed consent (and assent, if indicated per
patient*s age and institutional guidelines) (signed and dated) and any
authorizations
required by local law
2. At the time of informed consent, a patient must be >10 years of age, and
have signs or symptoms consistent with an ALS disease process (in the opinion
of the Investigator)
3. Genetic mutation in FUS confirmed by a testing laboratory that is CLIA
certified and CE-marked, or equivalent. Mutations must be reviewed and approved
by a variant classification committee.
4. Upright (sitting position) SVC is >50% of predicted value (as adjusted for
sex, age, and height) OR if SVC is < 50% of predicted value, must be
10 to 30 years of age (inclusive) at the time of informed consent AND had ALS
symptom onset within 12 months before the time of informed consent
5. Able and willing to meet all study requirements (in the opinion of the
Investigator), including travel to Study Center, procedures, assessments and
visits
6. A patient who is taking edaravone, riluzole, Relyvrio (sodium
phenylbutyrate/raurursodiol combination, called Abrioza in Canada), sodium
phenylbutyrate, or tauroursodeoxycholic acid (TUDCA. also known as taurursodiol
or urosodiol) must be on a stable dose for >= 28 days prior to Day 1, and
willing to continue on that dose throughout the duration of the study, unless
the Investigator determines that it should be discontinued for medical reasons,
in which case it may not be restarted during the study
7. Satisfies the following:
a. A female must be not be pregnant or lactating and must fulfill one of the
following:
i. is surgically sterile (e.g., hysterectomy, bilateral salpingectomy,
bilateral oophorectomy, or vasectomized male partner)
ii. is postmenopausal (defined as no menses for 12 months without an
alternative medical cause). A high follicle stimulating hormone (FSH) level in
the postmenopausal range may be used to confirm a postmenopausal state in women
not using hormonal contraception or hormonal replacement therapy. However, in
the absence of 12 months of amenorrhea, a single FSH measurement is
insufficient.
iii. is abstinent* or
iv. if engaged in sexual relations of childbearing potential, agree to use a
highly effective contraceptive method (refer to Section 6.3.1 from the time
of signing the ICF until at least 40 weeks after the last dose of Study Drug
b. A male must be abstinent*, surgically sterile (had a vasectomy with negative
semen analysis at follow-up, or has a surgically sterile non-pregnant female
partner), or if engaged in sexual relations with a woman of childbearing
potential (WOCBP), agree to use a highly effective contraceptive method (refer
to Section 6.3.1) from the time of signing the ICF until at least 40 weeks after
the last dose of Study Drug
* Only true abstinence (i.e., abstinence in line with the preferred and usual
lifestyle of the patient) is acceptable. 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.
8. Stable concomitant medications and nutritional support for at least 1 month
prior to Study Day 1. Concomitant medications or nutritional support that have
not been stable for at least 1 month prior to Study Day 1 may be allowed per
Investigator judgement.
9. Has an informant/caregiver who, in the Investigator*s judgment, has frequent
and sufficient contact with the patient to be able to provide accurate
information about the patient's cognitive and functional abilities throughout
the study. In addition, a patient who is < 18 years old must have a trial
partner (parent, caregiver or other) who is reliable, competent, at least 18
years of age, and willing to accompany the patient to trial visits.
Inclusion Criteria for Part 2:
1. Completed, or was rescued from, Part 1, or enrolled and received at least 1
dose of ION363 in the Investigator-initiated study (ISS). Patients from the IIS
must provide written informed consent (and assent, if indicated per patients'
age and institutional guidelines) (signed and dated) and any authorizations
required by law.
2. Satisfies the following:
a. A female must not be pregnant or lactating and must fulfill one of the
following:
i. is surgically sterile (e.g., hysterectomy, bilateral salpingectomy,
bilateral oophorectomy, or vasectomized male partner)
ii. is postmenopausal (defined as no menses for 12 months without an
alternative medical cause). A high follicle stimulating hormone (FSH) level in
the postmenopausal range may be used to confirm a postmenopausal state in women
not using hormonal contraception or hormonal replacement therapy. However, in
the absence of 12 months of amenorrhea, a single FSH measurement is
insufficient.
iii. is abstinent* or
iv. if engaged in sexual relations of childbearing potential, agree to use a
highly effective contraceptive method (refer to Section 6.3.1 from the time
of signing the ICF until at least 40 weeks after the last dose of Study Drug
b. A male must be abstinent*, surgically sterile (had a vasectomy with negative
semen analysis at follow-up, or has a surgically sterile non-pregnant female
partner), or if engaged in sexual relations with a woman of childbearing
potential (WOCBP), agree to use a highly effective contraceptive method (refer
to Section 6.3.1) from the time of signing the ICF until at least 40 weeks after
the last dose of Study Drug
* Only true abstinence (i.e., abstinence in line with the preferred and usual
lifestyle of the patient) is acceptable. 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.
3. Is suitable for study participation, in the opinion of the Investigator
Exclusion criteria
Exclusion Criteria for Part 1:
1. Requiring permanent ventilation (> 22 hours of mechanical ventilation
[invasive or noninvasive] per day for > 21 consecutive days) or tracheostomy
2. Any known genetic variant (other than those in the FUS gene) that is
pathogenic or likely to be pathogenic for the ALS-frontotemporal dementia (FTD)
spectrum of disease
3. Positive test result for:
a. Human immunodeficiency virus (HIV)
b. Hepatitis C (HCV), unless previously treated and has been serum/plasma HCV
RNA negative for at least 6 months after the end of treatment
c. Hepatitis B (HBV) by HBV surface antigen test, unless currently on
nucleotide/nucleoside analogue treatment
4. Clinically significant abnormalities in medical history (e.g., previous
acute coronary syndrome within 3 months before Screening, major surgery within
2 months before Screening) or physical examination
5. Active infection requiring systemic antiviral or antimicrobial therapy that
will not be completed prior to Study Day 1.
6. Uncontrolled hypertension (blood pressure [BP] > 160/100 mmHg)
7. Malignancy within 1 year before Screening, 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 have not recurred within 6 months may
also be eligible per Investigator judgement.
8. Obstructive hydrocephalus.
9. Presence of a functional ventriculoperitoneal shunt for the drainage of
cerebrospinal fluid (CSF) or an implanted central nervous system catheter.
10. Known significant brain or spinal disease that would interfere with the
lumbar puncture (LP) procedure, CSF circulation or safety assessment, including
tumors or abnormalities by magnetic resonance imaging (MRI) or computed
tomography (CT), subarachnoid hemorrhage, suggestion of raised intracranial
pressure on MRI or ophthalmic examination, spinal stenosis or curvature, chiari
malformation, obstructive hydrocephalus, syringomyelia, tethered spinal cord
syndrome and connective tissue disorders such as Ehlers-Danlos syndrome and
Marfan syndrome
11. Presence of significant cognitive impairment, not due to a developmental
disability, based on the Mini-Mental State Examination (MMSE) (score of < 20)
or an equivalent assessment, clinical dementia, or unstable psychiatric
illness, including psychosis, suicidal ideation, suicide attempt, or untreated
major depression, as determined by the Investigator
12. Concurrent participation in any other interventional clinical study
13. Previous or current treatment with an oligonucleotide (including small
interfering RNA [siRNA], tofersen). This exclusion criterion does not apply to
coronavirus disease 2019 (COVID-19) vaccinations, which are allowed.
14. Treatment with another investigational drug, biological agent, or device,
within 1 month before Screening or 5 half-lives of the investigational agent,
whichever is longer.
15. History of gene therapy or cell transplantation or any other experimental
brain surgery.
16. Anticipated need, in the opinion of the Investigator, for administration
of any antiplatelet or anticoagulant medication that cannot be safely paused
before and/or after an LP procedure according to local or institutional
guidelines and/or Investigator determination after consultation with the
appropriate treating physician. Low-dose aspirin (<= 100 mg/day, administered as
monotherapy) is permitted and may be continued through the LP procedure.
17. Clinically significant low platelet count (defined as < 100,000/mm3),
coagulation tests, or laboratory abnormalities that would render a patient
unsuitable for inclusion
18. Unwillingness to comply with study procedures, including follow-up, as
specified by this protocol, or unwillingness to cooperate fully with the
Investigator
19. Has any other condition that would make the patient unsuitable for
inclusion or could interfere with the patient participating in or completing
the study, in the opinion of the Investigator
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 | CTIS2024-512163-31-00 |
| EudraCT | EUCTR2020-005522-28-NL |
| ClinicalTrials.gov | NCT04768972 |
| CCMO | NL78827.000.22 |