| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Amyotrophic Lateral Sclerosis with Fused in Sarcoma mutations |
|
| E.1.1.1 | Medical condition in easily understood language |
| Amyotrophic Lateral Sclerosis |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10002026 |
| E.1.2 | Term | Amyotrophic lateral sclerosis |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the clinical efficacy of ION363 in clinical functioning and survival in Amyotrophic Lateral Sclerosis (ALS) patients with Fused in Sarcoma mutations (FUS-ALS). |
|
| E.2.2 | Secondary objectives of the trial |
| 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. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion Criteria for Part 1:
1.Must provide written informed consent
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 Clinical Laboratory Improvement Amendments (CLIA) certified and, European Conformity (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.Participants taking edaravone, riluzole, Relyvrio (sodium phenylbutyrate/taurursodiol combination called Albrioza 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. Females: must be non-pregnant and non-lactating and either:
i. surgically sterile
ii. post-menopausal
iii. abstinent*
or
iv. if engaged in sexual relations of childbearing potential, agree to use a highly effective contraceptive method from the time of signing the ICF until at least 40 Weeks after the last dose of Study Drug
b. Males must be abstinent*, surgically sterile (vasectomy with negative semen analysis at follow-up, or a surgically sterile non-pregnant female partner) or if engaged in sexual relations with a woman of childbearing potential (WOCBP), a highly effective
contraceptive method must be used (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
* Abstinence is only acceptable as true abstinence.
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's 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 all 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 IIS. Patients from the IIS 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. Satisfy the following:
a. Females: must be non-pregnant and non-lactating and either:
i. surgically sterile
ii. post-menopausal (defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the post-menopausal range may be used to confirm a post-menopausal 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. 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. Males must be abstinent*, surgically sterile (vasectomy with negative semen analysis at follow-up, or a surgically sterile non-pregnant female partner) or if engaged in sexual relations with a woman of childbearing potential (WOCBP), a highly effective contraceptive method must be used (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
* Abstinence is only acceptable as true abstinence.
3. Is suitable for study participation, in the opinion of the Investigator |
|
| E.4 | Principal 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) and/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 (CS) 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 which have not recurred within 6 months may also be eligible per Investigator judgment
8. Obstructive hydrocephalus
9. Presence of a functional ventriculoperitoneal shunt for the drainage of cerebrospinal fluid (CSF) or an implanted central nervous system (CNS) catheter
10. Known significant brain or spinal disease that would interfere with the LP process, CSF circulation or safety assessment, including tumors or abnormalities by 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, and 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
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, including, but not limited to sodium phenylbutyrate, within 1 month before Screening, or 5 half-lives of 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
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
- 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 1 of the following events:
a. Death
b. Permanent ventilation (> 22 hours of mechanical ventilation [invasive or noninvasive] per day for > 21 consecutive days in the absence of an acute reversible event)
ALSFRS-R measures functional disease severity. The scale measures four functional domains, bulbar function, gross motor skills, fine motor skills, and respiratory. The assessment will contain 12 questions scored from 0 (no function) to 4 (full function), with a total possible score of 48, which will indicate the highest level of function. ALSFRS-R will be a part of the combined assessment of joint rank analysis to assess efficacy in Part 1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From Baseline to Study Day 505 in Part 1 Cohort A |
|
| E.5.2 | Secondary end point(s) |
Evaluate the effects of ION363 vs. placebo on change (or geometric mean ratio, as appropriate) from Baseline to Study Day 505 in Part 1 Cohort A and B-on clinical assessments and biomarkers of disease severity, specifically on 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 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| From Baseline to Study Day 505 in Part 1 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Part 1 double blind; Part 2 and Part 3 open label |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Switzerland |
| Brazil |
| Canada |
| Japan |
| Korea, Republic of |
| United Kingdom |
| United States |
| Belgium |
| Germany |
| Ireland |
| Italy |
| Netherlands |
| Poland |
| Spain |
| Sweden |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
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