E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Amyotrophic Lateral Sclerosis with Fused in Sarcoma mutations |
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E.1.1.1 | Medical condition in easily understood language |
Amyotrophic Lateral Sclerosis |
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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 |
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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). |
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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. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion Criteria for Part 1:
1.Signs or symptoms consistent with an ALS disease process in the opinion of the Investigator 2.Participants in: Cohort A must be, at the time of informed consent, 12 – 65 years of age, inclusive, with signs or symptoms consistent with an ALS disease process in the opinion of the Investigator and if 30 to 65 years of age, inclusive, have an ALSFRS-R pre-study slope ≥ 0.4 points per month (calculated as [48-Screening ALSFRS-R score]/time in months since symptom onset)
Cohort B must be, at the time of informed consent, > 30 years of age, with signs or symptoms consistent with an ALS disease process in the opinion of the Investigator and have an ALSFRS-R pre-study slope < 0.4 points per month (calculated as [48-Screening ALSFRS-R score]/time in months since symptom onset) if between the ages of 30-65, or > 65 years of age with no ALSFRS-R pre-study slope criterion 3.Confirmed genetic mutation in FUS in a clinical laboratory improvement amendments (CLIA) certified, CE-marked, or equivalent testing laboratory . Mutations must be reviewed and approved by a variant classification committee 4.Upright (sitting position) slow vital capacity (SVC) as adjusted for sex, age, and height ≥ 50 percentage (%) of predicted value 5.Participants taking edaravone must be on a stable dose for ≥ 28 days prior to Screening and riluzole 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 6. Females: a) 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.
6.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 in consultation with the Sponsor Medical Monitor or designee. 7.Has an informant/caregiver who, in the Investigator's judgment, has frequent and sufficient contact with the participant as to be able to provide accurate information about the participant's cognitive and functional abilities at Screening. Participants < 18 years old at Screening must have a trial partner (parent, caregiver or other) who is reliable, competent and at least 18 years of age, is willing to accompany the participant to trial visits and to be available to the Study Center by phone if needed, and who (in the opinion of the Investigator) is and will remain sufficiently knowledgeable of participant's ongoing condition to respond to Study Center inquiries about the participant
Inclusion Criteria for Part 2: 1.Completed, or rescued from, Part 1, Enrolled and received at least 1 dose of ION363 in the Investigator-initiated EAP program 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.Patient meeting Criteria #1-2 is otherwise suitable for study participation, in the opinion of the Investigator
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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 ALS-associated mutations except FUS 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 of Screening, major surgery within 2 months of Screening) or physical examination, unless discussed and approved by the Sponsor Medical Monitor 5. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1 6. Uncontrolled hypertension (BP > 160/100 mm Hg) 7. Malignancy within 1 year of 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 no recurrence within 6 months may also be eligible per Investigator judgement 8. Obstructive hydrocephalus 9. Presence of a functional ventriculoperitoneal shunt for the drainage of CSF or an implanted 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, with either a score on the Mini-Mental State Examination (MMSE) < 20 or 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 13. Previous treatment with an oligonucleotide (including siRNA). This exclusion criterion does not apply to 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 of 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. Antiplatelet or anticoagulant therapy within the 14 days prior to Day 1 or anticipated use during the study, including but not limited to daily, low-dose aspirin (defined as ≤ 150 mg/day), clopidogrel, dipyridamole, warfarin, dabigatran, rivaroxaban and apixaban 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. 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
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from Day 1 through Study Day 505 in Part 1 in functional impairment Functional impairment to be measured by joint rank analysis of the combined assessment of: - In-clinic Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) Total Score; - time of rescue Rescue takes place if there is a deterioration to an ALSFRS-R total score of < 20 points 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. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From Baseline to Study Day 505 in Part 1 Cohort A |
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E.5.2 | Secondary end point(s) |
Evaluate the effects of ION363 vs. placebo on change and/or percent change, if appropriate, from Baseline to Study Day 505 in Part 1 Cohort A on clinical assessments and biomarkers of disease severity. Specifically, on the following endpoints: • Change from Baseline in Amyotrophic Lateral Sclerosis Specific Quality of Life - Revised (ALSSQOL-R) • Change from Baseline in in-clinic Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) • Survival • Change from Baseline in in-clinic Slow Vital Capacity (SVC) • Change from Baseline in Handheld Dynamometry (HHD) • Change from Baseline in Neurofilament light (NfL) concentration in CSF |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
From Baseline to Study Day 505 in Part 1 |
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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 and Part 2 open label |
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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 | 7 |
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 |
Brazil |
Canada |
Japan |
Korea, Democratic People's Republic of |
United States |
France |
Netherlands |
Germany |
Italy |
Belgium |
Turkey |
United Kingdom |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 5 |