| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Amyotrophic lateral sclerosis or frontotemporal dementia due to a genetic mutation called C9orf72 hexanucleotide repeat expansion |
|
| E.1.1.1 | Medical condition in easily understood language |
| Amyotrophic lateral sclerosis or frontotemporal dementia due to a genetic mutation called C9orf72 hexanucleotide repeat expansion |
|
| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10068968 |
| E.1.2 | Term | Frontotemporal dementia |
| 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 assess the safety and tolerability of TPN-101 in patients with C9ORF72 ALS/FTD |
|
| E.2.2 | Secondary objectives of the trial |
• To assess the concentrations of TPN-101 in plasma and cerebrospinal fluid (CSF)
• To assess target engagement of TPN-101 in blood
• To assess disease-related biomarkers
• To assess the PD effects of TPN-101 in blood and CSF
• To assess inflammatory biomarkers in blood and/or CSF
• To assess clinical and functional status
• To assess survival |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Males or females ≥ 18 years of age at the time of informed consent
2. Have documentation of a clinical genetic test demonstrating the presence of a confirmed hexanucleotide repeat expansion (HRE) in the C9orf72 gene from a laboratory using an assay that has the relevant mark of conformity (United Kingdom Conformity Assessed [UKCA], Conformitè Europëenne [CE], or CE United Kingdom Northern Ireland [UKNI]) or Clinical Laboratory Improvement Amendments (CLIA) certification in the United States (Note: The HRE in the C9orf72 gene is present in about 10-15% of patients with ALS or FTD. Therefore, confirmation of this mutation should be part of the pre-screening for inclusion in the study. Patients who are not already known to have this mutation should not be screened for inclusion, i.e., genetic testing for this mutation is not a part of the study procedures.)
3. If female, must be postmenopausal (for at least 2 years), surgically sterilized (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy), or agree to use highly effective methods of contraception, e.g., combined (estrogen and progestogen containing) or progestogen-only hormonal
contraception associated with inhibition of ovulation; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomized partner (provided that the partner is the sole sexual partner of the women of child-bearing potential [WOCBP] trial participant and that the vasectomized partner has received medical assessment of the surgical success); or sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments), from Screening through 3 months after the last dose of the study medication
4. If male, with a partner who is not postmenopausal (for at least 2 years) or surgically sterilized (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy), the patient must agree that he and his partner will use highly effective methods of contraception, e.g., combined (estrogen and progestogen containing) or progestogen-only hormonal contraception associated with inhibition of ovulation; IUD; IUS; bilateral tubal occlusion; vasectomy (provided that he has received medical assessment of the surgical success); or sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments), from Screening through 3 months after the last dose of the study
medication
5. Able to perform all protocol-specified assessments, including neuropsychological tests; and comply with taking study medication and the study visit schedule, as judged by the investigator
6. Have a reliable caregiver/informant to accompany the patient to all study visits. Caregiver/informant must be able to read, understand, and
speak local language fluently to ensure comprehension of informed consent and informant-based assessments of the patient. Caregiver/informant must also have frequent contact with patient (at least 3 hours per week at one time or at different times) and be willing to monitor the patient's health and concomitant medications throughout the study
7. Able to understand and provide written informed consent at Screening, or has a legally authorized representation (LAR) who can provide such consent
8. Patient or LAR agree to allow data sharing across observational longitudinal and interventional studies using an encrypted global unique identifier (GUID) so that potential prior or future data on biomarkers and disease progression can be made accessible to the sponsor
9. Stable doses of all concomitant medications for 1 month prior to Screening (e.g., edaravone, riluzole, dextromethorphan/quinidine, psychotropic medications, cognitive enhancers, etc.)
For patients with ALS (with or without FTD):
10. Diagnosis of ALS (probable, possible, laboratory-supported probable or definite) according to the World Federation of Neurology revised E1 Escorial criteria
11. Onset of weakness within 3 years prior to Screening
12. Slow vital capacity (SVC) ≥ 60% of predicted normal adjusted for
sex, age, and height (from the sitting position)
13. Able to perform reproducible pulmonary function tests. Patients must have an average variability of less than 15% on the 2 best trials, with a maximum of 5 trials allowed
14. ALS Functional Rating Scale-Revised (ALSFRS-R) ≥ 30 and score of 3 or 4 on Item #3 (swallowing) at Screening
For patients with FTD:
15. A gradual, progressive decline in behavior, language, or motor function consistent with C9orf72 hexanucleotide expansion-related syndrome such as mild cognitive impairment, mild behavioral impairment, mild cognitive/behavioral impairment, behavioral variant FTD, primary progressive aphasia, or amnestic syndrome
16. CDR Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains (CDR plus NACC FTLD) global score of 0.5-2.0 at Screening |
|
| E.4 | Principal exclusion criteria |
1. Presence of other significant neurological or psychiatric disorders
including, but not limited to, biomarker confirmed Alzheimer's disease;
dementia with Lewy bodies; prion disease; progressive supranuclear
palsy; Parkinson's disease; multiple sclerosis; other causes of
neuromuscular weakness; a
primary or severe psychotic disorder; severe bipolar or unipolar
depression
2. Prior history of suicidal thoughts or behavior that are believed to
represent a current safety risk, or a "Yes" response to Questions 4 or 5
on the Columbia Suicide Severity Rating Scale (C-SSRS) at Screening
3. History of clinically significant brain abnormality, including, but not
limited to, stroke due to hemorrhage or infarction; cerebral contusion;
encephalomalacia; aneurysm; vascular malformation (angiomas or other
benign vascular malformations that are judged by the investigator to be
stable and not clinically significant are not exclusionary); hydrocephalus;
epilepsy; space-occupying lesion (e.g., abscess or brain tumor); severe
head injury within the past 20 years; symptoms or signs of elevated
intracranial pressure (e.g., symptoms or history of head injury or
abnormal funduscopic exam). If there is history or evidence on
neurologic exam suggesting possible subdural hematoma (SDH),
patients should be fully evaluated, including magnetic resonance
imaging (MRI) if indicated, to exclude significant, new SDH
4. Active alcohol, drug, or substance abuse/dependence, or any other
reason that makes it unlikely that the patient will comply with study
procedures in the opinion of the investigator
5. Clinically significant intercurrent illness or medical condition (e.g.,
hematological, endocrine, cardiovascular, renal, hepatic, or
gastrointestinal disease) that would jeopardize the safety of the patient,
limit participation, or compromise the interpretation of the data derived
from the patient
6. Tracheostomy or diaphragmatic pacing
7. Autoimmune disease requiring treatment or management (quiescent
rheumatoid arthritis, psoriasis, or controlled Type 1 diabetes are
acceptable)
8. History of human immunodeficiency virus (HIV), hepatitis B, or any
active infection during Screening, unless the patient will have been
symptom-free for at least 30 days prior to randomization. Treated
hepatitis C with no laboratory evidence of active disease and liver
enzymes <2 × upper limit of normal (ULN) is allowed
9. History of cancer within 5 years of Screening, with the exception of
fully treated non-melanoma skin cancers
10. Receipt of an investigational agent within 30 days or 5 half-lives
prior to Screening, whichever is longer
11. Treatment with an immunomodulator within 6 months of Screening
12. Receipt of systemic corticosteroids within 30 days prior to Screening
13. Any vaccination within 30 days prior to randomization
14. Hypertension, defined as confirmed systolic blood pressure (SBP) >
170 mmHg and/or diastolic blood pressure (DBP) > 100 mmHg at Screening
15. Hypotension, defined as confirmed SBP < 90 mmHg and/or DBP < 60
mmHg at Screening
16. Any major surgery within 4 weeks of Screening or a planned major
surgery during the trial
17. Females who are pregnant (positive pregnancy test at Screening or
prior to administration of study drug) or breastfeeding
18. Contraindication to undergoing a lumbar puncture (LP) including, but
not limited to: inability to tolerate an appropriately flexed position for
the time necessary to perform an LP; international normalized ratio
(INR) > 1.4 or other coagulopathy; platelet count of < 120,000/μL;
infection at the desired LP site; taking anti-platelet or anti-coagulant
medication within 30 days of Screening (Note: low-dose aspirin is
permitted but should be stopped 5 days prior to the LP); severe
degenerative arthritis of the lumbar spine; suspected noncommunicating
hydrocephalus or intracranial mass; prior history of
spinal mass or trauma
19. Allergy to any of the components of the study drug
20. History of any significant drug allergy (such as anaphylaxis or
hepatotoxicity)
21. Clinically significant findings on Screening laboratory testing,
physical examination, or vital signs that are not specific to ALS/FTD that
could interfere with the conduct of the study, the interpretation of the
data, or increase patient risk, including the following:
* please refer to the Exclusion Criteria in the study protocol |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Incidence and severity of treatment-emergent adverse event (TEAEs) of TPN-101 administered for up to 48 weeks in patients with C9ORF72 ALS/FTD |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Concentrations of TPN-101 in plasma and cerebrospinal fluid (CSF)
• Target engagement of TPN-101 in blood as measured by LINE-1 (L1) complementary DNA (cDNA)
• Disease-related biomarkers
• Disease modification-related neuro-biomarkers, including neurofilament light chain (NfL) and neurofilament heavy chain (pNfH) in blood and CSF
• Inflammatory biomarkers in blood and/or CSF
• Clinical and functional status, as measured by ALS Functional Rating Scale-Revised (ALSFRS-R), ALS Assessment Questionnaire-40 item (ALSAQ-40), slow vital capacity (SVC), CDR Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains (CDR plus NACC FTLD-Sum of Boxes (SB), frontotemporal dementia (FTD) Rating Scale, Color Trails, Stroop Color and Word Test, Montreal Cognitive Assessment (MoCA), cortical basal ganglia functional scale (CBFS), Center for Neurologic Study – Bulbar Function Scale (CNS-BFS), ALS Cognitive Behavioral Scale (ALS-CBS), and Neuropsychiatric Inventory–Questionnaire (NPI-Q)
• Survival
• Other safety assessments, including clinically significant changes in physical examinations, neurological examinations, vital sign measurements, body weight, clinical laboratory tests, electrocardiograms (ECGs), and assessments of suicidality (i.e., C-SSRS) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Week 48 and monitored throughout the study |
|
| 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 | Yes |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
Disease-related biomarkers
Survival |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| 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) | No |
| 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 | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Part 1 is double blind period of 24 weeks followed by part 2 (open label) at week 25 for all patient |
|
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| 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 |
| Canada |
| United States |
| France |
| Netherlands |
| Spain |
| Germany |
| Belgium |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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