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 |
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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 |
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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.1.2 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 |
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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 assess the safety and tolerability of TPN-101 in patients with C9ORF72 ALS/FTD |
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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 |
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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 repeat expansion in the C9orf72 gene from a CLIA certified laboratory 3. Body weight range of ≥ 41 kg (90 lbs) to ≤ 118 kg (260 lbs) 4. Score ≥ 18 on the Mini-Mental State Exam (MMSE) at Screening 5. 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 from Screening through Week 52 6. 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 from Screening through Week 52 7. 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 8. Have a reliable caregiver to accompany the patient to all study visits. Caregiver 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 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 9. Able to understand and provide written informed consent at Screening 10. 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 11. 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): 12. Diagnosis of ALS (probable, possible, laboratory-supported probable or definite) according to the World Federation of Neurology revised E1 Escorial criteria 13. Onset of weakness within 3 years prior to Screening 14. SVC ≥ 60% of predicted normal adjusted for sex, age, and height (from the sitting position) 15. Able to perform reproducible pulmonary function tests 16. ALSFRS-R ≥ 30 at Screening
For patients with FTD: 17. A gradual, progressive decline in behavior, language, or motor function consistent with C9orf72 hexanucleotide expansion-related syndrome such as behavioral variant FTD, primary progressive aphasia, or amnestic syndrome 18. CDR plus NACC FTLD global score of 0.5-2.0 at Screening |
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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; Parkinson's disease; multiple sclerosis; a primary or severe psychotic disorder; severe bipolar or unipolar depression; prior history of suicidal thoughts or behavior that are believed to represent a current safety risk; seizure; brain tumor or other space-occupying lesion; history of stroke; or history of severe head injury within the past 20 years 2. History of significant brain abnormality, including, but not limited to, prior hemorrhage or infarct, cerebral contusion, encephalomalacia, aneurysm, vascular malformation, subdural hematoma, hydrocephalus, space-occupying lesion (e.g., abscess or brain tumor such as meningioma); 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 3. Active alcohol, drug abuse or substance abuse, or any other reason that makes it unlikely that the patient will comply with study procedures in the opinion of the investigator 4. 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 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. History of HIV infection, hepatitis B or hepatitis C, or any active infection 7. History of cancer within 5 years of Screening, with the exception of fully excised non-melanoma skin cancers 8. Receipt of an investigational agent within 30 days or 5 half-lives prior to Screening, whichever is longer 9. Prior treatment with any monoclonal antibody within 6 months of Screening 10. Receipt of systemic corticosteroids within 30 days prior to Screening 11. Any vaccination within 30 days prior to study drug administration 12. Has smoked or used tobacco products within 6 months prior to study drug administration 13. Hypertension, defined as confirmed systolic blood pressure (SBP) > 170 mmHg and/or diastolic blood pressure (DBP) > 100 mmHg at Screening 14. Hypotension, defined as confirmed SBP < 90 mmHg and/or DBP < 60 mmHg at Screening 15. Any major surgery within 4 weeks of Screening 16. Females who are pregnant (positive pregnancy test at Screening or prior to administration of study drug), breastfeeding, or unable or unwilling to use highly effective methods of contraception throughout the study 17. 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: aspirin is permitted); severe degenerative arthritis of the lumbar spine; suspected non-communicating hydrocephalus or intracranial mass; prior history of spinal mass or trauma 18. Allergy to any of the components of the study drug 19. History of any significant drug allergy (such as anaphylaxis or hepatotoxicity) 20. Physical and laboratory test findings, including the following: a. Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs, ECG, or clinical laboratory determinations beyond what is consistent with the target population b. Clinically significant abnormality on 12-lead ECG prior to study drug administration, confirmed by repeat testing c. Total bilirubin, alanine aminotransferase (ALT), or aspartate aminotransferase (AST) > 2 × upper limit of normal (ULN), confirmed by repeat testing d. Serum creatinine > 168μmol/L (1.9mg/dL), confirmed by repeat testing e. Hematocrit < 35% for males and < 32% for females, absolute neutrophil cell count of < 1500/μL f. Clinically significant abnormal thyroid stimulating hormone (TSH) test g. Abnormally increased number of white blood cells (> 7 cells/mm3) in the CSF obtained at the Screening Visit; if there is evidence that the spinal tap was traumatic, patients with > 7 cells/mm3 must be discussed with the medical monitor to determine if they may be eligible h. Hemoglobin A1C >7%, confirmed by repeat testing i. Positive blood screen for HIV, hepatitis C antibody, or hepatitis B surface antigen |
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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 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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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 -sum of boxes (CDR plus NACC FTLD-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) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Week 48 and monitored throughout the study |
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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 | 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 |
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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 |
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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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
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 |
Belgium |
France |
Germany |
Netherlands |
Spain |
United Kingdom |
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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
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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 | 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 |