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    EudraCT Number:2021-002251-11
    Sponsor's Protocol Code Number:TPN-101-C9-201
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2021-08-02
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2021-002251-11
    A.3Full title of the trial
    A Phase 2a Study of TPN-101 in Patients with C9ORF72 ALS/FTD (Amyotrophic Lateral Sclerosis and/or Frontotemporal Dementia)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study to learn whether a new drug, TPN-101, is safe when given to patients with amyotrophic lateral sclerosis or frontotemporal dementia due to a genetic mutation called C9orf72 hexanucleotide repeat expansion.
    A.4.1Sponsor's protocol code numberTPN-101-C9-201
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04993755
    A.5.4Other Identifiers
    Name:IND NumberNumber:153073
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorTransposon Therapeutics, Inc
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportTransposon Therapeutics, Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTransposon Therapeutics, Inc
    B.5.2Functional name of contact pointAndrew Satlin
    B.5.3 Address:
    B.5.3.1Street Address4660 La Jolla Village Drive; Suites 100 & 200
    B.5.3.2Town/ citySan Diego, CA
    B.5.3.3Post code92122
    B.5.3.4CountryUnited States
    B.5.4Telephone number18585354821
    B.5.5Fax number18772253670
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTPN-101
    D.3.2Product code TPN-101
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCENSAVUDINE
    D.3.9.1CAS number 634907-30-5
    D.3.9.2Current sponsor codeTPN-101
    D.3.9.4EV Substance CodeSUB33640
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Amyotrophic lateral sclerosis or frontotemporal dementia due to a genetic mutation called C9orf72 hexanucleotide repeat expansion
    E.1.1.1Medical condition in easily understood language
    Amyotrophic lateral sclerosis or frontotemporal dementia due to a genetic mutation called C9orf72 hexanucleotide repeat expansion
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10002026
    E.1.2Term Amyotrophic lateral sclerosis
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10068968
    E.1.2Term Frontotemporal dementia
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the safety and tolerability of TPN-101 in patients with C9ORF72 ALS/FTD
    E.2.2Secondary 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.2.3Trial contains a sub-study No
    E.3Principal 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
    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.4Principal 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
    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
    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
    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.5.1Primary 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.5.1.1Timepoint(s) of evaluation of this end point
    48 weeks
    E.5.2Secondary 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.5.2.1Timepoint(s) of evaluation of this end point
    Week 48 and monitored throughout the study
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Disease-related biomarkers
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E. 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.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA10
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    United States
    United Kingdom
    E.8.7Trial 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.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months1
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 20
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F. of subjects incapable of giving consent
    Based upon the judgement of Investigator, in case the patient will not be able to understand and sign the informed consent, then Investigator will ensure that consent must be obtained from a legal representative, if applicable to this study.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 20
    F.4.2.2In the whole clinical trial 40
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-11-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-12-06
    P. End of Trial
    P.End of Trial StatusCompleted
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