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    EudraCT Number:2010-019159-23
    Sponsor's Protocol Code Number:AL-108-231
    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:2010-08-27
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2010-019159-23
    A.3Full title of the trial
    A Phase 2/3, Randomised, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Davunetide for the Treatment of Progressive Supranuclear Palsy.
    Eine randomisierte; doppelblinde placebokontrollierte Studie der Phase 2/3 zur Beurteilung der Sicherheit und Wirksamkeit von Davunetide zur Behandlung von progressiver supranukleärer Blickparese.
    A.4.1Sponsor's protocol code numberAL-108-231
    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 SponsorAllon Therapeutics Inc
    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 support
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/10/728
    D.3 Description of the IMP
    D.3.1Product nameDavunetide
    D.3.2Product code AL-108
    D.3.4Pharmaceutical form Nasal spray
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntranasal use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDavunetide
    D.3.9.1CAS number 211439-12-2
    D.3.9.2Current sponsor codeAL-108
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number75
    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 Yes
    D. medicinal product typeSynthetic peptide
    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 placeboNasal spray
    D.8.4Route of administration of the placeboIntranasal use (Noncurrent)
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Progressive Supranuclear Palsy
    Progressive supranukleäre Blickparese
    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 14.1
    E.1.2Level PT
    E.1.2Classification code 10036813
    E.1.2Term Progressive supranuclear palsy
    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 evaluate davunetide 30 mg BID relative to placebo, when both are administered IN for 52 weeks, to subjects with PSP, with respect to:
    - Efficacy, as measured by change from baseline scores of the Progressive Supranuclear Palsy Rating Scale (PSPRS) at 52 weeks.
    - Efficacy, as measured by the change from baseline of the Schwab and England Activities of Daily Living Scale (SEADL) at 52 weeks.
    - Safety, as measured by reported adverse events (AEs), electrocardiograms (ECGs), nasal examination and clinical laboratory measures.
    E.2.2Secondary objectives of the trial
    To evaluate davunetide 30 mg BID relative to placebo, when both are administered IN to subjects with PSP, with respect to:
    • Efficacy, as measured by the Clinical Global Impression of Change (CGI-C) at 52
    • Brain atrophy, as measured by change from baseline of ventricular volumes measured by volumetric brain MRI at 52 weeks.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Title: Saccadic eye movements
    Date and version: Same as protocol amendment 2; no separate document, only sub-section in the protocol.

    At pre-selected sites, an exploratory substudy measuring visuallyguided
    horizontal saccades will be conducted. The objectives of this substudy are to assess whether davunetide treatment leads to changes in:
    - the dynamic properties of the saccades in individuals with PSP, and
    - the rate of progression of horizontal and vertical saccade abnormalties in PSP.

    Two other optional sub-studies : genetic optional study (protocol section 9.2.3) and lumbar puncture optional study for PK measures (protocol section 9.2.1) will be performed to patients giving their consent.
    E.3Principal inclusion criteria
    1. Probable or possible PSP defined as:
    1) at least a 12-month history of
    a) postural instability or falls during the first 3 years that symptoms are present and
    b) at screening (Visit 1) decreased downward saccade velocity defined as observable eye movement (deviation from the “main sequence” linear relationship between saccade amplitude and saccade velocity), or supranuclear ophthalmoplegia defined as 50% reduction in upward gaze or 30% reduction in downward gaze.
    2) age at symptom onset of 40 to 85 years by history; and
    3) an akinetic-rigid syndrome with prominent axial rigidity.
    2. Aged 41 to 85 years at the time of screening.
    3. Judged by investigator to be able to comply with neuropsychological evaluation at
    baseline and throughout the study.
    4. Must have reliable caregiver accompany subject to all study visits. Caregiver must read, understand, and speak local language fluently to ensure comprehension of informed consent form and informant-based assessments of subject. Caregiver must
    also have frequent contact with subject (at least 3 hours per week at one time or at different times) and be willing to monitor study medication compliance and the subject’s health and concomitant medications throughout the study.
    5. Modified Hachinski score ≤ 3 (Appendix 7). This modified Hachinski will not include the focal neurological signs, symptoms or pseudobulbar affect questions, given the prominence of all 3 in PSP.
    6. Score ≥ 15 on the mini-mental state examination (MMSE) at screening (Visit 1).
    7. Written informed consent provided by subject (or legally-appointed representative, as appropriate) and caregiver (if not the legally-appointed representative) who are both fluent local language speakers.
    8. Subject resides outside a skilled nursing facility or dementia care facility at the time of screening, and admission to such a facility is not planned. Residence in an assisted living facility is allowed.
    9. If the subject is receiving levodopa/carbidopa, levodopa/benserazide, a dopamine
    agonist, catechol-o-methyltransferase (COMT) inhibitor, or other Parkinson’s medication with the exeption of Azilect (rasagiline), the dose must have been stable for at least 60 days prior to the screening visit (Visit 1) and must remain stable for the duration of the study. No such medication can be initiated during the study. Subjects receiving rasagiline or CoQ10 must be on a stable dose for at least 90 days prior to the screening visit (Visit 1).
    10. Able to tolerate the MRI scan during screening with either no sedation or low dose lorazepam.
    11. Able to ambulate independently or with assistance defined as the ability to take at least 5 steps with a walker (guarding is allowed provided there is no contact) or the ability to take at least 5 steps with the assistance of another person who can only have contact with one upper extremity.
    12. Presence of symptoms for less than 5 years or the presence of symptoms for more than 5 years with a PSPRS baseline score ≥ 40.
    13. Stable on all other chronic medications for at least 30 days prior to the screening visit (Visit 1).
    E.4Principal exclusion criteria
    1. Insufficient fluency in local language to complete neuropsychological and functional assessments
    2. A diagnosis of ALS or other motor neuron disease
    3. Any of
    a. Abrupt onset of symptoms defined in IC1 associated with ictal events
    b. Head trauma related to onset of symptoms defined in IC1
    c. Severe amnesia within 6 m of the symptoms defined in IC1
    d. Cerebellar ataxia
    e. Choreoathetosis
    f. Early symptomatic autonomic dysfunction
    g. Tremor while at rest
    4. Presence of other significant neurological or psychiatric disorders including Alzheimer’s disease; dementia with Lewy bodies; prion disease; Parkinson’s disease; any psychotic disorder; severe bipolar or unipolar depression; seizure disorder; tumor or other spaceoccupying lesion; or history of stroke or head injury with loss of consciousness for at least 15 min within the past 20 y
    5. Within 4 w of screening or during the course of the study, concurrent treatment with memantine; acetylcholinesterase inhibitors; antipsychotic agents or mood stabilizers; or benzodiazepines
    a. Low dose lorazepam (NMT 2 mg) may be used for sedation prior to MRI scans for those subjects requiring sedation Neuropsychological testing may not be performed after lorazepam admin
    b. Subjects who take short acting benzodiazepines for sleep may continue to do so if they have been on a stable dose for 30 d prior to screening.
    c. Clonazepam may be used for treatment of dystonia or painful rigidity associated with PSP if the dose has been stable for 90 d prior to screening and is not expected to change during
    the course of the study.
    6. Treatment with lithium, methylene blue, tramiprosate, ketone bodies, latrepirdine or any putative disease-modifying agent directed at tau within 90 days of screening
    7. A history of alcohol or substance abuse within 1 y prior to screening and deemed to be clinically significant by the site investigator
    8. Any malignancy within 5 years of the screening visit (Visit 1) or current clinically significant hematological, endocrine, cardiovascular, renal, hepatic, gastrointestinal, or neurological disease. For the non-cancer conditions, if the condition has been stable for at least one year before the screening visit and is judged by the site investigator not to interfere with the subject’s participation in the study, the subject may be included
    9. Clinically significant laboratory abnormalities at screening, including creatinine ≥ 2.5 mg/dL, ALT or AST ≥ 3 times the upper limit of the normal reference range, vit B12 below the laboratory normal reference range, or TSH above laboratory normal reference range.
    10. The systolic blood pressure measurement is >190 or <85 mm Hg. The diastolic blood pressure measurement is >105 or <50 mm Hg at screening.
    11. Abnormal ECG tracing at screening and judged to be clinically significant by the site investigator.
    12. Treatment with any IMP or device within 90 d of screening.
    13. Known history of serum or plasma progranulin level less than one standard deviation below the normal subject mean for the laboratory performing the assay.
    14. Known presence of known disease-associated mutation in TDP-43, PGRN, CHMPB2, or VCP genes or any other FTLD causative genes not associated with underlying tau pathology (e.g Chromosome 9 ass FTD).
    15. History of DBS surgery other than sham surgery for DBS
    clinical trial
    16. History of early prominent REM sleep behavior disorder
    17. Women who are pregnant or lactating and women of childbearing potential who are not using at least two different forms of medically recognized and highly effective methods of birth control, resulting in a low failure rate when used consistently and correctly such as implants, injectables, combined oral contraceptives, some IUDs, sexual abstinence or vasectomised partner
    18. An employee or relative of an employee of the Sponsor, a clinical site, or CRO participating in the study
    19. Significant anatomical nasal abnormality or history of nasal turbinate surgery
    20. History of a clinically significant medical condition that would interfere with the subject’s ability to comply with study instructions, would place the subject at increased risk, or might confound the interpretation of the study results.
    21. Contraindication to MRI exam for any reason
    22. Structural abnormality on MRI that precludes diagnosis of PSP, such as cortical infarct in brain region that might account for subject’s symptoms
    23. In subjects receiving anti-Parkinson medication at the time of screening, in the opinion of the investigator substantial worsening of motor signs or symptoms compared with normal functioning following overnight withdrawal of anti-Parkinson medication
    24. Known hypersensitivity to davunetide or any ingredient of formulation
    E.5 End points
    E.5.1Primary end point(s)
    - Efficacy will be assessed as the change from baseline using the PSPRS (Appendix 1)
    at 52 weeks (Visit 7).
    - Efficacy will be assessed as the change from baseline of the SEADL (Appendix 3) at
    52 weeks (Visit 7).
    - Safety evaluations will be performed by recording clinical AEs and a nasal
    examination at each study visit. Additionally, samples will be collected for
    laboratory analysis at regular intervals. The 12-lead ECGs will be evaluated at the
    screening visit (Visit 1) and 52 weeks (Visit 7). Physical examinations will be
    performed at the screening visit (Visit 1), 6 and 52 weeks (Visits 3 and 7). Vital
    signs including blood pressure and heart rate will be obtained at screening (Visit 1)
    and 0, 3, 6, 13, 26, 39, and 52 weeks (Visits 2 through 7, inclusive), and clinical
    laboratory tests will be obtained at screening (Visit 1) and weeks 6, 13, 26, 39, and
    52 (Visits 3-7). Nasal examinations will be conducted at baseline (Week 0) and all
    follow-up visits (Weeks 3 to 52, inclusive).
    E.5.1.1Timepoint(s) of evaluation of this end point
    52 weeks (visit 7) for all these end points and additionally visit 1 and visits 1-7 depending on the case.
    E.5.2Secondary end point(s)
    - Efficacy will be assessed by the CGI-C (Appendix 2) at 52 weeks (Visit 7).
    - Brain atrophy will be assessed as the change from baseline of ventricular volumes measured by volumetric brain MRI at 52 weeks (Visit 7).
    E.5.2.1Timepoint(s) of evaluation of this end point
    52 weeks (visit 7)
    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 No
    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) Yes
    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 Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    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 No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA14
    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 Kingdom
    United States
    E.8.7Trial 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
    Visit 8, Day 372 (+/- 3 days) (Week 53), Telephone Contact
    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 months0
    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 months0
    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.1.3Elderly (>=65 years) Yes
    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
    PSP is a progressive neurodegenerative disease which produces progressive disability. If the patient is not capable of understanding and signing the consent form, such consent is required by the legally authorized representative.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state50
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 120
    F.4.2.2In the whole clinical trial 300
    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)
    There are no plans to continue treatment with the study drug after the subjects have ended participation in the trial.
    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 Decision2010-11-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-11-08
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2012-11-06
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