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    Summary
    EudraCT Number:2020-005971-11
    Sponsor's Protocol Code Number:AP101-02
    National Competent Authority:Sweden - MPA
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2021-04-26
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSweden - MPA
    A.2EudraCT number2020-005971-11
    A.3Full title of the trial
    A Phase 2a, multicenter, randomized, double-blind, placebo-controlled study to evaluate safety, tolerability, pharmacodynamic markers, and pharmacokinetics of AP-101 in patients with familial amyotrophic lateral sclerosis (fALS) and sporadic amyotrophic lateral sclerosis (sALS)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 2a study to evaluate, safety, tolerability, pharmacodynamic markers, and pharmacokinetics of AP-101 in patients with amyotrophic lateral sclerosis (ALS)
    A.4.1Sponsor's protocol code numberAP101-02
    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 SponsorAL-S Pharma, AG
    B.1.3.4CountrySwitzerland
    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 supportAL-S Pharma
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationEli Lilly and Company
    B.5.2Functional name of contact pointChorus Group
    B.5.3 Address:
    B.5.3.1Street AddressLilly Corporate Center, DC0825
    B.5.3.2Town/ cityIndianapolis, IN
    B.5.3.3Post code46285
    B.5.3.4CountryUnited States
    B.5.5Fax number+1317655 7264
    B.5.6E-mailchoruspharma@lists.lilly.com
    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 numberEMA/OD/030/17/1894
    D.3 Description of the IMP
    D.3.1Product nameAP-101
    D.3.2Product code AP-101
    D.3.4Pharmaceutical form Injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNot yet available
    D.3.9.2Current sponsor codeAP-101
    D.3.9.3Other descriptive nameAnti-(misfolded human superoxide dismutase 1) human IgG1m3 monoclonal antibody
    D.3.9.4EV Substance CodeSUB201641
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee 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) Yes
    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 placeboSolution for injection
    D.8.4Route of administration of the placeboIntravenous 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 (ALS)
    E.1.1.1Medical condition in easily understood language
    A disease that affects nerve cells in the brain and the spinal cord
    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.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Double-blind Phase
    • To determine the safety and tolerability of AP-101 after multiple intravenous (IV) doses over 6 months of treatment

    Open-label Extension
    • To determine the safety and tolerability of AP-101 after multiple IV doses
    E.2.2Secondary objectives of the trial
    Double-blind Phase
    • To determine the Pharmacokinetic (PK) profile of AP-101 after multiple IV dose administrations
    • To determine cerebrospinal fluid (CSF) penetration of AP-101 after multiple IV dosing
    • To determine effects of AP-101 on phospho-neurofilament heavy chain (pNfH) and neurofilament light chain (NfL) levels in CSF and plasma after multiple IV doses of AP-101

    Open-label Extension
    • To determine the PK profile of AP 101 after multiple IV dose administrations
    • To determine effects of AP-101 on pNfH and NfL levels in CSF and plasma after multiple IV doses of AP 101
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male and female participants. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
    a. Male participants who agree to use highly effective/effective methods of contraception may participate in this trial:
    i. All men should refrain from sperm donation for the duration of the study and for 6 months after the final administered dose of AP-101
    ii. Male participants with partners of childbearing potential must either remain abstinent (if this is their preferred and usual lifestyle), or must use condoms during intercourse for the duration of the study, and for 6 months after the final administered dose
    iii. Male participants who are in exclusively same sex relationships are not required to use contraception.
    b. Male participants must adhere to the contraception restrictions specified in Section 10.6 of the Protocol.
    c. Female participants of childbearing potential must adhere to contraception restrictions specified in Section 10.6 of the Protocol.
    Female participants should refrain from egg donation for the duration of the study and for 6 months following the final administered dose of AP101.
    d. Female participants are considered women not of child bearing potential if
    i. they have a congenital anomaly such as Mullerian agenesis,
    ii. they are infertile due to surgical sterilization, or
    iii. they are post- menopausal (as defined in protocol).
    2. Aged 18 years or over.
    3. Have possible, clinically probable, clinically probable-laboratory supported or definite familial or sporadic ALS in accordance with the El-Escorial criteria (Appendix 9, Section 10.9 of the Protocol) or who have a diagnosis of ALS as defined by the Gold Coast Criteria; progressive motor impairment documented by history or repeated clinical examination, preceded by normal motor development, and presence of upper and lower motor neuron dysfunction in at least 1 body region or lower motor neuron dysfunction in at least 2 body regions and investigations excluding other conditions.
    4. In familial ALS patients, a confirmed pathogenic SOD1 mutation.
    5. Onset of symptoms i.e., weakness within past 24 months prior to screening, at the time of obtaining informed consent.
    6. Have SVC of ≥50% of predicted values. Participants with SVC of <50% of predicted values may be permitted to enter the OLE, based on the opinion of the investigator.
    7. Absence of bilevel positive airway pressure (BiPAP)/proportional assist ventilation (PAV) >4 hours for symptoms attributable to ALS. Use of a CPAP for pre-existing conditions will be allowed.
    8. If on riluzole, must be on a stable dose for at least 30 days prior to baseline (randomization) and remain on a stable dose throughout the study. Riluzole cannot be initiated during the double blind phase of the study. Riluzole can be initiated during the OLE after Week 3 if needed based on the opinion of the investigator and the dose may be adjusted as appropriate.
    9. If on edaravone, must have completed 2 cycles at baseline (randomization) and are expected to remain on the same dose throughout the study. Edaravone cannot be initiated once the participant is randomized and for the duration of the double blind phase of the study. Edaravone can be initiated during the OLE after Week 3 if needed based on the opinion of the investigator and the dose may be adjusted as appropriate.
    10. If on sodium phenylbutyrate or taurursodiol, patients must be on a stable dose for at least 30 days prior to baseline (randomization) and remain on a stable dose throughout the study. Treatment with sodium phenylbutyrate or taurursodiol cannot be initiated during the doubleblind phase of the study. Treatment with sodium phenylbutyrate or taurursodiol can be initiated during the OLE after Week 3 if needed based on the opinion of the investigator and the dose may be adjusted as appropriate.
    11. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1.3), which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
    12. Have venous access sufficient to allow for blood sampling as per protocol.
    13. Have clinical laboratory test results within normal reference range for the population or study site, or results with acceptable deviations that are judged to be not clinically significant by the investigator.
    14. Are able to visit the study site for outpatient treatment.
    15. Are willing to make themselves available for the duration of the study and are willing to follow study specific procedures.
    E.4Principal exclusion criteria
    1. Are investigator or site personnel affiliated with this study, or the immediate family of any of these. Immediate family is defined as a spouse, parent, child or sibling, whether biological or legally adopted.
    2. Are participating in, or have participated in another clinical trial (or have taken an experimental therapy within the context of a clinical trial) within 5 half-lives of baseline (Day 1).
    3. Have undergone a tracheostomy for ALS symptoms.
    4. Are on nasal intermittent positive pressure ventilation (NIPPV) >4 hours per day for the treatment of ALS related symptoms.
    5. Have other causes of neuromuscular weakness.
    6. Have severe active psychiatric illness.
    7. Have a diagnosis of another neurodegenerative disease (e.g. Parkinson disease, Alzheimer’s disease).
    8. Have a significant pulmonary disorder not attributed to ALS or who require treatments that might complicate the evaluation of the effect of ALS on respiratory function.
    9. Have cognitive impairment, severe disease in the renal, cardiovascular or hematological system.
    10. Pregnant or nursing women.
    11. Have been exposed to any antisense treatment targeting SOD1, including tofersen, within 6 months of the baseline visit or have known allergies or reactions to AP-101 or any of its excipients.
    12. Have undergone stem cell therapy.
    13. In the opinion of the investigator or sponsor, are unsuitable for inclusion in the study for any reason.
    E.5 End points
    E.5.1Primary end point(s)
    Double-blind Phase
    • Incidence of AEs and SAEs including immunogenicity.
    • Incidence of abnormalities in vital signs, clinical laboratory assessments, physical and neurological examinations, electrocardiograms and changes in weight.

    Open-label Extension
    • Incidence of AEs and SAEs including immunogenicity
    • Incidence of abnormalities in vital signs, clinical laboratory assessments, physical and neurological examinations, electrocardiograms and changes in weight
    E.5.1.1Timepoint(s) of evaluation of this end point
    Double-blind Phase
    • AEs and SAEs from screening through 16 weeks post last dose or early termination
    • Immunogenicity from baseline through 16 weeks post last dose or early termination
    • Vital signs, laboratory measurements, electrocardiograms, changes in weight from screening through 16 weeks post last dose or early termination (excluding phone call)
    • Physical and neurological exam: screening, baseline, Dose 2, W3, W12, W24, 21 days - 16 weeks post last dose or early termination (excluding phone call)

    Open-label Extension
    • AEs and SAEs from baseline through 16 weeks post last dose or early termination
    • Immunogenicity: baseline, W3, W6 through 16 weeks post last dose or early termination
    E.5.2Secondary end point(s)
    Double-blind Phase
    • The primary PK parameters are AUC, concentration at the end of infusion and t1/2
    • AP-101 levels in the CSF
    • Measurement of pNfH and NfL levels in the CSF and plasma after multiple IV doses of AP-101

    Open-label Extension
    • The primary PK parameters are AUC, concentration at end of infusion and t1/2
    • Measurement of pNfH and NfL levels in CSF and plasma after multiple IV doses of AP-101
    E.5.2.1Timepoint(s) of evaluation of this end point
    Double-blind Phase
    • PK sampling from baseline through 16 weeks post last dose or early termination (excluding phone call)
    • CSF samples at baseline, W12, W24 and 16 weeks post last dose or early termination

    Open-label Extension
    • PK sampling at baseline, Dose 2 and 21 days - 16 weeks post last dose or early termination
    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 No
    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.7.1.3.1Other 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 Yes
    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 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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA8
    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
    Canada
    Korea, Republic of
    United States
    Belgium
    Germany
    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
    The end of the study is defined as the date after the last participant completed 6 months of study treatments and completed any applicable follow-up.
    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 months7
    E.8.9.1In the Member State concerned days29
    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 days28
    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: 32
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 31
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 26
    F.4.2.2In the whole clinical trial 63
    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)
    Following completion of 6 months of treatment, participants will be invited to join a 6-month open label extension (OLE) that will continue to evaluate long term safety for AP-101.
    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 Decision2021-06-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-10-20
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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