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    Summary
    EudraCT Number:2021-000250-26
    Sponsor's Protocol Code Number:A35-004
    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:2021-06-28
    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 number2021-000250-26
    A.3Full title of the trial
    A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial to Evaluate the Safety and Efficacy of AMX0035 Versus Placebo for 48-week Treatment of Adult Patients with Amyotrophic Lateral Sclerosis (ALS)
    En fas III, randomiserad, dubbelblindad, placebokontrollerad multicenterstudie för att utvärdera säkerhet och effekt hos AMX0035 jämfört med placebo vid 48 veckors behandling av vuxna patienter med amyotrofisk lateralskleros (ALS)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to investigate the safety and efficacy of AMX0035 in patients with Amyotrophic Lateral Sclerosis
    En studie för att utvärdera säkerhet och effekt hos AMX0035 jämfört med placebo av patienter med amyotrofisk lateralskleros
    A.3.2Name or abbreviated title of the trial where available
    Phoenix
    A.4.1Sponsor's protocol code numberA35-004
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT05021536
    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 SponsorAmylyx Pharmaceuticals 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 supportAmylyx Pharmaceuticals Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPPD, part of Thermo Fisher Scientific
    B.5.2Functional name of contact pointProject Manager
    B.5.3 Address:
    B.5.3.1Street AddressAvenida da Liberdade, 180 A, 4° Dt
    B.5.3.2Town/ cityLisbon
    B.5.3.3Post code 1250-146
    B.5.3.4CountryPortugal
    B.5.4Telephone number+351213500904
    B.5.6E-mailcristina.oliviera@ppd.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 numberEU/3/20/2284
    D.3 Description of the IMP
    D.3.2Product code AMX0035
    D.3.4Pharmaceutical form Oral powder in sachet
    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 INNphenylbutyrate
    D.3.9.1CAS number 1716-12-7
    D.3.9.4EV Substance CodeSUB127264
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNUrsodoxicoltaurine
    D.3.9.1CAS number 14605-22-2
    D.3.9.3Other descriptive nametaurursodiol
    D.3.9.4EV Substance CodeSUB218624
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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) 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) 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.IMP: 2
    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/3/20/2284
    D.3 Description of the IMP
    D.3.2Product code AMX0035
    D.3.4Pharmaceutical form Oral powder in sachet
    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 INNPHENYLBUTYRATE
    D.3.9.1CAS number 1716-12-7
    D.3.9.4EV Substance CodeSUB127264
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNUrsodoxicoltaurine
    D.3.9.1CAS number 14605-22-2
    D.3.9.3Other descriptive nametaurursodiol
    D.3.9.4EV Substance CodeSUB218624
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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) 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) 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 placeboOral powder in sachet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboOral powder in sachet
    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
    ALS (amyotrophic lateral sclerosis)
    E.1.1.1Medical condition in easily understood language
    ALS
    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
    1. To assess the safety and tolerability of AMX0035 treatment over 48 weeks compared to placebo in adult patients with ALS.
    2. To assess the impact of AMX0035 treatment compared to placebo on disease progression over 48 weeks based on change from baseline of ALSFRS-R and survival.
    E.2.2Secondary objectives of the trial
    1. To assess the impact of AMX0035 compared to placebo on Slow Vital Capacity (SVC) over 48 weeks.
    2. To assess patient quality of life (QOL; using the 40-item ALS assessment questionnaire [ALSAQ-40] patient-reported outcome [PRO]) during treatment with AMX0035 compared to placebo over 48 weeks.
    3. To assess AMX0035 compared to placebo on the time to any decline in King’s and MiToS stages as derived from ALSFRS-R data over 48 weeks.
    4. To assess the impact of AMX0035 compared to placebo on ventilation free survival (defined as death, tracheostomy for respiratory distress or permanent non-invasive ventilation [>22 hours per day for 7 consecutive days]) over 48 weeks.
    5. To assess AMX0035 compared to placebo on patient health status (using the EQ-5D descriptive system and the EQ visual analogue scale [EQ VAS] PRO during treatment with AMX0035 over 48 weeks.
    Finally, a secondary objective of the trial is to assess the long-term survival of patients treated with AMX0035 or placebo.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    A sub-study is included in the main protocol. Matched evaluation will be performed of QTc interval prolongation (evaluated by digital ECG with central read) and blood sample for evaluation of systemic exposure (measurement in plasma using a validated assay for PB and its major metabolite PAA, and taurursodiol and its major metabolites ursodiol and glycine conjugatedursodiol).
    E.3Principal inclusion criteria
    1. Male or female, at least 18 years of age.
    2. Diagnosis of ALS (definite or clinically probable), made by a physician who is experienced with management of ALS, as defined by the World Federation of Neurology revised El Escorial criteria.
    3. Time since onset of first symptom of ALS should be <24 months.
    4. If the participant is to be treated with riluzole and/or edaravone during the course of the trial, then treatment with riluzole and/or edaravone was, at the time of the screening visit, started and maintained at a stable regimen for at least 14 days for riluzole and/or for a full treatment cycle for edaravone.
    5. Capable of providing informed consent.
    6. Capable and willing to follow trial procedures including visits to the trial clinic and visit requirements.
    7. Women of childbearing potential (WOCBP; e.g., not post-menopausal for at least one year or surgically sterile*) must agree to use adequate birth control** for the duration of the trial and 3 months after the last dose of study drug.
    8. Women must not be pregnant or planning to become pregnant for the duration of the trial and 3 months after last dose of study drug.
    9. Men must agree to practice contraception for the duration of the trial and for at least 3 months after last dose of study drug;
    10. Men must not plan to father a child or to provide sperm for donation for the duration of the trial and 3 months after the last dose of study drug.
    * 12 months of spontaneous amenorrhea or 6 months of spontaneous amenorrhea with serum follicle stimulating hormone (FSH) levels > 40 mIU/ml or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy.
    ** Acceptable contraception for use in this trial are:
    - Hormonal methods, such as birth control pills, patches, injections, vaginal ring, or implants;
    - Barrier methods (such as a condom or diaphragm) used with a spermicide (a foam, cream, or gel that kills sperm);
    - Intrauterine device (IUD);
    - Abstinence (no heterosexual sex);
    - Unique partner who is surgically sterile (men) or not of childbearing potential (female).
    E.4Principal exclusion criteria
    1. Presence of tracheostomy or PAV.
    2. Slow Vital Capacity (SVC) less than 55%.
    3. History of known allergy to PB or bile salts.
    4. Abnormal liver function defined as bilirubin levels and/or aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 5 times the upper limit of the normal (obtained within 12 weeks from first dose).
    5. Renal insufficiency as defined by estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2 (obtained within 12 weeks from first dose).
    6. Pregnant women (confirmed by a pregnancy test within 7 days of first dose) or women currently breastfeeding.
    7. Current severe biliary disease which may result in the Investigator medical judgment in biliary obstruction including for example active cholecystitis, primary biliary cirrhosis, sclerosing cholangitis, gallbladder cancer, gangrene of the gallbladder, abscess of the gallbladder.
    8. History of Class III/IV heart failure (per New York Heart Association – NYHA).
    9. Participant under severe salt restriction where the added salt intake due to treatment would put the participant at risk, in the Investigator clinical judgment.
    10. Presence of unstable psychiatric disease, cognitive impairment, dementia or substance abuse that would impair ability of the participant to provide informed consent, according to Investigator judgment.
    11. Clinically significant unstable medical condition (other than ALS) (e.g., cardiovascular instability, systemic infection, untreated thyroid dysfunction, clinically significant
    laboratory test or ECG abnormality) that would pose a risk to the participant if he/she were to participate in the trial, according to Investigator judgment;
    12. Previous treatment for ALS with cellular therapies or gene therapies;
    13. Currently enrolled on another trial involving use of an investigational therapy;
    14. Previous treatment with PB or taurursodiol within 30 days from Screening;
    15. Implantation of Diaphragm Pacing System (DPS);
    16. Currently or previously treated within the last 30 days or planned exposure to any prohibited
    medications listed in Section 6.8 of the protocol.
    E.5 End points
    E.5.1Primary end point(s)
    Primary Safety Endpoints:
    o Incidence and severity of AE and SAEs
    o Incidence of abnormalities in clinical laboratory assessments
    o Withdrawal from the trial
    Primary Efficacy Endpoint
    o Joint assessment of ALSFRS-R total score progression over 48 weeks adjusted for mortality
    E.5.1.1Timepoint(s) of evaluation of this end point
    AEs and SAEs will be monitored continuously.
    Clinical laboratory safety assessments will be performed at Screening and baseline, and 24 and 48 weeks after start of treatment.
    ALSFRS-R will be assessed at baseline and every 4 weeks after start of treatment until 48 weeks after start of treatment.
    E.5.2Secondary end point(s)
    o Change from baseline to Week 48 of the SVC as percentage of normalized values for gender, body weight, age, and ethnicity
    o Change from baseline to Week 48 of the ALSAQ-40 total score
    o Time from baseline to transition through a King’s stage or through a MiToS stages (derived from ALSFRS-R data)
    o Time from baseline remaining ventilation free i.e., death, tracheostomy for respiratory distress, permanent non-invasive ventilation (PAV)
    o Change from baseline of the EQ-5D score and visual analog scale (VAS) at Week 48
    o Overall survival with all-cause mortality, assessed by independent confirmation of vitals status of all patients randomized into the trial extending after completion of the planned trial follow-up of 48 weeks
    E.5.2.1Timepoint(s) of evaluation of this end point
    SVC will be assessed at Screening and baseline, and every 4 weeks after start of treatment until 48 weeks after start of treatment.
    ALSAQ-40, King's stage, MiToS stage, EQ-5D-score and VAS scale will be assessed at baseline and every 12 weeks after start of treatment until 48 weeks after start of treatment.
    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 Yes
    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) No
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA36
    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
    Belgium
    France
    Germany
    Ireland
    Italy
    Netherlands
    Poland
    Portugal
    Spain
    Sweden
    United Kingdom
    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 trial will correspond to the last participant last EOT visit/phone contact per the trial schedule.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    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 years3
    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.1.2.1Number of subjects for this age range: 435
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 229
    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 state24
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 552
    F.4.2.2In the whole clinical trial 664
    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)
    Post trial, AMX0035 will be made available to participants completing the study period in accordance with each competent authority's regulatory guidance.
    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 Decision2021-08-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-07-14
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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