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    Summary
    EudraCT Number:2020-005969-13
    Sponsor's Protocol Code Number:AXA1665-101
    National Competent Authority:Poland - Office for Medicinal Products
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2021-07-02
    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 ConcernedPoland - Office for Medicinal Products
    A.2EudraCT number2020-005969-13
    A.3Full title of the trial
    A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of AXA1665 in Subjects With Liver Cirrhosis and Prior Overt Hepatic Encephalopathy (EMMPOWER)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy and Safety of AXA1665 in Cirrhotic Subjects With Prior Overt Hepatic Encephalopathy
    A.4.1Sponsor's protocol code numberAXA1665-101
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04816916
    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 SponsorAxcella Health, 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 supportAxcella Health Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAxcella Health, Inc.
    B.5.2Functional name of contact pointFranklin Vairinhos
    B.5.3 Address:
    B.5.3.1Street Address840 Memorial Drive, Third Floor
    B.5.3.2Town/ cityCambridge
    B.5.3.3Post codeMA 02139
    B.5.3.4CountryUnited States
    B.5.4Telephone number1-484-431-9562
    B.5.6E-mailfvairinhos@axcellatx.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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code AXA1665
    D.3.4Pharmaceutical form Powder for oral suspension
    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.3.9.1CAS number 61-90-5
    D.3.9.3Other descriptive nameL-LEUCINE
    D.3.9.4EV Substance CodeSUB21983
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1.6296
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 73-32-5
    D.3.9.3Other descriptive nameL-ISOLEUCINE
    D.3.9.4EV Substance CodeSUB21979
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.8147
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNL-VALINE
    D.3.9.1CAS number 72-18-4
    D.3.9.4EV Substance CodeSUB21995
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1.6296
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 657-27-2
    D.3.9.3Other descriptive nameL-LYSINE HCL
    D.3.9.4EV Substance CodeSUB183946
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.7631
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 71-00-1
    D.3.9.3Other descriptive nameL-HISTIDINE
    D.3.9.4EV Substance CodeSUB20034
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.6111
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 72-19-5
    D.3.9.3Other descriptive nameL-THREONINE
    D.3.9.4EV Substance CodeSUB21991
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.6111
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 3230-94-2
    D.3.9.3Other descriptive nameL-ORNITHINE L-ASPARTATE
    D.3.9.4EV Substance CodeSUB14714MIG
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3.0556
    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.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 placeboPowder for oral suspension
    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
    Overt Hepatic Encephalopathy in Subjects with Liver Cirrhosis
    E.1.1.1Medical condition in easily understood language
    Cirrhotic Subjects With Prior Overt Hepatic Encephalopathy
    E.1.1.2Therapeutic area Body processes [G] - Metabolic Phenomena [G03]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10019660
    E.1.2Term Hepatic encephalopathy
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10024667
    E.1.2Term Liver cirrhosis
    E.1.2System Organ Class 100000004871
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Demonstrate the efficacy of AXA1665 compared to placebo on neurocognitive function as assessed by the PHES over 24 weeks in cirrhotic subjects with a prior history of OHE.
    E.2.2Secondary objectives of the trial
    • Safety and tolerability of AXA1665
    • Changes in other cognitive function measures (Stroop Off+On time via the Stroop EncephalApp
    • Impact on OHE recurrence as assessed by the total number of OHE breakthrough events
    time to first OHE breakthrough event, and hospitalizations for OHE-related events
    • Impact on all-cause hospitalizations
    • Impact on physical function as assessed by the LFI and HR-QoL measures (Patient-
    Reported Outcomes Measurement Information System [PROMIS] Physical Function Short Form 8b
    • Changes in other general HR-QoL measures (PROMIS-29) and falls
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subjects are eligible to be included in the study only if all of the following criteria are met:
    1. Male or female adults, age ≥18 years
    2. History of cirrhosis and at least 1 prior episode of OHE prior to Screening
    3. A PHES of ≤-4 during Screening
    4. Absence of OHE at both Screening and prior to randomization, as assessed by a standardized questionnaire administered by the Investigator to assess alertness, orientation, and OHE medication use
    Note: If OHE is present at or after Screening and prior to randomization, the subject will be withdrawn; however, they may be rescreened after their active OHE episode has resolved and may be allowed to participate in the study provided they satisfy the eligibility criteria.
    5. MELD score of ≤22 at Screening
    6. Negative radiographic examination for hepatocellular carcinoma (HCC) within 24 weeks prior to Screening, whether conducted by ultrasound, computed axial tomography, or magnetic resonance imaging; or a negative ultrasound for lesions suspicious for HCC during Screening
    7. Able and willing to provide written informed consent. For subjects who are unable to provide written informed consent, a legally authorized representative (LAR) if allowable by local regulations) must be able and willing to give written informed consent. When the LAR provides informed consent, the subject must also provide written assent if able
    8. Support of a primary caregiver who is able and willing to give written informed consent. The identified primary caregiver must be willing to assist with assessing the subject’s level of alertness and orientation, filling out diaries, and attending scheduled and unscheduled study visits; to observe any changes in the subject’s health; and to remind the subject to take the study drug
    9. Willing to comply with specified procedures as stated in the protocol
    10. Agrees to abstain from alcohol consumption for the duration of the study, from Screening through the final study visit
    11. Negative urine ethyl glucuronide at Screening
    Note: If the subject’s urine ethyl glucuronide is confirmed to be positive during the course of the study, it would lead to the subject’s withdrawal from the study.
    12. Negative urine screen for drugs of abuse or legal substance abuse, including marijuana, at Screening
    13. If a subject is female, 1 of the following criteria must be met
    • Surgically sterile
    • Postmenopausal with ≥12 months of amenorrhea without an alternate medical cause
    • Follicle-stimulating hormone level consistent with postmenopausal state if amenorrhoeic for <12 months or is <55 years of age
    • Female of childbearing potential must have a negative serum pregnancy test at Screening, must not be lactating, and must agree to abstain from sexual activity or agree to use a highly effective method of contraception (failure rate <1%) for the duration of the study and for at least 30 days after the last dose of study drug
    14. If the subject is male, the following criteria must be met:
    • Male subjects with a female partner of childbearing potential must agree to abstain from sexual activity or agree to use a highly effective contraceptive method (failure rate <1%) for the duration of the study and for at least 3 months after the last dose of study drug
    • Male subjects capable of fathering a child must agree to refrain from sperm donation for the duration of the study and for at least 3 months after the last dose of study drug
    E.4Principal exclusion criteria
    Subjects will be excluded from the study if any of the following criteria are met:
    1. Hospitalization or serious medical illness (eg, hemorrhage, infections, myocardial infarction, stroke) within 4 weeks prior to randomization
    2. Initiation of any new medication, dose, or regimen for OHE management within 4 weeks prior to Screening
    Note 1: Lactulose/lactitol dose adjustments based on stool consistency are permitted.
    3. Initiation of any systemic antibiotic or antiviral medication within 4 weeks prior to randomization
    4. Presence of Child Pugh score ≥12, , hepato-renal syndrome(s), refractory ascites, or spontaneous bacterial peritonitis (SBP) within 12 weeks prior to Screening.
    Note: Subjects on secondary SBP prophylaxis are eligible if prophylaxis initiated at least 12 weeks prior to Screening.
    5. History of a surgical portosystemic or a transjugular intrahepatic portosystemic shunt (TIPS) placement
    6. Expectation of a liver transplant from Screening through the end of the study (ie, Week 28 visit)
    7. Presence of clinically significant comorbid illnesses that might preclude completion of the study, including but not limited to the following:
    a. Cardiovascular disorder (eg, myocardial infarction within 12 weeks prior to Screening, clinically significant arrhythmias, heart failure [New York Heart Association Class III or IV])
    b. Renal disorder (acute renal failure or dialysis requirement
    c. Poorly controlled Type 1 diabetes or frequent episodes of hyper- or hypoglycemia
    d. Respiratory disorder (eg, severe chronic obstructive pulmonary disease or asthma or exacerbations of the same within 12 weeks prior to Screening)
    e. Gastrointestinal disease with a clinical concern for ongoing malabsorption or presence of clinical symptoms (eg, malabsorption syndromes, pancreatic insufficiency, chronic pancreatitis, Crohn’s disease, ulcerative colitis, celiac disease, and other protein losing enteropathies; gastrointestinal hemorrhage requiring >2 units of blood transfusion within 12 weeks prior to Screening or noncirrhotic portal hypertension
    f. Inborn errors of metabolism such as urea cycle disorders
    g. Infections (eg, human immunodeficiency virus seropositive, hepatitis B with quantifiable deoxyribonucleic acid level, or hepatitis C virus ribonucleic acid [RNA] positive at Screening
    h. Neurologic conditions (eg, Alzheimer’s disease, Parkinson’s disease, seizure disorders, and nonhepatic metabolic encephalopathies
    i. Positive severe acute respiratory syndrome coronavirus 2 RNA at Screening or has significant contact (ie, household) with a known positive case of coronavirus disease 2019 during Screening
    8. Vision disorders including any history or presence of anamnestic red-green visual blindness or partial or complete blindness in 1 eye
    9. Alpha-fetoprotein >20ng/mL
    10. Estimated glomerular filtration rate <45 mL/min/1.73 m2
    11. Hemoglobin <8.0 g/dL at Screening
    12. Total bilirubin >4 times the upper limit of normal
    13. Fluid consumption restricted to < 1500 mL/day
    14. Any clinically significant dose adjustments/titrations or addition of psychoactive drugs such as antidepressants/mood stabilizers, antipsychotics, opioids, cannabidiol, and sedatives (eg, a change anticipated to impact the ability to participate in the study or interpret either safety or efficacy endpoints), within 4 weeks prior to Screening or anticipated during the study
    Note 1: Occasional (<2 weeks within 4 weeks prior) use of these agents for temporary relief of situational anxiety, pain, or insomnia are not exclusionary.
    Note 2: Clinically significant adjustments of these medications during the course of the study would lead to subject withdrawal.
    15. Any clinically significant dose adjustments/titrations or addition of medications for the subject’s stable chronic conditions (a change anticipated to impact the ability to participate in the study or interpret either safety or efficacy endpoints) within 4 weeks prior to Screening
    16. Use of the following prohibited medications within 4 weeks of Screening and during the
    E.5 End points
    E.5.1Primary end point(s)
    Proportion (%) of subjects with > or = +2 change in the PHES at 24 weeks
    E.5.1.1Timepoint(s) of evaluation of this end point
    24-week treatment period
    E.5.2Secondary end point(s)
    Key secondary endpoints:
    • Proportion (%) of subjects a PHES of >-4 at 24 weeks
    • Change from baseline in PHES
    • Change from baseline in the Stroop Off+On time by the Stroop EncephalApp
    • Proportion (%) of subjects experiencing at least 1 OHE event
    • Total number of OHE events
    • Time to first OHE breakthrough event
    • Time to first hospitalization for both OHE-related and all-cause hospitalizations
    • Proportion of and number of OHE events that resulted in hospitalization
    • Proportion of subjects with at least 1 hospitalization for both OHE and for any reason
    • Duration of hospitalizations for both OHE-related and all-cause hospitalizations
    • Total number of OHE-related and all cause hospitalizations
    • Change from baseline in LFI at 24 weeks
    • Proportion of subjects achieving LFI reduction of ≥0.3
    • Change from baseline in physical function as assessed by the PROMIS Physical Function Short Form 8b at 24 weeks.
    E.5.2.1Timepoint(s) of evaluation of this end point
    24-week treatment period
    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 No
    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 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.8.6 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
    United States
    France
    Germany
    Hungary
    Italy
    Poland
    Spain
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months10
    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: 110
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 40
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 70
    F.4.2.2In the whole clinical trial 150
    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)
    None
    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 Decision2021-09-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-09-13
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-07-06
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