E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Overt Hepatic Encephalopathy in Subjects with Liver Cirrhosis |
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E.1.1.1 | Medical condition in easily understood language |
Cirrhotic Subjects With Prior Overt Hepatic Encephalopathy |
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E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10019660 |
E.1.2 | Term | Hepatic encephalopathy |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10024667 |
E.1.2 | Term | Liver cirrhosis |
E.1.2 | System Organ Class | 100000004871 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main 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. |
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E.2.2 | Secondary 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); and • Changes in other general HR-QoL measures (PROMIS-29), caregiver burden (Zarit Burden Interview), and falls. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 documented prior episode of OHE within 24 weeks prior to Screening; Note: OHE documentation should be available with sufficient information for the Investigator to independently confirm a clinical diagnosis of OHE (eg, medical records or discharge summary) and treatments administered for that OHE episode (eg, lactulose/lactitol administered with or without rifaximin). 3. A PHES ≤-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-Na score of <20 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 or has a legally authorized representative (LAR) who is 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 for the entire duration of the study and the identified primary caregiver 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, 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 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 recreational 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; or • 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; and 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; and • 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.
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E.4 | Principal 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. History or presence of Child’s Pugh class C, hepato-renal syndrome(s), refractory ascites or spontaneous bacterial peritonitis (SBP), including SBP prophylaxis within 12 weeks of randomization; 5. History of a 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. Screening Alcohol Use Disorders Identification Test (AUDIT) score ≥8; 8. 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 of Screening, clinically significant arrhythmias, heart failure); b. Renal disorder (acute renal failure or dialysis requirement); c. Type 1 diabetes; d. Respiratory disorder (eg, severe chronic obstructive pulmonary disease or asthma or exacerbations of the same within 12 weeks of Screening); e. Gastrointestinal (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, non-cirrhotic portal hypertension); f. Inborn errors of metabolism such as urea cycle disorders; g. Infections (eg, human immunodeficiency virus [HIV] seropositive, hepatitis B surface antigen positive, or hepatitis C virus ribonucleic acid [RNA] positive at Screening); h. Neurologic conditions (eg, Alzheimer’s disease, Parkinson’s disease, seizure disorders, and non-hepatic metabolic encephalopathies); i. Positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA at screening or has significant contact (ie, household) with a known positive case of coronavirus disease 2019 (COVID-19) during Screening; j. 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 >3 times the upper limit of normal, unless documented Gilbert’s disease; 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, 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 study: • BCAAs, N-acetylcysteine, L-carnitine, creatine, ornithine, aspartate, L-ornithine L-aspartate • Cannabidiol • Amiodarone • Tamoxifen • Valproic acid • Testosterone, growth hormone or other androgens or anabolic agents • Chronic use of opioids or benzodiazepines (intermittent prescribed usage [e.g. <14 days] is permitted) • Chronic uses of systemic corticosteroids or immunosuppressants (intermittent prescribed usage [e.g. <14 days] is permitted). For further information, please go to protocol section 4.2 Exclusion criteria, page 43. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Proportion (%) of subjects with > or = +2 change in the PHES at 24 weeks |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Key secondary endpoints: Proportion (%) of subjects a PHES score >-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; and • Change from baseline in physical function as assessed by the PROMIS Physical Function Short Form 8b at 24 weeks. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 36 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If 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 |
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E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 10 |