Overt Hepatic Encephalopathy in Subjects with Liver Cirrhosis MedDRA version: 21.1 Level: PT Classification code 10019660 Term: Hepatic encephalopathy System Organ Class: 10029205 - Nervous system disorders MedDRA version: 20.0 Level: LLT Classification code 10024667 Term: Liver cirrhosis System Organ Class: 100000004871
Conditions
Interventions
Product Code: AXA1665
Pharmaceutical Form: Powder for oral suspension
CAS Number: 61-90-5
Other descriptive name: L-LEUCINE
Concentration unit: g gram(s)
Concentration type: equal
Concentration number
Sponsors
Axcella Health, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
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and OHE medication use Note: If OHE is present at or after Screening and prior to randomization, the subject will be withdrawn; however, they may be rescreened after their active OHE episode has resolved and may be allowed to participate in the study provided they satisfy the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 Are the trial subjects under 18? no Number of subjects for this age range:
Exclusion criteria
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 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 anx
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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. ;Secondary Objective: • 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 ;Primary end point(s): Proportion (%) of subjects with > or = +2 change in the PHES at 24 weeks;Timepoint(s) of evaluation of this end point: 24-week treatment period | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary 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. ;Timepoint(s) of evaluation of this end point: 24-week treatment period | — |
Countries
Canada, France, Germany, Hungary, Italy, Poland, Spain, United Kingdom, United States
Contacts
Public ContactFranklin Vairinhos
Axcella Health, Inc.
Outcome results
None listed