Non-alcoholic Steatohepatitis (NASH)
Conditions
Keywords
Steatohepatitis, NASH, NAFLD, Fatty Liver Disease, Liver, Liver fibrosis
Brief summary
The purpose of this study was to assess the safety, tolerability, and efficacy of a combination treatment of tropifexor (LJN452) and cenicriviroc (CVC) in adult patients with nonalcoholic steatohepatitis (NASH) and liver fibrosis.
Interventions
Comparison with monotherapy and different combination doses
Comparison with monotherapy and different combination doses
Sponsors
Allergan
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Written informed consent Male and female patients 18 years or older (at the time of the screening visit). Patients must weigh at least 50 kg (110 lb) and no more than 200 kg (440 lb) to participate in the study. Able to communicate well with the investigator, to understand and comply with the requirements of the study. Adequate liver biopsy sample for evaluation by Central Reader. Presence of NASH as demonstrated by histologic evidence based on liver biopsy - NASH with fibrosis stage F2/F3, demonstrated on liver biopsy during the screening period. Alternatively, a historical biopsy can be used if performed within 6 months prior to screening.
Exclusion criteria
Use of other investigational drugs within 5 half-lives of enrollment or within 30 days whichever is longer. History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar chemical classes. Previous exposure to elafibranor, CVC, tropifexor, obeticholic acid (OCA), LMB763 or other FXR agonist. Participated in a clinical trial and treated with any investigational product being evaluated for the treatment of liver fibrosis or NASH in the 6 months before screening. Patients taking medications prohibited by the protocol. History of treated or untreated malignancy of any organ system, other than localized basal cell carcinoma of the skin or treated cervical intraepithelial neoplasia, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases . Pregnant or nursing (lactating) women. Women of child-bearing potential. Current or history of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to screening (significant alcohol consumption is defined as more than 20 g/day in females and more than 30 g/day in males, on average) and/or a score on the modified AUDIT questionnaire ≥ 8. Inability to reliably quantify alcohol consumption. History or evidence of ongoing drug abuse, within the last 6 months prior to randomization. Prior or planned (during the study) bariatric surgery. Uncontrolled diabetes defined as HbA1c ≥ 9% at screening Clinical evidence of hepatic decompensation or severe liver impairment. Previous diagnosis of other forms of chronic liver disease. Calculated eGFR less than 60 mL/min (using the MDRD formula). History of biliary diversion History of liver transplantation or planned liver transplant. Known positivity for HIV. History or current diagnosis of ECG abnormalities indicating significant risk of safety for the patient to participate. History of inflammatory bowel disease. Patients who are not candidates for liver biopsy. Presence of cirrhosis on liver biopsy (F4 by NASH CRN System) or medical history Patients with an abnormal platelet count (referring to reference ranges from the central lab).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | AEs were collected from first dose of study treatment until end of study treatment at week 48 and then up to maximum duration of 66 weeks | Occurrence of adverse events and serious adverse events Adverse Events (AEs) are any untoward sign or symptom that occurs during the study treatment and then up to 66 weeks |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants Who Have at Least a One Point Improvement in Fibrosis | baseline to 48 Weeks | Efficacy of tropifexor + CVC in patients with Nonalcoholic steatohepatitis (NASH) with fibrosis stage F2/F3 as assessed by histological improvement after 48 weeks of treatment compared to monotherapies (tropifexor and CVC) compared to baseline biopsy |
| Proportion of Participants With Resolution of Steatohepatitis | baseline to 48 weeks | Efficacy of tropifexor + CVC in patients with Nonalcoholic steatohepatitis (NASH) with fibrosis stage F2/F3 as assessed by histological improvement after 48 weeks of treatment compared to monotherapies (tropifexor and CVC) compared to baseline biopsy |
Countries
Argentina, Belgium, Canada, Czechia, Egypt, France, Germany, India, Israel, Italy, Latvia, Russia, Singapore, Spain, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
193 participants enrolled at 65 sites in 17 countries
Pre-assignment details
450 of 643 subjects discontinued during screening phase
Participants by arm
| Arm | Count |
|---|---|
| Arm A: Tropifexor (LJN452) - Dose 1 tropifexor 140 mg, once daily | 50 |
| Arm B: Cenicriviroc (CVC) CVC 150 mg, once daily | 48 |
| Arm C: Tropifexor (LJN452) Dose 1 + CVC tropifexor 140 mg + CVC 150 mg, once daily | 47 |
| Arm D: Tropifexor Dose 2 + CVC tropifexor 90 mg + CVC 150 mg, once daily | 48 |
| Total | 193 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 9 | 3 | 8 | 1 |
| Overall Study | Protocol Violation | 2 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 4 | 1 | 3 |
Baseline characteristics
| Characteristic | Arm A: Tropifexor (LJN452) - Dose 1 | Arm B: Cenicriviroc (CVC) | Arm C: Tropifexor (LJN452) Dose 1 + CVC | Arm D: Tropifexor Dose 2 + CVC | Total |
|---|---|---|---|---|---|
| Age, Continuous | 54.8 years STANDARD_DEVIATION 13.35 | 53.7 years STANDARD_DEVIATION 11.79 | 54.7 years STANDARD_DEVIATION 12.65 | 54.9 years STANDARD_DEVIATION 12.29 | 54.5 years STANDARD_DEVIATION 12.52 |
| Age, Customized <65 | 35 Participants | 39 Participants | 37 Participants | 38 Participants | 149 Participants |
| Age, Customized >=65 | 15 Participants | 9 Participants | 10 Participants | 10 Participants | 44 Participants |
| Race/Ethnicity, Customized Asian | 7 Participants | 4 Participants | 5 Participants | 5 Participants | 21 Participants |
| Race/Ethnicity, Customized Black | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 41 Participants | 44 Participants | 40 Participants | 43 Participants | 168 Participants |
| Sex/Gender, Customized Female | 30 Participants | 31 Participants | 29 Participants | 23 Participants | 113 Participants |
| Sex/Gender, Customized Male | 20 Participants | 17 Participants | 18 Participants | 25 Participants | 80 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 50 | 0 / 48 | 0 / 47 | 0 / 48 |
| other Total, other adverse events | 39 / 50 | 30 / 48 | 33 / 47 | 32 / 48 |
| serious Total, serious adverse events | 5 / 50 | 3 / 48 | 4 / 47 | 10 / 48 |
Outcome results
Primary
Number of Participants With Adverse Events
Occurrence of adverse events and serious adverse events Adverse Events (AEs) are any untoward sign or symptom that occurs during the study treatment and then up to 66 weeks
Time frame: AEs were collected from first dose of study treatment until end of study treatment at week 48 and then up to maximum duration of 66 weeks
Population: Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-baseline safety assessment. Of note, the statement that a patient had no AEs also constituted a safety assessment. Patients were analyzed according to the treatment received
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: Tropifexor (LJN452) - Dose 1 | Number of Participants With Adverse Events | Deaths | 0 Participants |
| Arm A: Tropifexor (LJN452) - Dose 1 | Number of Participants With Adverse Events | Number of participants with at least one Serious Adverse Events (SAEs) | 5 Participants |
| Arm A: Tropifexor (LJN452) - Dose 1 | Number of Participants With Adverse Events | Number of participants with at least one Adverse Event (AE) | 42 Participants |
| Arm B: Cenicriviroc (CVC) | Number of Participants With Adverse Events | Deaths | 0 Participants |
| Arm B: Cenicriviroc (CVC) | Number of Participants With Adverse Events | Number of participants with at least one Adverse Event (AE) | 41 Participants |
| Arm B: Cenicriviroc (CVC) | Number of Participants With Adverse Events | Number of participants with at least one Serious Adverse Events (SAEs) | 3 Participants |
| Arm C: Tropifexor (LJN452) Dose 1 + CVC | Number of Participants With Adverse Events | Number of participants with at least one Serious Adverse Events (SAEs) | 4 Participants |
| Arm C: Tropifexor (LJN452) Dose 1 + CVC | Number of Participants With Adverse Events | Number of participants with at least one Adverse Event (AE) | 40 Participants |
| Arm C: Tropifexor (LJN452) Dose 1 + CVC | Number of Participants With Adverse Events | Deaths | 0 Participants |
| Arm D: Tropifexor Dose 2 + CVC | Number of Participants With Adverse Events | Deaths | 0 Participants |
| Arm D: Tropifexor Dose 2 + CVC | Number of Participants With Adverse Events | Number of participants with at least one Serious Adverse Events (SAEs) | 10 Participants |
| Arm D: Tropifexor Dose 2 + CVC | Number of Participants With Adverse Events | Number of participants with at least one Adverse Event (AE) | 42 Participants |
Secondary
Proportion of Participants Who Have at Least a One Point Improvement in Fibrosis
Efficacy of tropifexor + CVC in patients with Nonalcoholic steatohepatitis (NASH) with fibrosis stage F2/F3 as assessed by histological improvement after 48 weeks of treatment compared to monotherapies (tropifexor and CVC) compared to baseline biopsy
Time frame: baseline to 48 Weeks
Population: Full analysis set (FAS) - All participants to whom study treatment was assigned (excluding patients who were mis-randomized and did not take investigational drug. Mis-randomized participants were those who were not qualified for randomization but were inadvertently randomized into the study). Following the intent-to-treat (ITT) principle, patients were analyzed according to the treatment they had been assigned to at randomization.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A: Tropifexor (LJN452) - Dose 1 | Proportion of Participants Who Have at Least a One Point Improvement in Fibrosis | 10 Participants |
| Arm B: Cenicriviroc (CVC) | Proportion of Participants Who Have at Least a One Point Improvement in Fibrosis | 12 Participants |
| Arm C: Tropifexor (LJN452) Dose 1 + CVC | Proportion of Participants Who Have at Least a One Point Improvement in Fibrosis | 11 Participants |
| Arm D: Tropifexor Dose 2 + CVC | Proportion of Participants Who Have at Least a One Point Improvement in Fibrosis | 13 Participants |
p-value: 0.68895% CI: [0.25, 2.63]Cochran-Mantel-Haenszel
p-value: 0.98595% CI: [0.51, 1.99]Cochran-Mantel-Haenszel
p-value: 0.8795% CI: [0.3, 2.84]Cochran-Mantel-Haenszel
p-value: 0.7195% CI: [0.41, 3.61]Cochran-Mantel-Haenszel
Secondary
Proportion of Participants With Resolution of Steatohepatitis
Efficacy of tropifexor + CVC in patients with Nonalcoholic steatohepatitis (NASH) with fibrosis stage F2/F3 as assessed by histological improvement after 48 weeks of treatment compared to monotherapies (tropifexor and CVC) compared to baseline biopsy
Time frame: baseline to 48 weeks
Population: Full analysis set (FAS) - All participants to whom study treatment was assigned (excluding patients who were mis-randomized and did not take investigational drug. Mis-randomized participants were those who were not qualified for randomization but were inadvertently randomized into the study). Following the intent-to-treat (ITT) principle, patients were analyzed according to the treatment they had been assigned to at randomization.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A: Tropifexor (LJN452) - Dose 1 | Proportion of Participants With Resolution of Steatohepatitis | 8 Participants |
| Arm B: Cenicriviroc (CVC) | Proportion of Participants With Resolution of Steatohepatitis | 8 Participants |
| Arm C: Tropifexor (LJN452) Dose 1 + CVC | Proportion of Participants With Resolution of Steatohepatitis | 5 Participants |
| Arm D: Tropifexor Dose 2 + CVC | Proportion of Participants With Resolution of Steatohepatitis | 9 Participants |
p-value: 0.13695% CI: [0.08, 1.61]Cochran-Mantel-Haenszel
p-value: 0.74795% CI: [0.24, 2.9]Cochran-Mantel-Haenszel
p-value: 0.78495% CI: [0.18, 3.63]Cochran-Mantel-Haenszel
p-value: 0.52195% CI: [0.4, 5.69]Cochran-Mantel-Haenszel