Liver Stiffness, Primary Biliary Cholangitis
Conditions
Keywords
Setanaxib, Primary Biliary Cholangitis, Elevated Liver Stiffness
Brief summary
The primary objective of this study is to evaluate the effect of setanaxib on alkaline phosphatase (ALP) at Week 24 in participants with PBC and with elevated liver stiffness and intolerance or inadequate response to ursodeoxycholic acid (UDCA).
Interventions
DRUGSetanaxib
Oral tablets, 400mg per tablet
DRUGPlacebo
Oral tablets
Sponsors
Calliditas Therapeutics Suisse SA
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Intervention model description
Placebo-controlled 1:1:1 in double blind treatment period.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female participant aged ≥18 years, inclusive at the time of informed consent. * Willing and able to give written informed consent and to comply with the requirements of the study. * Definite or probable PBC diagnosis as demonstrated by the presence of ≥2 of the following 3 diagnostic factors: * Documented history of elevated ALP levels ≥1.67×ULN of the local reference range. * Documented history of positive antimitochondrial antibodies (AMA) titer or positive PBC-specific antibodies (anti-GP210 or anti-SP100 or antibodies against the major M2 components \[PDC-E2, 2-oxo-glutaric acid dehydrogenase complex\]). * Historical liver biopsy consistent with PBC. * Serum ALP ≥1.67×ULN at Screening. * Liver stiffness measured by transient elastography (FibroScan®) of ≥8.8 kilopascals (kPa) and an interquartile range over median ratio (IQR/med) of ≤30% at Screening, are taken with the results expressed in kilopascals). * Ursodeoxycholic acid (UDCA) prescriptional dose use for the past 6 months (at a stable dose for \>3 months prior to Screening) OR intolerant to UDCA (last dose of UDCA \>3 months prior to Screening). Intolerance to UDCA is defined as participants unable to tolerate the full-labelled dose of UDCA in PBC (13-15 mg/kg) due to frequently reported gastrointestinal symptoms such as diarrhea and abdominal pain. * For participants receiving obeticholic acid (OCA), fenofibrate, or bezafibrate treatment for at least 6 months and stable dose for \>3 months prior to Screening. * For participants intolerant to OCA, OCA must have been discontinued \>3 months prior to Screening. * For participants previously treated with bezafibrate or fenofibrate, and these agents were discontinued prior to screening, they must have been discontinued \>3 months prior to Screening. * Female participants of childbearing potential must use a highly effective method of contraception to prevent pregnancy for ≥4 weeks before Randomization and must agree to continue strict contraception up to 90 days after the last dose of investigational medicinal product (IMP). * For the purposes of this trial, women of childbearing potential are defined as Fertile, following menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. * Postmenopausal state is defined as no menses for 12 months without an alternative medical cause. In female participants who are not using hormonal contraception or hormonal replacement therapy but with suspected menopause and less than 12 months of amenorrhea, a high follicle stimulating hormone (FSH) level in the postmenopausal range will be required at Screening to confirm a postmenopausal state. Confirmation with more than one FSH measurement is required. * Highly effective contraception is defined as methods that can achieve a failure rate of less than 1% per year when used consistently and correctly. These methods are: * Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal) * Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or implantable) * Intrauterine device * Intrauterine hormone-releasing system * Bilateral tubal occlusion * Vasectomized partner * Sexual abstinence (refraining from heterosexual intercourse during the entire period of risk associate with the study treatments). The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the participant. Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method are not acceptable methods of contraception. Female condom and male condom should not be used together. * Female participants of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at Baseline/Randomization before dosing. * Male participants with female partners of childbearing potential must be willing to use a condom and require their partner to use a highly effective contraceptive method. This requirement begins at the time of informed consent and ends 90 days after receiving the last dose of IMP. * Male participants must be willing not to donate sperm, and female study participants must be willing not to donate eggs, from Baseline until 90 days after the last dose of IMP.
Exclusion criteria
* A positive pregnancy test or breastfeeding for female participants. * Any historical or current hepatic decompensation event defined as variceal/portal hypertension bleed and/or hepatic encephalopathy, spontaneous bacterial peritonitis, ascites requiring treatment, or liver transplantation list inclusion. * History of liver transplantation, current placement on a liver transplant list or current model for end stage liver disease (MELD) score of ≥12 unless the participant is on anticoagulant therapy, or a Child-Pugh Score of ≥6. * Cirrhosis with complications, including history or presence of hepatocellular carcinoma. * Total bilirubin \>2×ULN. In case of total bilirubin elevation \>ULN the Screening serum albumin must be within the reference range. * Plasma alanine aminotransferase (ALT) \>3×ULN and/or aspartate aminotransferase (AST) \>3×ULN. * International normalized ratio (INR) \>1.2 unless participant is on anticoagulant therapy. One repeat blood sampling (with analysis by the central laboratory) can be performed at the discretion of the Investigator at Screening Visit 2 for participants who meet this exclusion criterion at Screening Visit 1. If this exclusion criterion is not met at Screening Visit 2, the participant may be eligible for the study. * Estimated glomerular filtration rate (eGFR) \<60 mL/min/1.73 m\^2, as calculated by the central laboratory using the chronic kidney disease-epidemiology collaboration (CKD- EPI) equation. * Thyroid-stimulating hormone \>ULN at Screening. One repeat blood sampling (with analysis by the central laboratory) can be performed at the discretion of the Investigator at Screening Visit 2 for participants who meet this exclusion criterion at Screening Visit 1. If this exclusion criterion is not met at Screening Visit 2, the participant may be eligible for the study. * Competing etiology for liver disease (eg, hepatitis C \[unless effectively cured of hepatitis C, with a sustained virologic response for at least 6 months prior to Screening\], active hepatitis B \[HBsAg positive\], nonalcoholic steatohepatitis \[NASH\], alcoholic liver disease, autoimmune hepatitis, autoimmune hepatitis-PBC overlap syndrome, primary sclerosing cholangitis, Gilbert's Syndrome). * Medical conditions that could cause nonhepatic increases in ALP (eg, Paget's disease). * Known history of human immunodeficiency virus (HIV) infection. * Surgery (eg, stomach bypass) or medical condition that might significantly affect absorption of medicines (as judged by the Investigator). * Positive urine drug screen (if not due to prescriptional use of a concomitant medication, as confirmed by the Investigator) at Screening. Participants on stable methadone or buprenorphine maintenance treatment for at least 6 months prior to Screening Visit 1 may be included in the study. Medicinal cannabis and cannabidiol products are not exclusionary and may be allowed if the prescription and diagnosis are reviewed and approved by the Investigator. * Participants receiving prohibited medications within 3 months of Screening Visit 1. * Treatment with any investigational agent within 12 weeks of Screening Visit 1 or 5 half-lives of the IMP (if known) (whichever is longer) or current enrollment in an interventional clinical trial. * Evidence of any of the following cardiac conduction abnormalities: A QTc Fridericia interval \>450 milliseconds for males or \>470 milliseconds for females, as calculated by the central reader. Participants with a second- or third-degree atrioventricular block are to be excluded. * History of a malignancy within 5 years of Screening with the following exceptions: * Adequately treated carcinoma in situ of the cervix. * Adequately treated basal or squamous cell cancer or other localized nonmelanoma skin cancer. * The occurrence of any acute infection requiring systemic antibiotic therapy within the 2 weeks prior to Screening Visit 1. * A history of bone marrow disorder including aplastic anemia, or any current marked anemia defined as hemoglobin \<10.0 g/dL. * Prior treatment with setanaxib or participation in a previous setanaxib clinical trial. * Unstable cardiovascular disease. * Presence of any laboratory abnormality or condition that, in the opinion of the Investigator, could interfere with or compromise a participant's treatment, assessment, or compliance with the protocol and/or study procedures. * Any other condition which, in the opinion of the Investigator, constitutes a risk or contraindication for the participation of the participant in the study, or that could interfere with the study objectives, conduct, or evaluation. * Hypersensitivity or intolerance to setanaxib or to any of its excipients or placebo compounds.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in ALP at Week 24 Compared to Baseline | Baseline (Day 1) and Week 24 | Change in ALP at Week 24 Compared to Baseline, ratio of week 24 value to baseline value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Fatigue at Week 24 Compared to Baseline, as Assessed by the Patient's Global Impression of Severity (PGIS) Fatigue | Baseline (Day 1) and Week 24 | The Patient's Global Impression of Severity (PGIS)-Fatigue is a global index where subjects are asked to rate the severity of fatigue on a 5-point scale within the past 7 days, with choices of 1=None, 2=Mild, 3=Moderate, 4=Severe and 5=Very Severe. Higher scores indicate a worse assessment for fatigue. |
| Change in Fatigue at Week 24 Compared to Baseline, as Assessed by the Patient's Global Impression of Change (PGIC) Fatigue | Week 24 | The Patient's Global Impression of Change (PGIC)-Fatigue is a 7-point scale reflecting a subject's rating of overall improvement where subjects are asked to rate their overall improvement with fatigue with 1=Very much improved, 2=Much improved, 3=Minimally improved, 4=No change, 5=Worse, 6=Much worse, 7=Very much worse. Higher scores indicate a worse outcome for change in fatigue. |
| Change in Fatigue at Week 24 Compared to Baseline, as Assessed by the PBC-40 Questionnaire (PBC 40) Fatigue Domain | Baseline (Day 1) and Week 24 | PBC-40 fatigue domain includes 11 item questions, items scores range from 1 to 5. The individual item scores are summed to obtain a total domain score (Range for fatigue domain: 11 to 55), high scores represent high impact and low scores indicate low impact of PBC on the quality of life. |
| Change in Liver Stiffness at Week 24 Compared to Screening | Screening (Day -28) and Week 24 | Change in liver stiffness at Week 24 compared to Screening, as assessed by transient elastography (FibroScan®) |
| Change in Pruritus at Week 24 Compared to Baseline, as Assessed by the Worst Itch Numerical Rating Scale (WI-NRS) | Baseline (Day 1) and Week 24 | WI-NRS is a daily patient-reported measure of itch intensity using an 11-point scale where 0=no itch and 10=worst itching imaginable. The WI-NRS score is calculated by averaging the daily WI-NRS scores before the visit date (inclusive). Higher scores indicate worse functioning for pruritus on the WI-NRS. |
| Change in Pruritus at Week 24 Compared to Baseline, as Assessed by the PBC-40 Itch Domain | Baseline (Day 1) and Week 24 | Pruritus was assessed by answering 3 questions on the PBC-40 Itch domain from 1 to 5, which was also summed to obtain a total domain score (range 3 to 15). A high score represents a high impact, and a low score indicates low impact of pruritus on the quality of life. |
| Change in Fatigue at Week 24 Compared to Baseline, as Assessed by the PROMIS Short Form-Fatigue 7b Daily | Baseline (Day 1) and Week 24 | The Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form 7b measures the severity of fatigue since waking. There are 7 questions, each scored between 1 and 5, with a total score between 7 to 35. A higher score indicates worse fatigue. This raw score is converted to a T score (a standardized score with a mean of 50 and a SD of 10). |
| Change in Pruritus at Week 24 Compared to Baseline, as Assessed by the PGIC Pruritus | Week 24 | The PGIC-Pruritus is a 7-point scale reflecting a subject's rating of overall improvement where subjects are asked to rate their overall improvement with fatigue with 1=Very much improved, 2=Much improved, 3=Minimally improved, 4=No change, 5=Worse, 6=Much worse, 7=Very much worse. Higher scores indicate a worse outcome for change in pruritus. |
| Changes in Markers of Cholestasis at Week 24 | Baseline (Day 1) and Week 24 | Changes in markers of cholestasis as assessed by proportion of patients at Week 24 with: * ALP reduction to \<1.67×ULN and total bilirubin ≤1×ULN and a ≥15% or ≥30% or ≥40% or ≥70% ALP reduction from Baseline, respectively * ALP reduction to \<1.5×ULN and total bilirubin ≤1×ULN and a ≥40% ALP reduction from Baseline * ALP \<1×ULN and total bilirubin ≤1×ULN * Total bilirubin \<0.6×ULN |
| Change in ALP at Week 24 Compared to Baseline, Where Setanaxib Doses Are Combined | Baseline (Day 1) and Week 24 | Change in ALP at Week 24 Compared to Baseline, ratio of week 24 value to baseline value. Setanaxib doses are combined and the change from baseline is estimated using a mixed model-repeated measures approach with fixed factors for treatment, visit, log(baseline), treatment\*visit, and log(baseline)\*visit, subject is included as a random effect. The variance-covariance matrix is therefore not the same as in the three arm analysis, which causes treatment effects estimated in the placebo to group differ from those estimated in the analysis with three treatment arms. |
| Change in Fatigue at Week 24 Compared to Baseline, as Assessed by the PROMIS Short Form-Fatigue 7b Daily, Where Setanaxib Doses Are Combined | Baseline (Day 1) and Week 24 | The Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form 7b measures the severity of fatigue since waking. There are 7 questions, each scored between 1 and 5, with a total score between 7 to 35. A higher score indicates worse fatigue. This raw score is converted to a T score (a standardized score with a mean of 50 and a SD of 10). Setanaxib doses are combined and the change from baseline is estimated using a mixed model-repeated measures approach with fixed factors for treatment, visit, log(baseline), treatment\*visit, and log(baseline)\*visit, subject is included as a random effect. The variance-covariance matrix is therefore not the same as in the three arm analysis, which causes treatment effects estimated in the placebo to group differ from those estimated in the analysis with three treatment arms. |
| Change in Fatigue at Week 24 Compared to Baseline, as Assessed by the PBC-40 Questionnaire (PBC 40) Fatigue Domain, Where Setanaxib Doses Are Combined | Baseline (Day 1) and Week 24 | PBC-40 fatigue domain includes 11 item questions, items scores range from 1 to 5. The individual item scores are summed to obtain a total domain score (Range for fatigue domain: 11 to 55), high scores represent high impact and low scores indicate low impact of PBC on the quality of life. Setanaxib doses are combined and the change from baseline is estimated using a mixed model-repeated measures approach with fixed factors for treatment, visit, log(baseline), treatment\*visit, and log(baseline)\*visit, subject is included as a random effect. The variance-covariance matrix is therefore not the same as in the three arm analysis, which causes treatment effects estimated in the placebo to group differ from those estimated in the analysis with three treatment arms. |
| Change in Liver Stiffness at Week 24 Compared to Screening, Where Setanaxib Doses Are Combined | Screening (Day -28) and Week 24 | Change in liver stiffness at Week 24 compared to Screening, as assessed by transient elastography (FibroScan®). Setanaxib doses are combined and the change from baseline is estimated using a mixed model-repeated measures approach with fixed factors for treatment, visit, log(baseline), treatment\*visit, and log(baseline)\*visit, subject is included as a random effect. The variance-covariance matrix is therefore not the same as in the three arm analysis, which causes treatment effects estimated in the placebo to group differ from those estimated in the analysis with three treatment arms. |
| Change in Pruritus at Week 24 Compared to Baseline, as Assessed by the PGIS Pruritus | Baseline (Day 1) and Week 24 | PGIS-Pruritus is a global index where subjects are asked to rate the severity of pruritus on a 5-point scale within the past 7 days, with choices of 1=None, 2=Mild, 3=Moderate, 4=Severe and 5=Very Severe. Higher scores indicate a worse assessment for pruritus. |
Countries
Australia, Austria, Belgium, Canada, Czechia, France, Germany, Greece, Hungary, Israel, Italy, New Zealand, Poland, Spain, Sweden, Switzerland, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Setanaxib 1200 mg/Day Participants will be administered setanaxib at a dose of 1200 mg/day for the 24-week double-blind treatment period.
Setanaxib: Oral tablets, 400mg per tablet | 24 |
| Setanaxib 1600 mg/Day Participants will be administered setanaxib at a dose of 1600 mg/day for the 24-week double-blind treatment period.
Setanaxib: Oral tablets, 400mg per tablet | 25 |
| Placebo Participants will be administered a placebo for the 24-week double-blind treatment period.
Placebo: Oral tablets | 27 |
| Total | 76 |
Baseline characteristics
| Characteristic | Setanaxib 1600 mg/Day | Total | Setanaxib 1200 mg/Day | Placebo |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 7 Participants | 15 Participants | 6 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants | 61 Participants | 18 Participants | 25 Participants |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 2 Participants | 10 Participants | 2 Participants | 6 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 23 Participants | 63 Participants | 21 Participants | 19 Participants |
| Race/Ethnicity, Customized Ethnicity Not Reported | 0 Participants | 3 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Asian | 2 Participants | 2 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Not reported | 0 Participants | 3 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Other | 3 Participants | 5 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Unknown | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race White | 20 Participants | 65 Participants | 22 Participants | 23 Participants |
| Randomised Screening serum ALP strata < 3.0 × ULN | 18 Participants | 54 Participants | 18 Participants | 18 Participants |
| Randomised Screening serum ALP strata ≥ 3.0 × ULN | 7 Participants | 22 Participants | 6 Participants | 9 Participants |
| Sex: Female, Male Female | 24 Participants | 71 Participants | 22 Participants | 25 Participants |
| Sex: Female, Male Male | 1 Participants | 5 Participants | 2 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 25 | 0 / 25 | 0 / 26 |
| other Total, other adverse events | 14 / 25 | 18 / 25 | 17 / 26 |
| serious Total, serious adverse events | 4 / 25 | 2 / 25 | 3 / 26 |
Outcome results
Primary
Change in ALP at Week 24 Compared to Baseline
Change in ALP at Week 24 Compared to Baseline, ratio of week 24 value to baseline value.
Time frame: Baseline (Day 1) and Week 24
Population: Full Analysis Set
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Setanaxib 1200 mg/Day | Change in ALP at Week 24 Compared to Baseline | 0.89 ratio |
| Setanaxib 1600 mg/Day | Change in ALP at Week 24 Compared to Baseline | 0.84 ratio |
| Placebo | Change in ALP at Week 24 Compared to Baseline | 1.03 ratio |
p-value: 0.020695% CI: [0.746, 0.994]Mixed Model Repeated Measures
p-value: 0.005795% CI: [0.703, 0.939]Mixed Model Repeated Measures
Secondary
Change in ALP at Week 24 Compared to Baseline, Where Setanaxib Doses Are Combined
Change in ALP at Week 24 Compared to Baseline, ratio of week 24 value to baseline value. Setanaxib doses are combined and the change from baseline is estimated using a mixed model-repeated measures approach with fixed factors for treatment, visit, log(baseline), treatment\*visit, and log(baseline)\*visit, subject is included as a random effect. The variance-covariance matrix is therefore not the same as in the three arm analysis, which causes treatment effects estimated in the placebo to group differ from those estimated in the analysis with three treatment arms.
Time frame: Baseline (Day 1) and Week 24
Population: Full Analysis Set
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Setanaxib 1200 mg/Day | Change in ALP at Week 24 Compared to Baseline, Where Setanaxib Doses Are Combined | 0.87 ratio |
| Setanaxib 1600 mg/Day | Change in ALP at Week 24 Compared to Baseline, Where Setanaxib Doses Are Combined | 1.03 ratio |
p-value: 0.003995% CI: [0.743, 0.954]Mixed Model Repeated Measures
Secondary
Change in Fatigue at Week 24 Compared to Baseline, as Assessed by the Patient's Global Impression of Change (PGIC) Fatigue
The Patient's Global Impression of Change (PGIC)-Fatigue is a 7-point scale reflecting a subject's rating of overall improvement where subjects are asked to rate their overall improvement with fatigue with 1=Very much improved, 2=Much improved, 3=Minimally improved, 4=No change, 5=Worse, 6=Much worse, 7=Very much worse. Higher scores indicate a worse outcome for change in fatigue.
Time frame: Week 24
Population: Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Setanaxib 1200 mg/Day | Change in Fatigue at Week 24 Compared to Baseline, as Assessed by the Patient's Global Impression of Change (PGIC) Fatigue | 3.27 units on a scale | Standard Deviation 1.534 |
| Setanaxib 1600 mg/Day | Change in Fatigue at Week 24 Compared to Baseline, as Assessed by the Patient's Global Impression of Change (PGIC) Fatigue | 3.62 units on a scale | Standard Deviation 1.564 |
| Placebo | Change in Fatigue at Week 24 Compared to Baseline, as Assessed by the Patient's Global Impression of Change (PGIC) Fatigue | 3.58 units on a scale | Standard Deviation 1.427 |
Secondary
Change in Fatigue at Week 24 Compared to Baseline, as Assessed by the Patient's Global Impression of Severity (PGIS) Fatigue
The Patient's Global Impression of Severity (PGIS)-Fatigue is a global index where subjects are asked to rate the severity of fatigue on a 5-point scale within the past 7 days, with choices of 1=None, 2=Mild, 3=Moderate, 4=Severe and 5=Very Severe. Higher scores indicate a worse assessment for fatigue.
Time frame: Baseline (Day 1) and Week 24
Population: Full Analysis Set subjects who have both non-missing baseline and Week 24 results
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Setanaxib 1200 mg/Day | Change in Fatigue at Week 24 Compared to Baseline, as Assessed by the Patient's Global Impression of Severity (PGIS) Fatigue | -0.07 units on a scale | Standard Deviation 0.73 |
| Setanaxib 1600 mg/Day | Change in Fatigue at Week 24 Compared to Baseline, as Assessed by the Patient's Global Impression of Severity (PGIS) Fatigue | 0.12 units on a scale | Standard Deviation 0.857 |
| Placebo | Change in Fatigue at Week 24 Compared to Baseline, as Assessed by the Patient's Global Impression of Severity (PGIS) Fatigue | 0.22 units on a scale | Standard Deviation 1.003 |
Secondary
Change in Fatigue at Week 24 Compared to Baseline, as Assessed by the PBC-40 Questionnaire (PBC 40) Fatigue Domain
PBC-40 fatigue domain includes 11 item questions, items scores range from 1 to 5. The individual item scores are summed to obtain a total domain score (Range for fatigue domain: 11 to 55), high scores represent high impact and low scores indicate low impact of PBC on the quality of life.
Time frame: Baseline (Day 1) and Week 24
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Setanaxib 1200 mg/Day | Change in Fatigue at Week 24 Compared to Baseline, as Assessed by the PBC-40 Questionnaire (PBC 40) Fatigue Domain | -1.44 units on a scale |
| Setanaxib 1600 mg/Day | Change in Fatigue at Week 24 Compared to Baseline, as Assessed by the PBC-40 Questionnaire (PBC 40) Fatigue Domain | -1.83 units on a scale |
| Placebo | Change in Fatigue at Week 24 Compared to Baseline, as Assessed by the PBC-40 Questionnaire (PBC 40) Fatigue Domain | -1.85 units on a scale |
p-value: 0.567595% CI: [-4.454, 5.285]Mixed Model Repeated Measures
p-value: 0.503295% CI: [-4.886, 4.926]Mixed Model Repeated Measures
Secondary
Change in Fatigue at Week 24 Compared to Baseline, as Assessed by the PBC-40 Questionnaire (PBC 40) Fatigue Domain, Where Setanaxib Doses Are Combined
PBC-40 fatigue domain includes 11 item questions, items scores range from 1 to 5. The individual item scores are summed to obtain a total domain score (Range for fatigue domain: 11 to 55), high scores represent high impact and low scores indicate low impact of PBC on the quality of life. Setanaxib doses are combined and the change from baseline is estimated using a mixed model-repeated measures approach with fixed factors for treatment, visit, log(baseline), treatment\*visit, and log(baseline)\*visit, subject is included as a random effect. The variance-covariance matrix is therefore not the same as in the three arm analysis, which causes treatment effects estimated in the placebo to group differ from those estimated in the analysis with three treatment arms.
Time frame: Baseline (Day 1) and Week 24
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Setanaxib 1200 mg/Day | Change in Fatigue at Week 24 Compared to Baseline, as Assessed by the PBC-40 Questionnaire (PBC 40) Fatigue Domain, Where Setanaxib Doses Are Combined | -1.64 units on a scale |
| Setanaxib 1600 mg/Day | Change in Fatigue at Week 24 Compared to Baseline, as Assessed by the PBC-40 Questionnaire (PBC 40) Fatigue Domain, Where Setanaxib Doses Are Combined | -1.84 units on a scale |
p-value: 0.539395% CI: [-3.968, 4.381]Mixed Model Repeated Measures
Secondary
Change in Fatigue at Week 24 Compared to Baseline, as Assessed by the PROMIS Short Form-Fatigue 7b Daily
The Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form 7b measures the severity of fatigue since waking. There are 7 questions, each scored between 1 and 5, with a total score between 7 to 35. A higher score indicates worse fatigue. This raw score is converted to a T score (a standardized score with a mean of 50 and a SD of 10).
Time frame: Baseline (Day 1) and Week 24
Population: Full Analysis Set. This questionnaire was introduced after protocol version 1.0, so patients enrolled under protocol version 1.0 do not have a baseline value and are excluded from the number of participants analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Setanaxib 1200 mg/Day | Change in Fatigue at Week 24 Compared to Baseline, as Assessed by the PROMIS Short Form-Fatigue 7b Daily | -3.60 T-scores |
| Setanaxib 1600 mg/Day | Change in Fatigue at Week 24 Compared to Baseline, as Assessed by the PROMIS Short Form-Fatigue 7b Daily | -0.80 T-scores |
| Placebo | Change in Fatigue at Week 24 Compared to Baseline, as Assessed by the PROMIS Short Form-Fatigue 7b Daily | -1.43 T-scores |
p-value: 0.221495% CI: [-7.785, 3.458]Mixed Model Repeated Measures
p-value: 0.59195% CI: [-4.859, 6.12]Mixed Model Repeated Measures
Secondary
Change in Fatigue at Week 24 Compared to Baseline, as Assessed by the PROMIS Short Form-Fatigue 7b Daily, Where Setanaxib Doses Are Combined
The Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form 7b measures the severity of fatigue since waking. There are 7 questions, each scored between 1 and 5, with a total score between 7 to 35. A higher score indicates worse fatigue. This raw score is converted to a T score (a standardized score with a mean of 50 and a SD of 10). Setanaxib doses are combined and the change from baseline is estimated using a mixed model-repeated measures approach with fixed factors for treatment, visit, log(baseline), treatment\*visit, and log(baseline)\*visit, subject is included as a random effect. The variance-covariance matrix is therefore not the same as in the three arm analysis, which causes treatment effects estimated in the placebo to group differ from those estimated in the analysis with three treatment arms.
Time frame: Baseline (Day 1) and Week 24
Population: Full Analysis Set. This questionnaire was introduced after protocol version 1.0, so patients enrolled under protocol version 1.0 do not have a baseline value and are excluded from the number of participants analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Setanaxib 1200 mg/Day | Change in Fatigue at Week 24 Compared to Baseline, as Assessed by the PROMIS Short Form-Fatigue 7b Daily, Where Setanaxib Doses Are Combined | -2.12 T-scores |
| Setanaxib 1600 mg/Day | Change in Fatigue at Week 24 Compared to Baseline, as Assessed by the PROMIS Short Form-Fatigue 7b Daily, Where Setanaxib Doses Are Combined | -1.45 T-scores |
p-value: 0.390595% CI: [-5.496, 4.153]Mixed Model Repeated Measures
Secondary
Change in Liver Stiffness at Week 24 Compared to Screening
Change in liver stiffness at Week 24 compared to Screening, as assessed by transient elastography (FibroScan®)
Time frame: Screening (Day -28) and Week 24
Population: Full Analysis Set
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Setanaxib 1200 mg/Day | Change in Liver Stiffness at Week 24 Compared to Screening | 0.78 ratio |
| Setanaxib 1600 mg/Day | Change in Liver Stiffness at Week 24 Compared to Screening | 0.88 ratio |
| Placebo | Change in Liver Stiffness at Week 24 Compared to Screening | 0.92 ratio |
p-value: 0.049195% CI: [0.692, 1.033]Mixed Model Repeated Measures
p-value: 0.309995% CI: [0.783, 1.158]Mixed Model Repeated Measures
Secondary
Change in Liver Stiffness at Week 24 Compared to Screening, Where Setanaxib Doses Are Combined
Change in liver stiffness at Week 24 compared to Screening, as assessed by transient elastography (FibroScan®). Setanaxib doses are combined and the change from baseline is estimated using a mixed model-repeated measures approach with fixed factors for treatment, visit, log(baseline), treatment\*visit, and log(baseline)\*visit, subject is included as a random effect. The variance-covariance matrix is therefore not the same as in the three arm analysis, which causes treatment effects estimated in the placebo to group differ from those estimated in the analysis with three treatment arms.
Time frame: Screening (Day -28) and Week 24
Population: Full Analysis Set
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Setanaxib 1200 mg/Day | Change in Liver Stiffness at Week 24 Compared to Screening, Where Setanaxib Doses Are Combined | 0.83 ratio |
| Setanaxib 1600 mg/Day | Change in Liver Stiffness at Week 24 Compared to Screening, Where Setanaxib Doses Are Combined | 0.92 ratio |
p-value: 0.107995% CI: [0.759, 1.065]Mixed Model Repeated Measures
Secondary
Change in Pruritus at Week 24 Compared to Baseline, as Assessed by the PBC-40 Itch Domain
Pruritus was assessed by answering 3 questions on the PBC-40 Itch domain from 1 to 5, which was also summed to obtain a total domain score (range 3 to 15). A high score represents a high impact, and a low score indicates low impact of pruritus on the quality of life.
Time frame: Baseline (Day 1) and Week 24
Population: Full Analysis Set subjects who have both non-missing baseline and Week 24 results
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Setanaxib 1200 mg/Day | Change in Pruritus at Week 24 Compared to Baseline, as Assessed by the PBC-40 Itch Domain | -1.11 units on a scale | Standard Deviation 2.111 |
| Setanaxib 1600 mg/Day | Change in Pruritus at Week 24 Compared to Baseline, as Assessed by the PBC-40 Itch Domain | 0.32 units on a scale | Standard Deviation 2.647 |
| Placebo | Change in Pruritus at Week 24 Compared to Baseline, as Assessed by the PBC-40 Itch Domain | -0.70 units on a scale | Standard Deviation 3.114 |
Secondary
Change in Pruritus at Week 24 Compared to Baseline, as Assessed by the PGIC Pruritus
The PGIC-Pruritus is a 7-point scale reflecting a subject's rating of overall improvement where subjects are asked to rate their overall improvement with fatigue with 1=Very much improved, 2=Much improved, 3=Minimally improved, 4=No change, 5=Worse, 6=Much worse, 7=Very much worse. Higher scores indicate a worse outcome for change in pruritus.
Time frame: Week 24
Population: Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Setanaxib 1200 mg/Day | Change in Pruritus at Week 24 Compared to Baseline, as Assessed by the PGIC Pruritus | 2.73 units on a scale | Standard Deviation 1.751 |
| Setanaxib 1600 mg/Day | Change in Pruritus at Week 24 Compared to Baseline, as Assessed by the PGIC Pruritus | 3.38 units on a scale | Standard Deviation 1.244 |
| Placebo | Change in Pruritus at Week 24 Compared to Baseline, as Assessed by the PGIC Pruritus | 3.37 units on a scale | Standard Deviation 1.535 |
Secondary
Change in Pruritus at Week 24 Compared to Baseline, as Assessed by the PGIS Pruritus
PGIS-Pruritus is a global index where subjects are asked to rate the severity of pruritus on a 5-point scale within the past 7 days, with choices of 1=None, 2=Mild, 3=Moderate, 4=Severe and 5=Very Severe. Higher scores indicate a worse assessment for pruritus.
Time frame: Baseline (Day 1) and Week 24
Population: Full Analysis Set subjects who have both non-missing baseline and Week 24 results
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Setanaxib 1200 mg/Day | Change in Pruritus at Week 24 Compared to Baseline, as Assessed by the PGIS Pruritus | -0.50 units on a scale | Standard Deviation 0.941 |
| Setanaxib 1600 mg/Day | Change in Pruritus at Week 24 Compared to Baseline, as Assessed by the PGIS Pruritus | 0.25 units on a scale | Standard Deviation 0.775 |
| Placebo | Change in Pruritus at Week 24 Compared to Baseline, as Assessed by the PGIS Pruritus | -0.11 units on a scale | Standard Deviation 0.758 |
Secondary
Change in Pruritus at Week 24 Compared to Baseline, as Assessed by the Worst Itch Numerical Rating Scale (WI-NRS)
WI-NRS is a daily patient-reported measure of itch intensity using an 11-point scale where 0=no itch and 10=worst itching imaginable. The WI-NRS score is calculated by averaging the daily WI-NRS scores before the visit date (inclusive). Higher scores indicate worse functioning for pruritus on the WI-NRS.
Time frame: Baseline (Day 1) and Week 24
Population: Full Analysis Set subjects who have both non-missing baseline and Week 24 results
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Setanaxib 1200 mg/Day | Change in Pruritus at Week 24 Compared to Baseline, as Assessed by the Worst Itch Numerical Rating Scale (WI-NRS) | -0.23 units on a scale | Standard Deviation 2.28 |
| Setanaxib 1600 mg/Day | Change in Pruritus at Week 24 Compared to Baseline, as Assessed by the Worst Itch Numerical Rating Scale (WI-NRS) | 0.61 units on a scale | Standard Deviation 1.391 |
| Placebo | Change in Pruritus at Week 24 Compared to Baseline, as Assessed by the Worst Itch Numerical Rating Scale (WI-NRS) | -0.56 units on a scale | Standard Deviation 2.268 |
Secondary
Changes in Markers of Cholestasis at Week 24
Changes in markers of cholestasis as assessed by proportion of patients at Week 24 with: * ALP reduction to \<1.67×ULN and total bilirubin ≤1×ULN and a ≥15% or ≥30% or ≥40% or ≥70% ALP reduction from Baseline, respectively * ALP reduction to \<1.5×ULN and total bilirubin ≤1×ULN and a ≥40% ALP reduction from Baseline * ALP \<1×ULN and total bilirubin ≤1×ULN * Total bilirubin \<0.6×ULN
Time frame: Baseline (Day 1) and Week 24
Population: Full Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Setanaxib 1200 mg/Day | Changes in Markers of Cholestasis at Week 24 | ALP <1.67×ULN and Total Bilirubin ≤1×ULN and ≥30% ALP Reduction from Baseline | 1 participants |
| Setanaxib 1200 mg/Day | Changes in Markers of Cholestasis at Week 24 | ALP <1.50×ULN and Total Bilirubin ≤1×ULN and ≥40% ALP Reduction from Baseline | 0 participants |
| Setanaxib 1200 mg/Day | Changes in Markers of Cholestasis at Week 24 | ALP <1.67×ULN and Total Bilirubin ≤1×ULN and ≥70% ALP Reduction from Baseline | 0 participants |
| Setanaxib 1200 mg/Day | Changes in Markers of Cholestasis at Week 24 | ALP <1.67×ULN and Total Bilirubin ≤1×ULN and ≥15% ALP Reduction from Baseline | 1 participants |
| Setanaxib 1200 mg/Day | Changes in Markers of Cholestasis at Week 24 | Total bilirubin <0.6×ULN | 19 participants |
| Setanaxib 1200 mg/Day | Changes in Markers of Cholestasis at Week 24 | ALP <1.00×ULN and Total Bilirubin ≤1×ULN | 0 participants |
| Setanaxib 1200 mg/Day | Changes in Markers of Cholestasis at Week 24 | ALP <1.67×ULN and Total Bilirubin ≤1×ULN and ≥40% ALP Reduction from Baseline | 0 participants |
| Setanaxib 1600 mg/Day | Changes in Markers of Cholestasis at Week 24 | ALP <1.67×ULN and Total Bilirubin ≤1×ULN and ≥70% ALP Reduction from Baseline | 0 participants |
| Setanaxib 1600 mg/Day | Changes in Markers of Cholestasis at Week 24 | ALP <1.67×ULN and Total Bilirubin ≤1×ULN and ≥15% ALP Reduction from Baseline | 4 participants |
| Setanaxib 1600 mg/Day | Changes in Markers of Cholestasis at Week 24 | ALP <1.67×ULN and Total Bilirubin ≤1×ULN and ≥30% ALP Reduction from Baseline | 2 participants |
| Setanaxib 1600 mg/Day | Changes in Markers of Cholestasis at Week 24 | ALP <1.67×ULN and Total Bilirubin ≤1×ULN and ≥40% ALP Reduction from Baseline | 2 participants |
| Setanaxib 1600 mg/Day | Changes in Markers of Cholestasis at Week 24 | ALP <1.50×ULN and Total Bilirubin ≤1×ULN and ≥40% ALP Reduction from Baseline | 2 participants |
| Setanaxib 1600 mg/Day | Changes in Markers of Cholestasis at Week 24 | ALP <1.00×ULN and Total Bilirubin ≤1×ULN | 1 participants |
| Setanaxib 1600 mg/Day | Changes in Markers of Cholestasis at Week 24 | Total bilirubin <0.6×ULN | 18 participants |
| Placebo | Changes in Markers of Cholestasis at Week 24 | ALP <1.50×ULN and Total Bilirubin ≤1×ULN and ≥40% ALP Reduction from Baseline | 0 participants |
| Placebo | Changes in Markers of Cholestasis at Week 24 | ALP <1.67×ULN and Total Bilirubin ≤1×ULN and ≥30% ALP Reduction from Baseline | 0 participants |
| Placebo | Changes in Markers of Cholestasis at Week 24 | Total bilirubin <0.6×ULN | 19 participants |
| Placebo | Changes in Markers of Cholestasis at Week 24 | ALP <1.00×ULN and Total Bilirubin ≤1×ULN | 0 participants |
| Placebo | Changes in Markers of Cholestasis at Week 24 | ALP <1.67×ULN and Total Bilirubin ≤1×ULN and ≥70% ALP Reduction from Baseline | 0 participants |
| Placebo | Changes in Markers of Cholestasis at Week 24 | ALP <1.67×ULN and Total Bilirubin ≤1×ULN and ≥40% ALP Reduction from Baseline | 0 participants |
| Placebo | Changes in Markers of Cholestasis at Week 24 | ALP <1.67×ULN and Total Bilirubin ≤1×ULN and ≥15% ALP Reduction from Baseline | 1 participants |