Primary Objective: • Efficacy: To evaluate the treatment effect of seladelpar on composite biochemical improvement in cholestasis markers based on alkalinephosphatase (ALP) and total bilirubin at 12 months of treatment compared to placebo• Safety:…
ID
Source
Brief title
Condition
- Hepatic and hepatobiliary disorders
- Autoimmune disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Measures:
1. Proportion of subjects who are considered responders at 12 months based on
the following composite endpoint of ALP and total bilirubin at 12 months
requiring
a. ALP <1.67× ULN
b. >=15% decrease in ALP
c. Total bilirubin <=1.0× ULN
2. Assessment of treatment-emergent AEs (TEAEs) (National Cancer Institute
Common Terminology Criteria for Adverse Events Version 5.0),
biochemistry, and hematology
Secondary outcome
Key Secondary:
1. Proportion of subjects with ALP <=1.0× ULN at 12 months (ie, normalization)
2. Change from baseline in weekly averaged pruritus NRS in subjects with
baseline NRS >=4 at 6 months
Other Secondary:
1. Proportion of responders based on the composite endpoint of ALP and total
bilirubin at 6 months
2. Proportion of subjects with ALP <=1.0× ULN at 6 months
3. Proportion of subjects with ALP <1.67× ULN and ALP <1.5× ULN at 6 and 12
months
4. Absolute and relative changes in ALP at 3, 6, and 12 months
5. Proportion of subjects with a decrease in NRS >=2, NRS >=3, or NRS >=4 in
subjects with baseline NRS >=4 at each visit
6. Changes from baseline in pruritus NRS in subjects with baseline NRS >=4 at 3
and 12 months
7. Change from baseline in quality of life measure for use in PBC questionnaire
(PBC-40 QoL) at each visit (total score and domain score)
8. Change from baseline in United Kingdom - Primary Biliary Cirrhosis and
Global PBC Study Group risk scores by visit
9. Absolute and relative changes in ALT, AST, GGT, bilirubin (total, direct,
and indirect), and 5*-nucleotidase at each visit
10. The first occurrence of PBC related clinical outcomes as defined by the
following:
a. Overall death
b. Liver transplantation
c. MELD score >=15 for at least 2 consecutive visits
d. Ascites requiring treatment
e. Hospitalization for new onset or recurrence of any of the following:
i. Variceal bleeding
ii. Hepatic encephalopathy (as defined by a West Haven score >=2)
iii. Spontaneous bacterial peritonitis (confirmed by culture from diagnostic
paracentesis)
Exploratory:
1. Liver histology changes based on pathology review of biopsy tissues
2. PBC response criteria results (Barcelona, Paris I and II, Toronto I and II,
Rotterdam)
3. Changes from baseline in pruritus NRS based on additional thresholds for
improvement and baseline itch status
4. Changes from baseline in PBC-40 QoL itch domain and the 5-D pruritus scale
5. Absolute and relative changes in lipids, bile acids, sterols, and biomarkers
of bile acid synthesis: 7α-hydroxy-4-cholesten-3-one and fibroblast growth
factor 19
6. Plasma concentrations of seladelpar and its metabolites (M1, M2, M3)
7. Absolute and relative changes in markers of inflammation/immune reactivity
(e.g., high sensitivity C-reactive protein, fibrinogen, haptoglobin, tumor
necrosis factor-alpha, and anti-antibodies)
8. Absolute and relative changes in markers of enhanced liver fibrosis as
measured by liver stiffness using FibroScan®
9. Absolute and relative changes in markers of liver injury: CK18 (M65) and
miR-122
Background summary
Primary biliary cholangitis (PBC, formerly known as primary biliary cirrhosis)
is a serious and potentially life threatening
autoimmune disease of the liver characterized by impaired bile flow
(cholestasis) and accumulation of toxic bile acids (BA).
The first line therapy for PBC is ursodeoxycholic acid (UDCA), a non-cytotoxic
BA that has been the mainstay of treatment
for more than twenty years. However, up to 40 percent of patients have
persistent elevation of AP and/or bilirubin despite
UDCA and are considered inadequate responders.
Seladelpar (MBX-8025) is an oral, once-daily administered, potent and selective
peroxisome proliferator-activated receptors
(PPAR) δ agonist. Seladelpar is being developed for the treatment of PBC in
subjects with inadequate response to UDCA
or intolerance to UDCA and in nonalcoholic steatohepatitis (NASH).Seladelpar
demonstrated the potent and rapid decrease
in biochemical markers of cholestasis (AP, GGT, and total bilirubin), decrease
a marker of inflammation (hs-CRP) and
decrease LDL-C in PBC subjects who had an inadequate response or intolerance to
UDCA. In addition, the current data
suggest that seladelpar has a potential to improve PBC related pruritus. Lower
doses of seladelpar (up to 10 mg) were
generally safe and well tolerated. There was no evidence that seladelpar was
associated with transaminase elevations at
these doses. There was also no evidence that seladelpar induced or worsened
pruritus. The clinical experience with
seladelpar is nonetheless limited, and appropriate precautions are incorporated
into this protocol, with careful monitoring of
potential transaminase elevations
Study objective
Primary Objective:
• Efficacy: To evaluate the treatment effect of seladelpar on composite
biochemical improvement in cholestasis markers based on alkaline
phosphatase (ALP) and total bilirubin at 12 months of treatment compared to
placebo
• Safety: To evaluate the safety of seladelpar over 12 months of treatment
compared to placebo
Key Secondary Objectives:
• To evaluate the effect of seladelpar on the normalization of ALP values at 12
months of treatment compared to placebo
• To evaluate the effect of seladelpar on pruritus at 6 months of treatment
compared to placebo in subjects with baseline moderate to severe pruritus
Other Secondary Objectives:
• To evaluate the effect of seladelpar on quality of life (QoL)
• To evaluate the effect of seladelpar on other measures of cholestasis,
metabolic markers, and PBC prognostic criteria
• To evaluate the effect of seladelpar on PBC-associated clinical outcomes
Exploratory Objectives:
• To evaluate the effect of seladelpar on histology, additional measures of
quality of life (QoL), biomarkers of cholestasis and inflammation, lipids and
auto-antibody profiles, bile acid synthesis, liver fibrosis, and liver injury
• To evaluate the plasma concentrations of seladelpar and metabolites
Study design
This is an international, multicenter evaluation of seladelpar in a randomized,
double blind, placebo controlled, parallel group study in patients with PBC.
Approximately 180 subjects will be randomized in 2:1 ratio (seladelpar:
placebo) across approximately 150180 sites worldwide.
Enrolled subjects will have confirmed PBC as defined by having any 2 of the
following 3 diagnostic criteria: (1) history of ALP above 1.0× the upper limit
of normal (ULN) for at least 6 months; (2) positive antimitochondrial antibody
(AMA) titer (>1:40 on immunofluorescence or M2 positive by enzyme-linked
immunosorbent assay [ELISA]) or positive PBC-specific antinuclear antibodies
(ANAs); and (3) documented liver biopsy results consistent with PBC.
Enrolled subjects must have received UDCA for at least 12 months (>3 months of
stable dose prior to screening) or have intolerance to UDCA (last dose of UDCA
>3 months prior to screening). During the study, the study drug will be
administered as an add-on to UDCA therapy for subjects who tolerate UDCA; for
subjects with UDCA intolerance, the study drug will be administered as a
monotherapy.
Subjects with the presence or history of cirrhosis with complications,
Gilbert*s syndrome with elevated total bilirubin, primary sclerosing
cholangitis (PSC), current features of autoimmune hepatitis (AIH),
biopsy-confirmed nonalcoholic steatohepatitis (NASH), alcoholic liver disease,
or chronic hepatitis B or C will be excluded.
In order to establish the histological status of their liver before and after
treatment, all subjects will be encouraged to have a liver biopsy during the
Screening Period (unless a historical biopsy meeting quality standards can be
supplied) and after 1 year of treatment, or at Early Termination if the
subjects withdraw from the study, provided that they have received at least 6
months of treatment. A follow-up liver biopsy will be performed only in
subjects with baseline liver biopsy.
Transient elastography via FibroScan® will be performed to assess liver
stiffness at baseline and during the Treatment Period or at Early Termination
at select sites.
On Day 1, subjects will be randomized into 1one of 2two treatment arms
(seladelpar 10 mg or placebo) in a 2:1 ratio. Subjects will be stratified at
randomization according to ALP <350 U/L versus >=350 U/L and pruritus numerical
rating scale (NRS) (<4 versus >=4) to ensure even distribution across the
treatment groups.
The total duration of participation in the study for each subject will be up to
~14 months and consists of Screening Period (up to 23 weeks), a Run-in Period
(up to 2 weeks), a Treatment Period with a maximum duration of up to 12 months,
and a Safety Follow-up Period (2 weeks [14 days +3] after the last dose of
study drug1 month after the last dose, only for subjects who are not enrolled
in the long-term study).
The Screening Period will be up to 23 weeks, during which time subject
eligibility will be confirmed. The Run-in Period will start 2 weeks prior to
the planned Day 1 Visit; at this visit, subjects start their pruritus
evaluation using an e-diary. Liver biopsy will be performed at any time between
Screening and Day 1 for subjects willing to undergo the procedure and after
their eligibility is confirmed (unless a historical biopsy meeting quality
standards can be supplied). At Day 1, subjects will enter the Treatment Period.
Subjects will receive double-blinded treatment for 12 months. After the
completion of the Treatment Period, subjects will be invited to enroll into an
open label, long-term study (Study CB8025-31731-RE) in which each subject will
be administered seladelpar and subjects on placebo will initiate seladelpar
treatment. Subjects who declinedo not participate in the long-term study
participation will have a follow-up visit performed 1 month 2 weeks (14 days
+3) after the last dose of study drug.
During the 12-month Treatment Period, subjects will have a visit at Month 1 and
then every 3 months beginning from Month 3 through Month 12. Visits may occur
in clinic, with the assistance of a home health service, or using virtual
technologies.
Subjects will be asked to use an electronic diary (e-diary) to evaluate
pruritus and QoL during the study participation. E-diary will be dispensed at
the Run in Visit and will include the following questionnaires: pruritus NRS,
5-D Itch, Patient Global Impression of Severity (PGI S), Patient Global
Impression of Change (PGI-C), and PBC-40. Subjects will perform an evaluation
of their pruritus on a daily basis via pruritus NRS starting from the Run-in
Visit through the first 6 months of treatment. After 6 months, pruritus will be
evaluated on a monthly basis until Month 12 using pruritus NRS for 7
consecutive days each month. 5-D Itch scale will be evaluated biweekly from the
Run-in Visit up for the first 6 months of treatment and monthly after that.
PBC-40, PGI-S, and PGI-C will be evaluated after 1 month and every 3 months
from the treatment initiation and over the whole study duration.
During the study, subjects will be regularly evaluated for the progression of
their disease by collecting information about PBC clinical outcomes.
Subjects who discontinued study drug treatment for any reason other than a
defined PBC clinical outcome will be asked to stay in the study without study
drug intake. Subjects who discontinue study drug treatment anytime, and do not
stay in the study, will complete an Early Termination Visit. For subjects who
decline to stay in the study without study drug intake, or who do not
participate in the long-term study, a phone call will be performed for PBC
outcomes on an annual basis. Safety monitoring in the study implements
individual and study stopping criteria, criteria to be considered for stopping
the study, and safety criteria to monitor subjects with potential drug induced
liver injury (DILI), renal injury, muscle toxicity, or pancreatic injury with
actions to either stop the study drug or to investigate the case prior to
actions with the study drug based on protocol-specified monitoring criteria.
The study design also defines PBC clinical outcome criteria to evaluate the
subjects for the progression of PBC, for example, events related to hepatic
decompensation. The study drug might be down-titrated to a lower dose if deemed
necessary by the investigator for safety or tolerability reasons. Subjects
receiving 10 mg will be down-titrated to 5 mg, and subjects receiving placebo
will be down-titrated to placebo. Down-titration will be performed in a blinded
manner. Subjects who meet one of the defined PBC clinical outcome criteria will
discontinue study drug be terminated from the study and will complete an Early
Termination Visit.
PK Sample Collection
Subjects will be invited to participate in a pharmacokinetic (PK) sample
collection to evaluate the plasma concentrations of seladelpar and its
metabolites. Subjects who consent to participate in this PK sample collection
will provide 1 predose (-30 minutes prior to dosing) and 2 postdose samples at
1 hour ± 30 minutes and at 3 hours ± 30 minutes at Month 3 and at Month 12.
The primary efficacy outcome will be a responder analysis (composite
biochemical response) after 12 months of treatment with study drug.
A data safety monitoring board (DSMB) will be convened to review the study data
on a regular basis during study conduct to ensure subjects* welfare and
preserve study integrity.
A Critical Event Review Committee (CERC) will be established to analyze and
adjudicate clinical events that occur during the study.
A Pathology Review Committee (PRC) will be established to evaluate the biopsies
in accordance with a defined histopathology plan.
Intervention
Study subjects will be randomized 2:1 (seladelpar 10 mg:placebo)
Randomization will be stratified by the following factors:
• ALP level <350 U/L versus ALP level >=350 U/L
• Pruritus NRS <4 versus NRS >=4
Study burden and risks
Patients are asked to undergo procedures described on pages 24 - 25 of the
study protocol. These procedures include physical examination, blood draw (i.e.
Hepatitis B and C testing, etc.) urine sampling (i.e. drug screen, etc.), vital
signs, ECG, abdominal ultrasound, liver Elastography (at selected centers),
Liver biopsy, completion of questionnaire, answer questions of investigator and
study team and administration of study drug. Additionally, fertile subjects are
asked to use contraceptives, and female subjects of childbearing potential will
have pregnancy tests. Subject*s participation in this study will last
approximately 60 weeks (about 1 year and 2 months). This duration includes a
screening period (up to 2 weeks), a run-in period (up to 2 weeks), a 12-month
(52 weeks) treatment period, and a final follow-up visit (4 weeks). The study
medication is a nonregistered medication. Possible known side effects are
described in the IB and patient information and can also occur during this
study.
The following side effects were commonly reported in >= 10% of PBC patients (33
- 51 of 315 patients):
- Itching (Pruritus)
- Feeling sickness with the urge to vomit (nausea)
- Urinary tract infection
- Diarrhea
- Upper abdominal pain
The following side effects were occasionally reported in >= 5% and < 10% of PBC
patients (16 - 32 of 315 patients):
- Abdominal pain
- Fatigue
- Joint pain
- Headache
- Infection of nose and throat (Nasopharyngitis)
- Upper respiratory tract infection
- Dizziness
- Cough
- Constipation
- Indigestion (Dyspepsia)
- Back pain
- Vomiting
- Dry mouth
- Generalized itching
- Muscle pain (Myalgia)
- Gastroesophageal (acid) reflux disease
Furthermore, there may be risks associated with study procedures (i.e. blood
draw, abdominal ultrasound, liver elastography, etc.) Taking the study drug may
result in an improvement in subject's PBC and PBC-associated itch, but an
improvement is not guaranteed for all subjects. Some subjects may not improve
at all.
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Age
Inclusion criteria
Subjects must meet the following criteria to be eligible for study
participation:
1. Must have given written informed consent (signed and dated) and any
authorizations required by local law.
2. 18 to 75 years old (inclusive).
3. Male or female with a diagnosis of PBC based on any two of the following
criteria:
a. History of ALP above 1.0× ULN for at least 6 months.
b. Positive AMA titer (>1:40 on immunofluorescence or M2 positive by ELISA) or
positive PBC-specific ANA.
c. Documented liver biopsy results consistent with PBC.
4. UDCA for the past 12 months (stable dose for >3 months prior to screening)
OR intolerant to UDCA (last dose of UDCA >3 months prior to screening).
5. Laboratory parameters measured by the Central Laboratory at screening:
a. ALP >=1.67× ULN.
b. Aspartate aminotransferase (AST) <=3× ULN.
c. Alanine aminotransferase (ALT) <=3× ULN.
d. Total bilirubin <=2× ULN.
e. Estimated glomerular filtration rate >6045 mL/min/1.73 m2 (calculated by the
Modification of Diet in Renal Disease study equation).
f. International normalized ratio (INR) below 1.1× ULN
For subjects on anticoagulation therapy, INR must be maintained in the range
required for prophylaxis for their specific disease.
g. Platelet count >=100×103/µL.
NOTE: PT, INR, and platelets can be performed locally at the Screening Visit,
if deemed necessary by the investigator after consultation with the medical
monitor, in cases where centrally read samples are deemed invalid.
6. Females of reproductive potential (Section 8.1.1) must use at least 1
barrier contraceptive and a second effective birth control method during the
study and for at least 90 days after the last dose. Male subjects who are
sexually active with female partners of reproductive potential must use barrier
contraception, and their female partners must use a second effective birth
control method during the study and for at least 90 days after the last dose.
Exclusion criteria
Subjects must not meet any of the following criteria to be eligible for study
participation:
1. Previous exposure to seladelpar (MBX-8025).
2. A medical condition other than PBC that, in the investigator*s opinion,
would preclude full participation in the study (ege.g., cancer) or confound its
results (ege.g., Paget*s disease, any active infection).
3. Advanced PBC as defined by the Rotterdam criteria (albumin below the lower
limit of normal AND total bilirubin above 1.0× ULN).
4. Presence of clinically important hepatic decompensation, including the
following:
a. History of liver transplantation, current placement on liver transplantation
list, or current Model for End-Stage Liver Disease (MELD) score >=12. For
subjects on anticoagulation medication, evaluation of the baseline INR, in
concert with their current dose adjustments of their anticoagulant medication,
will be taken into account when calculating the MELD score. This will be done
in consultation with the medical monitor.
b. Complications of portal hypertension, including known esophageal varices,
history of variceal bleeds or related interventions (ege.g., transjugular
intrahepatic portosystemic shunt placement), ascites, and hepatic
encephalopathy.
c. Cirrhosis with complications, including history or presence of spontaneous
bacterial peritonitis, hepatocellular carcinoma, or hepatorenal syndrome.
5. Other chronic liver diseases:
a. Current features of AIH as determined by the investigator based on
immunoserology, liver biochemistry, or historic confirmed liver histology.
b. PSC determined by the presence of diagnostic cholangiographic findings.
c. History or clinical evidence of alcoholic liver disease.
d. History or clinical evidence of alpha-1-antitrypsin deficiency.
e. History of biopsy confirmed NASH.
f. History or evidence of Gilbert*s syndrome with elevated total bilirubin.
g. History or evidence of hemochromatosis.
h. Hepatitis B, defined as the presence of hepatitis B surface antigen.
i. Hepatitis C, defined as the presence of hepatitis C virus ribonucleic acid.
j. History, evidence, or high suspicion of hepatobiliary malignancy based on
imaging, screening laboratory values, and/or clinical symptoms.
6. Known history of human immunodeficiency virus (HIV) or positive antibody
test at screening.
7. Clinically important alcohol consumption, defined as more than 2 drink units
per day (equivalent to 20 g) in women and 3 drink units per day (equivalent to
30 g) in men, or inability to quantify alcohol intake reliably.
8. History of malignancy diagnosed or treated, active or within 2 years, or
ongoing evaluation for malignancy; localized treatment of squamous or
noninvasive basal cell skin cancers and cervical carcinoma in situ is allowed
if appropriately treated prior to screening.
9. Treatment with obeticholic acid (OCA), and fibrates (ege.g., bezafibrate,
fenofibrate, elafibranor, lanifibranor, pemafibrate, saroglitizar) 3 months6
weeks prior to screening.
10. Treatment with colchicine, methotrexate, azathioprine, or long-term
systemic corticosteroids (>2 weeks) during 2 months prior to screening. See
Section 7 for additional medications that may be excluded.
11. Treatment with anti-pruritic drugs (ege.g., cholestyramine, naltrexone,
rifampicin, sertraline, or any experimental approach) must be on a stable dose
within 1 month prior to screening.
12. Treatment with any other investigational therapy or device within 30 days
or within 5 half-lives, whichever is longer, prior to screening
13. For females, pregnancy or breastfeeding
14. Any other condition(s) that would compromise the safety of the subject or
compromise the quality of the clinical study, as judged by the investigator
15. Immunosuppressant therapies (ege.g., cyclosporine, tacrolimus, anti-TNF or
other immunosuppressive biologics).
16. Other medications that effect liver or GI functions, such as absorption of
medications or the roux-en-y gastric bypass procedure, may be prohibited and
should be discussed with the medical monitor on a case-by-case basis.
17. Active COVID-19 infection during Screening.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-004348-27-NL |
| ClinicalTrials.gov | NCT04250155 |
| CCMO | NL75532.091.20 |