Primary: • To evaluate the safety and effect on cholestasis of two seladelpar regimens (5 mg/day titrated to 10 mg/day and 10 mg/day) over 52 weeks of treatment compared to placeboKey Secondary: • To evaluate the effect of seladelpar on…
ID
Source
Brief title
Condition
- Autoimmune disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• Response on the composite endpoint of AP and total bilirubin at 12 months:
o AP < 1.67 × upper limit of normal (ULN), and
o >= 15% decrease in AP, and
o Total bilirubin <= ULN
• Assessment of treatment-emergent AEs (TEAEs) (National Cancer Institute [NCI]
Common Terminology Criteria for Adverse Events [CTCAE] Version 4.0),
biochemistry and hematology
Secondary outcome
Key Secondary:
• Proportion of subjects with AP <= 1.0 × ULN at 12 months
• Change from baseline in pruritus numerical rating scale (NRS) at 6 months
Other Secondary:
• PBC-40 QoL at 6 and 12 months
• PBC-40 QoL itch domain, and 5-D itch questionnaire
• Response on the composite endpoint at 6 months
• Proportion of subjects with AP < 1.67 × ULN and AP < 1.5 × ULN at 6 and 12
months
• Proportion of subjects with AP <= 1.0 × ULN at 6 months and 12 months
• Change from baseline in pruritus NRS at 12 months
• Absolute and relative changes in AP
• Proportion of subjects with PBC response criteria (Barcelona, Paris I and II,
Toronto I and II, Rotterdam)
• Change in UK-PBC and GLOBE risk scores
• Absolute and relative changes in alanine aminotransferase (ALT), aspartate
aminotransferase (AST), gamma-glutamyl transferase (GGT), bilirubin (total,
direct, and indirect), low density lipoprotein cholesterol (LDL-C), high
density lipoprotein cholesterol (HDL- C), triglycerides, and total cholesterol
• The first occurrence of any of the following events:
o Overall Death
o Liver transplantation
o MELD score >=15
o Uncontrolled ascites (diuretic resistant)
o Hospitalization for new onset or recurrence of any of the following:
* variceal bleeding
* hepatic encephalopathy (as defined by a West Haven score >= 2)
* spontaneous bacterial peritonitis (confirmed by culture from diagnostic
paracentesis)
o Hepatocellular carcinoma
o Advanced PBC as defined by the Rotterdam criteria (albumin below low limit of
normal (LLN) AND total bilirubin above ULN)
Exploratory Measures:
• C4 (7α-hydroxy-4-cholesten-3-one), fibroblast growth factor 19 (FGF19),
N-terminal type III collagen propeptide (Pro-C3)
• Haptoglobin, fibrinogen and high-sensitivity C-reactive protein (hs-CRP),
homocysteine, immunoglobulin M (IgM)
• Autotaxin
• Enhanced liver fibrosis (ELF) score, fibrosis-4 (FIB-4) score, Lok-Index,
non-alcoholic fatty liver disease (NAFLD) fibrosis score
• Liver elastography (at selected centers)
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:
• To evaluate the safety and effect on cholestasis of two seladelpar regimens
(5 mg/day titrated to 10 mg/day and 10 mg/day) over 52 weeks of treatment
compared to placebo
Key Secondary:
• To evaluate the effect of seladelpar on normalization of alkaline phosphatase
(AP) levels
• To evaluate the effect of seladelpar on pruritus
Other Secondary:
• To evaluate the effect of seladelpar on quality of life (QoL)
• To evaluate the effect of seladelpar on other measures of cholestasis,
metabolic outcomes, and PBC prognosis criteria
• To evaluate the effect of seladelpar on PBC clinical outcomes
Exploratory:
• To evaluate the effect of seladelpar on markers of inflammation, bile acid
synthesis, levels of autotaxin, and markers of liver fibrosis
Study design
Double-blind, randomized, placebo controlled, 52 weeks dose ranging (placebo,
5/10 mg/day, and 10 mg/day), parallel treatment groups
Subjects on 5/10 mg who are tolerating study drug but who are not responding to
the therapy based on composite endpoint, will have dose adjustment performed
after 6 months of treatment.
Intervention
Study subjects will be randomized 1:1:1 to one of following treatment arms:
• Seladelpar 5/10 mg
• Seladelpar 10 mg
• Placebo
Study burden and risks
Patients are asked to undergo procedures described on pages 26 - 27 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. Common adverse events that were reported with use of study drug (occur
in 1 in 10 people or more): Skin itching, Nausea (feeling sickness with the
urge to vomit), Abdominal distension (gas or fluid in the abdomen), Abdominal
pain, Arthralgia (joint pain), Diarrhea, Fatigue, Headache, Nasopharyngitis
(infection of nose and throat) and Urinary tract infection.
Other adverse event reported related to use of study drug (occur in less than 1
in 10 people): Asymptomatic hepatic enzyme (ALT and AST) increase, Peripheral
swelling or edema, Cough, Dizziness, Dry mouth, Muscle spasms, Oropharyngeal
pain (throat pain), Vomiting, Abdominal tenderness, Asthenia (weakness or loss
of strength), Back pain, Blood creatine phosphokinase increased, Bronchitis,
Chest discomfort, Constipation, Cystitis (urinary bladder inflammation),
Dyspepsia (indigestion), Erythema (skin inflammation or reddening),
Gastroesophageal reflux disease (GERD), Myalgia (muscle pain), Nasal congestion
and Neck pain. Furthermore, there may be risks asscoaited 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 all of 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, by at least two of the following criteria:
• History of AP above ULN for at least six months
• Positive anti-mitochondrial antibody (AMA) titers (>1/40 on immunofluorescence or M2 positive by enzyme linked immunosorbent assay [ELISA]) or positive PBC-specific antinuclear antibodies
• Documented liver biopsy result consistent with PBC
4. On a stable and recommended dose of UDCA for the past twelve months OR intolerant to UDCA (last dose of UDCA > 3 months prior to Screening)
5. AP >= 1.67 × ULN
6. Females of reproductive potential must use at least one 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 or confound its results (e.g., cancer)
3. AST above 3 × ULN
4. ALT above 3 × ULN
5. Total bilirubin above 2.0 × ULN
6. Advanced PBC as defined by the Rotterdam criteria (albumin below LLN AND total bilirubin above 1 × ULN)
7. Creatine kinase (CK) above 1.0 × ULN
8. eGFR below 60 mL/min/1.73 m2 (calculated by MDRD formula)
9. International normalized ratio (INR) above 1.0 × ULN
10. Platelet count below 100 × 103/µL
11. Presence of clinically significant hepatic decompensation, including:
- History of liver transplantation, current placement on liver transplantation list, or current MELD score >= 15
- Complications of portal hypertension, including known esophageal varices, history of variceal bleeds or related interventions (e.g., transjugular intrahepatic portosystemic shunt placement), relevant ascites, hepatic encephalopathy
- Cirrhosis with complications, including history or presence of spontaneous bacterial peritonitis
12. Other chronic liver diseases:
a. Current features of auto-immune hepatitis as determined by the investigator based on immunoserology, liver biochemistry and histology
b. Primary sclerosing cholangitis determined by 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. Biopsy confirmed nonalcoholic steatohepatitis
f. History or evidence of Gilbert* Syndrome with elevated total bilirubin
g. History or evidence of hemochromatosis
h. Hepatitis B defined as presence of hepatitis B surface antigen (HBsAg)
i. Hepatitis C defined as presence of HCV RNA
13. Known history of HIV
14. Evidence of significant alcohol consumption
15. Evidence of drug abuse
16. Subjects with inadequate response to obeticholic acid (OCA) or intolerance to OCA: OCA must be discontinued 30 days prior to Screening
17. Use of colchicine, methotrexate, azathioprine, or long-term systemic corticosteroids (> 2 weeks) within two months prior to Screening
18. Use of fibrates within 30 days prior to Screening
19. Use of simvastatin within 7 days prior to Screening
20. Use of an experimental or unapproved treatment for PBC within 30 days prior to Screening
21. Use of experimental or unapproved immunosuppressant within 30 days prior to Screening
22. Treatment with any other investigational therapy or device within 30 days or within five half-lives, whatever is longer, prior to Screening
23. For females, pregnancy or breast-feeding
24. 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
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 | EUCTR2018-001171-20-NL |
| ClinicalTrials.gov | NCT03602560 |
| CCMO | NL67407.091.18 |