Primary objective* To assess the efficacy of EP547 compared to placebo on pruritus as assessed by the Worst Itch Numeric Rating Scale (WI-NRS)Secondary* To assess the efficacy of EP547 compared to placebo on the following:* Pruritus-related quality…
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Source
Brief title
Condition
- Hepatic and hepatobiliary disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary estimand of the study is to assess the difference in severity of
pruritus in subjects with cholestatic pruritus due to PBC or PSC treated with
EP547 or placebo, as measured by change in weekly average WI-NRS after 6 weeks
of randomized treatment, regardless of treatment discontinuation and use of
prohibited and/or rescue medications.
Secondary outcome
na
Background summary
Patients with cholestatic liver disease, such as primary biliary cholangitis
(PBC) and primary sclerosing cholangitis (PSC), often suffer from chronic itch
or pruritus that is experienced by up to 70% to 80% of these patients over the
course of their disease (Mittal 2016).
Patients with cholestatic pruritus have difficulty coping with the intense
itching and develop associated stress. Pruritus has a clinically meaningful
negative effect on patients* quality of life, sleep, fatigue, emotional state,
and social relations (Bassari 2015, Ibrahim 2016), and contributes to the
development of skin and soft tissue lesions and/or infections (Ozen 2018).
The pathophysiology of cholestatic pruritus is not fully understood and the
itch-causing pruritogen(s) and their cognate receptor(s) have remained largely
elusive. Cholestatic pruritus is often nonresponsive to standard
pharmacological treatments, including antihistamines, and instead requires
physically removing the causative obstruction (such as gallstones), draining
the bile, or transplanting the liver to alleviate itch (Bergasa 2014). Because
these procedures are often highly effective, the responsible pruritogens are
hypothesized to originate from the liver and bile. Numerous candidate
pruritogens are present in bile and upregulated in cholestatic patients,
including opioids, lysophosphatidic acid, bilirubin, and bile acids. Therapies
targeting these mechanisms, such as opioid antagonists, rifampicin, ileal bile
acid transporter inhibitors, and bile acid-binding resins like cholestyramine,
are frontline therapy for cholestatic pruritus (Bassari 2015, Mittal 2016);
however, efficacy is variable and patients are poorly managed with these
medications (Bassari 2015, Mittal 2016).
Although a variety of interventions have been explored, the need for improved
treatment of cholestatic pruritus remains high. Therefore, development of
additional safe and effective, mechanistically based therapeutic options for
this condition is essential.
Study objective
Primary objective
* To assess the efficacy of EP547 compared to placebo on pruritus as assessed
by the Worst Itch Numeric Rating Scale (WI-NRS)
Secondary
* To assess the efficacy of EP547 compared to placebo on the following:
* Pruritus-related quality of life using the 5-D Itch Scale
* Pruritus severity using the Patient Global Impression of Severity (PGI-S)
* Overall pruritus response to therapy using the Patient Global Impression of
Change (PGI-C)
* To assess the safety and tolerability of EP547
* To assess the pharmacokinetics (PK) of EP547
Exploratory
* To assess the effects of EP547 compared to placebo on the following: o Sleep
using the Patient-Reported Outcomes Information System (PROMIS)
Short Form - Sleep Disturbance
* Fatigue using the Fatigue Impact Scale for Daily Administration (D-FIS)
* Overall quality of life using the 3-Level EuroQol-5D (EQ-5D-3L)
* Pruritus-related biomarkers (bile acids and heme metabolites)
Study design
EP-547-201 is a randomized, double-blind, placebo-controlled study to evaluate
the effects of EP547 on pruritus over 6 weeks in subjects with cholestatic
pruritus due to primary biliary cholangitis (PBC) or primary sclerosing
cholangitis (PSC). Where allowed per regulatory/local requirements, subjects
will be able to attend study visits at a physical study site as well as
remotely (hybrid model) or at a virtual site where all visits will be conducted
remotely (decentralized model). For both the hybrid and decentralized models, a
home health nurse visit at the subject's home or work and a telemedicine visit
with the study site staff (eg, smartphone or computer) will be arranged to
conduct procedures for each remote study visit.
The study includes a Screening Period of up to 4 weeks to assess subject
eligibility; a 6-week Double-Blind Treatment Period; a 6-week Open-Label
Extension Period; and a 2-week Safety Follow-Up Period after administration of
the last dose of study drug (EP547 or placebo). Approximately 58 subjects will
be randomized to receive either 100 mg doses of EP547 or placebo orally (PO)
once daily (QD) in a 1:1 ratio. In the Open-Label Extension Period, all
subjects will receive 100 mg doses of EP547.
Screening Period
The Screening Period will consist of 1 study visit (Visit 1). During this
period, subjects will undergo assessments to determine study eligibility. Visit
1 (Day-28 to Day -1) may be conducted over more than 1 day but must be
completed between Day -28 and Day -1.
Double-Blind Treatment Period
The Double-Blind Treatment Period will consist of 5 study visits (Visits 2, 3,
4, 5, and 6 [Day 1 and Weeks 1, 2, 3, and 6]). During this period, all subjects
who meet eligibility requirements will be enrolled into the study and
randomized to receive double-blind, PO, QD doses of EP547 or placebo for 6
weeks beginning on Visit 2 (Day 1). Subjects will be randomized to receive
either 100 mg doses of EP547 or placebo in a 1:1 ratio. Randomization will be
conducted centrally via an Interactive Web Response System (IWRS) and
stratified based on type of cholestatic disease (PBC, PSC). Visit 2 (Day 1)
will not have a visit window; however, for the decentralized model,
enrollment/randomization and the first dose of study drug may be separated by
up to 10 additional calendar days to allow for home delivery of study drug.
When enrollment/randomization and first dose of study drug are on separate
days, the first dose of study drug is considered Day 1. All other visits in the
Double-Blind Treatment Period will have a visit window of ±3 days.
Open-Label Extension Period
The Open-Label Extension Period will consist of 2 study visits (Visit 7 [Week
9] and Visit 8 [Week 12]). During this period, all subjects who complete the
Double-Blind Treatment Period and are still receiving study drug will receive
open-label 100 mg doses of EP547. Visit 7 and Visit 8 will have a visit window
of ±3 days.
Safety Follow-Up Period
Any subject who completes the Open-Label Extension Period or discontinues study
drug (EP547 or placebo) early will complete a follow-up visit (Visit 9)
approximately 2 weeks (±3 days) after the last dose of study drug.
Intervention
For the Double-Blind Treatment Period, tablets containing 25 mg or 75 mg of
EP547 or placebo will be taken orally as intact (swallowed whole, not chewed or
crushed) tablets, and taken with water. Doses are to be administered daily at
approximately the same time of day after a fast of at least 8 hours. For the
Open-Label Extension Period, tablets containing 25 mg or 75 mg of EP547 will be
supplied. Subjects receiving EP547 will take one 25-mg and one 75-mg EP547
tablet per dose (for a total dose of 100 mg) and subjects receiving placebo
will take 2 placebo tablets per dose.
Study burden and risks
There might be side effects of the study drug EP547, fe: allergic Reaction.
Some symptoms of allergic reactions are as follows:
• Rash
• Wheezing and difficulty breathing
• Dizziness and fainting
• Swelling around the mouth, throat, or eyes
• A fast pulse
• Sweating
Burden of the procedures in the study:
Blood draws via injection or IV: some discomfort or pain when blood is drawn.
Participants may faint or pass out. There is a risk of infection, bleeding, or
bruising at the site where the injection was.
Electro Cardio Gram (ECG): a mild rash or irritation cab develop where the ECG
pads are placed. The rash/irritation is generally mild and usually goes away
without treatment.
Other:
Extra time spend for the study: filling in of questionnaires, review of
personal information.
Physical examinations will be done.
Study tablets to swallow.
It is hoped that the study drug may provide relief of, or lessening of, itch,
one of the signs and symptoms that participants may experience as a result of
their liver condition.
Participation in the research study may benefit others by helping the
researchers gain valuable information on how people respond to the study drug
and whether there should be more clinical studies to see if the study drug may
help reduce itch in patients with liver disease.
Science Center Drive 10578, Suite 250
San Diego CA 92121
US
Science Center Drive 10578, Suite 250
San Diego CA 92121
US
Listed location countries
Age
Inclusion criteria
1. Age 18 to 80 years, inclusive
2. Has experienced self-reported daily or near-daily moderate to severe
pruritus before Screening
3. Has a mean daily WI-NRS score indicative of moderate to severe pruritus
(score >=4) as recorded using a study-issued electronic device or application
(app) during Screening (Day -7 through Day -1); data from at least 4 of the 7
days are required to be considered an acceptable profile
4. If currently taking medications to treat the cholestatic disorder
(obeticholic acid [OCA]), must be on a stable dose for >12 weeks before
Screening and plans to maintain the regimen throughout the study
5. If currently taking a fibrate, must be on a stable dose for >12 weeks before
Screening and plans to maintain the regimen throughout the study
6. Either is not treated with or has been on a stable regimen with any
medications to treat pruritus for >4 weeks before Screening and plans to
maintain the regimen throughout the study
7. If female, must have a negative serum pregnancy test at Screening and be
willing to not donate eggs from Screening until the last dose of study drug
8. Must be able to communicate well with the Investigator, understand and
comply with the requirements of the study, and understand and provide written
consent
9. For subjects with concomitant inflammatory bowel disease (IBD): a.
Colonoscopy (if subject has a colon) or other appropriate endoscopic procedure
within 18 months of Day 1 confirming no dysplasia or colorectal cancer b.
Subjects with Crohn*s disease (CD) must be in remission as defined by a Crohn*s
Disease Activity Index (CDAI) <150 at Screening c. Subjects with ulcerative
colitis (UC) must have a Partial Mayo Scoring Index score<=3 with no individual
sub-score exceeding 1 point at Screening
10. Documented history of PBC that is consistent with the American Association
for the Study of Liver Diseases (AASLD) Practice Guidelines (Lindor 2019),
defined as having >=2 of the following 3 factors upon diagnosis: a. History of
elevated alkaline phosphatase (ALP) levels b. Historic positive
antimitochondrial antibody (AMA) or AMA-M2 by immunofluorescence, enzyme linked
immunosorbent assay (ELISA), or immunoblot or if AMA is negative, positive for
PBC-specific antibodies (anti-GP210 and/or anti-SP100) c. Liver histology at
any point in time consistent with PBC
11. If currently taking ursodeoxycholic acid (UDCA), must be treated for >=1
year, and must be on a stable dose of not more than 20 mg/kg/day for >=12 weeks.
If not currently taking UDCA, must not be treated with UDCA within 12 weeks
before Screening or plan to be treated with UDCA during the study
12. Documented history of PSC based on either cholangiography (ie, magnetic
resonance cholangiopancreatography, endoscopic retrograde
cholangiopancreatography, or percutaneous transhepatic cholangiogram) or if
small duct PSC, confirmed by typical histologic evidence of PSC for >=1 year
13. If currently taking UDCA, must be treated for >=1 year, and must be on a
stable dose of not more than 23 mg/kg/day for >=12 weeks. If not currently
taking UDCA, must not be treated with UDCA within 12 weeks before Screening or
plan to be treated with UDCA during the study.
Exclusion criteria
1.Pruritus is attributed mainly to any disease unrelated to PBC or PSC
2.Prior liver transplant or presently listed for transplantation
3.Is receiving ongoing ultraviolet B (UVB) treatment or plasmapheresis or
anticipates receiving such treatments during the study
4.Evidence of compensated or decompensated cirrhosis based on ANY of the
following: Historical liver biopsy demonstrating cirrhosis b. Liver stiffness
as assessed by a FibroScan® score of >=16.9 kPa for subjects with PBC or >=14.4
kPa for subjects with PSC within 6 months of Screening c. History or presence
of portal hypertension with complications, including known gastric or
esophageal varices, ascites, spontaneous bacterial peritonitis, hepatic
encephalopathy, history of variceal bleeds, or related therapeutic or
prophylactic interventions
5.History of malignancy of any organ system, including but not limited to
hepatocellular carcinoma, cholangiocarcinoma, and gall bladder carcinoma,
treated or untreated, within the past 5 years (localized squamous cell or basal
cell carcinoma of the skin that have been excised or resolved is not
exclusionary)
6.Alternate causes of liver diseases such as hepatic sarcoidosis, alcoholic
liver disease, histology confirmed autoimmune hepatitis, overlap hepatitis, or
nonalcoholic steatohepatitis (NASH), or uncontrolled viral hepatitis as defined
in Protocol
7.Presence of documented secondary sclerosing cholangitis (eg, ischemic
cholangitis, recurrent pancreatitis, intraductal stone disease, severe
bacterial cholangitis, surgical or blunt abdominal trauma, recurrent pyogenic
cholangitis, choledocholithiasis, toxic sclerosing cholangitis due to chemical
agents, or any other cause of secondary sclerosing cholangitis) on prior
clinical investigations
8.Immunoglobulin G4 (IgG4) >4× upper limit of normal (ULN) at Screening or
evidence of systemic IgG4-related disease
9.Current evidence of clinically significant high-grade strictures or presence
of biliary stent at Screening
10.History of recurrent bacterial cholangitis or recent episode within 3 months
before Screening 11.Endoscopic interventions with therapeutic intent such as
biliary duct dilation within 3 months before Screening or planned during the
study
12.History of significant small bowel resection or short bowel syndrome
13.Presence of a concomitant disease or a history of any medical condition
that, in the opinion of the Investigator, could pose undue risk to the subject,
impede completion of the study procedures, or would compromise the validity of
the study measurements
14.Clinically relevant medical history, physical examination, vital sign,
standard 12-lead electrocardiogram (ECG), chemistry, hematology, urinalysis, or
coagulation results at Screening beyond what is expected for subjects with a
cholestatic disorder that would place the subject at undue risk as deemed by
the Investigator
15.Has any of the following laboratory results at Screening: a.Total bilirubin
>2.0 mg/dL; total bilirubin >2.0 mg/dL is acceptable for subjects with
medically documented Gilbert*s syndrome if direct bilirubin is <0.3 mg/dL
b.Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5× ULN
c.ALP >10× ULN d.International normalized ratio (INR) >1.3 e.Platelet count
<150,000/µL f.Urine albumin to creatinine ratio >=30 mg/g
16.Estimated glomerular filtration rate <60 mL/min/1.73 m2 as determined by the
Chronic Kidney Disease Epidemiology Collaboration equation at Screening
17.History of human immunodeficiency virus (HIV) or positive for HIV infection
at Screening 18.Significant history of abuse of drugs, solvents, or moderate
alcohol consumption (>=1 serving or unit/day on average for women and >=2
servings or units/day on average for men) in the past 2 years before Screening
19.Has received a prohibited medication within 2 weeks or 5 half-lives of Day
1, whichever is longer, as described in Protocol
20.Participation in any clinical study with an investigational or approved
drug/device within 30 days before Screening or is planning to participate in
another clinical study with an investigational or approved drug/device while
enrolled in this study
21.History of known or suspected hypersensitivity to any component of the study
drug
22.Female who is pregnant, nursing, or intends to become pregnant during the
study
23.Is directly affiliated with the study at the study site or is an immediate
family member (spouse, parent, child, or sibling; biological or legally
adopted) of personnel directly affiliated with the study at the study site
24.Is employed by Escient Pharmaceuticals, Inc., (that is an employee,
temporary contract worker, or designee responsible for the conduct of the
study) or is an immediate family member of an employee of Escient
Pharmaceuticals, Inc.
25.Subject in the opinion of the Investigator, not suitable to participate in
the study
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 | EUCTR2021-002526-25-NL |
| ClinicalTrials.gov | NCT05525520 |
| CCMO | NL82950.018.22 |