To evaluate the effect of Obeticholic Acid on clinical outcomes in subjects with primary biliary cholangitis
ID
Source
Brief title
Condition
- Hepatic and hepatobiliary disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary
To assess the effect of OCA compared to placebo, in conjunction with
established local standard of care, on clinical outcomes in subjects with
primary biliary cholangitis (PBC) as measured by time to first occurrence of
any of the following adjudicated events, derived as a composite event
endpoint:
- Death (all-cause)
- Liver transplant
- Model of end stage liver disease (MELD) score *15
- Hospitalization (as defined by a stay of 24 hours or greater) for new onset or
recurrence of:
- Variceal bleed
- Hepatic Encephalopathy (as defined by a West Haven score of *2)
- Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis)
- Uncontrolled ascites (diuretic resistant ascites requiring therapeutic
paracentesis at a frequency of at least twice in a month)
Secondary outcome
Secondary
To assess the effect of OCA compared to placebo on time to first occurrence of
each individual component of the primary endpoint as listed above.
To assess the effect of OCA compared to placebo on time to occurrence of
liver-related death.
To assess the effect of OCA compared to placebo on progression to cirrhosis.
To assess the effect of OCA compared to placebo on time to occurrence of
hepatocellular carcinoma (HCC).
To assess the effect of OCA compared to placebo on disease progression via the
following:
- Liver biochemistry
- Markers of inflammation and fibrosis
To assess the effect of OCA compared to historical controls on liver-related
clinical outcomes.
To characterize the pharmacokinetics (PK) of OCA and its conjugates in a subset
of subjects.
To assess health outcomes and pharmacoeconomics including cost-effectiveness,
resource utilization, and quality of life measures in subjects treated with OCA
compared to placebo.
To assess the safety and tolerability in subjects treated with OCA compared to
placebo.
Background summary
Primary Biliary Cirrhosis (PBC) is a serious, life-threatening, cholestatic
liver disease of unknown etiology that, without treatment, frequently
progresses to hepatic fibrosis and eventual cirrhosis, hepatic decompensation,
and necessitates liver transplantation or results in death. PBC
is a rare disease with reported prevalence in the US of 40.2/100,000 (Kim
2000). PBC disproportionately affects women approximately 10:1 and is typically
diagnosed in patients between 40 to 60 years of age.
Ursodeoxycholic acid (UDCA), a physiological constituent of human bile, is
currently the only treatment approved for PBC (Lindor 2009). While UDCA therapy
has a marked effect on the treatment of PBC, up to 50% of patients show a
suboptimal response or no response to UDCA.
Such patients are at significantly increased risk of a poor clinical outcome
due to PBC disease progression. There is a clear unmet medical need for better
therapies for patients with PBC that have an inadequate response to UDCA, or
those who cannot tolerate UDCA (typically due to
gastrointestinal adverse events [AEs]). Obeticholic acid (OCA) is being
developed for the treatment of PBC and to provide patients that have an
inadequate response to or poor tolerance of UDCA a novel treatment option that
is safe and effective.
OCA is a modified bile acid and farnesoid X receptor (FXR) agonist that is
derived from the primary human bile acid chenodeoxycholic acid (CDCA). OCA is
currently being developed in the United States (US) and Europe for the
treatment of PBC and other chronic liver diseases.
OCA has been granted Orphan Drug Designation in the US (09 Apr 2008) and Orphan
Medicinal Product Designation in the European Union (27 Jul 2010) for the
treatment of PBC.
Food and Drug Administration (FDA) has granted accelerated approval for OCA
(marketed as Ocaliva for the treatment of PBC. ), for the treatment of patients
with PBC in combination with UDCA in adults with an inadequate response to UDCA
or as monotherapy in adults unable to tolerate UDCA. In December 2016, the
European Commission granted conditional approval for Ocaliva for the same
indication.
OCA is a 6a-ethyl derivative of the naturally occurring primary human bile acid
CDCA, which is the endogenous ligand for FXR. FXR is a ligand-dependent
transcription factor that is part of the nuclear receptor superfamily. FXR
regulates a wide variety of target genes involved in the
control of bile acid, lipid, and glucose homeostasis and in the regulation of
immune responses.
OCA*s potent FXR agonist effects are believed to account for the predominant
efficacy of the investigational product. Some of the pharmacological properties
of OCA and other FXR agonists that have been elucidated in animal models of
chronic liver disease relevant to the
treatment of PBC include the following:
- Improvement in hepatic choleresis with reduced inflammation and necrosis
- Prevention and reversal of hepatic fibrosis
The key mechanisms of action of OCA, including its choleretic,
anti-inflammatory, and anti-fibrotic properties, underlie its hepatoprotective
effects and result in attenuation of injury and improved liver function in a
cholestatic liver disease such as PBC.
Intercept Pharmaceuticals, Inc. (the Sponsor) has completed a standard battery
of nonclinical safety pharmacology and toxicology studies. No major nonclinical
safety effects have been seen other than pharmacologic hepatic effects observed
at high doses. These pharmacologic hepatic
effects are consistent with the detergent effects of a bile acid at exceedingly
high hepatocellular exposure.
Study objective
To evaluate the effect of Obeticholic Acid on clinical outcomes in subjects
with primary biliary cholangitis
Study design
This Phase 4, double-blind, randomized, placebo-controlled, multicenter study
will evaluate the effect of OCA on clinical outcomes in subjects with PBC.
Subjects will be screened during a 1 to 8 week Screening period prior to
entering the study to allow for the collection of repeat serum chemistry
samples (at least 2 weeks apart) to confirm pretreatment alkaline phosphatase
(ALP) and total bilirubin values (refer to Section 9.7.3). Mean values for ALP
and total bilirubin will be calculated using all available screening values.
Subjects who meet all inclusion criteria and none of the exclusion criteria
will be randomized (1:1) to OCA or placebo treatment groups. The randomization
will be stratified by ursodeoxycholic acid (UDCA) treatment (yes/no) and
baseline bilirubin categories (>upper limit of normal [ULN]/ = ULN).
Investigational product (OCA or matched placebo) will be taken orally, once
daily. Subjects who are non-cirrhotic or classified as Child-Pugh A at
Screening will initiate investigational product once daily with 5-mg OCA or
matching placebo. After 3 months of once-daily treatment with investigational
product, the dose may be increased (to the maximum dose of 10 mg OCA or matched
placebo, in a blinded manner) at the 3-month visit or any subsequent study
visit based on tolerability.
Subjects with cirrhosis (see Section 9.7.3) and classified as Child-Pugh Class
B or Child-Pugh Class C will follow a modified dosing regimen, and will
initiate investigational product once weekly with the 5-mg OCA or matching
placebo dose. In addition, these subjects will follow a modified titration
plan, which is outlined in Protocol Appendix A.
Subjects will be seen at quarterly visits for the duration of the study.
Sub Study Genetic research (optional)
Sub Study Biopsy research (optional, n/a for NL)
Intervention
Subjects will receive either placebo or 5 mg OCA and should titrate to 10 mg
OCA (in a blinded manner) at the 3-month study visit or at any study visit
thereafter depending on tolerability.
Study burden and risks
All of the risks associated with taking the study drug in this study may not
currently be known. Very common side effect reported in more than 10% of
patients who have taken OCA is itching.
Common side effects, reported in more than 1%, but less than or equal to 10% of
patients who have taken OCA: abdominal bloating or pain, joint pain, bruising,
constipation, diarrhea, difficulty sleeping, dry eyes, feeling tired, headache,
irritated or chaffed skin, or skin wounds (i.e., due to itching), nausea, rash.
These side effects, reported by patients receiving OCA, may also have occurred
as part of the medical condition for which the patient was being treated, or
due to other reasons.
Use of OCA may also lead to changes in blood fat levels. Some of these changes
have generally been associated with undesirable effects on the heart and blood
vessels, such as narrowing of blood vessels. It is not clear if changes in
blood fat levels caused by OCA also lead to undesirable effects on the heart
and blood vessels.
Other less frequently reported (in less than 1% of patients) but significant
side effects include worsening in tests of liver health or function, jaundice
(yellowing of the skin and/or eyes), build-up of fluid in the stomach area, and
inflammation of the gallbladder.
Blood Samples
When blood samples are taken from a vein, there may be some minor pain and risk
of bruising at the needle site. Sometimes a patient may become dizzy or faint
when blood is drawn and there is a rare possibility of infection.
Electrocardiogram (ECG)
There are no risks associated with having an ECG other than possible minor
redness or irritation at the site where the sticky pads are placed. This is
temporary.
Fibroscan® (select centers only)
The Fibroscan® is an ultrasound of the liver with no known risks. Some sites do
not use this device, so this type of scan will not be performed.
Endoscopy
For the endoscopy exam of the patient's esophagus (windpipe), stomach and
duodemum (first section of the small intestine), a flexible tube with a light
and camera attached to it is passed through the patient's mouth and throat. The
doctor can view pictures of the patient's esophagus on a color TV monitor. In
rare cases (less than 1 in 100), bleeding can occur. Bleeding is usually minor
and does not require treatment, but in very rare cases (less than 1 in 1000)
blood transfusion may be required. Another rare risk (approximately 1 in 100)
with endoscopy is infection. Most infections are minor and can be treated with
antibiotics. The doctor may give the patient preventive antibiotics before the
procedure if the patient is at higher risk of infection. Tearing of the
esophagus, stomach or duodenum is a very rare complication of endoscopy. A tear
in esophagus may require hospitalization, and sometimes surgery to repair it.
The risk of this complication is very low (less than 1 in 1000).
Before the patient will undergo endoscopy the patient usually receives
medication for sedation. With these medications there is a very small risk of
heart attack, pneumonia, or stroke (poor blood flow to the brain).
Ultrasound Scan of the Liver
During an ultrasound, gel is applied to the skin of the patient and a trained
technician presses a small, hand-held device, about the size of a bar of soap,
against the skin of the patient over the area being examined, moving it as
necessary to capture an image. There are no known risks to having an ultrasound
of the liver.
Pregnancy
The effects of OCA on pregnancy and the unborn child (fetus) are unknown.
Females who are able to become pregnant must use at least one effective method
of birth control throughout the study period and for 30 days after taking the
last dose of study drug.
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Listed location countries
Age
Inclusion criteria
1. Definite or probable PBC diagnosis (consistent with American Association for
the Study of Liver Diseases [AASLD] and the European Association for the Study
of the Liver [EASL] practice guidelines; Lindor 2009; EASL 2009), as
demonstrated by the presence of *2 of the following 3 diagnostic factors:
a.History of elevated ALP levels for at least 6 months.
b.Positive antimitochondrial antibody (AMA) titer or if AMA negative or in low
titer (<1:80) PBC-specific antibodies (anti-GP210 and/or anti-SP100 and/or
antibodies against the major M2 components [PDC-E2, 2-oxo-glutaric acid
dehydrogenase complex]).
c.Liver biopsy consistent with PBC.
2. A mean total bilirubin >ULN and *5x ULN and/or a mean ALP >3x ULN
3. Either is not taking UDCA (no UDCA dose in the past 3 months) or has been
taking UDCA for at least 12 months with a stable dose for *3 months prior to
Day 0.
Exclusion criteria
1. History or presence of other concomitant liver diseases including:
- Hepatitis C virus infection
- Active hepatitis B infection; however, subjects who have seroconverted
(hepatitis surface antigen and hepatitis B e antigen negative) may be included
in this consultation with the medical monitor.
- Primary sclerosing cholangitis
- Alcoholic liver disease
- Definite autoimmune liver disease or overlap hepatitis
- Nonalcoholic steatohepatitis
- Gilbert*s Syndrome
2. Presence of clinical complications of PBC or clinically significant hepatic
decompensation, including:
- History of liver transplant, current placement on a liver transplant list, or
current MELD score >12. Subjects who are placed on a transplant list despite a
relatively early disease stage (for example per regional guidelines) may be
eligible as as they do not meet any of the other exclusion criteria.
- Cirrhosis with complications, including history (within the past 12 months)
presence of:
- Variceal bleed
- Uncontrolled ascites
- Encephalopathy
- Spontaneous bacterial peritonitis
- Known or suspected HCC
- Prior transjugular intrahepatic portosystemic shunt procedure
- Hepatorenal syndrome (type I or II) or Screening (visit 1 or 2) serum
creatinine >2 mg/dL (178 µmol/L)
3. Mean total bilirubin >5x ULN
4. Subjects who have undergone gastric bypass procedures (gastric lap band is
acceptable) or ileal resection or plan to undergo either of these procedures.
5. Other medical conditions that may diminish life expectancy, including known
cancers (except carcinomas in situ or other stable, relatively benign
conditions).
6. If female: plans to become pregnant, known pregnancy or a positive urine
pregnancy test (confirmed by a positive serum pregnancy test by the central
laboratory), or lactating.
7. Known history of human immunodeficiency virus infection.
8. Medical conditions that may cause non-hepatic increases in ALP (eg, Paget's
disease or fractures within 3 months prior to Day 0).
9. Other clinically significant medical conditions that are not well controlled
or for which medication needs are anticipated to change during the study.
10. History of alcohol abuse or other substance abuse within 1 year prior to
Day 0.
11. Participation in another investigational product, biologic, or medical
device study within 30 days prior to Screening. Participation in a previous
study of OCA is
allowed with 3 months washout prior to enrollment in this study.
12. Mental instability or incompetence, such that the validity of informed
consent or ability to be compliant with the study is uncertain.
13. History of known or suspected clinically significant hypersensitivity to
OCA or any of its components.
14. UDCA naïve (unless contraindicated)
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 | EUCTR2014-005012-42-NL |
| ClinicalTrials.gov | NCT02308111 |
| CCMO | NL54135.091.15 |