In patients with primary biliary cirrhosis (PBC) taking UDCA, to assess the effects of INT-747 on: Primary: - Alkaline phosphatase (AP) levels - SafetySecondary: - Hepatocellular injury and liver function - Disease-specific and general health…
ID
Source
Brief title
Condition
- Hepatic and hepatobiliary disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy endpoint is the effect of INT-747 on serum AP levels at
baseline (Day 0) and the end of the study (Day 85).
Secondary outcome
Safety and secondary efficacy endpoints will be evaluated by monitoring the
following:
- Adverse experiences
- Clinical laboratory values (including aminotransferase liver enzymes, protein
concentrations, and prothrombin time to assess hepatocellular injury and liver
function)
- Vital signs
- Disease-specific and general health questionnaires (PBC-40, 5D, and SF-36)
- Symptoms (pruritus VAS questionnaire)
- Liver inflammation and fibrosis biomarkers
- Plasma drug and metabolite concentrations
Background summary
PBC is a chronic liver disease characterized by inflammation of the liver,
progressive destruction of the hepatic bile ducts, liver fibrosis, increased
blood levels of bile salts and bile accumulation in the liver. When the disease
progresses, liver transplantation might be required and/or the patient may die.
The only registered therapy specifically for PBC is Ursodeoxycholacic
((UDCA/URSO®). In a subset of the patients treated with URSO®, liver enzymes
normalise over time. URSO® however does not appear to be effective on the bile
secretion or as an antifibrotic agent. In pre-clinical studies INT-747, does
seem to have an effect on the bile secretion and to have antifibrotic efficacy.
Because URSO® is standard therapy for the treatment of PBC and in case it can
be demontrated that INT-747 is safe and effective in this condition, a
combination of these two treatment options might be prescribed in the future.
This study assesses the effect of co-administration of the two therapies in
patients with PBC in who liverfunctiontests did not normalise on URSO®.
See also protocol pages 13 - 16.
Study objective
In patients with primary biliary cirrhosis (PBC) taking UDCA, to assess the
effects of INT-747 on:
Primary:
- Alkaline phosphatase (AP) levels
- Safety
Secondary:
- Hepatocellular injury and liver function
- Disease-specific and general health symptoms
- Biomarkers of hepatic inflammation and fibrosis
- Plasma trough concentrations of INT-747 and its major, known metabolites
Study design
Multi-center, randomized, double-blind, placebo-controlled, multi-dose,
parallel-group study.
Intervention
One daily dose in combination of Ursodeoxycholicacid:
Group 1: 10 mg INT-747
Group 2: 25 mg INT-747
Group 3: 50 mg mg INT-747
Group 4: Placebo
Study burden and risks
Physical Exam: screening + day 85
ECG: screening + day 85
PBC-40 QOL and 5D questionnaires: screening, baseline, day 29, day 57 and day 85
5D questionnaire: day 15
SF-36 QOL questionnaires: baseline and day 85
Pruritis VAS questionnaires: baseline, day 15, day 29, day 57 and day 85
Vital signs: on all visits except day 99 (follow-up)
Transient Elastography, Fibroscan: day 0 and day 85
Bloodsample collection for laboratory parameters: all visits (for specific
analysis per visit, see "schedule of study procedures" on page 27 and appendix
B of the protocol ). On day 0 and 85 the patient should be fasted for at least
8 hours prior to blood sample collection.
Risks:
Bloodsample collection: there is a chance of pain or brusing and infection when
taking a blood sample.
All assessments will be performed by qualified physicians, nurses and study
personel.
PBC is a chronic liver disease that eventually could result in liver cirrhosis
for which a liver transplantation might be required or which could result in
the patient's death. The only registered treatment for PBC is
ursodoxycholicacid (UDCA). The co-administration of INT-747 could possibly
increase the effectiveness of the treatment of PBC. Phase I study results
indicate that INT-747 doses used in this protocol are generally well
tollerated. There are no invasive interventions besides the blood sample
collections.
Risk Fibroscan: non-invasive method via ultrasound.
18 Debrosses Street
NY 10013
Verenigde Staten
18 Debrosses Street
NY 10013
Verenigde Staten
Listed location countries
Age
Inclusion criteria
•Male or female age 18 to 70 years.
•Stable dose of ursodeoxycholic acid (URSO®, UDCA) for at least 6 months prior to screening.
• Female patients must be postmenopausal, surgically sterile, or if premenopausal, prepared to use 1 effective method of contraception with all sexual partners during the study and for 14 days after the end of dosing. Effective methods of contraception are considered to be: o Barrier method, i.e., (a) condom (male or female) or (b) diaphragm with spermicide; or o Hormonal (e.g., contraceptive pill, patch); or o Intrauterine device (IUD); or o Vasectomy (partner).
• Male patients must be prepared to use 1 effective method of contraception with all sexual partners during the study unless they have had a prior vasectomy.
• Proven or likely PBC, as demonstrated by the patient presenting with at least 2 of the following 3 diagnostic factors:
o History of increased AP levels for at least 6 months prior to Day 0
o Positive AMA titer (>1:40 titer on immunofluorescence or M2 positive by ELISA) or PBC-specific antinuclear antibodies (antinuclear dot and nuclear rim positive)
o Liver biopsy consistent with PBC
• Screening AP level between 1.5 and 10 × ULN.
• Willing and able to give written informed consent
Exclusion criteria
• Administration of the following drugs at any time during the 3 months prior to screening for the study: colchicine, methotrexate, azathioprine, or systemic corticosteroids.
• Screening conjugated (direct) bilirubin >2 × ULN.
• Screening ALT or AST >5 × ULN.
• Screening serum creatinine >1.5 mg/dL (133 micromol/L).
• History or presence of hepatic decompensation (e.g., variceal bleeds, encephalopathy, or poorly controlled ascites).
• History or presence of other concomitant liver diseases including hepatitis due to hepatitis B or C virus (HCV, HBV) infection, primary sclerosing cholangitis (PSC), alcoholic liver disease, definite autoimmune liver disease or biopsy proven nonalcoholic steatohepatitis (NASH).
• Known history of human immunodeficiency virus (HIV) infection.
• History or presence of any other disease or condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs including bile salt metabolism in the large intestine (e.g., inflammatory bowel disease).
• Other clinically significant medical conditions, including renal insufficiency.
• Other medical conditions that are not well controlled or for which medication needs are anticipated to change during the study. Concomitant medications must be stable for 14 days prior to the first dose of study medication, and should be expected to remain stable during the course of the study.
• History of alcohol abuse (defined as consumption of more than 210 mL of alcohol per week; or the equivalent of 14 4-ounce glasses of wine, or 14 12-ounce cans/bottles of beer or wine coolers) or other substance abuse within the prior 1 year.
• Participation in another investigational drug, biologic, or medical device study within 30 days prior to Day 0.
• History of noncompliance with medical regimens, or patients who are considered to be potentially unreliable.
• Blood or plasma donation within 30 days prior to dosing.
• Mental instability or incompetence, such that the validity of informed consent or compliance with the study is uncertain.
• If female: pregnant, lactating, or positive serum or urine pregnancy test.
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 | EUCTR2007-001425-10-NL |
| ClinicalTrials.gov | NCT00550862 |
| CCMO | NL24341.078.08 |