Cholestasis, Intrahepatic | A Study to Evaluate the Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of Repeat Doses of GSK2330672 Administration in Subjects With Primary Biliary Cirrhosis (PBC) and Symptoms of Pruritus
Cholestasis, Intrahepatic research study
What is the primary objective of this study?
This will be a randomized, double-blind, placebo-controlled study to assess safety and tolerability of GSK2330672 administration in subjects with primary biliary cirrhosis (PBC) and symptoms of pruritus. It is a double-blind, crossover study with subjects receiving placebo or GSK23306772 in random order during two 14-day treatment periods. Additionally, the study will determine GSK2330672 exposure and interactions with ursodeoxycholic acid (UDCA). The total duration of subject participation will be 14 weeks for screening (45 days) and the treatment period. Subjects who are eligible for enrolment will participate in a 2-week placebo run-in period. Subjects will be randomized in a crossover fashion (Sequence 1 / Sequence 2) to receive placebo or GSK2330672 treatment during two consecutive 2-week study periods. Subjects will then participate in a 2-week placebo dosing follow-up period ending in final follow-up assessments. Study results will be utilized to form a benefit: risk profile for GSK2330672 in PBC that will determine plans for progression to exploratory efficacy trials
Who is eligible to participate?
Inclusion Criteria: - Male or female aged between 18 and 75 years of age inclusive, at the time of signing the informed consent. - Proven or likely PBC, as demonstrated by the subject presenting with at least 2 of the following: history of sustained increased alkaline phosphatise (AP) levels first recognized at least 6 months prior to Day 1; positive antimitochondrial antibodies (AMA) titer (>1:40 titer on immunofluorescence or M2 positive by enzyme-linked immunosorbent assay [ELISA]) or PBC-specific antinuclear antibodies (antinuclear dot and nuclear rim positive); liver biopsy consistent with PBC. - Screening AP value between <=<10 × upper limit of normal (ULN). - Subjects should be on stable doses of UDCA for >8 weeks at time of screening. Subjects not taking UDCA due to intolerance may be enrolled into this study following agreement by the GSK medical monitor. - Symptoms of pruritus as follows (one of the following): PBC subjects with severe symptoms of pruritus that significantly impact daily life and have proven refractory after at least one previous therapy has been discontinued due to inadequate clinical response, poor tolerability or adverse events. Temporary response to cooling, 1% menthol in aqueous cream, nasobiliary drainage or molecular adsorbent recirculating system (MARS) therapy is still compatible with refractory itch; PBC subjects with unresolved symptoms with use of a single antipruritic agent who can tolerate washout of current therapy for the duration of the trial; PBC subjects seeking treatment for pruritus that is newly diagnosed or previously untreated. - A female subject is eligible to participate if she is not pregnant, as confirmed by a negative serum human chorionic gonadotrophin (hCG) test or at least one of the following conditions applies: Non-reproductive potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) >40 milli-international units per milliliter and estradiol <40 picograms per milliliter (<147 picomole per liter) is confirmatory]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods along with either a second form of highly effective contraception or barrier protection (condoms with spermicide) if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment; Reproductive potential and agrees to follow one of the contraception options methods for the specified duration of time. - Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form Exclusion Criteria: - Screening total bilirubin >1.5x ULN. Isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%. - Screening alanine aminotransferase or aspartate aminotransferase >4x ULN. - Screening serum creatinine >2.5 milligrams per decilitre (221 micromole/liter). - 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 hepatitis or biopsy proven nonalcoholic steatohepatitis (NASH). - Administration of the following drugs at any time during the 3 months prior to screening for the study: colchicine, methotrexate, azathioprine, or systemic corticosteroids. - Current or chronic history of inflammatory bowel disease, chronic diarrhea, Crohn's disease or diarrhea related to malabsorption syndromes. - Fecal occult blood positive test at screening. - Based on averaged corrected QT interval (QTc) values of triplicate ECGs obtained at least 5 minutes apart: QTc >=450 milliseconds (msec); or QTc >=480 msec in subjects with Bundle Branch Block. - History of sensitivity to heparin or heparin-induced thrombocytopenia. - History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation. - History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 g of alcohol: a half-pint (approximately 240 milliliter [mL]) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits - A positive pre-study drug/alcohol screen. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines - Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period. - The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer). - Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
Which medical condition, disease, disorder, syndrome, illness, or injury is researched?
Interventions can include giving participants drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available or noninvasive approaches such as surveys, education, and interviews.
Drug:GSK2330672GSK2330672 oral preserved solution 1.5mg/g will be supplied in amber glass bottles and as per randomization schedule subject will receive 45 mg BID from Day 1 to 3 and 90 mg BID from Day 4 to 14 of one of the two treatment periods.
Drug:PlaceboPlacebo oral preserved solution will be supplied in amber glass bottles and as per randomization schedule subject will receive placebo BID from Day 1 to 14 of one of the two treatment periods. .
Drug:Ursodeoxycholic acidUDCA 250 mg will be supplied in capsule form. The subjects, who are taking UDCA at the time of Run-in-period, will be continued on the same total daily dose of drug but converted to a standardized formulation and a standardized dosing regimen administering the entire daily dose once daily in the evening before bedtime. Once daily dosing of UDCA will continue for the duration of the study.
Research studies and clinical trials typically have two or more research arms. An arm is a group of people who receive the same treatment in the study.
GSK2330672Subject will receive GSK2330672 45 mg BID from Day 1 to 3 and 90 mg BID from Day 4 to 14 of one of the two treatment periods. Patients were randomized to one of two sequences receiving either (i) GSK2330672 followed by placebo; OR (ii) placebo followed by GSK2330672.
PlaceboSubject will receive placebo BID from Day 1 to 14 of one of the two treatment periods. Patients were randomized to one of two sequences receiving either GSK2330672 followed by placebo; OR placebo followed by GSK2330672.
Start Date: March 10, 2014
Completed Date: October 7, 2015
Phase: Phase 2
Primary Outcome: Number of participants with any on-treatment adverse event (AE) or serious adverse event (SAE) from Baseline to Day 56
Secondary Outcome: Area under curve (AUC) of serum profiles of total bile acid concentrations (T-bile acid) at Day 14, Day 28, and Day 42
Study sponsors, principal investigator, and references
Principal Investigator: GSK Clinical Trials
Lead Sponsor: GlaxoSmithKline