Clinical trial NCT01899703: 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
Official title: A Randomised, Double-blind, Placebo-controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Repeat Doses of GSK2330672 Administration in Patients With Primary Biliary Cirrhosis (PBC) and Symptoms of Pruritus
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Cholestasis, Intrahepatic
Keywords: Intestinal bile acid transport inhibitor
Pruritus
Primary biliary cirrhosis
Ursodeoxycholic acid
GSK2330672
Pharmacokinetics
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2013-07-15
Enrollment: 22
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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


Eligibility criteria: 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.

Primary outcomes:
measure: Number of participants with any on-treatment adverse event (AE) or serious adverse event (SAE) from Baseline to Day 56
timeFrame: Up to Day 56
measure: Change from Baseline in white blood cell count (WBC), total neutrophil, lymphocyte, monocyte, eosinophil, basophil, and platelet counts at Day 28, Day 42, and Follow-up (Day 56)
timeFrame: Baseline, Day 28, Day 42 and Follow-up (Day 56)
measure: Change from Baseline in hemoglobin and mean corpuscle hemoglobin concentration (MCHC) at Day 28, Day 42, and Follow-up (Day 56)
timeFrame: Baseline, Day 28, Day 42 and Follow-up (Day 56)
measure: Change from Baseline in mean corpuscle volume (MCV) at Day 28, Day 42, and Follow-up (Day 56)
timeFrame: Baseline, Day 28, Day 42 and Follow-up (Day 56)
measure: Change from Baseline in hematocrit at Day 28, Day 42, and Follow-up (Day 56)
timeFrame: Baseline, Day 28, Day 42 and Follow-up (Day 56)
measure: Change from Baseline in red blood cells (RBC) and reticulocytes at Day 28, Day 42, and Follow-up (Day 56)
timeFrame: Baseline, Day 28, Day 42 and Follow-up (Day 56)
measure: Change from Baseline in alkaline phopshatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyl transferase (GGT) at Day 28, Day 42 and Follow-up (Day 56)
timeFrame: Baseline, Day 28, Day 42 and Follow-up (Day 56)
measure: Change from Baseline in direct and total bilirubin, creatinine, and uric acid at Day 28, Day 42 and Follow-up (Day 56)
timeFrame: Baseline, Day 28, Day 42 and Follow-up (Day 56)
measure: Change from Baseline in calcium, chloride, carbon dioxide (CO2) content/bicarbonate, glucose, potassium, sodium, and urea/blood urea nitrogen (BUN) at Day 28, Day 42 and Follow-up (Day 56)
timeFrame: Baseline, Day 28, Day 42 and Follow-up (Day 56)
measure: Change from Baseline in albumin and total protein at Day 28, Day 42, and Follow-up (Day 56)
timeFrame: Baseline, Day 28, Day 42, and Follow-up (Day 56)
measure: Change from Baseline in urine pH at Day 28, Day 42, and Follow-up (Day 56)
timeFrame: Baseline, Day 28, Day 42, and Follow-up (Day 56)
measure: Change from Baseline in electrocardiogram (ECG) parameters at Day 1, Day 14, Day 28, Day 42, and Follow-up (Day 56)
timeFrame: Baseline, Day 1, Day 14, Day 28, Day 42, and Follow-up (Day 56)
measure: Change from Baseline in heart rate (HR) at Day 14, Day 28, Day 42, and Follow-up (Day 56)
timeFrame: Baseline, Day 14 (Run-in Period), Day 28 (Period 1), Day 42 (Period 2), and Follow-up (Day 56)
measure: Change from Baseline in diastolic blood pressure (DBP) and systolic blood pressure (SBP) at Day 14, Day 28, Day 42, and Follow-up (Day 56)
timeFrame: Baseline, Day 14 (Run-in Period), Day 28 (Period 1), Day 42 (Period 2), and Follow-up (Day 56)
measure: Summary of responses to gastrointestinal symptom response system (GSRS) by dimension at Day 1, Day 13, Day 27, Day 41, and Follow-up (Day 56)
timeFrame: Day 1 and Day 13 (Run-in Period), Day 27 (Period 1), Day 41 (Period 2), and Follow-up (Day 56)
measure: Fecal Occult blood testing on Day 14, Day 28, Day 42 and Follow-up (Day 56)
timeFrame: Day 14, Day 28, Day 42 and Follow-up (Day 56)
Secondary outcomes:
measure: Area under curve (AUC) of serum profiles of total bile acid concentrations (T-bile acid) at Day 14, Day 28, and Day 42
timeFrame: Pre-dose, and at 2 and 5 hour (h) post-dose on Days 14, 28 and 42
measure: AUC of serum profiles of 7-alpha hydroxy 4-cholesten-3-one (C4) at Day 14, Day 28, and Day 42
timeFrame: Pre-dose, and at 2 and 5 hr post-dose on Days 14, 28 and 42
measure: Summary of derived trimmed mean participant-reported itch Scores on the Pruritus 0-10 point scale (Itch type: Worst, Intensity, Bothersome and Interference)
timeFrame: From Day 1 to Day 56
measure: Summary of Participant-reported Itch scores on the 5-D Itch scale (Domain=Degree, Direction, Disability, Distribution, Duration and Overall) on Day 1, Day 13, Day 27, Day 41 and Follow-up (Day 56)
timeFrame: Day 1 and Day 13 (Run-in Period), Day 27 (Period 1), Day 41 (Period 2) and Follow-up (Day 56)
measure: Participant reported outcome for primary biliary cirrhosis (PBC)-40 Quality of life (QOL) scale (Domain=Symptoms) on Day 1, Day 13, Day 27, Day 41 and Follow-up (Day 56)
timeFrame: Day 1 and Day 13 (Run-in period), Day 27 (Period 1), Day 41 (Period 2) and Follow-up (Day 56)
measure: Dose-normalized area under the concentration-time curve (DNAUC[0-24hr]) for UDCA and its metabolites taurodeoxycholic acid (TUDCA) and glycoursodeoxcholic acid (GUDCA) on Day 14, Day 28, and Day 42
timeFrame: Pre-dose and at 6, 12, 12.5, 13, 14, 15, 17, 19, 21 and 24 h on Days 14, 28 and 42
measure: Dose-normalized maximum plasma concentration (DNCmax) for UDCA and its metabolites TUDCA and GUDCA on Day 14, Day 28, and Day 42
timeFrame: Pre-dose and at 6, 12, 12.5, 13, 14, 15, 17, 19, 21 and 24 hours on Days 14, 28 and 42
measure: Plasma pharmacokinetics for GSK2330672 on Day 14, Day 28, and Day 42
timeFrame: Pre-dose and post-dose 2, 10, 12 hours on Days 14, 28 and 42
measure: Steady state maximum plasma concentration (Cmax) for ursodeoxycholic acid (UDCA) and its metabolites taurodeoxycholic acid (TUDCA) and glycoursodeoxcholic acid (GUDCA)
timeFrame: Pre-dose (0.0, of first dose of the day), 6.0, 12.0 (Pre-dose of second dose of the day), 12.5, 13.0, 14.0, 15.0, 17.0, 19.0, 21.0 and 24.0 hr on Day 14 (end of Run-in period), 28 (end of Period 1), and 42 (end of Period 2).
measure: Steady state time to Cmax (Tmax) for UDCA, TUDCA, and GUDCA
timeFrame: Pre-dose (0.0, of first dose of the day), 6.0, 12.0 (Pre-dose of second dose of the day), 12.5, 13.0, 14.0, 15.0, 17.0, 19.0, 21.0 and 24.0 hr on Day 14 (end of Run-in period), 28 (end of Period 1), and 42 (end of Period 2).
measure: Areas under the plasma concentration-time curve(AUC)0-24hr UDCA, TUDCA and GUDCA.
timeFrame: Pre-dose (0.0, of first dose of the day), 6.0, 12.0 (Pre-dose of second dose of the day), 12.5, 13.0, 14.0, 15.0, 17.0, 19.0, 21.0 and 24.0 hr on Day 14 (end of Run-in period), 28 (end of Period 1), and 42 (end of Period 2)
measure: Molar Ratio of AUC(0-24) between metabolites (TUDCA and GUDCA) and parent (UDCA)
timeFrame: Pre-dose (0.0, of first dose of the day), 6.0, 12.0 (Pre-dose of second dose of the day), 12.5, 13.0, 14.0, 15.0, 17.0, 19.0, 21.0 and 24.0 hr on Day 14 (end of Run-in period), 28 (end of Period 1), and 42 (end of Period 2).
Other outcomes:
Locations:
city: Birmingham
country: United Kingdom
facility: GSK Investigational Site
state: West Midlands
city: Cambridge
country: United Kingdom
facility: GSK Investigational Site
city: Newcastle upon Tyne
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Hegade VS, Kendrick SF, Dobbins RL, Miller SR, Thompson D, Richards D, Storey J, Dukes GE, Corrigan M, Oude Elferink RP, Beuers U, Hirschfield GM, Jones DE. Effect of ileal bile acid transporter inhibitor GSK2330672 on pruritus in primary biliary cholangitis: a double-blind, randomised, placebo-controlled, crossover, phase 2a study. Lancet. 2017 Mar 18;389(10074):1114-1123. doi: 10.1016/S0140-6736(17)30319-7. Epub 2017 Feb 8.
citation: Hegade VS, Kendrick SF, Dobbins RL, Miller SR, Richards D, Storey J, Dukes G, Gilchrist K, Vallow S, Alexander GJ, Corrigan M, Hirschfield GM, Jones DE. BAT117213: Ileal bile acid transporter (IBAT) inhibition as a treatment for pruritus in primary biliary cirrhosis: study protocol for a randomised controlled trial. BMC Gastroenterol. 2016 Jul 19;16(1):71. doi: 10.1186/s12876-016-0481-9.