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

• Register: ClinicalTrials.gov
• Last refreshed on: 16 December 2017
• Main ID: NCT01899703
• Date of registration: 03/07/2013
• Prospective Registration: Yes
• Primary sponsor: GlaxoSmithKline
• Public title: 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
• Scientific 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
• Date of first enrolment: March 10, 2014
• Target sample size: 22
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT01899703
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Crossover Assignment. Primary purpose: Treatment. Masking: Double (Participant, Investigator).
• Phase: Phase 2

Countries of recruitment

United Kingdom

Contacts

• Name: GSK Clinical Trials
• Affiliation: GlaxoSmithKline

Key inclusion & exclusion 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.



Age minimum: 18 Years
Age maximum: 75 Years
Gender: All

Health Condition(s) or Problem(s) studied

Cholestasis, Intrahepatic

Intervention(s)

Drug: GSK2330672

Drug: Placebo

Drug: Ursodeoxycholic acid

Primary Outcome(s)

Change from Baseline in heart rate (HR) at Day 14, Day 28, Day 42, and Follow-up (Day 56) [Time Frame: Baseline, Day 14 (Run-in Period), Day 28 (Period 1), Day 42 (Period 2), and Follow-up (Day 56)]

Change from Baseline in mean corpuscle volume (MCV) at Day 28, Day 42, and Follow-up (Day 56) [Time Frame: Baseline, Day 28, Day 42 and Follow-up (Day 56)]

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) [Time Frame: Baseline, Day 28, Day 42 and Follow-up (Day 56)]

Change from Baseline in direct and total bilirubin, creatinine, and uric acid at Day 28, Day 42 and Follow-up (Day 56) [Time Frame: Baseline, Day 28, Day 42 and Follow-up (Day 56)]

Change from Baseline in albumin and total protein at Day 28, Day 42, and Follow-up (Day 56) [Time Frame: Baseline, Day 28, Day 42, and Follow-up (Day 56)]

Change from Baseline in hematocrit at Day 28, Day 42, and Follow-up (Day 56) [Time Frame: Baseline, Day 28, Day 42 and Follow-up (Day 56)]

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) [Time Frame: Baseline, Day 28, Day 42 and Follow-up (Day 56)]

Change from Baseline in electrocardiogram (ECG) parameters at Day 1, Day 14, Day 28, Day 42, and Follow-up (Day 56) [Time Frame: Baseline, Day 1, Day 14, Day 28, Day 42, and Follow-up (Day 56)]

Change from Baseline in urine pH at Day 28, Day 42, and Follow-up (Day 56) [Time Frame: Baseline, Day 28, Day 42, and Follow-up (Day 56)]

Fecal Occult blood testing on Day 14, Day 28, Day 42 and Follow-up (Day 56) [Time Frame: Day 14, Day 28, Day 42 and Follow-up (Day 56)]

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) [Time Frame: Day 1 and Day 13 (Run-in Period), Day 27 (Period 1), Day 41 (Period 2), and Follow-up (Day 56)]

Change from Baseline in red blood cells (RBC) and reticulocytes at Day 28, Day 42, and Follow-up (Day 56) [Time Frame: Baseline, Day 28, Day 42 and Follow-up (Day 56)]

Number of participants with any on-treatment adverse event (AE) or serious adverse event (SAE) from Baseline to Day 56 [Time Frame: Up to Day 56]

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) [Time Frame: Baseline, Day 14 (Run-in Period), Day 28 (Period 1), Day 42 (Period 2), and Follow-up (Day 56)]

Change from Baseline in hemoglobin and mean corpuscle hemoglobin concentration (MCHC) at Day 28, Day 42, and Follow-up (Day 56) [Time Frame: Baseline, Day 28, Day 42 and Follow-up (Day 56)]

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) [Time Frame: Baseline, Day 28, Day 42 and Follow-up (Day 56)]

Secondary Outcome(s)

Molar Ratio of AUC(0-24) between metabolites (TUDCA and GUDCA) and parent (UDCA) [Time Frame: 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).]

Steady state time to Cmax (Tmax) for UDCA, TUDCA, and GUDCA [Time Frame: 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).]

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 [Time Frame: Pre-dose and at 6, 12, 12.5, 13, 14, 15, 17, 19, 21 and 24 h on Days 14, 28 and 42]

Steady state maximum plasma concentration (Cmax) for ursodeoxycholic acid (UDCA) and its metabolites taurodeoxycholic acid (TUDCA) and glycoursodeoxcholic acid (GUDCA) [Time Frame: 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).]

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) [Time Frame: Day 1 and Day 13 (Run-in Period), Day 27 (Period 1), Day 41 (Period 2) and Follow-up (Day 56)]

AUC of serum profiles of 7-alpha hydroxy 4-cholesten-3-one (C4) at Day 14, Day 28, and Day 42 [Time Frame: Pre-dose, and at 2 and 5 hr post-dose on Days 14, 28 and 42]

Summary of derived trimmed mean participant-reported itch Scores on the Pruritus 0-10 point scale (Itch type: Worst, Intensity, Bothersome and Interference) [Time Frame: From Day 1 to Day 56]

Areas under the plasma concentration-time curve(AUC)0-24hr UDCA, TUDCA and GUDCA. [Time Frame: 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)]

Plasma pharmacokinetics for GSK2330672 on Day 14, Day 28, and Day 42 [Time Frame: Pre-dose and post-dose 2, 10, 12 hours on Days 14, 28 and 42]

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) [Time Frame: Day 1 and Day 13 (Run-in period), Day 27 (Period 1), Day 41 (Period 2) and Follow-up (Day 56)]

Area under curve (AUC) of serum profiles of total bile acid concentrations (T-bile acid) at Day 14, Day 28, and Day 42 [Time Frame: Pre-dose, and at 2 and 5 hour (h) post-dose on Days 14, 28 and 42]

Dose-normalized maximum plasma concentration (DNCmax) for UDCA and its metabolites TUDCA and GUDCA on Day 14, Day 28, and Day 42 [Time Frame: Pre-dose and at 6, 12, 12.5, 13, 14, 15, 17, 19, 21 and 24 hours on Days 14, 28 and 42]

Secondary ID(s)

117213

Source(s) of Monetary Support

Please refer to primary and secondary sponsors