Study to Demonstrate the Efficacy and Safety of A4250 in Patients with Primary Biliary Cirrhosis and Cholestatic Pruritus

• Register: EUCTR
• Last refreshed on: 30 March 2021
• Main ID: EUCTR2014-004070-42-SE
• Date of registration: 15/10/2014
• Prospective Registration: Yes
• Primary sponsor: Sahlgrenska Academy
• Public title: Study to Demonstrate the Efficacy and Safety of A4250 in Patients with Primary Biliary Cirrhosis and Cholestatic Pruritus
• Scientific title: An Exploratory, Phase IIa Cross-Over Study to Demonstrate the Efficacy and Safety of A4250 in Patients with Primary Biliary Cirrhosis and Cholestatic Pruritus
• Date of first enrolment: 09/12/2014
• Target sample size: 12
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-004070-42
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: no; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: no
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Sweden

Key inclusion & exclusion criteria

Inclusion criteria:
• Diagnosis of PBC or PBC-Autoimmune hepatitis overlap as established
according to
AASLD/EASL definitions. Definite or probable PBC diagnosis, as
demonstrated by the presence of = 2 of the following 3 diagnostic
factors:
• History of elevated ALP levels (>1.67 ULN) for at least 6 months prior
to Day 1
• Positive antimitochondrial antibodies (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)
• Liver biopsy consistent with PBC

• UDCA non-responders defined as >6 months of UDCA and at the time
of enrolment a serum ALP >1.67 ULN.
• Laboratory markers of cholestasis identified within 3 months of Visit
1
• Treatment with cholestyramine at a dose >4g BID or colestipol > 5mg
for at least 3 months
• The patient has a VAS-Itch of at least 30 mm during the day before
baseline (Visit 2)
• The patient reports having understood and has signed both the ICF
and is willing to comply with all study visits and assessments;
• The patient is a male or non-pregnant female =18 years of age and =
80 years of age with body mass index (BMI) =18.5 but <35 kg/m2
• Women of childbearing capacity (WOCBC) must have a negative
serum pregnancy test upon inclusion in the trial. WOBC must agree to
maintain highly effective birth control or practice abstinence (i.e.
abstaining from penile-vaginal intercourse) if this is the subject's
preferred and usual lifestyle. The following methods for birth control,
when used consistently and correctly, offer protection from pregnancy
with a Pearl index of <1 (i.e. <1% per year) and can be accepted as
highly effective;
• Oral hormone contraceptives, with the exception of low-dose
gestagens (e.g. lynestrenol norestisteron)
• Injectable or implanted hormonal contraceptives
• Intrauterine devices
• Intrauterine systems (e.g. progestin-releasing coil)
The following conditions are also acceptable;
• Vasectomised male partner with appropriate post-vasectomy
documentation of the absence
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 7
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 5

Exclusion criteria:
English • Any condition that, in the opinion of the Investigator constitutes a risk for the patient or a contraindication for participation and completion
of the study, or could interfere with study objectives, conduct, or
evaluations.
• Jaundice of extrahepatic origin
• The patient has a structural abnormality of the GI tract.
• The patient has a known, active, clinically significant acute or chronic
infection, or any major episode of infection requiring hospitalization or
treatment with parenteral anti infectives within 4 weeks of treatment
start (study day 1) or completion of oral anti-infective treatment within
2 weeks prior to start of screening period;
• The patient has unexplained and clinically significant GI alarm signals
(e.g., lower GI bleeding or heme-positive stool, iron-deficiency anemia,
unexplained weight loss) or systemic signs of infection or colitis;
• The patient has rectal bleeding and/or is heme-positive in the
absence of known internal or external hemorrhoids;
• The patient has a history of cancer with last date of proven disease
activity/presence of malignancy within 5 years, except for adequately
treated basal cell carcinoma of the skin, cervical dysplasia, or carcinoma
in situ of the skin or the cervix
• Other reason for itching such as atopic dermatitis, other primary skin
diseases etc.
• Chronic kidney disease
• Active substance abuse in the year before screening
• The patient has a history of a psychiatric disorder requiring
hospitalization or suicide attempt in the 2 years prior to Screening;
• The patient has participated in any investigational clinical study
within 30 days prior to Screening or within 5 half-lives of the
investigated compound (whichever is longer) prior to Screening (unless
the patient was never randomized to study treatment), or plans to
participate in another clinical study during this study;
• The patient is a pregnant, breast-feeding or lactating female.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Digestive System Diseases [C06]

Primary biliary cirrhosis complicated by cholestatic pruritus.

Intervention(s)

Product Code: A4250
Pharmaceutical Form: Capsule

Primary Outcome(s)

Main Objective: The primary efficacy objective of this Phase IIa study is to demonstrate
the efficacy of once daily dosing of A4250, 1.5 - 3 mg orally during a
four-week treatment period to relieve patients with Primary Biliary
Cirrhosis (PBC) from cholestatic pruritus as determined by evaluation of
effects on pruritus using a visual analogue scale (VAS).

The primary safety objective of this study is to assess the safety and
tolerability of A4250, 1.5 - 3 mg orally during a four-week treatment
period, in patients with PBC and cholestatic pruritus, as determined by
the occurrence of treatment-emergent SAEs.

Primary end point(s): The primary efficacy endpoint is change in VAS-Itch (most severe itch
during last 24 hrs) during the fourth treatment week of A4250 compared
to the fourth week of treatment period 1.

The primary safety endpoint will be the occurrence of treatmentemergent
SAEs during the four weeks of treatment with A4250.

Secondary Objective: Secondary efficacy objectives of this study are to demonstrate the
efficacy of A4250 orally on other pruritus variables and on QoL and
lysophosphatidic acid formation.

Secondary safety objectives of this study include assessment of the
safety and tolerability of A4250 during a four-week treatment period, as
determined by the occurrence of treatment-emergent AEs and changes
in other safety parameters including liver and kidney function tests and
vital signs.

Timepoint(s) of evaluation of this end point: During the fourth treatment week of A4250 compared to the fourth week
of treatment period 1.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: At the end of the four weeks' treatment period with A4250

Secondary end point(s): Secondary efficacy endpoints are:
• Change in VAS-Itch (most severe itch during last 24 hrs) during the
fourth treatment week of A4250 compared to the fourth week of
treatment period 3 and compared to baseline
• Change in 5-D Pruritus scale and PBC40 from baseline and from week
4 of treatment period 1 to fourth week of A4250 treatment and from
week 4 of A4250 treatment to week 4 of the third treatment period
• Change in individual and total serum and fecal BAs, FGF19, C4 and
serum lysophosphatidic acid from baseline and from last day in week 4
of treatment period 1 to last day in week 4 of A4250 treatment and from
last day of week 4 of A4250 treatment to last day of week 4 of the third
treatment period
• Change in ALP, AST and ALT from baseline and from last day of week
4 of treatment period 1 to last day in week 4 of A4250 treatment and
from last day of week 4 of A4250 treatment to last day of week 4 of the
third treatment period
• Change in Composite endpoint of ALP and serum bilirubin from
baseline and from last day of week 4 of treatment period 1 to last day of
week 4 week of A4250 treatment and from last day of week 4 of A4250
treatment to last day of week 4 of the third treatment period
• Change from week 4 of first treatment period to week 4 of A4250 in
weekly stool consistency of BMs (BSFS) and from week 4 of A4250
treatment to week 4 of the third treatment period
• Change in gut microbiota composition

Secondary safety endpoints will include:
• Occurrence of TEAEs during the four A4250 treatment weeks.
Description and severity of any AE will also be reported;
• Changes in safety laboratory test results (including hematology,
clinical chemistry and urinalysis) from baseline to Day 28 of A4250
treatment;
• Discontinuations from treatment with reasons given.

Secondary ID(s)

A4250PBCpruritus

Source(s) of Monetary Support

Swedish Research Council

Ethics review

Status: Approved
Approval date: 04/12/2014
Contact: