Primary Objective (Cohort 1)To demonstrate a sustained effect of A4250 on serum bile acids and pruritus in children with progressive familial intrahepatic cholestasis (PFIC) Types 1 and 2.Primary Objective (Cohort 2)To evaluate the effect of A4250…
ID
Source
Brief title
Condition
- Hepatobiliary disorders congenital
- Hepatic and hepatobiliary disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Efficacy Endpoints
European Union (EU) and rest of world: Change from baseline in serum bile acids
after 72 weeks of treatment.
US: Change in pruritus, as indexed by caregiver-reported observed scratching,
from baseline over the treatment period i.e. up to 72 weeks, as measured by an
overall mean of weekly averages of the worst daily scratch score using the
Albireo observer-reported outcome (ObsRO) instrument.
Secondary outcome
Secondary Efficacy Endpoints
The baseline is calculated prior to initiation of A4250 treatment.
Secondary endpoints include:
• Proportion of positive pruritus assessments at the patient level over
the 72 week treatment period using the Albireo ObsRO instrument.
• Change from baseline in serum bile acids to Week 76
• Proportion of individual assessments meeting the definition of a
positive pruritus assessment at the patient level using the Albireo ObsRO
instrument to Week 70
• Proportion of individual AM assessments meeting the definition of a
positive pruritus assessment at the patient level using the Albireo ObsRO
instrument to Week 72
• Proportion of individual PM assessments meeting the definition of a
positive pruritus assessment at the patient level using the Albireo ObsRO
instrument to Week 72
• All-cause mortality, number of patients undergoing biliary diversion surgery
or liver transplantation. These parameters will be evaluated separately and
together at weeks 24, 48, 72 and 76.
• Change in growth from baseline to Weeks 24, 48, 72 and 76 after initiation of
A4250 treatment, defined as the linear growth deficit (height/length for age,
weight for age, mid-arm circumference and body mass index [BMI]) compared to a
standard growth curve (Z-score, standard deviation [SD] from P50)
• Change in aspartate aminotransferase (AST) to platelet ratio index (APRI)
score and fibrosis-4 (Fib-4) score from baseline to Week 72
• Change in pediatric end-stage liver disease (PELD)/model for end-stage liver
disease (MELD) score from baseline to Week 72
• Change in use of antipruritic medication at Weeks 24, 48, 72 and 76
Background summary
PFIC is a rare autosomal recessive cholestatic liver disease estimated to
affect between one in every 50,000 to 100,000 children born worldwide. PFIC
represents 10% to 15% of causes of cholestasis in children and 10% to 15% of
liver transplantation indications in children. All types of PFIC exist
worldwide and both sexes appear to be equally affected.
The common underlying pathogenesis of PFIC is disruption of bile formation and
bile transport through the liver [Jacquemin 2000]. The classification of PFIC
has evolved over the years. The most commonly used subclassification is PFIC
Types 1, 2, and 3 which is based on the associated affected gene and described
in more detail below.
• PFIC, Type 1: also referred to as *Byler disease* or *familial intrahepatic
cholestasis 1 (FIC1) protein deficiency.* FIC1 protein is located on the
canalicular membrane of hepatocytes and facilitates movement of
aminophospholipids from the outer to inner leaflet of the plasma membrane of
the hepatocyte. The ATP8B1 gene encodes FIC1 protein. Biallelic pathologic
variants in the ATP8B1 gene are associated with FIC1 dysfunction and classified
clinically as PFIC Type 1 disease.
• PFIC, Type 2: also referred to as *Byler syndrome* or *bile salt export pump
(BSEP) deficiency.* BSEP is a transporter protein that is expressed at the
canalicular membrane of hepatocytes, and is the primary exporter of bile acids.
The ABCB11 gene encodes the BSEP protein. Biallelic pathologic variations in
the ABCB11 gene is associated with BSEP dysfunction and is classified
clinically as PFIC Type 2 disease.
• PFIC, Type 3: is caused by a deficiency of the multidrug-resistance protein 3
(MDR3) due to mutations in the ABCB4 gene. MDR3 is a phospholipid translocase
critical for phospholipid secretion.
Severe pruritus is common in children diagnosed with PFIC. Itching (and
subsequent scratching) is a significant morbidity for these patients and their
families [Suchy 2007]. A more severe degree of pruritus is experienced compared
to patients with other forms of liver disease and to other pruritic conditions
such as atopic dermatitis [Murray 2011]. In patients with PFIC, liver biopsy
reveals canalicular cholestasis and, later, the appearance of portal fibrosis.
Serum biochemistry indicates cholestasis with hyperbilirubinemia, elevated
alanine aminotransferase (ALT) and aspartate aminotransferase (AST). The
concentrations of bile acids in serum are very high, while serum gamma-glutamyl
transferase (GGT) activity (the exception being MDR3 variants) and cholesterol
[Hori 2010] are normal. Symptoms of portal hypertension and liver failure will
develop during the course of the disease [Davit- Spraul 2009; Alissa 2008].
Symptoms develop early; median age at onset of symptoms is 2 months, and 78% of
PFIC patients present with jaundice [Pawlikowska 2010]. The life- threatening
and debilitating nature of PFIC is reflected by the fact that survival in those
not resorting to surgery is 50% at 10 years of age and almost zero at 20 years
of age. Approximately half of PFIC patients undergo liver transplantation
[Davit-Spraul 2009] and treatment resistant pruritus is the leading indication
for the surgical procedure partial external biliary diversion, mostly in PFIC
Type 1 and 2 patients.
PFIC is life-threatening and debilitating. Currently, the treatment for PFIC is
palliative and there is currently no pharmaceutical treatment approved for use
in PFIC. The therapeutic choices are restricted to non-specific therapy of the
symptoms and signs of the disease such as nutritional support, preventing
vitamin deficiencies, and treatment of extrahepatic features. Medical treatment
options include off-label use of ursodeoxycholic acid, rifampin,
antihistamines, and naltrexone. A minority of patients respond nominally and
transiently to these interventions. Biliary diversion is used to decrease
systemic bile acids through interruption of the enterohepatic circulation and
so avoid transplantation. Liver transplantation is typically only viewed as an
option when patients have failed medical treatment and/or biliary diversion and
have liver failure or persistent uncontrolled pruritus.
Study objective
Primary Objective (Cohort 1)
To demonstrate a sustained effect of A4250 on serum bile acids and
pruritus in children with progressive familial intrahepatic cholestasis
(PFIC) Types 1 and 2.
Primary Objective (Cohort 2)
To evaluate the effect of A4250 on serum bile acids and pruritus in patients
with PFIC who either (1) do not meet eligibility criteria for Study A4250-005
(PEDFIC 1) or (2) who do meet the eligibility criteria for Study A4250-005
after recruitment of Study A4250-005 has been completed.
Study design
This is a Phase 3, multi-center, open-label extension study to investigate the
long-term efficacy and safety of a 120 µg/kg/day daily dose of A4250 in
patients with PFIC, including episodic forms also referred to as BRIC. Cohort 1
will consist of children with PFIC Types 1 and 2 who have participated in study
A4250-005. Cohort 2 will consist of approximately 60 patients with PFIC who
have elevated serum bile acids and cholestatic pruritus and who either (1) do
not meet eligibility criteria for Study A4250-005 (PEDFIC 1) or (2) are
eligible for enrolment in A4250-005 after recruitment of study A4250-005 has
been completed. Up to 40 patients post biliary diversion surgery are allowed to
participate in Cohort 2. Eligible patients will be enrolled into this
open-label extension study and treated with a daily dose of 40 µg/kg/day1 or
120 µg/kg/day of A4250 for 72 weeks, or 40 µg/kg/day for the first 12 weeks
followed by 120 µg/kg/day for the remaining 60 weeks1. Patients not tolerating
the 120 µg/kg/day dose after a minimum of 1 week will have the option to
down-titrate to a lower dose (40 µg/kg/day).
1 As of Protocol Amendment 6, patients entering Cohort 2 will start treatment
at 40 µg/kg/day with the possibility to dose escalate to 120 µg/kg/day after 12
weeks if there is no improvement in pruritus based on investigator judgment.
Intervention
The treatment is a daily dose of A4250 capsules for 72 weeks.
Study burden and risks
A4250 has been evaluated in three Albireo-sponsored clinical studies: a
double-blind placebo-controlled study in healthy volunteers, a single-dose ADME
study, and a Phase 2 study in children with cholestatic pruritus. In addition,
an investigator-sponsored study has been conducted in patients with PBC.
A total of 98 subjects/patients have been exposed to A4250. Healthy subjects
have been exposed to up to 10 mg as a single dose and up to 3 mg daily as part
of a multiple-dose evaluation. Children with cholestatic liver disease have
been treated with up to 0.2 mg/kg/day (200 µg/kg/day) for 4 weeks. In total, 2
SAEs have been reported; both were judged by the physician to be not related to
the study drug.
Patients with cholestatic liver diseases suffer from excess bile acids in the
liver resulting in tissue damage. A commonly used treatment in these patients
is bile diversion surgery, whereby approximately 50% to 100% of the
enterohepatic circulation of bile acids is interrupted. Inhibition of IBAT with
A4250, thereby interrupting the enterohepatic circulation of bile acids, is
therefore a potential medical alternative to surgery which could be of benefit
to these patients if shown to be effective and safe. Data from the Phase 2
study showed efficacy of A4250 in reducing s-BA concentrations and pruritus in
such patients.
Based on the mode of action of an IBAT inhibitor, loose stools or diarrhea
could be expected. However, in the pediatric Phase 2 study with 4 weeks daily
treatment, only one patient had mild transient diarrhea after a single dose
that did not recur on multiple dosing.
Arvid Wallgrens backe 20
Göteborg 41346
SE
Arvid Wallgrens backe 20
Göteborg 41346
SE
Listed location countries
Age
Inclusion criteria
Cohort 1:
1. Completion of the 24-week Treatment Period of Study A4250-005 or withdrawn
from Study A4250-005 due to patient/caregiver judgment of intolerable symptoms
after completing at least 12 weeks of treatment. Patients who withdraw from
A4250-005 due to a study drug related AE will not be eligible.
2. Signed informed consent and assent as appropriate. Patients who turn 18
years of age (or legal age per country) during the study will be required to
re-consent to remain on the study
3. Patients expected to have a consistent caregiver for the duration of the
study
4. Caregivers (and age appropriate patients) must be willing and able to use an
eDiary device as required by the study
Cohort 2:
1. A male or female patient of any age, with a clinical diagnosis of PFIC,
including episodic forms (i.e. benign recurrent intrahepatic cholestatis
[BRIC]) and with a body weight greater or equal to 5 Kg at Visit S-1
2. Patient must have clinical genetic confirmation of PFIC.
3. Patients with PFIC, excluding BRIC, must have elevated serum bile acid
concentration.
4, Patients with PFIC, excluding BRIC, must have history of significant pruritus
5. Patients with episodic forms of PFIC (i.e., BRIC) must have an emerging
flare characterized by clinically significant pruritus and elevated serum bile
acid levels/cholestasis as judged by the investigator.
6. Patient and/or legal guardian must sign informed consent (and assent) as
appropriate.
7. Age appropriate patients are expected to have a consistent caregiver for the
duration of the study.
8. Caregivers and age-appropriate patients (greater or equal to 8 years of age
if able) must be willing and able to use an eDiary device as required by the
study.
Exclusion criteria
Patients meeting any of the following criteria at Visit 1 will not be eligible
for study participation:
Cohort 1:
1. Decompensated liver disease: coagulopathy, history, or presence of
clinically significant ascites, variceal hemorrhage, and/or encephalopathy
2. Sexually active males and females who are not using a reliable contraceptive
method with <=1% failure rate (such as barrier protection, hormonal
contraception, intra-uterine device, or complete abstinence) throughout the
duration of the study and 90 days thereafter (from signed informed consent
through 90 days after last dose of study drug). See Appendix 6 for further
details.
3. Patients not compliant with treatment in study A4250-005
4. Any other conditions or abnormalities which, in the opinion of the
investigator or Medical Monitor, may compromise the safety of the patient, or
interfere with the patient participating in or completing the study
Cohort 2:
1. Known pathologic variations of the ABCB11 gene that have been demonstrated
to result in complete absence of the BSEP protein
2. Patient with past medical history or ongoing presence of other types of
liver disease.
Note: Patients with clinically significant portal hypertension are allowed.
3. Patient has had a liver transplant, or a liver transplant is planned within
6 months of the Screening/Inclusion Visit
4. Decompensated liver disease, coagulopathy, history, or presence of
clinically significant ascites, variceal hemorrhage, and/or encephalopathy.
5. INR >1.4 (the patient may be treated with Vitamin K intravenously, and if
INR is less than or equal to 1.4 at resampling the patient may be included)
6. Serum ALT>10 x upper limit of normal (ULN) at Screening
7. Serum ALT>15 x ULN at any time point during the last 6 months unless an
alternate etiology was confirmed for the elevation
8. Total bilirubin >5 x ULN at Screening
9. Patient suffers from uncontrolled, recalcitrant pruritic condition other
that PFIC.
10. Administration of bile acid or lipid binding resins and medications that
slow GI motility.
11. Any other conditions or abnormalities which, in the opinion of the
investigator or Medical Monitor, may compromise the safety of the patient, or
interfere with the patient participating in or completing the study
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 |
|---|---|
| Other | 2017-002325-38 |
| EudraCT | EUCTR2017-002325-38-NL |
| CCMO | NL63749.028.18 |