E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients wih Cholestatic Pruritus |
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E.1.1.1 | Medical condition in easily understood language |
Chronic liver disease with impaired bile flow (cholestasis) causing a severe itch. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
1. Assess the safety and tolerability of A4250 orally administered first as a single dose and then during a four week treatment period as determined by the occurrence of treatment-emergent SAEs 2. Explore changes in serum total bile acids during a four week treatment period |
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E.2.2 | Secondary objectives of the trial |
Secondary safety objectives of this study include assessment of the safety and tolerability of A4250 first as a single administration and then during a four week treatment period, as determined by the occurrence of treatment-emergent AEs and changes in other safety parameters including laboratory tests and vital signs. Secondary efficacy objectives of this study are to: • Demonstrate the efficacy of A4250, orally administered during a four week treatment period, on liver biochemistry variables and on pruritus parameters • Evaluate the pharmacokinetic properties of A4250 orally administered first as a single dose and then after a four week treatment period • Evaluate changes in VAS-itching score after a four week treatment period
Exploratory objectives of this study include assessment of pharmacodynamic parameters of bile acid modulation such as C4 and FGF19 assessments. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
The inclusion criteria for study participation eligibility are: • Diagnosis of pruritus due to chronic cholestasis based on history and Investigator judgment -> This will include but will not be restricted to patients with PFIC, ALGS, Biliary Atresia and Sclerosing Cholangitis • Laboratory markers of cholestasis identified within 3 months of Visit 1 • Serum total bile acids at least 2 times above upper limit of normal • The patient has a VAS-itch of at least 3 on a 10-graded VAS at Visit 2 • The caretaker/patient reports having understood and has signed the ICF and is willing to comply with all study visits and assessments; • The patient is a male or non-pregnant female ≥12 months of age and <18 years of age with a body weight exceeding 7 kg
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E.4 | Principal exclusion criteria |
The exclusion criteria for study participation eligibility are: • 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. • Clinical or biochemical signs of decompensated liver disease (such as ascites) • Liver transplantation • Structural abnormality of the GI tract (biliary diversion procedures accepted). • Known, active, clinically significant acute or chronic infection, or any major episode of infection requiring hospitalization or treatment with parenteral anti-infective treatment 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; • 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 pruritus such as treatment refractory atopic dermatitis, other primary skin diseases etc. • Treatment with bile acid sequestrants (cholestyramine, colesevelam, colestipol or similar) during the screening period • Chronic kidney disease with an impaired renal function and GFR<70 ml/min1.73 m2 • Active substance abuse in the year before Screening • A history of a psychiatric disorder requiring hospitalization or suicide attempt in the 2 years prior to Screening; • Participation in any investigational clinical study, with the exception of the low dose of this study, within 30 days prior to Screening, or plans to participate in another clinical study during this study; • Ongoing pregnancy, breast-feeding or lactation.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is change in total serum bile acids from Baseline to the Day 42 i.e. before the last intake of A4250 in the 4 week treatment period.
The primary safety endpoint will be the occurrence of treatment-emergent SAEs during the four treatment weeks. Description and severity of any SAE will also be reported. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At the end of the four week treatment. |
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E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints will be assessed based upon patients’ reports, through the paper diary during week four of treatment of: • VAS-itch (average itch during previous 24 hours) during the last week of treatment compared to the week between Visit 1 and Visit 2 • Partial PO-SCORAD during the last week of treatment compared to the week between Visit 1 and Visit 2 • Whitington itching score during the last week of treatment compared to the week between Visit 1 and Visit 2 • Stool consistency using the Bristol Stool Form Scale during the last week of treatment compared to the week between Visit 1 and Visit 2 • Degree of global symptom relief using a rating scale during the last week of treatment compared to the week between Visit 1 and Visit 2 and the assessment of • PK at single dose administration and at end of the 4 week treatment period • Liver biochemistry evaluation (serum bile acids, ALP, GT, AST, ALT, conjugated and Total Bil, FGF19, C4, plasma autotaxin/ lysophosphatidic acid) with comparisons from pre-dose level at Visit 1 and from Visit 4 to the end of the 4 week treatment period (Visit 5)
Secondary safety endpoints will be assessed based upon information in patients’ diary reports; this will also be captured in the eCRF: • Occurrence of treatment-emergent AEs (TEAE) including severity and relatedness to study drug • Physical examinations at screening and at all clinic visits • Concomitant medication at all clinic visits • Vital sign measurements at all clinic visits • Laboratory test results (including haematology, clinical chemistry and urinalysis) at all clinic visits. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
At the end of four week treatment. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Cohort study (6 cohorts with increasing dose levels of A4250 from 0.01 up to 0.3 mg/kg BW) |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 6 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 0 |