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 |
The primary aims of this Phase II exploratory study in patients treated with A4250 due to cholestasis induced pruritus are to: • 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 • Explore changes in serum total bile acids after a four week treatment period |
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E.2.2 | Secondary objectives of the trial |
Secondary safety aims include assessment of 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 AEs and changes in safety parameters including laboratory tests and vital signs Secondary efficacy aims 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 aims 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 main inclusion criteria for study participation eligibility will be: • Diagnosis of pruritus due to chronic cholestasis based on history and investigator judgment o This will include but will not be restricted to patients with Progressive familial intrahepatic cholestasis (PFIC), Alagille syndrome (ALGS), Biliary Atresia and Sclerosing Cholangitis • Laboratory markers of cholestasis identified within 3 months before Visit 1 • Serum total bile acids at least 2 times above upper limit of normal • A VAS-itch of at least 3 (average of 7 days) 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 main exclusion criteria for study participation eligibility will be: • 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 than chronic cholestasis 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 a 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 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. The primary safety endpoint will be the occurrence of treatmentemergent 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 |
The end of the four week treatment |
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E.5.2 | Secondary end point(s) |
•VAS-itch •Whitington itching score •Pharmacokinetics •Liver biochemistry evaluation •Occurrence of treatment emergent adverse events during the whole study period. Description and severity of any AE will also be reported. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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 | No |
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 | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
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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For administrative and safety reporting purposes, the end of the study will be defined as the date of the final clinical database lock. |
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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 | 0 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 9 |
E.8.9.2 | In all countries concerned by the trial days | 1 |