E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with phenotypically mild Zellweger Spectrum Disorder (ZSD) or a Single Enzyme Defect (SED) in bile acid synthesis. |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To investigate the long-term safety of personalized magistral prepared cholic acid for the treatment of patients with bile acid synthesis defects. |
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E.2.2 | Secondary objectives of the trial |
To investigate the long-term effect of cholic acid treatment on clinical and biochemical parameters and the pharmacokinetics of cholic acid in this patient population. Another secondary objective is to determine the feasibility of personalized magistral prepared medicines for patients with a rare disease. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Zellweger spectrum disorder OR
• Single enzyme deficiency, deficiency in either:
o 3β-hydroxy-Δ5-C27-steroid oxidoreductase
o Δ4-3-oxosteroid-5β-reductase
o sterol 27-hydroxylase
o 2-methylacyl-CoA racemase
o cholesterol 7a-hydroxylase
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E.4 | Principal exclusion criteria |
-short life expectancy based on severe multiple organ dysfunction at the time of diagnosis,
-decompensated liver cirrhosis,
-high bilirubin serum levels (conjugated bilirubin > 20 µmol/L),
-prolonged prothrombin time (PT > 15s despite adequate vitamin K supplementation),
-kidney dysfunction (eGFR < 60),
-allergy to medication components |
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E.5 End points |
E.5.1 | Primary end point(s) |
Type and number of adverse events and side effects. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Tests are carried out during the standard outpatient treatments at t = 0, 2 and 6 weeks after the start of cholic acid treatment, followed by tests every 3 months in the first year and every 6 months from the second year. After a dose change, additional studies are scheduled after 2 and 6 weeks, after which the normal study schedule is resumed.
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E.5.2 | Secondary end point(s) |
- Degree of suppression of endogenous bile acid synthesis (decrease in urine DHCA and THCA bile acid intermediates and increase in FGF-19)
- Increase in normal primary bile acids (increase in urine CA)
- Change in serum ALT, AST, transminases, γ-glutamyltrans- peptidase, conjugated bilirubin, total bilirubin levels, gamma-GT, alkaline phosphatase, alpha-1-phetoprotein
- Change in liver protein synthesis
- Change in degree of coagulopathy (measured by PT, aPTT, Factor V and Factor VII)
- Change in weight gain (weight-for-height percentile)
- Change total body length growth rate (cm/year; only in those with remaining growth potential).
- Change in fat soluble vitamins (A,D,E) level and total cholesterol
- Development of fibrosis (determined by fibroscan and ELF-test)
- Development of decompensated cirrhosis |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Tests are carried out during the standard outpatient treatments at t = 0, 2 and 6 weeks after the start of cholic acid treatment, followed by tests every 3 months in the first year and every 6 months from the second year. After a dose change, additional studies are scheduled after 2 and 6 weeks, after which the normal study schedule is resumed.
The following additional procedures will be performed : during the standard care visits
- Ultrasound of the liver, at baseline and repeated when indicated.
- Fibroscan, at baseline and repeated yearly
- Serum, urine and feces sample for eventual additional analysis
The pharmacokinetic study is optional at which blood, urine and feces will be sampled. Blood samples will be taken at t 0, 1, 2, 4, 6, 8 and 12 hours. |
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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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 | No |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
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 | No |
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 | 5 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |