Several reports on SED have shown the beneficial effects of CA supplementation on the down regulation of bile acid synthesis, increasing levels of primary bile acids and stimulating bile flow. Improvement in hepatic dysfunction, clinical improvement…
ID
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Verkorte titel
Aandoening
Bile acid synthesis defects (BASD), 3β-hydroxy-Δ5-C27-steroid oxidoreductase, Δ4-3-oxosteroid-5β-reductase, cholesterol 7a-hydroxylase (CYP7A1), and α-methylacyl-CoA racemase (AMACR), Zellweger spectrum disorder
Ondersteuning
Onderzoeksproduct en/of interventie
Uitkomstmaten
Primaire uitkomstmaten
1. Degree of suppression of endogenous bile acid synthesis
2. Type and number of adverse events
3. Type and number of side effects
Achtergrond van het onderzoek
This study is an open label single centre, non-randomized intervention study. Patients with a bile acid synthesis defect caused by 3β-hydroxy-Δ5-C27-steroid oxidoreductase, Δ4-3-oxosteroid-5β-reductase, α-methylacyl-CoA racemase (AMACR) deficiency or cholesterol 7a-hydroxylase (CYP7A1) deficiency will be recruited for this study. CA naive patients and Zellweger patients that had a positive response on CA treatment during a previous study may participate.
CA will be supplemented with personalized magistral prepared capsules for up to 5 years in daily doses of 5-15 mg/kg/day once daily or divided in 2 or 3 equal doses depending on the number of capsules needed daily. In case of incomplete suppression of bile acid intermediates the dosage will be increased to a maximum of 20 mg/kg/day. In case necessary due to adverse events (diarrhoea, vomiting, liver dysfunction and others), the dose can be reduced with 33% to 10 or 5 mg/kg/day.
Doel van het onderzoek
Several reports on SED have shown the beneficial effects of CA supplementation on the down regulation of bile acid synthesis, increasing levels of primary bile acids and stimulating bile flow. Improvement in hepatic dysfunction, clinical improvement and long term survival have been reported44,48-51. In several reviews CA is recommended as the preferred therapy in SED due to superior effects compared to CDCA (hepatotoxic) and UDCA (no suppression of bile acid synthesis and no micell function)41,43,44,51.
Because previous study shows that CA can be potentially harmful for patients with advanced liver disease, we discourage to treat this subgroup of ZSD patients with CA. In milder patients, the treatment period of 1 year and 9 months was too short to be able to conclude whether CA has an effect on the clinical progression in patients with a ZSD, since this is a slowly progressive disorder. Therefore further studies are needed to investigate the long-term efficacy and safety of cholic acid treatment.
Onderzoeksopzet
T = 0, 2 and 6 weeks after starting treatment, followed by tests performed every 3 months in the first year of treatment.
After the first year tests are performed every 6 months or yearly depending on the test.
Onderzoeksproduct en/of interventie
Cholic Acid
Publiek
Wetenschappelijk
Belangrijkste voorwaarden om deel te mogen nemen (Inclusiecriteria)
Bile acid synthesis defect due to:
o single enzyme deficiency in either:
- 3β-hydroxy-Δ5-C27-steroid oxidoreductase
- Δ4-3-oxosteroid-5β-reductase
- α-methylacyl-CoA racemase (AMACR)
- cholesterol 7a-hydroxylase (CYP7A1)
o OR Zellweger spectrum disorder
At least one of the following hallmarks: steatorrhea (confirmed per local protocol), elevated transaminases, developmental delay, neurological symptoms
Belangrijkste redenen om niet deel te kunnen nemen (Exclusiecriteria)
Single enzyme deficiency patients will be excluded from participation when at least one of the following criteria is present:
- Short life expectancy of < 12 months (severe multiple organ dysfunction)
- Decompensated liver cirrhosis
- High bilirubin serum levels (conjugated bilirubin > 20 μmol/L)
- Prolonged prothrombin time (PT > 15s not due to vitamin K deficiency)
- Kidney dysfunction (eGFR < 60)
- Pregnancy and high total bile acid serum level ( > 40μmol/L)
- Allergy to one of the components of CA capsules.
Zellweger spectrum disorder patients will be excluded from participation when at least one of the following criteria is present:
- Increased liver enzymes during previous CA treatment
- Normal biochemical parameters (THCA and/or DHCA ≤1.0 μmol/L)
- Short life expectancy of < 12 months (severe multiple organ dysfunction)
- Decompensated liver cirrhosis
- High bilirubin serum levels (conjugated bilirubin > 20 μmol/L)
- Prolonged prothrombin time (PT > 15s not due to vitamin K deficiency)
- Kidney dysfunction (eGFR < 60)
- Pregnancy and high total bile acid serum level ( > 40μmol/L)
- Allergy to one of the components of CA capsules.
Opzet
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In overige registers
| Register | ID |
|---|---|
| NTR-new | NL8630 |
| Ander register | METC AMC : 2019_192 |