Long-term safety study of personalized cholic acid treatment in patients with bile acid synthesis defects

Bile acid synthesis defects such as single enzyme disorders in bile acid
synthesis (known as SED) and Zellweger spectrum disorder (ZSD) are severe
disabling disorders. At least some of the clinical abnormalities including
severe liver dysfunction and growth retardation are caused by the accumulation
of toxic bile acid intermediates. Bile acid supplementation by cholic acid (CA)
has been hypothesized to decrease endogenous bile acid production, stimulate
bile secretion and to improve bile flow and micellar solubilization in these
patients. CA treatment is an authorized therapy for SED patients in the
Netherlands. For ZSD, however, CA is only authorized in the United States. CA
is registered as an orphan drug and CA treatment is very expensive, however
research into CA treatment of bile acid synthesis defects is limited.
Personalized treatment with pharmacy prepared CA capsules could make costs of
CA treatment lower and more sustainable.

The primary objective is to investigate the long-term safety of personalized CA
treatment of patients with bile acid synthesis defects. Our secondary
objectives are to investigate the long-term effect (treatment of 5 years) of
cholic acid treatment on clinical and biochemical parameters and the
pharmacokinetics of CA in this patient population. Another secondary objective
is to determine the feasibility and sustainability of personalized treatment
for patients with a rare disease.

This study has been transitioned to CTIS with ID 2024-518652-23-00 check the CTIS register for the current data.

Investigating the long-term safety of personalized cholic acid treatment in
patients with defects in bile acid synthesis based on clinical and biochemical
parameters.

Open label, single centre and non-randomized intervention study. This design is
most suitable since patient numbers are small due to the rarity of the disease
and heterogeneous phenotype of the disorder. A single centre design was chosen
because of the expertise in ZSD and SED within the Academic Medical Center
(AMC). Moreover, almost all ZSD patients in the Netherlands visit the
outpatient clinic of the AMC. The duration of the study will be 5 years.

Cholic acid treatment

The burden on patients is limited as most examinations take place at the time
of regular outpatient visits and blood tests are a standard part of these
visits (650 uL extra blood is collected per visit).
The extra investigations during these outpatient visits consist of: collecting
urine portion through a urine collection bag, scoring neurological milestones,
fibroscan measurement. The scoring of neurological milestones is a small time
burden. Fibroscan is a 1-minute examination in the consultation room that is
not burdensome and free of rays. An additional visit to the hospital is
necessary in week 2 and 6 after start of treatment, or 4 weeks after a dose
change. During this visit, weight and height are measured, blood is collected
(550 µL) and urine is collected (minimum volume 5 ml).

Cholic acid is a body's own substance of which long-term safety data are known
when treating Zellweger Spectrum and other bile salt synthesis disorders.