A GnRH Agonist IN pre-menopausal women STudy to treat severe Polycystic Liver Disease

Polycystic liver disease (PLD) is a rare but severe disease, characterized by
enlargement of the liver due to the growth of numerous cysts. Two autosomal
dominant hereditary diseases are known to cause this phenotype: Autosomal
Dominant Polycystic Liver disease (ADPLD) and Autosomal Dominant Polycystic
Kidney Disease (ADPKD) the latter also causing cyst growth in the kidneys and
renal function decline. Together, approximately 4 per 100.000 subjects in the
general population suffer from PLD.

The large liver volume results in compression of stomach and bowels, and thus
to early satiety, decreased food intake, weight loss and constipation. The high
intra-abdominal pressure also leads to heart-burn, and umbilical and inguinal
herniation. These medical problems often force affected patients to stop
working. The large, protruding abdomen may also cause psychological problems,
because of a distorted body image and confronting questions about being
pregnant. The median liver growth is 3.9% per year, but can be as high as 20%
per year in some cases, resulting in liver volumes of up to 7.5 to 15 liters.
The only available treatment at this time is a somatostatin analogue, such as
lanreotide or octreotide, that is injected subcutaneously or intramuscular once
monthly. This drugs slows the rate of liver growth in polycystic liver
patients. However, especially in the patients with the fastest growth rates,
which are mostly young women, the liver continues to grow fast. These patients
have the risk of developing severe complaints, with reduced quality of life,
and finally even a need of a liver transplantation. These patients will be the
target group to be included in our study.

The last years, it has become clear that female hormones, including estrogen
and progesterone, have a stimulating effect on cyst growth in polycystic liver
disease. Estrogen receptors are present on cystic liver tissue but not on
normal liver tissue, in vitro, administration of estrogen enhances
proliferation and administration of estrogen blockers decreases proliferation.
It was already known from epidemiological studies that estrogen, for example in
oral contraceptives or hormone replacement therapy, promotes livergrowth in
polycystic liver disease. Very recently, data was published that showed that
liver growth, and sometimes even liver volumes, decreased after menopause.

The aforementioned recently published experimental and epidemiological data
have led us to hypothesize that lowering estrogen and progesterone levels in
women with severe PLD will ameliorate the disease process, by decreasing liver
growth and its related complaints, improving quality of life, and ultimately
preventing the need for liver transplantation. In this study, we will test this
hypothesis using the GnRH analogue leuprorelin to stop the production of
estrogens and progesterone.

This study has been transitioned to CTIS with ID 2023-506637-30-00 check the CTIS register for the current data.

The main objective of this study is to determine whether lowering estrogen and
progesterone levels with leuprorelin decreases liver growth rates in
pre-menopausal women with severe PLD.
Secondary objectives are to assess in these women the effect of leuprorelin on
PLD-related complaints, quality of life, tolerability and safety.

This is an investigator-driven, randomized, controlled open label trial with
blinded endpoint assessment (PROBE). Patients will be screened for in- and
exclusion criteria and counseled carefully about the treatment and possible
side effects. If eligible and after having given consent, patients will be
randomized to direct or delayed start (18 months later) of leuprorelin
treatment.

The randomization between direct and delayed start is important to distinguish
if any observed effect on the rate of growth is due to the natural course of
the disease while ageing, or due to the medical intervention (primary
endpoint). Patient blinding is not possible, since leuprorelin will induce
menopause. The trial is therefore open label. After 18 months, patients in the
delayed start group will start with leuprorelin treatment. The addition of a
delayed start group to the trial design has been introduced to replace the
traditional placebo group. This design reflects the urgency felt by patients
that we have consulted. Patients emphasized that, given the recent
epidemiological evidence, they would not participate in a trial if there would
be a chance to be in a control group, without treatment. Furthermore, this
switch to treatment after 18 months enables a paired analysis of
intra-individual change in rate of liver growth (comparing growth before and
after start of treatment) in all patients. Finally, it will render additional
tolerability data. The patients in the direct start group will not cross over
to no-treatment because of two reasons: first these patients will experience
menopause two times. Second, treatment in the first 1,5 year can have an
unexpected prolonged carry-over effects, so it could be questioned whether
these patients can serve as proper controls in the second phase.

At the end of study, but depending on the study site, patients will be allowed
to continue study medication, until study results are available. Treatment will
be stopped at age 55, since >= 95% of women will have reached natural menopause
by then.

At the start of the study, patients will be randomized between direct start of
treatment, and delayed start (after 1.5 years). Leuprorelin is a GnRH analogue
that stimulates the pituitary to produce LH and FSH. If used for a longer term,
desensitization occurs and the pitutary will produce no LH and FSH anymore. In
this way, a chemical menopause is induced, and the ovaries will not produce
estrogen and/or progsterone anymore.
Since the drug causes side-effects similar to menopause (for example cessation
of menopause), a blinded placebo controlled study design is not an option. We
therefore choose for a PROBE design (i.e. prospective, randomized, open label,
with blinded endpoint assessment).

Treatment is started as monthly subcutaneous injections of 3.75 mg for the
first three months, and when tolerated, as three-monthly injections of 11.25 mg
thereafter.

The study consists of 10 study visits in 3 years. During the study, 5 times and
MRI or CT scan will be made and laboratory measurements and vital signs will be
performed every visit.

The study treatment consists of (subcutaneous) injections, first monthly and
after 3 months, if tolerated, 3-monthly injections. The patient can
self-administer this injections to reduce the hospital visits.

Dependent on the study site, these study visits will replace part or most of
the regulary visits to the outpatient clinic.

Leuprorelin could lead to short-term side effect such as hot flushes,
palpitations, mood swings, vaginal dryness and other side effects related to
low estrogen levels. On the longer term, treatment could lead to reduced bone
density and a slightly enhanced cardiovascular risk.

All patients meeting the inclusioncriteria have a very severe form of
polycystic liver disease, leading to pain, reduced intake, reduced mobility,
and a decreased quality of life. For all patients participating in this trial,
there are currently no other treatment options available than a liver
transplantation, an invasive procedure bearing several short- and long-term
risks. In a focusgroup with 8 patients meeting the inclusion criteria, we
discussed wheter patient would we willing to try such a treatment or
participate in this trial weighing the side-effects of treatment versus the
prospects of their disease. All patients stated that they would be willing to
participate in the trial.