| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Severe polycystic liver disease in female patient |
|
| E.1.1.1 | Medical condition in easily understood language |
| Large cystic livers in female patien |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
| 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 main objective of this study is to determine whether lowering
estrogen and progesterone levels with leuproreline decreases liver
growth rates in pre-menopausal women with severe PLD |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives are to assess in these women the effect of
leuproreline on PLD-related complaints, quality of life, tolerability and
safety |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Female patients
- Diagnosis of polycystic liver disease defined as the presence of more than 10 liver cysts
- Age between 18 to 45 (inclusive) years;
- Very large liver for age, defined as the upper 10% of liver volumes in specific age
categories (based on a retrospective polycystic liver disease registry, n=1.600 patients)
o 18-30 yr; height adjusted TLV > 2.0 L/m
o 30-35 yr; height adjusted TLV > 2.2 L/m
o 35-40 yr; height adjusted TLV > 2.5 L/m
o 40-45 years; height adjusted TLV > 3.0 L/m
- Availability of at least 1 historical MRI or CT scan made between 5 to 1 years before
baseline visit of this study
- Ongoing liver growth, defined as an increase in absolute total liver volume between the
historical MRI or CT scan and the MRI at screening of this trial
- Since somatostatin analogues are proven efficacious therapy for polycystic liver
disease at this time it is required that:
o patients use a somatostatin analogue and still have confirmed liver growth; OR
o patient have a specific reason not to use this medication, .e.g. patient used a
somatostatin analogue in the past, but had to stop it due to inefficacy or because
he/she did not tolerate it, patient has a contra-indication for using somatostatin
analogues, no availability of somatostatin analogues
- Voluntary written informed consent before performance of any study-related
procedures not part of standard medical care, and able to read, comprehend, and
respond to study questionnaires. |
|
| E.4 | Principal exclusion criteria |
1. Post-menopausal status or (vasomotor) symptoms indicating upcoming menopause
2. Anti Mullerian Hormone (AMH) measurement at screening visit <0.03 ng/ml.
3. Patients who are pregnant or lactation, or who have an active desire to have children,
pregnancy or breast-feeding during the clinical study
4. A history of osteoporosis or osteoporosis determined by DEXA-scan at screening (T
score ≤ -2.5)
5. Patients diagnosed with a clinical depression and is or has been treated with antidepression medication.
6. Patients known with a prolongated QT time or who use medicinal products leading to
a QT prolongation including, but not restricted to: class IA (e.g. quinidine,
disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide)
antiarrhythmic medicinal products, methadone, moxifloxacin and antipsychotics.
7. Hypersensitivity to leuprorelin or other GnRH analogues, to polylactic acid or
poly(D,L-lactide-co-glycolide) (1:1)
8. Patients with epilepsy which is not well-controlled (defined as manifestation of >= 1
seizure in the last 12 months).
9. Patients with a confirmed hormone independence carcinoma.
10. Liver transplantation or liver surgery expected within 1.5 years, to the discretion of the
study doctor
11. Use of hormonal oral contra-conception containing estrogen and/or progesterone. In
contrast, a hormone containing uterine device is not an exclusion criteria.
12. Contra-indications for MRI assessments (such as implants) or not able or willing to
undergo MRI scan for other reasons (e.g. claustrophobia, profound obesity)
13. Kidney transplantation or chronic use of immunosuppressive agents (such as
cyclosporine, mycophenolic acid, tacrolimus but not prednisolone) for other indications
14. Severe hypertension, defined as a systolic blood pressure >160 mmHg and/or diastolic
blood pressure > 100 mm Hg.
15. Clinically significant, uncontrolled medical condition that, in the opinion of the
investigator, would put the safety of the patient at risk through participation, or which
would affect the efficacy of safety analysis if the condition exacerbated during the
study, or that may significantly interfere with study compliance, such as, but not
restricted to, recurrent cholangitis, recurrent ascites or hepato-venous outflow
obstruction
16. Participation in other clinical trials or treatments with other IMPs and its relevant
metabolites or previous therapies, whose toxicity (may) overlap with that of this
studies IMP and its relevant metabolites within five times the half-life of the drug
and/or metabolites (whichever is longer).
17. Participation in other interventional studies at the same time.
Exclusion criteria related to the historical MRI or CT scan to determine liver
growth before start of the study
- Start or stop of liver volume reducing therapy (medication e.g. somatostatin analogues
or surgical interventions) in the period between the historical scan and the baseline
MRI scan;
- The historical MRI or CT scan is performed <3 months after start or stop of a
somatostatin analogue or surgical volume reducing therapy.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary outcome is the livergrowth, in percent per year, calculated
from BL till t=1.5 years, compared between the direct start groep
(receiving leuproreline treatment in this period) and the delayed start
group (serving as a control group). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
At the end of the trial, the primary outcome will be analyzed, using the
calculated liver growth in percent per year during the first 18 months of
the trial, compared between the direct start group and the delayed start
group. |
|
| E.5.2 | Secondary end point(s) |
1. Polycystic liver disease related complaints, using the validated PLD
Questionnaire (8).
The change in the score on the PLD Questionnaire (Δ PLD-Q score) will
be compared between patients in the direct start group and the delayed
start group after 18 months of treatment (Δ BL-18 months in the direct
start group versus Δ BL-18 months in the delayed start group)
2. Liver growth rate (in % per year) compared within individuals before
start of treatment and during treatment (a paired analysis of growth
rates; in the direct start group of historical growth versus growht during
the frist 1.5 years of treatment, and in the delayed start group between
the first 1.5 years of the trial without treatment and the next 1.5 years
of the trial with treatment.
Exploratory outcomes:
- liver volume, compared between the direct and delayed start groep
after 1.5 years
- estrogen levels, compared at BL, 3 months after start treatment, 1.5
years, 21 months and 3 years
- acute effects of the treatment, using the MRI scans 6 months after
start of treatment
- safety and toleratability, incidence of (serious) adverse events,
bonedensity measured using DEXA-scans, drop-out rate
- Quality of life, assessed by het SF-36 and BD-II
- menopause related complaints, assessed by the MENQOL-questionnaire
In patients with polycystic kidney disease
- growth rate of kidney volume in the first 1.5 years, compared between
the direct start group and delayed start group
- growth rate of kidney volumes, compared within individuals, before
start of treatment and during treatment
- acute effects of the treatment, using the MRI scans 6 months after
start of treatment
- change in renal function in the first 1.5 years between direct and
delayed start group |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Endpoints will be evaluated if the last patient fulfulled the trial follow up.
For a detailed description of outcomes please see E.5.2.1. |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| At baseline, patients are randomized between direct or delayed start of treatment (after 1.5 years) |
|
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| 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 | 5 |
| 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
|
|
| 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 | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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