A GnRH Agonist IN Pre-menopausal Women STudy to Treat Severe Polycystic Liver Disease

Study Overview
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Brief Summary
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Multicenter trial on the effect of the GnRH analogue leuprorelin on the growth of total liver volume in pre-menopausal women with very severe polycystic liver disease who, despite available therapy, experience growth and are heading for liver transplantation.

Official Title
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A GnRH Agonist IN Pre-menopausal Women STudy to Treat Severe Polycystic Liver Disease

Conditions
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Polycystic Liver Disease, Autosomal Dominant Polycystic Kidney

Intervention / Treatment
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* Drug: Leuprorelin


Participation Criteria
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Eligibility Criteria
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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) 18-30 yr; height adjusted TLV > 2.0 L/m 30-35 yr; height adjusted TLV > 2.2 L/m 35-40 yr; height adjusted TLV > 2.5 L/m 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: patients use a somatostatin analogue and still have confirmed liver growth; OR 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. Exclusion Criteria: Post-menopausal status or (vasomotor) symptoms indicating upcoming menopause Anti Mullerian Hormone (AMH) measurement at screening visit <0.03 ng/ml. Active desire to have children, pregnancy or breast-feeding Contra-indications for leuprorelin, such as history of cardiovascular disease, history of osteoporosis or osteoporosis determined by DEXA-scan at screening (T score ≤ - 2.5), or a known intolerance for leuprorelin Liver transplantation or liver surgery expected within 1.5 years, to the discretion of the study doctor Use of hormonal oral contra-conception containing estrogen and/or progesterone. In contrast, a hormone containing uterine device is not an exclusion criteria. 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) Kidney transplantation or chronic use of immunosuppressive agents (such as cyclosporine, mycophenolic acid, tacrolimus but not prednisolone) for other indications Severe hypertension, defined as a systolic blood pressure >160 mmHg and/or diastolic blood pressure > 100 mm Hg. 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, (history of) depression Participation in other interventional studies at the same time.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, controlled trial in which patients are randomized between either 1. Direct start with treatment or 2. Delayed start with treatment which will start after 18 months of standard care with the study medication
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Direct start<br>36 months of treatment with study medication | Drug: Leuprorelin<br>* Treatment consist of leuprorelin 3.75 mg once monthly for the first 3 months followed by 3-monthly injections of 11.25 mg. The direct start group will use leuprorelin for 36 months. The delayed start group will use standard of care in the first 18 months.<br>|
| Other: Delayed start<br>First 18 months standard care, hereafter 18 months treatment with study medication | Drug: Leuprorelin<br>* Treatment consist of leuprorelin 3.75 mg once monthly for the first 3 months followed by 3-monthly injections of 11.25 mg. The direct start group will use leuprorelin for 36 months. The delayed start group will use standard of care in the first 18 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Liver growth | Liver volumes (in % per year) measured in the MRI at screening, 6 months, 18 months, 24 months and 36 months | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Polycystic liver disease related complaints | PLD related complaints assessed by the Polycystic liver disease-Questionnaire at baseline, 6 months, 18 months, 24 months and 36 months | 36 months | 
| Menopause related complaints | Menopause related complaints by using the validated MENQOL questionnaire at baseline, 6 months, 18 months, 24 months and 36 months | 36 months | 
| Patient reported mental health | Quality of life and as subset mental health will be measured by the validated RAND SF-36 questionnaires at baseline, 6 months, 18 months, 24 months and 36 months | 36 months | 
| Patient reported physical health | Quality of life and as subset physical health will be measured by the validated RAND SF-36 questionnaires at baseline, 6 months, 18 months, 24 months and 36 months | 36 months | 
| Kidney growth | Kidney volumes (in % per year) measured in the MRI at screening, 6 months, 18 months, 24 months and 36 months | 36 months | 
| Sex hormone levels | Anti Muller Hormone will be assessed at screening. Other Extensive laboratory includes estradiol, progesterone, AMH, FSH, LH levels at baseline, 6 months after start therapy and after 18 and 36 months. | 36 months | 
| Bone density | Bone density measured by a DEXA scan at screening, 18 months and 36 months. | 36 months | 
| Renal function | eGFR measurements and 24h urine analyisis (in ADPKD patients only) at baseline, 6 months, 18 months, 24 months and 36 months time | 36 months | 
| Bloodpressure | Manual blood pressure measurements in millimetres of mercury (measure 3 times with 2 minutes in between) at screening, baseline, 3 months, 6 months, 12 months, 18months, 21 months, 24 months, 30 months and 36 months . | 36 months | 
| Heart rate | Heart rate in beats per minute (measure 3 times with 2 minutes in between) measured at screening, baseline, 3 months, 6 months, 12 months, 18months, 21 months, 24 months, 30 months and 36 months . | 36 months | 
| Weight | Body weight in kilograms measured at screening, baseline, 3 months, 6 months, 12 months, 18months, 21 months, 24 months, 30 months and 36 months . | 36 months | 
| Upper-arm-circumference | Upper-arm-circumference in centimeters of the non-dominant arm measured at screening, baseline, 3 months, 6 months, 12 months, 18months, 21 months, 24 months, 30 months and 36 months. | 36 months | 
| Abdominal circumference | Abdominal circumference in centimeters (measured at the level of the umbilicus) measured at screening, baseline, 3 months, 6 months, 12 months, 18months, 21 months, 24 months, 30 months and 36 months . At screening, length will be collected to calculate Body Mass Index. | 36 months | 
| Length | At screening length in centimeters will be collected. | 1 month | 
| The number of participants experciencing a (serious) adverse events | During each physical or telephone contact, the adverse effects are queried and registered in accordance with national protocol | 36 months | 
| Symptoms of depression | Symptoms of depression measured by the validated BD-II questionnaires at baseline, 6 months, 18 months, 24 months and 36 months | 36 months |