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

Phase 2

Recruiting

• Conditions: Polycystic Liver Disease; Autosomal Dominant Polycystic Kidney
• Interventions: Drug: Leuprorelin

• Registration Number: NCT05478083
• Lead Sponsor: University Medical Center Groningen

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2022-05-09
• Study Start: 2022-06-01
• Study First Submitted QC: 2022-07-27
• Study First Posted: 2022-07-28
• Status Verified: 2022-11
• Last Update Submitted: 2022-11-03
• Last Update Posted: 2022-11-04
• Primary Completion: 2027-06-01
• Study Completion: 2027-10-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: Female
• Target Recruitment: 36

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Direct start	Leuprorelin	36 months of treatment with study medication
Delayed start	Leuprorelin	First 18 months standard care, hereafter 18 months treatment with study medication

Primary Outcome Measures

Name	Time	Method
Liver growth	36 months	Liver volumes (in % per year) measured in the MRI at screening, 6 months, 18 months, 24 months and 36 months

Secondary Outcome Measures

Name	Time	Method
Patient reported mental health	36 months	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
Patient reported physical health	36 months	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
Kidney growth	36 months	Kidney volumes (in % per year) measured in the MRI at screening, 6 months, 18 months, 24 months and 36 months
Sex hormone levels	36 months	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.
Bone density	36 months	Bone density measured by a DEXA scan at screening, 18 months and 36 months.
Bloodpressure	36 months	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 .
Weight	36 months	Body weight in kilograms measured at screening, baseline, 3 months, 6 months, 12 months, 18months, 21 months, 24 months, 30 months and 36 months .
Length	1 month	At screening length in centimeters will be collected.
Polycystic liver disease related complaints	36 months	PLD related complaints assessed by the Polycystic liver disease-Questionnaire at baseline, 6 months, 18 months, 24 months and 36 months
Renal function	36 months	eGFR measurements and 24h urine analyisis (in ADPKD patients only) at baseline, 6 months, 18 months, 24 months and 36 months time
Heart rate	36 months	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 .
Abdominal circumference	36 months	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.
Upper-arm-circumference	36 months	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.
Menopause related complaints	36 months	Menopause related complaints by using the validated MENQOL questionnaire at baseline, 6 months, 18 months, 24 months and 36 months
The number of participants experciencing a (serious) adverse events	36 months	During each physical or telephone contact, the adverse effects are queried and registered in accordance with national protocol
Symptoms of depression	36 months	Symptoms of depression measured by the validated BD-II questionnaires at baseline, 6 months, 18 months, 24 months and 36 months

Trial Locations

Locations (2)

Groningen universitair medical center; 🇳🇱 Groningen, Netherlands

Radboudumc; 🇳🇱 Nijmegen, Gelderland, Netherlands