A GnRH Agonist IN Pre-menopausal Women STudy to Treat Severe Polycystic Liver Disease (AGAINST-PLD)

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.

Study Overview

• Status: Recruiting
• Conditions: Autosomal Dominant Polycystic Kidney; Polycystic Liver Disease
• Intervention / Treatment: Drug: Leuprorelin

• Study Type: Interventional
• Enrollment (Anticipated): 36
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Ron T Gansevoort; Phone Number: +31 50 3610923; Email: r.t.gansevoort@umcg.nl
• Study Contact Backup: Name: Renée Duijzer; Email: renee.duijzer@radboudumc.nl

Study Locations

• Netherlands
  • Groningen, Netherlands, 9713 GZ
    • Recruiting
    • Groningen universitair medical center
    • Contact: Renée Duijzer, msc; Phone Number: +31(0)629669242; Email: r.duijzer@umcg.nl
    • Contact: Sophie Aapkes; Email: s.e.aapkes@umcg.nl
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6525 GA
      • Not yet recruiting
      • Radboudumc
      • Contact: Renée Duijzer; Phone Number: +31(0)629669242; Email: renee.duijzer@radboudumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Direct start; 36 months of treatment with study medication	Drug: Leuprorelin; 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.
Other: Delayed start; First 18 months standard care, hereafter 18 months treatment with study medication	Drug: Leuprorelin; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University Medical Center Groningen
• Collaborators: Radboud University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2022
• Primary Completion (Anticipated): June 1, 2027
• Study Completion (Anticipated): October 1, 2027

Study Registration Dates

• First Submitted: May 9, 2022
• First Submitted That Met QC Criteria: July 27, 2022
• First Posted (Actual): July 28, 2022

Study Record Updates

• Last Update Posted (Actual): November 4, 2022
• Last Update Submitted That Met QC Criteria: November 3, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Kidney Diseases; Urologic Diseases; Congenital Abnormalities; Genetic Diseases, Inborn; Pathological Conditions, Anatomical; Abnormalities, Multiple; Kidney Diseases, Cystic; Ciliopathies; Liver Diseases; Polycystic Kidney Diseases; Polycystic Kidney, Autosomal Dominant; Cysts; Physiological Effects of Drugs; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Reproductive Control Agents; Fertility Agents, Female; Fertility Agents; Leuprolide
• Other Study ID Numbers: 2020-005949-16 (EudraCT Number); 10140261910001 (Other Grant/Funding Number: ZonMw); U1111-1278-8976 (Registry Identifier: Universal Trial Number (UTN))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No