Urinary Tract, Sexual Organs, and Pregnancy Conditions

Diseases and Abnormalities at or Before Birth

All Conditions

Digestive System Diseases

Neoplasms

Symptoms and General Pathology

Rare Diseases

Polycystic Kidney Diseases

Polycystic Kidney, Autosomal Dominant

Liver Diseases

Cysts

Kidney Diseases

Gastrointestinal Diseases

Kidney Diseases, Cystic

Urologic Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Male Urogenital Diseases

Congenital Abnormalities

Abnormalities, Multiple

Ciliopathies

Genetic Diseases, Inborn

Pathological Conditions, Anatomical

Autosomal Dominant Multiple Pterygium Syndrome

Polycystic Liver Disease

Gastrointestinal Agents

All Drugs and Chemicals

Hematinics

Ursodeoxycholic Acid

Liver Extracts

This group will receive standard care (no treatment)

The intervention group will receive 15-20mg/kg/day UDCA for 24 weeks

Joost PH Drenth, dr.

Rationale: Polycystic liver disease (PLD) is a rare disorder characterized by \>20 fluid-filled hepatic cysts. Polycystic livers are present in the combination with renal cysts as a manifestation of autosomal dominant polycystic kidney disease (ADPKD), or isolated in the absence of renal cysts as autosomal dominant polycystic liver disease (ADPLD or PCLD). PLD patients are confronted with symptoms caused by the mass effect of their polycystic liver every day for the rest of their life. There is no standard therapeutic option for symptomatic PLD patients. Current options are fairly invasive or their efficacy is only moderate.

Preliminary data in our research lab have shown that ursodeoxycholic acid (UDCA) inhibited the proliferation of polycystic human cholangiocytes in vitro through the normalization of the intracellular calcium levels in cystic cholangiocytes. The investigators also found that daily oral administration of UDCA for 5 months to polycystic kidney disease (PCK) rats, an animal model of ARPKD that spontaneously develops hepato-renal cystogenesis, resulted in inhibition of hepatic cystogenesis.

The investigators hypothesize that UDCA is an effective therapeutic tool in reducing liver volume in PLD.

Objective: First, to demonstrate whether UDCA-therapy is effective in reducing total liver volume in PLD patients. Second, the investigators want to assess if UDCA modifies quality of life. Finally, the investigators want to assess safety and tolerability.

Study design: International, multicenter, randomized, controlled trial Study population: 34 subjects (18 ≤age ≤ 80 years) suffering from symptomatic polycystic liver disease with underlying diagnosis of (PCLD or ADPKD), defined as ≥ 20 liver cysts on CT-scan and liver volume of ≥ 2500. Symptomatic is defined as Eastern Cooperative Oncology Group- Performance Score (ECOG-PS) ≥ 1 and having at least three out of ten PLD symptoms.

Intervention: The patients will be randomized (1:1) into two groups. One group of patients will receive 15-20mg/kg/day UDCA for 24 weeks. The other group will receive standard care.

Main study endpoint: Proportional change of total liver volume in UDCA treated patients versus non treated patients, as assessed by CT at baseline and 6 months.

We investigated whether ursodeoxycholic acid was able to reduce total liver volume in polycystic liver disease.

Ursodeoxycholic Acid as Treatment for Polycystic Liver Disease

An International, Multicenter, Randomized Controlled Clinical Trial Assessing the Efficacy of Ursodeoxycholic Acid as a Volume Reducing Treatment in Symptomatic Polycystic Liver Disease

Proportional change of total liver volume in UDCA treated patients versus non treated patients, as assessed by CT at baseline and week 24

Absolute total liver volume at baseline and end of treatment (week 24) will be measured

Improvement in Gastrointestinal Symptom score

Proportion reduction in total liver volume

Change in total kidney volume after 24 weeks

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Radboud University Medical Center

Nervous System Diseases

Pain

Abdominal Pain

Hepatomegaly

Neurologic Manifestations

Signs and Symptoms, Digestive

Hypertrophy

Antineoplastic Agents

Octreotide

Antineoplastic Agents, Hormonal

Participants received Octreotide LAR® Depot injections (up to 40 mg) intramuscularly every 28 days (+/- 5 days) for one year

Participants received an injection of placebo (sham) medication intramuscularly every 28 days (+/- 5 day) for one year

Participants received Octreotide LAR® Depot injections (up to 40 mg)intramuscularly every 28 days (+/- 5 days) for one year

Placebo

Marie C. Hogan, M.D., Ph.D.

This study will evaluate the effect of Octreotide LAR® on the liver volumes of patients with severe polycystic liver disease who are not candidates or decline surgical treatments such as liver cyst fenestration, liver resection or liver transplantation. A total of 42 patients will be recruited -14 who will receive placebo and 28 the study drug. Preliminary evidence indicates that this drug is safe and non-toxic in other disease states. Treatment with this drug holds promise not only for individuals with liver involvement, but also for many more patients with polycystic kidney disease.

The primary aim of this study is to compare the effect of Octreotide LAR® Depot on the liver volume of patients with severe polycystic liver disease who are not candidates or decline surgical treatments such as liver cyst fenestration, liver resection or liver transplantation compared with placebo. The secondary aims of the study are: (1)Assess the effect of Octreotide LAR® Depot on the total kidney volume and iothalamate clearance in patients with polycystic kidney disease associated with severe polycystic liver disease who are not candidates or decline surgical treatments such as liver cyst fenestration, liver resection or liver transplantation. (2)Evaluate quality of life changes associated with the administration of Octreotide LAR® Depot in these patients. (3)Assess toxicity of Octreotide LAR® Depot in patients with polycystic liver disease (PLD).

Note: Subjects who completed this 1 year randomized trial were offered enrollment into an open-label (all subjects received Octreotide) extension trial for an additional two years of treatment.

Octreotide in Severe Polycystic Liver Disease

Pilot Study Of Long-Acting Octreotide (Octreotide LAR® Depot) In The Treatment Of Patients With Severe Polycystic Liver Disease

Percent change from baseline in liver volume, measured in milliliters by Magnetic Resonance Imaging (MRI)or Computed Tomography (CT) scans

Percent change from baseline in renal volume, measured in milliliters by MRI or CT scans

Percent change from baseline in renal function/GFR, measured by clearance of iothalamate with monitoring of bladder emptying using ultrasound

Scores on the Medical Outcomes Study 36-Item Short-Form General Health Survey (SF-36), version 2. Subjects completed the SF-36 which consists of 8 sub-scales which are additionally summarized into 2 summary components (physical and mental). The subscales and the summary scales both range from 0 to 100, with (0 = worst imaginable, 100 = best imaginable).

Novartis

National Center for Research Resources (NCRR)

Mayo Clinic

MD, PhD, Assistant Professor of Medicine, College of Medicine

Participants received Octreotide LAR® Depot injections intramuscularly every 28 days (+/- 5 days) for one year

Total

Age Continuous

Sex: Female, Male

United States

Region of Enrollment

Glomerular Filtration Rate measures how fast the kidneys are filtering. 13 subjects were excluded from the analysis of the kidney data: 4 subjects had renal transplant before enrollment (3 in octreotide and 1 in placebo groups), 8 subjects had a diagnosis of ADPLD (4 in each group), 1 placebo subject has missing kidney data due to incomplete image coverage.

Glomerular Filtration Rate

Body Mass Index (BMI) is a health index for comparing weight to height. BMI is a person's weight in kilograms (kg) divided by his or her height in meters squared. The body mass index is an indication if a person is at a suitable weight for his height on an approximation of body fat. A body mass index of under 20 is considered to be underweight, while a body mass index between 20 to 25 is considered healthy. A body mass index in the range of 25 to 30 is regarded as overweight. A body mass index over 30 is regarded as obese.

Body Mass Index

Body Weight

Creatinine in the serum is a blood test, and is an indicator of kidney function.

Serum creatinine

Fasting plasma glucose

A protein urine test measures the amount of proteins, such as albumin, found in a urine sample. Urine albumin is an indicator of kidney function.

Urine Albumin

Systolic blood pressure is the upper number on a blood pressure reading and measures contraction of the ventricles, or lower chambers of the heart

Systolic Blood Pressure

Diastolic blood pressure is the lower number on a blood pressure reading and measures dilation of the ventricles, or lower chambers of the heart.

Diastolic Blood Pressure

Liver volume was measured by magnetic resonance imaging (MRI) or computed tomography \[CT\].

Liver volume

Kidney volume was measured by magnetic resonance imaging (MRI) or computed tomography \[CT\].

13 subjects were excluded from the analysis of the kidney data: 4 subjects had renal transplant before enrollment (3 in octreotide and 1 in placebo groups), 8 subjects had a diagnosis of ADPLD (4 in each group), 1 placebo subject has missing kidney data due to incomplete image coverage. (Octreotide group n = 21 and placebo group n = 8).

Kidney volume

ADPKD genotype with PKD1 gene mutation

ADPKD genotype with PKD2 gene mutation

ADPKD genotype with no genetic mutation detected

ADPLD genotype with PRKCSH gene mutation

ADPLD genotype with SEC63 gene mutation

ADPLD genotype with no genetic mutation detected

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in one of two genes: PKD1 or PKD2, and is characterized by the development of kidney cysts and other manifestations, of which polycystic live disease (PLD) is most common. Autosomal dominant PLD (ADPLD) also exists as a genetically distinct disease with few or absent kidney cysts. Like ADPKD, ADPLD is genetically heterogeneous, with the 1st two genes identified (PRKCSH \& SEC63) accounting for approximately 1/3 to 1/2 of isolated ADPLD cases.

Genotypes and genetic mutations

Marie Hogan, MD, PhD, Assistant Prof of Medicine, College of Medicine

P values \<0.05 were considered statistically significant.

Percent Change in Liver Volume

13 subjects were excluded from the analysis of the kidney data: 4 subjects had renal transplant before enrollment (3 in octreotide and 1 in placebo groups), 8 subjects had a diagnosis of ADPLD (4 in each group), 1 placebo subject has missing kidney data due to incomplete image coverage.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Ursodeoxycholic Acid as Treatment for Polycystic Liver Disease	NCT02021110	Polycystic Live... Polycystic Kidn...	Ursodeoxycholic...	18 Years - 80 Years	Radboud University Medical Center
Octreotide in Severe Polycystic Liver Disease	NCT00426153	Polycystic Kidn... Polycystic Live... Hepatomegaly Liver Diseases Kidney, Polycys... Abdominal Pain	Octreotide Placebo	18 Years - 80 Years	Mayo Clinic

Spots Global Cancer Trial Database for polycystic kidney, autosomal dominant