Abdominal Pain, Hepatomegaly, Kidney, Polycystic, Liver Diseases, Polycystic Kidney, Autosomal Dominant, Polycystic Liver Disease
Conditions
Brief summary
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.
Detailed description
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.
Interventions
DRUGOctreotide
Participants received Octreotide LAR® Depot injections (up to 40 mg)intramuscularly every 28 days (+/- 5 days) for one year
DRUGPlacebo
Participants received an injection of placebo (sham) medication intramuscularly every 28 days (+/- 5 day) for one year
Sponsors
Novartis
National Center for Research Resources (NCRR)
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Age - 18 years and older * Diagnosis of Polycystic Liver Disease (PLD) associated with ADPKD or isolated Autosomal Dominant Polycystic liver Disease (ADPLD) * Severe PLD defined as a liver volume greater than 4000 mL or symptomatic disease due to mass effects from hepatic cysts * Not a candidate for or declining surgical intervention
Exclusion criteria
* Women of childbearing potential or their sexual partners who are unwilling to employ adequate contraception * Creatinine greater than 3mg/dL or hemodialysis dependent * Cancer or major systemic disease that could prevent completion of the planned follow-up or interfere with data collection or interpretation * Uncontrolled diabetes mellitus as defined by blood glucose levels of greater than or equal to 250 mg/dL on 2 or more consecutive daily readings despite antidiabetic therapy * Neurologic/psychologic conditions preventing appropriate informed consent * Symptomatic gallstones or biliary sludge * Variceal bleeding or hepatic encephalopathy within prior 30 days * Uncontrolled hypertension (Systolic blood pressure greater than 160 mmHg; Diastolic blood pressure greater than 100 mmHg) * Current, or prior use of somatostatin analogue (octreotide, lanreotide) in past 6 months * History of significant adverse reaction to a somatostatin analogue
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Liver Volume | Baseline, 12 months | Percent change from baseline in liver volume, measured in milliliters by Magnetic Resonance Imaging (MRI)or Computed Tomography (CT) scans |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Renal Volume | Baseline, 12 months | Percent change from baseline in renal volume, measured in milliliters by MRI or CT scans |
| Percent Change in Glomerular Filtration Rate (GFR) | Baseline, 12 months | Percent change from baseline in renal function/GFR, measured by clearance of iothalamate with monitoring of bladder emptying using ultrasound |
| Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | Baseline, 12 months | 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). |
Countries
United States
Participant flow
Recruitment details
42 participants were enrolled at Mayo Clinic in Rochester, Minnesota from 1/1/2007 to 5/19/2008.
Pre-assignment details
Following consent a tolerability test dose of 100 micrograms of short-acting octreotide was administered subcutaneously to subjects, followed by 4 hours of observation/vital signs. Randomized intramuscular dosing began the next day.
Participants by arm
| Arm | Count |
|---|---|
| Octreotide Participants received Octreotide LAR® Depot injections intramuscularly every 28 days (+/- 5 days) for one year | 28 |
| Placebo Participants received an injection of placebo (sham) medication intramuscularly every 28 days (+/- 5 day) for one year | 14 |
| Total | 42 |
Baseline characteristics
| Characteristic | Octreotide | Placebo | Total |
|---|---|---|---|
| Age Continuous | 49.7 years STANDARD_DEVIATION 9 | 50.3 years STANDARD_DEVIATION 7.3 | 49.9 years STANDARD_DEVIATION 8.4 |
| Body Mass Index | 26.3 kilograms/meter^2 STANDARD_DEVIATION 5.77 | 24.4 kilograms/meter^2 STANDARD_DEVIATION 2.98 | 25.7 kilograms/meter^2 STANDARD_DEVIATION 5 |
| Body Weight | 76.0 kilograms STANDARD_DEVIATION 20.2 | 70.9 kilograms STANDARD_DEVIATION 10.9 | 74.3 kilograms STANDARD_DEVIATION 17.8 |
| Diastolic Blood Pressure | 79.8 millimeters of mercury (mmHg) STANDARD_DEVIATION 8.9 | 79.1 millimeters of mercury (mmHg) STANDARD_DEVIATION 9.2 | 79.6 millimeters of mercury (mmHg) STANDARD_DEVIATION 8.9 |
| Fasting plasma glucose | 93.4 milligrams/deciliter STANDARD_DEVIATION 11.2 | 93.6 milligrams/deciliter STANDARD_DEVIATION 7.8 | 93.5 milligrams/deciliter STANDARD_DEVIATION 10.1 |
| Genotypes and genetic mutations ADPKD genotype with no genetic mutation detected | 3 Participants | 0 Participants | 3 Participants |
| Genotypes and genetic mutations ADPKD genotype with PKD1 gene mutation | 16 Participants | 9 Participants | 25 Participants |
| Genotypes and genetic mutations ADPKD genotype with PKD2 gene mutation | 5 Participants | 1 Participants | 6 Participants |
| Genotypes and genetic mutations ADPLD genotype with no genetic mutation detected | 1 Participants | 2 Participants | 3 Participants |
| Genotypes and genetic mutations ADPLD genotype with PRKCSH gene mutation | 3 Participants | 1 Participants | 4 Participants |
| Genotypes and genetic mutations ADPLD genotype with SEC63 gene mutation | 0 Participants | 1 Participants | 1 Participants |
| Glomerular Filtration Rate | 70 milliliters/minute per 1.73 m^2 STANDARD_DEVIATION 27 | 71 milliliters/minute per 1.73 m^2 STANDARD_DEVIATION 27 | 70 milliliters/minute per 1.73 m^2 STANDARD_DEVIATION 27 |
| Kidney volume | 1142.9 milliliters (ml) STANDARD_DEVIATION 826.9 | 803.0 milliliters (ml) STANDARD_DEVIATION 269.1 | 1049.2 milliliters (ml) STANDARD_DEVIATION 728.3 |
| Liver volume | 5907.7 milliliters (ml) STANDARD_DEVIATION 2915 | 5373.9 milliliters (ml) STANDARD_DEVIATION 3565.4 | 5729.8 milliliters (ml) STANDARD_DEVIATION 3113.1 |
| Region of Enrollment United States | 28 participants | 14 participants | 42 participants |
| Serum creatinine | 1.1 milligrams/deciliter STANDARD_DEVIATION 0.4 | 1.1 milligrams/deciliter STANDARD_DEVIATION 0.5 | 1.1 milligrams/deciliter STANDARD_DEVIATION 0.5 |
| Sex: Female, Male Female | 23 Participants | 13 Participants | 36 Participants |
| Sex: Female, Male Male | 5 Participants | 1 Participants | 6 Participants |
| Systolic Blood Pressure | 122.1 millimeters of mercury (mmHg) STANDARD_DEVIATION 13.2 | 120.5 millimeters of mercury (mmHg) STANDARD_DEVIATION 13.5 | 121.6 millimeters of mercury (mmHg) STANDARD_DEVIATION 13.2 |
| Urine Albumin | 65 milligrams/24 hours STANDARD_DEVIATION 123 | 130 milligrams/24 hours STANDARD_DEVIATION 237 | 87 milligrams/24 hours STANDARD_DEVIATION 171 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 21 / 28 | 4 / 14 |
| serious Total, serious adverse events | 3 / 28 | 0 / 14 |
Outcome results
Primary
Percent Change in Liver Volume
Percent change from baseline in liver volume, measured in milliliters by Magnetic Resonance Imaging (MRI)or Computed Tomography (CT) scans
Time frame: Baseline, 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Octreotide | Percent Change in Liver Volume | -5.0 percent change | Standard Deviation 6.77 |
| Placebo | Percent Change in Liver Volume | 0.9 percent change | Standard Deviation 8.33 |
Comparison: P values \<0.05 were considered statistically significant.p-value: 0.048Rank-sum test
Secondary
Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores
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).
Time frame: Baseline, 12 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Octreotide | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | Physical role at 12 months | 74.1 units on a scale | Standard Deviation 35 |
| Octreotide | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | Emotional role at baseline | 82.1 units on a scale | Standard Deviation 32.05 |
| Octreotide | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | Bodily Pain at baseline | 67.8 units on a scale | Standard Deviation 15.29 |
| Octreotide | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | General health at 12 months | 53.5 units on a scale | Standard Deviation 17.32 |
| Octreotide | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | Mental health at 12 months | 76.9 units on a scale | Standard Deviation 16.54 |
| Octreotide | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | Vitality at baseline | 49.6 units on a scale | Standard Deviation 21.81 |
| Octreotide | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | General health at baseline | 55.9 units on a scale | Standard Deviation 21.29 |
| Octreotide | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | Vitality at 12 months | 54.4 units on a scale | Standard Deviation 24.23 |
| Octreotide | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | Standardized mental component at baseline | 50.8 units on a scale | Standard Deviation 7.74 |
| Octreotide | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | Social functioning at baseline | 79.0 units on a scale | Standard Deviation 19.56 |
| Octreotide | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | Physical functioning at baseline | 74.8 units on a scale | Standard Deviation 21.96 |
| Octreotide | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | Social functioning at 12 months | 82.9 units on a scale | Standard Deviation 19.35 |
| Octreotide | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | Emotional role at 12 month | 91.4 units on a scale | Standard Deviation 23.74 |
| Octreotide | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | Physical functioning at 12 months | 77.0 units on a scale | Standard Deviation 21.32 |
| Octreotide | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | Standardized physical component at baseline | 42.6 units on a scale | Standard Deviation 9.73 |
| Octreotide | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | Bodily pain at 12 months | 75.7 units on a scale | Standard Deviation 19.02 |
| Octreotide | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | Standardized physical component at 12 months | 44.7 units on a scale | Standard Deviation 10 |
| Octreotide | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | Physical role at baseline | 59.8 units on a scale | Standard Deviation 42.13 |
| Octreotide | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | Standardized mental component at 12 month | 52.2 units on a scale | Standard Deviation 8.03 |
| Octreotide | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | Mental health at baseline | 76.0 units on a scale | Standard Deviation 14.12 |
| Placebo | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | Standardized mental component at 12 month | 51.3 units on a scale | Standard Deviation 11.15 |
| Placebo | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | Bodily pain at 12 months | 68.7 units on a scale | Standard Deviation 25.51 |
| Placebo | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | General health at baseline | 58.0 units on a scale | Standard Deviation 23.63 |
| Placebo | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | Emotional role at baseline | 73.8 units on a scale | Standard Deviation 37.39 |
| Placebo | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | Emotional role at 12 month | 81.0 units on a scale | Standard Deviation 38.6 |
| Placebo | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | Mental health at baseline | 75.4 units on a scale | Standard Deviation 18.75 |
| Placebo | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | Standardized physical component at 12 months | 46.1 units on a scale | Standard Deviation 9.51 |
| Placebo | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | Physical functioning at baseline | 80.4 units on a scale | Standard Deviation 23.73 |
| Placebo | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | Physical functioning at 12 months | 82.1 units on a scale | Standard Deviation 18.58 |
| Placebo | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | Physical role at baseline | 76.8 units on a scale | Standard Deviation 39.79 |
| Placebo | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | Physical role at 12 months | 75.0 units on a scale | Standard Deviation 41.6 |
| Placebo | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | General health at 12 months | 63.4 units on a scale | Standard Deviation 23.96 |
| Placebo | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | Vitality at baseline | 53.9 units on a scale | Standard Deviation 25.96 |
| Placebo | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | Vitality at 12 months | 54.6 units on a scale | Standard Deviation 27.91 |
| Placebo | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | Social functioning at baseline | 75.0 units on a scale | Standard Deviation 27.3 |
| Placebo | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | Social functioning at 12 months | 81.3 units on a scale | Standard Deviation 21.79 |
| Placebo | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | Mental health at 12 months | 80.7 units on a scale | Standard Deviation 18.76 |
| Placebo | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | Standardized physical component at baseline | 46.0 units on a scale | Standard Deviation 10.16 |
| Placebo | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | Standardized mental component at baseline | 48.4 units on a scale | Standard Deviation 10.96 |
| Placebo | Change in Subject Reported Outcomes Using Mean Health Related Quality of Life (HRQoL) Scores | Bodily Pain at baseline | 65.5 units on a scale | Standard Deviation 24.25 |
Secondary
Percent Change in Glomerular Filtration Rate (GFR)
Percent change from baseline in renal function/GFR, measured by clearance of iothalamate with monitoring of bladder emptying using ultrasound
Time frame: Baseline, 12 months
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Octreotide | Percent Change in Glomerular Filtration Rate (GFR) | -5.1 percent change | Standard Deviation 15.46 |
| Placebo | Percent Change in Glomerular Filtration Rate (GFR) | -7.2 percent change | Standard Deviation 13.21 |
p-value: 0.98Rank sum
Secondary
Percent Change in Renal Volume
Percent change from baseline in renal volume, measured in milliliters by MRI or CT scans
Time frame: Baseline, 12 months
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Octreotide | Percent Change in Renal Volume | 0.25 percent change | Standard Deviation 7.53 |
| Placebo | Percent Change in Renal Volume | 8.61 percent change | Standard Deviation 10.07 |
p-value: 0.045Rank sum