Autosomal Dominant Polycystic Kidney Disease, Autosomal Dominant Polycystic Liver Disease, Polycystic Liver Disease, Somatostatin Analogs
Conditions
Keywords
Polycystic Liver Disease, Autosomal dominant polycystic kidney disease, Autosomal dominant polycystic liver disease, Somatostatin analogs, Pasireotide LAR, SOM230
Brief summary
The purpose of this study is to compare SOM230 treatment to placebo. The investigators will also assess the efficacy and safety of SOM230 in reducing total liver volume and improving quality of life.
Detailed description
Pasireotide (SOM230) is a novel multi-receptor-targeted analog that has high affinity for four of the five SST receptor subtypes (SSTr1, SSTr2, SSTr3 and SSTr5); it has a 40-fold higher affinity and 158-fold higher functional activity for the SST5 receptor than octreotide. Because of its broad receptor binding profile, pasireotide may be more potent in Polycystic Liver Disease (PLD) than octreotide. In this randomized double blind placebo controlled trial the investigators will compare SOM230 treatment to placebo for 12 months in patients with PLD. The primary endpoints will be assessed at 12 months and patients receiving placebo then crossed over to SOM230, permitting all participants to receive SOM230 for the subsequent two years. Magnetic resonance imaging (MRI) will be used to assess liver volume - the primary endpoint, which will be assessed at baseline, end of years 1 and 3. This study will assess the efficacy and safety of SOM230 in reducing total liver volume and improving quality of life over 12 months. (The investigators will not be assessing efficacy at 24 months.) The therapy way be effective in PLD but also may prove to be effective for many more patients with Polycystic Kidney Disease (PKD) which will be evaluated using eGFR and kidney volume using MRI. The investigators plan to add other sub-sites in other locations.
Interventions
DRUGPasireotide LAR
Injectible, 60mg per month
DRUGPlacebo
To be injected once per month
Sponsors
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* Male or female Age ≥ 18 years. * Diagnosis of PLD associated with ADPKD (meeting the Modified Ravine's criteria) or isolated ADPLD (defined by the criteria described by Reynolds et al) * Severe PLD defined as a liver volume \>4000mL or symptomatic disease due to mass effects from hepatic cysts (must be able to undergo MRI or CT scan to determine this). * Not a candidate for or declining surgical intervention. * Capable of providing informed consent. * Life expectancy ≥ 12 weeks * Patients with a known history of impaired fasting blood glucose (glucose \>100 and \<126) may be included at the discretion of the PI. These patients should be monitored closely throughout the trial and antihyperglycemic treatment adjusted as necessary. Patients that are deemed non eligible due to elevated glucose can be re-screened after adequate medical treatment. * Adequate end organ function as defined by: * Adequate bone marrow function: * WBC ≥ 2.5 x 109/L * Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L * Platelets ≥ 100 x 109/L * Hb ≥ 9 g/dL * No evidence of significant liver disease: * Serum bilirubin ≤1.5 x ULN * INR \< 1.3 * ALT and AST ≤ 2 x ULN * Estimated glomerular filtration rate (eGFR) \>30 ml/min/m2 * Serum amylase and lipase ≤ 1.5 x ULN * Alkaline phosphatase ≤ 2.5 x ULN * Written informed consent obtained prior to any screening procedures * Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other study procedures
Exclusion criteria
* Patients will be considered ineligible for this study if they meet any of the following criteria: * Patients with a known hypersensitivity to SST analogs or any component of the pasireotide LAR or SQ formulations. * Patients with known malabsorption syndrome, short bowel or chologenic diarrhea not controlled by specific therapeutic means. * Patients with abnormal coagulation (PT or a PTT elevated by 30% above normal limits). * Patients on continuous anticoagulation therapy. Patients who were on anticoagulant therapy must complete a washout period of at least 10 days and have confirmed normal coagulation parameters before study inclusion. * Patients with symptomatic cholelithiasis. * Patients who are not biochemically euthyroid. * Patients with known history of hypothyroidism are eligible if they are on adequate and stable re-placement thyroid hormone therapy for at least 3 months. * Serum magnesium ≥ ULN * QT-related
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Liver Volume | baseline , 12 month | Percent change was calculated for liver volumes using the equation=\[(12 month value-baseline value)/baseline value\]\*100\*12/12 month |
| Change in Kidney Volume | baseline to 12 months | Percent change was calculated for kidney volumes using the equation=\[(12 month value-baseline value)/baseline value\]\*100\*12/12 month |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Blood Glucose | Baseline, 12 months | Blood glucose (mg/dLb) level at baseline and 12 months was used to calculate the percentage change by \[12 month value-baseline value)/baseline value\]\*100 |
| Percentage Change in Hemoglobin A1C | Baseline, 12 months | Hemoglobin A1C level at baseline and 12 months was used to calculate the percentage change by \[12 month value-baseline value)/baseline value\]\*100 |
| Percentage Change in Estimated Glomerular Filtration Rate (eGFR) | Baseline, 12 months | eGFR was measured using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. This value at baseline and 12 months was used to calculate the percentage change by \[12 month value-baseline value)/baseline value\]\*100 |
| Change in Quality of Life | Baseline, 12 months | Measured using the SF-36 health survey, which consist of eight subscales each scored on a range of 0 to 100 (0=worst imaginable, 100=best imaginable). Change calculated from baseline = 12 month value-baseline value |
| Percentage Change in Heart Rate | Baseline, 12 months | Heart rate, measured in beats per minute (BPM), at baseline and 12 months was used to calculate the percentage change by \[12 month value-baseline value)/baseline value\]\*100 |
| Percentage Change in Serum Creatinine | Baseline, 12 months | Serum creatinine level at baseline and 12 months was used to calculate the percentage change by \[12 month value-baseline value)/baseline value\]\*100 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pasireotide LAR (SOM230) Active Pasireotide LAR
Pasireotide LAR: Injectible, 60mg per month | 33 |
| Placebo Injection Placebo: To be injected once per month | 15 |
| Total | 48 |
Baseline characteristics
| Characteristic | Placebo Injection | Pasireotide LAR (SOM230) | Total |
|---|---|---|---|
| Age, Continuous | 51.40 years STANDARD_DEVIATION 7.97 | 50.16 years STANDARD_DEVIATION 8.63 | 50.55 years STANDARD_DEVIATION 8.37 |
| Race/Ethnicity, Customized African American | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 3 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 15 Participants | 29 Participants | 44 Participants |
| Region of Enrollment United States | 15 participants | 33 participants | 48 participants |
| Sex: Female, Male Female | 12 Participants | 31 Participants | 43 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 33 | 1 / 15 |
| other Total, other adverse events | 33 / 33 | 15 / 15 |
| serious Total, serious adverse events | 4 / 33 | 1 / 15 |
Outcome results
Primary
Change in Kidney Volume
Percent change was calculated for kidney volumes using the equation=\[(12 month value-baseline value)/baseline value\]\*100\*12/12 month
Time frame: baseline to 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pasireotide LAR (SOM230) | Change in Kidney Volume | -1.37 percentage of change | Standard Deviation 3.52 |
| Placebo Injection | Change in Kidney Volume | 3.85 percentage of change | Standard Deviation 4.49 |
p-value: 0.003ANCOVA
Primary
Change in Liver Volume
Percent change was calculated for liver volumes using the equation=\[(12 month value-baseline value)/baseline value\]\*100\*12/12 month
Time frame: baseline , 12 month
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pasireotide LAR (SOM230) | Change in Liver Volume | -3.36 percentage of change | Standard Deviation 7.33 |
| Placebo Injection | Change in Liver Volume | 6.29 percentage of change | Standard Deviation 6.97 |
p-value: 0.001ANCOVA
Secondary
Change in Quality of Life
Measured using the SF-36 health survey, which consist of eight subscales each scored on a range of 0 to 100 (0=worst imaginable, 100=best imaginable). Change calculated from baseline = 12 month value-baseline value
Time frame: Baseline, 12 months
Population: Data for 19 participants in the pasireotide LAR (SOM230) group and 9 participants from the placebo injection group was available for analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pasireotide LAR (SOM230) | Change in Quality of Life | Physical functioning | 4.7 units on a scale | Standard Deviation 16 |
| Pasireotide LAR (SOM230) | Change in Quality of Life | Physical role | 7.9 units on a scale | Standard Deviation 36 |
| Pasireotide LAR (SOM230) | Change in Quality of Life | Bodily pain | 5.5 units on a scale | Standard Deviation 22 |
| Pasireotide LAR (SOM230) | Change in Quality of Life | General health | -6.2 units on a scale | Standard Deviation 14 |
| Pasireotide LAR (SOM230) | Change in Quality of Life | Vitality | 4.5 units on a scale | Standard Deviation 14 |
| Pasireotide LAR (SOM230) | Change in Quality of Life | Social functioning | 0.0 units on a scale | Standard Deviation 18 |
| Pasireotide LAR (SOM230) | Change in Quality of Life | Role emotional | 0.0 units on a scale | Standard Deviation 22 |
| Pasireotide LAR (SOM230) | Change in Quality of Life | Mental health | 1.5 units on a scale | Standard Deviation 12 |
| Placebo Injection | Change in Quality of Life | Mental health | -1.8 units on a scale | Standard Deviation 11 |
| Placebo Injection | Change in Quality of Life | Physical functioning | -1 units on a scale | Standard Deviation 8 |
| Placebo Injection | Change in Quality of Life | Vitality | -2 units on a scale | Standard Deviation 17 |
| Placebo Injection | Change in Quality of Life | Physical role | -3 units on a scale | Standard Deviation 38 |
| Placebo Injection | Change in Quality of Life | Role emotional | 11 units on a scale | Standard Deviation 5 |
| Placebo Injection | Change in Quality of Life | Bodily pain | 7 units on a scale | Standard Deviation 12 |
| Placebo Injection | Change in Quality of Life | Social functioning | -3 units on a scale | Standard Deviation 8 |
| Placebo Injection | Change in Quality of Life | General health | 2 units on a scale | Standard Deviation 15 |
Comparison: Physical functioningp-value: 0.31t-test, 2 sided
Comparison: Physical rolep-value: 0.48t-test, 2 sided
Comparison: Bodily painp-value: 0.89t-test, 2 sided
Comparison: General healthp-value: 0.18t-test, 2 sided
Comparison: Vitalityp-value: 0.28t-test, 2 sided
Comparison: Social functioningp-value: 0.66t-test, 2 sided
Comparison: Role emotionalp-value: 0.43t-test, 2 sided
Comparison: Mental healthp-value: 0.51t-test, 2 sided
Secondary
Percentage Change in Estimated Glomerular Filtration Rate (eGFR)
eGFR was measured using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. This value at baseline and 12 months was used to calculate the percentage change by \[12 month value-baseline value)/baseline value\]\*100
Time frame: Baseline, 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pasireotide LAR (SOM230) | Percentage Change in Estimated Glomerular Filtration Rate (eGFR) | -0.3 percentage of change | Standard Deviation 14 |
| Placebo Injection | Percentage Change in Estimated Glomerular Filtration Rate (eGFR) | -2.2 percentage of change | Standard Deviation 17.7 |
p-value: 0.79t-test, 2 sided
Secondary
Percentage Change in Heart Rate
Heart rate, measured in beats per minute (BPM), at baseline and 12 months was used to calculate the percentage change by \[12 month value-baseline value)/baseline value\]\*100
Time frame: Baseline, 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pasireotide LAR (SOM230) | Percentage Change in Heart Rate | -0.15 percentage of change | Standard Deviation 0.2 |
| Placebo Injection | Percentage Change in Heart Rate | -0.1 percentage of change | Standard Deviation 0.1 |
p-value: 0.73t-test, 2 sided
Secondary
Percentage Change in Hemoglobin A1C
Hemoglobin A1C level at baseline and 12 months was used to calculate the percentage change by \[12 month value-baseline value)/baseline value\]\*100
Time frame: Baseline, 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pasireotide LAR (SOM230) | Percentage Change in Hemoglobin A1C | 18 percentage of change | Standard Deviation 11 |
| Placebo Injection | Percentage Change in Hemoglobin A1C | 1.6 percentage of change | Standard Deviation 3.3 |
p-value: 0.001t-test, 2 sided
Secondary
Percentage Change in Serum Creatinine
Serum creatinine level at baseline and 12 months was used to calculate the percentage change by \[12 month value-baseline value)/baseline value\]\*100
Time frame: Baseline, 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pasireotide LAR (SOM230) | Percentage Change in Serum Creatinine | 1.8 percentage of change | Standard Deviation 12 |
| Placebo Injection | Percentage Change in Serum Creatinine | 3.4 percentage of change | Standard Deviation 15.6 |
p-value: 0.79t-test, 2 sided
Secondary
Percent Change in Blood Glucose
Blood glucose (mg/dLb) level at baseline and 12 months was used to calculate the percentage change by \[12 month value-baseline value)/baseline value\]\*100
Time frame: Baseline, 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pasireotide LAR (SOM230) | Percent Change in Blood Glucose | 39 percentage of change | Standard Deviation 30 |
| Placebo Injection | Percent Change in Blood Glucose | 2.2 percentage of change | Standard Deviation 15.2 |
p-value: 0.001t-test, 2 sided