Patient case: 54-year-old male with malignant hyperthermia; genetic feature: RYR1

Clinical trial: Pasireotide LAR in Severe Polycystic Liver Disease

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.

Eligibility: 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 exclusion criteria:
  -  QTcF at screening > 470 msec
  -  Patients with a history of syncope or family history of idiopathic sudden death
  -  Patients who have sustained or clinically significant cardiac arrhythmias
  -  Risk factors for Torsades de Pointes such as hypokalemia, hypomagnesemia, cardiac failure, clinically significant/symptomatic bradycardia, or high-grade AV block
  -  Patients with concomitant disease(s) that could prolong QT such as autonomic neuropathy (caused by diabetes, or Parkinson's disease), HIV, cirrhosis, uncontrolled hypothyroidism or cardiac failure
  -  Family history of long QT syndrome
  -  Concomitant medications known to prolong the QT interval.
  -  Potassium < or = to 3.5
  -  Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:
  -  Patients who have Uncontrolled diabetes as defined by HbA1c>8%* despite adequate therapy
  -  Patients with the presence of active or suspected acute or chronic uncontrolled infection or with a history of immunodeficiency, including a positive HIV test result (ELISA and Western blot). An HIV test will not be required; however, previous medical history will be reviewed.
  -  Non-malignant medical illnesses that are uncontrolled or whose control may be jeopardized by the treatment with this study treatment.
  -  Liver disease such as cirrhosis, decompensated liver disease, chronic active hepatitis or chronic persistent hepatitis.
  -  Baseline ALT or AST >3x ULN
  -  Patients with life-threatening autoimmune and ischemic disorders.
  -  Uncontrolled hypertension
  -  Patients who have a history of a primary malignancy, with the exception of locally excised non-melanoma skin cancer and carcinoma in situ of uterine cervix. (Patients who have had no evidence of disease from primary cancer for 3 or more years are allowed to participate in the study.)
  -  History of pancreatitis
  -  Patients with a known history of hepatitis B or C
  -  Presence of Hepatitis B surface antigen (HbsAg)
  -  Presence of Hepatitis C antibody (anti-HCV)
  -  Patients with a history of, or current, alcohol misuse/abuse within the past 12 months
  -  Known gallbladder or bile duct disease, acute or chronic pancreatitis
  -  Patients who have any current or prior medical condition that may interfere with the conduct of the study or the evaluation of its results in the opinion of the Investigator or the Sponsor's Medical Monitor
  -  Use of an investigational drug within 1 month prior to dosing
  -  Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will not be able to complete the entire study

Relevance to patient case: not relevant