Study of the Safety and Tolerability Associated With PPD10558 Versus Atorvastatin in Patients Previously Intolerant to Statins Due to Statin-associated Myalgia (SAM)

Study Overview
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Brief Summary
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The purpose of this study is to assess the incidence of statin-associated myalgia (SAM) with treatment with PPD10558 versus atorvastatin in patients previously intolerant to statins. To assess the safety and tolerability of PPD10558 compared to atorvastatin in patients previously intolerant to statins.

Official Title
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A Double-blind, Randomized, Placebo-controlled and Active-comparator-controlled Phase 2b Study to Evaluate Statin-associated Myalgia Incidence, Lipid Profile Effect, and Safety and Tolerability Associated With PPD10558 Versus Atorvastatin in Patients With Primary Hypercholesterolemia, Fredrickson IIa or IIb, Who Have Discontinued Two or More Prior Statin Therapies Due to Statin-associated Myalgia

Conditions
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Myalgia, Hypercholesterolemia, Hyperlipidemia

Intervention / Treatment
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* Drug: PPD10558
* Drug: Atorvastatin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: diagnosis of primary hypercholesterolemia (heterozygous familial and nonfamilial) Fredrickson types IIa or IIb. history of statin-associated myalgia, as defined by being unable to tolerate two previous statins due to muscle pain, aches, weakness, or cramping that begins or increases during statin therapy and stops when statin therapy is discontinued. History of statin-associated myalgia will be captured on the historical questionnaire on statin-associated myalgia. LDL-C > 110 mg/dL and triglycerides < 500 mg/dL at Prescreening. prescreening hemoglobin value of ≥10 g/dL for females and ≥12 g/dL. patient agrees to stop all other antihyperlipidemic agents (including but not limited to niacin, probucol, ezetimibe, fibrates and derivatives, bile acid-sequestering agents, other 3-hydroxy-3-methylglutaryl-coenzyme A(HMG-CoA) reductase inhibitors, fish oils, flaxseed oil, and red yeast rice). patient agrees to stop all Coenzyme Q10 supplements. if taking other nonexcluded medications, patients must be on a stable dose for 4 weeks before screening. Exclusion Criteria: history of chronic pain and currently experiences chronic pain unrelated to statins that requires chronic use of pain medications, has been diagnosed with fibromyalgia or has severe neuropathic pain. requires the chronic use of pain medications, including acetaminophen, non-steroidal anti-inflammatory medications, narcotics, and other analgesics. vitamin D insufficiency (current insufficiency is defined as Vitamin D3 < 20 ng/mL [50 nmol/L] measured at Prescreening. hypothyroidism or abnormal thyroid function test as confirmed by thyroid-stimulating hormone ≥ 5 mcIU/mL and free thyroxine (T4) < 0.7 ng/dL at Prescreening history of rhabdomyolysis (defined as evidence of organ damage with creatinine kinase(CK) > 10,000 IU/L). history of liver disease history of significant renal dysfunction as defined by serum creatinine clearance < 30 mL/min Nephrotic-range proteinuria. HbA1C >9% at Prescreening. CK levels >5 times the upper limit of normal at Prescreening. congestive heart failure, even with current therapy has had myocardial infarction, cardiac intervention, cerebrovascular accident/stroke or transient ischemic attack less than 6 months prior to prescreening. patient is pregnant (confirmed by laboratory testing) or breastfeeding. history of cancer (other than basal cell and/or squamous cell carcinoma of the skin and/or Stage I squamous cell carcinoma of the cervix) that has not been in full remission for at least 1 year before Screening. patient has positive test results for hepatitis B surface antigen (HBsAg), hepatitis C antibody, or human immunodeficiency virus types 1 or 2 at Prescreening.

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PPD10558<br>Dosing will be forced-titrated as follows: 40 mg orally twice daily for 4 weeks and 80 mg orally twice daily for 8 weeks | Drug: PPD10558<br>* PPD10558 40 mg capsule and matching placebo capsule twice a day for 4 weeks, then PPD10558 80 mg (two 40 mg capsules) twice a day for 8 weeks<br>|
| Active Comparator: Atorvastatin<br>Dosing will be forced titrated as 40 mg orally once daily for 4 weeks, and 80 mg orally once daily for 8 weeks | Drug: Atorvastatin<br>* Atorvastatin 40 mg capsule and matching placebo capsule in the morning and 2 placebo capsules in the evening for 4 weeks, then Atorvastatin 80 mg (two 40 mg capsules) in the morning and 2 placebo capsules in the evening for 8 weeks<br>|
| Placebo Comparator: Placebo<br>Dosing will be 2 placebo capsules twice daily for 12 weeks | Drug: Placebo<br>* 2 placebo capsules twice daily for 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of stopping treatment with double-blinded study drug due to statin-associated myalgia. | Patients who withdraw from participating in the study prior to Week 12 and who also stop study drug due to SAM, or patients who become lost to follow up will be considered to have stopped treatment with double-blinded study drug. | Up to week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in fasting lipid profile components (low density lipoprotein-cholesterol(LDL-C), high density lipoprotein-cholesterol(HDL-C), triglyceride(TG), total cholesterol(TC), Apolipoprotein B(ApoB), HDL-TG, LDL/HDL ratio and TC/HDL ratio) |  | Up to week 12 | 
| Change from baseline in muscle strength measurements (Sit-to-stand(STS) performance and hand grip strength by Jamar Hydraulic Hand Dynamometer) |  | Up to week 12 | 
| Frequency of pain rescue medication |  | Up to week 12 | 
| Change from Baseline in inflammatory markers (Tumor necrosis factor α (TNF-α), C-reactive protein (CRP), and lipoprotein-associated phospholipase A2 (Lp-PLA2)) |  | Up to week 12 | 
| Change in patients' functional health and well-being as measured by the Short Form-36v2 Health Survey (SF-36) |  | Up to week 12 | 
| Time to onset of statin -associated myalgia (SAM) |  | Up to week 12 | 
| Time to stopping treatment with study drug due to SAM |  | Up to week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hyperlipidemia, Dyslipidemia, Metabolic diseases, Lipid metabolism disorders, Hyperlipoproteinemia Type IIa, Hyperlipoproteinemia Type IIb, Hypercholesterolemia, Autosomal Dominant, Hypercholesterolemia, Autosomal Dominant, Type B, Frederickson Type IIa, Frederickson Type IIb Hyperlipidemia