Simvastatin effects on portal hypertension in cirrhotic patients

PRIMARY OUTCOME

decrease in HVPG of at least 20% from baseline or to ≤12 mmHg

EXPECTED OUTCOMES

1. **Primary Endpoint:** 22-28% of simvastatin-treated patients will achieve ≥20% HVPG reduction or HVPG ≤12 mmHg at Week 12, compared to 6-10% in the placebo arm (absolute difference 15-19%, OR 3.2-4.1). 2. **HVPG Magnitude:** Among responders, mean HVPG reduction will be 28-34% (absolute reduction 4-6 mmHg from mean baseline of 16-18 mmHg). 3. **Hemodynamic Effects:** Simvastatin will reduce hepatic vascular resistance by 18-25% (assessed by Doppler ultrasound), with no significant change in cardiac output (+2 ± 8%). 4. **Biochemical Response:** LDL-cholesterol will decrease by 35-42% in the simvastatin arm (mean reduction 1.8-2.2 mmol/L), with no change in placebo arm. 5. **Inflammatory Markers:** hs-CRP will decrease by 30-40% and IL-6 by 25-35% in simvastatin-treated patients, reflecting anti-inflammatory effects independent of lipid-lowering. 6. **Safety Profile:** 8-12% of simvastatin patients will experience myalgias; 3-5% will have CK elevation >3× ULN; 1-2% will require dose reduction or discontinuation due to transaminase elevation >3× ULN. 7. **Endothelial Function:** von Willebrand factor will decrease by 20-28% and angiopoietin-2 by 25-35% in the active treatment arm, indicating improved endothelial homeostasis. ---

SUCCESS CRITERIA

- **Primary Outcome:** Statistically significant greater proportion of patients achieving ≥20% HVPG reduction or HVPG ≤12 mmHg in simvastatin vs placebo (p < 0.01, chi-square test; critical z-value 2.576 for 80% power, NNT 5-7). - **HVPG Secondary:** Mean HVPG reduction significantly greater in simvastatin arm (difference 2.5-4.0 mmHg, p < 0.001, t-test, effect size Cohen's d = 0.65-0.80). - **Safety Threshold:** No more than 2% of simvastatin-treated patients develop rhabdomyolysis (CK >40× ULN with myoglobinuria); transaminase elevations >5× ULN in <1% (stopping rule threshold). - **Child-Pugh Score:** No significant worsening of hepatic function; mean CP score change ≤1 point from baseline to Week 12 in both arms (non-inferiority margin Δ = 1.5 points, p < 0.05). - **MELD Score:** Simvastatin arm shows no increase in mean MELD score (Δ ≤1 point), confirming no hepatotoxic effect (95% CI upper bound <2 points). - **Cardiac Safety:** No increase in mean NT-proBNP >50% from baseline; no cases of decompensated heart failure attributable to study drug (p < 0.05 for non-inferiority). - **Quality of Life:** No significant deterioration in CLDQ (Chronic Liver Disease Questionnaire) total score (non-inferiority margin Δ = 0.5 points, p < 0.05).

PROTOCOL

**Study Title:** Randomized, Double-Blind, Placebo-Controlled Phase II/III Clinical Trial of Simvastatin for Reduction of Portal Hypertension in Cirrhotic Patients **Study Acronym:** SIMPORT (Simvastatin Portal Hypertension Trial) --- ### PHASE I: Screening & Baseline Assessment (Weeks -4 to 0) **Timepoints:** - Week -4: Initial screening visit - Week -2: Confirmatory assessments - Week 0: Randomization and baseline HVPG measurement **Screening Procedures:** 1. **Inclusion Criteria Verification:** - Age 18-75 years - Cirrhosis confirmed by liver biopsy (METAVIR stage F4) or clinical/radiological criteria - Portal hypertension documented by HVPG ≥12 mmHg at baseline - Child-Pugh score A or B (CP-A: 5-6 points; CP-B: 7-9 points) - MELD score ≤18 2. **Exclusion Criteria:** - Active variceal bleeding within 4 weeks - Severe pulmonary hypertension (mean PAP >40 mmHg) - Active infection or inflammatory disease - Creatinine clearance <50 mL/min - Prior statin intolerance or allergy - Current use of potent CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin) - Uncontrolled diabetes (HbA1c >9%) 3. **Baseline HVPG Measurement:** - Periprocedural care with fasting >6 hours - Right femoral vein access using Seldinger technique - Introduce 7F balloon-tipped catheter (Volcano, Rancho Cordova, CA) - Measure free hepatic vein pressure (FHVP) and wedged hepatic vein pressure (WHVP) - Calculate HVPG = WHVP - FHVP - Triplicate measurements with 60-second intervals - Acceptable reproducibility: coefficient of variation <10% 4. **Laboratory Assessments:** - Complete metabolic panel (CMP) - Complete blood count (CBC) - INR, PT, aPTT - Fasting lipid panel (total cholesterol, LDL-C, HDL-C, triglycerides) - hs-CRP, IL-6, TNF-α (inflammatory markers) - N-terminal pro-brain natriuretic peptide (NT-proBNP) - FibroScan with CAP (controlled attenuation parameter) --- ### PHASE II: Treatment Period (Weeks 0 to 12) **Treatment Arms:** - **Active Arm:** Simvastatin 40 mg oral daily (after initial 20 mg daily for Week 0-2) - **Placebo Arm:** Matching placebo capsule oral daily **Dosing Schedule:** - **Weeks 0-2:** 20 mg simvastatin or placebo daily (run-in period for tolerability) - **Weeks 3-12:** 40 mg simvastatin or placebo daily (target dose) **Concomitant Medications:** - Non-selective beta-blockers (propranolol or nadolol) permitted if on stable dose ≥4 weeks - Diuretics permitted for ascites management - Lactulose and rifaximin permitted for hepatic encephalopathy - PPI use acceptable **Safety Monitoring (Weeks 2, 4, 8, 12):** - Adverse event assessment - Physical examination (weight, blood pressure, heart rate) - CBC with differential - CMP including AST, ALT, bilirubin, creatinine kinase (CK) - Pregnancy test for women of childbearing potential --- ### PHASE III: Primary Efficacy Assessment (Week 12) **Timepoint:** End of treatment (Visit 5, Day 84 ± 3 days) **HVPG Measurement Protocol:** - Repeat HVPG measurement using identical technique as baseline - Same operator preferred when possible - Same catheter type and calibration - Measurement performed 24 hours after last dose - Primary endpoint: ≥20% decrease from baseline OR absolute HVPG ≤12 mmHg **Hemodynamic Assessment:** - Cardiac output measurement via echocardiography - Systemic vascular resistance calculation - Aortic pulse wave velocity (applanation tonometry) **Laboratory Biomarkers:** - Plasma simvastatin concentrations (pharmacokinetics) - Endothelial function markers: von Willebrand factor, angiopoietin-2 - Fibrosis markers: hyaluronic acid, TIMP-1, procollagen III - Lipid profile (fasting) --- ### PHASE IV: Extended Safety Follow-up (Weeks 13-24) **Purpose:** Monitor for delayed adverse events and assess durability of response **Assessments (Weeks 16 and 24):** - Physical examination - Laboratory panel (CBC, CMP, CK) - Lipid panel - Adverse event recording - Compliance pill count --- ### PHASE V: Optional Open-Label Extension (Weeks 25-52) **Eligibility:** Patients completing primary endpoint assessment who demonstrate clinical benefit **Protocol:** - All patients receive simvastatin 40 mg daily - Quarterly safety monitoring - HVPG measurement at Week 52 (optional) --- ### PHASE VI: Long-Term Outcome Tracking (Annual) **Post-Trial Monitoring:** - Incidence of variceal bleeding - Development of ascites requiring paracentesis - Hepatic encephalopathy episodes - Hepatocellular carcinoma development - Liver transplantation or death - Major adverse cardiovascular events (MACE) --- ### Reagent & Equipment Specifications | Item | Specification | Supplier | |------|--------------|----------| | Simvastatin | 20 mg, 40 mg tablets, USP grade | Generic manufacturer | | Placebo | Matching lactose capsules | In-house pharmacy | | HVPG catheter | 7F balloon-tipped, 110 cm | Volcano/Crux BioSystems | | Manometer | Water-filled, calibrated to 100 mmHg | Brewer Instrument | | Echocardiography | Standard transthoracic protocol | Philips CX50 | | FibroScan | CAP-enabled device | Echosens, Paris | | Statin assay | HPLC-MS/MS, LLOQ 0.5 ng/mL | In vitro diagnostics lab | --- ### Statistical Considerations **Sample Size Calculation:** - Expected treatment effect: 25% responder rate (HVPG reduction ≥20%) vs 8% placebo - Power: 80% - Alpha: 0.05 (two-sided) - Required n: 120 per arm (240 total) - Accounting for 15% dropout: 280 patients randomized **Analysis Sets:** - Intent-to-treat (ITT) population: all randomized - Per-protocol population: all compliant patients - Safety population: all receiving ≥1 dose ---

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