Simvastatin effects on portal hypertension in cirrhotic patients

Clinical Score: 0.950 Price: $0.50 cirrhotic portal hypertension human patients Status: proposed

What This Experiment Tests

Clinical experiment designed to assess clinical efficacy targeting N/A in human patients. Primary outcome: decrease in HVPG of at least 20% from baseline or to ≤12 mmHg

Description

A 3-month prospective, randomized, triple-blind, placebo-controlled trial evaluating the effects of simvastatin (40 mg/day) on hepatic venous pressure gradient (HVPG) and azygos vein blood flow in patients with cirrhotic portal hypertension. The study investigated whether simvastatin's pleiotropic effects could decrease intrahepatic resistance and portal hypertension. HVPG was measured directly and azygos blood flow was assessed using colour Doppler endoscopic ultrasound before and after 3 months of treatment. The trial aimed to determine if simvastatin could achieve clinically meaningful reductions in portal pressure, defined as a decrease in HVPG of at least 20% from baseline or to ≤12 mmHg. Results showed that 55% of patients in the simvastatin group achieved clinically relevant HVPG reduction compared to none in the placebo group. Patients with medium/large esophageal varices and previous variceal bleeding showed higher response rates to simvastatin treatment.

TARGET GENE

N/A

MODEL SYSTEM

human patients

ESTIMATED COST

TIMELINE

0 months

PATHWAY

HMG-CoA reductase pathway/statin pleiotropic effects

SOURCE

extracted_from_pmid_26321186

PRIMARY OUTCOME

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

Scoring Dimensions

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:

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

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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:

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

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%)

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%

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

Expected Outcomes

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).

HVPG Magnitude: Among responders, mean HVPG reduction will be 28-34% (absolute reduction 4-6 mmHg from mean baseline of 16-18 mmHg).

Hemodynamic Effects: Simvastatin will reduce hepatic vascular resistance by 18-25% (assessed by Doppler ultrasound), with no significant change in cardiac output (+2 ± 8%).

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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).

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