A Study Evaluating the Efficacy and Safety of Pregabalin Against Frequent Muscle Cramp in Patients With Liver Cirrhosis

Study Overview
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Brief Summary
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Muscle cramp is defined as a paroxysmal, involuntary, and painful contraction of skeletal muscle. Cirrhotic patients can encounter with muscle cramp frequently, which might be associated with poor quality of life. Gabapentin can be prescribed for muscle cramp. However, patients with liver cirrhosis have limited access to gabapentin which is metabolized primarily in liver. Pregabalin with a similar mechanism of action to gabapentin undergoes negligible metabolism owing to its improved pharmacokinetic properties. Thus, pregabalin might be a promising therapeutic option for patients with liver cirrhosis who are suffering from muscle cramp and susceptible to drug-induced hepatotoxicity. Therefore, the investigators hypothesize that pregabalin could effectively reduce painful symptoms derived from muscle cramp. In the current study, the investigators are going to evaluate the efficacy and safety of pregabalin by comparing outcomes between two groups (treatment group vs. placebo group).

Detailed Description
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The investigators are planning to recruit patients with liver cirrhosis and muscle cramp, and collect the baseline clinical and laboratory data during the 4-week run-in period for each subject. After a run-in period, there will be the second step of patient selection to achieve a more homogenous study population. Then, patients will be randomly allocated into the treatment (pregabalin) and placebo (dummy) arms, by a web-based randomization program. After a treatment period (75 mg twice daily during the first 1 week as titration, 150 mg twice daily for 4 weeks as standard dose), the investigators will gather further study information of a standard dose period (150mg twice daily for 4 weeks) from the target population and the study subjects will enter the 1-week tapering period (75mg twice a day) to discontinuation. The primary outcome will be the difference in the frequency of muscle cramps between the run-in and treatment phases. The investigators also intend to assess the response rate, defined as the proportion (%) of patients showing ≥50% reduction in the number of muscle cramps, mean change in the average pain intensity, mean change in the score of the Short Form 36 (SF-36, QualityMetric) health survey questionnaire, mean change in the frequency of muscle cramps during sleep, and mean change in the average cramp threshold frequency by the neurophysiologic study (nerve excitability test) and analyze the reasons for drop-out cases.

Official Title
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A Randomized, Double-blinded, Placebo-controlled Study Evaluating the Efficacy and Safety of 6-week Treatment of Pregabalin Against Frequent Muscle Cramp in Patients With Liver Cirrhosis

Conditions
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Muscle Cramp, Liver Cirrhosis

Intervention / Treatment
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* Drug: Pregabalin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: (should follow all conditions described below) Etiology : Liver cirrhosis patients of any etiology, whether viral or non-viral Occurrence of muscle cramp equal to or more than 2 times a week over the last month Exclusion Criteria: Preexisting disease : Occlusive vascular disease, thyroid disease, peripheral neuropathy Drugs within 2 months : Digitalis, cimetidine, clofibrate, lithium, opiate, nifedipine, beta-agonist, beta-blocker, penicillamine, gabapentin, pregabalin, tricyclic anti-depressant, carbamazepine, phenytoin, quinidine, antispastic drugs, verapamil, vitamin E, branched chain amino acid, excessive alcohol consumption (male >40 g/day, female >20 g/day) Underlying disease : Renal impairment (Ccr < 60 mL/min), neuromuscular disease (stroke, cerebral palsy, multiple sclerosis, Parkinson disease, progressive muscular dystrophy, epilepsy), suicidal attack, drug allergy, pregnancy, heart failure Liver status : Serious complications resulting from decompensated cirrhosis except ascites, such as portosystemic encephalopathy, acute variceal bleeding within the past 3 months from study entry central nervous system (CNS) or peripheral nervous system (PNS) or muscular disease, stroke, cerebral palsy, multiple sclerosis, Parkinson disease, progressive muscular dystrophy, epilepsy The previous episode of suicidal attack Drug hypersensitivity Subjects receiving antiepileptic drugs Patients manipulating machines or driving cars Pregnant women Subjects with congestive heart failure requiring medications Galactose-Lactose metabolic abnormality Refractory ascites to medical treatment

Ages Eligible for Study
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Maximum Age: 75 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Pregabalin<br>30 randomly allocated patients after a 4-week run-in period, who will take part in a 6-week treatment period with pregabalin. Treatment period : 75 mg twice daily during the first 1 week as titration + 150mg twice daily for 4 weeks as standard dose period + 75mg twice a day for a week as tapering period. | Drug: Pregabalin<br>* drug form : capsule, 75/150mg. Pregabalin will be provided to treatment arm subjects for 6-week Treatment period. Treatment period : 75 mg twice daily during the first 1 week as titration + 150mg twice daily for 4 weeks as maintenance + 75mg twice a day as tapering<br>* Other names: Brand name of drug : Lyrica;|
| Placebo Comparator: Placebo<br>30 randomly allocated patients after a 4-week run-in period, who will take part in a 6-week treatment period with placebo. Treatment period : 75 mg twice daily during the first 1 week as titration + 150mg twice daily for 4 weeks as standard dose period + 75mg twice a day for a week as tapering period. | Drug: Placebo<br>* drug form : capsule, 75/150mg. Pregabalin will be provided to treatment arm subjects for 6-week Treatment period. Treatment period : 75 mg twice daily during the first 1 week as titration + 150mg twice daily for 4 weeks as maintenance + 75mg twice a day as tapering<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in the frequency of muscle cramps between run-in and treatment phases (/week) | The frequency is defined as muscle cramps per week. | after 4 weeks of standard dose treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rates , Mean change in the average cramp pain intensity , peripheral nerve excitability , the quality of life, quality of sleep , safety | Response rates : the proportion (%) of patients showing ≥50% reduction in the number of muscle cramps. Mean change in the average cramp pain intensity : a sum of the pain rating scale divided by a total number of muscle cramps. Peripheral nerve excitability as measured by nerve stimulation test. The quality of life as measured by mean change in the score of the SF-36. Quality of sleep as measured by mean change in the number of muscle cramps during sleep. Safety as measured by dose-reduction or discontinuation rates, treatment-emergent adverse events, and vital signs. | after 4 weeks of standard dose treatment period or over a 6-week treatment period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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muscle cramp, liver cirrhosis, pregabalin