Clinical trial NCT03176966
Conditions: Muscle Cramp Cirrhosis
Sponsor: Vanderbilt University Medical Center
Start date: 2016-09-02; Completion date: 2021-10-22
Enrollment: 31 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The investigator's aim is to compare the efficacy of Ropinirole (Requip) to vitamin E in the treatment of muscle cramps in cirrhotic patients.

Detailed description:
Muscle cramps are common in liver disease, especially in patients with cirrhosis. Despite the association of muscle cramps with liver disease, there is a paucity of information regarding treatment in these patients. Many treatment options have been reported in the literature but no standard of treatment has been established.

Oral vitamin E replacement has been used successfully in the management of nocturnal muscle cramps in cirrhotic patients. Ropinirole is primarily used for treatment of restless leg syndrome. An off label trial of low dose Ropinirole in clinical practice has shown some success in providing relief of muscle cramps in patients with cirrhosis. This study will compare Ropinirole to vitamin E treatment in a prospective cross-over study.

Arms: arm 1: Patients will be provided with vitamin E, 400 international units (IU), at baseline. Patient demographics will be collected along with baseline lab data including magnesium, potassium, albumin, and total bilirubin levels. After 3 months, patients will be switched to Ropinirole. Surveys measuring muscle cramp frequency and intensity will be collected at baseline, 3 months, and 6 months. arm 2: Patients will be prescribed ropinirole at baseline. Patient demographics will be collected along with baseline lab data including magnesium, potassium, albumin, and total bilirubin levels. After 3 months, patients will be switched to vitamin E, 400 international units (IU). Surveys measuring muscle cramp frequency and intensity will be collected at baseline, 3 months, and 6 months.
Interventions: intervention 1: Vitamin E intervention 2: Ropinirole intervention 3: Muscle cramp survey
Intervention descriptions: intervention 1: Patients will take 400 IU vitamin E nightly for 3 months. intervention 2: Patients will take 0.5mg ropinirole nightly for 3 months. intervention 3: Patients will complete a survey of muscle cramp frequency and severity at baseline, 3 months, and 6 months.

Protocol documents:
Prot_SAP_000.pdf: 
 
Ropinirole for the treatment of muscle cramps in patients with cirrhosis 
NCT 03176966 
August 11, 2016 
 


Principal Investigator:  Michael Porayko, MD 
Study Title: Ropinirole for the treatment of muscle cramps in patients with cirrhosis 
Institution/Hospital: Vanderbilt University Medical Center 
 
Research Protocol  
I. Aims  
The purpose of the study is to evaluate the efficacy of Ropinirole in treatment of muscle cramps 
in patients with cirrhosis. 
II. Background and Rationale 
Muscle cramps are common in liver disease, especially in patients with cirrhosis. The prevalence 
of muscle cramps among patients with chronic liver disease is estimated to be 22-88%. Patients 
with cirrhosis who experience muscle cramps report that they are extremely painful and they 
often occur at rest and frequently during sleep. The severity of muscle cramps in some patients 
has resulted in presentation to an acute care facility for pain relief with short acting opioids. 
Muscle cramps impact many areas of life including sleep, physical functioning and mobility, 
general health, mental health, energy levels and social isolation. Despite the association of 
muscle cramps with liver disease, there is a paucity of information regarding treatment in these 
patients. Many treatment options have been reported in the literature but no standard of 
treatment has been established. Different options include Zinc, 1-alpha-hydroxy Vitamin D, 
Vitamin E, branched chain amino acids, taurine, L-carnitine, eperisone hydrochloride, 
intravenous albumin and quinidine. Oral vitamin E replacement has been used successfully in the 
management of nocturnal muscle cramps in cirrhotic patients. In a group of 23 cirrhotic patients 
(16 and 7 Child’s-Pugh category A and B respectively), oral vitamin E (tocopherol acetate) 200 mg 
t.i.d. significantly improved the frequency, duration and pain associated with nocturnal cramping 
without untoward effects. Quinine and quinidine have also been used with success in the 
treatment of cirrhosis-associated muscle cramps, but their potential for cardiac and 
gastrointestinal toxicity make them less desirable therapeutic choices. Similarly, another study 
comparing the effect of 325 mg of quinine versus vitamin E 400 IU at bedtime found reduction in 
frequency of leg cramps to 3.6 and 3.3% respectively (95% confidence interval, -3.8, +3.2), 
suggesting similar efficacy. Considering the potential toxicity of quinine, vitamin E is 
recommended as the initial treatment of choice for patients on dialysis with leg cramps. Our aim 
is to compare the efficacy of Ropinirole, to Vitamine E in the treatment of these cramps in 
cirrhotic patients. Ropinirole is primarily used for treatment of restless leg syndrome. However, 
off label trial of low-dose Ropinirole in clinical practice has shown some success in providing relief 
of muscle cramps in patients with cirrhosis.  


 
. Procedures  
A. Research Design: Prospective Randomized cross-over design 
B. Sample 
a. Number of subjects: 60; 30 in Group A; 30 in Group B 
b. Inclusion criteria: Patients age >/= 18 years of age with diagnosis of cirrhosis who self-
report regular muscle cramping. 
c. Exclusion criteria: patients without cirrhosis, patients under age 18, pregnant women 
C. Study procedures 
a. Patients will be recruited from a panel of patients at Vanderbilt University Medical Center 
Hepatology clinics. Patients meeting inclusion criteria will be randomized to two groups; 
group A (Vitamin E 400 I.U) or group B (Ropinirole). Patients will remain in their 
prospective groups until 3 months at which time they will be switched to the other group.  
Total study duration will be six months.  Patient demographics to be collected include 
patient age, gender, height, weight, BMI, race/ethnicity, etiology of cirrhosis. Baseline lab 
data to be collected include Magnesium, Potassium, Albumin, and total bilirubin. Child-
Turcotte-Pugh class will be calculated using the five measures of severity of chronic liver 
disease (Total bilirubin, INR, albumin, presence of ascites or hepatic encephalopathy). 
Baseline data regarding diuretic usage including Furosemide, Spironolactone, Bumex, 
Metolazone, Inspra will be obtained. A survey (attached) will be given to each group of 
patients in the beginning of the study period and 3 and 6 months after study initiation. 
b. Participants will be given a prescription for Ropinirole.  Vitamin E will be provided by the 
GI clinical research office at no cost to the patients. 
c. Adverse event reporting: Serious adverse events will be reported to the VU IRB per VU 
IRB policy.  All adverse events will be captured and reported to the VU IRB at the time of 
continuing renewal or upon study closure, whichever occurs first.  
d. Withdrawal procedures: If a patient suffers an adverse event, which in the judgment of 
the investigator is an unacceptable consequence or risk to the patient, the patient can be 
withdrawn from the study. Patients may withdraw from the study at any time for any 
reason, and without prejudice to further treatment. A patient can withdraw their consent 
to participate in the study at their own request or be withdrawn from participation in the 
study at the request of their legally authorized representative at any time for any reason. 
e. Privacy and confidentiality issues: Consent will be obtained by the study personnel in a 
private location within the TVC.   No PHI will be collected prior to obtaining informed 


consent. The PI and his research staff will have access to this information.  Consent forms 
will be maintained in a locked cabinet in the GI clinical research office.  PHI will be 
collected during the course of this research study from the medical records of consented 
individuals. Initially, an inclusion log will be created and maintained by the study staff.  
This log will contain subject initials, medical record numbers, assigned study number and 
date of inclusion.  The only person who will have access to this inclusion log is the PI and 
study coordinator.  The data collected will be entered into a REDCap database (attached) 
and will not include any information that could link the data to a specific individual. This 
database will be maintained by the research staff and raw data as well as results will be 
held by the GI Clinical Research Office indefinitely.  The PI, other key study staff and 
statistician will have access to the REDCap database. 
f. Follow up: patients will have follow up at 3 and 6 months after initiation of the study 
followed by their regularly scheduled appointments after completion of the study. 
 
D. Data Analysis: paired t-test will be used for data analysis. Preparation of data listings, tables, and 
overall statistical support for generation of the data will be managed independently by a 
statistician who will remain isolated from the clinical personnel involved in the study operations. 
 
IV. Bibliography  
1. Angeli, P. 'Cirrhosis And Muscle Cramps: Evidence Of A Causal Relationship'. Hepatology 23.2 
(1996): 264-273.  
2. Corbani, A. et al. 'Muscle Cramps In Cirrhosis'. Digestive and Liver Disease 40.9 (2008): 794-799.  
3. Mehta, Shivang Sarvottam, and Michael B. Fallon. 'Muscle Cramps In Cirrhosis: A Moving Target'. 
Clinical Gastroenterology and Hepatology 13.8 (2015): 1544-1546.  
4. Mehta, Shivang S., and Michael B. Fallon. 'Muscle Cramps In Liver Disease'. Clinical 
Gastroenterology and Hepatology 11.11 (2013): 1385-1391. 
5. Vidot, H. et al. 'Systematic Review: The Treatment Of Muscle Cramps In Patients With Cirrhosis'. 
Alimentary Pharmacology & Therapeutics 40.3 (2014): 221-232.  
6. Konikoff F, Ben-Amitay G, Halpern Z, Weisman Y, Fishel B, Theodor E, Rattan J, Gilat T: Vitamin E 
and cirrhotic muscle cramps. Isr J Med Sci 27: 221–223, 1991. 
7. Lee FY, Lee SD, Tsai YT, Lai KH, Chao Y, Lin HC, Wang SS, Lo KJ: A randomized controlled trial of 
quinidine in the treatment of cirrhotic patients with muscle cramps. J Hepatol 12: 236–240, 1991.