Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT03708237 |
| Other study ID # |
Pro00084427 |
| Secondary ID |
|
| Status |
Terminated |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
February 19, 2019 |
| Est. completion date |
December 11, 2019 |
Study information
| Verified date |
June 2021 |
| Source |
University of Alberta |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Restless legs syndrome (RLS) is a neurologic disorder characterized by 1) an urge to move the
legs, 2) uncomfortable sensations in the legs, 3) symptoms that are often worse the evening
or when at rest , and 4) may be temporarily relieved by physical activity.
The overall prevalence of RLS in the general population is estimated to be around 10%,
however, it is significantly in the end stage kidney disease (ESKD) population is
significantly higher (approximately 30%). Studies have shown that RLS has a substantial
negative impact on both the physical and the mental health dimensions of quality of life
(QOL), such as depression, anxiety, pain, fatigue and sleep disorder.
While non-pharmacological treatments should be considered for all patients, pharmacological
management of RLS is indicated when the affects patient's sleep or quality of life.
Gabapentin and dopamine agonists such as ropinirole are usually the first choices in treating
RSL. Although these medications are also used in patients with renal impairment, few studies
provide treatment data for the hemodialysis population. Treatment recommendations for this
population are largely based on data obtained in the general population.
This study aims to evaluate effectiveness of ropinirole and gabapentin for the treatment of
restless legs syndrome in patients on maintenance hemodialysis.
Description:
Purpose
Restless legs syndrome (RLS), also known as Willis-Eskbom disease, is a neurologic disorder
characterized by 1) an urge to move the legs, 2) uncomfortable sensations in the legs, 3)
symptoms that are often worse the evening or when at rest , and 4) may be temporarily
relieved by physical activity. While the precise pathogenic mechanisms responsible for uremic
RLS remain unknown, there is evidence to support involvement of dopaminergic dysfunction and
reduced iron stores.
RLS is separated into primary/idiopathic and secondary forms. Secondary RLS is usually
associated with underlying medical conditions such as end-stage kidney disease (ESKD). The
overall prevalence of RLS in the general population is estimated to be around 10%. However,
the prevalence of RLS in the ESKD population is significantly higher. A systematic review
calculated weighted mean RLS prevalence of 30% (range: 8-52%) in ESKD. Studies have shown
that RLS has a substantial negative impact on both the physical and the mental health
dimensions of quality of life (QOL), such as depression, anxiety, pain, fatigue and sleep
disorder.
While non-pharmacological measure should be considered for all patients, pharmacological
treatment for RLS is indicated when the symptoms lead to significant insomnia or impaired
quality of life. Although only two medications have been approved by Health Canada, there is
a long list of medications that have been used in management of RLS symptoms. Gabapentin and
dopamine agonists are usually the first choices in treating RSL. Although marketed in Canada,
gabapentin and ropinirole have not been approved by Health Canada for the treatment of
moderate-severe restless legs sydnrome.
Unfortunately, the prolonged treatment of RLS using dopaminergic drugs, such as the approved
pramipexole, can lead to a phenomenon called augmentation in which patients experience an
increase in symptom severity, an earlier onset of symptoms during the night, the appearance
of daytime symptoms, and/or the spread of symptoms to other parts of the body. Although,
ropinirole is a dopamine agonist it appears to have a lower risk of augmentation and
tolerance than other dopaminergic drugs, such as levodopa.
This study aims to evaluate effectiveness of the off-label use of ropinirole and gabapentin
for the treatment of restless legs syndrome in patients on maintenance hemodialysis.
Hypothesis
Testing Superiority: The mean RLS symptom severity change in the ropinirole group is greater
than placebo.
Testing Superiority: The mean RLS symptom severity change in the gabapentin group is greater
than placebo.
Testing Equivalence: The mean RLS symptom severity change in the ropinirole group is within
10% of the gabapentin group.
Justification
Although these medications are considered first time pharmacologic treatment for patients
with ESKD, few published studies provide treatment data for these patients. Treatment
recommendations for this population are largely derived from extrapolation of data obtained
in the general population, even though the pathophysiology for RLS in ESKD (termed "uremic
RLS") may differ.
Restless legs syndrome is a chronic condition with fluctuating severity. The majority of the
available published studies in the hemodialysis population were of short duration and small
sample sizes. A six month intervention period will be used to evaluate the long-term
effectiveness of ropinirole and gabapentin for the treatment of RLS symptoms in the
hemodialysis population.
Primary Objectives
Evaluate the effectiveness of ropinirole and gabapentin on the severity of RLS symptoms in
the hemodialysis population using the International Restless Legs Syndrome Study Group (IRLS)
rating scale.
Secondary Objectives:
Evaluate the impact of ropinirole and gabapentin on the quality of life using the EQ-5D-5L is
a two part standardized health status instrument.
Evaluate the impact of ropinirole and gabapentin on the quality of sleep using the Medical
Outcomes Study Sleep Scale.
Evaluate the impact of ropinirole and gabapentin on the symptom burden using the Edmonton
Symptom Assessment System Revised Renal.
Validate the addition of RLS and difficulty sleeping items on the Edmonton Symptom Assessment
System Revised: Renal (ESAS-r: Renal).
Research Method/Procedures
Screening/Recruitment
A Nephrologist, Clinical Nurse Educator (CNE), and/or designate from the NARP, will identify
patients meet the study criteria using minimal data from the Nephrology Information System
(NIS). NIS is an electronic database used by NARP to record health for all patients in the
program. Nephrologists and CNEs in the Northern Alberta Renal Program have access to the
patient information in NIS as part of routine clinical care.
Initial contact with a potentially eligible participant will be made by an AHS NARP employee
already involved in the clinical care of the patient, who will then determine the
individual's willingness to be approached by the research study staff regarding participation
and obtain their written consent to release their contact information to the researcher. The
consent forms will be passed along to the researcher.
If the potential participant is agreeable a trained study coordinator will approach the
eligible patient to introduce the study. The formal consent of a participant, using an
HREB-approved consent form, will be obtained before that participant is submitted to any
study intervention.
Potential participants will be advised (verbally and in written information) that
participation is not required and refusal will not affect their health care or relationship
with dialysis unit staff. Also, participants will be advised that they are free to leave the
study at any time and would not be required to give a reason for withdrawal.
Potential participant initials will be used to track participants during recruitment so as
not to approach the same patient multiple times. Recruitment information, such as reasons for
refusal and date approached, will be recorded on Screening and Recruitment log.
Once eligible participants are recruited a baseline assessment will be completed and the
participant will be randomized to the study groups. The participant will be instructed to
start taking the study drug the same evening before bed. A follow up will be completed weekly
for two months following the baseline date. Additional follow ups will occur at four and six
months.
A total of 63 subjects will be enrolled and randomized into 3 groups: 23 participants will
receive gabapentin, 23 participants will receive ropinirole, 17 participants will receive a
placebo.
Study Design:
A six month, randomized, single-blind, placebo-controlled, parallel, multicenter, clinical
trial comparing the effectiveness of ropinirole and gabapentin for the treatment of restless
legs syndrome in patients on maintenance hemodialysis.
Intervention:
Once eligible participants are recruited a baseline assessment will be completed and the
participant will be randomized to the study groups. The participant will be instructed to
start taking the study drug the same evening before bed. A follow up will be completed weekly
for two months following the baseline date to allow for monitoring and appropriate dose
titration. Additional follow ups will occur at four and six months.
All patients treated with ropinirole will be started with a single dose of 0.25 mg once daily
by mouth prior to bed as per the Alberta Kidney Care restless legs syndrome clinical
guidelines used by the Northern Alberta Renal Program. Since the action of dopamine agonists
generally starts 90 to 120 minutes after ingestion study participants will be instructed to
take the ropinirole two hours before bed prior to symptom onset. Ropinirole may be taken with
or without food. The ropinirole dose may be titrated upward in 0.25 mg increments every seven
days as tolerated by the patient until symptom relief has been achieved or a maximum dose of
2.0 mg/day has been reached. In general, the effective dose for ropinirole is typically 2.0
mg or less and dosages higher than 2.0 mg have not been studied in the hemodialysis
population.
All patients treated with gabapentin will be started with a single dose of 100mg once daily
by mouth two hours prior to bed as per the Alberta Kidney Care restless legs syndrome
clinical guidelines. Gabapentin may be taken with or without food. The dose may be increased
in 100 mg increments every seven days as tolerated by the patient until symptom relief has
been achieved or until a maximum study dose has been reached. As per the gabapentin product
monograph dosing recommendations and current clinical RLS guidelines the maximum study
gabapentin dose will 300 mg/day.
A placebo group will be used for comparison.
Plan for Data Analysis
The primary analysis will test changes in subject's IRLS scores between baseline and end of
study (six month) follow up. Three separate analyses will be conducted, to test either
superiority (gabapentin vs. placebo and ropinirole vs placebo), or equivalency (gabapentin
vs. ropinirole). A t-test on the difference of means will be used for each superiority study;
on the difference of mean percentage change for the equivalence study (with a set equivalence
limit of 10%). For each treatment, a 50% decrease in IRLS scores from baseline will be
considered clinically relevant, although a 30% decrease will be interpreted as a small
improvement. An intent-to-treat (ITT) approach will be used in the primary analysis, although
a per-protocol (PP) analysis will also be conducted for robustness.
Secondary analyses will test the mean change in subject's EQ-5D-5L quality of life scores,
and MOS-SS sleep quality scales. Analyses on the differences between mean changes in scores
will mirror those in the primary analysis. Analyses to validate the ESAS-r: Renal RLS and
sleep quality measures will also be conducted. Criterion validity measured by Pearson
correlation coefficient and multivariate regression analyses will be assessed using changes
in IRLS scores to validate the RLS component, and changes in MOS-SS scores to validate the
sleep quality component.
