Observation of Efficacy and Safety of Novel Calcium Channel Modulators in the Treatment of Restless Legs Syndrome and Its Variant Subtypes
Phase: PHASE1
Conditions: Restless Leg Syndrome (RLS), Variant Restless Legs Syndrome
Sponsor: Beijing Friendship Hospital

Beijing Friendship Hospital Affiliated to Capital Medical University Research Protocol_V3.0/2026-01-08
Clinical Research Protocol
Efficacy and Safety Observation of a Novel Calcium
Channel Modulator in the Treatment of Patients with
Restless Legs Syndrome and Its Variant Types
Sponsor
Beijing Friendship Hospital Affiliated to Capital Medical University
Principal Investigator
Houzhen Tuo
Version Number
V3.0
Version Date
2026-01-08

Beijing Friendship Hospital Affiliated to Capital Medical University Research Protocol_V3.0/2026-01-08
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1. Research Background
Restless Legs Syndrome (RLS), also known as Willis-Ekbom disease, is a common
neurological sensorimotor disorder in clinical practice. Its typical manifestation is an
irresistible urge to move the legs. Symptoms mostly occur in the evening or at night,
worsen during rest or inactivity, and can be relieved by movement. RLS seriously
affects patients' quality of life, especially leading to insomnia, depression and
anxiety[1]. Patients describe various uncomfortable sensations, such as crawling,
creeping, burning, distension, pulling, tightness, tearing and even pain[1]. Such
discomfort is most prominent in the calves. Current research shows that RLS can
involve a wide range of anatomical sites, including the abdomen, bladder, external
genitalia, oral/facial region, chest and back. When the discomfort involves body parts
other than the lower limbs and meets the diagnostic criteria of the International
Restless Legs Syndrome Study Group (IRLSSG)[2], it is referred to as variant RLS[3].
According to the involved sites, variant RLS is classified into subtypes such as
restless mouth syndrome[4], restless chest syndrome[5], restless bladder syndrome[6],
restless back syndrome[7], restless abdomen syndrome[8], restless arms syndrome[9],
and restless genital syndrome[10]. In addition, studies have shown that both the legs
and other body parts can be involved simultaneously in RLS patients[11].
At present, drug treatments for typical RLS[12-13] are as follows: dopaminergic drugs
are the first-line option for moderate to severe patients, such as non-ergot dopamine
receptor agonists including pramipexole and ropinirole. These drugs relieve
symptoms by regulating dopamine function in the brain. However, in clinical practice,
some patients experience decreased efficacy (commonly observed after 6-12 months
of medication), and some patients discontinue treatment due to adverse reactions like
nausea and impulse control disorders. Alternative treatments include calcium channel
modulators (e.g., gabapentin enacarbil, gabapentin, pregabalin) and opioid drugs,
which are applicable for patients intolerant to dopaminergic drugs. Nevertheless,
gabapentin has limited effect on improving sleep efficiency and is associated with

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common side effects such as dizziness, drowsiness and fatigue. Opioid drugs are only
used for refractory cases due to the risk of addiction, with their clinical application
subject to strict restrictions. For secondary factors such as iron deficiency, oral iron
supplements can alleviate symptoms but are ineffective in non-iron-deficient patients.
Due to the lack of unified and standardized diagnostic criteria for variant RLS, its
treatment regimens are mostly referenced from those for typical RLS, which have
significant limitations: uncertain efficacy and insufficient evidence support. Current
treatment studies on variant RLS are mostly case reports or small-sample observations.
Clinical treatment often relies on physicians' experience, resulting in poor treatment
standardization.
Crisugabalin Besilate Capsules is a novel calcium channel modulator (the
third-generation calcium channel modulator). It is a structural derivative of the
neurotransmitter
γ -aminobutyric acid, featuring an innovative tricyclic cage
structure that enhances molecular rigidity. It has high target selectivity and binding
affinity for the α 2 δ
subunit of voltage-gated calcium channels in the central
nervous system. By reducing calcium influx into neurons, it decreases the release of
excitatory neurotransmitters such as glutamate and norepinephrine, thereby effectively
controlling neuropathic pain. It has shown potential in the treatment of neuropathic
pain[14]. As a new-generation highly selective α2δ ligand, Crisugabalin Besilate
Capsules is expected to become a new option for RLS treatment. At present, data on
the efficacy and safety of this drug in the clinical treatment of RLS (especially variant
RLS) are limited. Therefore, this study intends to enroll patients with typical RLS and
variant RLS, treat them with Crisugabalin Besilate Capsules, and systematically
evaluate the efficacy and safety of the drug. This will not only provide a potential
treatment option for patients with variant RLS, but also fill the research gap in this
field and offer evidence-based basis for the update of clinical diagnosis and treatment
guidelines.
[1] Sleep Group of Neurology Physicians Branch of Chinese Medical Doctor
Association, Sleep Disorders Group of Neurology Branch of Chinese Medical
Association, Sleep Disorders Professional Committee of Chinese Sleep Research

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3
Society. Guidelines for the diagnosis and treatment of restless legs syndrome in China
(2021 edition)[J]. Chinese Medical Journal, 2021, 101(13): 908-925.
[2]
Allen
RP,
Picchietti
DL,
Garcia-Borreguero
D,
et
al.
Restless
legs
syndrome/Willis-Ekbom disease diagnostic criteria: updated International Restless
Legs Syndrome Study Group (IRLSSG) consensus criteria--history, rationale,
description, and significance. Sleep Med. 2014;15(8):860-873.
[3] Turrini A, Raggi A, Calandra-Buonaura G, Martinelli P, Ferri R, Provini F. Not
only limbs in atypical restless legs syndrome. Sleep Med Rev. 2018;38:50-55.
[4] Jung Y, Hassan A, St Louis EK, Robertson CE. Restless mouth syndrome. Neurol
Clin Pract. 2017;7(3):e29-e30.
[5] Ishizuka K, Ohira Y. Restless Chest Syndrome: A Rare Variant of Restless Legs
Syndrome. Eur J Case Rep Intern Med. 2022;9(7):003398.
[6] Antelmi E, Coccagna G, Ferini-Strambi L, Marelli S, Provini F. 'Restless bladder'
and the boundaries of the restless legs syndrome. Eur J Neurol. 2013;20(11):e128.
[7] Sun F, Tao H, Jin W. Restless Back Syndrome: A Case Report and Literature
Review. Psychiatry Clin Psychopharmacol. 2022;32(4):351-354. Published 2022 Dec
1.
[8] Pérez-Díaz H, Iranzo A, Rye DB, Santamaría J. Restless abdomen: a phenotypic
variant of restless legs syndrome. Neurology. 2011;77(13):1283-1286.
[9] Webb AT. Letter: Restless arms syndrome. JAMA. 1976;236(7):822.
[10] Waldinger MD, Schweitzer DH. Persistent genital arousal disorder in 18 Dutch
women: Part II. A syndrome clustered with restless legs and overactive bladder[J]. J
Psychosom Obstet Gynaecol, 2003,24(4):221-229.
[11] Suzuki K, Suzuki S, Miyamoto M, et al. Involvement of legs and other body
parts in patients with restless legs syndrome and its variants. J Neurol Sci.
[12] Trenkwalder C, Allen R, Högl B, et al. Comorbidities, treatment, and
pathophysiology in restless legs syndrome. Lancet Neurol. 2018;17(11):994-1005.
[13] Sleep Group of Neurology Physicians Branch of Chinese Medical Doctor
Association, Sleep Disorders Group of Neurology Branch of Chinese Medical
Association, Sleep Disorders Professional Committee of Chinese Sleep Research

Beijing Friendship Hospital Affiliated to Capital Medical University Research Protocol_V3.0/2026-01-08
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Society. Guidelines for the diagnosis and treatment of restless legs syndrome in China
(2021 edition)[J]. Chinese Medical Journal, 2021, 101(13): 908-925.
[14] Expert Group of Guidelines for the Treatment of Diabetic Peripheral Neuropathic
Pain with Crisugabalin. Guidelines for the Treatment of Diabetic Peripheral
Neuropathic Pain with Crisugabalin[J]. International Journal of Endocrinology and
Metabolism, 2024, 44(06): 446-449.
2. Research Objectives
The main objective of this study is to prospectively observe the improvement of
symptoms in patients with RLS and its variant types after treatment with Crisugabalin
Besilate Capsules, objectively evaluate the efficacy and safety of this novel calcium
channel modulator, and provide high-level evidence-based medical evidence for the
individualized drug treatment of patients with RLS and its variant types.
3. Research Content
This study plans to adopt a prospective observational cohort study design and enroll
outpatients diagnosed with RLS and its variant types in the Department of Neurology.
All patients will be treated with Crisugabalin Besilate Capsules. Through baseline
visit and follow-up visits at Week 2, Week 4, Week 8 and Week 12 after treatment, the
study will systematically collect patients' scores of the International Restless Legs
Syndrome Rating Scale (IRLS), sleep quality and quality of life, and closely monitor
drug-related adverse events. The study aims to objectively evaluate the efficacy and
safety of the novel calcium channel modulator and provide high-level evidence-based
medical evidence for the individualized drug treatment of patients with RLS and its
variant types.
4. Research Protocol
4.1 Study Design Type
Experimental prospective single-arm study
4.2 Study Subjects
4.2.1 Study Population
Subjects admitted to the outpatient department or inpatient ward of the Department of
Neurology, Beijing Friendship Hospital Affiliated to Capital Medical University.

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4.2.2 Study Center
Beijing Friendship Hospital Affiliated to Capital Medical University
4.2.3 Planned Enrollment
A total of 20 subjects are planned to be enrolled in the study, including patients with
RLS and variant RLS.
4.2.4 Inclusion and Exclusion Criteria
(1) Inclusion Criteria
Subjects can be enrolled in this study only if they meet all the following inclusion
criteria:
1.Aged 18-75 years old, regardless of gender;
2.Meet the diagnostic criteria of the International RLS Study Group (for typical RLS)
and the expert-confirmed diagnostic criteria for variant RLS;
3.Patients with moderate to severe RLS (IRLS score ≥11 points according to the
International Restless Legs Syndrome Study Group Rating Scale);
4.Understand and agree to comply with the study protocol, and consent to enrollment
and sign the informed consent form.
(2) Exclusion Criteria
1.Secondary RLS: such as iron deficiency anemia (serum ferritin < 30μg/L), renal
insufficiency (eGFR < 30ml/min), pregnancy/lactation period, thyroid dysfunction,
drug-induced RLS (e.g., antipsychotics, antidepressants that cannot be adjusted);
2.Severe central nervous system diseases (e.g., status epilepticus, severe dementia,
stroke within the recent 3 months);
3.Severe
cardiovascular
diseases
(e.g.,
congestive
heart
failure,
uncontrolled
hypertension (systolic blood pressure ≥180mmHg or diastolic blood pressure ≥
110mmHg));
4.Severe hepatic and renal insufficiency (ALT/AST > 3 times the upper limit of
normal, eGFR < 30 mL/min/1.73m²);
5.Active mental illnesses (e.g., schizophrenia, acute episode of bipolar disorder);
6.Drug contraindications: hypersensitivity to Crisugabalin Besilate Capsules or its
excipients;

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7.Others: participation in other drug clinical trials within the recent 1 month, inability
to cooperate with follow-up (e.g., cognitive impairment, language disorder), history of
substance abuse (e.g., alcohol, opioids);
8.Severe cognitive impairment or mental illness that prevents completion of scale
assessment;Pregnant or lactating women.
4.3 Research Process
4.3.1 Subject Screening and Enrollment Process
This is a prospective observational cohort study. All enrolled subjects are from the
outpatient and inpatient departments of the Department of Neurology in our hospital.

Screening Site and Source: The study subjects include patients who visit Beijing
Friendship Hospital Affiliated to Capital Medical University or participate in
research projects related to neurodegenerative diseases.

Screening Basis: Two neurologists will make clinical diagnosis of RLS and
variant RLS according to international guidelines (such as IRLSSG international
diagnostic criteria). Pre-enrollment assessment includes preliminary medical
history collection, physical and neurological examinations, and strict evaluation
in accordance with inclusion and exclusion criteria.
4.3.2 Information Collection Content and Methods
The information required for this study includes:

Demographic information: age, gender, education level, marital status;

Medical history information: course of main diagnosis, onset time, accompanying
symptoms, past medical history, medication history;

Clinical assessment: International Restless Legs Syndrome Study Group Severity
Rating Scale (IRLS), RLS Quality of Life Questionnaire (QoL-RLS);

Mood, sleep and functional assessment: Hamilton Depression Scale (HAMD);
Hamilton Anxiety Scale (HAMA); Activities of Daily Living Scale (ADL);
Pittsburgh Sleep Quality Index (PSQI).
4.3.3 Intervention Measures
All
enrolled
patients
will
be
treated
with
Crisugabalin
Besilate
Capsules
(Manufacturer: [Simeining], Approval Number: [H20240018]), 40mg per dose, twice

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daily, for oral administration. The treatment cycle is 12 weeks. During the study
period, the use of other drugs that may affect the efficacy of this study is prohibited,
including
neurotransmitter-affecting
drugs
(antidepressants,
antipsychotics,
benzodiazepines) and drugs with drug interactions (potent CYP3A4 inhibitors such as
ketoconazole, itraconazole, clarithromycin, ritonavir and potent CYP3A4 inducers
such
as
rifampicin,
carbamazepine,
phenytoin
sodium).
Continuous
oral
administration of iron supplements (at a stable dose) is allowed.
4.3.4 Follow-up
The severity of patients' symptoms will be assessed before treatment and at Week 2,
Week 4, Week 8 and Week 12 of treatment, including the above-mentioned clinical
assessment as well as mood, sleep and functional assessment.
4.4 Observation Indicators
This study adopts a prospective observational cohort study design, enrolls patients
with RLS and variant RLS, treats them with Crisugabalin Besilate Capsules, and
objectively evaluates the efficacy and safety of this novel calcium channel modulator.
(1) Primary Outcome Measures (Tier 1 Indicators)
Evaluate the change in IRLS score of patients with RLS after 12 weeks of treatment
with Crisugabalin Besilate Capsules compared with the baseline. Calculate the change
value and response rate of IRLS score before and after treatment (response rate =
(score before treatment - score after treatment)/score before treatment × 100%). A
response rate ≥50% is defined as treatment effective.
(2) Secondary Outcome Measures (Tier 2 Indicators)
1.Evaluate the improvement effect of Crisugabalin Besilate Capsules on patients'
sleep quality (using the Pittsburgh Sleep Quality Index (PSQI) or relevant scales).
2.Evaluate the improvement effect of Crisugabalin Besilate Capsules on patients'
quality of life (using general scales such as the RLS Quality of Life Questionnaire
(RLS-QoL)).
3.Evaluate the improvement effect of Crisugabalin Besilate Capsules on patients'
mood (using general scales such as HAMA and HAMD).
4.Evaluate the incidence, severity and outcome of drug-related adverse events during

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treatment.
4.5 Sample Size Determination
This study is a prospective single-arm observational cohort, with the primary
endpoint set as "the change value of total IRLS score at Week 12 of treatment
compared with baseline (continuous variable)". Referring to a published double-blind,
crossover controlled study on gabapentin (also a calcium channel modulator) for the
treatment of RLS (doi: 10.1212/WNL.59.10.1573), after 6 weeks of active treatment
in 24 RLS patients in that study, the mean IRLS score decreased by 8.4 points (SD ≈
6.1 points). Assuming that Crisugabalin Besilate Capsules has equivalent efficacy at
the conventional dose, the parameters of this study are set as follows: expected
decrease value δ = 8.4 points, standard deviation of paired differences σ = 6.1 points,
two-sided α = 0.05, power 1-β = 90%. Using the sample size formula for paired t-test:
The basic sample size n = 17 cases is obtained. Considering that the dropout rate of
observational design is higher than that of RCT (estimated 15%) and the data quality
disqualification rate is 5%, it is expected to complete 20 cases, which can meet the
statistical robustness when the overall primary endpoint power is ≥90% and the
dropout rate is < 20%.
4.6 Informed Consent
Informed consent form must be signed.
4.7 Risk Control and Management Measures
1.Risk of drug-related adverse events: Based on existing data, the study drug
Crisugabalin Besilate Capsules may cause common adverse reactions such as
dizziness, drowsiness and fatigue. Control measures: Clearly inform all potential
common adverse reactions in the Informed Consent Form. Actively inquire about and
record all adverse events using non-leading questions during each follow-up visit, and
document in detail the occurrence time, severity, frequency, measures taken and
outcome of each adverse event. In case of serious adverse events, researchers will

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immediately conduct medical treatment and report to the Institutional Ethics
Committee within 24 hours. Meanwhile, assist subjects in obtaining corresponding
medical compensation.
2.Risk of privacy leakage: The medical information and scale data collected during
the study involve personal privacy. Control measures: Assign a unique identification
code to each subject, and mark all study data with codes. Electronic data are stored in
encrypted form, and paper documents are kept under lock and key. Access rights are
strictly restricted to authorized researchers. When publishing research results in the
future, ensure that no personally identifiable information is included.
3.Study-related discomfort and burden: Multiple follow-up visits and scale filling
may bring time burden and mild discomfort to subjects. Control measures: Clearly
explain the study process and required time to subjects before the start of the study.
Arrange follow-up visit time as far as possible according to the convenience of
subjects. Clearly inform subjects that they have the right to withdraw from the study
unconditionally at any time, and their medical rights and interests will not be affected.
4.Risk of protocol deviation and dropout: Subjects may fail to follow up as planned
or withdraw from the study, resulting in data loss. Control measures: Establish a good
relationship: maintain good communication with subjects and remind them of
follow-up dates. Record in detail the reasons for all dropped cases, and adopt
appropriate methods to handle missing data in the final statistical analysis and
evaluate its impact on the results.
4.8 Confidentiality of Research Information
The personal information of all enrolled subjects will be processed, stored and used in
a de-identified manner. All clinical data will be reviewed and preserved by the study
sponsor. Only the research team members designated by the study sponsor can access
the personal information and clinical data related to the subjects. The information and
data generated during the study will be properly kept in accordance with regulations.
The publication of research results after the completion of the study will not disclose
the personal information of the subjects.
5. Technical Route

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6. Statistical Methods
Data analysis in this study will be performed using SPSS and Graphpad Prism
software. For measurement data, if they conform to normal distribution, they will be
described by mean±standard deviation; if they do not conform to normal distribution,
they will be described by median (interquartile range). For count data, they will be
described by case number (percentage). For before-and-after comparison of a single
group, measurement data will first undergo normality test (Shapiro-Wilk method). If
the data conform to normal distribution, paired t-test will be used for data analysis; if
not, non-parametric Wilcoxon signed-rank test will be adopted. McNemar test will be
used for count data. A P value < 0.05 will be considered statistically significant for all
statistical difference analyses.
7. Quality Control
1.Subject screening and enrollment: This study is carried out relying on the
Department of Neurology of our hospital, which has well-equipped scientific research
and clinical platforms. The Department of Neurology has a high-level diagnosis and

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treatment team for sleep disorders and movement disorders, with experience in
participating in many large-scale domestic and foreign clinical studies. The outpatient
clinic for sleep disorders and movement disorders receives more than 300 patients
including those with RLS every month, among which 10-15 are new patients,
ensuring the enrollment of a sufficient number of eligible clinical subjects and healthy
controls for the study. All researchers in this study have received GCP training and
obtained certificates, and have passed consistency training on scales such as IRLS,
PSQI and CGI-I to ensure assessment quality.
2.Quality control measures during the study: Establish a clear subject screening
path to ensure that each enrolled patient strictly meets the inclusion and exclusion
criteria, and retain the original signed Informed Consent Form. All scale assessments
and fillings must be completed on-site during the visit to avoid recall bias. Follow-up
management: Set up a special follow-up reminder system (such as telephone and short
message appointment) to minimize the loss of follow-up. For any dropped subject, the
reason must be recorded and every effort should be made to find out the cause of
dropout.
3.Ethical and compliance supervision: The entire research process is subject to the
supervision and review of the Institutional Ethics Committee. Any modification to the
study protocol must be reported to the Ethics Committee for approval before
implementation.
8. Qualifications and Division of Labor of Team Members
Name
Qualification
Department
Division of Labor
Houzhen Tuo
Chief Physician
Department of
Neurology
Overall coordination, protocol
formulation, etc.
Xinran Xu
Resident
Physician
Department of
Neurology
Subject screening and enrollment
review, handling of emergencies
Wenlu Zhao
PhD Candidate
Department of
Neurology
Signing of informed consent form, data
collection and analysis
Shiya Wang
PhD Candidate
Department of
Neurology
Signing of informed consent form, data
collection
Ying Cui
PhD Candidate
Department of
Neurology
Signing of informed consent form, data
collection
Bingyu Han
PhD Candidate
Department of
Signing of informed consent form, data

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Neurology
collection
Xiaolong Ma
Master
Candidate
Department of
Neurology
Signing of informed consent form, data
collection
Sichen Wang
Master
Candidate
Department of
Neurology
Signing of informed consent form, data
collection
Hao Zheng
Master
Candidate
Department of
Neurology
Signing of informed consent form, data
collection

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