Efficacy and Safety of memanTine in the Treatment Of Frequently symPtomatic Atrial Premature Beats: a Multicenter Randomized Double-blind Placebo-controlled Study
Phase: PHASE2
Conditions: Atrial Premature Beats, Contractions, or Systoles
Sponsor: Shanghai East Hospital

 
Efficacy and Safety of Memantine in the Treatment of Patients 
With Frequent Symptomatic Atrial Premature Beats: A 
Multicenter, Randomized, Double-Blind, Placebo-Controlled 
Adaptive-Design Study (STOP-AP) 
 
 
Research Unit:  
Shanghai East Hospital, Tongji University 
Principal Investigator: 
Yi-Han Chen  
Department in charge: 
Department of Cardiology 
Contact phone number: 021-38804518 
Team Leader Unit: 
Shanghai East Hospital, Tongji University 
Version number: 
Version 2.1 
Version Date: 
June 28, 2024 
 
Confidentiality statement 
All information in this protocol is confidential and intended exclusively for use by the 
clinical investigators. Unless disclosure is mandated by applicable laws or regulations, 
the contents may not be revealed. © [2025] Yi-Han Chen Team, Shanghai East Hospital, 
Tongji University. No part of this document may be reproduced or distributed to anyone 
not involved in this clinical study unless that individual has executed a confidentiality 
agreement with the Yi-Han Chen Team, Shanghai East Hospital, Tongji University.

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
1 
Catalogs 
Catalogs.......................................................................................................................... 1 
Abstract of the Research Program ................................................................................. 4 
1. Background .............................................................................................................. 10 
2. Study Objectives and Endpoints .............................................................................. 12 
2.1 Objectives ..................................................................................................... 12 
2.2 Endpoints ...................................................................................................... 12 
2.2.1 Efficacy Endpoints ........................................................................... 12 
2.2.2 Safety Endpoints .............................................................................. 13 
3. Study Design ............................................................................................................ 13 
3.1 Overall Design .............................................................................................. 13 
3.2 Study Centers ................................................................................................ 14 
3.3 Randomization and Blinding ........................................................................ 15 
3.3.1 Randomization and Blinding ............................................................ 15 
3.3.2 Blinding ............................................................................................ 15 
3.3.3 Emergency Unblinding .................................................................... 15 
3.3.4 Interim Analysis Unblinding ............................................................ 16 
3.3.5 Final Unblinding .............................................................................. 16 
4. Study Population ...................................................................................................... 16 
4.1 Inclusion Criteria .......................................................................................... 16 
4.2 Exclusion Criteria ......................................................................................... 17 
4.3 Withdrawal Criteria ...................................................................................... 19 
4.3.1 Participant-Initiated Withdrawal ...................................................... 19 
4.3.2 Investigator-Initiated Withdrawal ..................................................... 19 
4.4 Procedures for Early Withdrawal .................................................................. 19 
5. Investigational Products ........................................................................................... 20 
5.1 Product Characteristics ................................................................................. 20 
5.2 Dosing Regimen ........................................................................................... 21 
5.3 Supply, Packaging and Labeling of Investigational Product ........................ 21 
5.4 Investigational Product Accountability ........................................................ 22 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
2 
5.5 Return and Destruction of Investigational Product ...................................... 22 
5.6 Concomitant Medications ............................................................................. 23 
5.7 Prohibited Medications ................................................................................. 23 
6. Study Procedures and Visit Schedule....................................................................... 23 
6.1 Study  Flow Diagram .................................................................................... 24 
6.2 Study Procedure ............................................................................................ 29 
6.2.1 Screening Period (Visit 1) ................................................................. 29 
6.2.2 Treatment Phase ............................................................................... 30 
6.2.3 Follow-up Phase ............................................................................... 30 
7. Statistical Analysis ................................................................................................... 30 
7.1 Sample-Size Determination .......................................................................... 30 
7.2 Analysis Sets ................................................................................................. 31 
7.3 Analysis Plan ................................................................................................ 31 
7.3.1 Statistical Hypothesis ....................................................................... 31 
7.3.2 General principles ............................................................................ 31 
7.3.3 Study Disposition and Participant Flow ........................................... 32 
7.3.4 Demographics and Baseline Characteristics .................................... 32 
7.3.5 Medication Adherence...................................................................... 32 
7.3.6 Efficacy Analyses ............................................................................. 32 
7.3.7 Safety Analysis ................................................................................. 33 
7.3.8 Mid-term Analysis ............................................................................ 33 
7.3.9 Multiplicity Adjustment ................................................................... 34 
7.3.10 Handling of Missing Data .............................................................. 34 
8. Safety Evaluation ..................................................................................................... 34 
8.1 Definitions .................................................................................................... 34 
8.1.1 AEs ................................................................................................... 34 
8.1.2 Serious Adverse Events (SAEs) ....................................................... 35 
8.2 AE Assessment ............................................................................................. 36 
8.2.1 Seriousness ....................................................................................... 36 
8.2.2 Severity Grading .............................................................................. 36 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
3 
8.2.3 Causality ........................................................................................... 36 
8.2.4 Measures taken with Regard to Study Treatment ............................ 38 
8.2.5 Measures Taken for Adverse Events  .............................................. 39 
8.2.6 Outcome ........................................................................................... 39 
8.3 AE Reporting ................................................................................................ 39 
8.4 Observation and Management of Special Adverse Events ........................... 41 
9. Ethical Principles and Requirements for Clinical Research .................................... 44 
9.1 Ethical Standards .......................................................................................... 44 
9.2 Ethics Committee ......................................................................................... 45 
9.3 Informed Consent ......................................................................................... 46 
9.3.1 Informed Consent Process and Documentation ............................... 46 
9.3.2 Confidentiality of Participant Information ....................................... 46 
10. Data Management and Quality Control ................................................................. 47 
10.1 Data Management ....................................................................................... 47 
10.2 Monitoring .................................................................................................. 49 
11. Study Management ................................................................................................ 50 
11.1 Quality Control and Quality Assurance ...................................................... 50 
11.2 Document Retention ................................................................................... 50 
12. Responsibilities of All Parties and Other Relevant Provisions .............................. 51 
12.1 Responsibilities of the Lead Study Institution ............................................ 51 
12.2 Responsibilities of Clinical Research Sites (Study Centers) ...................... 52 
13. Reference ............................................................................................................... 53 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
4 
Abstract of the Research Program 
Title 
Efficacy and safety of memantine in the treatment of frequent symptomatic atrial 
premature beats: a multicenter, randomized, double-blind, placebo-controlled, 
adaptive-design study 
Objective 
MAIN OBJECTIVE: To evaluate the effectiveness of memantine in the treatment of 
frequent symptomatic atrial premature beats. 
SECONDARY OBJECTIVE: To evaluate the safety of memantine in the treatment of 
frequent symptomatic atrial premature beats. 
Principal 
Investigator 
and Lead 
Institution 
Yi-Han Chen, Shanghai East Hospital, Tongji University. 
Sample Size 
A total of 256 patients with frequent symptomatic atrial premature beats are to be 
recruited, with the sample size potentially adjusted based on interim analysis results. 
Inclusion 
Criteria 
(1) Age: 18 to 80 years, inclusive. 
(2) Symptomatic premature atrial contractions (PACs): Documented at screening 
as ≥ 1,000 PACs during a 24-hour ambulatory electrocardiogram (ECG) recording.  
(3) Informed consent: Ability and willingness to understand and comply with all 
study procedures and to sign the written informed-consent form before any protocol-
specific activities are performed. 
Exclusion 
criteria 
(1) Atrial or ventricular arrhythmias 
Atrial fibrillation, atrial flutter, or persistent atrial tachycardia documented by 12-lead 
ECG within 6 months before screening or detected on the baseline 72-hour patch-type 
ambulatory ECG. 
Ventricular tachycardia (excluding brief nocturnal runs) or ventricular fibrillation. 
(2) Recent cerebrovascular or cardiac events 
Ischemic or hemorrhagic stroke, or transient ischemic attack, within 6 months before 
screening. 
Cardiac surgery, myocardial infarction, percutaneous coronary intervention, or cardiac 
radiofrequency ablation within 6 months before screening. 
(3) Severe left-sided cardiac dysfunction 
Left-ventricular ejection fraction ≤ 40 %. 
New York Heart Association class III or IV heart failure. 
(4) Clinically significant conduction disease 
Sick-sinus syndrome without a permanent pacemaker. 
Second-degree type II or higher atrioventricular block, or bifascicular block. 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
5 
Diagnosed systemic or metabolic condition that could lead to severe bradycardia or 
conduction abnormalities, such as cardiac sarcoidosis or untreated severe 
hypothyroidism. 
(5) Recent antiarrhythmic therapy 
Amiodarone within 4 weeks before screening. 
Any other antiarrhythmic agent—including herbal preparations with antiarrhythmic 
properties—within 2 week before screening. 
(6) Other serious cardiac conditions 
Unstable angina, severe congenital heart disease (except patent foramen ovale), prior 
prosthetic heart-valve replacement, acute myocarditis or endocarditis, rheumatic 
valvular disease, hypertrophic cardiomyopathy, congenital long QT syndrome, 
congenital short QT syndrome, Brugada syndrome, or catecholaminergic polymorphic 
ventricular tachycardia. 
(7) Limited life expectancy 
Any comorbid condition with an anticipated survival of < 1 year. 
(8) Hepatic impairment 
Active hepatitis or clinically significant liver dysfunction (ALT or AST > 3 × ULN, 
or total bilirubin > 3 × ULN). 
(9) Renal impairment 
Estimated glomerular filtration rate < 40 mL · min⁻¹ · 1.73 m⁻² (CKD-EPI formula). 
(10) Concurrent investigational therapy 
Use of any investigational drug or device within 1 month—or five elimination half-
lives, whichever is longer—before screening. 
(11) Pregnancy or lactation 
Pregnant or breastfeeding women, or a positive serum pregnancy test before 
randomization. 
(12) Metabolic, surgical, or pulmonary instability 
The presence of atrial premature beats due to potential reversible causes, such as 
hyperthyroidism, cardiovascular surgery, electrolyte imbalances, etc. APBs decrease 
and symptoms significantly improve after the removal of triggers (e.g., alcohol abuse, 
acute exacerbation of chronic obstructive pulmonary disease (AECOPD) with 
respiratory failure, or unresolved infections). 
(13) Neurologic or psychiatric disorders 
History of epilepsy, seizures, or psychiatric illness that could interfere with study 
participation. 
(14) Drug hypersensitivity 
Known allergy to memantine hydrochloride or any excipient of the study drug. 
(15) Current memantine therapy 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
6 
Ongoing treatment with memantine for moderate-to-severe Alzheimer’s disease. 
(16) Other contraindications 
Any condition that, in the investigator’s judgment, makes the participant unsuitable 
for enrollment in the study.  
Research 
Design 
This study is a multicenter, randomized, double-blind, parallel-group, placebo-
controlled superiority trial. 
Efficacy 
Endpoints 
Primary Efficacy Endpoint: The percentage change from baseline in the 24-hour 
mean number of premature atrial contractions (PACs) at Week 6. 
Secondary Efficacy Endpoints: 
(1) The change from baseline in the 24-hour mean number and burden of PACs at 
Weeks 4, 6, and 8； 
(2) The change from baseline in the 24-hour mean number and burden of non-
sustained atrial tachycardia (NSAT) at Weeks 4, 6, and 8; 
(3) The change from baseline in the number of episodes of sustained atrial 
tachycardia, atrial fibrillation, and atrial flutter over a 24-hour period at Weeks 4, 6, 
and 8. 
(4) The change from baseline in the SF-36 quality of life score at Week 6. 
Safety 
Endpoints 
 
The incidence of adverse events (including psychiatric symptoms, seizures, 
bradycardia, new-onset heart failure, etc.), serious adverse events, laboratory test 
abnormalities, and abnormal electrocardiogram findings. 
Study 
Overview 
This is a multicenter, randomized, double-blind, parallel-group, placebo-controlled 
superiority trial aimed at enrolling 256 patients aged 18 to 80 years with frequent 
symptomatic PACs. 
Eligible patients, following initial screening, will undergo 72-hour continuous 
ambulatory ECG monitoring to establish baseline PAC counts. Based on the 
monitoring data, eligibility will be confirmed. Qualified participants will then be 
randomly assigned in a 1:1 ratio on Day 0 to either the memantine group or the placebo 
group. A total of 256 participants will be enrolled, with 128 in each group. 
Stratification factors will include age (≥65 years vs. <65 years) and baseline PAC 
count (≥5000 per 24 hours vs. <5000 per 24 hours). 
The study is comprised of a screening period (≤ 7 days), a treatment period (Day 
42 ± 3 days), and a follow-up period (Day 56 ± 3 days). The study design is presented 
in the figure below. 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
7 
 
Notes: 
a) The drug administration period for this study spans from Day 42 to Day 45. The 
72-hour ambulatory ECG monitoring at visits V3, V4, and V5 is scheduled to begin 
on Day 25 to Day 28 for V3, Day 39 to Day 42 for V4, and Day 53 to Day 56 for V5. 
For the V4 visit, the ECG monitoring must commence 3 days prior to the end of the 
administration period. For example, if drug administration concludes on Day 42, the 
72-hour ambulatory ECG monitoring must begin on Day 39. Should the monitoring 
occur on Day 42, drug administration must continue until Day 45. 
(2) Other procedures during the V3 to V5 visits should be conducted after completing 
the 3-day Holter monitoring. 
The memantine group: participants will receive memantine according to the 
following regimen: 
Week 1: ½ tablet per dose (5 mg per dose), twice daily, to be taken at the same time 
each morning and evening (with a recommended dosing interval of 12 hours ± 2 
hours). 
Weeks 2 to 6: 1 tablet per dose (10 mg per dose), twice daily, to be taken at the same 
time each morning and evening (with a recommended dosing interval of 12 hours±
2 hours). 
The placebo group: participants will receive placebo tablets according to the 
following regimen: 
Week 1: ½ tablet per dose, twice daily, to be taken at the same time each morning 
and evening (with a recommended dosing interval of 12 hours ± 2 hours). 
Weeks 2 to 6: 1 tablet per dose, twice daily, to be taken at the same time each morning 
and evening (with a recommended dosing interval of 12 hours ± 2 hours). 
Duration of administration 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
8 
The duration of drug administration in this study will be from Day 42 to Day 45. 
Prohibited 
Medications 
The following medications are prohibited throughout the study period: 
a) NMDA antagonists, including amantadine, ketamine, dextromethorphan, and 
others.  
b) Levodopa, dopamine receptor agonists, anticholinergic agents, and barbiturates. 
c) Antiarrhythmic drugs 
d) Antispasmodic agents, including dantrolene, baclofen, and others. 
e) Other medications that, in the investigator’s judgment, may interfere with the 
efficacy or safety assessments. 
Calculation of 
Sample size 
Based on the results of our preliminary exploratory single-arm study evaluating the 
efficacy of memantine in the treatment of PACs, the 24-hour mean reduction in PACs 
was 75.4%. Considering the robustness of results from the small-sample trial and 
potential sampling error, we conservatively estimated a 50% reduction in the 24-hour 
mean burden of PACs following treatment with memantine, while the placebo group 
is expected to show a 30% reduction, with a standard deviation of 35%. The dropout 
rate is assumed to be 15.0%. Using EAST 6.5 software for sample size calculation 
with a one-sided α = 0.025 and a 1:1 allocation ratio between the memantine and 
placebo groups, a total of 256 participants will be enrolled, providing more than 95% 
power to detect the pre-specified between-group difference. 
Interim Analysis 
This study plans to conduct a non-blinded sample size re-estimation after 
approximately 128 participants (50%) have completed the primary endpoint 
assessment. The table below presents the superiority boundaries for the primary 
endpoint: 
Analysis 
Event Information Fraction 
α = 0.025 
Interim 
Analysis 
50% 
(approximately 
128 
subjects) 
Superiority Boundary: z = 
2.963 
Final Analysis 
100% (256 subjects) 
Superiority Boundary: z = 
1.969 
Note: The superiority boundaries are calculated using the Lan-Demets approximation 
of the O’Brien-Fleming boundaries with a spending function. These boundaries will 
be adjusted based on the actual number of participants observed. 
In addition to early termination for efficacy, if the conditional power derived from the 
actual observed results of both groups falls between 40% and 90% at the time of the 
interim analysis, a sample size adjustment will be made. 
The interim analysis will be conducted by an independent analysis team, and the 
results will be reviewed by an independent Data Monitoring Committee (IDMC), 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
9 
which will provide recommendations. The specific decision rules are outlined in 
Section 7.3.8. 
Statistical 
Analysis 
General Principle 
For continuous data, statistical descriptions will include the number of cases, mean, 
standard deviation, median, minimum, and maximum. 
For categorical data, statistical descriptions will include the number and percentage of 
cases. Percentages will be calculated using the number of participants in the 
corresponding group as the denominator, unless otherwise specified. 
Efficacy Analysis 
The difference between the two groups for the primary endpoint will be assessed by 
calculating the mean difference in the percentage reduction of 24-hour mean PACs at 
Week 6 between the memantine and placebo groups, along with its 95% confidence 
interval (CI). 
Descriptive statistics will be applied to the secondary efficacy endpoints. 
Safety Analysis 
All adverse events will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA), categorized by System Organ Class (SOC) and Preferred Term 
(PT). 
The number and incidence rate of adverse events (AEs), serious adverse events 
(SAEs), and AEs leading to death will be summarized. AEs, SAEs, and those resulting 
in death will also be summarized by SOC and PT, with the corresponding number of 
cases and incidence rates reported. 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
10 
1. Background  
The incidence of PACs increases with age [1,2]. Previously, PACs were considered 
benign arrhythmias with minimal clinical significance. However, recent studies have 
shown that frequent PACs may indicate subclinical cardiovascular disease. After 
adjusting for multiple variables, patients with frequent PACs have a 2- to 4-fold 
increased risk of developing AF, a 2- to nearly 3-fold increased risk of first stroke, a 39% 
to 100% increased risk of all-cause mortality, and a 74% increased risk of coronary 
artery disease [3]. 
The association between frequent PACs and AF, stroke, and mortality may be mediated 
by three distinct mechanisms: First, frequent PACs are more likely to progress to 
subclinical AF, which in turn increases the risk of stroke and death. Second, PACs are 
associated with traditional cardiovascular risk factors. Third, frequent PACs may 
indicate atrial cardiomyopathy, a condition characterized by electrophysiological 
abnormalities and a hypercoagulable state, which may still lead to thrombus formation 
in sinus rhythm, thus increasing stroke risk [1-2,4]. The growing recognition of the 
potential risks associated with frequent PACs has prompted clinicians to reconsider 
their clinical significance, suggesting that they should no longer be regarded as a benign 
condition. 
The European Heart Rhythm Association (EHRA) consensus on the management of 
asymptomatic arrhythmias recommends monitoring rhythm, addressing cardiovascular 
risk factors, and assessing for structural heart disease in patients with frequent PACs. 
For patients with >500 PACs/24 hours or any continuous episode of more than 20 PACs, 
especially if brief episodes of AF are observed, individualized anticoagulation therapy 
should be considered [5]. However, due to the lack of clinical evidence supporting 
antiarrhythmic drug treatment for PACs, the consensus does not recommend 
pharmacological therapy. Limited evidence from previous studies suggests that for 
patients with persistent symptomatic PACs, after minimizing potential triggers (e.g., 
smoking, caffeine, alcohol, stress), β-blockers may be used to reduce PAC frequency 
and associated symptoms, provided there are no contraindications. However, the 
effectiveness of β-blockers is uncertain and varies among patients. A cohort study 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
11 
investigating the use of low-dose β-blockers to improve the long-term prognosis of PAC 
patients found that, after propensity score matching, mortality was significantly lower 
in the treated group in the high-load subgroup (≥100 PACs/day) over a mean follow-up 
of approximately three years, although the incidence of new-onset stroke and AF was 
similar between groups [6]. Class IA, IC, and III antiarrhythmic drugs have been shown 
to reduce the frequency of symptomatic PACs and suppress arrhythmias such as AF, 
AFL, and atrioventricular reentrant tachycardia [7-9]. However, these drugs have not 
been subjected to controlled studies, and their use must be carefully weighed against 
the potential risk of pro-arrhythmia. Furthermore, digoxin, calcium channel blockers, 
and class IB antiarrhythmic drugs have not shown clear benefits in patients with 
symptomatic PACs. Therefore, there is an urgent need to develop novel drugs for the 
treatment of PACs and conduct prospective studies on antiarrhythmic therapies. 
The glutamate neurotransmitter system is a crucial signaling pathway that regulates the 
excitability and conduction of neurons. Similarly, myocardial cells, as excitable cells, 
also exhibit excitability and conduction properties. Yi-Han Chen's team first discovered 
that rat atrial myocardial cells have an intrinsic, rich glutamatergic neurotransmitter 
system, which regulates myocardial cell excitability and conduction by controlling 
ionotropic glutamate receptors (iGluRs). Under resting potential, activation of 
glutamate receptors in rat atrial muscle cells induces transient inward currents, 
facilitating the generation of action potentials, thus increasing cell excitability and 
conduction. Importantly, specific glutamate receptor inhibitors block this effect. 
Furthermore, a similar glutamatergic system with electrophysiological regulatory 
functions has been identified in human atrial myocardial cells [10,11].  
Memantine (Mem) is a voltage-dependent, non-competitive N-methyl-D-aspartate 
(NMDA) receptor antagonist that inhibits the activity of ionotropic glutamate receptors 
(iGluRs) [12]. It is used as a first-line treatment for moderate to severe Alzheimer's 
disease, with a good safety profile and patient tolerance [13]. Notably, preclinical studies 
conducted by Yi-Han Chen’s team have shown that memantine effectively reduces the 
incidence of AF induced by three different pathophysiological conditions (stretch-
induced, cholinergic, and ischemic AF) in isolated rat hearts in a concentration-

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
12 
dependent manner. In in vivo experiments, memantine effectively prevented and 
terminated AF induced by three different pathophysiological conditions (aortic 
constriction, acetylcholine, and hypoxia) in rats. The primary mechanism of action is 
that memantine blocks glutamate currents in atrial myocardial cells, reducing calcium 
leakage, and effectively reducing trigger activity, delayed afterdepolarization, and 
ectopic beats, thereby reducing AF triggers and effectively preventing AF. Additionally, 
memantine significantly decreased the number of reentrant circuits in the atrial 
myocardium, thus effectively terminating AF. Furthermore, memantine was shown to 
reduce the incidence of AF-like abnormal electrophysiological events and delayed 
afterdepolarization in human-induced pluripotent stem cell-derived atrial myocardial 
cells (iPSC ACMs), suggesting that this drug may also exert electrophysiological 
regulatory effects on human myocardial cells. Previous animal and clinical studies have 
demonstrated that memantine has a favorable safety profile, reducing the occurrence of 
reperfusion arrhythmias and slowing heart rate without prolonging the QT interval [15-
17], thus not increasing the risk of torsades de pointes. Based on these findings, we 
hypothesize that memantine may be an ideal treatment for rapid atrial arrhythmias. The 
repurposing of an existing drug significantly shortens the drug development timeline 
and reduces research costs. Therefore, this study aims to explore the efficacy and safety 
of memantine in patients with frequent PACs. 
2. Study Objectives and Endpoints 
2.1 Objectives 
Primary Objective — To evaluate the efficacy of memantine in treating frequent 
symptomatic PACs. 
Secondary Objective — To assess the safety profile of memantine in patients with 
frequent symptomatic PACs. 
2.2 Endpoints 
2.2.1 Efficacy Endpoints  

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
13 
Primary Efficacy Endpoint: The percentage change from baseline in the 24-hour 
mean number of PACs at Week 6. 
Secondary Efficacy Endpoints: 
1) The change from baseline in the 24-hour mean number and burden of PACs at 
Weeks 4, 6, and 8； 
2) The change from baseline in the 24-hour mean number and burden of non-
sustained atrial tachycardia (AT) at Weeks 4, 6, and 8; 
3) The change from baseline in the number of episodes of sustained atrial 
tachycardia, atrial fibrillation, and atrial flutter over a 24-hour period at Weeks 4, 6, and 
8. 
4) The change from baseline in the SF-36 quality of life score at Week 6; 
2.2.2 Safety Endpoints  
The incidence of AEs (including psychiatric symptoms, seizures, bradycardia and new-
onset heart failure, etc.), SAEs, laboratory test abnormalities, and abnormal ECG 
findings. 
3. Study Design 
3.1 Overall Design 
This investigator-initiated, multicenter, randomized, double-blind, parallel-group, 
placebo-controlled two-stage adaptive-design will enroll 256 adults (18–80 years of age) 
with frequent symptomatic PACs. 
After an initial eligibility screen, all candidates will undergo 72-hour continuous 
patch-based ambulatory electrocardiographic monitoring to quantify baseline PAC 
burden. Participants who meet the inclusion criteria will be randomly assigned on Day 0, 
in a 1:1 ratio, to receive oral memantine or matched placebo. Randomization will be 
stratified according to age (≥65 vs. <65 years) and baseline PAC burden 
(≥5000 vs. <5000 PACs per 24 hours), yielding 128 participants per group (total, 256). 
The protocol specifies five visits: 
• 
Visit 1 (Screening; ≤ 7 days before randomization) — Baseline clinical 
assessments and 72-hour ambulatory ECG monitoring. 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
14 
• 
Visit 2 (Day 7 ± 2 days) — Telephone contact to assess treatment compliance 
and solicit adverse events. 
• 
Visit 3 (Day 28 ± 3 days), Visit 4 (Day 42 ± 3 days; end of treatment), and Visit 5 
(Day 56 ± 3 days; end of study) — On-site evaluations, each including repeat 
72-hour ambulatory ECG monitoring. 
A schematic of the study procedures is provided in Figure 1. 
 
Figure 1 Study Design Flowchart 
The treatment phase will last 42 to 45 days. Seventy-two-hour ambulatory ECG will 
be initiated on study days 25–28 for Visit 3 (V3), days 39–42 for Visit 4 (V4), and 
days 53–56 for Visit 5 (V5). For V4, monitoring must begin 72 hours before the final 
scheduled dose; thus, if dosing concludes on day 42, monitoring must start on day 39. 
Conversely, if monitoring is initiated on day 42, study medication must continue 
through day 45.  
Other procedures during the V3 to V5 visits should be performed after completing 72 
hours (3 days) of continuous Holter monitoring. 
3.2 Study Centers 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
15 
The trial will be conducted at approximately 20 hospitals across China; the number of 
participating sites may be adjusted on the basis of operational considerations. 
3.3 Randomization and Blinding 
3.3.1 Randomization and Blinding 
Eligible participants will be randomly assigned, in a 1:1 ratio, to receive either 
memantine or matching placebo. A stratified block design will be used, with 
randomization stratified by baseline 24-hour PAC burden (≥5000 vs. <5000 PACs per 
24 hours) and age (≥65 vs. <65 years). An independent statistical team which is 
otherwise unaffiliated with the study will generate the randomization list and 
corresponding treatment-allocation list with SAS software (version 9.4 or higher). Both 
lists will be uploaded to an interactive response technology (IRT) system, which will 
assign each participant a unique randomization number and the corresponding 
study-drug kit on Day 0. Randomization and kit numbers, once issued, will not be 
reused. Participants who withdraw from the study—irrespective of drug exposure—
will not be re-enrolled. 
3.3.2 Blinding 
This is a double-blind trial: investigators, participants, and site personnel—including 
monitors, data managers, and statisticians—will remain unaware of treatment 
allocation until the prespecified unblinding conditions are met. Placebo tablets are 
identical to active tablets in appearance, odor, weight, packaging, and dosing schedule 
but contain no active memantine. Blinding will be maintained from generation of the 
randomization code through drug dispensing, data collection, monitoring, data 
management, and statistical analysis. 
3.3.3 Emergency Unblinding 
Unblinding is permitted only when a participant experiences a medical emergency in 
which knowledge of the assigned treatment is indispensable for appropriate 
management. If emergency unblinding is not required to manage the event, the blind 
must be maintained. 
• 
The investigator must document the date, time, reason, and personnel involved 
in the unblinding and notify the study monitor without delay. 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
16 
• 
A safety report must be submitted to the institutional ethics committee as soon 
as possible. 
• 
The participant must discontinue study medication but will remain in the study 
for continued follow-up; the reason for treatment discontinuation must be 
recorded in the case-report form. 
• 
At study close-out, the frequency, reasons, extent, and timing of all emergency 
unblinding will be summarized and evaluated for their potential impact on 
efficacy and safety analyses. 
In the event of an unexpected SAE, individual unblinding will be performed according 
to the same procedure to determine whether the SAE constitutes a suspected unexpected 
serious adverse reaction (SUSAR). All other study personnel will remain blinded, and 
the participant will not be considered lost to follow-up. 
3.3.4 Interim Analysis Unblinding 
Interim analysis unblinding: At the pre-specified time point for interim analysis, 
following database lock, population stratification, and finalization of the statistical 
analysis plan, unblinding will occur. Group assignment information will be disclosed 
only to the Data Monitoring Committee and its independent statistical team for analysis 
and reporting. 
3.3.5 Final Unblinding 
After the database lock, confirmation of analysis populations, and finalization of the 
statistical analysis plan, the study statistician will submit a written request for final 
unblinding. The request must be countersigned by the principal investigator and the 
statistician. Upon receipt of the signed approval, the randomization manager will 
release the treatment codes. 
4. Study Population 
4.1 Inclusion Criteria 
(1) Age: 18 to 80 years, inclusive. 
(2) Symptomatic PACs: Documented at screening as ≥ 1,000 PACs during a 24-
hour ambulatory ECG recording.  

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
17 
(3) Informed consent: Ability and willingness to understand and comply with all 
study procedures and to sign the written informed-consent form before any protocol-
specific activities are performed. 
4.2 Exclusion Criteria 
(1) Atrial or ventricular arrhythmias 
Atrial fibrillation, atrial flutter, or persistent atrial tachycardia documented by 12-lead 
ECG within 6 months before screening or detected on the baseline 72-hour patch-type 
ambulatory ECG. 
Ventricular tachycardia (excluding brief nocturnal runs) or ventricular fibrillation. 
(2) Recent cerebrovascular or cardiac events 
Ischemic or hemorrhagic stroke, or transient ischemic attack, within 6 months before 
screening. 
Cardiac surgery, myocardial infarction, percutaneous coronary intervention, or cardiac 
radiofrequency ablation within 6 months before screening. 
(3) Severe left-sided cardiac dysfunction 
Left-ventricular ejection fraction ≤ 40 %. 
New York Heart Association class III or IV heart failure. 
(4) Clinically significant conduction disease 
Sick-sinus syndrome without a permanent pacemaker. 
Second-degree type II or higher atrioventricular block, or bifascicular block. 
Diagnosed systemic or metabolic condition that could lead to severe bradycardia or 
conduction abnormalities, such as cardiac sarcoidosis or untreated severe 
hypothyroidism. 
(5) Recent antiarrhythmic therapy 
Amiodarone within 4 weeks before screening. 
Any other antiarrhythmic agent—including herbal preparations with antiarrhythmic 
properties—within 2 week before screening. 
(6) Other serious cardiac conditions 
Unstable angina, severe congenital heart disease (except patent foramen ovale), prior 
prosthetic heart-valve replacement, acute myocarditis or endocarditis, rheumatic 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
18 
valvular disease, hypertrophic cardiomyopathy, congenital long QT syndrome, 
congenital short QT syndrome, Brugada syndrome, or catecholaminergic polymorphic 
ventricular tachycardia.. 
(7) Limited life expectancy 
Any comorbid condition with an anticipated survival of < 1 year. 
(8) Hepatic impairment 
Active hepatitis or clinically significant liver dysfunction (ALT or AST > 3 × ULN, or 
total bilirubin > 3 × ULN). 
(9) Renal impairment 
Estimated glomerular filtration rate < 40 mL · min⁻¹ · 1.73 m⁻² (CKD-EPI formula). 
(10) Concurrent investigational therapy 
Use of any investigational drug or device within 1 month—or five elimination half-
lives, whichever is longer—before screening. 
(11) Pregnancy or lactation 
Pregnant or breastfeeding women, or a positive serum pregnancy test before 
randomization. 
(12) Metabolic, surgical, or pulmonary instability 
The presence of atrial premature beats due to potential reversible causes, such as 
hyperthyroidism, cardiovascular surgery, electrolyte imbalances, etc. APBs decrease 
and symptoms significantly improve after the removal of triggers (e.g., alcohol abuse, 
acute exacerbation of chronic obstructive pulmonary disease (AECOPD) with 
respiratory failure, or unresolved infections). 
(13) Neurologic or psychiatric disorders 
History of epilepsy, seizures, or psychiatric illness that could interfere with study 
participation. 
(14) Drug hypersensitivity 
Known allergy to memantine hydrochloride or any excipient of the study drug. 
(15) Current memantine therapy 
Ongoing treatment with memantine for moderate-to-severe Alzheimer’s disease. 
(16) Other contraindications 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
19 
Any condition that, in the investigator’s judgment, makes the participant unsuitable for 
enrollment in the study. 
4.3 Withdrawal Criteria 
4.3.1 Participant-Initiated Withdrawal 
Participants have the right to withdraw from the study at any time, as outlined in the 
informed consent form. This includes situations where a participant withdraws consent, 
discontinues the study medication or related assessments, or is lost to follow-up (which 
is also considered a withdrawal or dropout). The reasons for withdrawal should be 
documented whenever possible. Participants may choose to withdraw for various 
reasons, including but not limited to lack of efficacy, adverse events, or for no specific 
reason. 
4.3.2 Investigator-Initiated Withdrawal 
If a participant who has been enrolled in the study experiences any of the following 
conditions during the study, the investigator will decide whether the participant should 
be withdrawn from the study: 
(1) The investigator determines, from an ethical standpoint, that it is necessary to 
withdraw the participant. 
(2) The participant demonstrates poor adherence (e.g., failing to follow the study 
protocol for medication use or missing more than half of scheduled follow-up visits). 
(3) The participant is unable to tolerate symptoms related to atrial premature beats. 
(4) The participant experiences allergic reactions, neuropsychiatric symptoms, or other 
serious adverse events, and the investigator deems withdrawal necessary. 
(5) The participant experiences an emergency requiring treatment that is not part of the 
study protocol. 
In the event of withdrawal due to the reasons mentioned above, the study assessments 
or telephone follow-ups will continue. 
4.4 Procedures for Early Withdrawal 
For participants who withdraw early from the study, if the participant is unwilling to 
continue participating but agrees to follow-up for safety monitoring, relevant exit visits 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
20 
should be conducted. Every effort should be made to collect pertinent information, 
including the withdrawal date, reason for withdrawal, and any other relevant details. 
(1) If a participant voluntarily requests to withdraw from the study, the reason for 
discontinuing the study medication should be inquired about, along with any 
adverse events that may have occurred. If adverse events are reported, the 
investigator should identify and document the adverse event data, record it in the 
CRF, and conduct follow-up on the adverse event. 
(2) Every effort should be made to capture all available data from participants who 
discontinue, with special attention to potential endpoint events. Complete loss to 
follow-up threatens data integrity and should be avoided whenever possible. 
(3) Participants who discontinue the study should continue to be followed at scheduled 
visit time points whenever possible, and data should be collected in accordance with 
the study protocol. If a participant declines in-person visits and assessments but 
agrees to modified follow-up by telephone, telephone follow-up should be 
conducted until the end of the study. If the participant declines all forms of follow-
up, he or she will be formally withdrawn from the study, and this should be 
documented in the electronic case report form (eCRF). 
(4) Study medication must be retrieved from all participants who discontinue the study, 
and proper documentation of the return must be maintained. 
5. Investigational Products 
5.1 Product Characteristics 
 Table 1  Investigational Product Information 
Parameter 
Memantine Hydrochloride 
(Active) 
Placebo 
Dosage form 
Film-coated tablet 
Film-coated tablet 
Strength 
10 mg per tablet 
Not applicable 
Route of 
administration 
Oral 
Oral 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
21 
Parameter 
Memantine Hydrochloride 
(Active) 
Placebo 
Storage conditions Sealed container, 10–30 °C 
Sealed container, 10–30 °C 
Shelf life 
48 months 
48 months 
Manufacturer 
Lundbeck A/S, (Denmark) 
Qilu Pharmaceutical Co., Ltd., 
(China) 
The placebo tablets are indistinguishable from the active tablets in appearance, weight, 
taste, packaging, and dosing schedule but contain no memantine hydrochloride. 
5.2 Dosing Regimen 
Beginning on Day 1, participants in both the memantine and placebo groups will 
receive one-half tablet (5 mg) twice daily for 7 days. From Week 2 onward, the dose 
will be increased to one tablet (10 mg) twice daily and continued through the end of 
Week 6. The complete dosing schedule is summarized in Table 1. 
Participants assigned to either memantine or matching placebo will follow a two-step, 
twice-daily schedule: 
                          Table2   Dosing Regimen 
Study Week Dose per administration Total daily dose 
Administration details* 
Week 1 
½ tablet (5 mg) 
10 mg 
Orally, at consistent morning and evening times 
(recommended interval, 12 h ± 2 h) 
Weeks 2 – 6 1 tablet (10 mg) 
20 mg 
Orally, at consistent morning and evening times 
(recommended interval, 12 h ± 2 h) 
* Each active tablet contains 10 mg memantine. Placebo tablets are identical in appearance, 
weight, packaging, and schedule but contain no active ingredient. The planned treatment duration 
is 42–45 days. 
5.3 Supply, Packaging and Labeling of Investigational Product 
Sufficient quantities of investigational product will be supplied to each study site for 
the full duration of the trial. All products will be packaged and labelled in compliance 
with applicable regulatory requirements. 
The memantine and matching placebo will be packaged identically. Each outer carton 
will display the statement “For Clinical Trial Use Only” together with the product 
name, kit number, batch number, expiration date, storage conditions, and sponsor name. 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
22 
Cartons and labels will be identical except for the unique kit number assigned to each 
package. 
5.4 Investigational Product Accountability 
Designated pharmacy personnel at each study site are responsible for the receipt, 
storage, dispensing, and reconciliation of all investigational product (IP). Complete, 
contemporaneous documentation must be maintained throughout the trial. 
Table 3    Study Drug Handling and Accountability 
Process 
Requirements 
Receipt 
Upon delivery, the site pharmacist (or authorized designee) verifies the shipment 
against the packing list, completes and signs the drug-receipt form, and 
documents the date of receipt. 
Storage 
IP must be stored in a locked, access-controlled cabinet under the temperature 
conditions specified on the label (10 – 30 °C). Storage and handling procedures 
must comply with all applicable regulations. 
Dispensing 
IP is dispensed according to each participant’s randomization number and 
corresponding kit number, as assigned by the IRT system. 
Reconciliation 
For every kit, the following details must be entered promptly and indelibly in the 
drug-accountability log: date dispensed, quantity issued, kit number, participant 
randomization number, return of empty packaging, and quantity of unused tablets 
returned or destroyed. 
Inspection 
All IP accountability records are subject to review by study monitors, auditors, 
and regulatory inspectors. 
Any discrepancies must be documented, investigated, and resolved in accordance with 
the sponsor’s standard operating procedures. 
5.5 Return and Destruction of Investigational Product 
At study close-out, all unused, partially used, and empty investigational-product 
containers—together with their original packaging—must be returned to the sponsor 
for authorized destruction. Each shipment shall be accompanied by a fully completed, 
dated, and signed Drug-Accountability/Return Form. 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
23 
The outer shipping carton must be clearly labelled with the protocol number, study-site 
identifier, and the statement “Clinical Trial Material – Return for Destruction.” 
5.6 Concomitant Medications 
From the signing of informed consent until the final study visit, any pharmacotherapy 
given for comorbid conditions or to treat adverse events must be documented in full. 
Required details include the medication name, indication, dose, dosing frequency, start 
and stop dates/times, and route of administration. 
5.7 Prohibited Medications 
The following medications are prohibited throughout the study period: 
(1) NMDA antagonists, including amantadine, ketamine, dextromethorphan, and 
others.  
(2) Levodopa, dopamine receptor agonists, anticholinergic agents, and barbiturates. 
(3) Antiarrhythmic drugs. 
(4) Antispasmodic agents, including dantrolene, baclofen, and others. 
(5) Other medications that, in the investigator’s judgment, may interfere with the 
efficacy or safety assessments. 
6. Study Procedures and Visit Schedule 
The trial is divided into three phases: a screening period (Visit 1, V1), a treatment period 
(Visits 2– 4, V2–V4), and a follow-up visit (Visit 5, V5). Participants will attend all 
visits as outlined in the protocol. Any AE occurring during the study will be followed 
until the event resolves, stabilities, or the participant is lost to follow-up. 
An overview of scheduled activities is provided in the study‐flow diagram, and detailed 
requirements for each assessment are listed in Table 2. For participant safety, the 
investigator may increase the frequency of scheduled assessments or add unscheduled 
assessments not specified in the flow diagram whenever clinically warranted (e.g., in 
response to an AE). 
 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
24 
6.1 Study  Flow Diagram 
 
Screening 
period 1 
(≤ 7d) 
treatment period 
follow-up 
period 
early withdrawal 
Visits 2 
Symptom 
initiation 
additional visit 
manipulate 
V1 
V2 
V3 
V4 
V5 
 
 
D7±2d 
D28±3d 
D42±3d 
D56±3d 
Day of exit  +7d 
 
Signed informed consent 
 
 
 
 
 
 
 
Symptom assessment 3 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
 
 
 
 
 
 
Demographic information 
 
 
 
 
 
 
 
Basic information 4 
 
 
 
 
 
 
 
Prior 
and 
co-morbidities, 
smoking and drinking, history 
of allergies5 
 
 
 
 
 
 
 
History of prior non-drug 
treatment, prior drug therapies 
6 
 
 
 
 
 
 
 
Vital signs 7 
 
 
 
 
 
 
 
NYHA 
Cardiac 
Function 
Classification 
 
 
 
 
 
 
 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
25 
Cardiac ultrasound 
 
 
 
 
 
 
 
Hematology tests 8 
 
 
 
 
 
 
 
Urine PH 
 
 
 
 
 
 
 
Blood or urine HCG9 
 
 
 
 
 
 
 
12-lead ECG 
 
 
 
 
 
 
 
3-day 
cardiac 
patch 
monitoring 10 
 
 
 
 
 
 
 
Randomization 
(D0) 
 
 
 
 
 
 
Issuance and collection of 
diary cards 
(Issuance 
only) 
 
 
 
 
( Collection) 
 
Return of experimental drugs 
 
 
 
 
 
(If applicable) 
 
Adjustment of medication 
 
 
 
 
 
 
 
AEs and co-medication 
 
 
 
 
 
 
 
SF-36 Health Questionnaire 
Scores 
 
 
 
 
 
 
 
Table 4  Study  Flow Diagram 
Notes: 
1. The screening period examination of this study can accept the relevant examination results of our center within 1 month prior to the informed date (acceptable at the judgment of the investigator, 
otherwise the relevant examination is required). 
2. If a subject withdraws from the study after completing the end - of - treatment visit (V4), for the relevant examinations related to early withdrawal (excluding the 3 - day ECG patch monitoring), 
if the time interval from the V4 visit is ≤ 7 days or the investigator determines that repetition is unnecessary, these examinations do not need to be repeated. However, the reason for not conducting 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
26 
the examinations should be described in the original case report. Pregnancy tests should be carried out as required. If a subject withdraws before V4, regardless of whether the V3 visit has been 
completed, all relevant procedures for early withdrawal must be performed. 
3. Symptom assessment: the assessment includes the nature of the PACs symptoms, the frequency and duration of the episodes, and whether the nature of the symptoms has changed. 
Nature of symptoms: Palpitations, a fluttering or pounding sensation in the heart, a sense of the heart skipping beats, fatigue, weakness, shortness of breath, discomfort in the chest or precordial 
area, dizziness, etc. 
Frequency of episodes: daily, weekly, monthly, etc; 
Duration: minutes, hours, sustained; 
Symptom scores: 
Score 0: No symptoms; 
Score 1: Mild symptoms, occasional palpitations that do not affect daily life; 
Score 2: Moderate symptoms, frequent palpitations, mildly interfering with daily life; 
Score 3: Severe symptoms with persistent palpitations that significantly interfere with daily life; 
4. Basic information including height, weight, waist circumference, education level, etc; 
5. Past medical history: hemorrhagic/ischemic stroke, transient ischemic attack, myocardial infarction, history of epilepsy or seizures, and psychiatric disorders; 
6. History of prior medications: medication use within 4 weeks prior to screening; history of non-drug therapy (including surgery): history of non- drug therapy within 6 months prior to screening; 
collection of a full history of prior cardiac-related surgery; 
7. Vital signs include temperature, blood pressure, pulse, and respiration; 
8, Including routine blood, liver function (alanine aminotransferase, glutamic aminotransferase, gamma glutamyl transpeptidase, total bilirubin, direct bilirubin, indirect bilirubin), thyroid function 
(fT3, fT4, TSH), renal function (creatinine, urea nitrogen or urea, glomerular filtration rate), electrolytes (blood sodium, potassium, magnesium, calcium), blood lipids (total cholesterol, triglyceride, 
HDL cholesterol, LDL cholesterol ester), fasting blood glucose, glycated hemoglobin, NT-pro BNP or BNP.  
9. Female subjects of childbearing age should undergo blood or urine HCG test to exclude pregnancy. 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
27 
10. The duration of drug administration in this study was 42-45 days, and the start time of 3-day (72h) ECG recorder monitoring for V3~V5 visits was D25~D28 for V3, D39~D42 for V4, and 
D53~D56 for V5, respectively. ECG monitoring for the V4 visit should be started 3 days prior to the end of the drug administration, and the 3 consecutive days (72h) of ECG recorder monitoring 
should be performed at D39, if the administration of drug was ended at D42. recorder monitoring needs to be performed at D39. If 3 consecutive days (72h) of ECG monitoring is performed at 
D42, the drug must be administered until D45; other operations for V3~V5 visits are performed after completing the 3-day ECG recorder monitoring. 
Table 5  Specific requirements for each inspection item 
Inspection item 
Requirements and observables 
vital signs 
Temperature, blood pressure, pulse, respiration. 
12-lead ECG 
Heart rate, P-R interval, QRS wave duration, Q-Tc interval (calculated by Bazett’s formula), presence of AFL, presence of AF, presence 
of atrioventricular block 
Blood or urine 
pregnancy 
Blood/urine human chorionic gonadotropin, fertile women only. For infertile women, please note the reason, e.g. menopause ≥ 1 year, 
hysterectomy, sterilization, etc.  
Laboratory tests 
➢ 
Routine blood count: white blood cell count, neutrophil ratio and count, lymphocyte ratio and count, red blood cell count, hemoglobin 
amount, red blood cell pressure volume, platelet count 
➢ 
Liver function: alanine aminotransferase, glutamine aminotransferase, gamma glutamyl transpeptidase, total bilirubin, direct bilirubin, 
indirect bilirubin. 
➢ 
Thyroid function: fT3, fT4, TSH; 
➢ 
Renal function: creatinine, urea nitrogen or urea, glomerular filtration rate; 
➢ 
Electrolytes: blood sodium, blood potassium, blood magnesium, blood calcium 
➢ 
Lipids: total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol esters 
➢ 
Fasting glucose, glycosylated hemoglobin, NT-pro BNP or BNP 
➢ 
Urine PH 
Ambulatory 
electrocardiograph 
monitoring 
➢ 
24-hour average number and load of PACs, 24-hour average number and load of bouts of NSAT, 24-hour average episodes count of 
NSAT, SAT, AF, AFL 
➢ 
Monitoring start time and end time, monitoring duration 
 
Cardiac ultrasound 
➢ 
Left atrial internal diameter (mm), septal thickness (mm), left ventricular end-systolic internal diameter (mm), left ventricular end-
diastolic internal diameter (mm), left ventricular ejection fraction (LVEF %) 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
28 
Inspection item 
Requirements and observables 
NYHA Cardiac 
Function Classification 
➢ 
Class I, II, III, IV 
 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
29 
6.2 Study Procedure 
6.2.1 Screening Period (Visit 1) 
Informed consent. Written informed consent must be obtained before any 
study-specific procedure performed. 
Medical interview and data collection. 
Demographics: age, sex, height, weight, waist circumference, race/ethnicity, and 
highest educational level. 
Medical history: past and current illnesses (within 6 months before screening), 
allergy history, smoking and alcohol use, prior non-drug cardiac interventions (e.g., 
percutaneous coronary intervention, coronary-artery bypass grafting, catheter ablation), 
participation in clinical trials, concomitant medications, and prior surgeries. 
Physical examination. 
Vital signs: pulse, respiratory rate, blood pressure, and body temperature. 
NYHA functional class. 
Laboratory and diagnostic tests. 
Complete blood count. 
Urine pH. 
Serum or urine human chorionic-gonadotropin (hCG) test, as appropriate. 
Standard 12-lead ECG. 
Health-related quality-of-life assessment using the SF-36 questionnaire. 
Baseline ambulatory ECG. 
Candidates who meet the above criteria undergo 72-hour continuous patch-based ECG 
monitoring to quantify PACs and confirm eligibility. Randomization is based on these 
data. 
Randomization and study materials. 
Eligible participants are randomized, then provided with study medications and diaries. 
Ambulatory ECG data points. 
The 72-hour recording captures: 
24-hour mean PAC count and burden. 
24-hour mean number and burden of NSAT episodes. 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
30 
Episodes of SAT, AF, and AFL. 
Incidence of new-onset SAT, AF, or AFL during any 72-hour recording window. 
Any AE identified during screening is followed until it resolves, stabilizes, or the 
participant is lost to follow-up. 
6.2.2 Treatment Phase 
Day 1 (D1) marks the initiation of study drug administration. Participants will 
self-administer the investigational product per the dosing regimen described in 
Section 6.2 and will attend all protocol-specified visits. 
The treatment phase consists of three scheduled visits: 
• 
Visit 2 (Day 7 ± 2 days; telephone) — Evaluate treatment adherence, review 
AEs, and document concomitant medications. 
• 
Visit 3 (Day 28 ± 3 days; on-site) — Conduct a clinical assessment and initiate 
72-hour continuous patch-based ambulatory ECG monitoring. 
• 
Visit 4 (Day 42 ± 3 days; on-site; end of treatment) — Perform a clinical 
assessment and repeat 72-hour ambulatory ECG monitoring. 
All procedures will be conducted in strict accordance with the protocol to ensure 
consistent safety and efficacy assessments. 
6.2.3 Follow-up Phase 
A single post-treatment follow-up visit will be conducted on Day 56 ± 3 days. All 
evaluations will be performed in accordance with the study-flow schedule. 
7. Statistical Analysis 
7.1 Sample-Size Determination 
In our preliminary exploratory single-arm study, memantine produced a 75.4 % mean 
reduction in 24-hour PAC burden. Considering the robustness of results from the small-
sample trial and potential sampling error, the present trial conservatively assumes a 50 % 
reduction in the memantine group and a 30 % reduction in the placebo group, with a 
common standard deviation of 35 %. Factoring in a 15 % dropout rate, a one-sided α 
level of 0.025, and a 1:1 randomization ratio, a sample-size calculation performed with 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
31 
EAST software (version 6.5) indicates that 256 participants (128 per group) will 
provide >95 % statistical power to detect the prespecified between-group difference. 
7.2 Analysis Sets 
Full Analysis Set (FAS) — Includes all randomized participants who receive at 
least one dose of investigational product; analyzed in the treatment groups to which 
they were randomly assigned (intention-to-treat principle). 
• Per-Protocol Set (PPS) — Includes all randomized participants who received at 
least one dose of investigational product, underwent at least one post-baseline efficacy 
assessment, and had no major protocol deviations that could affect evaluation of the 
primary efficacy endpoints. 
• Safety-analysis-set (SS)— Includes all randomized participants who received at 
least one dose of investigational product; safety endpoints are analyzed according to 
the treatment actually received. 
7.3 Analysis Plan 
7.3.1 Statistical Hypothesis 
The primary efficacy endpoint is the percentage change from baseline to Week 6 in the 
24-hour mean count of PACs. 
• 
Null hypothesis (H0): The mean percentage reduction in the memantine group 
is ≤ the mean percentage reduction in the placebo group. 
• 
Alternative hypothesis (H1): The mean percentage reduction in the memantine 
group is > the mean percentage reduction in the placebo group. 
These hypotheses will be tested at a two-sided α of 0.05.  
A one-sided p-value of less than 0.025 indicates that the null hypothesis can be rejected, 
suggesting that the treatment group is superior to the placebo group. 
7.3.2 General principles 
• 
Continuous variables will be summarized by the number of observations (n), 
mean, standard deviation, median, minimum, and maximum values. 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
32 
• 
Categorical variables will be summarized by the number of observations (n) 
and corresponding percentage. Unless otherwise specified, all percentages will 
use the relevant analysis-population denominator. 
Comprehensive statistical methods are detailed in the Statistical Analysis Plan (SAP), 
which will be finalized before database lock. This protocol provides only an overview 
of the planned analyses; in the event of any discrepancy, the SAP will take precedence. 
7.3.3 Study Disposition and Participant Flow 
The number and percentage of participants who were screened, experienced screen 
failure, were randomized, received at least one dose of study medication, and completed 
the trial will be summarized. Principal reasons for treatment discontinuation and/or 
study withdrawal will be tabulated according to the categories recorded in the electronic 
case-report form (eCRF). Final counts for each analysis population will also be 
provided. 
7.3.4 Demographics and Baseline Characteristics 
Demographic and baseline variables will be summarized descriptively for each 
treatment group. Key parameters will include (but are not limited to) age, sex, 
race/ethnicity, body-mass index, relevant medical history, and previous therapies. All 
summaries will be performed on the FAS. 
7.3.5 Medication Adherence 
(1) Study-drug exposure and adherence will be described for each treatment group 
using descriptive statistics. 
(2) Concomitant medications will be tabulated and analyzed as appropriate. 
7.3.6 Efficacy Analyses 
All efficacy evaluations will be conducted on the FAS. 
• 
Primary endpoint — The between-group difference in the percentage change 
from baseline to Week 6 in 24-hour premature atrial contraction (PAC) burden 
will be estimated, and the mean difference will be presented with its two-sided 
95 % confidence interval. 
• 
Secondary endpoints—Descriptive statistics will be applied to the secondary 
efficacy endpoints. 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
33 
7.3.7 Safety Analysis 
7.3.7.1 Adverse-Event Analyses 
All AEs will be coded using the MedDRA and classified by SOC and PT. The analysis 
will focus on treatment-emergent adverse events (TEAEs)—events that first occur or 
worsen after the initial dose of study drug. Unless otherwise specified, AE denotes 
TEAEs throughout this section. 
• 
Overall incidence — For each treatment group, the number of participants (n) 
and proportion (%) with any TEAE, SAE, or AE leading to death will be 
summarized. 
• 
Incidence by SOC and PT — TEAEs, SAEs, and fatal events will also be 
tabulated by SOC and PT, with counts and percentages reported for each group. 
7.3.7.2 Other Safety Assessments 
Additional safety parameters—such as clinical laboratory results, vital signs, and 
12-lead ECG findings—will be summarized descriptively. 
7.3.8 Mid-term Analysis 
This study plans to conduct a sample size re-estimation in an unblinded manner after 
approximately 128 participants (50%) have completed the primary endpoint evaluation. 
The table below presents the superiority boundaries for the primary endpoint. 
 Table 6  Interim analysis  
Analysis 
Event Information Ratio 
α = 0.025 
Interim Analysis 
50% (approximately 128 
subjects) 
Superiority Boundary: z = 2.963 
Final Analysis 
100% (256 subjects) 
Superiority Boundary: z = 1.969 
Note: The superiority boundaries were calculated using the Lan-Demets approximation of the O’
Brien-Fleming boundaries with a spending function. These boundaries will be adjusted based on the 
actual number of participants observed. 
In addition to early termination for efficacy, if the conditional power based on the actual 
observed results of the two groups falls between 40% and 90% at the time of the interim 
analysis, a sample size adjustment will be made. 
The interim analysis will be conducted by an independent analysis team, with the results 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
34 
reviewed by an independent Data Monitoring Committee (IDMC), which will provide 
corresponding recommendations. The decision rules are shown in the figure below: 
 
       Figure 2  Interim analysis for sample size re-estimation 
Note: Conditional power (CP) is calculated based on the efficacy observed at the time of the interim 
analysis. The calculation of the difference is based on a standard deviation of 0.35; different standard 
deviations will yield different values for the difference. 
7.3.9 Multiplicity Adjustment 
The Lan-Demets spending function with the O’ Brien-Fleming approximation, in 
combination with the CHW method, will be used to strictly control the one-sided Type 
I error rate at α = 0.025. 
7.3.10 Handling of Missing Data  
In the event that data on the number of premature beats at Week 6 is missing, LOCF 
will be applied. If required, sensitivity analyses will be provided in the SAP. 
Missing values for other secondary and safety endpoints will not be imputed. 
8. Safety Evaluation 
8.1 Definitions 
8.1.1 AEs  
An AE is any untoward medical occurrence in a participant who has received the 
investigational product. Manifestations may include clinical signs or symptoms, new 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
35 
illnesses, or clinically significant laboratory abnormalities, irrespective of an 
established causal relationship with the study drug. 
Because pre-dose safety information provides essential context for interpreting 
on-treatment findings, AE recording begins at the signing of the informed-consent form. 
These data establish the participant’s baseline status and assist in determining whether 
subsequent events are study related. 
TEAE is an AE that first appears—or an existing event that worsens in severity—after 
the initial dose of study medication. Unless otherwise noted, the term AE in this 
protocol refers to TEAEs. 
8.1.2 Serious Adverse Events (SAEs) 
An SAE is any untoward medical occurrence that, after administration of the 
investigational product, satisfies one or more of the following criteria: 
(1) Results in death 
Death is an outcome and should not be used as the event term. 
If the death is sudden and the cause is initially unclear, report the event as “sudden 
unexplained death.” Continue follow-up until the cause is established; once confirmed, 
update the SAE term to reflect the specific cause of death. 
(5) Is life- threatening 
The participant was, at the time of the event, at immediate risk of death; events that 
could have become life-threatening if they had progressed are not included. 
(3) Requires inpatient hospitalization or prolongation of existing hospitalization 
Hospitalization (or extension of an existing stay) is not classified as an SAE if it meets 
any of the following conditions: 
Inpatient stay < 12 hours. 
Admission planned before the first study dose (e.g., elective surgery or a 
protocol-mandated procedure). 
Admission unrelated to an AE (e.g., social or respite care). 
Elective admission for treatment of a pre-existing condition that has not worsened 
relative to baseline. 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
36 
 Note: Any SAE that otherwise meets serious criteria and occurs during such a hospital 
stay must still be reported. 
(4) Results in persistent or significant disability/incapacity 
A substantial disruption in a participant’s ability to conduct normal daily activities. 
(5) Results in a congenital anomaly or birth defect 
(6) Other medically important events 
Events that may not immediately result in death, be life-threatening, or require 
hospitalization but, in the investigator’s judgment, could jeopardise the participant or 
require medical or surgical intervention to prevent one of the outcomes listed above. 
Examples include emergency treatment for severe bronchospasm, seizures managed 
outside the hospital, clinically significant cachexia, or the development of drug 
dependence or addiction. 
8.2 AE Assessment 
All AEs will be assessed and documented by the investigator according to the categories 
outlined below. 
8.2.1 Seriousness 
Each AE will be evaluated for seriousness in accordance with the protocol definition of 
a SAE. 
8.2.2 Severity Grading 
AEs will be classified as mild, moderate, or severe: 
• 
Mild events are transient or easily tolerated, do not interfere with daily activities, 
and require no treatment or only minimal intervention. 
• 
Moderate events interfere to some extent with daily activities, may partially 
impair normal function, and generally warrant medical intervention. 
• 
Severe events prevent normal daily activities, entail marked functional 
impairment, and require systemic therapy or other intensive treatment; they may 
be life-threatening or disabling. 
Severity describes the intensity of an event and is distinct from its seriousness; the two 
attributes are assessed independently. 
8.2.3 Causality 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
37 
The investigator is responsible for assessing the causality between each AE recorded in 
the eCRF and the investigational product. This evaluation will be based on all available 
information at the time of completing the eCRF and is a clinical judgement. 
The causality will be classified into one of five categories based on the plausibility of a 
relationship between the AE and the investigational product: related, very likely related, 
possibly related, possibly unrelated, and unrelated. Events classified as related, very 
likely related, or possibly related will be considered to have a potential or cannot be 
excluded as related to the study treatment, and will be classified as related. Events 
categorized as possibly unrelated or unrelated will be classified as unrelated. 
When assessing the causal relationship between an AE and the study treatment, the 
following factors should be considered: 
Related: There is a reasonable temporal relationship; the event aligns with the known 
pharmacological mechanism, characteristics, or known adverse effects of the 
investigational product; the event is positively dechallenged; no other reasonable 
explanation exists for the event; and the event is positively rechallenged. 
Very Likely Related: There is a reasonable temporal relationship; the event aligns with 
the known pharmacological mechanism, characteristics, or known adverse effects of 
the investigational product; the event is positively dechallenged; no other reasonable 
explanation exists for the event; and there is no evidence of positive rechallenge. 
Possibly Related: There is a reasonable temporal relationship; there is no evidence of 
positive rechallenge; and the event falls into one of the following categories: 
(1) The event is consistent with the known pharmacological mechanism, 
characteristics, or known adverse effects of the investigational product; the 
event is positively dechallenged, but other plausible explanations exist. 
(2) The event is consistent with the known pharmacological mechanism, 
characteristics, or known adverse effects of the investigational product; there is 
no evidence of positive dechallenge, and no other plausible explanations exist. 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
38 
(3)  The event is not consistent with the known pharmacological mechanism, 
characteristics, or known adverse effects of the investigational product; the 
event is positively dechallenged, and no other plausible explanations exist. 
(4) The event is not consistent with the known pharmacological mechanism, 
characteristics, or known adverse effects of the investigational product; the 
event is positively dechallenged, but other plausible explanations exist. 
(5) The event is not consistent with the known pharmacological mechanism, 
characteristics, or known adverse effects of the investigational product; there is 
no evidence of positive dechallenge, and no other plausible explanations exist. 
Possibly Unrelated: There is a reasonable temporal relationship; no evidence of 
positive dechallenge or positive rechallenge; and the event falls into one of the 
following categories: 
(1) The event is inconsistent with the known pharmacological mechanism, 
characteristics, or known adverse effects of the investigational product, and other 
reasonable explanations exist. 
(2) The event is consistent with the known pharmacological mechanism, 
characteristics, or known adverse effects of the investigational product, but other more 
plausible explanations exist. 
Unrelated: From a medical perspective, there is no reasonable temporal relationship; 
the event is inconsistent with the known pharmacological mechanism, characteristics, 
or known adverse effects of the investigational product; there is no evidence of positive 
dechallenge or positive rechallenge; and other reasonable explanations exist. 
8.2.4 Measures taken with Regard to Study Treatment  
Any actions taken regarding the study treatment following an AE should be recorded 
according to the following classification criteria: 
No Change 
Permanent Discontinuation 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
39 
Not Applicable 
Unknown 
8.2.5 Measures Taken for Adverse Events 
During the study, any specific treatments administered for AEs will be recorded 
according to the following categories: 
• 
None 
• 
Pharmacological treatment 
• 
Other therapeutic interventions 
8.2.6 Outcome  
The outcome of each AE will be recorded using the following categories: 
• 
Recovered/Resolved 
• 
Improved 
• 
Recovered/Resolved with sequelae 
• 
No Improvement 
• 
Death 
• 
Unknown 
8.3 AE Reporting 
All clinically significant abnormalities occurring from the time the participant signs the 
informed consent form through to the final visit (or withdrawal visit) must be fully 
documented in the participant's eCRF. This includes abnormalities observed by the 
investigator, reported by the participant, or identified through clinical symptoms, 
laboratory abnormalities, or other clinically relevant findings. Abnormalities that occur 
during the screening period up until the administration of the study drug should be 
recorded as part of the participant’s medical history. Abnormalities occurring after the 
administration of the study drug, up to the final visit, will be recorded as AEs. If a 
clinically significant abnormality is present at baseline and does not worsen during the 
study, it should not be recorded as an AE. 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
40 
The investigator is responsible for the ongoing monitoring of all AEs until they resolve, 
return to baseline, stabilize, or no further information can be obtained. The outcome of 
each AE should be documented in the participant’s source records. 
After the AE reporting period, only SAEs that are suspected to be related to the study 
treatment should be reported, and these should be followed up accordingly. 
AEs should be recorded using appropriate medical terminology, with a preference for a 
definitive medical diagnosis. If a definitive diagnosis is not available, symptoms or 
signs should be used. Once a definitive diagnosis is made, the AE record should be 
updated to reflect the diagnosis in place of the symptoms or signs. Each AE should be 
documented as a single event; a diagnosis, sign, or symptom must be recorded as an 
individual AE. Terms such as hospitalization, surgery, and death are not considered AEs 
by themselves, but the underlying cause leading to these outcomes should be 
documented as an AE. 
The investigator is responsible for grading the severity of all AEs according to the 
predefined categories. Additionally, the investigator should assess the seriousness and 
causality of each event. For SAEs, the SAE-specific fields in the eCRF must be 
completed. 
For each AE, the following details should be recorded: the date of onset and resolution, 
severity, causal relationship with the study drug, possible alternative explanations (e.g., 
comorbidities or concomitant medications), actions taken with regard to the study 
treatment, any treatment administered for the AE, and the final outcome. 
In cases of death, the cause of death should be recorded as the AE term. The term “death” 
should not be used as the AE term itself. The cause of death should be documented as 
the AE outcome. If the cause of death is initially unknown, it should be reported as 
“cause of death unknown” and monitored until the cause is determined. Once the cause 
of death is clarified, the SAE term should be updated to reflect the specific cause of 
death. 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
41 
The investigator must independently assess all SAEs, evaluating their expectedness, 
severity, and the causal relationship with the investigational product. 
8.4 Observation and Management of Special Adverse Events 
(1) In clinical trials, investigators must closely monitor participants for any AEs or 
SAEs that occur following the administration of the investigational product, to ensure 
prompt identification and management. 
(2) For participants experiencing common adverse reactions associated with the 
investigational product, the investigator must immediately report the event to the 
Principal Investigator (PI). Based on the severity of the event, the investigator will 
determine the necessary diagnostic and therapeutic measures, and decide whether 
discontinuation of the trial is required. All AEs must be followed up, with detailed 
records of the actions taken and outcomes. Follow-up should continue until the event 
is resolved or the participant's condition stabilizes. If laboratory abnormalities occur, 
monitoring should continue until the values return to normal. The method of follow-up 
(e.g., inpatient, outpatient, home visit, telephone, or written communication) should be 
chosen based on the severity of the AE. 
(3) For serious adverse events, the investigator should immediately provide emergency 
treatment according to standard operating procedures (SOP) and document the actions 
taken. A consultation with the relevant medical specialists should be requested. In 
urgent situations, the participant should be transferred to the ICU with medical staff 
accompaniment. The PI at the study site must be notified immediately, and the sponsor 
should be informed without delay. 
(4) After any serious adverse event in a clinical trial, the investigator is required to 
report the SAE to the sponsor and the ethics committee immediately, and no later than 
24 hours after becoming aware of the event. Relevant reports and information will be 
compiled in the investigator’s file and updated as necessary. 
In the case of death, the investigator must provide the sponsor and the ethics committee 
with all necessary documentation, such as the autopsy report and final medical report. 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
42 
The investigator must continue to follow up on all SAEs. Any new information obtained 
after the initial report should be submitted in a follow-up SAE report, which should be 
submitted in the same format and within the same timeframe as the initial report. 
(5) If an SAE is determined to be related to the study, any medical or living expenses 
incurred, as well as compensation for damages, will be covered by clinical trial 
insurance purchased by the sponsor, in accordance with applicable regulations. 
(6) Management of Potential Adverse Events in This Study 
1) Psychiatric Symptoms: 
Symptoms such as delirium, hallucinations, anxiety, depression, and agitation may 
arise after randomization. If any of these symptoms occur during the study, a 
consultation with a specialist should be conducted. If necessary, further evaluations, 
including electroencephalogram (EEG), self-assessment symptom questionnaires (e.g., 
SCL-90), and cranial MRI, should be performed. For mild symptoms, the study 
medication may be withheld for observation; for moderate to severe symptoms, 
hospitalization for specialist care is required. Regardless of symptom severity, all 
participants will complete the SCL-90 questionnaire at the end of the treatment period. 
If any abnormalities are detected, further EEG, cranial MRI, and appropriate medical 
interventions should be carried out. 
2) Seizures: 
If a participant, with no prior history of epilepsy, experiences a seizure after study 
initiation, and EEG confirms the event, other potential causes unrelated to the study 
drug, such as trauma, stroke, or intracranial hemorrhage, must be excluded. If the event 
is deemed related to the investigational treatment, a neurologist's consultation is 
required. For mild cases, the study medication should be discontinued, and the 
participant monitored, with a follow-up EEG after one month. For moderate to severe 
cases, the study drug should be discontinued, and the participant should be hospitalized 
for further evaluation and treatment. Post-discharge, the participant should undergo 
close follow-up. 
3) New or Worsening Heart Failure: 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
43 
If a participant develops new symptoms or signs of heart failure, or if pre-existing 
symptoms worsen, and they meet the criteria outlined in the table below, the 
investigator must promptly document these symptoms and assess the possibility of new 
or worsening heart failure. NT-pro BNP or BNP levels should be measured, and chest 
X-ray or lung ultrasound and echocardiography should be performed. If NT-pro BNP ≥ 
300 ng/L or BNP ≥ 100 ng/L, with X-ray or lung ultrasound indicating pulmonary 
congestion, and echocardiography showing cardiac structural or functional 
abnormalities, the event should be classified as new or worsening heart failure. The 
cause of heart failure should be investigated: if related to the underlying disease, 
continue treatment; if related to memantine, for mild heart failure, discontinue the 
medication and prescribe anti-heart failure medications in an outpatient setting; for 
moderate to severe heart failure, hospitalization is required. 
Table 7  Clinical manifestations of acute heart failure 
Left Heart Failure Symptoms 
Left Heart Failure Signs 
exertional dyspnea 
Wet rales in the lungs 
Nocturnal paroxysmal dyspnea 
Widened apical beat range 
Resting dyspnea or sit-up breathing 
Pathologic 3rd heart sound (gallop rhythm) 
Coughing at night or lying down 
 
Decreased exercise tolerance 
 
Right Heart Failure Symptoms 
Right Heart Failure Signs 
Loss of appetite (poor appetite), 
abdominal bloating, nausea 
Elevated jugular venous pressure (engorged or 
raging external jugular veins) 
 
Positive hepatic jugular venous reflux sign 
 
Peripheral edema (lower extremities or low hanging 
body parts) 
 
Pleural effusion, abdominal effusion and other 
plasma cavities 
4) Bradycardia: 
If a participant’s daytime or ambulatory ECG shows an average heart rate of <50 bpm, 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
44 
or even <40 bpm, with or without symptoms such as dizziness, fatigue, weakness, poor 
concentration, syncope, chest tightness, palpitations, or shortness of breath, the 
following management steps should be taken: 
If the heart rate is <50 bpm, discontinue the study drug and monitor. 
If the heart rate is 40–50 bpm and associated with symptoms, hospitalization and 
management are required. 
If asymptomatic, discontinue the drug and closely monitor, with daily reporting of 
heart rate and symptoms. 
If the heart rate is <40 bpm, hospitalization is required for further management. 
9. Ethical Principles and Requirements for Clinical Research 
This clinical study will be conducted in accordance with the Declaration of Helsinki as 
adopted by the World Medical Association, as well as the Ethical Review Procedures 
for Biomedical Research Involving Human Participants issued by the National Health 
and Family Planning Commission of the People's Republic of China, and other relevant 
regulations. The study will adhere to principles related to informed consent, privacy 
protection, compensation and reimbursement for participation, risk management, 
protection of vulnerable populations, and compensation for research-related harm. 
Prior to the initiation of the study, approval must be obtained from the Ethics Committee 
of Shanghai East Hospital. Before enrolling in the study, each participant will be 
thoroughly informed by the investigator about the study’s objectives, procedures, and 
potential risks. Written informed consent will be obtained from the participant and/or 
their legal representative. Participants will be informed that their participation in the 
study is entirely voluntary, and they have the right to refuse participation or withdraw 
from the study at any point without facing discrimination or retaliation. Their medical 
treatment and rights will not be affected by their decision to participate or withdraw. 
The informed consent document will be retained as part of the clinical study records 
and will be available for review. The privacy and confidentiality of participant data will 
be rigorously protected throughout the study. 
9.1 Ethical Standards 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
45 
The investigator will ensure that this study is conducted in full compliance with Chinese 
legal requirements and internationally recognized principles for the protection of study 
participants. 
Prior to the implementation of the study, the protocol must be reviewed and approved 
in writing by the hospital's Ethics Committee. The following documents must be 
provided to the Ethics Committee: the study protocol, any protocol amendments, the 
informed consent form, and other relevant documents such as recruitment 
advertisements. This clinical trial must adhere to the Declaration of Helsinki and 
applicable regulatory requirements. The study can only commence once approval has 
been granted by the Ethics Committee. 
No changes to the study protocol may be made without the investigator’s consent. The 
investigator may modify the protocol only if necessary to eliminate immediate or direct 
harm to participants. Any such modifications must be made prior to approval by the 
Ethics Committee/Institutional Review Board (IRB). All modifications or deviations, 
along with their justifications, should be promptly submitted to the Ethics 
Committee/IRB for review. The investigator must provide explanations and document 
any protocol deviations. 
During the course of the clinical trial, any amendments to the protocol must be 
submitted to the Ethics Committee for review. If necessary, other study documents 
should be updated accordingly and submitted for review and/or approval by the Ethics 
Committee. The investigators are responsible for submitting interim reports to the 
ethics committee as required, and must notify the ethics committee when the study has 
been completed. 
9.2 Ethics Committee 
The study protocol, informed consent form, recruitment materials, and all participant-
related documents will be submitted to the Ethics Committee for review and approval. 
Participants may only be enrolled after the protocol and informed consent form have 
been approved. Any amendments to the protocol must be reviewed and approved by the 
Ethics Committee before implementation. Similarly, any revisions to the informed 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
46 
consent form must also receive approval from the Ethics Committee. The Ethics 
Committee will determine whether participants who have already signed a previous 
version of the informed consent form need to sign the updated version. 
9.3 Informed Consent 
The informed consent form includes all elements required by applicable regulations and 
adheres to the ethical principles set forth in the Declaration of Helsinki. It provides a 
comprehensive description of the investigational product and study procedures, along 
with a clear explanation of the associated risks. Written informed consent must be 
obtained from the participant prior to the initiation of any study-related procedures. 
The informed consent form also outlines that the participant's personal information will 
remain confidential, but that access to the participant’s data may be granted to the 
hospital, its authorized personnel, and regulatory authorities for monitoring and 
compliance purposes. 
9.3.1 Informed Consent Process and Documentation 
The informed consent process begins prior to a participant’s decision to join the clinical 
study and continues throughout the study. The risks and potential benefits of 
participation will be thoroughly explained to the participant. The participant will be 
asked to read and review the informed consent form, which has been approved by the 
Ethics Committee. The investigator will provide an explanation of the clinical study 
and address any questions the participant may have. Participants may only begin their 
participation after signing the informed consent form. Throughout the study, 
participants have the right to withdraw their consent at any time. Two copies of the 
informed consent form will be made: one for the participant and one for the study site. 
9.3.2 Confidentiality of Participant Information 
The confidentiality of participant information will be strictly maintained by the 
investigator, study staff, and their supervisors. This confidentiality extends not only to 
clinical data but also to biological samples and genetic testing results. All study 
documents, data, and information generated will be treated as confidential. 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
47 
Without breaching confidentiality or violating applicable regulations, monitors, the 
Ethics Committee, and regulatory authorities may access the participant's original 
medical records to verify the study’s conduct and data integrity. 
Participant contact information will be securely stored at the study site and will be used 
solely for purposes related to the study. After the study is completed, all records will be 
securely archived for the duration required by the study site and regulatory guidelines. 
10. Data Management and Quality Control 
10.1 Data Management 
This study will utilize an electronic data capture (EDC) system for data collection and 
management. The system has been thoroughly validated to ensure proper audit trail 
tracking and effective management of user accounts and permissions. System 
administrators will create user accounts for various roles, including Data Managers 
(DM), Investigators, Clinical Research Associates (CRA), and Clinical Research 
Coordinators (CRC), and assign appropriate access levels. The creation, modification, 
and deactivation of accounts will be strictly controlled. 
Data management personnel will design the case report forms (CRFs) based on the 
study protocol, following CDISC standards. The CRFs will be used to develop data 
entry guidelines and validation rules. Database designers will configure the electronic 
case report forms (eCRFs) in the EDC system, implementing data validation checks. 
Data management personnel will conduct database testing, and the system will only be 
launched once it passes these tests. Before using the EDC system, all users must 
undergo sufficient training and be provided with the appropriate login credentials. 
The investigator is responsible for collecting participant data in accordance with 
regulatory requirements and the study protocol. The investigator or CRC must enter the 
data into the EDC system following the eCRF completion guidelines, ensuring accuracy, 
completeness, and compliance with the protocol within the specified time frame. Once 
the data is saved, it may still be edited in the EDC system. The EDC system will 
automatically perform logical checks, and if the data meet the validation criteria, any 
discrepancies or queries will be triggered for review. The investigator or CRC will 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
48 
review the data against the original source documents, address any queries, and either 
correct or confirm the data, providing necessary explanations. Data management 
personnel will review all modifications or responses to queries and may issue additional 
queries as needed, until all issues are resolved or clarified. 
The CRA will ensure that all data entered into the EDC system are accurate and 
consistent with the source data (source documents). Data management personnel will 
manually review data to ensure integrity, consistency, and accuracy. Medical coders 
will review clinical data requiring coding, while medical personnel will perform 
necessary medical reviews of the clinical data. During source data verification and data 
review, these four roles may raise manual queries in the EDC system. The investigator 
or CRC will respond to these queries in the system, modifying data when necessary. If 
queries remain unresolved, reviewers may raise the queries again until all issues are 
addressed or clarified. All data modifications and query responses will be stored in the 
EDC system’s audit trail. 
Once all queries are resolved and data review confirms accuracy, the principal 
investigator will electronically sign all eCRFs in the EDC system, confirming the 
authenticity of the data. If any data are updated after signing, the updated eCRFs must 
be re-signed by the investigator. 
After data cleaning is completed, a data review meeting will be held, attended by the 
principal investigator, medical personnel, statistical analysts, data management 
personnel, and project managers. The team will review the data, discuss and resolve 
any data issues, finalize the definition and classification of analysis populations, and 
approve the data management team to lock the database. 
Once the database is locked, no further modifications should be made. If data errors are 
identified after database locking, the project team (including medical personnel, 
statistical analysts, data management staff, project managers, etc.) must assess the 
potential impact of these errors on the safety and efficacy analyses. A discussion will 
be held to determine how to handle these errors. Data errors will be documented in the 
statistical analysis report and clinical study report. If it is determined that modifications 
are needed after database locking, the project team members must sign the relevant 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
49 
documents to unlock the database for data modification. After the data are modified and 
cleaned, the data management team will lock the database again. The final data will be 
exported by the data management team and provided to the statistical team for analysis. 
Upon completion of the study, the data management team will prepare a data 
management report and ensure the archiving of both paper and electronic documents. 
All data will be securely stored and backed up, and the EDC system will be deactivated 
(taken offline) by the EDC system administrator. 
Unless local regulations or institutional policies require a longer retention period, the 
investigator must ensure that study-related records and documents (including signed 
informed consent forms) are retained for a minimum of 10 years following study 
completion. No records may be destroyed during the retention period without written 
approval from the sponsor. Records may not be transferred to other locations or to third 
parties without written notification from the principal investigator. 
Before submission, all eCRFs must be electronically signed by the investigator. Any 
obvious errors or omissions in the data or forms must be clarified by directly contacting 
the medical center responsible for the data source for verification. 
10.2 Monitoring 
The study will be monitored in accordance with applicable Chinese regulations and 
standard operating procedures. Throughout the study, the sponsor or designated 
personnel will monitor the conduct of the study sites to ensure the following: 
• 
Data are accurate, complete, and reliable. 
• 
The safety and rights of participants are protected. 
• 
The study is conducted in compliance with the most recent version of the 
approved protocol, including the administration of the investigational treatment 
as per the protocol. 
• 
The study adheres to all other study agreements and regulatory requirements. 
Before data are entered into the eCRF, source documentation must be available. The 
monitor will verify whether the data entered into the eCRF is complete, in compliance 
with the protocol, and consistent with regulatory requirements. The monitor will 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
50 
compare the eCRF data with the original source data. All source documents must be 
maintained by the study site and must be available for review. 
11. Study Management 
11.1 Quality Control and Quality Assurance 
Qualifications of Research Institutions: Clinical research institutions must be 
accredited and authorized to conduct pharmaceutical clinical trials. 
Qualifications of Researchers: Researchers must undergo appropriate training and 
perform their tasks under the supervision of qualified professionals. 
Laboratory Quality Control Measures: Laboratories must comply with relevant 
regulations and establish SOPs for experimental observation metrics and quality control 
procedures. 
Clinical Research Quality Control Measures: 
(1) Prior to the commencement of the clinical trial, all researchers and study-related 
personnel at the research institutions must receive training on the study protocol. 
(2) All necessary equipment for the study must be fully operational, meet the required 
testing conditions, and be free from malfunctions. The equipment must undergo a 
preliminary testing phase to confirm its functionality. 
(3) Investigational products must be handled by designated personnel and stored 
according to the conditions outlined in the study protocol. Any remaining 
investigational products should be stored separately, with a detailed log of the 
remaining quantities, and returned to the sponsor upon completion of the study. 
11.2 Document Retention 
In compliance with relevant regulations, both the researchers and the medical 
institutions they are affiliated with must ensure that they have adequate facilities and 
conditions for storing essential clinical trial documents. The storage conditions must 
prevent direct exposure to light, be waterproof, and provide an environment conducive 
to the long-term preservation of documents. Additionally, document management 
policies and SOPs must be established. 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
51 
Retained documents must be easily identifiable, accessible, retrievable, and properly 
organized. Any documents generated during the clinical trial that are not listed in the 
essential document management directory for each phase of the trial must also be 
included in the researchers’ and institutions’ essential document archives. 
12. Responsibilities of All Parties and Other Relevant Provisions 
12.1 Responsibilities of the Lead Study Institution 
(1) Design and develop the clinical study protocol and execute the clinical study 
protocol contract. 
(2) Provide relevant training to clinical research sites prior to the commencement of the 
study. 
(3) Prepare, compile, and maintain clinical data and documentation. 
(4) Develop, collect, and maintain relevant documents, including the clinical protocol, 
medical records, ethics committee approvals, adverse event reports, statistical analysis 
and raw data, and the final clinical report. 
(5) Ensure the documentation and reporting of adverse events to the appropriate 
regulatory authorities, and collaborate with clinical research sites to conduct study 
reviews. 
(6) Verify that research sites enroll participants in accordance with the established study 
protocol and procedures. 
(7) Monitor the enrollment progress at each research site. 
(8) Oversee the quality of data collection and reporting at each research site. 
(9) Collaborate with clinical research sites to evaluate the potential termination of the 
study when necessary. 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
52 
12.2 Responsibilities of Clinical Research Sites (Study Centers) 
(1) Investigators must thoroughly review and comprehend the study protocol and 
adhere strictly to its guidelines. 
(2) Complete the clinical study within the prescribed timeline, in accordance with 
the established “Clinical Study Protocol,” including conducting in-person or 
telephone follow-up visits at the designated time points. 
(3) Submit the clinical study protocol to the relevant ethics committee for review, 
obtain feedback and suggestions, and communicate the results to the 
investigators. 
(4) Investigators must be fully familiar with the nature, mechanism of action, 
efficacy, and safety profile of the investigational drug. 
(5) Clinical studies must be conducted in medical institutions with adequate 
medical facilities, laboratory equipment, and appropriate staffing. The 
institution must be equipped to handle emergencies to ensure participant safety, 
and laboratory results must be accurate and reliable. 
(6) Investigators must obtain approval from the medical institution or relevant 
governing body to ensure sufficient time and resources to conduct the study 
within the specified timelines. 
(7) Investigators must ensure that participants are well-informed about the 
investigational drug and have sufficient time to consider participation in the 
study before providing written informed consent. 
(8) AEs occurring during the study must be accurately documented. Investigators 
must promptly notify the lead study institution and ethics committee of any 
SAEs within 24 hours of discovery and implement appropriate therapeutic 
measures. Investigators must swiftly assess any SAEs and take necessary 
actions to safeguard participant safety and rights. 
(9) Investigators must ensure that all clinical data, including medical records (such 
as photos and videos) and eCRFs, are recorded truthfully, accurately, completely, 
in a timely manner, and in compliance with legal and regulatory requirements. 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
53 
(10) Investigators must cooperate with monitoring and auditing activities 
conducted by the lead study institution to ensure the quality and integrity of the 
clinical study. 
(11) Investigators must ensure that the study does not conflict with or interfere with 
other concurrent clinical trials. 
(12) In the event of an emergency, the protection of participant welfare must take 
precedence. Investigators must assess whether it is necessary to deviate from 
the clinical study protocol, which should not be considered a protocol violation, 
but must be clearly explained and documented in the final report. 
(13) Any modifications to the clinical study protocol that may impact participant 
safety or the scientific validity of the study must be communicated to the ethics 
committee, with approval from the implementing institution, along with the 
rationale for the changes. 
(14) In the event of unforeseen circumstances or increased risks, investigators must 
promptly inform participants or their primary healthcare providers and may 
discontinue the study if necessary. 
(15) Investigators are primarily responsible for ensuring the accuracy, clarity, and 
reliability of all study-related documents. 
(16) Investigators must maintain confidentiality regarding all aspects of the 
investigational drug and related clinical processes and documentation. 
13. Reference 
1.  Meng L, Tsiaousis G, He J, et al. Excessive supraventricular ectopic activity and 
adverse cardiovascular outcomes: a systematic review and meta-analysis. Curr 
Atheroscler Rep. 2020;22:14. 
2.  Himmelreich JCL, Lucassen WAM, Heugen M, et al. Frequent premature atrial 
contractions are associated with atrial fibrillation, brain ischaemia, and mortality: a 
systematic review and meta-analysis. Europace. 2019;21:698–707. 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
54 
3.  Farinha JM, Gupta D, Lip GYH. Frequent premature atrial contractions as a 
signalling marker of atrial cardiomyopathy, incident atrial fibrillation, and stroke. 
Cardiovasc Res. 2023;119(2):429–439. 
4.  Huang B, Huang F, Peng Y, et al. Relation of premature atrial complexes with 
stroke and death: systematic review and meta-analysis. Clin Cardiol. 2017;40:962–
969. 
5.  Arnar DO, Mairesse GH, Boriani G, et al. Management of asymptomatic 
arrhythmias: a European Heart Rhythm Association (EHRA) consensus document, 
endorsed by the Heart Failure Association (HFA), Heart Rhythm Society (HRS), Asia 
Pacific Heart Rhythm Society (APHRS), Cardiac Arrhythmia Society of Southern 
Africa (CASSA), and Latin America Heart Rhythm Society (LAHRS). Europace. 
2019;21:844–845. 
6.  Huang TC, Lee PT, Huang MS, et al. The beneficial effects of beta blockers on the 
long-term prognosis of patients with premature atrial complexes. Front Cardiovasc Med. 
2022;9:806743. 
7.  Arif M, Laidlaw JC, Oshrain C, et al. A randomized, double-blind, parallel group 
comparison of disopyramide phosphate and quinidine in patients with cardiac 
arrhythmias. Angiology. 1983 ;34:393. 
8.  Carrasco HA, Vicuña AV, Molina C, et al. Effect of low oral doses of disopyramide 
and amiodarone on ventricular and atrial arrhythmias of chagasic patients with 
advanced myocardial damage. Int J Cardiol 1985; 9:425. 
9.  Coumel P, Leclercq JF, Assayag P. European experience with the antiarrhythmic 
efficacy of propafenone for supraventricular and ventricular arrhythmias. Am J Cardiol. 
1984;54:60D. 
10.  Liang D, Xue Z, Xue J, et al. Sinoatrial node pacemaker cells share dominant 
biological properties with glutamatergic neurons. Protein Cell. 2021;12(7):545–556. 

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
55 
11.  Xie D, Xiong K, Su X, et al. Identification of an endogenous glutamatergic 
transmitter system controlling excitability and conductivity of atrial cardiomyocytes. 
Cell Res. 2021;31(9):951–964. 
12.  Uzunova G, Hollander E, Shepherd J. The role of ionotropic glutamate receptors 
in childhood neurodevelopmental disorders: autism spectrum disorders and fragile X 
syndrome. Curr Neuropharmacol. 2014;12(1):71–98. 
13.  Frederiksen KS, Cooper C, Frisoni GB, et al. A European Academy of Neurology 
guideline on medical management issues in dementia. Eur J Neurol. 2020;27:1805–
1820. 
14.  Xie D, Xiong K, Su X, et al. Memantine targets glutamate receptors in atrial 
cardiomyocytes to prevent and treat atrial fibrillation. Cell Discov. 2022;8:76. 
15.  D'Amico M, Di Filippo C, Rossi F, Rossi F. Arrhythmias induced by myocardial 
ischaemia-reperfusion are sensitive to ionotropic excitatory amino acid receptor 
antagonists. Eur J Pharmacol. 1999;366(2-3):167–174. 
16. Kambayashi R, Goto A, Hagiwara-Nagasawa M, et al. Analysis of clinically-
reported, memantine-induced cardiovascular adverse responses using the halothane-
anesthetized dogs: reverse translational study. J Pharmacol Sci. 2022;148(4):343–350. 
17.  Park JW, Kim KA, Park JY. Effect of memantine on QT/QTc interval in a healthy 
Korean population. Clin Pharmacol Drug Dev. 2021;10(10):1209–1215. 
18.  Mehta C, Pocock SJ. Adaptive increase in sample size when interim results are 
promising: a practical guide with examples. Stat Med. 2011;30:3267–3284. 
19.  Mauer M, Collette L, Bogaerts J, European Organisation for Research and 
Treatment of Cancer Statistics Department. Adaptive designs at European Organisation 
for Research and Treatment of Cancer (EORTC) with a focus on adaptive sample size 
re-estimation based on interim-effect size. Eur J Cancer. 2012;48(9):1386–1391. 
20.  Mehta CR. Software for adaptive sample size re-estimation of confirmatory time 
to event trials. Cytel Webinar, Cambridge, MA. October 28, 2010.

Memantine Hydrochloride Tablets 
 
 Version number: 2.1 
Version date: June 28, 2024 
56