Clinical Study of Lipoic Acid on Ischemic Heart Failure
Phase: PHASE4
Conditions: Ischemic Heart Failure
Sponsor: Shanghai Zhongshan Hospital

1
Clinical Study of Lipoic Acid on
Ischemic Heart Failure
Study Protocol
Research initiating unit: Zhongshan Hospital, Fudan
University
Research units:
Zhongshan Hospital, Fudan University
Affiliated Zhongshan Hospital of Dalian University
the First Affiliated Hospital of Sun Yat-sen University
Shanxi Cardiovascular Hospital
Type of study: Multicenter, double-blind, randomized,
placebo-controlled, parallel-group, exploratory
Principal investigator: Aijun Sun
Project ID: B2018-120
ClinicalTrials.gov Identifier: NCT03491969
Version: 11.0
Date: July, 5th, 2018

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TABLE OF CONTENTS
一、Background.........................................................................3
二、Objectives............................................................................6
三、Protocol...............................................................................6
3.1 Design...............................................................................6
3.2 Population..........................................................................6
3.3 Number of Cases and Grouping Method.................................8
3.4 Investigational Drugs...........................................................9
3.5 Research Procedures..........................................................10
3.6 Study Endpoint.................................................................12
四、Adverse Event....................................................................13
4.1 Definitions.......................................................................13
4.2 Severity...........................................................................14
4.3 Documentation and Reporting procedure..............................14
4.4 Risk Prevention and Management........................................14
五、Statistic Method.................................................................15
5.1 Sample Size Calculation.....................................................15
5.2 Statistical Analysis ...........................................................16
六、Ethics...................................................................................17
6.1 Ethical Committee Review.................................................17
6.2 Informed Consent..............................................................18
七、Confidentiality Measures..................................................18
八、References...........................................................................19

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一、Background
Heart failure is the common endpoint of various structural or
functional heart diseases and represents the leading cause of death from
cardiovascular diseases, with a 5-year mortality rate exceeding 50% [1-3].
Ischemic heart disease most frequently manifests as the clinical syndrome
of heart failure, which is associated with high rates of morbidity and
mortality, thereby garnering significant clinical attention. Current clinical
treatments for ischemic heart failure primarily include pharmacological
therapy,
revascularization,
therapeutic
angiogenesis,
and
heart
transplantation. Despite advancements in interventional techniques and
the establishment of treatment strategies based on the "neuroendocrine,"
"hemodynamic disorders," and "immune-inflammatory" theories, which
have partially improved clinical outcomes in patients with ischemic heart
failure, these improvements fall far short of clinical needs. There is an
urgent necessity to explore new therapeutic targets for heart failure from
innovative perspectives.
Abnormalities in myocardial energy metabolism constitute a crucial
pathological basis for heart failure, with mitochondria playing a pivotal
role as the primary site for ATP production. Elucidating the role of
mitochondrial energy metabolic remodeling in the pathogenesis of
different types of heart failure and its potential for therapeutic
intervention could facilitate the early identification of risk factors for
heart failure and lead to more effective improvements in prognosis. Our
previous research has focused on mitochondria in failing myocardium,
and through proteomic analysis, we have identified nearly a hundred
differentially expressed mitochondrial proteins,
including
aldehyde
dehydrogenase 2 (ALDH2). ALDH2 is a key enzyme involved in
mitochondrial glycolipid metabolism[4], possessing a redox-sensitive

4
thiol group at its active site. An increase in endogenous oxygen free
radicals promotes the formation of disulfide bonds at the ALDH2 active
site, leading to its inactivation [5]. Given the abundant distribution of this
enzyme in the myocardium, we have conducted a series of studies on the
role of ALDH2 in myocardial injury and protection. Our findings indicate
that ALDH2 exerts cardioprotective effects by maintaining mitochondrial
metabolic homeostasis under cardiovascular pathological stimuli such as
ischemia, hypoxia, and alcohol exposure [6-12]. Furthermore, we have
demonstrated that ALDH2 is a prerequisite for enhancing the therapeutic
efficacy of stem cell transplantation in the treatment of heart failure
[13-14]. Our research has pioneered international efforts in confirming
the significant advantages of ALDH2 in preventing cardiovascular
diseases and diabetes, sparking a global research fervor into the
protective effects of ALDH2 in various disease contexts. Additionally,
our findings have garnered international attention regarding ALDH2 as a
potential target for drug development. The significance of ALDH2 in
numerous human diseases is gradually being elucidated, with substantial
evidence
from
domestic
and
international
peers
indicating
its
irreplaceable
role
in
preventing
other
cardiovascular
diseases,
cerebrovascular diseases, hematological disorders, and malignant tumors,
among others [15-18]. Autologous bone marrow-derived aldehyde
dehydrogenase-bright (ALDH^br) cells, which express highly active
ALDH2, have been proven safe and effective in patients with chronic
myocardial ischemia [19]. Given its pivotal role in cellular protection and
its significance in various human diseases, ALDH2 may represent a novel
therapeutic target for the treatment of multiple diseases [20-21].
Lipoic acid (LA), a vitamin B-class compound, features a closed
cyclic structure composed of sulfur and carbon atoms, conferring
relatively high electron density and thus strong antioxidant properties. LA

5
has demonstrated favorable preventive and therapeutic effects on diabetes
and its complications, various brain and neurodegenerative diseases, and
aging [22-24]. The role of LA in cardiovascular diseases has increasingly
attracted attention, with studies confirming that LA can restore ALDH2
activity by reducing disulfide bonds at its active site in mitochondria,
thereby enhancing nitrate tolerance [25]. Subsequently, scholars have
discovered that lipoic acid (LA) also exerts protective effects on diabetic
cardiomyopathy and acute ischemia-reperfusion injury by restoring the
activity of ALDH2 [26-28]. Given the protective role of ALDH2 in
ischemic heart failure and the ability of LA to reduce ALDH2 activity,
we propose the following scientific hypothesis: during the recovery phase
of post-ischemic heart failure, lipoic acid can improve myocardial
mitochondrial energy metabolism and inhibit oxidative stress by reducing
the activity of ALDH2 in myocardial mitochondria, thereby protecting
against
post-ischemic
heart
failure.
Currently,
due
to
its
potent
antioxidant properties and rare adverse effects, lipoic acid has been
widely promoted for clinical use. Clinically available forms of lipoic acid
include intravenous injections and oral capsules, with indications for
sensory abnormalities caused by diabetic peripheral neuropathy. Adverse
reactions are extremely rare, with an incidence rate of <1/10,000,
primarily manifesting as gastrointestinal symptoms such as nausea and
vomiting, cutaneous allergic reactions, abnormal taste perception, or
hypoglycemia.
This study employs a prospective, multicenter, randomized, and
controlled research design to assess the clinical outcomes of patients with
heart failure following myocardial infarction (MI) who are treated with a
combination of lipoic acid capsules and standard pharmacological therapy.
The evaluation will be conducted using a range of indicators, including
primary endpoint events, secondary endpoint events, control of risk

6
factors, and surveys on medication adherence. The primary objective is to
elucidate the significant role of lipoic acid capsules in managing post-MI
heart failure, thereby paving the way for innovative approaches in heart
failure treatment.
This structured approach ensures a rigorous and comprehensive
assessment, allowing us to draw meaningful conclusions about the
efficacy and safety of lipoic acid capsules in this patient population. By
integrating multiple evaluation metrics, we aim to provide a holistic view
of the treatment's impact on patient outcomes, ultimately contributing to
the
advancement
of
evidence-based
practices
in
heart
failure
management.
二、Objectives
The clinical outcomes of lipoic acid capsules combined with
standard pharmacological therapy in patients with heart failure following
myocardial infarction are evaluated through indicators such as primary
endpoint events, secondary endpoint events, control of risk factors, and
surveys on medication adherence.
三、Protocol
3.1 Design
This is a multicenter, double-blind, randomized, placebo-controlled,
parallel-group, exploratory trial.
3.2 Population
Inclusion criteria: 1. Patients aged 18 years or older who had been
diagnosed with acute myocardial infarction (AMI) for more than 30 days.
The diagnosis of AMI was based on the Fourth Universal Definition of
Myocardial Infarction, which encompassed clinical evidence of acute

7
myocardial ischemia and with detection of a rise and/or fall of cardiac
troponin (cTn) values, with at least 1 value above the 99th percentile
upper reference limit (URL) and at least 1 of the following: symptoms of
myocardial
ischemia;
new
ischemic
electrocardiogram
changes;
development of pathological Q waves; imaging evidence of new loss of
viable myocardium or new regional wall motion abnormality in a pattern
consistent with an ischemic etiology, identification of a coronary
thrombus by angiography; 2. Patients were diagnosed with chronic heart
failure (NYHA class Ⅱ-Ⅳ) with a documented LVEF≤50%. The
diagnosis of chronic heart failure was based on the global definition[16]:
Symptoms and signs of HF with elevated natriuretic peptides (BNP)
(NTproBNP＞600pg/ml or BNP≥150pg/ml; NT-proBNP≥400 pg/mL or
BNP≥100 pg/mL, if patients were hospitalized for heart failure within 12
months; 3. The patients were clinically stable and had received optimal
medical treatment with a fixed dosage for at least 4 weeks; 4. Patients
were fully informed about this study and provided written informed
consent.
Exclusion criteria: patients who were allergic to drugs of similar
chemical
classes
(Vitamin
B)
as
well
as
known
or
suspected
contraindications to the study drugs; already used other investigational
drugs at the time of enrollment, or within 30 days or over 5 half-lives of
the
drug
prior
to
enrollment;
with
a
history
of
intolerance
to
recommended target doses of ALA; have been diagnosed with acute
decompensated HF (exacerbation of chronic HF manifested by signs and
symptoms that may require intravenous therapy); with systolic blood
pressure < 100 mmHg; severe liver function abnormalities (alanine
aminotransferase (ALT) or aspartate aminotransferase (AST) more than 3
times the upper limit of normal); an estimated glomerular filtration rate
(eGFR) < 30 mL/min/1.73m2, as measured by the simplified MDRD

8
formula; a serum potassium > 5.2 mmol/L; were pregnant or planning to
become pregnant.
Withdrawal criteria: 1. The participant themselves requests to
withdraw from the trial; 2. The participant experiences an intolerable
adverse event, or an adverse event that, in the investigator's opinion,
necessitates withdrawal from the study; 3. The participant is unable to
adhere to the study protocol for treatment, demonstrates poor compliance,
or is deemed by the physician to be unsuitable for continued participation
in the study group.
3.3 Number of Cases and Grouping Method
The overall trial plans to enroll 300 patients who meet the inclusion
criteria, and they will be randomly assigned to either the treatment group
or the control group, with 150 patients in each group. This study is a
prospective, multicenter, randomized, and controlled trial. It is planned to
include 100 cases from our hospital, 100 cases from Affiliated Zhongshan
Hospital of Dalian University, 50 cases from the First Affiliated Hospital
of Sun Yat-sen University and 50 cases from Shanxi Cardiovascular
Hospital.
Randomization: The randomization method employed in this study
is block randomization. The statistician generated a random number table
using computer software and conducted drug blinding based on it.
Blinding Procedure: Participants who are randomly assigned to the
placebo group will also take capsules that are identical in appearance to
those containing lipoic acid. Investigators at each center will be unaware
of the difference between the two. Under normal circumstances, the blind
will be maintained until all participants have completed the study and the
database has been finally locked. Emergency unblinding may only occur
when the participant's treatment status is required to determine special

9
emergency treatment. The date, time, and reason for unblinding will be
recorded in the original documents and CRF (Case Report Form) tables.
3.4 Investigational Drugs
3.4.1 Investigational Medicinal Products:
Investigational Drug: Lipoic Acid Capsules
Placebo: Contains starch as the inert ingredient, with an identical
appearance to the investigational drug
3.4.2
Dosage
Form,
Dose,
Route
of
Administration,
Administration Method, Frequency of Administration, and
Treatment Duration
Dosage Form: 100mg capsules
Dose: 600mg per day
Route of Administration: Oral
Frequency of Administration: 200mg per dose, administered three
times daily
Treatment Duration: 24 months
3.4.3 Packaging and Labeling
For research only
Protocol ID：2018-120
Lipoic Acid Capsules for Clinical Trial Use
Drug ID:
Name Abbreviation: _________
Dispensing Date: ____________
Dosage and Administration: Take 2 capsules at a time, three times daily.
Packaging: Each bottle contains xx capsules.
Storage: Keep the container tightly closed.
Expiration Date: XXXX
All unused medication, along with its original packaging, must be returned
to the investigator.
Keep out of reach of children
3.4.4 Drug Interactions
Lipoic acid acts as a metal chelator, hence particular caution should
be exercised to avoid taking it concurrently with medications containing
metal
components
(such
as
iron
and
magnesium
preparations).

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Additionally, it should not be taken simultaneously with milk due to its
calcium content. If lipoic acid is administered half an hour before
breakfast, iron and magnesium preparations can be taken during lunch or
dinner.
Lipoic acid may potentiate the hypoglycemic effects of insulin and
oral antidiabetic drugs. Therefore, it is recommended to monitor blood
glucose levels regularly, especially when initiating treatment with this
product. In some patients, to prevent the occurrence of hypoglycemic
symptoms, it may even be necessary to reduce the dosage of insulin and
oral antidiabetic medications.
3.5 Research Procedures
3.5.1 Screening and Enrollment Period
At the hospital's heart failure outpatient clinic and inpatient ward,
consecutive patient screening was initiated based on inclusion and
exclusion criteria. Detailed information about the study objectives,
significance, and procedures was provided to patients. Their consent was
obtained, and informed consent forms were signed.
Eligible patients were randomized in a 1:1 ratio to either the lipoic
acid capsule group or the control group. Patients continued their current
optimized medications and additionally received the study drug.
ALA Group:
Standard treatment for post-myocardial infarction heart failure +
lipoic acid capsules (1 capsule/dose, 3 times/day for the first week,
escalated to 2 capsules/dose, 3 times/day thereafter, swallowed with
warm water).
Placebo Group:

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Standard treatment for post-myocardial infarction heart failure +
placebo (1 capsule/dose, 3 times/day for the first week, escalated to 2
capsules/dose, 3 times/day thereafter, swallowed with warm water).
Concomitant Standard Therapy (Medications and Devices):
Patients should adhere to current treatment guidelines[29], with
therapies tailored by clinicians based on individual conditions. Risk
factors such as blood glucose, blood pressure, and lipids should be
controlled. Patients should receive dietary guidance for cardiac health
(e.g.,
low-salt diet)
and lifestyle
modifications,
including weight
monitoring, physical exercise, smoking cessation, and alcohol restriction.
Device-based therapies, including but not limited to stent implantation,
may be administered according to current guidelines and patient
conditions.
3.5.2 Follow-up Period
Patients underwent baseline visits on Day 0 post-randomization,
followed by visits at Months 6, 12, and 24, totaling 4 on-site visits for
efficacy, compliance, and safety assessments until study completion. The
follow-up period lasted 24 months.
Visit 1 (Screening and Enrollment Period)
Inclusion and exclusion criteria
Informed consent signing
Past medical history and comorbidities
Comprehensive physical examination
Detailed documentation of medical history, comorbidities, treatment,
concomitant
medications,
blood
pressure,
heart
rate,
weight
measurement.
Cardiac function assessment (6-minute walk test: 6MWD)
Electrocardiogram (ECG)
Echocardiography

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Laboratory
tests:
blood/urine/biochemical
parameters,
brain
natriuretic peptide (BNP), coagulation function
Distribution of study medication
Instructions for the next follow-up visit date and brief physical
examination
Visit 2 (Month 6 post-randomization), Visit 3 (Month 12
post-randomization), Visit 4 (Month 24 post-randomization)
Heart failure symptoms and signs
Comprehensive physical examination
Blood pressure, heart rate, weight measurement
Documentation of primary and secondary endpoint events
Adverse event recording
Cardiac function assessment (6MWD)
ECG
Echocardiography
Laboratory
tests
(blood/urine/biochemical
parameters,
BNP),
coagulation function
Distribution/collection of study medication
Instructions for the next follow-up visit date or study termination
During months without on-site visits, researchers should contact
patients via telephone to inquire about adverse events, endpoint events,
and changes in concomitant medications, completing corresponding
records.
3.6 Study Endpoint
3.6.1 Primary Endpoint:
A composite endpoint of all-cause death and rehospitalization due to
heart failure during the 24-month follow-up period.

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3.6.2 Secondary Endpoints:
The second endpoints included all-cause death and rehospitalization
due to heart failure, non-fatal MI or non-fatal stroke during the
24-month follow-up period. The changes of LVEF and 6MWD were also
assessed from baseline to 24 months.
3.6.3 Endpoint Definitions
All-cause death is defined as death due to any cause.
Rehospitalization due to heart failure is defined as nonelective repeat
hospitalization in all patients alive at discharge for heart failure.
MI is defined based on the Fourth Universal Definition of
Myocardial Infarction, which encompassed clinical evidence of acute
myocardial ischemia and with detection of a rise and/or fall of cardiac
troponin (cTn) values, with at least 1 value above the 99th percentile
upper reference limit (URL) and at least 1 of the following: symptoms of
myocardial
ischemia;
new
ischemic
electrocardiogram
changes;
development of pathological Q waves; imaging evidence of new loss of
viable myocardium or new regional wall motion abnormality in a pattern
consistent with an ischemic etiology, identification of a coronary
thrombus by angiography
Stroke is defined on the basis of the presence of acute infarction as
demonstrated by imaging or based on the persistence of symptoms.
四、Adverse Event
4.1 Definitions
Adverse Event (AE): Any untoward medical occurrence in a patient
or clinical trial subject following the administration of a pharmaceutical
product, which does not necessarily have a causal relationship with the
treatment.

14
Serious Adverse Event (SAE): An event occurring during the
clinical trial that results in hospitalization, prolongation of hospitalization,
disability, impairment of work ability, life-threatening condition, death,
congenital anomaly, or other significant medical events.
4.2 Severity
Mild: The event is tolerable to the subject, does not affect treatment,
requires no special intervention, and has no impact on the subject's
recovery.
Moderate: The event is intolerable to the subject, requires special
intervention, and has a direct impact on the subject's recovery.
Severe: The event is life-threatening, leads to death or disability, and
requires immediate emergency intervention.
4.3 Documentation and Reporting of Adverse Events
Clinical adverse events may occur during the subject's treatment.
Once an adverse event (including significant adverse events) occurs, the
following details should be recorded in detail on the Case Report Form
(CRF): time of occurrence, clinical manifestations, management, duration,
outcome, and relationship to the study drug. For subjects with abnormal
laboratory test results, follow-up should be conducted until the results
return to normal, to the pre-treatment level, or until it is confirmed that
the abnormalities are unrelated to the study drug. In the case of a serious
adverse event, a Serious Adverse Event Form should be completed and
reported to the sponsor, ethics committee, CFDA Safety Monitoring
Department, and health administrative department within 24 hours.
4.4 Risk Prevention and Management
The investigator should assess the clinical significance of abnormal
laboratory
results
and
provide
possible
explanations.
Laboratory
abnormalities resulting from previously reported adverse events should

15
also be recorded as adverse events in the Adverse Event Form.
Laboratory abnormalities with clinical significance that meet one or more
of the following criteria should be recorded as independent diagnoses in
the Adverse Event section of the CRF (excluding abnormalities resulting
from previously reported adverse events):1.Accompanied by clinical
symptoms；2.Leading to changes in clinical medication；3.Requiring
modification of concomitant therapy.
For unexplained abnormal laboratory values, repeat testing should
be performed, and follow-up should continue until the value returns to the
normal reference range or baseline, and/or a reasonable explanation is
found. If a clear explanation is identified, it should be documented on the
CRF.
During the clinical trial, investigators should closely monitor the
occurrence of serious adverse events. Upon the occurrence of a serious
adverse event, necessary measures should be taken first to ensure the
safety of the subject, followed by reporting to the sponsor, contract
research organization (CRO), and the ethics committee of the center
within 24 hours.
All safety follow-up visits will be conducted 15 days after the end of
the study visit. For subjects who withdraw prematurely, safety follow-up
will also be conducted 15 days after the end of the study visit, unless the
investigator deems it necessary for the subject to return to the hospital for
follow-up measurements due to persistent adverse events at the end of
treatment or clinically significant abnormalities in laboratory tests or vital
signs. Safety follow-up may be conducted via telephone.
五、Statistic Method
5.1 Sample Size Calculation

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This pilot and feasibility study was designed to evaluate the efficacy
and safety of ALA in IHF patients and get the reference data on outcomes
related to clinical events for the future RCT with large sample size. As a
feasibility trial, 300 patients were expected to be enrolled during the
study period. Assumptions for sample size calculation included the
following: the event rate for primary outcomes was 35% at 24 months in
the control group[30]; the HR for the ALA group was estimated to be
0.60 and a withdrawal rate of 5% at 24 months in both groups. A total of
300 (150 per group) subjects followed up for a fixed period of 24 months
provides 80% power to reject the null hypothesis at the two-sided 0.1
significance level.
5.2 Statistical Analysis of Research Data
5.2.1 Analysis Variables
The analysis variables include subject characteristics at baseline,
laboratory indicators, auxiliary examination indicators (electrocardiogram;
echocardiogram), and endpoint event indicators.
5.2.2 Analysis Populations
All patients who meet the screening criteria and commence
treatment with lipoic acid capsules should be included in the Safety
Population (SP). The analysis of the primary endpoint and other endpoint
was based on the FAS dataset (Full Analysis Set). The FAS set is defined
as the set that adheres to the ITT (Intent-to-Treat) principle with the
additional condition that the investigational drug has been used for at
least one month, allowing for reasonable exclusions and enabling the
reflection of the investigational drug's efficacy and safety to the greatest
extent possible. Per-protocol analysis (PP set):Refers to subjects who do
not have serious protocol violations in terms of inclusion and exclusion

17
criteria, treatment, and measurement of main indicators. The analysis was
performed after the population withdrew from the study.
5.2.3 Statistical Methods
All statistical analyses were performed with R version 4.0.2. Normally
distributed continuous variables were reported as the mean±SD, and
non-normally distributed continuous variables were expressed as the
median and interquartile range. Categorical data were expressed as
absolute values and percentages and analyzed using the chi-square or
Fisher’s exact test. The Student’s t-test or Wilcoxon rank-sum test was
performed to determine differences between groups. Survival analyses
were based on the time to the first event. The cumulative incidence of the
time-to-event end points is expressed as Kaplan-Meier curves over 24
months after randomization. Cox proportional hazard models were used
to estimate HR and 2-sided 95% CI. A linear mixed-effects model was
used to analyze the differences in changes of LVEF and 6MWD between
the ALA group and the placebo group, with study centers included as
random effects. Subgroup analysis was performed for age (whether≤65
years old), sex, smoking status, past medical history (hypertension,
diabetes mellitus, atrial fibrillation), NYHA functional class, NT-proBNP
levels, LVEF(whether≤30%), and whether the patient received triple
therapy.
The analysis of safety and efficacy was performed in full analysis set
(FAS) adhering to the intention-to-treat principle. The type Ⅰerror rate
(2-sided α) was set at 0.05.
六、Ethics
6.1 Ethical Committee Review

18
This protocol, the written informed consent form, and materials
directly related to the subjects must be submitted to the ethical committee
for review. Formal initiation of the study may proceed only upon
obtaining written approval from the ethical committee. Investigators must
submit periodic (if applicable) progress reports to the ethical committee.
Upon termination and/or completion of the study, investigators must
notify the ethical committee in writing. Investigators must promptly
report all changes occurring during the study (such as revisions to the
protocol and/or informed consent form) to the ethical committee and must
not implement these changes without prior approval from the ethical
committee, unless the changes are made to eliminate obvious and
immediate risks to the subjects. In such cases, the ethical committee will
be notified.
6.2 Informed Consent
Investigators must provide subjects or their legal representatives
with an easily understandable informed consent form that has been
approved by the ethical committee. Subjects or their legal representatives
must be given sufficient time to consider participation in the study. No
subject may be enrolled until a signed written informed consent form has
been obtained. During the subject's participation, all updated versions of
the informed consent form and written information will be provided to
the subjects. The informed consent form shall be retained as an important
document of the clinical trial for future reference.
七、Confidentiality Measures
The results of this study may be published in medical journals.
However, we will ensure the confidentiality of patient information in

19
compliance with legal requirements. Patient personal information will not
be disclosed unless required by relevant laws. When necessary,
government regulatory authorities, the hospital's ethics committee, and
relevant
personnel
may
access
patient
data
in
accordance
with
regulations.
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