Conditions: Ischemic Heart Failure
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 300
Healthy volunteers: no

Brief summary:
The study will evaluate the efficacy of alpha-lipoic acid(α-LA) on mortality in patients with ischemic heart failure (NYHA Class II - IV and EF =\< 50%).

Detailed description:

Arms:
arm 1: Double blind treatment period consisted of treatment with CHF standard treatments, followed by α-LA 200 mg tid over a total duration of 24 months. arm 2: Double blind treatment period consisted of treatment with CHF standard treatments, followed by Placebo 200 mg tid over a total duration of 24 months.

Interventions: intervention 1: Alpha-Lipoic Acid(α-LA) intervention 2: Placebos
Intervention descriptions: intervention 1: 200 mg, po, tid intervention 2: 200 mg, po, tid

Protocol document:
Prot_000.pdf: 
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


2
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


3
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).


10
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:


11
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


12
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.


13
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


16
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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activity
enhances


21
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MAPK signaling pathway. Biomed Pharmacother 65(8): 590-3, 2011.
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Biol 34(4): 894-901, 2014.
[14] Sun X, Zhu H, Dong Z, Liu X, Ma X, Han S, Lu F, Wang P, Qian S,
Wang C, Shen C, Zhao X, Zou Y, Ge J, Sun A. Mitochondrial aldehyde
dehydrogenase-2 deficiency compromises therapeutic effect
of ALDH
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new protector against age-independent myocardial senescence. Int J
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H, Miyano S, Nakamura J, Kojima S, Ogawa S, Matsuo K, Takata M,
Yabe M. Variant ALDH2 is associated with accelerated progression of
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Fernandes MR, Keller LH, Quan X, Coulter SA, Moore WH, Herlihy JP,


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SAP_001.pdf: 
1
Clinical Study of Lipoic Acid on
Ischemic Heart Failure
Statistical Analysis Plan
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: 4.0
Date: January, 1st, 2025


2
TABLE OF CONTENTS
一、Introduction.........................................................................3
二、Objectives............................................................................5
三、Study Design.......................................................................6
四、General Statiscal considerations.......................................6
4.1 General Principles...............................................................6
4.2 Handling of Noncomplicance to Study .......................................7
4.3 Handling of Missing Data........................................................8
4.4 Determination of Sample Size...............................................9
五、Analysis Set........................................................................10
5.1 Assignment of Analysis Sets...............................................10
5.2 Intention-to-treat Analysis Set (ITT)....................................10
5.3 Full Analysis Set (FAS).....................................................10
5.4 Safety Analysis Set............................................................10
5.5 Per-protocol Analysis Set...................................................10
六、Statistical Methodology....................................................10
6.1 Population Characteristics..................................................10
6.2 Endpoints.........................................................................12
七、Reference...........................................................................13


3
一、Introduction
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]. 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
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,


5
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.
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
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.
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.


6
三、Study Design
This is a multicenter, double-blind, randomized, placebo-controlled,
parallel-group, exploratory trial.
The aim of this study is to observe the efficacy and safety of ALA as
a complementary therapy in patients with ischemic heart failure (IHF).
Participants with IHF with myocardial infarction (MI) history and left
ventricular ejection fraction (LVEF)≤50% were randomized 1:1 to
receive ALA (600mg daily) or placebo on top of standard care for 24
months.
The
primary
endpoint
was
the
composite
endpoint
of
hospitalization for HF or all-cause mortality events. The second endpoints
included non-fatal MI, non-fatal stroke, changes of LVEF, 6 minute
walking distance (6MWD) from baseline to 24 months.
四、General Statistical Considerations
4.1 General Principles
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


7
random effects. The analysis of safety and efficacy was performed in full
analysis set (FAS) adhering to the intention-to-treat principle. The type Ⅰ
error rate (2-sided α) was set at 0.05.
4.2 Handling of Noncompliance to Study
Individuals who provide their consent by signing an informed
consent form but subsequently withdraw from the study prior to
randomization, for whatever reason (such as not fulfilling the inclusion
and exclusion criteria), are categorized as "screening failures".
Irrespective of the cause, a participant who was randomized but
permanently ceased the study treatment prior to their scheduled End of
Treatment Visit was deemed to have permanently discontinued the study
medication. This category also encompasses those who were randomized
but did not commence taking any study medication at all. The decision to
permanently halt the administration of the study medication will be made
in accordance with the reason for discontinuation.
When participants permanently discontinue the study medication,
various follow-up approaches are deliberated upon to gather data on
outcome events and vital status. These methods may encompass
scheduled study visits, routine telephone communications with the patient
or their primary care physician, or a contact at the study's conclusion. In
cases where patients decline to participate in regular study visits, the
investigator will strive, to the fullest extent possible, to persuade them to
attend at least one concluding evaluation visit, as stipulated for the End of
Treatment Visit.
All participants who have been randomized into the study will be
actively encouraged to persist with the study treatment and remain under
observation throughout the entire duration of the research. It's important
to note that withdrawing informed consent cannot be achieved simply by
discontinuing the study treatment. In situations where participants express


8
a desire to "no longer continue," investigators are tasked with clarifying
whether this pertains to halting the study treatment, a reluctance to attend
follow-up appointments, an unwillingness to engage in telephone
communication, a general disinterest in maintaining any form of contact
with study staff, or a refusal to permit contact with a third party, such as a
family member or their doctor. To ascertain the survival status of all
participants at the study's conclusion, every feasible effort will be
undertaken to follow up with them. It is anticipated that only a negligible
number of individuals will have incomplete follow-up (in any capacity)
during the course of this trial.
A participant will be considered to have incomplete follow-up or be
classified as lost to follow-up (meaning they have entirely failed to
comply with follow-up procedures) if, despite exhaustive attempts, all
investigators and dedicated site staff are unable to establish contact with
the participant or a designated third party (such as a family member or
doctor). In accordance with local legal provisions, every endeavor will be
undertaken to reach the participant or a third party, with the aim of
ascertaining the endpoint, survival status, and the rationale behind
treatment discontinuation. However, the participant will not be deemed
lost to follow-up if the database confirms that they are alive at the
conclusion of the study.
4.3 Handling of Missing Data
In the subject data listing, all missing or partially recorded data will
be presented exactly as they appear on the Case Report Form (CRF).
This includes the best estimate date provided by site investigators (as
detailed below), which is gathered during clinical data collection. When
an exact event date is unknown, site investigators are requested to furnish
their most informed approximation of the event date. Even though the
precise occurrence date remains uncertain, investigators often possess


9
information that can suggest an approximate date, such as the first week
of a month, the autumn season of a year, the midpoint of a specific year,
or at least the last date the subject was observed or contacted. By
incorporating this contextual information into the computer program, the
estimated date it generates is likely to be more accurate than that
produced by a program lacking such knowledge. The estimated date
should represent the midpoint of the period during which the event is
known to have occurred. For instance, if the event took place in the first
week of a month, the middle date of that month should be used as the
estimate. Similarly, if the event occurred in the autumn, the middle date
of that season should serve as the approximation. When no prior
information about the subject is available before the event (start date of
the plausible time period) and only the date of contact when information
about the event became known (end date of the plausible time period) is
available, the midpoint of this plausible time period should be recorded as
the estimated date. This approach has been widely adopted in numerous
studies and is endorsed by Dubois for date estimation purposes.As a
precautionary measure, if the date/time information is insufficient to
ascertain whether an event occurred before or after randomization, the
event will be considered an outcome. In such cases, the event start date
will be imputed no earlier than the randomization date.
4.4 Determination of Sample Size
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[29]; the HR for the ALA group was estimated to be


10
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.
五、Analysis Set
5.1 Assignment of Analysis Sets
All subjects who were randomized in the study were eligible for
assignment tothe analysis sets.
5.2 Intention-to-treat Analysis Set (ITT)
All participants who were randomly assigned will be included in the
intention-to-treat analysisset, also known as the full analysis set in the
International Conference on Harmonization(ICH) E9 standard.
5.3 Full Analysis Set (FAS)
The FAS set is defined as the set that adheres to the ITT 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. The analysis of the primary endpoint and other
endpoint was based on the FAS dataset.
5.4 Safety Analysis Set
All randomized subjects who received at least one dose of study
medication will be included in the safety analysis set.
5.5 Per-protocol Analysis Set
Subjects who do not have serious protocol violations in terms of
inclusion and exclusion criteria, treatment, and measurement of main
indicators.
六、Statistical Methodology
6.1 Population Characteristics


11
In the FAS set, baseline characteristics and demographic data will be
summarized by treatment group. Continuous variables will be presented
using summary statistics to provide a concise overview. For categorical
variables, frequency tables will be utilized to display the distribution of
responses across different categories.
6.1.1 Demographics and Medical History
An individual's demographic information includes their age, sex,
body weight, systolic blood pressure, diastolic blood pressure and heart
rate, which will be given as continuous variables.
We will employ frequency tables to assess the medical history data.
These tables will illustrate the number of subjects who have medical
history entries (such as previously diagnosed conditions, diseases, or
surgeries documented on the CRF) that commenced prior to signing the
informed consent and are deemed pertinent to the study.
6.1.2 Protocol Deviations
The frequency tables show the number of subjects with major
protocol deviations overall grouped by type of deviation. The analysis
will be based on FAS data. Types of major protocol deviations include
significant inclusion criteria not fulfilled, significant exclusion criteria
fulfilled, failure to obtain informed consent, prohibited medication use,
failure to report SAE, failure to report outcome event.
6.1.3 Prior and Concomitant Medications
Frequency tables will be generated, categorized by the type of
medication. These tables will present data on prior medications taken
before randomization. Additionally, separate frequency tables will be
compiled
for
concomitant
medications
that
were
continued
after
randomization. These tables will detail medication usage at Visit 1, Visit
3 the 12-month follow-up, and at the End of Treatment (EOT). The
analyses will be conducted both by treatment group and in the FAS set.


12
6.2 Endpoints
6.2.1 Primary Endpoints
The primary endpoint is the time from randomization to the first
occurrence of any of the components of the composite outcome,
including the hospitalization for HF and all-cause mortality events during
24-month follow-up period.
6.2.2 Secondary Endpoints
The secondary endpoint included the time from randomization to the
first occurrence of the hospitalization for HF and all-cause mortality
events, non-fatal MI or non-fatal stroke. The changes of LVEF and
6MWD from baseline to 24 months were also assessed.
6.2.3 Analysis of the Primary endpoints
The primary analysis will include events adjudicated by the ICAC
and will be based on the FAS analysis set. To evaluate whether ALA
could prolong the time to a primary endpoints in patients with IHF. The
following null hypothesis (H0) will be tested at the significance level of
0.05 using a Cox proportional hazards model:
Ho: HR≤1
H1: HR>1
HR is the hazard ratio of primary outcome for ALA group in
comparison to the placebo group.
6.2.4 Subgroup Analyses
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.
6.2.5 Analysis of the Secondary endpoints


13
To evaluate whether ALA could prolong the time to a secondary
endpoints (SE) defined as the time from randomization to the first
occurrence of any of the components of the hospitalization for HF,
all-cause mortality events, non-fatal MI or non-fatal stroke in patients
with IHF.
The following null hypothesis (H0) will be tested at the significance
level of 0.05 using a Cox proportional hazards model:
Ho: HR≤1
H1: HR>1
HR is the hazard ratio of secondary outcome for ALA group in
comparison to the placebo group.
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.
七、References
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Luan P, Liu AJ. Heavy ethanol consumption aggravates the ischemic
cerebral injury by inhibiting ALDH2. Int J Stroke 10(8): 1261-9, 2015.
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H, Miyano S, Nakamura J, Kojima S, Ogawa S, Matsuo K, Takata M,
Yabe M. Variant ALDH2 is associated with accelerated progression of


16
bone marrow failure in Japanese Fanconi anemia patients. Blood 122(18):
3206-9, 2013.
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Yang YC, Lin X, Chen X, Luo GJ, Zhu Y, Tang S, Zhang J, Liu H, Gu Q,
Zhao LH, Li Y, Liu L, Zhou W, Wang H. Aldehyde dehydrogenase-2
(ALDH2) opposes hepatocellular carcinoma progression by
regulating
AMP-activated protein kinase signaling in mice. Hepatology 65(5):
1628-1644, 2017.
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Fernandes MR, Keller LH, Quan X, Coulter SA, Moore WH, Herlihy JP,
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injection of autologous aldehyde dehydrogenase-bright stem cells in
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[21] Gross ER, Zambelli VO, Small BA, Ferreira JC, Chen CH,
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D.
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