BIO monitorinG in Patients With Preserved Left ventricUlar Function AfteR Diagnosed Myocardial Infarction
Phase: NA
Conditions: Myocardial Infarction, Myocardial Infarction, Acute, Myocardial Infarction Old
Sponsor: Biotronik SE & Co. KG

 
BIOGUARD-MI 
Clinical Studies  
Protocol Modification Notification 
 
Date 06-APR-2021 
Page 1 of 10 
T206B-r2 02/20 
 
Date:  April 06, 2021 
To: 
BIOGUARD-MI Clinical Study Sites 
From: Silke Krueger, BIOGUARD-MI Project Manager 
CC: 
BIOTRONIK BIOGUARD-MI Study Team 
FCSEs and RCRAs  
Applicable BIOTRONIK Study Field Personnel 
Date of previous protocol:  12 June 2019 
The BIOGUARD-MI study aims to investigate whether continuous arrhythmia monitoring and 
detection, using an ICM (BioMonitor 2 or market released successor, hereafter referred to as 
BioMonitor) in patients after a myocardial infarction (MI) with LVEF > 35% but with other 
cardiovascular risk factors, decreases the risk of MACE if patients are appropriately examined 
and treated for the observed arrhythmias. The population selected for this clinical 
investigation is expected to have an increased risk of cardiac arrhythmias. It is expected that 
the BioMonitor will facilitate early diagnosis of cardiac arrhythmias and result in treatment of 
the arrhythmias or other cardiac conditions that may present, to prevent clinical endpoints 
and disease progression. This study will enroll up to 2900 subjects at up to 80 clinical study 
sites worldwide. Up to 360 subjects at up to 20 study sites are planned within the United 
States. 
Date of protocol amendment:  April 06, 2021 
Description of protocol changes: 
Implementation of final study termination visit: 
Changes are made to implement an in-office final study termination visit for all active subjects 
within 2021. After a complete medical record review for adverse events, the study personnel 
will interview the subject about any adverse events that occurred during study participation. 
Additionally, the interview may be supported by obtaining additional information about 
adverse events from family members, primary care providers or other hospitals where care 
was provided.  
At the study termination visit, NYHA classification, recording of current cardiovascular 
medications, and a subject interview will be performed to analyze the data regarding the 
change in health status of the subjects in both groups. 
Statistical changes: 
The statistics section has been updated in accordance with change of the subject visit 
schedule. By triggering the termination phase with this protocol amendment, the study 
protocol deviates from the initial planned study concept which defined a specific number of 
primary endpoints prior to study termination.  
According to the original statistical planning, the study was designed as a three-stage adaptive 
group sequential test procedure according to O’Brian Fleming with survival endpoint, where 
the inverse normal method is used to combine the separate stage information. This strategy 
is replaced with a final analysis of all data after study completion. An interim analysis has 
been conducted according to the initial strategy, and the influence of this interim analysis on 
the alpha-error will be considered to maintain the pre-planned global alpha error. The first 
interim analysis was conducted according to the initial statistical plan. The planned second 

 
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Protocol Modification Notification 
 
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Page 2 of 10 
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interim analysis will not be done. Due to the O’Brien Fleming design with a very low αinterim1 = 
0.00025 for the first interim analysis, an adjusted significance level for the final analysis:  αfinal 
= 0.02476 will maintain the global 1-sided significance level α= 0.025. 
 
With the implementation of the protocol amendment dated April 06, 2021, the intended 
number of endpoints may not be reached. 
Update of authorship criteria: 
The authorship guidelines have been updated. The scoring system for determination of 
authorship has been changed and will consider four components:  
è Enrollment of patients,  
è Prompt classification of arrhythmias detected by the ICM,  
è Unhesitating contact to the patient, and 
è Conducting an in-office termination visit. 
Rationale for changes: 
Implementation of final study termination visit: 
Based on the results of the first pre-specified interim analysis conducted in March 2020, the 
DSMB expressed concerns about a potential imbalance in adverse event reporting due to the 
more frequent investigator contacts of patients with an implantable cardiac monitor which 
may have a direct impact on the primary study outcome. Consequently, the DSMB requested 
the Steering Committee and the sponsor identify the root cause of the reporting bias and 
amend the study protocol accordingly. Based on this unforeseen development the sponsor 
decided to suspend subject enrollment which was communicated to sites on April 22, 2020.   
Since the DSMB recommendation, the sponsor and the Steering Committee have been 
working to determine reasons for this potential underreporting. During this data analysis, 
there was some evidence of local differences in the number of reported adverse events 
between some sites, as well as between countries.  
After the events described above, monitoring efforts were intensified at study sites outside of 
the U.S. which identified a number of unreported events, but failed to reduce the reporting 
bias substantially. This remaining bias, along with delays between adverse event onset and 
reporting, led to the conclusion that treatment group subjects may have a stronger tendency 
(than control group subjects) to visit the study site for cardiac care.  
In January 2021, the Steering Committee and DSMB agreed with the approach to implement 
in-person termination visits for all active study participants.  Conducting in-person termination 
visits at the study site is intended to complement the regular phone calls used to identify all 
adverse events and has been identified as being a crucial step to support an unbiased 
assessment of the primary study objective. The termination visit is intended to establish 
complete adverse event reporting and therefore do not extend the range of collected data, 
but rather increase data completeness and quality. 
Statistical changes: 
The original plan assumed that 372 primary events would be required to accept the primary 
alternative hypothesis with 80% statistical power given an assumed hazard ratio in the 
population of 0.7452, and the study was to be terminated after this number of endpoints had 
been collected.  

 
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Protocol Modification Notification 
 
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As it was decided to enter the termination phase without any further delay, the intended 
number of endpoints may not be reached, and the study may be underpowered for the 
primary endpoint.  
Steering Committee and sponsor determined that seeing all remaining subjects at a study 
termination visit takes precedence over a longer study period to capture the required number 
of endpoint events.  
Update of authorship criteria: 
The authorship criteria were updated to further define specific reactions to Home Monitoring 
that will be evaluated as prompt classification of arrhythmias and consecutive contact with 
subjects is critical for the study concept to be effective. In addition, conducting the in-office 
termination visit for all active subjects was added as this is important for a complete adverse 
event reporting.   
Impact of changes: 
As noted above, the decision to move into the termination phase and complete the analysis 
after study completion instead of after the required number of endpoint events may result in 
the study being underpowered for the primary endpoint analysis. However, the scientific 
intent of the study is not altered. The in-person termination visit does not impact the subject’s 
rights, safety, or welfare, there are no changes to the benefits or risks to the study 
participants. The noted protocol changes also have no effect on the study devices or study 
medical procedures. The IDE risk remains unchanged from previously being determined as a 
significant risk study.  
FDA and IRB Review Requirements: 
The noted change includes an early study termination, an update of the study design, and 
change to statistical analysis plan. According to the FDA guidance "Changes or Modifications 
During the Conduct of a Clinical Investigation; Final Guidance for Industry and CDRH Staff", 
FDA approval may be required for protocol changes impacting the subject number and study 
termination as this may impact the scientific soundness of the study. Additionally, as the 
primary endpoint analysis may be impacted by the early study termination, approval by FDA 
is required prior to implementation of the protocol change as well as full board IRB approval.  
No changes of the ICF are required. 
 
Table 1:  Summary of Protocol Changes  
BIOGUARD-MI Protocol 
(Version 12 JUN 2019) 
BIOGUARD-MI Protocol Amendment 
(Version 06 APR 2021) 
Summary Study duration: 
The follow-up period of the individual 
subject is dependent on the time of entry 
into the study. All study subjects will be 
followed until the number of needed 
endpoints for the final analysis is reached 
or the DSMB determines a premature study 
termination. 
 
Summary Study duration: 
The follow-up period of the individual 
subject is dependent on the time of entry 
into the study. All study subjects will be 
followed until completion of the final study 
termination visit or the sponsor determines 
a 
premature 
study 
termination 
after 
consultation with the DSMB and Steering 
Committee. 

 
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Protocol Modification Notification 
 
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Summary Follow-up scheme 
Termination 
· 
Final subject contact, either via office 
visit or telephone contact 
 
Summary Follow-up scheme 
Final Study Termination Visit 
· 
Final subject in-office visit at the site. 
Section 4: Study Design 
The second phase is currently planned to 
last until approximately 2021. As study stop 
will be announced once the required 
number of endpoints is reached, the 
individual time for subject participation 
depends on time of enrollment of the 
subject in the study. As U.S. subjects will 
start in phase 2 of the study, the estimated 
individual 
subject 
study 
participation 
duration is between 0 and 35 months. 
Section 4: Study Design 
The second phase is currently planned to 
last until approximately 2021. Study stop 
will be announced once all active subjects 
have 
completed 
their 
final 
study 
termination visit or as determined by the 
sponsor after consultation with the DSMB 
and Steering Committee. 
Section 4: Study Design 
The follow-up period of the individual 
subject is dependent on the time of entry 
into the study. All subjects will be followed 
until the number of needed endpoints for 
the final analysis is reached or the DSMB 
determines a premature study termination. 
Section 4: Study Design 
The follow-up period of the individual 
subject is dependent on the time of entry 
into the study. All subjects will be followed 
until a final study termination visit has been 
completed or the Sponsor determines a 
premature 
study 
termination 
after 
consultation with the DSMB and Steering 
Committee. 
No section available 
New section 4.2.4: Final Study Termination 
Visit 
All active subjects will be asked to visit the 
study site for a final study termination visit. 
After a complete subject medical record 
review for adverse events, the study 
personnel will interview the subject about 
any adverse events that occurred during 
study 
participation. 
Additionally, 
the 
interview may be supported by obtaining 
additional 
information 
about 
adverse 
events from family members, primary care 
providers or other hospitals where care was 
provided. 
Section 6.1.1: Group sequential design 
The study is designed as a three-stage 
adaptive group sequential test procedure 
according to O’Brian Fleming with survival 
endpoint, where the inverse normal method 
Section 6.1.1: Statistical design 
According to original statistical planning, 
the study was designed as a three-stage 
adaptive group sequential test procedure 
according to O’Brian Fleming with survival 

 
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Clinical Studies  
Protocol Modification Notification 
 
Date 06-APR-2021 
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is used to combine the separate stage 
information. 
endpoint, where the inverse normal method 
is used to combine the separate stage 
information. 
This strategy is replaced with a final 
analysis of all data after study completion. 
An interim analysis has been conducted 
according to the initial strategy, and the 
influence of this interim analysis on the 
alpha-error will be considered to maintain 
the pre-planned global alpha error. 
Section 6.1.4: Statistical methods 
Inferential 
analysis 
of 
the 
primary 
hypothesis: 
The 
inverse 
normal 
combination test is used to combine the 
independent increment to a global test 
statistic. A one-sided logrank test is 
performed in the context of a confirmatory 
analysis of the primary hypothesis at every 
interim and the final analysis. 
Section 6.1.4: Statistical methods 
Inferential 
analysis 
of 
the 
primary 
hypothesis: A one-sided log-rank test is 
performed in the context of a confirmatory 
analysis of the primary hypothesis at the 
interim and the final analysis. 
Section 6.2: Sample Size 
It is expected that there will be pC1year = 5% 
subjects with at least one MACE per year in 
the control group and pBioM1year = 3.75% 
subjects with at least one MACE per year in 
the BioMonitor group, which results in a 
Hazard Ratio = 0.7452 in favour of the 
BioMonitor.  
According 
to 
the 
approximation 
of 
Schoenfeld 43 363 events are needed. 
However, there is a slight increase of the 
sample size due to the group-sequential 
design of O’Brien Fleming. The interim 
analyses and the final analysis should be 
conducted with 124, 248, and 372 subjects 
with at least one MACE during the clinical 
investigation, respectively. 
In total, up to 2900 subjects may be 
enrolled. The subject number of up to 2900 
is based on an expected endpoint-rate of 
5%/3.75% per subject year required to 
reach the study goal of 372 endpoint 
events. 
The subject number 
will 
be 
automatically adjusted in the event the 
endpoint rate deviates from the expected 
rate. All subjects will be followed until the 
end of the clinical investigation. The study 
Section 6.2: Sample Size 
The original plan assumed that 372 primary 
events would be required to accept the 
primary alternative hypothesis with 80% 
statistical power given an assumed hazard 
ratio in the population of 0.7452, and the 
study was to be terminated after this 
number of endpoints had been collected.  
With the implementation of the protocol 
amendment dated April 06, 2021, the 
intended number of endpoints may not be 
reached. 
 

 
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Clinical Studies  
Protocol Modification Notification 
 
Date 06-APR-2021 
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duration will be approximately 3 years, but 
ultimately study closure is dependent on 
when the number of needed endpoints for 
the final analysis is reached. 
This accounts also for loss of information 
due to drop-outs which remain in the 
analysis set. According to the adaptive 
group-sequential design, the sample size 
can also be adjusted after the first or 
second interim analysis based on the 
recommendations of the DSMB. However, 
the sponsor must confirm any sample size 
increase and has the right to refuse it. 
There is no adjustment of the significance 
value for stopping for futility. 
Section 6.3: Level of significance and the 
power of the study 
The global significance level is of the 1-
sided hypothesis is 2.5%. The significance 
level of the interim analyses and final 
analysis is given by the O’Brien Fleming  
method: ainterim1 = 0.00025, ainterim2 = 
0.007, and afinal = 0.0225. 
 
Section 6.3: Level of significance and the 
power of the study 
The global significance level of the 1-sided 
hypothesis is 2.5%. The first interim 
analysis has been performed. The planned 
second interim analysis will not be done. 
Due to the O’Brien Fleming design with a 
very low ainterim1 = 0.00025 for the first 
interim analysis, an adjusted significance 
level for the final analysis:  afinal = 0.02476 
will maintain the global 1-sided significance 
level α= 0.025. 
Section 6.7: Provision for an interim 
analysis 
There are two interim analyses based on 
1/3 and 2/3 of the total number of subjects 
with at least one MACE. 
Section 6.7: Provision for an interim 
analysis 
One interim analysis has been completed. 
No 
further 
interim 
analysis 
will 
be 
performed. 
 
Section 6.8: Termination criteria 
The sponsor may decide to discontinue the 
study due to organizational reasons based 
on the observed event rates and the 
general feasibility of the study. Based on 
the recommendations of the DSMB for the 
study after the first and second interim 
analysis, the study will be stopped for 
futility when there is a low chance for 
rejection of the Alternative hypothesis at 
the final analysis or the need for an increase 
of the sample size, which is refused by the 
sponsor. 
Section 6.8: Termination criteria 
The sponsor may decide to discontinue the 
study due to organizational reasons based 
on the observed event rates and the 
general feasibility of the study. Based on 
the recommendations of the DSMB for the 
study after the first interim analysis, the 
study will be stopped for futility when there 
is a low chance for rejection of the 
Alternative hypothesis at the final analysis 
or the need for an increase of the sample 
size, which is refused by the sponsor. 

 
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Clinical Studies  
Protocol Modification Notification 
 
Date 06-APR-2021 
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Stopping for superiority is achieved in case 
the 1-sided p-value at the interim analyses 
is below the O’Brien Fleming significance 
values ainterim1 = 0.00025 and ainterim2 = 
0.007, respectively. 
 
Stopping for superiority is achieved in case 
the 1-sided p-value at the interim analyses 
is below the O’Brien Fleming significance 
value ainterim1 = 0.00025. 
 
Section 6.11: Procedure for accounting of 
all data for analysis 
Data exports from the Clinical Data 
Management System and the BIOTRONIK 
Clinical 
Data 
Warehouse 
with 
Home 
Monitoring data will be analyzed with 
common statistical software packages, e.g. 
SAS Version 9.3 or IBM SPSS Version 21 for 
Windows or higher. 
 
Section 6.11: Procedure for accounting of 
all data for analysis 
Data 
exports from 
the 
Clinical 
Data 
Management System and the BIOTRONIK 
Clinical 
Data 
Warehouse 
with 
Home 
Monitoring data will be analyzed with 
common statistical software packages, e.g. 
SAS Version 9.4. 
 
Section 7.1: Subject Population 
Every investigator can enroll as many 
subjects as desired until the sample size for 
the entire study has been reached. 
Section 7.1: Subject Population 
By decision of the Steering Committee and 
the sponsor, enrollment was suspended on 
April 22, 2020. 
Section 7.2: Electronic CRFs and Forms 
 
Section 7.2: Electronic CRFs and Forms 
Added eCRF to listing after Discharge eCRF: 
· 
Termination visit eCRF 
Section 7.2, Table 1: Overview eCRFs and 
Procedures 
Section 7.2, Table 1: Overview eCRFs and 
Procedures  
Added required data collection in table for 
Termination: 
NYHA, 
Cardiovascular 
medication, Subject interview 
Section 8: Study Procedures 
Subjects who have successfully been 
enrolled in the study will be evaluated at 
discharge, phone calls every 6 months and 
a termination visit. 
Section 8: Study Procedures 
Subjects 
who have 
successfully 
been 
enrolled and are still active in the study will 
be evaluated at discharge, phone calls 
every 6 months, 
and 
a final 
study 
termination visit. 
Section 8.8: Study Termination 
 
Section 8.8: Study Termination 
Added new paragraph after current first 
paragraph: 
All active subjects will be asked to visit the 
study site for a final study termination visit. 
After a complete subject medical record 
review for adverse events, the study 
personnel will interview the subject about 
any adverse events that occurred during 

 
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study 
participation. 
Additionally, 
the 
interview may be supported by obtaining 
additional 
information 
about 
adverse 
events from other sources, in accordance 
with local regulations, e.g. from family 
members, primary care providers or other 
hospitals where care was provided. 
Section 9.2: Point of enrollment and study 
termination 
Regular point of termination for all subjects 
is the date when the formal study 
termination is announced. 
Section 9.2: Point of enrollment and study 
termination 
Regular point of termination for the 
individual subject is the respective date of 
the final study termination visit. 
Section 14.2: Reporting Deviations 
All deviations will be reported in the interim 
and final clinical investigation reports.  
 
BIOTRONIK, Inc. categorizes protocol non-
compliance instances as either protocol 
violations or protocol deviations. Both 
protocol violations and deviations will be 
reported in the interim and final clinical progress 
reports. 
 
Section 14.2: Reporting Deviations 
All deviations will be reported in the annual 
and final clinical investigation reports.  
 
BIOTRONIK, Inc. categorizes protocol non-
compliance instances as either protocol 
violations or protocol deviations. Both 
protocol violations and deviations will be 
reported in the annual and final clinical 
progress reports. 
Section 17.2.4: Justification and rules for 
the assessment of “acquisition of data” 
A 
scoring 
system 
will 
consider 
two 
components: enrollment of subjects and 
the complete documentation of the reaction 
to HM containing the classification of an 
arrhythmia detected by the ICM, the 
resulting subject contact and, if a change in 
therapy 
is 
indicated, 
also 
the 
documentation of the therapy changes. 
Enrollment: The importance of subject 
enrollment for the success of the study is 
obvious. All subjects are counted if they are 
randomized and included in the analysis 
population. 
Reaction 
to 
HM: 
The 
thoroughly 
conducted 
diagnostic 
work-up 
and 
consequent treatment, if required, after 
ICM 
detected 
arrhythmias 
is 
the 
mechanism by which the study attempts to 
improve the outcome in the treatment arm. 
Since the study does not enforce therapy, 
documented cases of arrhythmia and 
subject contact will be acknowledged 
Section 17.2.4: Justification and rules for 
the assessment of “acquisition of data” 
A 
scoring 
system 
will 
consider 
four 
components:  
è Enrollment of patients,  
è Prompt 
classification 
of 
arrhythmias detected by the ICM  
è Unhesitating 
contact 
to 
the 
patient 
è Conducting an in-office final study 
termination visit. 
Justification:  
The importance of enrollments for the 
study’s success is evident. Without prompt 
classification 
of 
arrhythmias 
and 
consecutive contact with patients, the study 
concept cannot be effective. The conduction 
of in-office final study termination visits is 

 
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independent of the question whether it 
resulted in a therapy or not.  
Besides the assumed influence on the 
primary study outcome, the complete 
documentation of event chains is an 
important secondary objective of the study. 
To be counted, the following requirements 
must be fulfilled: 
- 
An arrhythmia reported by the CEMB 
was classified by the investigator 
- 
The 
subject 
was 
contacted, 
if 
applicable 
- 
If 
a 
diagnostic 
work-up 
was 
considered 
necessary, 
the 
diagnostic 
results 
and 
therapy 
changes are reported  
- 
The overall delay from CEMB report 
to classification by the investigator 
did not exceed 7 days 
- 
The information was recorded in the 
corresponding eCRFs and no open 
queries remain at study termination. 
To calculate the value of reaction to HM 
cases, the following rules apply: The time 
from CEMB notification to subject contact 
must not exceed 7 days. Within this period, 
the investigator must have studied the HM 
content and classified the subject’s rhythm, 
and must have contacted the subject, if 
applicable.  
If this timeline is met, the full value is 
granted for the case.  
important for a complete adverse event 
reporting.   
All four elements can be objectively 
calculated from the study database and 
together, 
they 
provide 
an 
objective 
quantification of the contribution of a study 
site. 
 
Section 17.2.5: Calculation of total score 
For all randomized subjects together, 1000 
points are granted. For each randomized 
subject, the number of granted points to 
the study site is 1000 divided by the 
number of randomized subjects.  
For all Reaction to HM cases fulfilling the 
defined conditions together, 1000 points 
are granted. For each case, the value 
granted to the study site is 1000 divided by 
the total number of cases. These points 
Section 17.2.5: Calculation of total score  
For each of the four elements, 1000 points 
are granted. 
è For each randomized subject, the 
number of granted points to the 
investigational site is 1000 divided 
by 
the 
number of 
randomized 
subjects.  

 
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may be reduced if the delays occurred, as 
defined above.  
The points are added for all study sites. If, 
for example 3000 subjects will be enrolled 
and 5000 cases of arrhythmia and contact 
are documented, all sites will receive 0.33 
points per enrolled subject, and 0.2 points 
per timely documented event chain. 
The sites will then be ranked by the number 
of points. 
 
è Further 1000 points are distributed 
evenly 
over 
all 
classified 
arrhythmias, 
which 
have 
been 
completed within 5 working days 
after onset of the arrhythmia. 
è Equally, further 1000 points are 
distributed evenly over all contacts 
to subjects after arrhythmias, which 
were done within 7 working days of 
the arrhythmia. 
è For each subject seen in-office for 
the final study termination visit, the 
number of points is 1000 divided by 
the total number of subjects seen in-
office for the final study termination 
visit. 
The sites will then be ranked by the sum of 
points from the four categories. 
For all publications after the primary 
publication, investigators who have not 
been authors of accepted publications will 
be considered preferentially. The number of 
authors of a study site on all publications 
(weighted by the journals’ latest impact 
factors) shall be proportional to the data 
contribution measured by the score, which 
is described here.  
 
 
BIOTRONIK contact information for questions 
 
Silke Krüger, Project Manager, 503-451-8053, silke.krueger@biotronik.com  
Lulu Yang, Clinical Research Associate, 503-451-8073, lulu.yang@biotronik.com