Integrated Diagnostics Driven Diuretic and Chronic Medication Management for Heart Failure
Phase: NA
Conditions: Heart Failure
Sponsor: Medtronic Cardiac Rhythm and Heart Failure

 
 
 
 
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INTERVENE-HF 
Integrated Diagnostics Driven 
Diuretic and Chronic Medication Management 
for Heart Failure 
 
 
Clinical Investigation Plan 
Version 5.0 
29Sep2017 
IDE Number: G150234 
 
 
 
 
 
 
 
 
 
Regional Sponsor and Contact  
United States 
Medtronic, Inc. 
8200 Coral Sea Street NE 
Mounds View, MN U.S.A. 55112 
1-800-328-2518 

 
 
 
 
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TABLE OF CONTENTS 
INTERVENE-HF ....................................................................................................................................... 1 
TABLE OF CONTENTS ........................................................................................................................... 2 
LISTING OF TABLES .............................................................................................................................. 6 
LISTING OF FIGURES ............................................................................................................................ 6 
ADMINISTRATIVE INFORMATION......................................................................................................... 7 
SPONSOR CONTACT INFORMATION .................................................................................................. 7 
CRO AND CORE LABS ........................................................................................................................... 7 
1. INTRODUCTION .................................................................................................................................. 8 
1.1 Study Purpose ............................................................................................................. 8 
1.2 Study Description ......................................................................................................... 8 
2. BACKGROUND AND JUSTIFICATION ............................................................................................. 9 
3. SYSTEM DESCRIPTION AND INTENDED USE ............................................................................. 12 
3.1 System Process & Component Overview ................................................................... 12 
3.2 Component Details ..................................................................................................... 13 
4. REGULATORY COMPLIANCE ........................................................................................................ 19 
5. METHODOLOGY .............................................................................................................................. 20 
5.1 Study objectives ......................................................................................................... 20 
5.2 Subject selection criteria ............................................................................................ 21 
5.2.1 Inclusion criteria 
21 
5.2.2 Exclusion criteria 
22 
5.3 Minimization of Bias ................................................................................................... 22 
6. STUDY PROCESS OVERVIEW ....................................................................................................... 22 
6.1 A) Screening Visit....................................................................................................... 23 
6.1.1 Patient Informed Consent & Screening 
23 
6.2 B) Baseline & Programming Visit ............................................................................... 24 
6.2.1 Investigator Writes Standing Order for Medication Intervention and Establishes 
Subject Specific Safety Parameters 
24 
6.2.2 Subject Added/Transferred to Virtual CareLink-HF Clinic 
24 
6.2.3 Silent OptiVol CareAlert Turned ON in CRT-D device with 2090 Programmer25 
6.2.4 CommanderFLEX™ In-Home Biometric Monitoring Equipment Sent to Subjects 
Home 
25 
6.3 C) Data Transmitted to ISCC ..................................................................................... 25 
6.2.1 Daily CommanderFLEX™ Biometric Data 
25 
6.2.2 CRT-D Device Diagnostics Data 
26 
6.3 D) Risk Categorization and Intervention Determination .............................................. 26 
6.3.1 Subject Risk Categorization 
26 
6.3.2 Determining if Intervention is Warranted 
28 
6.4 E) Interventions .......................................................................................................... 28 
6.4.1 ISCC Executed Acute Medication Intervention (PRN and Counseling) 
29 

 
 
 
 
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6.4.2 Investigator Executed Chronic Medication Intervention 
33 
6.5 F) Ensuring Subject Safety ......................................................................................... 33 
6.5.1 Criterion for not initiating or continuing with a PRN Intervention 
33 
6.6 G) HCU Data Collection ................................................ Error! Bookmark not defined. 
6.7 H) Exit Visit ................................................................................................................ 35 
7 SITE RELATED PROCEDURES ...................................................................................................... 35 
7.1 Investigator/Investigation site selection ...................................................................... 35 
7.2 Site activation ............................................................................................................. 36 
7.3 Equipment requirements ............................................................................................ 37 
7.4 Data Collection ........................................................................................................... 38 
7.5 Role of the sponsor representatives ........................................................................... 40 
7.6 Patient informed consent process .............................................................................. 40 
7.7 Screening Visit ........................................................................................................... 42 
7.7.1 OptiVol Threshold Verification 
Error! Bookmark not defined. 
7.7.2 Bloodwork Eligibility 
Error! Bookmark not defined. 
7.8 Baseline and Programming Visit ................................................................................ 43 
7.9 Scheduled follow-up phone calls ................................................................................ 43 
7.10 
ISCC Communication & Notifications to Site ............................................. 44 
7.11 
Unscheduled follow-up visits ..................................................................... 45 
7.12 
Healthcare Utilization ................................................................................ 46 
7.13 
System Modification .................................................................................. 46 
7.14 
Study Exit ................................................................................................. 46 
7.15 
Medications .............................................................................................. 48 
8 INVESTIGATIONAL DEVICE/SOFTWARE STORAGE, HANDLING AND TRACEABILITY ......... 49 
8.1 Investigational Device/Software Storage, Handling and Traceability .......................... 49 
8.2 Final Product Disposition ............................................................................................ 49 
9 STUDY DEVIATIONS ........................................................................................................................ 50 
10 ADVERSE EVENTS AND DEVICE DEFICIENCIES ........................................................................ 52 
10.1 
Adverse Event and Device Deficiency definitions ...................................... 52 
10.2 
Adverse Event and Device Deficiency Assessment .................................. 55 
10.2.1 Adverse Events 
55 
10.2.2 Device Deficiencies 
56 
10.2.3 Processing Updates and Resolution 
56 
10.3 
Events Classification and Reporting .......................................................... 57 
10.4 
Adverse Event and Device Deficiency Reporting Requirements ............... 58 
10.5 
Subject Death ........................................................................................... 60 
10.5.1 Death data collection 
60 
10.5.2 Death classification and reporting 
61 
10.6 
Clinical Events Committee (CEC) review .................................................. 61 

 
 
 
 
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10.7 
Product Complaint Reporting .................................................................... 62 
11 RISK ANALYSIS ............................................................................................................................... 63 
11.1 Risk Minimization ..................................................................................................... 63 
11.2 Potential Benefits ..................................................................................................... 65 
11.3 Additional Considerations ........................................................................................ 66 
12 PLANNED STUDY CLOSURE, EARLY TERMINATION OF STUDY OR STUDY SUSPENSION . 66 
12.1 
Planned study closure ............................................................................... 66 
12.2 
Early termination or suspension ................................................................ 66 
12.2.1 Study-wide termination or suspension 
66 
12.2.2 Investigator/center termination or suspension 
67 
12.3 
Procedures for termination or suspension ................................................. 67 
12.3.1 Medtronic-initiated and regulatory authority-initiated 
67 
12.3.2 Investigator-initiated 
67 
12.3.3 IRB-initiated 
68 
13 STATISTICAL METHODS AND DATA ANALYSIS ......................................................................... 69 
13.1 
Sample size determination ........................................................................ 69 
13.2 
General considerations ............................................................................. 70 
13.3 
Primary Objective #1................................................................................. 70 
13.3.1 Hypothesis 
70 
13.3.2 Endpoint Definition 
71 
13.3.3 Performance Requirements 
71 
13.3.4 Rationale for Performance Criteria 
71 
13.3.5 Analysis Methods 
71 
13.3.6 Determination of Patients/Data for Analysis 
71 
13.3.7 Sample Size 
71 
13.4 
Primary Objective #2................................................................................. 73 
13.4.1 Hypothesis 
73 
13.4.2 Endpoint Definition 
73 
13.4.3 Performance Requirements 
74 
13.4.4 Rationale for Performance Criteria 
74 
13.4.5 Analysis Methods 
74 
13.4.6 Determination of Patients/Data for Analysis 
74 
13.4.7 Sample Size 
74 
13.5 
Ancillary Objective .................................................................................... 74 
13.5.1 Hypothesis 
74 
13.5.2 Endpoint Definition 
74 
13.5.3 Analysis Methods 
74 
13.5.4 Determination of Patients/Data for Analysis 
75 
13.6 
 Preliminary Safety Interim Data Analysis ................................................. 75 
13.6.1  Hypothesis 
75 
13.6.2 Endpoint Definition 
75 
13.6.3 Analysis Methods 
75 
13.6.4 Determination of Patients/Data for Analysis 
75 
14 DATA AND QUALITY MANAGEMENT ............................................................................................ 75 

 
 
 
 
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15 WARRANTY/INSURANCE ............................................................................................................... 77 
16 MONITORING ................................................................................................................................... 77 
16.1 
Monitoring Visits ....................................................................................... 77 
17 REQUIRED RECORDS AND REPORTS ......................................................................................... 78 
17.1 
Investigator records .................................................................................. 78 
17.2 
Investigator reports ................................................................................... 79 
APPENDIX A:  DRAFT DATA COLLECTION ELEMENTS (CASE REPORT FORMS) ...................... 82 
APPENDIX B: ISCC REPORTS TO PHYSICIAN .................................................................................. 82 
APPENDIX C: INFORMED CONSENT TEMPLATES ........................................................................... 88 
APPENDIX D: PARTICIPATING INVESTIGATORS AND INSTITUTIONS .......................................... 88 
APPENDIX E: COMMITTEES ................................................................................................................ 88 
APPENDIX F: IRB .................................................................................................................................. 88 
APPENDIX G: LABELING ..................................................................................................................... 88 
APPENDIX H: BIBLIOGRAPHY ............................................................................................................ 89 
APPENDIX I: PRELIMINARY PUBLICATION PLAN ............................................................................ 91 
APPENDIX J: ABBREVIATIONS .......................................................................................................... 93 
APPENDIX K: MODIFICATIONS TO THE CLINICAL INVESTIGATION PLAN .................................. 94 
 
 
 

 
 
 
 
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LISTING OF TABLES 
 
 
Table 1: US Study sponsor contact information ............................................................... 7 
Table 2: CRO and core lab information ........................................................................... 7 
Table 3: System component #1 (CRT-D Device) ........................................................... 13 
Table 4: Model numbers of CRT-D devices used in the INTERVENE-HF study. ........... 13 
Table 5: System component #2 (Programmer with Research Software) ........................ 14 
Table 6: System component #3 (CareLink Monitor) ....................................................... 14 
Table 7: System component #4 (CareLink Network)...................................................... 15 
Table 8: System component #5 (INTERVENE STUDY COMMUNICATION CENTER) . 16 
Table 9: System component #6 (CommanderFLEX™ Biometric Equipment) ................ 17 
Table 10: Biometric HF Symptom Questions Collected by the CommanderFlex™ ........ 27 
Table 11: Safety Thresholds for Cessation of Medication Intervention (PRN) ................ 34 
Table 12: Data Collection Table .................................................................................... 38 
Table 13: Data collection and study procedure requirements at subject phone call ....... 44 
Table 14: Adverse Event definitions .............................................................................. 52 
Table 15: Adverse Event classification responsibilities .................................................. 57 
Table 16: Reporting requirements ................................................................................. 58 
Table 17: Potential risks and risk minimization .............................................................. 64 
Table 18: Number of OptiVol crossings expected from 110 (55% of 200) subjects ........ 70 
Table 19: Table of the 95% Confidence Interval for 70-100 independent episodes ....... 72 
Table 20: Investigator reports applicable for all geographies per Medtronic requirements79 
Table 21: Additional Investigator reports applicable to the ............................................. 80 
Table 22: Sponsor reports for the United States ............................................................ 80 
Table 23: Change history .............................................................................................. 94 
 
LISTING OF FIGURES 
 
Figure 1: Schematic of the INTERVENE-HF System Components & the Clinical Process.12 
Figure 2: Top view of the CommanderFLEX™ device. .................................................. 18 
Figure 3: Back view of the CommanderFLEX™ device. ................................................ 18 
Figure 4: General study process for INTERVENE-HF. .................................................. 23 
Figure 5: Intervention in INTERVENE-HF study. ........................................................... 29 
Figure 6: Example Scenario of One Round of Medication Intervention (PRN). .............. 30 
Figure 7: Example Scenario of Two Rounds of Medication Intervention (PRN). ............ 31 
Figure 8: Recovery Criteria Illustration........................................................................... 32 
Figure 9: Graph of the 95% Confidence Interval for 70 to 100 independent episodes .... 73 
 
 
 

 
 
 
 
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ADMINISTRATIVE INFORMATION  
SPONSOR CONTACT INFORMATION 
Medtronic contact information is provided below. Contact information for study management 
and monitoring personnel may be updated under separate cover during the course of the 
study. Current information is as follows:  
 
Table 1: US Study sponsor contact information 
 
 
 
Medtronic 
8200 Coral Sea Street NE 
Mounds View, MN U.S.A. 
55112 
1-800-328-2518 
 
Contact 
Phone 
E-mail 
Joe Hobbs 
Clinical Research Specialist 
1-763-269-2994 
joe.hobbs@medtronic.com 
Taryn Randall 
Clinical Monitoring Manager 
1-763-250-0785 
taryn.randall@medtronic.com 
Vinod Sharma 
Sr. Principal Scientist 
1-763-526-0139 
vinod.sharma@medtronic.om 
 
CRO AND CORE LABS 
Table 2: CRO and core lab information 
 
Contact Information  
Duties performed 
Cognizant Technology Solutions 
500 Frank W. Burr Blvd. 
Teaneck, NJ 07666 
Direct Phone: (201) 801-0233 
Direct Fax: (201) 801-0243 
• 
Development of study electronic case report forms, edits 
checks, and study management reports. 
• 
Review of electronic case report forms, management of 
discrepancies, and coding of medications and deviations. 
 
Any changes/additions to CRO or core labs may be distributed under separate cover. 
  
 
 

 
 
 
 
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1. INTRODUCTION 
1.1 Study Purpose 
 
Medtronic, Inc. is sponsoring Integrated Diagnostics Driven Diuretic and Chronic Medication 
Management for Heart Failure (INTERVENE-HF), a prospective, non-randomized, multi-
center, feasibility study. The purpose of this clinical feasibility study is to gain experience with 
a research system that combines a device diagnostic based risk stratification algorithm with a 
guided work flow process managed by a centralized communication center. Findings from 
this feasibility study will be used to guide subsequent efforts to develop a heart failure patient 
management solution that may include integrated device diagnostics, a centralized 
communication center and medication intervention as key components. 
 
1.2 Study Description 
 
The INTERVENE-HF study is a prospective, non-randomized, multi-center (US only), 
investigational, feasibility study. Patients with heart failure that have an implanted 
commercially available Medtronic cardiac resynchronization therapy defibrillator (CRT-D) 
device will be enrolled in the study. The basic INTERVENE-HF research system is comprised 
of the pre-existing Medtronic, CRT-D device, investigational 2090 programmer software 
capable of turning ON/OFF the silent OptiVol® wireless CareAlert, and the INTERVENE 
Study Communication Center (ISCC). The ISCC will reside with the Care Management 
Service (formerly Cardiocom) business unit of Medtronic. The INTERVENE-HF study will 
have a dedicated team of licensed nurses at ISCC that will guide and monitor subjects 
through an individualized, physician prescribed medication intervention for diuretics and other 
acute volume management drugs after their silent OptiVol CareAlert has been transmitted 
and medication intervention is warranted.   
 
The study is expected to be conducted at up to 20 centers located in the United States. Up to 
400 subjects will be enrolled to yield up to 200 eligible subjects that meet screening criteria.  
This study will be conducted in subjects with an implanted, commercially available, 
Medtronic, CRT-D device. A detailed list of these devices and model numbers is provided in 
Table 4. To ensure a widespread distribution of data and minimize center bias in study 
results, the maximum number of subjects enrolled at a single center is 30 subjects. It is 
estimated that subject enrollment will take approximately 12 to 18 months. Each enrolled 
subject will be followed every 2 months from time of enrollment to end of the study. It is 
anticipated that subjects will participate in the study for a minimum duration of 12 months and 
up to approximately 30 months. The study will end after the last enrolled subject completes 
the 12-month follow-up. Because INTERVENE-HF is a feasibility study, it is not intended to 
show an outcome of improvement. Rather the objective is to test the operational feasibility 
and safety of device diagnostics plus an intervention system as set forth in the primary and 
secondary objectives. Interim analyses of these objectives will take place and if data are 
deemed to sufficiently characterize the study objectives by the sponsor at one of these 
analyses, enrollment and/or follow-up will be stopped.      
 

 
 
 
 
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2. BACKGROUND AND JUSTIFICATION 
 
Assessment of risk to guide appropriate medical care has become a necessary tool in the 
management of cardiovascular disease. Published guidelines for managing cardiovascular 
disease are based in large part on identifying subjects at risk and then treating patients in a 
manner to reduce that risk.1 The development of risk prediction models for cardiovascular 
diseases dates back to at least the 1960s.2,3  Since that time, new and updated risk models 
have continued to be developed.4-7 Risk prediction models also exist for specific 
cardiovascular diseases. For example, the Seattle Heart Failure Model was developed to 
predict survival in patients with congestive heart failure8 and the CHADS2 score was 
developed to predict the risk of stroke in patients with atrial fibrillation.9  
 
These risk models, while clinically useful, are generally static in nature and cannot 
necessarily respond to dynamic changes in the many factors that may impact patient risk. For 
example, these models can likely predict which patient is at higher risk of developing frequent 
HF worsening events, but when exactly such an event might occur temporally cannot be 
predicted. Because device diagnostics dynamically vary with patient status (see description 
of various device diagnostic parameters below), they have the potential to be a robust and 
dynamic cardiovascular risk assessment tool to help guide appropriate medical intervention. 
 
CRT-D devices, such as those included in this study, collect valuable clinical diagnostics 
data. These diagnostic variables can be combined to generate patient risk status using a 
variety of methodologies. One methodology uses a Bayesian Belief Probabilistic model to 
categorize patients into three risk categories – Low, Medium and High.  The details of the 
model have been discussed in a paper by Cowie et al.10  Briefly, the model uses 5 distinct 
variables as input - thoracic impedance, activity, heart rate variability, heart rate, and a 
combination variable based on arrhythmia and shock related information collected by the 
device.  All of these variables have a mechanistic link with worsening heart failure, and 
several of them have been shown to have a prognostic value for heart failure event in the 
literature. Below is a brief description of each of the device variables that are input into 
integrated diagnostics algorithm. 
 
a. Intrathoracic impedance (OptiVol): As a patient’s HF status worsens, it is generally 
associated with rise in atrial filling pressure and retention of fluid in the pulmonary 
circulation. If sustained over time, this can eventually lead to fluid infiltration into 
interstitial space, thus leading to worsening pulmonary congestion.11 Since blood and 
interstitial fluid are highly conductive, their accumulation in the pulmonary system 
leads to a reduction in thoracic impedance. Thus, intrathoracic impedance appears to 
have mechanistic link with worsening HF.11-13 
 
 
b. Heart rate variability (HRV): HRV is a marker of autonomic tone and has been 
shown to provide prognostic information for mortality risk.14 Research has 
demonstrated a correlation between the decrease in HRV and increased sympathetic 
tone.  Cardiac resynchronization therapy, that has been shown to improve heart 
failure status, results in an increased HRV indicative of shift away from sympathetic 

 
 
 
 
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dominance.15 Using HRV device diagnostic data, Adamson et al.16 showed that 
patients with low HRV (<100 ms) are at a higher combined risk of death and 
hospitalization. The same study showed that patients with HRV < 50 ms were even at 
higher risk than those with HRV in the range of 50-100 ms. 
 
c. Heart Rate: Similar to HRV, elevated heart rate is a marker of elevated sympathetic 
tone and has been shown to have prognostic value for worsening HF. Night Heart 
Rate (NHR) (measured between midnight and 4 AM) is a better metric than the day 
time heart rate, which can be confounded by varying activity level (e.g. rest and 
exercise). A study in implantable device patients demonstrated that patients with high 
NHR (75±25 bpm) were at higher risk of being hospitalized or dying than those who 
had low NHR (73±11 bpm).16  
 
d. Activity: As patients retain fluid in the pulmonary circulation resulting in pulmonary 
congestion, they can easily develop dyspnea, thus limiting their functional capacity 
and activity level. In patients with a CRT device, patient activity declined from 
188±109 min/day at baseline to 164±118 min/day at the time of hospitalization.16 
Thus, decline in patient activity is associated with worsening HF status and potentially 
has value for predicting HF hospitalization. 
 
e. Combination variable: The final variable that is input into the integrated diagnostic 
algorithm combines pacing and arrhythmia related information. Specifically, one of the 
components of this variable is substantial decrease (>8%) in CRT pacing, which is 
associated with high HF events.17 A decline in CRT pacing can occur because of 
rapid conduction during AF. Thus, mean ventricular rate ≥ 90 bpm and atrial 
fibrillation (AF) burden ≥ 6 hours/day and shocks delivered to Ventricular 
Fibrillation/Ventricular Tachycardia (VT/VF) are also components of this variable.  
 
 
Each of the five variables input into the Heart Failure Risk Status - Integrated Diagnostics 
Algorithm (ID1.0 HFRS-ID) has a prognostic value for HF. Combining these variables into a 
single HF risk metric yields a prognostic indicator that is better than each of the individual 
components alone because these variables capture slightly orthogonal information (e.g. while 
decrease impedance is an indicator of elevated pulmonary pressure, HRV is an indicator of 
autonomic imbalance), and hence add to provide a better overall snapshot of patient status. 
Our model development data indicate that a patient with a risk score in the ‘high’ group were 
10 times more likely to have an Heart Failure Hospitalization (HFH) in the next 30 days 
compared with ‘low’ risk patients.10 A patient with  ‘medium’ risk status is at 2x higher risk of 
hospitalization in the next 30 days. 10  
 
While a high performance diagnostic is necessary for effective HF patient management, 
previous clinical trials have shown that diagnostic information alone is not sufficient to 
improve patient management. For example, the COMPASS-HF18 and REDUCE-HF19 trials 
that provided clinically relevant estimated pulmonary artery (PA) pressure measurements to 
physicians for HF management did not show statistically significant difference in HF based 
outcomes between PA pressure management arm and control arm. This lack of outcome 
improvement was attributed to lack of clinical actions in response to changes in PA pressure. 

 
 
 
 
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In contrast, in the CHAMPION trial20 using another version of a PA pressure measuring 
device, the treatment arm using PA pressures to manage patients yielded a significant 
decrease in HF events compared to the control arm (~30% reduction at 6 months and 40% 
reduction at 15 months in HF hospitalization). In addition, alert mechanism and workflow are 
also important as they can influence healthcare utilization.21 The key attribute of the 
CHAMPION trial that presumably led to positive outcome results was that actions to control 
the PA pressure were in fact mandated as part of the trial. And in fact, CHAMPION reported 
significant medication changes from the baseline not only in the diuretic doses, but also in 
other medications such as beta-blockers, ACE inhibitors, Angiotensin receptor blockers and 
nitrates among other drugs.18, 19 
 
Therefore, combining a prescribed medication regimen with a diagnostic variable seems to 
be a necessary condition to drive actions and improve patient outcomes. Thus, the goal of 
the INTERVENE-HF study is to test the feasibility of combining an integrated device 
diagnostics-based risk stratification algorithm with a guided work flow process managed by a 
centralized communication center. INTERVENE-HF is a feasibility study with a single-arm 
design and a limited number of subjects, and is not intended to show an outcome of 
improvement. Rather, the objective is to test the operational feasibility of diagnostics plus an 
intervention system, and quantification of the operation effectiveness and safety as set forth 
in the primary and secondary objectives.  
 
 
 

 
 
 
 
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3. SYSTEM DESCRIPTION AND INTENDED USE 
 
The study will be conducted using the following components described in Figure 1 below. 
Additional CRT-D devices listed may be used during the course of the study as they become 
FDA approved. Instructions for use of the devices used in this study are provided in their 
respective manuals.  
The INTERVENE-HF system consists of the following investigational and non-investigational 
components depicted in Figure 1 and listed in the tables below. 
 
3.1 System Process & Component Overview  
 
Figure 1: Schematic of the INTERVENE-HF System Components & the Clinical 
Process.  
 
 
 
 

 
 
 
 
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3.2 Component Details 
 
Each research system component as it relates to the study is described below. 
 
Table 3: System component #1 (CRT-D Device) 
 
Figure 1 
Component # 
Component 
Description 
Market-Released or 
Investigational? 
1 a/b 
Medtronic CRT-D 
device with 
OptiVol CareAlert 
transmission 
Capability enabled 
Medtronic CRT-D device with OptiVol 
CareAlert enabled that allows for 
transmission of device diagnostics data, 
including intrathoracic impedance fluid index, 
to CareLink when set OptiVol threshold is 
met.  
Investigational 
 
Medtronic implantable cardiac resynchronization therapy – defibrillator (CRT-D) devices (1a) 
currently have several diagnostic parameters, including the OptiVol Fluid Status Monitoring 
Feature. The OptiVol Fluid Status Monitoring Feature itself is not investigational; however the 
ability to perform CareAlert transmissions upon crossing of OptiVol Fluid threshold is 
investigational (1b). Therefore, an existing CRT-D device that has the OptiVol CareAlert 
capability turned ON is considered Investigational. No change will be made to therapy 
delivered by the CRT-D device. Any subsequent market released device with the OptiVol 
capability will be included in this study once the device is FDA approved. 
 
Table 4: Model numbers of CRT-D devices used in the INTERVENE-HF study. 
 
CRT-D Device Name 
Model Numbers 
Market-Released or 
In Development 
Protecta XT CRT-D 
 
D314TRM 
D314TRG 
Market-Released 
Viva Quad C CRT-D 
DTBX1QQ 
Market-Released 
Viva Quad XT CRT-D 
DTBA1QQ 
DTBA1Q1 
Viva XT CRT-D 
DTBA1D1 
DTBA1D4 
Viva Quad S CRT-D 
DTBB1QQ 
DTBB1Q1 
Viva S CRT-D 
DTBB1D4 
DTBB1D1 
Consulta CRT-D 
D204TRM 
D224TRK 
Market-Released 
Concerto II CRT-D 
D274TRK 
Market-Released 
 
NOTE: Any subsequent market released device with the OptiVol capability will be included in this 
study once the device is FDA approved. 

 
 
 
 
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Table 5: System component #2 (Programmer with Research Software) 
 
Figure 1 
Component # 
Component 
Description 
Market Released or 
Investigational? 
2a/b 
Medtronic   
Programmer 
Model 2090 with 
INTERVENE-HF 
Research Software 
Rev. 1.0 
CRT-D programmer 
used to interrogate and 
program CRT-D devices 
with investigational 
INTERVENE HF 
application software to 
turn ON/OFF OptiVol 
CareAlert 
 
 
Investigational 
 
The INTERVENE-HF Research Software will be installed on Model 2090 programmers (2a). 
The research software provides a user interface that allows the user to turn ON the OptiVol 
CareAlert in the subject’s CRT-D device (1b) and then later turn the OptiVol CareAlert OFF at 
the time of study termination/subject exit. 
Since the INTERVENE-HF investigational software will be distributed electronically through 
the Medtronic Software Distribution Network (SDN), physical media labeling is not required 
(see Section 8 for software handling information).  
The study center will need authorization from Medtronic in order for the software to be made 
available on the SDN as described in the User Manual. Only the 2090 programmer can be 
used for this study. Therefore, the site must have access to, or maintain, a 2090 programmer 
for the duration of the study. 
When the investigational INTERVENE-HF Research Software is downloaded onto the 
Medtronic 2090 Programmer (2b),that programmer becomes investigational and will be 
labeled to indicate that it contains investigational software until the INTERVENE-HF software 
is removed.  
Table 6: System component #3 (CareLink Monitor) 
 
Figure 1 
Component # 
Component 
Description 
Market Released or 
Investigational? 
3 
Medtronic CareLink 
Patient Monitor 
Model 2490C or 
24950 
A home-based monitor used to 
transmit device data via the 
CareLink Network where the 
data is accessed by 
INTERVENE Study 
Communication Center (ISCC) 
and investigator.  
 
Market-Released 
 
The Medtronic CareLink Monitor Model 2490C or 24950 are indicated for use in the transfer 
of patient/subject data from some Medtronic implantable cardiac devices based on 
investigator instructions and as described in the product manual. OptiVol triggered 
transmission will occur automatically without patient/subject requiring any action. All study 

 
 
 
 
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subjects will be required to have a CareLink Monitor that is appropriately powered by 
plugging into wall and is capable of transmitting data via wired or wireless/cellular connection.  
 
Table 7: System component #4 (CareLink Network) 
 
Figure 1  
Component # 
Component 
Description 
Market Released or 
Investigational? 
4a 
 
Model 2491 CareLink 
Network Device Data 
Management 
Application (DDMA) 
Converts device data in human readable 
form that can be stored to the network 
directly from the CareLink Monitor 
located at patient’s home. 
 
 
 
Market-Released 
Medtronic CareLink 
Network 
A secure, web based application that 
allows the viewing of device data 
transmitted via the CareLink Monitor. 
Data is loaded to the network directly 
from the CareLink Monitor located at the 
subject’s home. 
 
 
 
 
Market-Released 
4b 
Heart Failure Risk 
Status Integrated 
Diagnostics Feature 
(ID1.0 HFRS) 
A diagnostic feature based on an 
algorithm (referred to as HFRS-ID) that 
runs on the Medtronic CareLink Network 
and uses existing device diagnostic 
parameters (OptiVol Fluid Index, shocks, 
patient activity night heart rate, heart rate 
variability, atrial tachyarrhythmia, 
ventricular rate during AT/AF, ventricular 
arrhythmia and percent ventricular 
pacing) and adjudicated heart failure 
events from historical Medtronic clinical 
studies to produce a dynamically-
updated individual patient risk (Low, 
Medium or High) of having a heart failure 
hospitalization in the next 30 days.  The 
HFRS will be displayed on the Medtronic 
CareLink Network on the Heart Failure 
Management Report that will be received 
by the INTERVENE Study 
Communication Center for this study. 
 
 
 
Investigational 
4c 
Mainspring Pathway 
The CareLink Network pathway for 
relaying transmissions from the CareLink 
Network to the INTERVENE Study 
Communication Center. 
 
 
Market-Released 
The Medtronic CareLink Network (4a) is indicated for use in the transfer of patient data from 
some Medtronic implantable cardiac devices based on the investigator instructions and as 
described in the product manual. The Medtronic CareLink Network enables subjects to 
remotely transfer data from their device to the CareLink network via phone line or wireless 

 
 
 
 
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network. Clinic personnel can access the data, including the Cardiac Compass Report and/or 
Heart Failure Management Report, by logging onto the CareLink website via the Internet.  
In this study, CRT-D device data will be utilized in an investigational Heart Failure Risk 
Status-Integrated Diagnostic (ID1.0 HFRS) feature (4b) to calculate a heart failure risk score 
(see Section 2 for HFRS-ID algorithm background). The risk score and CareLink reports will 
then be relayed to the INTERVENE Study Communication Center (ISCC) via the Mainspring 
pathway (4c). The HFRS with OptiVol is intended to be used by the ISCC nurse as a source 
of information to help identify which patients may require closer attention and therefore 
initiate medication intervention for fluid volume management. 
The investigational ID 1.0 HFRS (4b) feature is based on an algorithm that runs on the 
Medtronic CareLink Network and uses existing device diagnostic data including OptiVol to 
produce a dynamically-updated individual patient/subject risk (Low, Medium or High) of 
having a heart failure hospitalization in the next 30 days. The HFRS will be displayed on the 
Medtronic CareLink Network on the Heart Failure Management Report. 
 
Table 8: System component #5 (INTERVENE STUDY COMMUNICATION CENTER) 
 
Figure 1 
Component # 
Component 
Description 
Market Released or 
Investigational? 
5a 
Virtual CareLink-HF 
Clinic managed by 
ISCC 
A satellite heart failure clinic 
managed by INTERVENE Study 
Communication Center (ISCC) 
residing at Medtronic Care 
Management Services (formally 
known as Cardiocom).   
 
 
NA 
5b 
INTERVENE Study 
Communication 
Center (ISCC) 
ISCC is managed by dedicated 
licensed nurses who along with the 
physicians will use the device data 
(HFRS score and other health failure 
related information from CareLink) 
and in-home biometrics as an 
additional source of information to 
manage study subjects. 
 
 
NA 
5c 
Omnivisor® Pro 
Patient Management 
System 
A patient (subject) software 
management system used by the 
ISCC nurse along with a guided 
workflow process that standardizes 
subject care and provides efficient 
remote subject monitoring. 
 
 
Market-Released 
 
As part this study, the investigator/site will agree to transfer their patient into the virtual 
CareLink-HF clinic (5a) that will be managed by the INTERVENE Study Communication 
Center (ISCC) (5b) that will reside at the Medtronic Care Management Services. However, 
the CRT-D subject will still be maintained and managed for arrhythmia and device/lead 
related events through the CareLink EP clinic. The EP clinic will continue to have the 

 
 
 
 
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uninterrupted access to the subject’s device and clinical information while enrolled in the 
study. The EP clinic will also receive device data initiated by OptiVol CareAlert transmission 
once the subject is enrolled into the study. However the EP clinic will be able to clearly see in 
their software that that their patient is an INTERVENE-HF study subject and will be trained to 
not take action on unscheduled transmissions related to the study.  
Device information from CareLink and data from the CommanderFLEX™ are relayed to 
OmniVisor® Pro (5c) for use by the ISCC nurse(s). With that information, ISCC nurse(s) will 
implement a validated guided workflow process that the ISCC nurse will follow to standardize 
subject care and provide efficient remote subject monitoring. 
 
Table 9: System component #6 (CommanderFLEX™ Biometric Equipment) 
 
Figure 1 
Component # 
Component 
Description 
Market Released or 
Investigational? 
6a 
CommanderFLEX™ 
A Class II Medtronic (formally 
Cardiocom) device for 
collecting and wirelessly 
transmitting subject’s 
biometric information to 
ISCC. 
 
 
Market-Released 
6b 
Blood Pressure Cuff 
In-home blood pressure cuff 
that is compatible with 
CommanderFLEX™ device. 
 
Market-Released 
6c 
Weight Scale 
Medtronic (formally 
Cardiocom) in-home scale 
with maximum weight of 
500lbs. 
 
Market-Released  
 
The CommanderFLEX™ is a device for in-home use to collect and transmit “YES/NO” health 
symptom questions and patient/subject biometric information (blood pressure and weight) 
data from the subject to the ISCC. The device is similar to a simple personal computer with a 
built-in cellular modem that stores and transmits data wirelessly to remote locations.   
It is recommended that the subject’s health symptoms related answers, blood pressure, and 
weight be provided on a daily basis and the data will be automatically transmitted to and 
managed by ISCC nurses. The CommanderFLEX™ is cleared for use with the blood 
pressure cuff (6b) and weight scale (6c).  
 

 
 
 
 
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Figure 2: Top view of the CommanderFLEX™ device. 
 
Figure 3: Back view of the CommanderFLEX™ device. 
 
 

 
 
 
 
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4. REGULATORY COMPLIANCE 
 
This INTERVENE-HF study will be conducted in compliance with international ethical and 
scientific quality standards, known as good clinical practice (GCP). GCP includes review and 
approval by an independent IRB before initiating and obtaining and documenting the freely 
given informed consent of a subject before initiating the study. 
The INTERVENE-HF study was designed to reflect the GCP principles outlined in ISO 
14155:2011. These include the protection of the rights, safety and well-being of human 
subjects, controls to ensure the scientific conduct and credibility of the clinical investigation 
and the definition of responsibilities of the sponsor and investigators. In accordance with the 
ISO standard, the sponsor shall avoid improper influence on, or inducement of, the subject, 
monitor, any investigator(s) or other parties participating in, contributing to, the clinical 
investigation. All investigators shall avoid improper influence on or inducement of the subject, 
sponsor, monitor, other investigator(s) or other parties participating in or contributing to the 
clinical investigation.  
The study will be conducted according to federal, national and local laws, regulations, 
standards, and requirements of the countries/geographies where the study is being 
conducted. The principles of the Declaration of Helsinki have been implemented through the 
patient informed consent (PIC) process, IRB approval, study training, clinical trial registration, 
preclinical testing, risk-benefit assessment and publication policy. 
All investigators are required to complete financial disclosure, as outlined in 21 CFR Part 54 
and all sites will need to comply with: 
• 
21 CFR Part 11 
• 
21 CFR Part 50 
• 
21 CFR Part 56 
• 
21 CFR Part 812 
The study will be publicly registered on http://clinicaltrials.gov prior to first enrollment in 
accordance with the 2007 Food and Drug Administration Amendments Act (FDAAA) (PL 110-
85, Section 801(a)) and the Declaration of Helsinki. 
Approval of the CIP is required from the following groups prior to any study procedures at a 
study center:  
• 
Medtronic  
• 
An Institutional Review Board at each individual study center 
Similarly, approval of subsequent revisions to the CIP is required at each study center from 
the above mentioned groups prior to implementation of the revised CIP at that center.  
 

 
 
 
 
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5. METHODOLOGY 
5.1 Study objectives 
 
INTERVENE-HF is a prospective, non-randomized, single-arm feasibility study to evaluate 
the system that combines integrated device diagnostics based risk stratification algorithm 
with a guided work flow process managed by a centralized communication center to manage 
HF patients. This system, for purposes of defining study objectives will be termed the 
“Integrated Diagnostics Medication Intervention Strategy”. Details of this system are available 
in Section 3. Findings from this feasibility study will be used to guide subsequent planning of 
a pivotal study.  
 
As a feasibility trial, the INTERVENE-HF study is not designed to be powered for specific 
endpoints. Therefore, it does not require justification on sample size. The following two 
primary objectives are proposed to determine effectiveness and safety of the Integrated 
Diagnostics Medication Intervention Strategy. No secondary objectives are proposed. 
Additionally, one ancillary objective characterizing the occurrence of HF events in the study 
population will be assessed.  
 
Primary Objectives: 
1. To characterize the effectiveness of the Integrated Diagnostics Medication 
Intervention Strategy in resolving the subject risk. 
 
2. To characterize the safety of the Integrated Diagnostics Medication Intervention 
Strategy in resolving the subject risk. 
 
Ancillary Objectives: 
1. To characterize the occurrence of HF events in the study subjects.  
 
NOTE: Intervention for heart failure decompensation (HF event) is defined as an event 
requiring invasive intervention (i.e. IV diuretics, ultrafiltration, or equivalent) or inpatient 
hospitalization. 
 
 
 
 
 

 
 
 
 
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5.2 Subject selection criteria 
 
Patients must meet all of the inclusion and none of the exclusion criteria prior to being 
enrolled.  
5.2.1 Inclusion criteria 
• 
Subject (or subject’s legally authorized representative) is willing and able to provide 
written informed consent 
• 
Subject has been implanted with a CRT device for at least 9 months and has had a 
wireless Medtronic CRT-D device (see Table 4 for Applicable Model Numbers) for at least 
34 days  
• 
Subject has >1 year life expectancy 
• 
Subject’s CRT-D device has at least 18 months of device longevity left 
• 
Subject has an eGFR> 25 ml/min/1.73 m2   
• 
Subject is NYHA Class II or III  
• 
Subject has elevated BNP values (BNP>400 or NTpro BNP>800) within the last 3 months 
OR  
Subject has had at least one OptiVol threshold crossing in the last 9 months  
OR  
Subject has had a HF event within the last 9 months   
 
HF event is defined as meeting any one of the following two criteria: 
 
 
1. Subject was admitted to the hospital for worsening HF    
OR 
2. Subject has received Intravenous HF therapy (e.g. IV diuretics/vasodilators) or 
ultrafiltration at any settings including: 
o Emergency Department 
o Ambulance 
o Observation Unit 
o Urgent Care 
o HF/Cardiology Clinic 
o Patient’s Home 
 
• 
Subjects who are currently prescribed and taking medications for the management of 
heart failure and are able to tolerate transient increases in diuretic dosage 
• 
Subject is willing and able to comply with the protocol, including screening, baseline and 
programming visit(s), remote care directions, follow-up visits, and exit visit. 
• 
Subject can send device transmissions and daily biometric data with in-home patient 
devices. 
 
 

 
 
 
 
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5.2.2 Exclusion criteria 
 
• 
Subject has systolic BP of < 90 mmHg at the time of enrollment 
• 
Subject not responsive to diuretic therapy or is on chronic renal dialysis 
• 
Subject unable to undergo one round of medication intervention (3 day up-titration of 
diuretic) without requiring safety check 
• 
Subjects enrolled in a concurrent study that may confound the results of this study 
without documented pre-approval from a Medtronic study manager 
• 
Subject weighs more than 500 pounds 
• 
Subject is younger than 18 years of age 
• 
Subject has hemodynamic monitoring device implanted 
5.3 Minimization of Bias 
 
Selection of subjects, treatment of subjects, and evaluation of study data are potential 
sources of bias. Methods incorporated in the study design to minimize potential bias include 
(but are not limited to): 
 
• 
Subject demographics assessment information will be collected on possible differences 
that may affect outcome. Information gathered on subject will include gender, race, 
height, weight and medical background 
• 
Data are collected using standardized electronic Case Report Forms (CRFs) to provide 
uniform data collection 
• 
Site and sponsor study personnel will be trained using standardized training materials 
provided by Medtronic 
• 
Subjects will be screened to confirm eligibility for enrollment with defined 
inclusion/exclusion criteria prior to enrollment  
• 
The limitation on maximum subjects (30) a site can enroll  
• 
Standardize data collection requirements and study procedures across sites. 
• 
Training sites and MDT personnel of the study based on the protocol 
• 
An independent clinical events committee (CEC) will be utilized to regularly review and 
adjudicate reported adverse events. 
 
 
In summary, potential sources of bias that may be encountered in this clinical study have 
been considered and minimized by careful study design. 
6. STUDY PROCESS OVERVIEW 
 
The INTERVENE-HF study process is outlined in Figure 4 and is described below. Site 
related procedures are described in Section 7.  
 

 
 
 
 
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Figure 4: General study process for INTERVENE-HF.  
 
 
6.1  A) Screening Visit 
6.1.1 Patient Informed Consent & Screening 
 
The consent and screening process will take place prior to the baseline & programming visit. 
Bloodwork and CRT-D device values will need to be verified for study eligibility. These values 

 
 
 
 
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and procedures are described in section 7.7. If the subject does not meet eligibility, the 
subject will be exited and documented as a screen failure. 
 
6.2 B) Baseline & Programming Visit 
6.2.1  Investigator Writes Standing Order for Medication Intervention and Establishes 
Subject Specific Safety Parameters  
 
Once the subject has completed the consent and screening processes the subject’s 
investigator will conduct the baseline visit. At this baseline visit the investigator will create an 
individualized medication intervention plan that is customized to the subject. This physician 
prescribed medication intervention plan is focused on the use of routine volume management 
medication, i.e. a transient elevation in diuretics or other volume management drugs (e.g. 
nitrates), and will include instructions for changes in the subject’s diuretic dose for up to two 
rounds of medication intervention during a single episode. (One round = 3 days of taking 
medication that was prescribed at baseline. Two rounds = 6 days of taking baseline 
prescribed medication). This medication intervention of transient increase in volume 
management drugs is referred to as PRN (pro re nata or ‘as needed’) in the remaining text 
below.  
Prescription(s) and adequate refills will be provided to the subject by the subject’s primary 
care provider or investigator. The subject’s individualized medication intervention plan will 
reside on file at the subject’s participating clinic/hospital and also at the INTERVENE Study 
Communication Center (ISCC). The investigator (or responsible care team provider under the 
supervision of investigator) will be allowed to make changes to this prescription any time they 
deem necessary and will be required to notify ISCC with any changes within 24 hours with 
supplied forms. 
In addition to the customized medication intervention plan, the investigator will collect 
information on the subject’s chronic baseline medication and establish subject specific safety 
parameters for blood pressure changes and weight loss thresholds. 
6.2.2 Subject Added/Transferred to Virtual CareLink-HF Clinic 
 
For study purposes, a virtual CareLink-HF clinic will be created to host all study subjects. The 
virtual clinic will be managed by ISCC, and only designated ISCC nurses will have access to 
this virtual CareLink-HF clinic for scheduling and monitoring transmissions. Monitoring 
transmissions are needed to assess the effect of the PRN intervention(s).  For the duration of 
the study, the investigator/site will agree to add the subject into the virtual ISCC CareLink-HF 
clinic. If the investigator/site currently utilizes a HF CareLink Clinic, the enrolled subject shall 
be transferred into the virtual CareLink-HF clinic for the duration of the study. 
The CRT-D subject will still be maintained and managed for defibrillation events through the 
CareLink EP clinic. The EP will continue to have the uninterrupted access to the subject’s 
device and clinical information while enrolled in the study.  The EP will also receive any 
manual downloads and device data initiated by CareAlert transmission once the subject is 
enrolled into the study. However the EP will be able to clearly see in CareLink Network that 

 
 
 
 
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their patient is an INTERVENE-HF study subject. The EP will be trained to not take action on 
unscheduled transmissions related to the study.  
6.2.3 Silent OptiVol CareAlert Turned ON in CRT-D device with 2090 Programmer 
 
With the use of a Medtronic 2090 programmer installed with investigational programmer 
software, enrolled subjects will have their CRT-D devices programmed to allow for silent 
OptiVol CareAlert transmissions to take place when the OptiVol Fluid Index programmed 
threshold value is exceeded (see Table 5 in section 3 for information on the 2090 
Programmer and Investigational Software). This threshold value will be programmed 
uniformly to 70 Ohm-Days for all study subjects. Physician adjustment of OptiVol threshold 
value will not be allowed during the course of the study. If necessary, the OptiVol threshold 
may be changed during the course of the study. However, this change will be applied 
uniformly to all study subjects.  
 
At the study exit, each subject will have their OptiVol CareAlert turned OFF by the same 
investigational software used to turn it ON at the beginning of the study. Verification of 
OptiVol CareAlert enable (at baseline) and disable (at exit) will take place by printing the 
information report from the 2090 and placing it into the subject’s file. This information will also 
be captured by electric Case Report Forms (eCRF). The investigational software on the 2090 
programmer should not be removed from the programmer until all study subjects are exited. 
 
6.2.4 CommanderFLEX™ In-Home Biometric Monitoring Equipment Sent to Subjects 
Home 
 
This study will leverage Care Management Services (formerly Cardiocom) biometric 
monitoring equipment and nursing staff as part of the ISCC. Each enrolled subject will 
receive a CommanderFLEX™ device, including a weight scale, blood pressure cuff and 
console that will allow the subject to perform measurements of weight, blood pressure, and 
prompts the subject to answer Yes or No questions related to their HF symptoms (see Figure 
2, Figure 3 and Table 9 in Section 3 for images and description and of the 
CommanderFLEX™ device and accessories). The CommanderFLEX™ kit will be provided at 
no cost, for use in their home during the length of the study. This kit will be be drop shipped 
to the subject’s place of residence after the subject has completed the baseline and 
programmer visit. At the end of the study, the subject will be required to return the 
CommanderFLEX™ and accessories.  
6.3 C) Data Transmitted to ISCC 
6.2.1 Daily CommanderFLEX™ Biometric Data  
 
The subjects will be asked to collect daily blood pressure, weight and HF symptom 
information via the in-home CommanderFLEX™ kit they received after the baseline and 
programming visit. These data will be transmitted directly to ISCC. The ISCC nurse will place 

 
 
 
 
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a call to the subject at 5 days and then 21 days after the baseline and programming visit if 
the subject has not set-up the CommanderFLEX™ and encourage data transmission by the 
subject.  
6.2.2 CRT-D Device Diagnostics Data 
 
Once the silent OptiVol CareAlert is turned ON, the subject will not hear or notice anything 
different from their previous experience with their implanted CRT-D device. They can return 
to normal routines and activities. The CRT-D device will now monitor the subject’s OptiVol 
Fluid Index for any threshold crossings. When the OptiVol Fluid Index value crosses the 
programmed threshold, the device will perform an automatic wireless CareLink transmission 
of the device diagnostics data to ISCC. The ISCC nurse will then make arrangements for the 
CRT-D device to transmit data at set intervals within the next 28 days to continue 
assessment of the fluid index for either therapy initiations, recovery criteria to stop medication 
intervention, and/or an OptiVol reset when applicable. 
6.3 D) Risk Categorization and Intervention Determination  
6.3.1 Subject Risk Categorization 
 
Transmissions sent to the ISCC virtual CareLink-HF clinic integrate all device diagnostics 
data and assign a numerical value that corresponds to a risk status (Low, Medium or High). 
This risk status is based on OptiVol Fluid Index and other device diagnostics data (i.e. 
intrathoracic impedance, heart rate variability, activity, night heart rate, and other variables) 
using the published algorithm as described by Cowie et al.10 (Further information on this 
published algorithm is provided in the Section 2). 
Upon receiving the transmission, the ISCC nurse will use the most recent value listed on the 
transmission record to categorize the numerical value provided by the algorithm to a 
corresponding risk status in the following way: 
• 
Value is between 0 and less than 5.4 = Low  
• 
Value is greater than or equal to 5.4 and less than 20 = Medium  
• 
Value is greater than or equal to 20 = High  
 
A transmission that is categorized as ‘High’ will result in an overall subject risk status of ‘High’ 
and the ISCC nurse will contact the subject for further assessment. When ‘Medium’ 
transmissions are received, the weight and HF symptom data from the previous 7-days are 
considered to determine if the overall subject risk status of the subject is ‘High’.  
For example, a transmission category of ‘Medium’ AND weight gain and/or symptom data 
indicating the presence of one or more HF symptoms from questions listed in Table 10, will 
assign the subject with an overall risk status of ‘High’ and the subject will be contacted by the 
ISCC nurse for further assessment. This will also be true for a subject that has a ‘Medium’ 
transmission AND the subject has weight gain of more than 2 pounds in one day or 5 pounds 
in 7 days.   

 
 
 
 
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Note: CareAlert transmission will arrive to the ISCC after 5 p.m. of the subject’s time zone, 
therefore subject contact will be attempted the day following the receipt of transmission.  
 
Table 10: Biometric HF Symptom Questions Collected by the CommanderFlex™ 
 
Questions in Table 10 will be asked of the subject by the CommanderFlex™ unit and 
collected/reviewed by the ISCC nurse when determining the overall risk status of a subject 
with a ‘Medium’ transmission.  
 
 
 
If the biometric or symptom data are missing from the day of the CareAlert transmission, the 
day the CareAlert transmission is reviewed, or the subject has provided less than three days 
of biometric data in the 7 days prior to receiving the CareAlert transmission, the ISCC nurse 
will contact the subject to assess the presence of HF related symptoms from questions 
outlined in Table 10. If any of these symptoms are present, the subject will be assigned an 
overall risk status of ‘High’ and further evaluation will be performed to assess if medication 
intervention is warranted (see section 6.3.2 for information on determining warranted 
intervention). If no weight gain or symptoms are present and the transmission is categorized 
as ‘Medium’ the subject status will be monitored remotely by the ISCC after receiving the 
transmission.  
 
Are you feeling more short of breath?  
If Yes then,  
Feel more short of breath with activity? 
 
If Yes then,  
Are you more short of breath at rest? 
 
If Yes then, 
Are you getting enough air? 
Awaken during night short of breath? 
If Yes then, 
Feel more short of breath lying down? 
 
If Yes then, 
Did you need extra pillows last night? 
 
If Yes then,  
Did you sleep sitting up last night? 
Are your ankles or feet more swollen? 
Are you coughing more than usual? 
If Yes then, 
Is your cough different today? 
 
If Yes then, 
Does lying flat cause coughing? 

 
 
 
 
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6.3.2 Determining if Intervention is Warranted 
 
To ensure that the intervention is warranted, the ISCC nurse will first determine that the 
subject is not hypotensive per the following criteria. (If the subject is hypotensive a 
notification in the form of a  ‘Interim Patient Report’ is sent to the site and intervention will not 
proceed).   
 
• 
The subject has no signs of hypotension. For the subject to be considered 
hypotensive, systolic BP < 85 mmHg or diastolic BP <40 mmHg.  
 
The ISCC nurse will also ask the subject a series of questions to ensure the OptiVol crossing 
is HF related.  
 
• 
Have you had a CRT-D device change or lead revision? 
• 
Have you been discharged from a hospital within the last 2 days and did you receive 
intravenous fluids for 1 or more days while in the hospital?  
• 
Are you experiencing chills/shivering, shaking or muscle aches? 
• 
Have you recently been treated for a COPD exacerbation? 
• 
Any changes in baseline diuretic medication in the past 3 weeks? 
 
If the subject answers YES to any of the above questions, the OptiVol crossing is deemed to 
not be HF related and the intervention will not proceed. Once the nurse has ensured that the 
OptiVol crossing is HF-related, the nurse will initiate the prescribed PRN intervention on file 
that was created at the baseline visit by the subject’s investigator.    
6.4 E) Interventions 
 
The medication intervention will have two components. The first component is the ISCC 
acute medication intervention for acute volume management executed by ISCC as per 
investigator’s standing orders (left arm in Figure 5 below and Section 6.4.1). In addition, the 
ISCC nurse will perform dietary and medication counseling when applicable.  
 
The second component of the medication intervention will be the responsibility of the 
investigator (right arm in Figure 5 below and Section 6.4.2). ISCC will provide notifications to 
the participating site to alert the investigator when a re-evaluation of the subject’s chronic 
medication is requested (see Appendix B: ISCC Reports to Physician for an example of this 
report). 
 

 
 
 
 
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Figure 5: Intervention in INTERVENE-HF study.  
 
The Intervention for this study has two components: ISCC executed intervention (left arm) 
and Investigator executed intervention (right arm).  
 
6.4.1 ISCC Executed Acute Medication Intervention (PRN and Counseling) 
 
The ISCC facilitated intervention component will consist of providing reinforcement and 
direction to the subject as to when they are to self-administer up to two rounds of investigator 
prescribed PRN to the subject per single transmission that warrants action. The investigator 
prescribed PRN is initiated after ISCC nurse has ensured that subject has been compliant 
with their baseline medication regimen including diuretic medications.  Each round of PRN 
will be 3 days long. Thus, no more than 6 days of PRN medication will be administered to the 
subject.  
The example scenario in Figure 6 below is an illustration of this ISCC executed intervention. 
Referring to Figure 6, the day of the transmission is considered Day 0. Since the OptiVol 
CareAlert transmission is initiated by the device at 5 PM, the nurse will attempt to contact the 
patient on the following day (includes weekends). Thus, the ISCC nurse will call the subject 
via phone on Day 1 (1 day post initial transmission), and upon subject contact, guide the 
subject to take their first round of investigator prescribed diuretic for 3 days if intervention is 
warranted (Section  6.3.2 above).  

 
 
 
 
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The ISCC nurse will notify the subject’s investigator using a ‘Interim Patient Report’ indicating 
that the first round of PRN has been initiated (see Appendix B: ISCC Reports to Physician for 
an example of this report).  
 
 
 
Figure 6: Example Scenario of One Round of Medication Intervention (PRN).  
 
The efficacy of the PRN is evaluated using raw impedance based recovery criterion. (Refer to 
section 6.4.1.1 and Figure 8 for a detailed description of determining recover criterion.) 
Recovery criterion is evaluated on Day 4 (when possible) (4 days post initial transmission or 
3 days post PRN initiation) and then again on day 8 (when possible) after first PRN. If the 
recovery criterion is not met on day 4, a second round of PRN is initiated. The ISCC nurse 
will notify the subject’s investigator using a ‘Interim Patient Report’ indicating that the second 
round of PRN has been initiated. Figure 7 illustrates this example scenario of 2 rounds of 
successive PRNs.   
 

 
 
 
 
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Figure 7: Example Scenario of Two Rounds of Medication Intervention (PRN).  
 
The efficacy of the second round of PRN will be evaluated on Day 8 (when possible) (8 days 
post initial transmission or 7 days post first day of first round of PRN). If the recovery criterion 
is met, subject is deemed as recovered and no further action is taken. If the recovery criterion 
is not met after second round of PRN, an Interim Report and Baseline Medication Report is 
sent by the ISCC nurse to the investigator for review and asked to re-evaluate the subject’s 
chronic baseline medications (Right Arm of Figure 5) 
In the event that it has been determined on initial subject contact, that the subject has been 
non-compliant with baseline medications for one or more days prior to contact, the subject 
will be instructed to take baseline medications for three days. Recovery criterion will be 
evaluated for effectiveness of reinstituting baseline medications on day 4 and day 8 in the 
same fashion as described above. If recovery criterion is not met on either of these two 
evaluations, the first PRN will be initiated and the same schedule takes place and evaluation 
scheme thereafter is similar to as described above for a compliant subject except for a shift of 
at least 4 days. 
 
If the subject has not been compliant with baseline medications but returning to baseline 
medications is not possible (e.g. unavailability of medications), subject will be instructed to 
contact their investigator immediately. An ‘Interim Report’ will be sent to the participating 
investigator (see Appendix B: ISCC Reports to Physician for an example of this report).  
 
 

 
 
 
 
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6.4.1.1 Criterion for Evaluating PRN Efficacy in ISCC Medication Intervention  
 
A recovery criterion will be computed by the ISCC nurse to evaluate PRN efficacy  using raw 
intrathoracic impedance since it responds dynamically to patient volume status. Computation 
of recovery criterion requires the difference between raw intrathoracic impedance and the 
reference impedance. Reference impedance is a component of market approved OptiVol 
feature in Medtronic devices. Daily values for both raw and reference impedance are 
included with all device diagnostic transmissions spanning duration of up to 14 months.  
The difference between raw and reference impedances on four days is required to compute 
recovery criterion (RC) – the day CareAlert is received (x0), and the three PRN intervention 
days prior to the day RC is evaluated (x1, x2 and x3), Recovery criterion is then computed 
according to the following equation and as illustrated in the figure below: 
 
RC = 100 ∗ (𝑥𝑥0 −𝑥𝑥1 ) + (𝑥𝑥0 −𝑥𝑥2 ) + (𝑥𝑥0 −𝑥𝑥3 )
𝑥𝑥0
 
 
 
 
Figure 8: Recovery Criteria Illustration  
 
If the value of RC is greater than a threshold value of 70 (i.e. cumulative impedance recovery 
over the last 3 days is 70% or more from Day 0 of receiving the initial transmission), the 
intervention is deemed to be successful. If the value of RC is less than or equal to 70, the 
intervention is deemed to be not a success and appropriate follow-up action (i.e. second PRN 
or notification to the investigator) is taken. 
6.4.1.2  ISCCC Timeframe for Patient Contact to Initiate Intervention 
 

 
 
 
 
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If the ISCC nurse is unable to contact the patient during the first attempt for initiation of first or 
second rounds of PRN, the following schedule will be used to establish subject contact:  
 
For initiating a first round of PRN: The ISCC nurse will make 1 attempt per day, for a total of 
8 subsequent attempts to establish the contact (including weekends). If the ISCC nurse is 
unable to establish subject contact, a notification will be sent to the investigator. The day of 
successful subject contact will then be the first day of the medication intervention.  
 
For initiating the second round PRN (or for any medication surveillance on days 8, 12, and 16 
post initiation of the first day of medication intervention): The ISCC nurse will make 1 attempt 
per day of any CareLink transmission to establish subject contact. If unable to establish 
contact, an ‘Exception Report’ will be sent to the investigator with continued monitoring per 
the protocol (see Appendix B: ISCC Reports to Physician for an example of this report). 
 
6.4.2 Investigator Executed Chronic Medication Intervention 
 
The investigator will be responsible for performing the re-evaluation of the subject’s chronic 
medications or HF treatment. Any changes in baseline medications will need to be reported 
to the ISCC. If no changes were made, rationale as to why changes were not made will need 
to be provided. In absence of an investigator intervention or documented rationale, lack of 
intervention by the investigator will be considered a protocol deviation. To aid the investigator 
in making such changes, a summary of the subject’s heart failure related medications at 
baseline along with guideline recommended doses for these medications will be provided to 
the investigator as part of the notification (see Appendix B: ISCC Reports to Physician for an 
example of this report). 
 
6.5 F) Ensuring Subject Safety 
6.5.1 Criterion for not initiating or continuing with a PRN Intervention 
At the time of subject contact, (following the CareLink transmission and subject having been 
stratified as High risk), the ISCC nurse will make sure that the subject is not hypotensive 
based on the blood pressure measurement for the day of contact. If the subject has not yet 
transmitted the blood pressure measurement for the day of contact, the nurse will instruct the 
subject to obtain blood pressure measurement while on the phone. If the subject’s systolic 
blood pressure is below 85 mmHG with associated hypotensive symptoms, the intervention 
will not be initiated. Additionally in the instance that the subject is unable or unwilling to 
provide a blood pressure measurement, the subject will be assessed for potential 
hypotensive symptoms – if positively reported, the medication intervention will not be 
initiated. ISCC will send an ‘Interim Patient Report’ to the subject’s investigator noting the 
reason for not initiating PRN intervention. Subject’s investigator will be required to further 
evaluate the subject, take necessary actions, and document them in eCRFs.  
To ensure subject safety while a PRN intervention is underway, the subject’s will be asked to 
provide a blood pressure and weight daily. If a predefined, physician specified, patient 
specific, safety threshold is crossed for either weight or blood pressure the subject will be 

 
 
 
 
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contacted by ISCC nurse. The nurse will telephonically evaluate the subject for symptoms 
known to suggest that intervention may not be safe (Table 11). If any one of the two 
symptoms is present, PRN will be stopped and the investigator will be sent an ‘Exception 
Report’ to assist with further subject follow-up (see Appendix B: ISCC Reports to Physician 
for an example of this report). The ISCC nurse will make one attempt to establish the contact 
with subject to evaluate subject symptoms to potentially stop PRN intervention. If the nurse is 
unable to establish the subject contact, a report will be sent to the investigator and/or phone 
call will be made to the site to notify that values were outside threshold(s). 
 
Table 11: Safety Thresholds for Cessation of Medication Intervention (PRN) 
 
PRN Cessation and Safety Threshold(s): 
Hold/Discontinue PRN Diuretic use if telephonically assessed to have met 
Weight or BP threshold and Symptom(s): 
Weight Loss: 
Weight  < 150lbs:     
3 lbs/2days 
Weight 151-300lbs:  
4 lbs/2 days 
Weight > 301lbs:      
5 lbs/2days 
 
 
Or 
  
_____lbs/ _____days 
(Physician specified range) 
OR 
Blood 
Pressure:  
Systolic of < 85 
mmHG or a diastolic 
of <40 mmHg 
Or 
<  _____ /_____ mmHg 
(Physician specified value) 
AND 
Telephonically 
Assessed 
Symptom(s): 
  
New lightheadedness when moving from sitting to standing 
or 
Muscle cramping or Charlie horses  
 
6.5.1.1  Criteria to Perform Blood work and Related Actions 
 
Blood work will be performed by the site if PRN intervention is stopped anytime because of 
safety concern. Blood work will also be performed if 2 rounds PRNs are completed 
irrespective of whether the intervention is deemed success or failure after 2 PRNs. The 
participating site will be notified by ISCC via  Interim Patient Report to notify site to perform 
blood work for the subject. Blood work and evaluation by the participating investigator will be 
required to be performed within 7 days of the notification and associated eCRF will need to 
be completed. Blood work, at a minimum, should include creatinine (needed to estimate 
eGFR) and electrolytes (K+ and Na+). Investigators will be required to record creatinine, 

 
 
 
 
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eGFR, K+ and Na+ in the eCFR. Any actions taken along with the rationale will also be 
recorded in the eCFR. If the action is updating of HF medications or PRN prescription, the 
updated medication and PRN forms will be sent to ISCC within 24 hours. Lack of completing 
this blood work eCFR in its entirety will be considered a deviation. 
 
6.5.1.2   Safety Monitoring Using External Biometric Data 
 
Outside of the PRN medication intervention window, subject’s blood pressure will be 
monitored for hypotension per nominal safety threshold of a systolic blood pressure of <85 
mmHG or a diastolic blood pressure <40 mm Hg or physician specified threshold, if different. 
If the hypotension criterion is met, subject will be contacted and assessed for presence of two 
hypotensive symptoms. These hypotensive symptoms will be assessed by asking the 
following two questions: Are they experiencing new lightheadedness when moving from 
sitting to standing? And, are they experiencing any cramping or Charlie horses? If any of the 
two symptoms or both symptoms are present, the subject will be asked to contact their 
physician. An ‘Exception Report’ will be sent to the investigator including a note about their 
patient’s safety issue (see Appendix B: ISCC Reports to Physician for an example of this 
report). The Investigator will be required to review the report and determine if clinical actions 
are necessary. Actions along with rationale will be documented in the eCRF. If no actions are 
needed, rationale for that will also be recorded in the eCRF. If the action is updating of HF 
medications or PRN prescription, updated medication and PRN forms will be sent to ISCC 
within 24 hours. Lack of completing eCFR in its entirety will be considered a protocol 
deviation. 
6.6 H) Exit Visit  
 
Please refer to section 7.14 for details on exiting procedures.  
7 SITE RELATED PROCEDURES 
Prior to performing study related procedures, all sites must have IRB and associated 
regulatory authority approval (if applicable) as well as documentation from Medtronic of site 
readiness. 
7.1 Investigator/Investigation site selection 
All clinical investigators managing the subject’s heart failure must be qualified practitioners 
and experienced in the diagnosis and treatment of subjects with heart failure.   
The role of the investigator is to implement and manage the day-to-day conduct of the clinical 
investigation as well as ensure data integrity and the rights, safety and well-being of the 
subjects involved in the clinical investigation. 
The investigator shall: 
• 
Be qualified by education, training, and relevant experience appropriate to the use of 
the product and associated procedures as defined below: 

 
 
 
 
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• 
Diagnoses/Treats patients with HF 
 
• 
Willing to partner with ancillary service provider hosted at Medtronic to guide 
medication intervention for acute HF volume management under physician standing 
order. 
 
• 
Center is willing to coordinate with their CareLink Manager to transfer patient into the 
Virtual CareLink-HF clinic for the duration of the study. (The patient will still be part of 
the CareLink EP). 
 
• 
Disclose potential conflicts of interest, including financial, that interfere with the 
conduct of the clinical investigation or interpretation of results 
The investigator shall be able to demonstrate that the proposed investigational site has 
adequate resources, including, as applicable, facilities, laboratories, equipment, and a 
qualified trial site team. Center personnel training will be completed prior to participation in 
this clinical study. 
 
The investigator shall have access to an adequate number of patients with the following:  
• 
Center should have a pool of patients with implanted Medtronic CRT-D devices 
with wireless telemetry.  
 
• 
Center should have a pool of patients with NYHA Class II and/or Class III Heart 
Failure. 
 
 
7.2  Site activation  
 
During the activation process (prior to subject enrollment), Medtronic will train site personnel 
on the clinical investigation plan, relevant standards and regulations, if needed, informed 
consent, and on data collection and reporting tools. If new members join the study center 
team, they will receive training on the applicable clinical study requirements relevant to their 
role before contributing to the clinical study. 
Prior to performing study related activities, all local regulatory requirements shall be fulfilled, 
including, but not limited to the following:  
• 
IRB approval of the current version of the CIP and Patient Informed Consent.  
• 
Regulatory authority approval or notification (as required per local law)  
• 
Fully executed Clinical Trial Agreement (CTA)  
• 
Financial Disclosure   
• 
Curriculum Vitae (CV) of investigators  
• 
Documentation of delegated tasks 

 
 
 
 
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• 
Documentation of study training  
Additional requirements imposed by the IRB and regulatory authority shall be followed, if 
appropriate.  
In addition, all participating site staff must be trained on the current version of the CIP and 
must be delegated by the investigator to perform study related activities.   
Medtronic will provide each study center with documentation of study center/investigator 
readiness; this letter must be received prior to subject enrollment. 
7.3  Equipment requirements 
The following equipment must be available at each center to support study activities: 
• 
Fax machine (Or fax account) 
• 
Medtronic Programmer Model Number 2090 
 
 

 
 
 
 
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7.4  Data Collection  
Data collection requirements are summarized in Table 12 below. 
Table 12: Data Collection Table 
 
DATA 
COLLECTION 
Screening  
Baseline/Programming  
ISCC Notification to Site 
 
Scheduled call 
Study Exit 
Intervention not initiated   
(OptiVol artifact/non-HF) 
First PRN Initiated 
Unable to contact subject   
 Safety Criteria met During 
PRN OR 2 PRNs given  
One of Three Criteria met for 
chronic meds/PRN review 
OptiVol not reset at 28 days 
Safety criteria met outside 
PRN Window 
Patient Informed 
Consent 
 
√ 
 
 
 
 
 
 
 
 
 
 
Eligibility Verification 
√ 
 
 
 
 
 
 
 
 
 
 
Bloodwork/Labs 
√ 
 
 
 
 
√ 
 
 
 
 
√ 
 
Demographic 
Information 
 
√ 
 
 
 
 
 
 
 
 
 
Individualized 
Medication 
Intervention Plan 
(PRN Regimen) 
 
√ 
 
 
 
 
 
 
 
 
 
Cardiovascular  
Medication Regimen 
Information 
 
√ 
 
 
 
 
 
 
 
√ 
√ 
HF Event (6 mos. 
prior to enrollment) 
 
√ 
 
 
 
 
 
 
 
 
 
Safety Parameter 
Thresholds for PRN 
Cessation 
 
√ 
 
 
 
 
 
 
 
 
 
OptiVol Information 
Report from 2090 
Programmer 
 
√ 
 
 
 
 
 
 
 
 
√ 
 
 

 
 
 
 
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DATA 
COLLECTION 
Baseline/Programming 
ISCC Notification to Site 
 
Scheduled call 
Study Exit 
Intervention not initiated   
(OptiVol artifact/non-HF) 
First PRN Initiated 
Unable to Contact Subject  
Safety Criteria met During 
PRN OR 2 PRNs given  
One of Three Criteria met 
for chronic meds/PRN 
OptiVol not reset at 28 days 
Safety criteria met outside 
PRN Window 
   
Symptoms, 
Compliance, HCU 
utilization & Actions 
 
 
 
 
 
√ 
 
 
 
 
√ 
 
OptiVol Artifact/Non-
HF Related Event  
 
 
√ 
 
 
 
 
 
 
 
 
Device Diagnostics 
Review and Actions 
 
 
√ 
√ 
√ 
 
 
 
 
 
 
ISCC Unable to 
Contact Subject  
 
 
 
 
√ 
 
 
 
 
 
 
Chronic Meds/PRN 
Assessment  
 
 
 
 
 
√ 
 
 
 
 
 
OptiVol Review & 
Resetting 
 
 
 
 
 
 
√ 
√ 
 
 
 
Safety Review 
 
 
 
 
 
 
 
 
√ 
 
 
Device Data  
(Save-to-Disk) 
 
√ 
 
 
 
 
 
 
 
 
√ 
CareLink Transfer 
Verification 
 
√ 
 
 
 
 
 
 
 
 
√ 
 Adverse Events  
Upon Occurrence  
 
System modification 
Study Deviation 
Death 
 
 
 

 
 
 
 
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7.5 Role of the sponsor representatives 
 
Sponsor representatives may provide support as required for the study under supervision of 
the Investigator, including: 
• 
Provide study training relevant and pertinent to the involvement of personnel 
conducting study activities and investigator responsibilities 
• 
Technical support study visits under the supervision of a study investigator, but no 
data entry, shall be performed by Medtronic personnel or their representatives at 
sites 
• 
Monitoring and auditing activities  
7.6  Patient informed consent process 
 
Patient informed consent (PIC) is defined as a legally effective documented confirmation of a 
subject’s voluntary agreement to participate in a particular clinical study after information has 
been given to the subject on all aspects of the clinical study that are relevant to the subject’s 
decision to participate. This process includes obtaining a Patient Informed Consent Form that 
has been approved by the study center’s IRB and an Authorization to Use and Disclose 
Personal Health Information/Research Authorization/other privacy language as required by 
law which are signed and dated by the subject. A subject may only consent after information 
has been given to the subject on all aspects of the clinical investigation that are relevant to 
the subject’s decision to participate.  
Prior to enrolling subjects, each center’s IRB Committee will be required to approve the PIC 
Form. The document(s) must be controlled (i.e. versioned and/or dated) to ensure it is clear 
which version(s) were approved by the IRB.  Any adaptation of the sample Consent Form 
must be reviewed and approved by Medtronic and the IRB reviewing the application prior to 
enrolling subjects.  
The investigator must notify the subject of any significant new findings about the study that 
become available during the course of the study which are pertinent to the safety and well-
being of the subject, as this could impact a subject’s willingness to participate in the study. If 
relevant, approval may be requested from subjects to confirm their continued participation. 
The sample Patient Informed Consent Form(s) will be provided under separate cover. 
Prior to initiation of any study-specific procedures, patient informed consent must be obtained 
from the subject. Likewise, privacy or health information protection regulation may require 
subjects to sign additional forms to authorize centers to submit subject information to the 
study sponsor. The informed consent process must be conducted by the investigator or an 
authorized designee, and the Patient Consent Form and Authorization to Use and Disclose 
Personal Health Information/Research Authorization/other privacy language as required by 
law must be given to the subject in a language he/she is able to read and understand. The 
process of patient informed consent must be conducted without using coercion or undue 
improper influence on or inducement of the subject to participate by the investigator or other 
center personnel. The informed consent process shall not waive or appear to waive subject’s 

 
 
 
 
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legal right. The language used shall be as non-technical as possible and must be 
understandable to the subject and the impartial witness, where applicable.  
The subject must have ample time and opportunity to read and understand the informed 
consent form, to inquire about details of the study, and to decide whether or not to participate 
in the clinical study. All questions about the study should be answered to the satisfaction of 
the subject. 
When the subject decides to participate in the clinical study, the PIC must be signed and 
personally dated by the subject and investigator or authorized designee, as required by the 
Patient Consent Form. If applicable, the witness shall also sign and personally date the 
consent form to attest that the information in the PIC was accurately explained and clearly 
understood by the subject, and that informed consent was freely given. 
A copy of the Patient Consent Form and  the Authorization to Use and Disclose Personal 
Health Information/Research Authorization/other privacy language, signed and dated as 
required by law, must be provided to the subject.  
If the PIC is obtained the same day the subject begins participating in study-related 
procedures, it must be documented in the subject’s case history that consent was obtained 
prior to participation in any study-related procedures. It is best practice for the informed 
consent process to be documented in the subject’s case history, regardless of circumstance. 
In the event the subject cannot read and/or write, witnessed (impartial third party) patient 
informed consent will be allowed, provided detailed documentation of the process is recorded 
in the subject’s case history and the witness signs and dates the patient informed consent. 
The subject should “make his mark” (sign or otherwise physically mark the document so as to 
indicate consent) on the ICF as well. The Consent Form should document the method used 
for communication with the prospective subject and the specific means by which the 
prospective subject communicated agreement to participate in the study.  
The original of the signed Patient Consent Form must be filed in the hospital/clinical chart 
and/or with the subject’s study documents.  
The Patient Consent Form and Authorization to Use and Disclose Personal Health 
Information/Research Authorization/other privacy language as required by law must be 
available for monitoring and auditing. Any Medtronic Field personnel who support the 
INTERVENE-HF study must be able to review the subject’s signed and dated Consent Form 
and verify its completeness prior to proceeding with any study procedures. In the event the 
Medtronic Field personnel identify patient informed consent as being incomplete, the 
INTERVENE-HF study procedures will not be allowed to occur until the consent of the 
subject can be adequately and appropriately obtained. 
When a patient and the principal investigator or authorized designee, as required have 
personally signed and dated the Consent Form, the patient is considered a subject enrolled 
in the study. The date the subject signed the Consent Form and data protection authorization 
must be documented in the subject’s medical records.  
 
 
 

 
 
 
 
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7.7 Screening Visit 
 
During the screening visit, the subject’s OptiVol Fluid Index and bloodwork will be verified to 
confirm subject eligibility.  
7.7.1 OptiVol Fluid Index Verification 
 
The subject’s OptiVol Fluid Index on the day of screening must be below prescribed 
threshold to be eligible.  
 
If the subject’s OptiVol Fluid Index is above threshold, then the subject can return at a later 
date for OptiVol reevaluation. If the subject does not return for a later OptiVol reading, they 
shall be exited and reported as a screen failure.  
 
If at the time of screening the OptiVol Fluid Index is equal to or greater than threshold and is 
deemed to be an artifact by the investigator and the subject is otherwise stable and 
euvolemic, a reference reset can be performed at the time of the baseline visit and the 
patient shall stay in the study and proceed to the next step. 
 
7.7.2 Bloodwork Eligibility  
 
To be considered eligible for the baseline and programming visit, the subject’s most current 
bloodwork results (within the past 6 months) must meet the values listed below. If no prior lab 
data is available, then new labs should be taken at the screening visit as long as OptiVol is 
below threshold.  
 
• 
eGFR> 25 ml/min/1.73 m2   
• 
Hemoglobin value of ≥ 9.0 g/dl  
• 
Potassium (K+) values in the range of 3.5 to 5.5 mmol/L  
• 
Sodium (Na+) values ≥ 130 mmol/L 
 
Once the Investigator has reviewed the lab values and verified they are within the ranges 
listed above, the site will contact all subject(s) to inform them of their eligibility to continue. 
Eligible subjects will be scheduled to return to the site within 30 days from the screening visit 
for the baseline and programming visit to occur. Non-eligible subjects (i.e. lab values are out 
of the ranges listed above) will be documented as screen failures and exited as described in 
section 7.14. 
 
 
The following information is required to be collected at the screening visit: 
 
• 
Patient Informed Consent 
• 
Eligibility Verification (Inclusion/Exclusion Assessment) 

 
 
 
 
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• 
Confirmation of bloodwork eligibility (within 6 months)  
• 
Confirmation of OptiVol eligibility 
• 
 
  
7.8 Baseline and Programming Visit  
 
Upon successful screening per section 7.7, the subject will return to the site for the baseline 
and programming visit.  
 
The following information is required to be collected at the baseline and programming visit: 
• 
Demographic Information 
• 
Individualized Medication Intervention Plan (PRN Regimen) 
• 
Baseline Cardiovascular Medication Regimen Information 
• 
HF Event History in the last 6 months 
• 
Safety Parameters Thresholds for PRN Cessation 
• 
OptiVol Information Report from 2090 Programmer  
• 
Device Data (Save to Disk) 
• 
CareLink Transfer Verification 
 
If the threshold value is changed during the study by the sponsor, the subject will be notified 
and asked to return to the site for a reprogramming visit. Re-programming visits will be 
performed in the same manner as the initial programming visit.  
 
For information regarding investigational software handling, storage and traceability, refer to 
section 8.  
 
7.9 Scheduled follow-up phone calls 
 
Data analyses include follow-up phone calls, regardless of whether the phone call occurs 
within the window. Therefore, should contact to the subject not be established within the pre-
specified window, a late phone call is preferred over a missed phone call.  
The participating investigator/study coordinator will attempt to reach the subject for this 
follow-up phone call for up to ±14 calendar days from target date listed in Table 13.  Follow-
up visit windows are based on the day post-OptiVol CareAlert was turned ON.  
 
Note: Because the study is estimated to be completed in approximately 30 months (includes 
approximately 18 months of enrollment and 12 months of follow-up from the last enrolled 
subject) window dates are provided for 30 months.  If follow up phone calls need to continue 
beyond 30 months, the windows will continue at 60 day intervals with ±14 day windows. 

 
 
 
 
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Table 13: Data collection and study procedure requirements at subject phone call 
 
Study  
Follow-up 
Phone Call 
Window 
(Based on Day OptiVol CareAlert was turned ON) 
Window Start 
(days post-
OptiVol CareAlert 
turned ON ) 
Target 
(days post-OptiVol 
CareAlert 
turned ON ) 
Window End 
(days post-
OptiVol 
CareAlert 
turned ON ) 
2-Month 
46 
60 
74 
4-Month 
106 
120 
134 
6-Month 
166 
180 
194 
8-Month 
226 
240 
254 
10-Month 
286 
300 
314 
12-Month 
346 
360 
374 
14-Month 
406 
420 
434 
16-Month 
466 
480 
494 
18-Month 
526 
540 
554 
20-Month 
586 
600 
614 
22-Month 
646 
660 
674 
24-Month 
706 
720 
734 
26-Month 
766 
780 
794 
28-Month 
826 
840 
854 
30-Month 
886 
900 
914 
 
The following information is required to be collected at the follow-up phone call: 
• 
Current Medications or changes in medication 
• 
Document any reportable AEs (refer to section 10 for Adverse Events and 
Device Deficiencies)  
• 
Record any changes to the CRT-D implanted system 
• 
Worsening HF symptoms 
• 
Recent hospitalizations or surgeries 
• 
Change in co- morbidities 
 
7.10  ISCC Communication & Notifications to Site  
 

 
 
 
 
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Throughout the duration of the study, notifications from ISCC to the Site will be sent to the 
sites when the following events occur: 
 
• 
Intervention not initiated (OptiVol artifact/non-HF) 
• 
First PRN Initiated  
• 
Unable to contact subject  for 1st PRN 
 
• 
Unable to Contact Subject  for 2nd  PRN or After Safety Issue 
  
• 
Safety Criteria met During PRN OR 2 PRNs given  
 
• 
One of Three Criteria met for chronic meds/PRN review  
• 
OptiVol not reset at 28 days 
• 
Safety criteria met outside PRN Window 
    
• 
Adverse Event 
 
Upon receiving the notifications from ISCC, the site will be directed in the notification to 
complete the appropriate forms. These forms include: 
 
• 
Bloodwork/Labs Form 
• 
Symptoms, Compliance, HCU utilization and Actions Form 
• 
OptiVol Artifact/Non-HF Related Event Form 
• 
Device Diagnostics Review and Actions Form 
• 
ISCC Unable to Contact Subject Form 
• 
Chronic Meds/PRN Assessment Form 
• 
OptiVol Review and Resetting Form 
• 
Safety Review Form 
• 
Device Data (Save-to-Disk) 
• 
CareLink Transfer Verification Form 
• 
Adverse Event Notification Form 
 
Additionally, if any of the following circumstances occur, a notification will be sent to the 
investigator to prompt for Chronic Medication Evaluation in the subject:  
 
• 
Mean 90 day impedance less than 66 ohms  
• 
Subject does not recover after 2 consecutive rounds of medication intervention  
• 
Two or more medication interventions were performed in the last 3 months 
7.11 Unscheduled follow-up visits 
 

 
 
 
 
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An unscheduled visit is defined as any non-standard of care visit to the study site for reasons 
related to the INTERVENE-HF system including any device alerts. The following procedures 
are required at each unscheduled visit: 
 
• 
Document any reportable AEs (refer to section 10 Adverse Events and Device 
Deficiencies) 
 
7.12 Healthcare Utilization 
 
In this study, Health Care Utilization information will be collected at specified study 
events as listed in Table 12 above.  
7.13 System Modification 
 
The subject will be exited if a device or lead replacement takes place or if the device is 
taken out of service (e.g. repositioned, explanted or capped). The subject must be 
exited from the study after all system and/or procedure related AEs have been resolved 
or remain unresolved with no further action planned. All explanted product (device, 
leads, etc.) should be returned to Medtronic for analysis when permissible by local laws 
and regulations (see section 8.2 for final product disposition details). 
 
A system modification will be reported in the event the device and/or leads require 
invasive modification (e.g., generator or lead explant, generator or lead replacement, 
lead repositioning).  
 
For a system modification the following activities are required: 
 
• 
Participating investigative site shall notify the INTERVENE Study Communication 
Center of any system modifications within 24 hours with the appropriate eCRF.  
 
7.14 Study Exit 
 
At study exit, an eCRF is required for all subjects except in the case of death.  Prior to 
exiting a subject from the study, it is recommended to follow the subject until all 
ongoing system and/or procedure related AEs are resolved or unresolved with no 
further actions planned.  Following exit, subjects will continue to receive standard 
medical care with their primary/enrolling physician.  Upon exiting from the study, no 
further study data will be collected and no further study visits will occur for the subject.  
All data available through the time of the subject’s exit will be used for analysis.  

 
 
 
 
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Subjects are urged to remain in the study as long as possible but may be exited from 
the study for any of the following situations: 
• 
Subject has completed follow-up 
• 
Subject lost to follow-up 
• 
Subject death 
• 
Subject has an explant without the intent to re-implant 
• 
Subject did not meet inclusion/exclusion criteria  
• 
Subject did not provide consent or data use protection authorization 
• 
Subject chooses to withdraw (e.g., consent withdrawal, relocation to another 
geographic location)  
• 
Investigator deems withdrawal necessary (e.g., medically justified, 
inclusion/exclusion criteria not met, failure of subject to maintain adequate study 
compliance) 
• 
Lead or generator replacement 
If subject is not lost to follow up, the OptiVol alert will be turned off at study exit and the 
following information is required to be collected: 
• 
Reason for exit (eCRF) 
• 
AE 
• 
Blood work: Includes but not limited to Potassium and Sodium (K+ and Na+), 
eGFR, and Hemoglobin. 
• 
OptiVol Information Report from 2090 Programmer: Print AFTER using the 
software to disable the OptiVol alert.  See User Manual for instructions on how 
to access the software and how to turn off the OptiVol alert.   
 
Note that an in-person visit will be required to turn OFF the OptiVol alert in the CRT-D device 
by use of a Medtronic 2090 programmer. See User Manual for instructions on how to access 
the software and how to turn off the OptiVol alert.   
 
In the case that the subject is determined to be lost to follow-up, details of a minimum of two 
attempts and the method of attempt (e.g., one letter and one phone record or two letters) to 
contact the subject must be recorded. In addition, follow the regulations set forth by the 
governing IRB.  
 
If discontinuation is because of safety or lack of effectiveness, the subject shall be asked to 
be followed for collecting safety data outside the clinical investigation. 
 
 
Additionally, the CommanderFlex™ unit and accessories will need to be returned upon study 
exit. 

 
 
 
 
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7.15 Medications 
 
Record the use of all Cardio vascular  medications (including HF medications), anti-platelet, 
anticoagulant, antibiotics, corticosteroids, insulin, or oral diabetic agents at baseline with the 
appropriate eCRF and send to the INTERVENE Study Communication Center at baseline 
visit and any time changes are made to the subject’s medications. 
 
 

 
 
 
 
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8 INVESTIGATIONAL DEVICE/SOFTWARE STORAGE, 
HANDLING AND TRACEABILITY 
8.1 Investigational Device/Software Storage, Handling and Traceability 
 
The CRT-D devices used in this study are commercially available, however once the 
INTERVENE-HF research software that was downloaded onto the 2090 programmer is used 
to turn ON the OptiVol CareAlert feature, the CRT-D device will be considered an 
investigational product. 
 
When the INTERVENE-HF investigational software is downloaded on the 2090 programmer, 
the programmer becomes investigation as well and should only be used in the clinical study 
according to the CIP. When the INTERVENE-HF software is downloaded or removed from 
the 2090 programmer, the programmer/software distribution log must be updated. The 
investigational device will be tracked via Investigational Product Distribution logs. 
Programmers or study devices that have the INTERVENE-HF software removed will no 
longer be considered investigational after the time of removal. 
 
The INTERVENE-HF software will be distributed to a center only when Medtronic has 
received all required documentation and has notified the center of center readiness. 
Distribution of the INTERVENE-HF software to study centers during the clinical study will be 
managed by Medtronic. The INTERVENE-HF software will be distributed via Medtronic’s 
Secure Download Network (SDN). Software distributed via the SDN will be downloaded onto 
study 2090 programmers over a secure internet connection.  
 
It is the responsibility of the investigator to correctly handle, store and track the 
investigational products (2090 programmers with the INTERVENE-HF software installed and 
devices with the OptiVol CareAlert feature turned ON).  
Investigational Product Disposition records must be maintained for each center to track 
investigational product information. Investigational Product Disposition records consist of: 
• 
Software/Programmer Disposition Log (eCRF) 
• 
CRT-D Device Disposition Log (eCRF) 
 
 
8.2 Final Product Disposition 
At the end of the study, the OptiVol CareAlert feature will need to be turned to OFF and the 
investigational software on all study programmers must be removed. The 
software/programmer disposition log and CRT-D device disposition Log must be updated at 

 
 
 
 
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that time. In the case that software cannot be manually removed, the 2090 programmer must 
be returned to Medtronic for removal of the software. 
 
 
In the event of a CRT-D explant, all explanted devices (devices or leads) should be returned 
to Medtronic for analysis when permissible by local laws and regulations. If the products are 
explanted but not returned, a justification will be reported on the appropriate case report 
forms or disposition logs. The Investigational Device Distribution Log must be updated for 
explanted devices. To receive a Returned Product Mailer Kit, please contact your local 
Medtronic field personnel. The Investigational Product Disposition Log must be updated with 
the final device disposition of investigational product. 
 
9  STUDY DEVIATIONS 
 
A study deviation is defined as an event within a study that did not occur according to the 
Clinical Investigation Plan or the Clinical Trial Agreement. 
Prior approval by Medtronic is expected in situations where the investigator anticipates, 
contemplates, or makes a conscious decision to deviate. Prior approval is not required when 
a deviation is necessary to protect the safety, rights or well-being of a subject in an 
emergency or in unforeseen situations beyond the investigator’s control (e.g. subject failure 
to attend scheduled follow-up visits, inadvertent loss of data due to computer malfunction, 
inability to perform required procedures due to subject illness). 
For medically justifiable conditions which preempt a subject’s ability to complete a study-
required procedure, it may be permitted to report only one deviation which will apply to all 
visits going forward. This may also apply for other unforeseen situations (e.g. the subject 
permanently refuses to complete a study required procedure and the data will not contribute 
to the primary end point analysis). However, prior approval from Medtronic is required for 
such situations.  
 
All study deviations must be reported on the Case Report Form regardless of whether 
medically justifiable, pre-approved by Medtronic, an inadvertent occurrence, or taken to 
protect the subject in an emergency. The deviation must be recorded with an explanation.  
Multiple deviations of the same type at the same visit may be reported on one case report 
form if they occur at the same date/visit and they have the same root cause.  
In the event the deviation involves a failure to obtain a subject’s consent, or is made to 
protect the life or physical well-being of a subject in an emergency, the deviation must be 
reported to the Institutional Review Board (IRB) as well as Medtronic within five (5) working 
days. Reporting of all other study deviations should comply with IRB policies and/or local 
laws and must be reported to Medtronic as soon as possible upon the center becoming 
aware of the deviation. Reporting of deviations must comply with IRB policies, local laws, 
and/or regulatory agency requirements.  

 
 
 
 
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Medtronic is responsible for analyzing deviations, assessing their significance, and identifying 
any additional corrective and/or preventive actions (e.g. amend the Clinical Investigation 
Plan, conduct additional training, and terminate the investigation). Repetitive or serious 
investigator compliance issues may result in initiation of a corrective action plan with the 
investigator and site, and in some cases, necessitate suspending enrollment until the 
problem is resolved or ultimately terminating the investigator's participation in the study. 
Medtronic will provide center-specific reports to investigators summarizing information on 
deviations that occurred at the investigational site on a periodic basis.  
 
 

 
 
 
 
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10 ADVERSE EVENTS AND DEVICE DEFICIENCIES 
Timely, accurate, and complete reporting and analysis of safety information for clinical 
studies are crucial for the protection of subjects. Reporting and analysis of safety data are 
mandated by regulatory authorities worldwide. Medtronic has established procedures in 
conformity with worldwide regulatory requirements to ensure appropriate reporting of safety 
information. This study is conducted in accordance with these procedures and regulations. 
Since the safety reporting requirements and classification systems vary for each regulatory 
agency, requirements from all geographies are taken into account for the collection and 
reporting of safety information. 
10.1Adverse Event and Device Deficiency definitions 
Where the definition indicates “device”, it refers to any device used in the study. This might 
be the device under investigation, or any market released component of the system. 
Table 14: Adverse Event definitions 
 

 
 
 
 
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General 
Adverse Event (AE) 
Any untoward medical occurrence, unintended disease or 
injury, or untoward clinical signs (including abnormal laboratory 
findings) in subjects, users or other persons, whether or not 
related to the investigational medical device 
 
NOTE 1: This definition includes events related to the 
investigational medical device or the comparator. 
NOTE 2: This definition includes events related to the 
procedures involved. 
NOTE 3: For users or other persons, this definition is restricted 
to events related to investigational medical devices. 
(ISO 14155:2011, 3.2) 
NOTE 4: The initiation of an PRN by the ISCC nurse will not be 
considered an AE 
Adverse Device Effect (ADE) 
 
 
 
Adverse event related to the use of an investigational medical 
device 
 
NOTE 1: This definition includes adverse events resulting from 
insufficient or inadequate instructions for use, deployment, 
implantation, installation, or operation, or any malfunction of the 
investigational medical device. 
NOTE 2: This definition includes any event resulting from an 
error use or from intentional misuse of the investigational 
medical device. (ISO 14155:2011, 3.1) 
 
Device Deficiency (DD) 
Inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety or performance.  
 
NOTE: Device deficiencies include malfunctions, use errors and 
inadequate labeling (ISO 14155:2011, 3.15) 
NOTE 2: CareLink connectivity related DD will not be collected 
on an eCRF 
Relatedness 

 
 
 
 
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System Related 
An adverse event that results from the presence or 
performance (intended or otherwise) of the system component. 
 
• 
Device Related: An adverse event that results from 
the 
presence or performance (intended or otherwise) of the 
CRT-D device 
 
• 
RA Lead Related: An adverse event that results 
from 
the presence or performance (intended or otherwise) 
of the right atrial lead 
 
• 
RV Lead Related: An adverse event that results 
from 
the presence or performance (intended or otherwise) 
of the right ventricular lead 
 
• 
LV Lead Related: An adverse event that results from 
the presence or performance (intended or otherwise) 
of the left ventricular lead 
 
• 
Other system component related: An adverse event that 
results from the presence or performance (intended or 
otherwise) of another system component 
 
Cardiovascular Related 
An adverse event related to the heart and blood vessels or the 
circulation. 
Heart Failure Related 
An AE related to the hearts inability to meet the metabolic 
demands of the body. A heart failure adverse event would include 
worsening heart failure signs and symptoms such as hypervolemic 
and hypovolemic status requiring the administration, alteration, 
adjustment or augmentation of HF therapy (diuretics, inotropes 
and/or vasodilators etc.) or the utilization of certain treatment 
devices. 
 
PRN Treatment Related: 
An AE related to the utilization of PRN Medication Intervention as 
defined in Section 6. 
Seriousness 

 
 
 
 
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Serious Adverse Event (SAE) 
Adverse event that 
a) led to death, 
b) led to serious deterioration in the health of the subject, that 
either resulted in 
1) a life-threatening illness or injury, or 
2) a permanent impairment of a body structure or a body 
function, or 
3) in-patient or prolonged hospitalization, or 
4) medical or surgical intervention to prevent life-threatening 
illness or injury or permanent impairment to a body structure 
or a body function, 
c) led to fetal distress, fetal death or a congenital abnormality 
or birth defect (ISO 14155:2011, 3.37) 
NOTE: Planned hospitalization for a pre-existing condition, or a 
procedure required by the CIP, without serious deterioration in 
health, is not considered a serious adverse event.  
Serious Adverse Device Effect 
(SADE) ISO 14155:2011 
Adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event. 
(ISO 14155:2011, 3.36) 
 
Unanticipated Adverse Device Effect 
(UADE) 
21 CFR 812 
Any serious adverse effect on health or safety or any life-
threatening problem or death caused by, or associated with, a 
device, if that effect, problem, or death, was not previously 
identified in a nature, severity, or degree of incidence in the 
investigational plan or application (including a supplementary 
plan or application), or any other unanticipated serious problem 
associated with a device that relates to the rights, safety, or 
welfare of subjects. (21 CFR 812.3(s)) 
Timing 
Pre-PRN initiation 
An adverse event that occurs on the day of PRN treatment initiation, 
but before the subject implemented the medication adjustment.   
Post-PRN initiation 
An adverse event that occurs on the day of PRN treatment initiation, 
but after the subject implemented the medication adjustment.   
10.2Adverse Event and Device Deficiency Assessment 
10.2.1 Adverse Events 
 
All system related events, all cardiovascular-related events, all events that may be 
associated with the PRN intervention and all SAEs will be collected throughout the study 
duration, starting at the time of signing the consent form.  
An exception to this subset of collected events mentioned above, would be the protocol-
initiated PRN intervention, which will not be collected on the Adverse Event form (AE CRF). 

 
 
 
 
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When the protocol initiated PRN intervention occurs, it will be collected on the ISCC 
Notification form. 
 
Reporting of these events to Medtronic will occur on an Adverse Event (AE) Form, including 
a description of AE, date of onset of AE, date of awareness of site, treatment, resolution, 
assessment of both the seriousness and the relatedness to the investigational device. Each 
AE must be recorded on a separate AE Form. Subject deaths are also required to be 
reported. Refer to section 10.5 for Subject Death collection and reporting requirements. 
 
Documented pre-existing conditions are not considered AEs unless the nature or severity of 
the condition has worsened. Adverse events impacting users or other persons are also 
reportable during the course of the study. 
 
For AEs that require immediate reporting, initial reporting may be done by phone, secure file 
transfer system, or on the eCRF completing as much information as possible. The AE eCRF 
must be completed as soon as possible. Refer to the study contact list provided in the 
center’s study documents binder/investigator site file or refer to the contact information 
provided on the title page. 
 
10.2.2 Device Deficiencies 
Device deficiency information will be collected throughout the study and reported to 
Medtronic. Note that device deficiencies that result in an adverse device effect (ADE) to the 
subject should be captured as an Adverse Event only. 
Device related issues that involve the subject’s Carelink monitor will not be collected on the 
Device Deficiency form, 
10.2.3 Processing Updates and Resolution 
For any changes in status of a previously reported adverse event (i.e. change in actions 
taken, change in outcome, change in relatedness), an update to the original AE must be 
completed. All adverse events must be followed until the adverse event has been resolved, is 
unresolved with no further actions planned, the subject exits the study or until study closure, 
whichever occurs first.  
 
In the event that a subject is exited from the study prior to study closure, all efforts should be 
made to continue following the subject until all unresolved or system related adverse events, 
as classified by the investigator, are resolved or they are unresolved with no further actions 
planned.  
 
At the time of study exit, all adverse events with an outcome of “Unresolved, further actions 
or treatment planned” must be reviewed and an update to the original AE must be reported. 
At a minimum, if there are no changes to the description, relatedness, test and procedures or 
actions taken, the outcome must be updated to reflect “Unresolved at time of study closure.” 

 
 
 
 
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10.3 Events Classification and Reporting 
Upon receipt of adverse events at Medtronic, a Medtronic representative will review the 
adverse event/device deficiency for completeness and accuracy and when necessary will 
request clarification and/or additional information from the Investigator. AEs will be classified 
by the investigator for relatedness and seriousness, according to the definitions provided.  
 
Medtronic will utilize MedDRA, the Medical Dictionary for Regulatory Activities, to assign a 
MedDRA term for each adverse event based on the information provided by the investigator.  
 
Regulatory reporting of events will be completed according to local regulatory requirements. 
Refer Table 16 for a list of required investigator and Medtronic reporting requirements and 
timeframes. It is the responsibility of the investigator to abide by any additional AE reporting 
requirements stipulated by the IRB responsible for oversight of the study. 
 
Foreseeable adverse event information associated with the market released system 
components are provided in the device labeling that is included with each system component. 
Additionally, information related to possible risks associated with the utilization of the system 
components and software can be found in Table 17.  
 
For emergency contact regarding a UADE, SAE and/or SADE, contact a clinical study 
representative immediately. Refer to the study contact list provided in the center’s study 
documents binder/investigator site file or refer to the contact information provided on the title 
page. 
 
Adverse Events and Deaths will be classified according to the standard definitions as outlined 
below: 
 
 
Table 15: Adverse Event classification responsibilities 
 

 
 
 
 
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What is 
classified? 
Who 
classifies? 
Classification Parameters 
Timing of the 
Event 
Investigator 
Pre-PRN initiation, Post PRN initiation  
Relatedness 
Investigator 
System Related 
Sponsor 
HF Related, PRN Related1 
Seriousness 
Investigator 
SAE, UADE  
Sponsor 
SAE, UADE 
Diagnosis 
Investigator 
Based on presenting signs and symptoms and 
other supporting data 
Sponsor 
MedDRA term assigned based on the data 
provided by Investigator 
Death 
Classification 
Investigator 
Sudden Cardiac, Non-sudden Cardiac, Non-
Cardiac, Unknown2 
 
1 The CEC will adjudicate all AEs for system relatedness, HF, and PRN relatedness    
2  CEC will adjudicate deaths to relatedness and death classification. All other adjudication information 
for deaths will be taken from the corresponding AE with the outcome of death. 
 
10.4 Adverse Event and Device Deficiency Reporting Requirements 
Regulatory reporting of AEs/DDs will be completed according to local regulatory 
requirements. Refer to Table 16 for a list of required investigator reporting requirements and 
timeframes, and of required Medtronic reporting requirements and timeframes. 
 
It is the responsibility of the investigator to abide by any additional AE/DD reporting 
requirements stipulated by the IRB responsible for oversight of the study. 
 
For AEs/DDs that require immediate reporting, initial reporting may be done by contacting the 
study sponsor per the sponsor contact information provided in this document.  
 
 
Table 16: Reporting requirements 
 

 
 
 
 
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Serious Adverse Events (SAEs) 
Investigator submit to: 
Medtronic 
US: Submit in a timely manner after the investigator first learns of the event 
IRB 
US: Submit per local IRB requirement. 
Serious Adverse Device Effects (SADEs) 
Investigator submit to: 
Medtronic 
US: Submit in a timely manner after the investigator first learns of the event. 
IRB 
US: Submit per local IRB requirement. 
Unanticipated Adverse Device Effects (UADEs) 
Investigator submit to: 
Medtronic 
US: Submit as soon as possible, but no later than within 10 working days 
after the investigator first receives notice of the effect. (21 CFR 
812.150(a)(1)) 
 
IRB 
US: Submit as soon as possible, but no later than within 10 working days 
after the investigator first receives notice of the effect. (21 CFR 
812.150(a)(1)) 
 
Sponsor submit to: 
Investigator US: Notification as soon as possible, but no later than 10 working days after 
the sponsor first learns of the effect. (21 CFR 812.150(b)(1)) 
Regulatory 
authorities 
US: Notification as soon as possible to FDA, but no later than 10 working 
days after the sponsor first receives notice of the effect. (21 CFR 
812.150(b)(1)) 
IRB 
US: Notification as soon as possible, but no later than 10 working days after 
the sponsor first learns of the effect. (21 CFR 812.150(b)(1)) 
All other reportable Adverse Events (system, cardiovascular-related, and PRN 
related) 
Investigator submit to: 
Medtronic 
US: Submit in a timely manner after the investigator first learns of the event. 
Regulatory 
Authorities  US: Submit or report as required per local reporting requirement. 
IRB 
US: Submit per local IRB requirement. 
All other Device Deficiencies 
Investigator submit to: 
Medtronic 
US: Submit in a timely manner after the investigator first learns of the event. 

 
 
 
 
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Regulatory 
Authorities  US: Submit or report as required per local reporting requirement. 
IRB 
US: Submit per local IRB requirement. 
 
10.5Subject Death 
10.5.1 Death data collection 
All subject deaths must be reported by the investigator to Medtronic on a Subject Death form 
as soon as possible after the investigator first learns of the death. Document the Adverse 
Event that led to the subject death on an Adverse Event form.  
 
In the event of a subject’s death, the implanted system should be explanted and returned to 
Medtronic for analysis whenever possible. Local laws and procedures must be followed 
where applicable. For the CRT-D devices used in this study, the VT and VF detection 
capabilities must be disabled to avoid inadvertent shocks. 
 
 
System Interrogation Data Recommendations: 
• 
After the subject has died but prior to explant, the system shall be interrogated 
and a full summary interrogation (Interrogate All) performed when possible.   
• 
Make the interrogation file before any programming to prevent overwriting 
information in the CRT-D device’s memory and/or distinguishing between 
events detected during versus before the explant procedure 
• 
Recommend obtaining the exact date and time of death as lower temperatures 
after death can cause ERI and other “event flags” to be stored in the CRT-D 
device memory 
 
If the system is not interrogated, an explanation must be entered on the Subject Death form. 
If any system component is returned to Medtronic, internal return product reporting systems 
may be used to gather additional information about the returned device/component. 
A copy of the death certificate, if available and allowed by state/local law, should be sent to 
the Medtronic clinical study team. When a death occurs in a hospital, a copy of the death 
summary report and all relevant hospital records should be sent to the Medtronic clinical 
study team, if available. If an autopsy is conducted, the autopsy report should also be sent to 
the Medtronic clinical study team if available and allowed by state/local law. When the death 
occurs at a remote site, it is the investigative center’s responsibility to attempt retrieval of 
information about the death. Additionally, device disposition information should be updated. 
In summary, the following data will be collected: 
• 
Date of death 
• 
Detailed description of death 

 
 
 
 
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• 
Cause of death  
• 
Relatedness 
• 
Device interrogation (if available) 
• 
Device disposition information 
• 
Death summary/hospital records (if available and allowed by state/local law) 
• 
Autopsy report (if available and allowed by state/local law) 
• 
Death certificate (if available and/or allowed by state/local law) 
10.5.2 Death classification and reporting 
Sufficient information will be required in order to properly classify the subject’s death. The 
Investigator shall classify each subject death per the following definitions: 
 
Cardiac Death: A death directly related to the electrical or mechanical dysfunction of the 
heart. 
 
Sudden Cardiac Death (SCD): Natural death due to cardiac causes, indicated by abrupt loss 
of consciousness within one hour of the onset of acute symptoms; preexisting heart disease 
may have been known to be present, but the time and mode of death are unexpected. If time 
of onset cannot be determined, SCD will alternatively be defined as any unexpected cardiac 
death occurring out of the hospital or in the emergency room as dead on arrival. 
 
Non-sudden Cardiac Death: All cardiac deaths that are not classified as sudden deaths, 
including all cardiac deaths of hospitalized subjects on inotropic support. 
 
Non-cardiac Death: A death not classified as a cardiac death. 
 
Unknown Classification: A death in which there is no clinical evidence to support. Unknown 
death classification is intended for use only when there is insufficient or inadequate 
information to classify the death 
 
The CEC will review deaths and provide a final adjudication of the primary cause of death, 
relatedness, and death classification. 
 
Regulatory reporting of Subject Deaths will be completed according to local regulatory 
requirements. Refer to Table 16 for a list of required investigator and sponsor reporting 
requirements and timeframes. 
10.6Clinical Events Committee (CEC) review 
At regular intervals, an independent CEC will review and adjudicate at a minimum, all end-
point related AEs and deaths for subjects participating in the study.  

 
 
 
 
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The CEC will consist of a minimum of three (3) non-Medtronic employed physicians that are 
not participating investigators for the study, including a CEC chairperson. At least two out of 
three CEC members must adjudicate, at a minimum, all deaths. All other AEs may be 
adjudicated by at least one physician member of the CEC.  
Medtronic personnel may facilitate and participate in a CEC meeting but will be non-voting 
members. 
For adverse events and deaths reviewed by the CEC, Medtronic will provide the CEC with 
the Investigator’s description and classification. The CEC is responsible for reviewing the 
Investigator’s assessment and supportive documentation (when available), reviewing 
applicable definitions, and determining final classifications for all adjudication parameters. 
Additionally, the CEC will provide an adjudication of the death and relatedness.  
If the CEC disagrees with the investigator’s classification of the event, the rationale will be 
provided to the investigator. If the investigator agrees with the CEC’s adjudication, the case 
report form documenting the AE will be updated accordingly by the site. 
If the investigator does not agree with the CEC’s adjudication classification, both 
determinations will be provided within the final report; however the CEC’s adjudication will be 
used for data analysis. The disagreement will also be included in reporting to ethic 
committees and regulatory authorities, if required. 
10.7 Product Complaint Reporting 
In geographies where devices are market-released, product complaint reporting is applicable. 
This includes when an AE is related to a market-released device during the study.  The 
reporting of product complaints is not part of the clinical study and should be done in addition 
to the Adverse Event reporting requirements.  Refer to local regulations for reporting 
requirements. 
Product Complaint: Any written, electronic or oral communication that alleges deficiencies 
related to the identity, quality, durability, reliability, safety, effectiveness or performance of a 
medical device that has been placed on the market. 
It is the responsibility of the investigator to report all product complaint(s) associated with a 
medical device distributed by Medtronic, regardless whether they are related to intended use, 
misuse or abuse of the product. Reporting must be done immediately and via the regular 
channels for market-released products.  
Medtronic will notify the regulatory authorities (e.g. Competent Authority) as applicable for the 
following incidents immediately upon learning of them: 
• 
Any malfunction or deterioration in the characteristics and/or performance of a 
device, as well as any inadequacy in the labeling or instructions for use which 
led or might have led to the death or serious deterioration in the state of health 
of a patient, user, or other person. 
• 
Any technical or medical reason resulting in withdrawal of a device from the 
market by the manufacturer. 
• 
A serious deterioration in the state of heath includes: 

 
 
 
 
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o Life-threatening illness or injury 
o Permanent impairment of a body function or permanent damage to a 
body structure 
o A condition necessitating medical or surgical intervention to prevent 
permanent 
 
 
 
11  RISK ANALYSIS 
 
Medtronic follows rigorous Quality Assurance and Control procedures throughout the 
development and clinical study of a research system. The formal Hazard/ Risk Analysis for 
the INTERVENE-HF research system is completed according to ISO 14971 (Medical Device 
Risk Management), and will be used to ensure that the level of risk is acceptable prior to 
starting the INTERVENE-HF clinical study.   
 
The INTERVENE-HF system includes commercially available systems and investigational 
software. The investigational software is on the programmer and it enables and disables the 
OptiVol wireless alert in selected CRT devices.  Software design and interfaces between 
system components are assessed as part of the Hazard Analysis to ensure any potential risk 
is minimized.  Assessment for acceptable end-to-end system connectivity, as well as system 
design verification and validation activities also form part of the Risk Management process 
followed for the INTERVENE-HF study. 
 
The INTERVENE-HF study risks have been analyzed, evaluated, and controls are put in 
place to address all identified risks. During the course of the study, risks will be continuously 
monitored, assessed and documented by the investigators. 
 
The risks are reduced as much as possible, with residual risk being documented within the 
Risk Management Report and disclosed in the Patient Informed Consent (PIC) forms 
provided to subjects. 
 
A list of potential risks and risk reduction strategies associated with the INTERVENE- HF 
study is summarized in the table below.  The comprehensive Research System Hazard 
Analysis is documented in DSN018588, INTERVENE Research Study Risk Management 
Report. 
 
11.1 Risk Minimization 
The potential risks associated with the INTERVENE-HF study were identified and have been 
successfully mitigated. Any potential risks associated with this study are further minimized by 

 
 
 
 
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selecting qualified investigators and training study personnel on the Clinical Investigation 
Plan.  
 
Medtronic has further minimized the possibility of risks by performing pre-clinical testing prior 
to the INTERVENE-HF clinical study, implementing quality control measures into software 
development processes, providing guidelines for subject selection and evaluation, and 
providing adequate training instructions and labeling.  
 
Subjects in the INTERVENE-HF clinical study will be followed remotely and at regular 
intervals to monitor the condition of their heart failure.  At each protocol required in person 
follow-up, the investigator will interrogate the patient’s CRT device to verify appropriate 
functionality and to assess any adverse events.  
 
 
Table 17: Potential risks and risk minimization 
 
Risks and Risk Reduction Strategy 
Risk 
Mitigations/ Risk Controls 
Improper/ unauthorized access to 
research system via the 
programmer 
• Access code controls for appropriate access to the 
investigational programing software  
Improper investigational software 
install and uninstall 
• 
Software verification and validation testing 
• 
Data integrity checks and distribution of software via 
secure Medtronic Software Distribution Network 
• 
Install/ uninstall instructions are provided via the User 
Manual 
• 
Investigational software identification/ labeling provided 
in the Programmer software  
Improper enabling of the OptiVol 
CareAlert on CRT-D devices 
 
• 
System design with preconditions for enabling, and 
disabling of the OptiVol CareAlert functionality for only 
selected CRT models (which have the HF Risk Score) 
Delay, missing, misleading or 
misinformation leading to 
inappropriate medical intervention 
• 
System end-to-end (CRT device to HF Clinic) data 
connectivity assessment 
• 
Software design verification and validation testing 
• 
Patient selection and exclusion criteria to exclude more 
vulnerable patients or those who may be prone to 
impedance data inaccuracies  
• 
Investigational software identification/ labeling provided 
in the Programmer software 
• 
Pre-clinical integrated diagnostics algorithm for 
accuracy 
• 
Remote patient monitoring, and review of subject data 
and symptoms by licensed ISCC nurse 

 
 
 
 
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Risks and Risk Reduction Strategy 
 
Note: Patients lost to follow-up may not have their OptiVol 
alert disabled. This may cause minor confusion in review of 
their device data outside of the study for geographies where 
the OptiVol feature is not approved, including the United 
States.  
Premature System Revision 
• Limited longevity impact to the implanted device 
based on minimal current drain impact from low 
expected number of OptiVol crossings and 
associated transmissions during the INTERVENE-HF 
study  
- 
For 1-4 crossings per year, longevity impact 
could be up to approximately 2 weeks in one 
year and 5 weeks for the 30 month study 
duration. 
- 
For 10 crossings per year, longevity impact 
could be approximately 5 weeks in one year, 
and 3 months for the entire 30 month study 
duration.  
•  
• 
Procedural risks 
associated with 
coordinating care between 
two teams (two teams = 
site personnel and ISCC 
nurse), which results in 
missed or duplicated 
efforts, orders, or 
medications 
• 
Study and site training for personnel, and subject 
training will address study protocols and the care 
that is provided by each health care team 
involved. 
• 
Risk disclosure: Patient Informed Consent 
discloses risks associated with coordinating care 
between two teams, (two teams = site personnel 
and ISCC nurse), which could include missed or 
duplicated efforts, orders or medications.  
 
11.2 Potential Benefits 
 
The INTERVENE-HF study may offer no benefit. Potential benefits of participating in the 
INTERVENE-HF study include having the OptiVol alert turned on and monitored remotely. 
This remote intrathoracic impedance monitoring, partnered with the external diagnostic 
information for risk stratification, may provide more individualized medication intervention that 
could lead to improved Heart Failure management. 
 
The information gained from this study could result in the improved management of other 
Heart Failure study specific information. Additionally, information collected from this study 
may assist in the design of new product(s)/therapy(ies) and/or instructions for use.  
  

 
 
 
 
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11.3 Additional Considerations 
 
The INTERVENE-HF study does not require exclusion of any aspects of standard of care in 
managing heart failure (HF) patients. Thus, physicians and nurses at a participating center 
can continue to manage their patients as per their clinic’s standard of care practices. The 
INTERVENE-HF study provides additional opportunity for care interventions including use of 
PRN medications as per physician’s standing orders (required) and reminders for 
assessment and adjustment to baseline medications (medication change or rationale for not 
changing medication required). These differences (between the standard of care for the 
subject as compared to the care provided to the subject when participating in the study) are 
described in further detail in the Patient Informed Consent (PIC) Template.  
 
12 PLANNED STUDY CLOSURE, EARLY TERMINATION OF 
STUDY OR STUDY SUSPENSION 
12.1 Planned study closure 
 
Study Closure is a process initiated by distribution of a study closure letter. Study 
closure is defined as closure of a clinical study that occurs when Medtronic and/or 
regulatory requirements have been satisfied per the Clinical Investigation Plan and/or 
by a decision by Medtronic or regulatory authority), whichever occurs first. The study 
closure process is complete upon distribution of the Final Report or after final 
payments, whichever occurs last. Ongoing IRB oversight is required until the overall 
study closure process is complete. Refer to section 7.14 for additional information 
regarding study exit procedures. 
12.2 Early termination or suspension 
 
Early Termination of the Study is the closure of a clinical study that occurs prior to 
meeting defined endpoints. This is possible for the whole study or a single center. 
Study Suspension is a temporary postponement of study activities related to enrollment 
and distribution of the product. This is possible for the whole study or a single center. 
12.2.1 Study-wide termination or suspension 
Possible reasons for considering study suspension or termination of the study 
include but are not limited to: 
• 
Adverse events associated with the system or product under investigation which 
might endanger the safety or welfare of the subject 
• 
Observed/suspected performance different from the product’s design intent 
• 
Decision by Medtronic or regulatory body (where the study is operating under 
regulatory body authority)  
• 
Technical issues during the manufacturing process 

 
 
 
 
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12.2.2 Investigator/center termination or suspension 
Possible reasons for clinical investigator or center termination or suspension include 
but are not limited to: 
• 
Failure to obtain initial IRB approval or annual renewal of the study 
• 
Persistent non-compliance to the clinical investigation (e.g. failure to adhere to 
inclusion/exclusion criteria, failure to follow subjects per scheduled follow-ups)  
• 
Lack of enrollment 
• 
Noncompliance to regulations and the terms of the Clinical Trial Agreement 
(e.g. failure to submit data in a timely manner, failure to follow-up on data 
queries and monitoring findings in a timely manner, etc.)  
• 
IRB suspension of the center 
• 
Fraud or fraudulent misconduct is discovered (as defined by local law and 
regulations)  
• 
Investigator request (e.g. no longer able to support the study)  
 
12.3 Procedures for termination or suspension 
12.3.1 Medtronic-initiated and regulatory authority-initiated 
• 
Medtronic will promptly inform the clinical investigators of the termination or 
suspension and the reasons and inform the regulatory authority(ies) where 
required 
• 
In the case of study termination or suspension for reasons other than a 
temporary IRB approval lapse, the investigator will promptly inform the IRB  
• 
In the case of study termination, the investigator must inform the subjects and 
may inform the personal physician of the subjects to ensure appropriate care 
and follow-up is provided 
• 
In the case of a study suspension, subject enrollment must stop until the 
suspension is lifted by Medtronic 
• 
In the case of a study suspension, enrolled subjects should continue to be 
followed out of consideration of their safety, rights and welfare 
12.3.2 Investigator-initiated 
• 
The investigator will inform Medtronic and provide a detailed written explanation 
of the termination or suspension 
• 
The investigator will promptly inform the institution (where required per 
regulatory requirements)  
• 
The investigator will promptly inform the IRB 
• 
The investigator will promptly inform the subjects and/or the personal physician 
of the subjects to ensure appropriate care and follow-up is provided 

 
 
 
 
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• 
In the case of a study suspension, subjects enrolled should continue to be 
followed out of consideration of their safety, rights and welfare 
12.3.3 IRB-initiated 
• 
The investigator will inform Medtronic and provide a detailed written explanation 
of the termination or suspension within 5 business days 
• 
Subject enrollment must stop until the suspension is lifted 
• 
Subjects already enrolled should continue to be followed in accordance with 
IRB policy or its determination that an overriding safety concern or ethical issue 
is involved 
• 
The investigator will inform his/her institution (where required per local 
requirements)  
• 
The investigator will promptly inform the subjects, or legally-authorized 
designees or guardians and/or the personal physician of the subjects, with the 
rationale for the study termination or suspension 
 
 
 

 
 
 
 
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13 STATISTICAL METHODS AND DATA ANALYSIS 
13.1 Sample size determination 
 
INTERVENE-HF is a feasibility study to evaluate the system that combines integrated device 
diagnostics based risk stratification algorithm with a guided work flow process managed by a 
centralized communication center to manage HF patients. This system, for purposes of 
defining study objectives, will be termed the “Integrated Diagnostics Medication Intervention 
Strategy.” Findings from this feasibility study will be used to guide subsequent planning of a 
pivotal study. 
As a feasibility trial, the INTERVENE-HF study is not designed to be powered for specific 
endpoints. However, the sample size for this study was chosen with the goal of gaining a first 
time experience with the Integrated Diagnostic Medication Intervention Strategy in a broad 
number of patients to understand the safety, effectiveness and potential patient benefit of the 
strategy.  
The study plans to enroll up to 400 subjects to yield up to 200 eligible subjects that meet 
screening criteria from 20 centers in the US with follow up for at least 12 months. The study 
is estimated to be completed in approximately 30 months including 18 months of enrollment 
and 12 months of follow-up from the last enrolled subject. The objectives of the study focus 
on the effectiveness and safety of the Integrated Diagnostics Medication Intervention 
Strategy. Interim analyses of these objectives will take place and if data are deemed to 
sufficiently characterize the study objectives by the sponsor at one of these analyses, 
enrollment and/or follow-up will be stopped. In addition, in order to have an early check on 
the subjects’ safety, a preliminary safety interim data analysis will take place after 10 PRN 
interventions have been implemented and the last PRN intervention has been followed up for 
14 days.      
The unpublished data of a Medtronic sponsored study (OptiLink HF) shows that among the 
subjects who had had CRT-D implanted for at least nine months and had NYHA class II or III 
nine months post implantation, 58% had at least one OptiVol crossing within the next 12 
months of follow-up (of which 39%, 28%, 19%, 9% and 5% had one, two, three, four and 
more than four OptiVol crossings, respectively). Furthermore, about two-thirds of the subjects 
in that study had OptiVol version 1 and the rest had OptiVol version 2 and it is known that 
OptiVol version 2 generates fewer alerts. Therefore, we assume in the INTERVENE-HF 
study that: 
(1) 55% of the enrolled subjects who meet screening criteria and complete the baseline 
and programming visit will have at least one OptiVol crossing within the 12 months of 
follow-up; and  
(2) The distribution for those experiencing OptiVol crossings during the 12 months of 
follow up is the same as the results from the unpublished data.  
As shown in Table 18, this leads to approximately 233 OptiVol crossings in 110 subjects 
(55% of 200 subjects) to be observed in the INTERVENE-HF study. Furthermore, literature 

 
 
 
 
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has indicated that 45% of OptiVol crossings are HF related20. This means about 105 out of 
the 233 OptiVol crossings would require PRN implementation in this study.  
 
Table 18: Number of OptiVol crossings expected from 110 (55% of 200) subjects 
 
Assumption 
Estimation 
Crossing(s) 
% of subjects having 
the crossing(s) 
Expected # of subjects 
having the crossings 
Expected # of 
crossings  
1 
39% 
43 
43*1=43 
2 
28% 
31 
31*2=62 
3 
19% 
21 
21*3=63 
4 
9% 
10 
10*4=40 
>4 
5% 
5 
5*5=25 
Total 
110 
233 
 
13.2 General considerations 
Medtronic employees or designees will perform all statistical analyses.  
 
A separate Statistical Analysis Plan (SAP) will be created and will include a comprehensive 
description of the statistical methods and analyses to be included in reports that include 
analysis of endpoints. Any change to the data analysis methods described in the CIP will 
require an amendment only if it changes a principal feature of the CIP. Any other change to 
the data analysis methods described in the CIP, and the justification for making the change, 
will be described in the clinical study report. 
In addition, the SAP will further describe pre-specified data handling rules. Additional 
exploratory analyses of the data may be conducted as deemed appropriate. 
All objectives will be analyzed once the last enrolled subject has completed the 12-month 
follow-up visit and/or during interim analyses (interim analyses performed after 100 and 150 
subjects are enrolled and have completed the baseline and programming visit). The primary 
analysis for each objective will not account for missing data. If missing data is an issue, a 
sensitivity analysis will be performed accordingly. The analysis results will be included in the 
study report(s). 
13.3  Primary Objective #1 
To characterize the effectiveness of the Integrated Diagnostic Medication Intervention 
Strategy in resolving subject risk. 
13.3.1 Hypothesis 
There is no statistical hypothesis for this objective 

 
 
 
 
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13.3.2 Endpoint Definition 
Once initiated, the Integrated Diagnostic Medication Intervention Strategy will be regarded as 
being effective if all the following criteria are met: 
 
• 
The intrathoracic impedance of a subject recovers per defined criterion after 
completion of the Integrated Diagnostic Medication Intervention;  
• 
The subject has no HF-related event (as adjudicated by the CEC) during or in the 
next 14 days after completion of the Integrated Diagnostic Medication Intervention; 
 
NOTE: Intervention for heart failure decompensation (HF event) is defined as an 
event requiring invasive intervention (i.e. IV diuretics, ultrafiltration, or equivalent) or 
inpatient hospitalization. 
 
• 
The subject has not experienced any adverse events that are related to the Integrated 
Diagnostic Medication Intervention per CEC adjudication and require medical care.   
13.3.3 Performance Requirements 
There are no performance requirements for this objective. 
13.3.4 Rationale for Performance Criteria 
Rational for performance criteria is not applicable for this objective. 
13.3.5 Analysis Methods 
For each episode that requires intervention as determined by this protocol, the effectiveness 
of Integrated Diagnostic Medication Intervention Strategy will be evaluated as a binary 
outcome variable, where 1 = effective and 0 = not effective. During the course of the study, a 
subject could experience more than one intervention. Therefore, a generalized linear model 
with the generalized estimating equation (GEE) method will be used to analyze this 
correlated binary data. The effectiveness rate and its 95% confidence interval (CI) will be 
calculated based on the log of odds estimated using the GEE. 
13.3.6 Determination of Patients/Data for Analysis  
All subjects who have received the Integrated Diagnostic Medication Intervention per 
protocol.   
13.3.7 Sample Size 
As the above-mentioned, based on the experience from previous studies we expect to 
observe about 233 OptiVol crossings from 110 enrolled subjects in this trial and of them 105 
OptiVol crossings would require Integrated Diagnostic Medication Intervention. There are no 
data to help us predict the percentage of OptiVol crossings receiving Integrated Diagnostic 
Medication Intervention or the effectiveness rate of Integrated Diagnostic Medication 
Intervention Strategy. We consider different scenarios in Table 19 and Figure 9 to estimate 
the precision on measuring the effectiveness rate of Integrated Diagnostic Medication 
Intervention Strategy.  

 
 
 
 
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The width of 95% CI for the effectiveness rate represents the measurement precision. Using 
the first row in Table 19 as an example, a total of 70 independent episodes with Integrated 
Diagnostic Medication Intervention produces a two-sided 95% CI with an actual width of 
0.225 when the observed proportion of having effective treatment among those episodes is 
0.7. This is based on the exact Clopper-Pearson confidence interval for one proportion 
assuming independent effectiveness status of Integrated Diagnostic Medication Intervention. 
Note that each episode is an OptiVol crossing that lead to the initiation of an Integrated 
Diagnostic Medication Intervention. Note also that for each scenario, we expect a narrower 
width (i.e. better precision) of 95% CI for the effectiveness rate in the framework of 
generalized linear model with GEE method. This is because GEE method takes the 
correlation among the effectiveness status of multiple episodes from the same subject into 
account, thus presumably results in a smaller standard error of the effectiveness rate.  
 
Figure 9 is a visual illustration of Table 19. 
 
 
Table 19: Table of the 95% Confidence Interval for 70-100 independent episodes 
 
Sample 
Confidence Size 
Actual 
Proportion Lower 
Upper 
Level 
(N) 
Width 
(P) 
Limit 
Limit 
0.950 
70 
0.225 
0.700 
0.579 
0.804 
0.950 
70 
0.199 
0.800 
0.687 
0.886 
0.950 
70 
0.154 
0.900 
0.805 
0.959 
0.950 
80 
0.210 
0.700 
0.587 
0.797 
0.950 
80 
0.186 
0.800 
0.696 
0.881 
0.950 
80 
0.143 
0.900 
0.812 
0.956 
0.950 
90 
0.198 
0.700 
0.594 
0.792 
0.950 
90 
0.174 
0.800 
0.702 
0.877 
0.950 
90 
0.135 
0.900 
0.819 
0.953 
0.950 
100 
0.187 
0.700 
0.600 
0.788 
0.950 
100 
0.165 
0.800 
0.708 
0.873 
0.950 
100 
0.127 
0.900 
0.824 
0.951 
 
 
 

 
 
 
 
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Figure 9: Graph of the 95% Confidence Interval for 70 to 100 independent episodes 
 
13.4 Primary Objective #2 
To characterize the safety of the Integrated Diagnostic Medication Intervention Strategy in 
resolving the subject risk.  
13.4.1 Hypothesis 
There is no statistical hypothesis for this objective. 
13.4.2 Endpoint Definition 
 
Once initiated, the Integrated Diagnostic Medication Intervention Strategy will be regarded as 
being safe if all the following criteria are met: 
 
• 
The Integrated Diagnostic Medication Intervention applied to an episode is not 
terminated due to safety issues; 
 
NOTE: Safety issues include hypotension with/without patient contact and weight loss 
with patient contact. 
C.I. Width vs N by P with C.L.=0.95 C.I. One Proportion
0.700
0.800
0.900
C.I. Width
P
N
0.10
0.15
0.20
0.25
60
70
80
90
100

 
 
 
 
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• 
And, the Integrated Diagnostic Medication Intervention applied to an episode has not 
caused treatment-related adverse events (as adjudicated by the CEC).  
13.4.3 Performance Requirements 
There are no performance requirements for this objective 
13.4.4 Rationale for Performance Criteria 
Rationale for performance criteria is not applicable for this objective. 
13.4.5 Analysis Methods 
Similar to the effectiveness endpoint of Integrated Diagnostic Medication Intervention 
Strategy, the safety endpoint of Integrated Diagnostic Medication Intervention Strategy is a 
correlated binary outcome with 1=safe and 0=not safe. It will be analyzed using a generalized 
linear model with GEE method. The safety rate and its 95% CI will be calculated based on 
the log of odds estimated using GEE. 
 
13.4.6 Determination of Patients/Data for Analysis  
All subjects who have received the Integrated Diagnostic Medication Intervention. 
13.4.7 Sample Size 
The same estimates on the precision of measuring effectiveness rate of Integrated 
Diagnostic Medication Intervention Strategy under different scenarios illustrated in Table 19 
and Figure 9 above are applicable to the safety rate as well.  Again, using the first row in 
Table 19 as an example, a total of 70 independent episodes with Integrated Diagnostic 
Medication Intervention produces a two-sided 95% CI with an actual width of 0.225 when the 
observed proportion of having safe treatment among those episodes is 0.7.  
 
13.5 Ancillary Objective 
To characterize the occurrence of Heart Failure (HF) events in the study subjects. 
13.5.1 Hypothesis  
There is no statistical hypothesis for this objective 
13.5.2 Endpoint Definition  
The endpoint of this objective is the number of HF events per subject, as adjudicated by 
CEC.  
13.5.3 Analysis Methods 
The number of HF events will be summarized using frequency and percentage, and stratified 
by the implementation status of Integrated Diagnostic Medication Intervention (1=have ever 
received the intervention, 0=have never received the intervention). A Poisson regression 
model will be used to analyze the number of HF events, adjusting for the implementation of 

 
 
 
 
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Integrated Diagnostic Medication Intervention. The fit of the Poisson regression model will be 
checked. If over dispersion is a concern, a negative binomial model may be considered. It is 
important to note, that those who have received the Integrated Diagnostic Medication 
Intervention might be sicker when compared to subjects who have never received the 
Integrated Diagnostic Medication Intervention, and therefore, are more likely to have HF 
events. Thus, the number of HF events before and after the intervention will be summarized 
using descriptive statistics for the subjects who have received such intervention.             
 
13.5.4 Determination of Patients/Data for Analysis  
All the enrolled subjects who have completed the baseline and programming visit will be 
included.  
 
13.6  Preliminary Safety Interim Data Analysis 
To summarize preliminary safety of PRN intervention. 
13.6.1  Hypothesis  
There is no statistical hypothesis for this analysis. 
13.6.2 Endpoint Definition  
The endpoint of this analysis includes any adverse event reported per protocol.  
13.6.3 Analysis Methods 
The analysis will occur when 10 PRN interventions have been implemented and the last PRN 
intervention has been followed up for 14 days. Descriptive statistics such as count and 
percentage will be used. The seriousness and relatedness of adverse events will be based 
on the CEC adjudication. If an adverse event has not been adjudicated by the CEC by the 
time of the analysis, study investigators’ assessment (if available) will be considered. The 
primary interest in the relatedness of adverse events includes but is not limited to safety 
issues leading to termination of PRN interventions, treatment-related adverse events after 
implementation of PRN interventions, and HF events occurring within 14 days after 
completion of PRN intervention. Adverse events occurring before and after PRN interventions 
will be summarized separately.             
13.6.4 Determination of Patients/Data for Analysis  
All the subjects who have completed the baseline and programming visit by the time of the 
analysis. 
14 DATA AND QUALITY MANAGEMENT 
 
Data will be collected using an electronic data management system for clinical studies.  
eCRF data will be stored in a secure, password-protected database which will be backed up 
nightly.  Data will be reviewed using programmed and manual data checks.  Data queries will 
be made available to centers for resolution.  Study management reports may be generated to 

 
 
 
 
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monitor data quality and study progress.  At the end of the study, the data will be frozen and 
will be retained indefinitely by Medtronic. 
All records and other information about subjects participating in this study will be treated as 
confidential. Data will be transferred and processed by Medtronic or a third party designated 
by Medtronic in a key coded form, unless it’s impossible to make it anonymous, for instance, 
where the patient’s name cannot be removed from the data carrier, such as fluoroscopy 
images.   
Procedures in the CIP require source documentation.  Source documentation will be 
maintained at the site. Source documents, which may include, but not limited to, worksheets, 
patient medical records, lab results, ECGs, programmer printouts, and interrogation files, 
must be created and maintained by the investigational site team. In some cases, the data 
reported in the eCRFs may be considered source, as long as there is evidence of it in the 
subject’s record. The eCRF may serve has the primary source for the following data points 
but is not limited to the list below (refer to the study-specific monitoring plan for complete 
listing). 
 
The data reported on the eCRFs shall be derived from source documents and be consistent 
with these source documents, and any discrepancies shall be explained in writing. If 
applicable, the eCRF may be considered source for the following data collection elements but 
not limited to: 
• 
Enrollment Notification 
o Site assigned patient reference 
• 
Baseline 
o Administrative Information 
o Cardiac Disease Classification 
• 
Adverse Event eCRF 
o Date study center became aware of event 
o Relatedness of adverse event 
• 
Device Deficiency eCRF 
o Date study became aware of event 
• 
Subject Death 
o Date study became aware of death 
o Relatedness of death 
o System Explant Information 
• 
System Modification 
o Justification for explanted product not being returned to Medtronic 

 
 
 
 
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• 
Deviations 
 
Device data from transmissions will be uploaded to secure servers.  Save-to-disk data 
collected at office visits will be sent to Medtronic.  Upon receipt, device data will be 
maintained with databases and retrieved for analysis and reporting. 
The sponsor or a regulatory authority may audit or inspect the study center to evaluate the 
conduct of the study. The clinical investigator(s)/institution(s) shall allow study related 
monitoring, audits, IRB review and regulatory inspection by providing direct access to source 
data/documents. 
 
It has been determined that a data monitoring committee (DMC) would not be appropriate for 
this feasibility study.  
 
15 WARRANTY/INSURANCE 
Warranty information is provided in the product packaging for the commercially released 
CRT-D device and additional copies are available upon request. 
 
Medtronic maintains appropriate Clinical Trial liability insurance coverage as required under 
applicable laws and regulations and will comply with applicable local law and custom 
concerning specific insurance coverage. If required, a Clinical Trial insurance 
statement/certificate will be provided to the IRB. 
16 MONITORING 
It is the responsibility of Medtronic to ensure proper monitoring of this clinical study.  Trained 
Medtronic personnel or delegates appointed by Medtronic may perform study monitoring at 
the study center in order to ensure that the study is conducted in accordance with the CIP, 
the Clinical Trial Agreement, and applicable regulatory and local requirements. Medtronic, or 
delegates, must therefore be allowed access to the subjects’ case histories (clinic and 
hospital records, and other source data/documentation) upon request as per the Subject 
Informed Consent, Research Authorization (where applicable) and Clinical Trial Agreement.  
The investigator should also be available during monitoring visits.   
16.1 Monitoring Visits 
Frequency of monitoring visits may be based upon subject enrollment, duration of the study, 
study compliance, number of adverse events, number of deviations, findings from previous 
monitoring visits and any suspected inconsistency in data that requires investigation. 
Regulatory documents may be reviewed at each study center. Monitoring for the study, 
including site qualification visits, site initiation visits, interim monitoring visits, and closeout 
visits, will be done in accordance to the study-specific monitoring plan. 
Monitoring visits may be conducted periodically to assess site study progress, the 
investigator’s adherence to the CIP, regulatory compliance including but not limited to 

 
 
 
 
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IRB/IRB approval and review of the study, maintenance of records and reports, and review of 
source documents against subject eCRFs. Monitors review site regulatory and study 
compliance by identifying findings of non-compliance and communicating those findings 
along with recommendations for preventative/corrective actions to site personnel.  Monitors 
may work with study personnel to determine appropriate corrective action recommendations 
and to identify trends within the study or at a particular center.  
17 REQUIRED RECORDS AND REPORTS 
17.1   Investigator records 
The investigator is responsible for the preparation and retention of the records cited below. 
All of the below records, with the exception of case history records and case report forms, 
should be kept in the Investigator Site File (i.e., the study binder provided to the investigator) 
or Subject Study Binder. Electronic CRFs must be maintained and signed electronically 
within the electronic data capture system during the study. The following records are subject 
to inspection and must be retained for a period of two years (or longer as local law or hospital 
administration requires) after product approval or the date on which the investigation is 
terminated.  
• 
All correspondence between the IRB, sponsor, monitors, FDA or other regulatory 
agencies, including required reports that pertain to this study 
• 
Subject’s case history records, including:  
o Signed and dated informed consent form signed by subject.  
o Observations of adverse events/adverse device effects/device deficiencies 
o Medical history 
o Implant and follow-up data (if applicable) 
o Documentation of the dates and rationale for any deviation from the protocol 
• 
List of investigation sites 
• 
Financial disclosure 
• 
Normal value(s)/range(s) for subject and clinical laboratory test 
• 
Lab certificate (if applicable) 
• 
Disposition Logs including, but not limited to, record of receipt, use, or disposition of 
investigational software, device serial number, subject ID, date of turning ON and OFF 
OptiVol Care Alerts 
• 
All approved versions of the CIP and PIC  
• 
Signed and dated Clinical Trial Agreement  
• 
Current curriculum vitae of principal investigators  
• 
Documentation of delegated tasks 
• 
IRB approval documentation. Written information that the investigator or other study staff, 
when member of the IRB, did not participate in the approval process. Approval 
documentation must include the IRB composition, where required per local law.   

 
 
 
 
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• 
Regulatory authority notification, correspondence and approval, where required per local 
law 
• 
Study training records for site staff 
• 
Any other records that FDA and local regulatory agencies require to be maintained (e.g. 
financial disclosure) 
• 
Final Study Report including the statistical analysis 
17.2 Investigator reports 
The investigator is responsible for the preparation (review and signature) and submission to 
the sponsor of all case report forms, adverse events and adverse device effects (reported per 
the country-specific collection requirements), device deficiencies, deaths, and any deviations 
from the clinical investigation plan; other reports are listed in Table 12. If any action is taken 
by an IRB with respect to this clinical study, copies of all pertinent documentation must be 
forwarded to Medtronic in a timely manner. Reports are subject to inspection and to the 
retention requirements as described above for investigator records.  
Safety data investigator reporting requirements are listed in section 10 of the Adverse Event 
section. The investigator shall prepare and submit in a complete, accurate and timely manner 
the reports listed in this section. 
Medtronic records and reports will be maintained in a password-protected document 
management system, and paper documents (where applicable) will be stored in stored in 
secured file cabinets at Medtronic during the course of this study.  
 
After closure of the study Medtronic will archive records and reports indefinitely. 
 
 
Table 20: Investigator reports applicable for all geographies per Medtronic 
requirements 
 
Report  
Submit to 
Description/Constraints 
Withdrawal of 
IRB approval 
Sponsor and 
Relevant 
Authorities 
The investigator must report a withdrawal of approval by the 
reviewing IRB of the investigator’s part of the investigation within 
5 working days. 
Study Deviations Sponsor and 
IRB 
Any deviation from the clinical investigational plan shall be 
recorded together with the explanation of the deviation. 
Notice of deviations from the CIP to protect the life or physical 
well-being of a subject in an emergency shall be given as soon as 
possible, but no later than 5 working days after the emergency 
occurred.  Except in such emergency, prior approval is required 
for changes in the plan or deviations.  
Final Report 
IRBs and  
Relevant 
Authorities 
This report must be submitted within 3 months of study 
completion or termination. 
 
 
 

 
 
 
 
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Table 21: Additional Investigator reports applicable to the 
United States per FDA regulations 
 
Report  
Submit to 
Description/Constraints 
Withdrawal of 
IRB approval 
(either 
suspension or 
termination) 
Sponsor 
The investigator must report a withdrawal of approval by the reviewing IRB of 
the investigator’s part of the investigation within 5 working days.  (21 CFR 
812.150(a)(2)) 
Progress report  Sponsor and 
IRB 
The investigator must submit this report to the sponsor and IRB at regular 
intervals, but in no event less than yearly. (21 CFR 812.150 (a)(3)).   
Study deviations  Sponsor and 
IRB 
Notice of deviations from the CIP to protect the life or physical wellbeing of a 
subject in an emergency shall be given as soon as possible, but no later than 
5 working days after the emergency occurred.  Except in such emergency, 
prior approval is required for changes in the plan or deviations.  If the 
deviation may affect the scientific soundness of the plan or the rights, safety 
and welfare of the subjects, the deviation must be approved by Medtronic, 
the IRB, and the FDA/applicable regulatory authorities.  If the deviation does 
not affect these issues then only Medtronic must approve it.  (21 CFR 
812.150(a)(4)) 
Failure to obtain 
informed consent 
prior to 
investigational 
device use 
Sponsor and 
IRBs 
If an investigator uses a device without obtaining informed consent, the 
investigator shall report such use within 5 working days after device use.  (21 
CFR 812.150(a)(5)) 
Final report 
Sponsor 
IRBs 
Relevant 
Authorities 
This report must be submitted within 3 months of study completion or 
termination of the investigation or the investigator’s part of the investigation.  
(21 CFR 812.150(a)(6)) 
Other 
IRB and FDA 
An investigator shall, upon request by a reviewing IRB, FDA or any other 
regulatory agency, provide accurate, complete, and current information about 
any aspect of the investigation. (21 CFR 812.150(a)(7)) 
 
Table 22: Sponsor reports for the United States 
 
Report  
Submit to 
Description/Constraints 
Withdrawal of IRB 
approval 
Investigators, IRB, 
FDA, and 
relevant 
authorities 
Notification within five working days.  (21 CFR 812.150(b)(2))   
Withdrawal of 
FDA approval 
Investigators, 
IRB, and 
relevant 
authorities 
Notification within five working days.  (21 CFR 812.150(b)(3)) 
Investigator List 
FDA 
Submit at 6-month intervals, a current list of the names and addresses of all 
investigators participating in the investigation.  (21 CFR 812.150(b)(4)) 
Progress Reports IRB and  
FDA 
Progress reports will be submitted at least annually.  (21 CFR 812.150(b)(5), 
812.36(f)   

 
 
 
 
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Report  
Submit to 
Description/Constraints 
Recall and device 
disposition 
Investigators, 
Head of 
Institution, 
IRB, 
relevant 
authorities, and  
FDA 
Notification within 30 working days and will include the reasons for any 
request that an investigator return, repair, or otherwise dispose of any 
devices.  (21 CFR 812.150(b)(6)) 
Failure to obtain 
informed consent  FDA 
Investigator’s report will be submitted to FDA within five working days of 
notification.  (21 CFR 812.150(b)(8)) 
Final report 
Investigators, 
IRB,  
Regulatory 
authorities upon 
request, and FDA 
Medtronic will notify FDA within 30 working days of the completion or 
termination of the investigation.  A final report will be submitted to the FDA, 
investigators, and IRBs within six months after completion or termination of 
this study.  (21 CFR 812.150(b)(7)) 
Study deviation  
Investigators 
Ensure that all deviations from the Clinical Investigation Plan are reviewed 
with the appropriate clinical investigator(s), are reported on the case report 
forms and the final report of the clinical investigation.  
Site specific study deviations will be submitted to investigators periodically.   
Other 
IRB, FDA 
Accurate, complete, and current information about any aspect of the 
investigation. (21 CFR 812.150(b)(10)) 
 
 
 

 
 
 
 
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APPENDIX A:  DRAFT DATA COLLECTION ELEMENTS 
(CASE REPORT FORMS) 
 
Draft Case Report Forms for the INTERVENE-HF study will be provided under separate 
cover.  Final eCRFs will be provided to sites via the electronic data management system after 
the site has fulfilled all requirements for database access. 
APPENDIX B: ISCC REPORTS TO PHYSICIAN 
 
Below are sample reports that will be sent to the participating physician by ISCC at defined 
moments during the study. Each form has an area for customized text, so the form can be 
updated with notes and/or other information pertinent to the subject.  
 
The investigator will be contacted by ISCC with the following reports in the following 
circumstances:  
 
1) Medication Evaluation Report:  
 
Medical evaluation report if any of three chronic med/PRN med evaluation criterion met. 
 
• 
Mean 90 day impedance less than 66 Ω 
• 
Not recovered after 2 PRNs were initiated in the same treatment protocol 
• 
Two or more PRN diuretic titrations in the last 3 months 
 
2) Interim Patient Report: 
 
• 
Initiation of PRN 1 
• 
Initiation of PRN 2 
• 
If unable to contact the patient within 8 days of intervention trigger 
• 
If unable to contact the patient within 4 days of PRN 2 start date 
• 
If patient is contacted and OptiVol is found to non-HF related 
• 
Safety criteria met during Integrated Diagnostic Medication Intervention Strategy 
 
 
3) Exception Report: 
 
• 
Alert criterion based on external diagnostics met outside PRN execution window 
• 
Cessation of PRN intervention due to meeting safety criteria during PRN  
 
 
 

 
 
 
 
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Medical Evaluation Report Sample 
 
 
 
 
 
 

 
 
 
 
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Interim Patient Report Sample 
 
 
 
 
 

 
 
 
 
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APPENDIX C: INFORMED CONSENT TEMPLATES 
The Patient Informed Consent template for INTERVENE-HF will be provided under separate 
cover. 
APPENDIX D: PARTICIPATING INVESTIGATORS AND 
INSTITUTIONS 
At the time of INTERVENE-HF Clinical Investigation Plan Version 1.0 completion, center 
confirmation was not finalized. A complete list of participating investigators and institutions 
where study activities will be conducted will be distributed under a separate cover when 
available. 
 
APPENDIX E: COMMITTEES 
A complete list of committees used for this study (including steering committee) will be 
provided, distributed and updated under separate cover.  
 
APPENDIX F: IRB  
At the time of INTERVENE-HF Clinical Investigation Plan Version 1.0 completion, center 
confirmation was not finalized. Therefore, a complete list of participating IRBs and the 
Chairperson(s) will be distributed under a separate cover when available. 
 
APPENDIX G: LABELING 
Since the INTERVENE-HF software will be distributed electronically through the Software 
Distribution Network (SDN), physical media labeling is not required.  INTERVENE-HF 
Research System set-up instructions will be included in the User Manual.  
 
Investigational labeling requirements for the software INTERVENE-HF User Manual will 
include the following statement:  
 
“CAUTION-Investigational device. Limited by Federal Law (USA) to Investigational use.”  
 
 

 
 
 
 
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APPENDIX H: BIBLIOGRAPHY 
 
1. Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJ, Ponikowski P, Poole-Wilson PA, 
et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 
2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart 
Failure 2008 of the European Society of Cardiology. Developed in collaboration with the 
Heart Failure Association of the ESC (HFA) and endorsed by the European Society of 
Intensive Care Medicine (ESICM). European heart journal. 2008; 29:2388-442. 
2. Walker SH, Duncan DB. Estimation of the probability of an event as a function of several 
independent variables. Biometrika. 1967; 54:167-79. 
3. Truett J, Cornfield J, Kannel W. A multivariate analysis of the risk of coronary heart 
disease in Framingham. Journal of chronic diseases. 1967; 20:511-24. 
4. Kannel WB, McGee D, Gordon T. A general cardiovascular risk profile: the Framingham 
Study. Am J Cardiol. 1976; 38:46-51. 
5. Anderson KM, Wilson PW, Odell PM, Kannel WB. An updated coronary risk profile. A 
statement for health professionals. Circulation. 1991; 83:356-62. 
6. Wilson PW, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction 
of coronary heart disease using risk factor categories. Circulation. 1998; 97:1837-47. 
7. Conroy RM, Pyorala K, Fitzgerald AP, Sans S, Menotti A, De Backer G, et al. Estimation 
of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. European 
heart journal. 2003; 24:987-1003. 
8. Levy WC, Mozaffarian D, Linker DT, Sutradhar SC, Anker SD, Cropp AB, et al. The 
Seattle Heart Failure Model: prediction of survival in heart failure. Circulation. 2006; 
113:1424-33. 
9. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of 
clinical classification schemes for predicting stroke: results from the National Registry of 
Atrial Fibrillation. Jama. 2001; 285:2864-70. 
10. Cowie MR, Sarkar S, Koehler J, Whellan DJ, Crossley GH, Tang WH, et al. Development 
and validation of an integrated diagnostic algorithm derived from parameters monitored in 
implantable devices for identifying patients at risk for heart failure hospitalization in an 
ambulatory setting. European heart journal. 2013; 34:2472-80. 
11. Wang L. Fundamentals of intrathoracic impedance monitoring in heart failure. Am J 
Cardiol. 2007; 99:3G-10G. 
12. Yu CM,  Wang L, Chau E, Chan RHW, Kong SL, Tan MO, Christensen J,  et al.  
Intrathoracic impedance monitoring in patients with HF: Correlation with fluid status and 
feasibility of early warning preceding hospitalization. Circulation. 2005; 112: 841-848. 
13. Vollmann D, Naegele H, Scauerte P, Wiegand U, Butter, C, Zanotto G, Quesada A, et al. 
Clinical utility of intrathoracic impedance monitoring to alert patients with an implanted 
device of deteriorating chronic heart failure.European Heart Journal. 2007; 28:1835-40. 
14. La Rovere MT, Pinna GD, Maestri R, Mortara A, Capomolla S, Febo O, et al. Short-term 
heart rate variability strongly predicts sudden cardiac death in chronic heart failure 
patients. Circulation. 2003; 107:565-70. 
15. Adamson PB, Kleckner KJ, VanHout WL, Srinivasan S, Abraham WT. Cardiac 
resynchronization therapy improves heart rate variability in patients with symptomatic 
heart failure. Circulation. 2003; 108:266-9. 

 
 
 
 
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16. Adamson PB, Smith AL, Abraham WT, Kleckner KJ, Stadler RW, Shih A, et al. 
Continuous autonomic assessment in patients with symptomatic heart failure: prognostic 
value of heart rate variability measured by an implanted cardiac resynchronization device. 
Circulation. 2004; 110:2389-94. 
17. Koplan BA, Kaplan AJ, Weiner S, Jones PW, Seth M, Christman SA. Heart failure 
decompensation and all-cause mortality in relation to percent biventricular pacing in 
patients with heart failure: is a goal of 100% biventricular pacing necessary? J Am Coll 
Cardiol. 2009; 53:355-60. 
18. Bourge RC, Abraham WT, Adamson PB, Aaron MF, Aranda JM, Jr., Magalski A, et al. 
Randomized controlled trial of an implantable continuous hemodynamic monitor in 
patients with advanced heart failure: the COMPASS-HF study. J Am Coll Cardiol. 2008; 
51:1073-9. 
19. Adamson PB, Gold MR, Bennett T, Bourge RC, Stevenson LW, Trupp R, et al. 
Continuous hemodynamic monitoring in patients with mild to moderate heart failure: 
results of The Reducing Decompensation Events Utilizing Intracardiac Pressures in 
Patients With Chronic Heart Failure (REDUCEhf) trial. Congest Heart Fail. 2011; 17:248-
54. 
20. Abraham WT, Adamson PB, Bourge RC, Aaron MF, Costanzo MR, Stevenson LW, et al. 
Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a 
randomised controlled trial. Lancet. 2011; 377:658-66. 
21. van Veldhuisen DJ, Braunschweig F, Conraads V, Ford I, Cowie MR, Jondeau G, et al. 
Intrathoracic impedance monitoring, audible patient alerts, and outcome in patients with 
heart failure. Circulation. 2011; 124:1719-26. 
 
 
 
 

 
 
 
 
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APPENDIX I: PRELIMINARY PUBLICATION PLAN 
 
If findings from this study are to be published, the following plan will be handled according to 
Cardiac Rhythm Disease Management Standard Operating Procedures and as indicated in 
the Clinical Trial Agreement.  
 
Publication Committee 
 
Medtronic may form the INTERVENE-HF Publication Committee from study investigators.  
Medtronic personnel may serve as members of the committee.  This committee will manage 
study publications with the goal of publishing findings from the data. The Publication 
Committee will develop the final Publication Plan as a separate document.   
 
The Publication Committee’s role is to: 1) manage elements addressed in the publication 
plan as outlined in this appendix, 2) develop the final Publication Plan under separate cover, 
3) execute the Publication Plan, 4) oversee the publication of primary, secondary and 
ancillary study results, 5) review and prioritize publication proposals, 6) provide input on 
publication content, and 7) determine authorship.  In addition, the committee will apply and 
reinforce the authorship guidelines set forth in the Publication Plan.   
 
Membership in the Publication Committee does not guarantee authorship.  The committee 
will meet at as needed. 
 
Management of Primary, Secondary and Ancillary Publications 
 
The Publication Committee reviews, prioritizes, and manages all publications including 
primary, secondary and ancillary publications.  Primary and secondary publications are those 
that address analyses of any or all primary objectives or secondary objectives, respectively, 
as specified in the Clinical Investigation Plan.  
An ancillary publication is any publication that does not address the study objectives 
identified in the Clinical Investigation Plan.  They include publications proposed and 
developed by other Medtronic departments or entities, clinicians participating in this clinical 
study, and clinicians not participating in this clinical study.  The committee will work with 
Medtronic to ensure that requests do not present conflicts with other proposals, are not 
duplicative, and to determine which ancillary publication proposals, if any, will be supported.   
The committee may decide that no publications, including abstracts, will be published prior to 
the end of the study or with individual center data.  Requests for publications on study 
objectives utilizing subset data (e.g., regional) will be evaluated for scientific validity and the 
ability of Medtronic to provide resources.   
 
Criteria for Determining Authorship 
 
Publications will adhere to authorship criteria defined by the International Committee of 
Medical Journal Editors (ICMJE, Uniform requirements for manuscripts submitted to 
biomedical journals, www.icmje.org).  Individual authorship criteria defined by the target 
journal or conference will be followed when it differs from ICMJE criteria. 

 
 
 
 
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Authors, including Medtronic personnel, must at a minimum meet all of the conditions below: 
• 
Substantial contribution to conception and design, or acquisition of data, or 
analysis and interpretation of data 
• 
Drafting the article or revising it critically for important intellectual content 
• 
Final approval of the version to be published 
 
Decisions regarding authorship and contributor-ship will be made by the committee. The 
selected authors will be responsible for drafting the publication. All selected authors must 
fulfill the authorship conditions stated above to be listed as authors, and all contributors who 
fulfill the conditions must be listed as authors. 
All investigators not listed as co-authors will be acknowledged as the “Medtronic 
INTERVENE-HF Clinical Study Investigators” and will be individually listed according to the 
guidelines of the applicable scientific journal when possible and affiliation. Any other 
contributors will be acknowledged by name with their specific contribution indicated. 
 
Transparency 
 
Transparency of study results will be maintained by the following means: 
• 
a final report, describing the results of all objectives and analysis, will be 
distributed to all investigators, IRBs and Competent Authorities of 
participating countries when required by local law 
• 
registering and posting the study results on ClinicalTrials.gov based on the 
posting rules stipulated  
• 
submitting for publication the primary study results after the study ends  
• 
disclosing conflicts of interest (e.g., financial) of the co-authors of 
publications according to the policies set forth by the corresponding 
journals and conferences  
• 
making an individual centers study data accessible to the corresponding 
investigator after the completion of the study, if requested 
 
 

 
 
 
 
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APPENDIX J: ABBREVIATIONS 
 
 
AE  
 
 
Adverse Event 
ADE   
 
Adverse Device Effect 
AF 
 
 
Atrial Fibrillation 
BPM  
 
Beats Per Minute  
CEC  
 
Clinical Events Committee 
CIP   
 
Clinical Investigation Plan 
CRT   
 
Cardiac Resynchronization Therapy 
CRT-D  
 
Cardiac Resynchronization Therapy device with defibrillation capabilities 
CTA  
 
Clinical Trial Agreement 
CV  
 
 
Curriculum Vitae 
DMC  
 
Data Management Committee 
DTL   
 
Delegated Task Log 
eCRF  
 
Electronic Case Report Form 
eGFR  
 
Estimated Glomerular Filtration Rate  
EP  
 
 
Electrophysiology 
FDA   
 
Food and Drug Administration 
GEE  
 
Generalized Estimating Equation 
HCU  
 
Health Care Utilization  
HF 
 
 
Heart Failure 
HFH  
 
Heart Failure Hospitalization  
HFRS  
 
Heart Failure Risk Status  
HIPAA  
 
Health Insurance Portability and Accountability Act 
HRV  
 
Heart Rate Variability 
ID 
 
 
Integrated Diagnostics 
IDE 
 
 
Investigational Device Exemption 
INTERVENE  
Integrated Diagnostics Driven Diuretic and Chronic Medication Management 
IRB   
 
Institutional Review Board 
ISCC  
 
INTERVENE Study Communication Center 
NHR  
 
Night Heart Rate 
PA 
 
 
Pulmonary Artery  
PIC   
 
Patient Informed Consent 
PRN  
 
Pro re nata, used as abbreviation for the medication intervention 
S2D   
 
Save-to-Disk 
SAE   
 
Serious Adverse Event 
SADE  
 
Serious Adverse Device Effect 
SAV   
 
Sensed Atrioventricular 
SCD   
 
Sudden Cardiac Death 
SDN   
 
Software Distribution Network 
SOP   
 
Standard Operating Procedure 
UADE  
 
Unanticipated Adverse Device Effect 
US  
 
 
United States 
USADE  
 
Unanticipated Serious Adverse Device Effect 
VF 
 
 
Ventricular Fibrillation 
VT 
 
 
Ventricular Tachycardia 

 
 
 
 
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APPENDIX K: MODIFICATIONS TO THE CLINICAL 
INVESTIGATION PLAN 
 
This table will be used to summarize modifications made from current version 1.0 of the 
Clinical Investigation Protocol (CIP).  
Table 23: Change history 
 
Version Applicable Sections 
Change 
Rationale 
1.0 
Initial Document 
NA 
NA 
2.0 
Cover Page 
Added final IDE# 
IDE# was not assigned 
at the time of CIP 
approval. 
2.0 
Risk Analysis Section 11 
Added additional 
information regarding 
proposed care 
management plan vs. 
standard of care, risks 
associated with proposed 
care management, and 
battery life impact. 
FDA conditional 
approval requirement 
2.0 
Statistical Section 13 
Updated to include plan 
for a preliminary safety 
data analysis report. 
FDA conditional 
approval requirement 
 
3.0 
Exclusion Criteria Section 
5.2.2 & Bloodwork 
Eligibility Section 7.7.2  
Corrected units on 
hemoglobin levels from 
mg/dl to g/dl 
Clerical error 

 
 
 
 
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4.0 
Table 1, 3.2, Inclusion 
Criteria 5.2.1, Exclusion 
Criteria 5.2.2, 
Screening Visit 7.7, 13, 
Throughout  
 
 
• 
Table 1: updated trial 
lead name to Joe 
Hobbs  
• 
3.2: added 
recommended for 
daily transmissions  
• 5.2.1 Revised Subject 
inclusion criteria to clarify 
that patient needs >9 of 
CRT therapy and not 9 
months with current 
device, removed 
Medtronic only leads, 
added OptiVol crossing in 
the last nine months as 
an additional OR for 
inclusion, removed renal 
testing  
• 5.2.2 removed renal test 
from exclusion criteria  
• 
6.4.2: deleted word 
daily 
• 7.7 Screening visit 
removed test after 
passing OptiVol crossing  
• 
Changed language to 
only include patients 
that have passed 
screening in analysis 
• Throughout: removed 
the word Fax(ed)  
 
 
• 
Clerical  
• 
3.2 revised to 
clarify daily 
commander flex 
transmissions are 
not required but 
requested 
• Inclusion was revised 
to expand the patient 
pool, internal analysis 
showed subjects that 
have had an OptiVol 
crossing in the last 9 
months are likely to 
have another in the 
next year, streamlining 
testing to allow for 
standard of care for 
renal testing on file  
• Exclusion was revised 
to allow for streamlining 
when enrolling and 
adhere to sites 
standard of care  
• 
revised to clarify 
daily commander 
flex transmissions 
are not required but 
requested 
• 
removed word daily 
to clarify that 
transmissions are 
requested not 
required 
• Renal testing was 
expanded to allow for 
values on file with in six 
months to allow for 
smoother screening 
and follow sites 
standard of care  
• 
Clarified analysis to 
include only 
patients that 
passed screening 

 
 
 
 
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Version Applicable Sections 
Change 
Rationale 
• Fax(ed) was removed 
to allow for additional 
secure file transfer 
systems.  
 
5.0 
6.2.2 
Changed: make 
arrangements for 
schedule 
Allows for manual 
downloads when a 
follow up download 
cannot be scheduled 
on the correct day  
 
Figure 6 
Added: (when possible) Same as above 
 
Figure 7 
Added: (when possible) Same as above 
 
6.4.1.2 
Changed: a total of 8 
subsequent attempts up 
to 8 days; scheduled 
downloadCareLink 
transmission 
Same as above 
 
6.5.1 
Added: will be asked to 
provide  
To clarify that daily 
commander flex 
transmissions are not 
required but 
requested  
 
6.6 
Deleted: all of section 
6.6 
HCU information is 
collected within the 
AE eCRF and not in 
a standalone form 
 
7.4 (Table 12) 
Changed header to: 
scheduled call 
Same as above  
 
7.14 
HCU removed from exit 
section 
Same as above  

 
 
 
 
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Version Applicable Sections 
Change 
Rationale 
 
10.1 
Added: The initiation of 
an PRN by the ISCC 
nurse will not be 
considered an AE and 
CareLink connectivity 
related DD will not be 
collected on an eCRF 
Initiation of a PRN is 
collected on the 
ISCC notification 
form and does not 
need to be collected 
as an AE, CareLink 
connectivity issues 
are reported via 
complaint handling 
by our ISCC nurses 
and do not need to 
be collected on the 
device deficiency 
eCRF 
 
10.2.1 
Added: Added: An 
exception to this subset 
of collected events 
mentioned above, 
would be the protocol-
initiated PRN 
intervention, which will 
not be collected on the 
Adverse Event form 
(AE CRF).  When the 
protocol initiated PRN 
intervention occurs, it 
will be collected on the 
ISCC Notification form. 
Same as change in 
10.1 
 
10.2.2 
Added: Device related 
issues that involve the 
subject’s Carelink 
monitor will not be 
collected on the Device 
Deficiency form. 
Same as change in 
10.1 
 
Figure 8 
Adjusted recovery 
calculation window  
Adjusted days used 
in recovery 
calculation to reflect 
what is actually used