# Presentation: 004089

## Slide 1

## Cardima, Inc.’sRevelation Tx Microcatheter with NavAblatorTM RF Ablation System

- FDA Circulatory System Devices Panel Meeting
-  P020039
- May 29, 2003

## Overview of Presentation

- FDA Review Team
- History of FDA Interactions with Cardima
- Non-clinical Evaluation
- Clinical & Statistical Evaluation
- Conclusions
- Panel Questions

##  PMA Review Team

- Cindy Demian, MSBE, Lead Reviewer
- Lesley Ewing, MD, Clinical Review
- Heng Li, PhD, Statistical Review
- Nick Jensen, DVM, MS, Animal Review
- James Cheng, MSEE, Electrical Engineering Review
- Lisa Kennell, Sterilization Review
- Barbara Crowl, Bioresearch Monitoring Review

## Proposed Indications for Use

*"The Cardima**** Inc., REVELATION**** Tx Microcatheter with*
*NavAblator**TM** RF Ablation System is indicated for treatment of Atrial*
*Fibrillation in patients with drug refractory paroxysmal atrial*
*fibrillation by mapping, pacing, and ablating with a compatible*
*radiofrequency generator, creating a set of continuous linear *
*lesions along the lateral and septal walls and along the isthmus in *
*the right atrium.*
*The REVELATION**** Tx is intended for the creation of continuous *
*linear lesions for the purpose of interrupting arrhythmia pathways.*
*The NavAblator**TM** is intended for the creation of lesions at the *
*isthmus for the purpose of interrupting arrhythmia pathways when*
*the REVELATION**** Tx is not used to complete the isthmus region."*

## Proposed Indications for Use

*"The Cardima**** Inc, REVELATION**** Tx*
*Microcatheter Ablation System is indicated for*
*treatment of Atrial Fibrillation in patients*
*with drug refractory paroxysmal atrial fibrillation*
*by mapping, pacing, and ablating with a set of *
*continuous linear lesions in the right atrium.”*

##  Brief History of FDA Interactions with Cardima

***December 1997****	*
**	****Feasibility study approved**
**10 patients**
***July 1998***
**	****FDA Advisory Committee makes recommendations for atrial fibrillation clinical study designs**
- Single arm, patient serves as own control
- Reduction (75%) or cure as clinically significant endpoints

## History (cont’d)

***August 1998****	**	*
**	****First progress report (n=5)**
**Problems with creating isthmus line with Revelation Tx**
**Sponsor opted to design standard 4mm catheter ****(which was necessary to complete the procedure)**
**Agency informed Cardima that use of non-investigational device would be considered **
**	****a failure in terms of the clinical trial**
***December 1998***
**	****Progress report on next 5 patients (total n=10)**
- Still widespread (7/10) use of **non-investigational catheters**

## History (cont’d)

***May 2000***
**Approval to begin the pivotal trial, Phase III**
**Addition of**** NavAblator (4mm) Catheter**
- Sample Size (n=80) for Phase III
- Sample Size was based on confidence
- 	interval width*** ***
**FDA continues to state that use of non-investigational catheters were considered failures**

## History (cont’d)

***June 2000***
**Cardima states that feasibility patients will not be pooled with the pivotal patients**
***May 2001***
**	****Progress report on Phase IIb patients**
**FDA concerns for conduct of pivotal trial based on feasibility study results**
**Patient non-compliance with transtelephonic monitoring (TTM)**
**Varying definitions of acute success**

## System Components

*Catheters*
- RevelationTM Tx Micro Ablation Catheter (3.7 F)
- NavAblatorTM (4mm) Ablation Catheter (8F)
*Accessories*
- NaviportTM Guiding Catheter
- RevelationTM Tx Select Switch Box
- RevelationTM Tx Cables
***No Generator***
- RF Generator Compatibility

## Revelation Tx Microcatheter  

- 3.7 French single use catheter, steerable, non-deflectable with an atraumatic distal tip coil, flexible, non-electrically active tip
- 8 electrodes & 8 thermocouples temperatures sensors on distal end of the catheter
- Ablation electrodes - 6mm long 90%Pt/ 10% Ir tip
- RF is applied to each individual electrode to produce thin linear radiofrequency ablation lines
- Used with a deflectable guiding catheter (Naviport) to properly position the distal tip*  *

## NavAblatorTM Catheter 

- 8 French (4mm) Ablation catheter, single use, deflectable with an electrically active tip
- 4 electrodes, including one embedded in its tip just proximal to a thermocouple
- Intended to create spot lesions
- Used without a guiding catheter
- Control mechanism in handle that activates a pull wire to steer and deflect the tip

## NaviportTM Guiding Catheter

- Aids in the positioning of the RevelationTM Tx
- Sterile, single use only, dual lumen (a device lumen and closed pull wire lumen)
- Cleared through 510(k)
- Deflecting mechanism allows tip to be straightened while being inserted into & deflected while in the heart
- Friction-locking mechanism permits the distal tip to retain its deflected shape once the catheter is in position for ablation

## FDA Preclinical Review Goals

- Safety
- ensure that the device has been appropriately designed and tested, and that safety features have been qualified
- 	for use
- Reliability
-  – ensure that the device design and
- 		manufacture provides assurance of 	consistency with performance 	specifications

## CatheterPreclinical Qualification

- Biocompatibility of catheter materials
- Reliability of catheter design
- Mechanical testing of catheter performance
- Electrical testing of catheter performance
- Qualification of sterilization procedures

## Preclinical Testing Conclusions

- Preclinical testing performed by the sponsor is designed appropriately and met the pre-specified pass/fail criteria
- Testing shows that the device can be reliably manufactured to meet the product specifications

## Device Failures- Observed in Clinical Trial

- 	Electrical Failure
- 	Complaints-
- Thermocouples never registered temperature
- Electrodes did not ablate
- Noisy ECG Signals
- Electrode noise or
- 	Cross talk

| Coagulum | 5 |
| --- | --- |
| Delamination of THV coating on catheter shaft  | 7 |
| Electrical Failures* | 21 |

**Revelation Tx**

***[Customer Experience Reports]**** *

## Lesley Ewing, M.D.

- Lesley Ewing, M.D.

## Proposed Indications for Use

*       *The Cardima Inc, REVELATION Tx Microcatheter with NavAblatorTM RF Ablation System is indicated for treatment of Atrial Fibrillation in patients with drug refractory paroxysmal atrial fibrillation by mapping, pacing, and ablating with a compatible radiofrequency generator, creating a set of continuous linear lesions along the lateral and septal walls and
- 	along the isthmus in the right atrium.

## Proposed Indications for Use

- The REVELATION Tx is intended for the creation of continuous linear lesions for the purpose of interrupting arrhythmia pathways.
- The NavAblatorTM is intended for the creation of lesions at the isthmus for the purpose of interrupting arrhythmia pathways when the REVELATION Tx is not used to complete the isthmus region"

## Study Design 

- Single arm, non-randomized,
- 	multi-center study which began in 1997
- Three study phases
- 	PMA data from phases IIb & III

## Inclusion Criteria

- Symptomatic paroxysmal atrial fibrillation (PAF) refractory to at least two antiarrhythmic drugs (AAD) or one if amiodarone
- Three or more episodes during the
- 	30 day baseline period
- 21 to 80 years
- Normal sinus rhythm at eps or can be converted

## Exclusion Criteria

- Prior acute ablation failure within 2 months
- AMI within 6 weeks
- Contraindication or unable to comply with long-term anticoagulation
- Valvular disease, aneurysm or LVH with NYHA class III or IV
- Coagulopathy or bleeding diathesis
- CVA or TIA within 6 months
- Intra-cardiac thrombus
- Echocardiographic PFO or ASD
- LA dimension > 5cm

## Baseline Pre-Ablation Procedure

- 30 day baseline screening period with minimum of 3 episodes of PAF to be eligible for ablation
- Patients were aware than a minimum number of episodes were required
- Re-screening allowed
- Re-screening total time period was 90 days with a total of 9 episodes required

## Ablation Procedure

- Three linear lesions specified in protocol
- Posterolateral
- Posteroseptal
- Tricuspid Isthmus
- Anterior lesion optional
- All lesions to be attempted first with the REVELATION Tx and if tricuspid isthmus lesion was not successful then NavAblator catheter to be used

## Follow-up

- Assessments at 1, 3, 6, 12 & 24 months
- QOL questionnaires at 3 & 6 months
- Transtelephonic monitor (TTM) up
- 	to 6 months
- Weekly TTM “compulsory” during the 1st, 3rd, 6th month post ablation even without symptoms

## Primary Effectiveness Endpoint

- Reduction in frequency of symptomatic episodes during the 6th month post ablation procedure compared to the baseline period while on same medication/s or reduced dosage
- 50% less if at baseline 5 or greater episodes
- 75% less if at baseline 3 or 4 episodes
- Episodes to be documented by transtelephonic monitoring (TTM)

## Secondary Effectiveness Endpoint

- 	Improvement in the quality of life assessed by SF-36 and Atrial Fibrillation Severity Scale (AFSS) compared to baseline

## Procedural Success

- 	Demonstration of one of the following at the lines of ablation during sinus rhythm:
- Reduction in the amplitude, fragmentation or widening of local electrograms
- Split potentials
- Increase in pacing threshold
- _Requirement to measure deleted from phase III protocol_

## Safety Endpoint

- 	Incidence of complications-
- 	major complications in the first 7 days post ablation and adverse events in the
- 	24 months follow-up period

## Study Results

- 120 patients have had the linear ablation procedure, 116 with verified data
- 89/116 male (76.6%)
- Mean age of all patients 56.9  10.9 years
- 72.4% had other heart disease
- 8 patients with pre-existing pacemaker
- 33/116 had had a prior ablation

## Ablation Procedure

- Mean procedure time 250  123 minutes,
- 	range 100 to 755 minutes
- Mean fluoroscopy time 47  46 minutes,
- 	range 2 to 265 minutes

## Safety cohort

- n=120

- Verified data
**Safety cohort**
- N=116

- Unverified data
- N=4

- Ambiguous baseline episodes
- N=5

- Unambiguous baseline episodes
- N=111

**Effectiveness cohort**
- N=88

- Less than 6 months f/u
- n=21

- Lost to f/u
- N=2

## Study Results

**Safety cohort**** = 116 patients**
**Effectiveness cohort**** = 88 patients**

## AF Episodes at Baseline

|  | # of patients | % of total |
| --- | --- | --- |
| ≤5 | 41 | 38.7 |
| 6-10 | 38 | 35.9 |
| 11-15 | 11 | 10.4 |
| 16-20 | 7 | 6.6 |
| 21-25 | 2 | 1.9 |
| >26 | 7 | 6.6 |

**excluding 5 patients with disputed baseline numbers**

## % of All Transmissions that were Diagnosed to be Atrial Fibrillation

## Baseline AF Episodes

- Percent of symptomatic transmissions that were diagnosed to be AF ranged from 12.9% to 100%
- Unknown whether each transmission represents a discrete AF episode

## Ablation Procedure Performed

- Patients did not all have the same lesion set performed
- Revelation Tx catheter used for all septal and lateral linear lesions
- Some patients had only a non-investigational catheter used for the tricuspid isthmus lesion
- The non-investigational catheters used were from 5 different manufacturers and included a cooled tip catheter

## Ablation Lesions Performed

| Lesion lines | Number of patients  | % |
| --- | --- | --- |
| ABC (protocol) | 95 | 82.6 |
| AB | 7 | 6.1 |
| ACD | 6 | 5.2 |
| AC | 2 | 1.7 |
| ABCD | 3 | 2.56 |
| BC | 1 | 0.8 |
| BCD | 1 | 10.8 |
| Total | 115 | 100 |

**Ablation Lesions Performed**
**A=lateral, B=septal, C=isthmus, D=anterior**

## Devices used to create tricuspid isthmus lesion

| 
Catheters | Number of patients (%) |  |  |
| --- | --- | --- | --- |
|  | Phase IIb
n=33 | Phase III
n=75 | Total
N=108 |
| Revelation Tx only | 14 (42.4) | 7 (9.3) | 21 (19.4) |
| Revelation Tx, other | 7 (21.2) | 1 (1.3) | 8 (7.4) |
| Revelation Tx, NavAblator | n/a | 2 (2.7) | 2 (1.9) |
| NavAblator only | n/a | 47 (62.7) | 47 (43.5) |
| NavAblator, other | n/a | 10 (13.3) | 10 (9.3) |
| Other only | 12 (36.4) | 8 (10.7) | 20 (18.5) |

## NavAblator Use

- Per protocol to be used if REVELATION Tx unsuccessful at the tricuspid isthmus
- Used in 59/116 patients (51%)
- 57/59 was first catheter used at isthmus
- 10/59 a non-investigational catheter was also required
- Successful bidirectional conduction block at tricuspid isthmus in 42/59 (71%)
- Non-investigational catheters used alone at tricuspid isthmus 19/19 (100%) successful bidirectional conduction block

## Procedural Success

**“****Sufficient data to demonstrate either**
** ****success or failure for the procedural**
** ****endpoint are not available****”**
- 					*[page 48, Clinical Summary]*

## TTM in the 6th Month Post Procedure

- Data submitted on 83 patients
- 22 patients with no TTM
- 31 patients had 1-3 TTM
- 53/83 (63.9%) poor compliance with TTM in the 6th month

## Primary Effectiveness Endpoint

**Primary Effectiveness Endpoint**

***[From Figure 1***
***FDA clinical review]***

## Investigational Device System Success

## Patients thatFailed Primary Endpoint

- 8 had AV node ablation prior to the 6th month
- 5 had pacer prior to the 6th month
- 1 withdrew due to failure to improve
- 9 did not have sufficient episode reduction
- 21 did have episode reduction but with new AAD or increased dose (includes 2 patients with a pacemaker implantation)
- 2 had both increase in AAD and an insufficient reduction in episodes

## Patients with No AF Events in the 6th Month 

- 43/88 reported/transmitted no events in this month
- 2/43 have had an AV node ablation,
- 	one prior to the 6th month and one after
- 1/43 had a surgical MAZE after the 6th month
- 1/43 had an atrial defibrillator after the 6th month
- 7/43 had had amiodarone added prior
- 	to the 6th month

## AAD in the 6th Month

- Data on 82/88 available
- 14 patients on no AAD or no Class I or III 6/14 unchanged from baseline
- 26 patients had increase in AAD
- Amiodarone added in 6 & removed in 10

## AV Node Ablation & Surgical MAZE Post Ablation Procedure

- 10/88 patients had an AV node ablation procedure after the linear percutaneous ablation procedure
- 2/88 patients had a surgical MAZE procedure after the linear percutaneous ablation procedure

## Secondary Effectiveness Endpoint

- 	Improvement in the quality of life assessed by SF-36 and Atrial Fibrillation Severity Scale compared to baseline

## Clinically Significant Improvement Quality of Life Scores

| Measurement Scale  | Total(freq/n, (%)) |
| --- | --- |
| SF-36 |  |
| Physical Functioning | 29/76 (38.2) |
| Role Physical | 35/80 (43.8) |
| Role Emotional | 26/78 (33.3) |
| Bodily Pain | 37/81 (45.7) |
| General Health | 28/79 (35.4) |
| Vitality | 45/80 (56.3) |
| Social Functioning | 39/80 (48.8) |
| Mental Health | 23/80 (28.8) |
| AFSS |  |
| Episode Frequency | 42/68 (61.8) |
| Episode Duration | 27/66 (40.9) |
| Episode Severity | 45/75 (60.0) |
| AFSS Total  | 35/64 (54.7) |

**Clinically Significant Improvement Quality of Life Scores**

## Major Complications

| Patient ID |  |
| --- | --- |
| III 606 | Sinus node damage, pacing required  |
| III 514 | Tamponade requiring pericardial window |
| III 1702 | AV fistula requiring surgical repair |
| IIb 508 | Sinus node dysfunction requiring urgent temporary pacing and implant within 3 days of procedure |
| IIb | Embolic stroke in patient with protein C deficiency |

- Three other patients required a pacemaker within two weeks of the procedure:
-      two for bradycardia and one for an abnormal SNRT

## Safety

- 5/116 or 4.3% (1.7%, 9.4%) patients had one or more major complication
- Possible safety concern:
- 20 patients had pacemaker implanted
- 	1 day to 1.5 years after ablation,
- 	9 of these had AV node ablation also
- 7/88 (8%) had pacemakers implanted within 6 months of the ablation procedure without AV node ablation

## Heng Li, Ph.D.
Division of Biostatistics

- Heng Li, Ph.D.
- Division of Biostatistics

## Study Design

**Single arm, non-randomized, multi-**
**center, with subjects serving as their **
**own controls, i.e., with treatment effect **
**evaluated by comparing post**
**treatment measurements with the**
**corresponding pre-treatment**
**measurements**

## Investigational Protocol

**Absence of a proposed rule that**
**specifies what the study results have**
**to be in order for the investigational**
**device to be approved**

## General Pitfalls

- History
- Maturation
- Placebo Effect
- Selection

## Pitfall: Placebo Effect

**The secondary effectiveness endpoints**
**are subjective self evaluations and are**
**therefore particularly vulnerable to**
**Placebo effect.**

## Pitfall: Maturation

**The motivation to record AF episodes**
**and the ability to avoid multiple**
**recording of single episode may**
**change over time, affecting the**
**evaluation of the primary effectiveness**
**endpoint**

## Pitfall: Selection

**Patients with overall AF frequency**
**lower than 3 per 30 day period may be**
**selected, and those patients may**
**experience ‘regression to the mean’**

## A Unique Issue: Non-Investigational Devices

**Study procedures were performed**
**using non-investigational devices on a**
**number of study subjects who are not**
**randomly selected**

## A Unique Issue:  Non-Investigational Devices

**The patients who are treated only with**
**investigational devices do not form a**
**random subgroup of all the study**
**subjects **

## Clinical & Statistical Summation

- Lesley Ewing, M.D.

## The ablation procedure (lesions made and catheters used) was not the same for all patients in the study.
There were a variety of investigational and non-investigational catheters used for one of the lesions.

A small number (38/116 or 33%) of patients had the ablation procedure performed using the investigational device system as specified by the protocol.

Some patients did not have the lesion set performed as specified by the protocol.

**There were a variety of investigational and non-investigational catheters used for one of the lesions**.
**A small number (38/116 or 33%) of patients had the ablation procedure performed using the investigational device system as specified by the protocol**.
**Some patients did not have the lesion set performed as specified by the protocol**.

## As a result of the unblinded study design there could be bias toward reporting AF episodes at baseline and against reporting in the 6th month.

Acute procedural success can not be assessed for the procedures in the study due to incomplete reporting of the various acute procedural endpoints.

Some patients had further procedures to treat PAF after the linear ablation procedure.

- Acute procedural success can not be assessed for the procedures in the study due to incomplete reporting of the various acute procedural endpoints.
- Some patients had further procedures to treat PAF after the linear ablation procedure.

## 20 patients had a pacemaker implanted 1 day to 1.5 years post procedure.

There was poor compliance with “compulsory” TTM during the 6th month.

More than 50% of patients had clinically significant improvement in two AFSS domains.  The QOL results include data from patients with ambiguous number of baseline episodes and some patients who had an AV node ablation procedure.

- There was poor compliance with “compulsory” TTM during the 6th month.
- More than 50% of patients had clinically significant improvement in two AFSS domains.  The QOL results include data from patients with ambiguous number of baseline episodes and some patients who had an AV node ablation procedure.

## Conclusion

**From the clinical and statistical**
**perspective****, it is not clear if the data can**
**support any conclusion about the safety**
**and effectiveness of the investigational**
**device system.**

## Slide 69

## Baseline TTM

- Detailed information submitted on 89 patients
- 62/89 transmitted multiple times per day on at least one day of the 30 days
- 5 patients with AF transmission twice within 5 minutes
- 7 patients with AF transmission at least twice within 30 minutes
- 26 patients with AF transmission twice between one and three hours