BIOSync CLS: Benefit of Dual-chamber Pacing With Closed Loop Stimulation (CLS) in Tilt-induced Cardioinhibitory Reflex Syncope

• Sponsor: Biotronik SE & Co. KG (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02324920
• Collaborator: (none)
• Enrollment: 128
• Locations: 24
• Arms: 2
• Actual Duration (Months): 57
• Patients Per Site: 5.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to assess whether the Closed Loop Stimulation (CLS) in addition to the DDD pacing is effective in reducing syncopal recurrences. The study hypothesis is that DDD pacing with CLS stimulation is able to prevent syncopal recurrences completely or partially by transforming syncope in pre-syncope.

Condition or Disease	Intervention/Treatment	Phase
Syncope	Device: DDD-CLS; Device: ODO	N/A

Study Design

• Study Type: Interventional
• Actual Enrollment: 128 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Benefit of Dual-chamber Pacing With Closed Loop Stimulation (CLS) in Tilt-induced Cardioinhibitory Reflex Syncope. A Randomized Double-blind Parallel Trial.
• Actual Study Start Date: Oct 1, 2015
• Actual Primary Completion Date: Apr 1, 2020
• Actual Study Completion Date: Jul 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: DDD+CLS The pacemaker will be programmed in a dual-chamber DDD pacing mode with the Closed Loop Stimulation (CLS) function ON.	Device: DDD-CLS
Placebo Comparator: ODO The pacemaker will be programmed in ODO mode.	Device: ODO

Outcome Measures

Primary Outcome Measures

1. Patients With Recurrence of Syncopal Episode [24 months]

Secondary Outcome Measures

1. Patients With Recurrence of Pre-syncope or Syncope [24 months]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Patients affected by clinical diagnosis of reflex syncope who meet all the following criteria:

• age >=40 years

• significant limitation of social and working life due to unpredictable or frequent syncope recurrences, ≥2 within the last year.

• type 2B cardio-inhibitory response to TT (according to the VASIS classification).

• Alternative therapies have failed or were not feasible.

• exclusion of other possible competitive causes of syncope.

Exclusion Criteria:

• Any other indication to IPG, implantable defibrillator (ICD), cardiac resynchronization therapy (CRT), according to current guidelines

Any cardiac dysfunctions possibly leading to loss of consciousness:

• overt heart failure;

• ejection fraction (LVEF) <40% (Echo-assessed within 3-month prior to study participation);

• myocardial infarction;

• diagnosis of hypertrophic or dilated cardiomyopathy;

• clinically significant valvular disease;

• sinus bradycardia <50 bpm or sinoatrial block;

• Mobitz I second-degree atrioventricular block;

• Mobitz II second or third-degree atrioventricular block;

• bundle-branch block;

• rapid paroxysmal supraventricular tachycardia or ventricular tachycardia;

• preexcited QRS complexes;

• prolonged QT interval;

• Brugada syndrome;

• arrhythmogenic right ventricular cardiomyopathy

• Symptomatic orthostatic hypotension diagnosed by standing BP measurement;

• Nonsyncopal loss of consciousness (eg, epilepsy, psychiatric, metabolic, drop-attack, cerebral transient ischemic attack, intoxication, cataplexy).

• Symptomatic cardioinhibitory carotid sinus hypersensitivity.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	CHUS Sherbrooke	Sherbrooke		Canada
2	Pais d'Aix	Aix-en-Provence		France
3	Hopital de la Timone	Marseille		France
4	Clinique Pasteur	Toulouse		France
5	Azienda Ospedaliera Pia Fondazione di Culto e Religione Cardinale G. Panico	Tricase	BA	Italy
6	Policlinico Consorziale	Bari		Italy
7	Ospedale Centrale di Bolzano	Bolzano		Italy
8	A.O. Pugliese-Ciaccio	Catanzaro		Italy
9	Ospedale San Martino	Genova		Italy
10	Azienda Ospedaliera Niguarda Ca' Granda	Milano		Italy
11	A.O. Dei Colli - Monaldi - University of Campania "Luigi Vanvitelli"	Napoli		Italy
12	Azienda Ospedaliera Universitaria Federico II	Napoli		Italy
13	A.O.U. San Luigi Gonzaga	Orbassano		Italy
14	AO di Parma	Parma		Italy
15	Arcispedale Santa Maria Nuova	Reggio Emilia		Italy
16	Policlinico Casilino	Roma		Italy
17	AMC Academic Medical Center	Amsterdam		Netherlands
18	Rijnstate Ziekenjuis	Arnhem		Netherlands
19	Zuyderland Medisch Centrum	Heerlen		Netherlands
20	Santa Marta	Lisboa		Portugal
21	Hospital De Bellvitge	Barcelona		Spain
22	Hospital Universitario Vall d'Hebròn	Barcelona		Spain
23	Hospital Universitario Nuestra Senora de la Candelaria	Santa Cruz		Spain
24	Hospital Virgen del Rocio	Sevilla		Spain

Sponsors and Collaborators

• Biotronik SE & Co. KG

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Jun 20, 2016
• Statistical Analysis Plan - Feb 19, 2019

More Information

Publications

None provided.

• Responsible Party: Biotronik SE & Co. KG
• ClinicalTrials.gov Identifier: NCT02324920
• Other Study ID Numbers: BA103
• First Posted: Dec 24, 2014
• Last Update Posted: Nov 17, 2021
• Last Verified: Jul 1, 2020

• Keywords provided by Biotronik SE & Co. KG: Syncope; Closed Loop Stimulation; CLS
• Additional relevant MeSH terms: Syncope; Syncope, Vasovagal

Study Results

Participant Flow

Arm/Group Title	Active Pacing (DDD+CLS)	Inactive Pacing (ODO)
Arm/Group Description	The pacemaker will be programmed in a dual-chamber DDD pacing mode with the Closed Loop Stimulation (CLS) function ON. DDD-CLS	The pacemaker will be programmed in ODO mode. ODO
Period Title: Overall Study
STARTED	64	64
COMPLETED	63	64
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Active Pacing (DDD+CLS)	Inactive Pacing (ODO)	Total
Arm/Group Description	The pacemaker will be programmed in a dual-chamber DDD pacing mode with the Closed Loop Stimulation (CLS) function ON. DDD-CLS	The pacemaker will be programmed in ODO mode. ODO	Total of all reporting groups
Overall Participants	63	64	127
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	63	63	63
Sex: Female, Male (Count of Participants)
Female	18 28.6%	27 42.2%	45 35.4%
Male	45 71.4%	37 57.8%	82 64.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	63 100%	64 100%	127 100%

Outcome Measures

1. Primary Outcome

Title	Patients With Recurrence of Syncopal Episode
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Active Pacing (DDD+CLS)	Inactive Pacing (ODO)
Arm/Group Description	The pacemaker will be programmed in a dual-chamber DDD pacing mode with the Closed Loop Stimulation (CLS) function ON. DDD-CLS	The pacemaker will be programmed in ODO mode. ODO
Measure Participants	63	64
Count of Participants [Participants]	10 15.9%	34 53.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Pacing (DDD+CLS), Inactive Pacing (ODO)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.22
	Confidence Interval	(2-Sided) 95%; 0.11 to 0.46
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Additional models were implemented to control for country and investigational sites effect on primary endpoint.

2. Secondary Outcome

Title	Patients With Recurrence of Pre-syncope or Syncope
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Active Pacing (DDD+CLS)	Inactive Pacing (ODO)
Arm/Group Description	The pacemaker will be programmed in a dual-chamber DDD pacing mode with the Closed Loop Stimulation (CLS) function ON. DDD-CLS	The pacemaker will be programmed in ODO mode. ODO
Measure Participants	63	64
Count of Participants [Participants]	24 38.1%	40 62.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Pacing (DDD+CLS), Inactive Pacing (ODO)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.45
	Confidence Interval	(2-Sided) 95%; 0.27 to 0.75
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	median follow-up period of 14.1 months
Arm/Group Title	Active Pacing (DDD+CLS)		Inactive Pacing (ODO)
Arm/Group Description	The pacemaker will be programmed in a dual-chamber DDD pacing mode with the Closed Loop Stimulation (CLS) function ON. DDD-CLS		The pacemaker will be programmed in ODO mode. ODO
All Cause Mortality
	Active Pacing (DDD+CLS)		Inactive Pacing (ODO)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/64 (0%)		0/64 (0%)
Serious Adverse Events
	Active Pacing (DDD+CLS)		Inactive Pacing (ODO)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/64 (6.3%)		4/64 (6.3%)
Cardiac disorders
NSTEMI	0/64 (0%)	0	1/64 (1.6%)	1
atrial fibrillation	1/64 (1.6%)	1	0/64 (0%)	0
pericarditis	1/64 (1.6%)	1	0/64 (0%)	0
lead dislodgement	1/64 (1.6%)	1	0/64 (0%)	0
lead was not properly connected to the pacemaker	0/64 (0%)	0	1/64 (1.6%)	1
Musculoskeletal and connective tissue disorders
Subtalar arthrodesis	0/64 (0%)	0	1/64 (1.6%)	1
inguinal hernia	1/64 (1.6%)	1	0/64 (0%)	0
Nervous system disorders
syncope	0/64 (0%)	0	1/64 (1.6%)	1
Other (Not Including Serious) Adverse Events
	Active Pacing (DDD+CLS)		Inactive Pacing (ODO)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/64 (31.3%)		39/64 (60.9%)
Cardiac disorders
presyncope	5/64 (7.8%)	5	2/64 (3.1%)	2
palpitations	1/64 (1.6%)	1	0/64 (0%)	0
inappropriate pacing due to undersensing	1/64 (1.6%)	1	0/64 (0%)	0
chest pain	1/64 (1.6%)	1	1/64 (1.6%)	1
Nervous system disorders
syncope	10/64 (15.6%)	10	33/64 (51.6%)	33
Renal and urinary disorders
incontinence	1/64 (1.6%)	1	0/64 (0%)	0
Respiratory, thoracic and mediastinal disorders
fatigue (mild obstructive sleep apnea syndrome)	0/64 (0%)	0	1/64 (1.6%)	1
Skin and subcutaneous tissue disorders
Keloid formation	0/64 (0%)	0	1/64 (1.6%)	1
mild pocket bleeding	0/64 (0%)	0	1/64 (1.6%)	1
unspecified pain around the chest/ pocket.	1/64 (1.6%)	1	0/64 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.