SyncopePhase 4NCT00359203
ISSUE3: International Study on Syncope of Uncertain Etiology 3
A Phase 4 study testing Dual chamber pacemeker in people with Syncope, run by Medtronic Cardiac Rhythm and Heart Failure at 1 site in Italy.
Trial summary
ISSUE 3 is a multi-center, prospective, randomised controlled double-blind study aimed to assess the effectiveness of pacemaker therapy for prevention of asystolic neurally-mediated syncope. Read more about this study
- Who is it for?
- Ages 40 years and older
- Conditions the study is for
- Syncope
- What is being tested?
- Dual chamber pacemeker
- Type of treatment
- Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 511 participants
- Where
- 1 siteItaly
- Study dates
- Sep 2006to Nov 2012
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 40 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Suspected or certain neurally-mediated syncope, based on the Guidelines recently published by the Task Force on Syncope of the European Society of Cardiology 2,3 (Appendix 1);
- More than 3 syncope episodes in the last 2 years;
- Clinical presentation of syncope of sufficient severity requiring treatment initiation in the physician's and patient's judgement.
- Age > 40 years.
- Negative carotid sinus massage.
- Patients accept to have an ILR implantation.
Who cannot join
- Carotid sinus hypersensitivity
- Suspected or certain heart disease and high likelihood of cardiac syncope:
- Symptomatic orthostatic hypotension diagnosed by standing blood pressure measurement;
- Loss of consciousness different from syncope (e.g. epilepsy, psychiatric, metabolic, drop-attack, TIA, intoxication, cataplexy);
- Subclavian steal syndrome;
- Psychologically or physically (due to any other illness) or cognitively unfit for participation in the study according to the opinion of the investigator;
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- Patient compliance doubtful;
- Patient geographically or otherwise inaccessible for follow-up;
- Patient unwilling or unable to give informed consent;
- Life expectancy <1 year.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: ISSUE3: International Study on Syncope of Uncertain Etiology 3 Pacemaker Therapy for Patients With Asystolic Neurally-mediated Syncope
ISSUE 3 is a multi-center, prospective, randomised controlled double-blind study aimed to assess the effectiveness of pacemaker therapy for prevention of asystolic neurally-mediated syncope.
Read the detailed description
In asystolic neurally-mediated syncope (NMS) documented by Implantable Loop recorder (ILR), ISSUE-2, an observational trial, showed that pacemaker was effective in reducing the 1-year first syncope recurrence rate from 33% rate before implant (ILR phase 1) to 5% rate after implant (phase 2). Moreover, the control non-asystolic group still continued to have a 41% recurrence rate after the first recurrence of syncope, thus supporting the conclusion that the reduction with pacemaker was due to the beneficial effect of pacemaker itself and not to other factors. However a formal controlled trial is needed to confirm these findings.
- Conditions
- Syncope
- Being tested
- Dual chamber pacemeker
- Keywords
- syncope, implantable loop recorder
- Medical subject headings
- Syncope
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Dual chamber pacemekerDevice
Also called Any model of Medtronic pacemakers with Rate Drop Respons algorhythm:, K700, K900, Enpulse, Advisa, Versa
| Study group | Role | What they receive |
|---|---|---|
| Dual chamber pacemaker | Placebo comparator | Dual chamber pacemaker programmed ODO (switched OFF) Receives: Device: Dual chamber pacemeker |
| Dual chamber pacemeker | Active comparator | Medtronic dual chamber pacemaker programmed ON and with Rate Drope Response programmed ON Receives: Device: Dual chamber pacemeker |
What is being measured
The primary outcome is the main question the study is designed to answer.
Syncope Recurrence Rate
Intention to treat analysis of percentage of patients with syncope recurrence at 2 years follow-up after study arm assignement
Measured: 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Aug 2006 (estimated)
- Study startSep 2006
- Primary completionSep 2011
- Study completionNov 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for SyncopeStudies of the same condition, open and under way.
- More trials run by Medtronic Cardiac Rhythm and Heart FailureThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 511 participants (actual)
Sponsor and investigators
- Lead sponsor
- Medtronic Cardiac Rhythm and Heart Failure
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Michele Brignole, MD, Principal investigator, Ospedali del Tigullio, Lavagna
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00359203
- Sponsor's protocol ID
- ISS3
- Status last verified
- Sep 2015
- First submitted
- 31 Jul 2006
- Last updated
- 18 Jul 2025
- Results posted
- Yes, on ClinicalTrials.gov
Publications
Brignole M, Menozzi C, Moya A, Andresen D, Blanc JJ, Krahn AD, Wieling W, Beiras X, Deharo JC, Russo V, Tomaino M, Sutton R; International Study on Syncope of Uncertain Etiology 3 (ISSUE-3) Investigators. Pacemaker therapy in patients with neurally mediated syncope and documented asystole: Third International Study on Syncope of Uncertain Etiology (ISSUE-3): a randomized trial. Circulation. 2012 May 29;125(21):2566-71. doi: 10.1161/CIRCULATIONAHA.111.082313. Epub 2012 May 7.
PubMed 22565936
Study at a glance
From the registry record, last updated by the sponsor on 18 Jul 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- ISSUE3: International Study on Syncope of Uncertain Etiology 3 Pacemaker Therapy for Patients With Asystolic Neurally-mediated Syncope
- ClinicalTrials.gov ID
- NCT00359203
- Acronym / sponsor ID
- ISS3
- Conditions
- Syncope
- Keywords
- syncope, implantable loop recorder
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 511 participants (actual)
- Lead sponsor
- Medtronic Cardiac Rhythm and Heart FailureIndustry (pharma, biotech, devices)
- Study start
- Sep 2006
- Primary completion
- Sep 2011 (actual)
- Study completion
- Nov 2012 (actual)
- First posted
- 1 Aug 2006 (estimated)
- Results
- Posted 18 Nov 2013
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
ISSUE 3 is a multi-center, prospective, randomised controlled double-blind study aimed to assess the effectiveness of pacemaker therapy for prevention of asystolic neurally-mediated syncope.
Detailed description
In asystolic neurally-mediated syncope (NMS) documented by Implantable Loop recorder (ILR), ISSUE-2, an observational trial, showed that pacemaker was effective in reducing the 1-year first syncope recurrence rate from 33% rate before implant (ILR phase 1) to 5% rate after implant (phase 2). Moreover, the control non-asystolic group still continued to have a 41% recurrence rate after the first recurrence of syncope, thus supporting the conclusion that the reduction with pacemaker was due to the beneficial effect of pacemaker itself and not to other factors. However a formal controlled trial is needed to confirm these findings.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Dual chamber pacemaker | Placebo comparator | Device: Dual chamber pacemekerDual chamber pacemaker programmed ODO (switched OFF) |
| Dual chamber pacemeker | Active comparator | Device: Dual chamber pacemekerMedtronic dual chamber pacemaker programmed ON and with Rate Drope Response programmed ON |
Who may qualify
- Ages
- 40 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Suspected or certain neurally-mediated syncope, based on the Guidelines recently published by the Task Force on Syncope of the European Society of Cardiology 2,3 (Appendix 1);
- More than 3 syncope episodes in the last 2 years;
- Clinical presentation of syncope of sufficient severity requiring treatment initiation in the physician's and patient's judgement.
- Age > 40 years.
- Negative carotid sinus massage.
Key exclusion criteria (10 listed)
- Carotid sinus hypersensitivity
- Suspected or certain heart disease and high likelihood of cardiac syncope:
- Symptomatic orthostatic hypotension diagnosed by standing blood pressure measurement;
- Loss of consciousness different from syncope (e.g. epilepsy, psychiatric, metabolic, drop-attack, TIA, intoxication, cataplexy);
- Subclavian steal syndrome;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Dual chamber pacemekerAlso: Any model of Medtronic pacemakers with Rate Drop Respons algorhythm:, K700, K900, Enpulse, Advisa, Versa | Device | Dual chamber pacemaker, Dual chamber pacemeker |
Primary outcome
Syncope Recurrence Rate
Time frame: 2 years
Intention to treat analysis of percentage of patients with syncope recurrence at 2 years follow-up after study arm assignement
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Jul 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 22565936Brignole M, Menozzi C, Moya A, Andresen D, Blanc JJ, Krahn AD, Wieling W, Beiras X, Deharo JC, Russo V, Tomaino M, Sutton R; International Study on Syncope of Uncertain Etiology 3 (ISSUE-3) Investigators. Pacemaker therapy in patients with neurally mediated syncope and documented asystole: Third International Study on Syncope of Uncertain Etiology (ISSUE-3): a randomized trial. Circulation. 2012 May 29;125(21):2566-71. doi: 10.1161/CIRCULATIONAHA.111.082313. Epub 2012 May 7.
- ISSUE3 main results publication PubMedLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Michele Brignole, MD principal investigator
Ospedali del Tigullio, Lavagna
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Dual chamber pacemeker in people with Syncope, run by Medtronic Cardiac Rhythm and Heart Failure at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 18 Jul 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 18 Nov 2013). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Syncope Recurrence Rate (time frame: 2 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00359203, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Jul 2025.