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AnesthesiaPhase 4ISEPNCT02489097

International Substudy Enigma2 on Postoperative Cognitive Disorders

A Phase 4 study testing Nitrous Oxide in people with Anesthesia and Delirium, Dementia, Amnestic, Cognitive Disorders, run by University Hospital, Geneva at 2 sites in 2 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

The study is a substudy of the Enigma2 trial (NCT00430989) which aims at investigating the effectiveness and safety of nitrous oxide (N2O) in anaesthesia.The substudy focus is on postoperative cognitive disorders. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Nitrous Oxide
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
140 participants
Where
2 sitesin 2 countries
Study dates
Sep 2013to May 2016
Phase
Phase 4
Are there results?
None posted in the registry

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 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Adult males and females aged ≥ 45 years, undergoing noncardiac surgery and general anaesthesia that exceeds two hours.
  • At increased risk of cardiac events, defined as any of:
  • history of coronary artery disease (angina, MI, Coronary revascularisation-Coronary Artery Bypass Graft (CABG) and Percutaneous Transluminal Coronary Angiography ( PTCA)-, positive stress testing, angiography/other imaging, Q waves on ECG)
  • heart failure
  • cerebrovascular disease due to atherothrombotic disease
  • aortic or peripheral vascular disease
  • OR
  • three or more of the following risk factors: age ≥70 years, history of heart failure, diabetes (medicated), hypertension (medicated), preoperative serum creatinine >175 mmol/L, cholesterol ≥6.2 mmol/L, history of a transient ischemic attack (TIA),

Who cannot join

  • Dementia (MMS test≤24)
  • Parkinson Disease
  • Patients taking regularly (>2 weeks) tricyclic antidepressants or neuroleptics
  • Patients suffering from Alcohol Dependency (WHO CRITERIA )
  • Patients suffering from severe hypoacusis or visual loss or any other reason hindering the CANTAB battery testing process
  • Patients with untreated deficit in Vitamin B6, B12 and folic acid
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  • Patients with marked impairment of gas-exchange requiring Fi02> 0.5 intraoperatively
  • Patients with specific circumstances where N2O is contraindicated (eg. volvulus, pulmonary hypertension, raised intracranial pressure) or the use of supplemental oxygen is planned (eg. colorectal surgery)
  • N2O unavailable

Trial locations and contacts

2 sites in 2 countries.

2 sites in 2 countries

China1 site

  • The Chinese University of Hong Kong Prince of Wales Hospital

    Hong Kong, Hong Kong

Other trials in China

Switzerland1 site

  • Geneva University Hospitals

    Geneva, 1203

Other trials in Switzerland

About this study

Official title: Evaluating the Incidence and Association Between Nitrous Oxide and Postoperative Cognitive Disorders in Anaesthesia

The study is a substudy of the Enigma2 trial (NCT00430989) which aims at investigating the effectiveness and safety of nitrous oxide (N2O) in anaesthesia.The substudy focus is on postoperative cognitive disorders.

Substudy Hypothesis: In patients undergoing anaesthesia for major surgery, administration of N2O will reduce postoperative cognitive disorders when compared with otherwise identically managed surgical patients not receiving N2O as a component of their anaesthesia.

Read the detailed description

Numerous studies questioned the routine use of nitrous oxide (N2O), the oldest anaesthetic agent used since the development of anaesthesia care. Despite its wide use, there is sufficient doubt as to the risk-benefit profile.

There is strong evidence that N2O is a major risk factor for postoperative nausea and vomiting. It is clear that (even) brief exposure to N2O impairs methionine synthetase, an enzyme required for DNA production, red and white blood cell formation. Tissue hypoxia may be more common. These adverse effects are enhanced in "sick" patients (ie. those at highest risk, with increased hospital length of stay and healthcare expenditure), and will be more likely in longer surgery. At the same time, observational studies and subgroup analysis of published trials suggest that N2O may have beneficial effects in preventing pain and postoperative cognitive disorders

Outcome trial data on postoperative cognitive disorders are lacking in this area for an anaesthetic gas used in more than 90% of all surgery around the world. The enigma2 substudy as a nested study of the large Enigma2 randomised controlled trial aims at answering this question.

The investigators aim at recruiting 420 patients in 2 of the 25 centres participating to the Enigma 2 trials, who are undergoing major surgery.

Being tested
Nitrous Oxide, Placebo
Medical subject headings
Neurocognitive Disorders

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Nitrous OxideDrug

    Also called N2O

    Administration of a concentration of 70% Nitrous Oxide with 30% Oxygen in the anaesthetic gas mixture

  • PlaceboOther

    Also called Air/Oxygen

    Administration of a concentration of 70% Air with 30% Oxygen in the anaesthetic gas mixture

Study groups in NCT02489097
Study groupRoleWhat they receive
Nitrous OxideActive comparatorReceives a mixture of 70% Nitrous Oxide in 30% Oxygen
Receives: Drug: Nitrous Oxide
Air/Oxygen (placebo)Placebo comparatorReceives a mixture of 70% Air in 30% Oxygen
Receives: Other: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Memory, Executive function, Attention and psychomotor speed testing battery

    Validated Computerized testing battery developed by the University of Cambridge for cognitive testing (CANTAB). Patients are tested for baseline cognitive function before surgery

    Measured: Baseline before surgery

  2. Memory, Executive function, Attention and psychomotor speed using CANTAB Cognitive testing battery at 7days following surgery

    Validated Computerized testing battery developed by the University of Cambridge for cognitive testing (CANTAB). Patients are tested for changes from the baseline cognitive function (before surgery) at 7 days after surgery

    Measured: First assessment (7 days)

  3. Memory, Executive function, Attention and psychomotor speed using CANTAB Cognitive testing battery at 3 months following surgery

    Validated Computerized testing battery developed by the University of Cambridge for cognitive testing (CANTAB). Patients are tested for changes from the baseline cognitive function (before surgery) at 3 months after surgery

    Measured: Second assessment (3 months)

Secondary outcomes (3)

  1. ICU stay

    Planned and unplanned admission to the ICU and ICU duration of stay; Follow up to be performed for the whole duration of hospital stay and up to a maximum of 3 months

    Measured: up to a maximum of 3 months

  2. Hospital stay

    Duration of stay in Hospital; Follow up to be performed for the whole duration of hospital stay and up to a maximum of 3 months

    Measured: up to a maximum of 3 months

  3. Quality of life

    Use of the validated EuroQol test (EQ-5D questionnaire http://www.euroqol.org/)

    Measured: 3 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted2 Jul 2015 (estimated)
  2. Study startSep 2013
  3. Primary completionMay 2016
  4. Study completionMay 2016

Why it stopped: Interim analysis results showed futility

Resources

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
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Triple blind
Who is masked
Participant, Investigator, Outcomes assessor
Enrolment
140 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02489097
Sponsor's protocol ID
NAC 08-021
Other IDs
Enigma II nested NCT00430989
Acronym
ISEP
Status last verified
Dec 2020
First submitted
26 Jun 2015
Last updated
16 Dec 2020
Results posted
No
Data monitoring committee
Yes

Publications

  • Chan MTV, Wan ACM, Gin T, Leslie K, Myles PS. Chronic postsurgical pain after nitrous oxide anesthesia. Pain. 2011 Nov;152(11):2514-2520. doi: 10.1016/j.pain.2011.07.015. Epub 2011 Sep 1.

    PubMed 21889262

  • Sanders RD, Weimann J, Maze M. Biologic effects of nitrous oxide: a mechanistic and toxicologic review. Anesthesiology. 2008 Oct;109(4):707-22. doi: 10.1097/ALN.0b013e3181870a17.

    PubMed 18813051

  • Myles PS, Leslie K, Chan MT, Forbes A, Paech MJ, Peyton P, Silbert BS, Pascoe E; ENIGMA Trial Group. Avoidance of nitrous oxide for patients undergoing major surgery: a randomized controlled trial. Anesthesiology. 2007 Aug;107(2):221-31. doi: 10.1097/01.anes.0000270723.30772.da.

    PubMed 17667565

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Nitrous Oxide in people with Anesthesia and Delirium, Dementia, Amnestic, Cognitive Disorders, run by University Hospital, Geneva at 2 sites in 2 countries.

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 8 inclusion and 9 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: stopped early, as of the sponsor's last update on 16 Dec 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in China, Switzerland. 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?

The study was stopped early (reason given: Interim analysis results showed futility). Results are not available in the source record.

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?

Memory, Executive function, Attention and psychomotor speed testing battery (time frame: Baseline before surgery). The study lists 3 primary outcomes in all. 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 NCT02489097, which also lists 3 linked publications.

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 16 Dec 2020.

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