Ischemic StrokePhase 3COTTIS-2NCT06301412
Combination of Hypothermia and Thrombectomy in Acute Stroke
A Phase 3 study testing hypothermia in people with Ischemic Stroke and Large Vessel Occlusion, run by University of Freiburg at 1 site in Germany.
Trial summary
The goal of this clinical trial is to test the combination of hypothermia and endovascular treatment in acute stroke patients with large vessel occlusion. The main question it aims to answer is: does an additional cooling to 35°C result in a benefit on clinical outcome ? Participants receive immediate cooling using a… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Ischemic Stroke, Large Vessel Occlusion, Endovascular Treatment
- What is being tested?
- hypothermia
- Type of treatment
- Medical device
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 400 participants
- Where
- 1 siteGermany
- Study dates
- 7 Jul 2024to 18 Jun 2026
- Phase
- Phase 3
- Are there results?
- Not yet: the study is under way
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
- Pre-stroke modified Rankin Scale (mRS) 0-2 [7-point scale rating from 0 (no symptoms) to 6 (dead)]
- Acute ischemic stroke with NIHSS >5
- Intracranial occlusion of the M1 or M2 segment of the middle cerebral artery (MCA) or internal carotid artery (ICA) or tandem occlusion on CT-angiography or MR-angiography with indication for endovascular treatment:
- Time window 0-24h:
- Last seen normal to groin puncture < 6h: native CT or MRI-DWI with ASPECTS >5
- Last seen normal to groin puncture 6-24h or unknown time window: significant mismatch imaging according to the eligibility criteria of the DEFUSE-3 trial
Show all 10Show fewer
- Infarct core <70ml (DWI oder CBF<30%)
- Penumbra > 15ml (Tmax >6sec)
- Ratio penumbra/core >1.8
- with or without iv thrombolysis with rtPA
Who cannot join
- Patients with an intranasal obstruction that prevents complete insertion of the nasal cannula should not be treated with the RhinoChill system.
- Known severe hemorrhagic diathesis (International Normalized Ratio (INR) >3.0, partial thromboplastin time (PTT) > 70s, platelet count < 50.000/μl)
- Brain trauma or neurovascular surgery/intervention <3 months
- Severe infection
- Pregnant women or women of childbearing potential (women of childbearing potential with negative pregnancy test may be included)
- Known cerebral vasculitis
- Proof of bleeding in cerebral CT or MRI (cerebral microbleeds in MRI [hypertensive or in the context of cerebral amyloid angiopathy] is permitted).
- Known life expectancy < 6 months
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Germany1 site, 1 recruiting
- Recruiting
University of Freiburg, Department of Neurology
Freiburg im Breisgau, 79106
Juergen Bardutzky, Prof., 015237729739, juergen.bardutzky@uniklinik-freiburg.de
About this study
Official title: Combination of Targeted Temperature Management and Thrombectomy After Acute Ischemic Stroke (COTTIS-2) - a Randomised Controlled Study
The goal of this clinical trial is to test the combination of hypothermia and endovascular treatment in acute stroke patients with large vessel occlusion.
The main question it aims to answer is: does an additional cooling to 35°C result in a benefit on clinical outcome ? Participants receive immediate cooling using a noninvasive transnasal cooling technique (RhonoChill) and are maintained at 35°C for 6 hours after reopening of the vessel using surface cooling, and then slowly rewarmed.
Researchers will compare the intervention group (hypothermia and endovascular treatment and best medical treatment including iv thrombolysis) and control group (only endovascular treatment and best medical treatment including iv thrombolysis) to see if additional hypothermia leads to a better outcome after 3 months without relevant complications.
Read the detailed description
Despite the well-established benefit of endovascular treatment (EVT) for acute ischemic stroke due to large vessel occlusion (LVO), more than half of patients treated with EVT remain functionally dependent despite high reperfusion rates. Thus, new strategies such as additional neuroprotection using hypothermia need to be explored, first to bridge time to reperfusion and second, to attenuate reperfusion injury.
Although therapeutic hypothermia has consistently demonstrated robust neuroprotection in animal ischemic-reperfusion models, randomized trials in acute stroke patients have failed to demonstrate the efficacy of induced hypothermia. The reasons for this treatment failure are diverse and include treatment delay, the unfeasibility of inducing and maintaining hypothermia due to intolerance and shivering in awake patients, the missing recanalization in a large proportion of patients, the heterogeneity of patients included, and too deep (32-34°C) hypothermia associated with an increase in side effects.
In the pilot study COTTIS-1, we could demonstrate the feasibility and safety of immediately induced intraischemic hypothermia to 35°C with non-invasive transnasal cooling by RhinoChill® (BrainCool) followed by surface cooling for 6h after recanalization in sedated and intubated patients with LVO undergoing EVT. By combining this cooling technique with thrombectomy we have tried to address the above mentioned reasons for hypothermia failure. In COTTIS-1, the target temperature of 35°C was reached within 30 min, corresponding to a cooling rate of 2.6°C/h. All patients reached the target temperature, and 86% of the patients had reached ≤35°C at recanalization by thrombectomy. 68% of patients had a good outcome (independency) after 3 months. There were only asymptomatic side effects during hypothermia.
As a consequence, the present COTTIS-2 study is planned to evaluate the efficiency of this cooling protocol in a multicentric, randomized, controlled, end-point-blinded study in Germany.
- Being tested
- hypothermia
- Keywords
- hypothermia, neuroprotection
- Medical subject headings
- Ischemic Stroke, Hypothermia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
hypothermiaDevice
hypothermia is started after intubation for endovascular treatment and induced by transnasal cooling (RhinoChill) to a target temperature of 35°C and hypothermia is then maintained at 35°C for 6 hours after recanalisation by surface cooling followed by slow rewarming by 0.2°C per hour to 36.5°C
| Study group | Role | What they receive |
|---|---|---|
| EVT group | No intervention | standard endovascular treatment (EVT) for large vessel occlusion (LVO) without hypothermia |
| EVT group plus hypothermia group | Active comparator | standard endovascular treatment (EVT) for large vessel occlusion (LVO) combined with hypothermia Receives: Device: hypothermia |
What is being measured
The primary outcome is the main question the study is designed to answer.
functional outcome
The presence of patients with good neurological outcome after 3 months as defined by modified Rankin Scale (mRS; on which scores range from 0 to 6, with 0 means no symptoms and 6 means death) of 0-2 or back to baseline before stroke
Measured: 3 months
Secondary outcomes (13)
infarction volume
Infarction volume assessed in the standard CT 24 hours after thrombectomy
Measured: 24 hours
increase in infarction
increase of the infarct core based on imaging at the time of admission (DWI-MRI or CBF<30% of contralateral side at CT-Perfusion) and CT after 24 hours
Measured: 24 hours
recanalization result
Recanalization result (by mTICI score: successful recanalization mTICI 2b-3) after thrombectomy (based on angiography during/after thrombectomy) and 24 hours after thrombectomy (based on ultrasound of the cerebral vessels)
Measured: after thrombectomy and 24 hours
neurological improvement
Change of at least 8 points on the National Institutes of Health Stroke Scale (NIHSS; on which scores range from 0 to 42, with higher scores indicating a greater deficit) at 48 hours after thrombectomy
Measured: 48 hours
outcome at discharge
modified Rankin Score (mRS; on which scores range from 0 to 6, with 0 means no symptoms and 6 means death) upon discharge/transfer in rehabilitation
Measured: up to 3 months
shift in functional outcome
ordinal shift across the range of modified Rankin Score (mRS; on which scores range from 0 to 6, with 0 means no symptoms and 6 means death)
Measured: 3 months
very good clinical outcome
Presence of patients with very good clinical outcome after 3 months (mRS 0-1)
Measured: 3 months
mortality
Mortality during acute hospitalisation and after 3 months
Measured: 3 months
Length of ventilation
Length of mechanical ventilation
Measured: 3 months
Length of stay
Length of ICU stay and hospital stay
Measured: 3 months
body temperature
Temperature at admission, at recanalization, and first 6 hours after recanalization, and at 24 hours
Measured: 24 hours
time to groin puncture
Time from arrival until groin puncture
Measured: baseline, pre-intervention
time to recanalization
Time from arrival until recanalization
Measured: periprocedurally
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Mar 2024
- Study start7 Jul 2024
- Primary completion18 Mar 2026 (estimated)
- Study completion18 Jun 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Ischemic StrokeStudies of the same condition, open and under way.
- 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 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 400 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Freiburg
- Sponsor type
- University, hospital or other
- Collaborators
- European Union, E+E CRO consulting, Vienna, Austria, University of Vienna
- Responsible party
- Principal investigator, Juergen Bardutzky, University of Freiburg
- Investigators
- Juergen Bardutzky, Prof., Principal investigator, University of Freiburg, Department of Neurology, Germany
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06301412
- Sponsor's protocol ID
- COTTIS-2_Version4.0-13Nov23
- Acronym
- COTTIS-2
- Status last verified
- Jan 2025
- First submitted
- 22 Feb 2024
- Last updated
- 6 Jan 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Individual patient data (after anonymization), on which the results of the present study are based, can be made available to scientists upon request (methodologically meaningful evaluation proposal approved by a committee specifically appointed for this evaluation proposal) (6 months to 36 months after publication of the study)
Study at a glance
From the registry record, last updated by the sponsor on 6 Jan 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Combination of Targeted Temperature Management and Thrombectomy After Acute Ischemic Stroke (COTTIS-2) - a Randomised Controlled Study
- ClinicalTrials.gov ID
- NCT06301412
- Acronym / sponsor ID
- COTTIS-2 / COTTIS-2_Version4.0-13Nov23
- Keywords
- hypothermia, neuroprotection
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 400 participants (estimated)
- Lead sponsor
- University of FreiburgUniversity, hospital or other
- Collaborators
- European Union, E+E CRO consulting, Vienna, Austria, University of Vienna
- Study start
- 7 Jul 2024 (actual)
- Primary completion
- 18 Mar 2026 (estimated)
- Study completion
- 18 Jun 2026 (estimated)
- First posted
- 8 Mar 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The goal of this clinical trial is to test the combination of hypothermia and endovascular treatment in acute stroke patients with large vessel occlusion.
The main question it aims to answer is: does an additional cooling to 35°C result in a benefit on clinical outcome ? Participants receive immediate cooling using a noninvasive transnasal cooling technique (RhonoChill) and are maintained at 35°C for 6 hours after reopening of the vessel using surface cooling, and then slowly rewarmed.
Researchers will compare the intervention group (hypothermia and endovascular treatment and best medical treatment including iv thrombolysis) and control group (only endovascular treatment and best medical treatment including iv thrombolysis) to see if additional hypothermia leads to a better outcome after 3 months without relevant complications.
Detailed description
Despite the well-established benefit of endovascular treatment (EVT) for acute ischemic stroke due to large vessel occlusion (LVO), more than half of patients treated with EVT remain functionally dependent despite high reperfusion rates. Thus, new strategies such as additional neuroprotection using hypothermia need to be explored, first to bridge time to reperfusion and second, to attenuate reperfusion injury.
Although therapeutic hypothermia has consistently demonstrated robust neuroprotection in animal ischemic-reperfusion models, randomized trials in acute stroke patients have failed to demonstrate the efficacy of induced hypothermia. The reasons for this treatment failure are diverse and include treatment delay, the unfeasibility of inducing and maintaining hypothermia due to intolerance and shivering in awake patients, the missing recanalization in a large proportion of patients, the heterogeneity of patients included, and too deep (32-34°C) hypothermia associated with an increase in side effects.
In the pilot study COTTIS-1, we could demonstrate the feasibility and safety of immediately induced intraischemic hypothermia to 35°C with non-invasive transnasal cooling by RhinoChill® (BrainCool) followed by surface cooling for 6h after recanalization in sedated and intubated patients with LVO undergoing EVT. By combining this cooling technique with thrombectomy we have tried to address the above mentioned reasons for hypothermia failure. In COTTIS-1, the target temperature of 35°C was reached within 30 min, corresponding to a cooling rate of 2.6°C/h. All patients reached the target temperature, and 86% of the patients had reached ≤35°C at recanalization by thrombectomy. 68% of patients had a good outcome (independency) after 3 months. There were only asymptomatic side effects during hypothermia.
As a consequence, the present COTTIS-2 study is planned to evaluate the efficiency of this cooling protocol in a multicentric, randomized, controlled, end-point-blinded study in Germany.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| EVT group | No intervention | –standard endovascular treatment (EVT) for large vessel occlusion (LVO) without hypothermia |
| EVT group plus hypothermia group | Active comparator | Device: hypothermiastandard endovascular treatment (EVT) for large vessel occlusion (LVO) combined with hypothermia |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- Pre-stroke modified Rankin Scale (mRS) 0-2 [7-point scale rating from 0 (no symptoms) to 6 (dead)]
- Acute ischemic stroke with NIHSS >5
- Intracranial occlusion of the M1 or M2 segment of the middle cerebral artery (MCA) or internal carotid artery (ICA) or tandem occlusion on CT-angiography or MR-angiography with indication for endovascular treatment:
- Time window 0-24h:
- with or without iv thrombolysis with rtPA
Key exclusion criteria (8 listed)
- Patients with an intranasal obstruction that prevents complete insertion of the nasal cannula should not be treated with the RhinoChill system.
- Known severe hemorrhagic diathesis (International Normalized Ratio (INR) >3.0, partial thromboplastin time (PTT) > 70s, platelet count < 50.000/μl)
- Brain trauma or neurovascular surgery/intervention <3 months
- Severe infection
- Pregnant women or women of childbearing potential (women of childbearing potential with negative pregnancy test may be included)
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 |
|---|---|---|
| hypothermiahypothermia is started after intubation for endovascular treatment and induced by transnasal cooling (RhinoChill) to a target temperature of 35°C and hypothermia is then maintained at 35°C for 6 hours after recanalisation by surface cooling followed by slow rewarming by 0.2°C per hour to 36.5°C | Device | EVT group plus hypothermia group |
Primary outcome
functional outcome
Time frame: 3 months
The presence of patients with good neurological outcome after 3 months as defined by modified Rankin Scale (mRS; on which scores range from 0 to 6, with 0 means no symptoms and 6 means death) of 0-2 or back to baseline before stroke
13 secondary outcomes
infarction volume
Time frame: 24 hours
increase in infarction
Time frame: 24 hours
recanalization result
Time frame: after thrombectomy and 24 hours
neurological improvement
Time frame: 48 hours
outcome at discharge
Time frame: up to 3 months
shift in functional outcome
Time frame: 3 months
very good clinical outcome
Time frame: 3 months
mortality
Time frame: 3 months
Length of ventilation
Time frame: 3 months
Length of stay
Time frame: 3 months
body temperature
Time frame: 24 hours
time to groin puncture
Time frame: baseline, pre-intervention
time to recanalization
Time frame: periprocedurally
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Jan 2025.
- Results of the pilot study COTTIS-1 on feasibility and safetyLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. Individual patient data (after anonymization), on which the results of the present study are based, can be made available to scientists upon request (methodologically meaningful evaluation proposal approved by a committee specifically appointed for this evaluation proposal) (6 months to 36 months after publication of the study)
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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.
Juergen Bardutzky, Prof. principal investigator
University of Freiburg, Department of Neurology, Germany
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing hypothermia in people with Ischemic Stroke and Large Vessel Occlusion, run by University of Freiburg at 1 site in Germany.
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 10 inclusion and 8 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: looking for participants now, as of the sponsor's last update on 6 Jan 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 Germany. 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. 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 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Juergen Bardutzky, Prof. (+49-15237729739, juergen.bardutzky@uniklinik-freiburg.de), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
functional outcome (time frame: 3 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 6 Jan 2025.