Volatile Anesthetics for COVID-19

(SAVE-ICU Trial)

Recruiting at 12 trial locations

Overseen By Iman Hussain

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Sunnybrook Health Sciences Centre

Must be taking: Intravenous sedatives

Must not be taking: Inhaled prostacyclin

Disqualifiers: Severe brain injury, Neuromuscular disorder, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 30 days

800 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

Patients suffering lung failure, possibly from COVID-19 or hypoxic lung failure, will need life-saving support from a breathing machine. Any patient needing this support requires drugs to keep them sleepy, or "sedated" to be comfortable on this machine. Sedation is made possible by using drugs given through a vein. Unfortunately, these drugs are in short supply worldwide due to the high number of COVID-19 patients needing these machines. Another way to provide sleep is by using gases that are breathed in. These are used every day in operating rooms to perform surgery. These gases, also called "inhaled agents" can also be used in intensive care units and may have several important benefits for patients and the hospital. Research shows they may reduce swelling in the lung and increase oxygen levels, which allows patients to recover faster and reduce the time spent on a breathing machine. In turn, this allows the breathing machine to be used again for the next sick patient. These drugs may also increase the number of patients who live through their illness. Inhaled agents are widely available and their use could dramatically lesson the pressure on limited drug supplies. This research is a study being carried out in a number of hospitals that will compare how well patients recover from these illnesses depending on which type of sedation drug they receive. The plan is to evaluate the number who survive, their time spent on a breathing machine and time in the hospital. This study may show immediate benefits and may provide a cost effective and practical solution to the current challenges caring for patients and the hospital space, equipment and drugs to the greatest benefit. Furthermore, the study will be investigating inflammatory profile and neuro-cognitive profiles in ventilated patients. Finally, this trial will be a team of experts in sedation drugs who care for patients with proven or suspected COVID-19 who need lifesaving treatments.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, it mentions that patients already receiving certain intravenous sedatives are eligible, so you might be able to continue some medications.

Is the use of volatile anesthetics like sevoflurane and isoflurane generally safe for humans?

Sevoflurane and isoflurane are commonly used anesthetics in surgeries for both adults and children, and they are generally considered safe when used properly. However, there are concerns about exposure levels for surgical staff, as high concentrations can cause adverse effects on the nervous system, heart, and lungs. Proper safety measures and monitoring are important to minimize these risks. ^{1 2 3 4 5}

How is the drug Isoflurane and Sevoflurane unique for treating COVID-19?

Isoflurane and Sevoflurane are unique for treating COVID-19 because they are inhaled anesthetics, typically used during surgeries to keep patients asleep, and their use for COVID-19 is novel as they are not standard treatments for this condition. This approach is different from other COVID-19 treatments, which are usually administered orally or intravenously. ^{6 7 8 9 10}

Are You a Good Fit for This Trial?

Adults over 18, on mechanical ventilation for severe lung failure possibly due to COVID-19, and expected to need it for at least another day. They should have been sedated via IV for no more than 72 hours and not allergic to the trial drugs. Excluded are those with high brain pressure, severe brain injury, certain lung or neuromuscular conditions, contraindications to specific sedatives, pregnant women or patients unlikely to survive a day.

Inclusion Criteria

You are currently using a breathing machine and will still need it tomorrow.

I am on IV sedation for less than 72 hours to help with mechanical breathing.

I was moved to a trial site and needed more help with breathing within the last 3 days.

Exclusion Criteria

I have a severe brain injury likely to cause prolonged unconsciousness.

Known pregnancy

I might have high pressure inside my skull.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1 week

Treatment

Participants receive either intravenous or inhaled volatile-based sedation, randomized within 72 hours of sedation start

30 days

Daily visits in ICU

Follow-up

Participants are monitored for safety and effectiveness after treatment, with assessments at 30, 60, 90, and 365 days post-enrollment

12 months

Telephone or database follow-up at specified intervals

Neuro-cognitive and Biomarker Assessment (optional)

Participants have the option to participate in additional neuro-cognitive and biomarker assessments

What Are the Treatments Tested in This Trial?

Interventions

• Isoflurane Inhalant Product
• Sevoflurane inhalant product

Trial Overview The study compares inhaled anesthetics Sevoflurane and Isoflurane as alternatives for IV sedation in ICU patients with respiratory failure. It aims to see if these gases can improve survival rates, reduce time on ventilators and in hospitals by reducing lung inflammation and improving oxygen levels.

How Is the Trial Designed?

Group I: Inhaled - volatile anesthetic Experimental Treatment 2 Interventions

The ICU patient will be randomized to either Isoflurane or Sevoflurane, whichever is available at the hospital. Dosage will be modified as per health care team guidance for the best treatment of the participant.

Group II: Non-randomized Active Control 1 Intervention

In this arm, ICU patients who cannot be randomized will receive inhaled or IV sedation as per available in their unit. This is done to try to obtain the maximum amount of information available from the patients present to our ICUs.

Group III: Standard Care Active Control 1 Intervention

The ICU patient will be randomized to standard of care, which is any IV sedation supplied by the hospital. Dosage will be modified as per health care team guidance for the best treatment of the participant.

Isoflurane Inhalant Product is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Forane for:

• General anesthesia
• Maintenance of anesthesia

Approved in European Union as Isoflurane for:

• Induction and maintenance of general anesthesia

Approved in Canada as Isoflurane for:

• General anesthesia

Approved in Japan as Isoflurane for:

• General anesthesia

Who Is Running the Clinical Trial?

Sunnybrook Health Sciences Centre

Lead Sponsor

Trials

693

Recruited

1,569,000+

Published Research Related to This Trial

The proposed maximum admissible concentrations (MAC) for sevoflurane and isoflurane are 55 mg/m3 (7 ppm) and 32 mg/m3 (4 ppm), respectively, which aim to protect surgical staff from potential health risks associated with these anesthetics.

Establishing these MAC values is crucial as it provides a guideline for employers to assess and manage exposure to these inhalant anesthetics in the workplace, ensuring the safety of healthcare workers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Assessment of health risk of sevoflurane and isoflurane exposure among surgical staff: a problem for employers]. Kupczewska-Dobecka, M., Soćko, R.[2018]

Sevoflurane, an inhalation anesthetic, is available in the U.S. as both a brand (Ultane) and a generic version, with the FDA rating them as therapeutically equivalent despite differences in their manufacturing processes.

Ultane is produced through a single-step process and contains more water (>300 ppm) compared to the generic version, which is made in a three-step process and contains less water (≤130 ppm), potentially affecting stability and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sevoflurane: are there differences in products? Baker, MT.[2018]

Four out of 13 sevoflurane vaporizers were contaminated with water and Staphylococcus epidermidis, indicating a potential safety risk in their use.

The contamination was linked to water accumulation in the vaporizers, which can lead to the production of harmful metabolites, including urea and other organic compounds, highlighting the importance of proper maintenance and monitoring of anesthesia equipment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sevoflurane Contamination: Water Accumulation in Sevoflurane Vaporizers Can Allow Bacterial Growth in the Vaporizer. Wallace, AW.[2022]

Desflurane allowed for significantly faster recovery times, specifically in time to eye-opening, compared to sevoflurane and isoflurane, making it a quicker option for ambulatory surgeries.

Isoflurane was found to be the most cost-effective anesthetic agent, with lower overall costs while maintaining comparable safety and recovery profiles to sevoflurane and desflurane.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized Comparison of Isoflurane versus Sevoflurane and Desflurane for Maintenance of Ambulatory Anesthesia. Kurhekar, P., Vinod, K., Krishna, JSD., et al.[2022]

In a study involving 143 adult patients, sevoflurane was found to allow for a quicker recovery from general anesthesia compared to isoflurane, with shorter times for extubation, eye opening, and command response.

Both sevoflurane and isoflurane demonstrated similar safety profiles, as there were no significant differences in renal and hepatic function before and after surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Maintenance and recovery characteristics of sevoflurane anaesthesia in adult patients. A multicenter, randomized comparison with isoflurane. Ranieri, R., Martinelli, G., Pagani, I., et al.[2018]

Ustekinumab, recently approved for treating Crohn's disease and ulcerative colitis, can cause immediate infusion reactions in some patients, as observed in three therapy-refractory cases.

Two of the patients who had an infusion reaction also experienced subsequent reactions to subcutaneous injections, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immediate Infusion Reaction to Intravenous Ustekinumab in Three Crohn's Disease Patients: A Case Report and Review of the Literature. Thomas, PWA., Ferwerda, G., West, RL., et al.[2021]

Ustekinumab has been shown to be effective in treating autoimmune conditions like psoriasis and is generally well tolerated and safe in short-term studies.

The review discusses important factors such as the pharmacokinetics of ustekinumab, its safety profile, and considerations for use in pregnancy, highlighting its potential for long-term use despite ongoing investigations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety of ustekinumab in psoriasis. Famenini, S., Wu, JJ.[2015]

The study demonstrated that a magnetocontrollable sorbent effectively reduced proinflammatory cytokines IL-12 and IL-23 by up to 99.9% in patients with psoriatic arthritis, indicating a strong efficacy in targeting these key inflammatory markers.

The procedure did not significantly alter blood cell counts, suggesting that this method of cytokine removal using Ustekinumab-based sorbents is safe and could be beneficial in managing psoriatic arthritis without adverse effects on blood health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sorption of Interleukins 12 and 23 Using the Developed Magnetocontrollable Ustekinumab-Based Sorbent. Gontar, IP., Emelyanova, OI., Rusanova, OA., et al.[2022]

Ustekinumab, an anti-IL-12/IL-23 monoclonal antibody, shows a positive exposure-response relationship in treating moderately to severely active ulcerative colitis, indicating that higher drug exposure correlates with better clinical outcomes such as response and remission.

The pharmacokinetics of ustekinumab were well characterized by a 2-compartment model, and while factors like body weight and sex influenced drug levels, they did not require dose adjustments, supporting the use of a standard dosing regimen for effective treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population Pharmacokinetics and Exposure-Response Modeling Analyses of Ustekinumab in Adults With Moderately to Severely Active Ulcerative Colitis. Xu, Y., Hu, C., Chen, Y., et al.[2021]

In a study of 23 patients with inflammatory bowel disease (IBD) who had a partial or lost response to subcutaneous ustekinumab (SC UST), 82.6% achieved a clinical response after 12 weeks of intravenous (IV) UST maintenance treatment.

The treatment was safe, with no adverse events reported, and 43.5% of patients reached clinical remission, indicating that IV UST can effectively recapture response in patients previously on SC UST.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous ustekinumab maintenance treatment in patients with loss of response to subcutaneous dosing. Argüelles-Arias, F., Valdés Delgado, T., Maldonado Pérez, B., et al.[2023]

Citations

1. Poland pubmed.ncbi.nlm.nih.gov

[Assessment of health risk of sevoflurane and isoflurane exposure among surgical staff: a problem for employers]. [2018]

2. United States pubmed.ncbi.nlm.nih.gov

Sevoflurane: are there differences in products? [2018]

3. United States pubmed.ncbi.nlm.nih.gov

Sevoflurane Contamination: Water Accumulation in Sevoflurane Vaporizers Can Allow Bacterial Growth in the Vaporizer. [2022]

4. India pubmed.ncbi.nlm.nih.gov

Randomized Comparison of Isoflurane versus Sevoflurane and Desflurane for Maintenance of Ambulatory Anesthesia. [2022]

5. Italy pubmed.ncbi.nlm.nih.gov

Maintenance and recovery characteristics of sevoflurane anaesthesia in adult patients. A multicenter, randomized comparison with isoflurane. [2018]

6. England pubmed.ncbi.nlm.nih.gov

Immediate Infusion Reaction to Intravenous Ustekinumab in Three Crohn's Disease Patients: A Case Report and Review of the Literature. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

The safety of ustekinumab in psoriasis. [2015]

8. Russia (Federation) pubmed.ncbi.nlm.nih.gov

Sorption of Interleukins 12 and 23 Using the Developed Magnetocontrollable Ustekinumab-Based Sorbent. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Population Pharmacokinetics and Exposure-Response Modeling Analyses of Ustekinumab in Adults With Moderately to Severely Active Ulcerative Colitis. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Intravenous ustekinumab maintenance treatment in patients with loss of response to subcutaneous dosing. [2023]