The effect of esketamine on the hypoxic ventilatory response
| ISRCTN | ISRCTN42617929 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN42617929 |
| EudraCT/CTIS number | 2023-504229-37-00 |
| Secondary identifying numbers | 2 |
- Submission date
- 20/06/2023
- Registration date
- 27/06/2023
- Last edited
- 20/11/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Respiratory
Plain English summary of protocol
Background and study aims
Opioids and anesthetics are given to patients before surgery and have an important effect on breathing. While we know that opioids are potent respiratory depressants, including depression of the hypoxic ventilatory response (HVR; the increase in breathing caused by low blood oxygen), few human studies have addressed the effect of ketamine on the hypoxic ventilatory response. Since esketamine is frequently used to reduce opioid consumption before surgery and hypoxia following surgery is quite common, it is important to study the effect of ketamine (this study will use esketamine) on the hypoxic ventilatory response in a population of healthy male and female volunteers. In the first set of experiments, the researchers expect to observe that esketamine alone does not affect the HVR. Next, they will test whether the reduced HVR by the opioid remifentanil is restored by adding esketamine.
Who can participate?
Healthy volunteers aged 18 - 45 years
What does the study involve?
In part 1 of the study the researchers will infuse four esketamine doses and during each dose they will measure the HVR. In part 2, they will test the dose that effectively sustains the HVR in part 1, and will determine whether that dose is able to reverse remifentanil‐induced depression of the HVR.
What are the possible benefits and risks of participating?
Participants will not benefit from participating in this study. The benefit lies within the gained knowledge about how to treat, reverse and prevent opioid-inducted respiratory depression in patients treated with opioids and people with an opioid use disorder. The burden of the study is related to the measurements and interventions. The used drugs have side effects. The application of IV lines could cause short-lasting pain and might result in a temporary, self-resolving hematoma (bruise).
Where is the study run from?
Leiden University Medical Center (the Netherlands)
When is the study starting and how long is it expected to run for?
February 2023 to April 2024
Who is funding the study?
Leiden University Medical Center (the Netherlands)
Who is the main contact?
S. C. Jansen, s.c.jansen@lumc.nl
Contact information
Scientific
Albinusdreef 2
H5-P
Leiden
2333ZA
Netherlands
 ORCID ID |
0000-0002-1175-5877 |
|---|---|
| Phone | +31 (0)7198638 |
| s.c.jansen@lumc.nl |
Study information
| Study design | Part 1: Single-center dose-finding study; Part 2: Single-center randomized placebo-controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | University/medical school/dental school |
| Study type | Safety, Efficacy |
| Participant information sheet | Not available in web format, please use the contact details to request a patient information sheet |
| Scientific title | Hypoxic ventilatory response (HVR): Effect of Esketamine |
| Study acronym | HE-o-E |
| Study objectives | Opioids and anesthetics are given to patients perioperatively and have an important effect on breathing. While it is known that opioids are potent respiratory depressants, including depression of the hypoxic ventilatory response (HVR), few human studies addressed the effect of ketamine on the hypoxic ventilatory response. Since esketamine is frequently used to reduce opioid consumption postoperatively and hypoxia following surgery is quite common, it is important to study the effect of ketamine (this study will use the S-enantiomer, esketamine) on the hypoxic ventilatory response in a population of healthy male and female volunteers. In the first set of experiments, the researchers expect to observe that esketamine alone does not affect the HVR. Next, they will test whether the reduced HVR by the opioid remifentanil is restored by adding esketamine. It was showed earlier that esketamine enhances remifentanil-induced depressed isohypercapnic ventilation in healthy volunteers. The researchers will do so in a randomized controlled trial of esketamine versus placebo during remifentanil infusion. |
| Ethics approval(s) |
Approved 12/06/2023, Medisch-Ethische Toetsingscommissie Leiden | Den Haag | Delft (LUMC Albinusdreef 2 Secretariaat: Kamer P5-22, routenummer 953 Spreekkamer: Kamer P5-40, routenummer 953, Leiden, 2333 ZA, Netherlands; Monday +31(0)71 52 63241; Tuesday +31(0)71 52 66045; Wednesday +31(0)71 52 63003; Thursday +31(0)71 52 66963; Friday +31(0)71 52 63241; metc-ldd@lumc.nl), ref: P23.039 |
| Health condition(s) or problem(s) studied | The effect of esketamine on the hypoxic ventilatory response |
| Intervention | The study intervention is the administration of esketamine. In part 1 of the study the researchers will infuse four esketamine doses and during each dose, they will measure the HVR: In part 1 of the study, for esketamine the dosing regimen is set at dose 0 (control condition for 60 min), followed by dose 16 (16 mg given over 60 min), dose 24 (24 mg given over 60 min) and finally dose 32 (32 mg over 60 min); all doses are per 70 kg. This dosing regimen is identical to that used earlier by (Jonkman et al. BJA 2018; https://clinicaltrialregister.nl/nl/trial/24921). In part 2, the researchers will test the dose that effectively sustains the HVR in part 1, and will perform an RCT (esketamine vs placebo) to determine whether that dose is able to reverse remifentanil‐induced depression of the HVR. Participants will be studied three times with at least 2 days in between study visits. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | Pharmacokinetic, Pharmacodynamic |
| Phase | Phase III/IV |
| Drug / device / biological / vaccine name(s) | Remifentanil, esketamine |
| Primary outcome measure | Hypoxic ventilatory response as determined from the change in ventilation and the change in oxygen saturation, ie. ΔVentilation/ΔSaturation with unit L/min per % desaturation, where Δ stands for the difference between the variable observed at baseline and observed during hypoxia. Measured through measuring minute ventilation by facemask during the exposure period (i.e. l/min/% desaturation). |
| Secondary outcome measures | 1. Plasma esketamine concentrations over time, measured using blood samples at 0, 2, 5, 30, 60, 62, 65 and 75 min following the start of each of the esketamine infusions 2. Psychomimetic side effects assessed by the Bowdle and Bond & Lader questionnaires during hypoxic breathing |
| Overall study start date | 22/02/2023 |
| Completion date | 23/04/2024 |
Eligibility
| Participant type(s) | Healthy volunteer |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Upper age limit | 45 Years |
| Sex | Both |
| Target number of participants | 18 |
| Total final enrolment | 18 |
| Key inclusion criteria | 1. Aged 18 - 45 years 2. Body mass index 19-30 kg/m² 3. Ability to read and understand the subject information in the Dutch language |
| Key exclusion criteria | 1. A history of clinically significant (as deemed by the investigators) medical or psychiatric disease; These include: clinically significant illness or disease (e.g., psychiatric disorders, disorders of the gastrointestinal tract, liver, kidney, respiratory system, endocrine system, hematological system, neurological system, or cardiovascular system, or any clinically significant abnormal symptom or organ impairment, as judged by the investigator, found by medical history, physical examinations or vital signs at screening 2. Any allergy to food or medication 3. Weekly alcohol intake of more than 3 units/day or more than 21 units/week in women and 5 units/day and 35 units/week in men; 4. Pregnancy or lactation 5. Women of childbearing potential (defined as all women who are not surgically sterile or postmenopausal for at least 1 year prior to informed consent) must have a negative urine pregnancy test prior to enrolment and must agree to use a medically acceptable means of contraception from screening through at least 1 month after the last dose of study drug. By contraception we mean for women: intrauterine device (IUD), diaphragm with spermicide, oral contraceptive, injectable progesterone, subdermal implant or a tubal ligation. Males who are sexually active and whose partners are females of childbearing potential must agree to use condoms 6. Participation in an investigational drug trial in the 3 months before the current study 7. Illicit drug use in the 30 days before the current study 8. A positive drug urine dipstick on the screening or study days |
| Date of first enrolment | 31/07/2023 |
| Date of final enrolment | 01/01/2024 |
Locations
Countries of recruitment
- Netherlands
Study participating centre
Albinusdreef 2
Leiden
2333 ZA
Netherlands
Sponsor information
University/education
Albinusdreef 2
H5-P
Leiden
2333ZA
Netherlands
| Phone | +31 (0)7198638 |
|---|---|
| s.c.jansen@lumc.nl | |
| Website | https://www.lumc.nl/?setlanguage=English&setcountry=en |
"ROR" |
https://ror.org/05xvt9f17 |
Funders
Funder type
Government
Government organisation / Local government
- Alternative name(s)
- Leiden University Medical Center, LUMC
- Location
- Netherlands
Results and Publications
| Intention to publish date | 01/07/2024 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | The data will be published in a peer-reviewed scientific journal as soon as the data have been analyzed and the manuscript has been written, without any restrictions. This is in agreement with the CCMO statement that (https://english.ccmo.nl/publications/publications/2002/03/01/ccmostatement- on-publication-policy). |
| IPD sharing plan | The datasets generated during and/or analysed during the current study will be available upon request from Albert Dahan (a.dahan@lumc.nl) |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Results article | 07/11/2024 | 20/11/2024 | Yes | No |
Editorial Notes
20/11/2024: Publication reference and total final enrolment added.
10/04/2024: The following changes were made to the study record:
1. The overall study end date was changed from 23/02/2024 to 23/04/2024.
2. The intention to publish date was changed from 01/04/2024 to 01/07/2024.
21/06/2023: Study's existence confirmed by the Medisch-Ethische Toetsingscommissie Leiden | Den Haag | Delft.
