Intranasal Ketamine + Dexmedetomidine for Procedural Sedation

(Ketodex Trial)

Overseen By Kamary Coriolano, PhD

Age: < 18

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: Lawson Health Research Institute

Disqualifiers: Schizophrenia, Psychosis, Hypertension, others

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

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 4 hours

400 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new method to help children feel comfortable during procedures for broken bones, such as forearm or finger fractures, or dislocated shoulders or elbows. Instead of using an IV, it uses a nasal spray with a mix of two sedatives, ketamine and dexmedetomidine (also known as Precedex), to evaluate its effectiveness for sedation. The trial seeks children who need sedation for these injuries and have clear nasal passages for the spray. The goal is to make the experience less painful and stressful for both children and their caregivers. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of children, offering a chance to contribute to innovative care.

Do I need to stop my current medications to join the trial?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of intranasal dexmedetomidine and ketamine, often called "IN Ketodex," is generally well-tolerated in children. Studies have found that this combination provides effective sedation and acts faster than other methods. Previous patients reported fewer issues with blood pressure and heart rate, making this option safer for many children.

Although the studies did not identify any major safety concerns, it is important to remember that this treatment is still under investigation. As the trial progresses, evidence suggests the treatment is safe in humans. However, as with any medical study, there may be side effects or risks that are not fully understood yet.

Overall, IN Ketodex shows promise for safe and effective sedation in children needing procedures without the pain of IV insertion. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the intranasal combination of ketamine and dexmedetomidine because it offers a unique method for procedural sedation. Unlike traditional options like intravenous midazolam or propofol, this treatment is delivered intranasally, which can be less invasive and more convenient. The combination of ketamine and dexmedetomidine may also provide a synergistic effect, potentially leading to more effective sedation with a better safety profile. Additionally, the use of a mucosal atomizer device for delivery could enhance patient comfort and compliance. Overall, this innovative approach could revolutionize how we manage sedation during procedures.

What evidence suggests that this trial's treatments could be effective for procedural sedation in children with orthopedic injuries?

Research has shown that a nasal spray called IN Ketodex, which combines dexmedetomidine and ketamine, can effectively calm children without using a needle. In this trial, participants will receive one of the IN Ketodex formulations, such as D4K2, D3K3, or D2K4, or they may receive IV ketamine as a comparator. Studies have found that IN Ketodex works as well as the usual IV ketamine, often used for procedures like fixing broken bones in children. Specifically, one study found that children become calm faster with IN Ketodex. Another study showed that it provides good calming effects while maintaining steady heart rate and blood pressure. This suggests that IN Ketodex could be a less painful option than IV ketamine, making procedures less stressful for children. ^{1 2 3 6 7}

Who Is on the Research Team?

Naveen Poonai, MD

Principal Investigator

Western University

Are You a Good Fit for This Trial?

This trial is for children aged 4-17 with orthopedic injuries like forearm fractures or dislocations needing sedation, weighing up to 60 kg. They must be able to follow the study's procedures and have no severe health issues like heart disease, uncontrolled hypertension, or cognitive impairments that prevent consent.

Inclusion Criteria

I have had a dislocated shoulder or elbow.

Your fracture is not severe or very short.

I am undergoing a painful medical procedure.

Exclusion Criteria

I have obstructive sleep apnea.

American Society of Anesthesiologists (ASA) class 3 or greater;

Your doctor has determined that your heart or blood pressure is not stable.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive intranasal dexmedetomidine plus ketamine for procedural sedation during closed reduction of fractures

4 hours

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including adverse effects and satisfaction

72 hours

What Are the Treatments Tested in This Trial?

Interventions

• Dexmedetomidine
• Ketamine

Trial Overview The trial tests intranasal dexmedetomidine plus ketamine (IN Ketodex) against IV ketamine for sedation in kids during bone setting. It aims to see if IN Ketodex can provide deep enough sedation without the pain of an IV line.

How Is the Trial Designed?

Group I: IN Ketodex (D4K2) Experimental Treatment 1 Intervention

Dexmedetomidine (Pfizer, Kirkland, Quebec), single-dose, 4 mcg/kg (0.04 mL/kg) of 100 mcg/mL solution, maximum of 200 mcg (2 mL) THEN Ketamine (Sandoz, Mississauga, Ontario), single dose, 2 mg/kg (0.04 mL/kg) of 50 mg/mL solution, maximum of 200 mg (4 mL) (D4K2), both delivered intranasally using a mucosal atomizer device (MAD) and divided to both nares AND 0.9% normal saline 0.03 mL/kg delivered intravenously to a maximum of 2 mL

Group II: IN Ketodex (D3K3) Experimental Treatment 1 Intervention

Dexmedetomidine (Pfizer, Kirkland, Quebec), single-dose, 3 mcg/kg (0.03 mL/kg) of 100 mcg/mL solution, maximum of 200 mcg (2 mL) THEN Ketamine (Sandoz, Mississauga, Ontario), single dose, 3 mg/kg (0.06 mL/kg) of 50 mg/mL solution, maximum of 300 mg (6 mL) (D3K3), both delivered intranasally using a mucosal atomizer device (MAD) and divided to both nares AND 0.9% normal saline 0.03 mL/kg delivered intravenously to a maximum of 2 mL

Group III: IN Ketodex (D2K4) Experimental Treatment 1 Intervention

Dexmedetomidine (Pfizer, Kirkland, Quebec), single-dose, 2 mcg/kg (0.02 mL/kg) of 100 mcg/mL solution, maximum of 200 mcg (2 mL) THEN Ketamine (Sandoz, Mississauga, Ontario), single dose, 4 mg/kg (0.08 mL/kg) of 50 mg/mL solution, maximum of 400 mg (8 mL) (D2K4), both delivered intranasally using a mucosal atomizer device (MAD) and divided to both nares AND 0.9% normal saline 0.03 mL/kg delivered intravenously to a maximum of 2 mL

Group IV: IV Ketamine Active Control 1 Intervention

Ketamine, single dose, 1.5 mg/kg (0.03 mL/kg) of 50 mg/mL solution delivered intravenously, to a maximum of 100 mg (2 mL) AND two aliquots of 0.9% normal saline in 3 possible combinations: (i) 0.04 mL/kg (max 2 mL) then 0.04 mL/kg (max 4 mL) (placebo D4K2), (ii) 0.03 mL/kg (max 2 mL) then 0.06 mL/kg (max 6 mL) (placebo D3K3), (iii) 0.02 mL/kg (max 2 mL) then 0.08 mL/kg (max 8 mL) (placebo D2K4), delivered intranasally using a MAD and divided to both nares

Ketamine is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Ketalar for:

• Anesthesia
• Treatment-resistant depression

Approved in European Union as Ketalar for:

• Anesthesia
• Treatment-resistant depression

Approved in United States as Spravato for:

• Treatment-resistant depression

Approved in European Union as Spravato for:

• Treatment-resistant depression

Approved in Canada as Spravato for:

• Treatment-resistant depression

Who Is Running the Clinical Trial?

Lawson Health Research Institute

Lead Sponsor

Trials

684

Recruited

432,000+

Naveen Poonai

Lead Sponsor

Trials

3

Recruited

830+

Published Research Related to This Trial

In a study involving 84 preschoolers, all three sedation regimens (intranasal ketamine and midazolam, oral ketamine and midazolam, and oral midazolam) provided moderate sedation for dental procedures, with no significant differences in effectiveness or adverse events among the groups.

Minor adverse events occurred in 44% of the children, indicating that the sedation methods were generally safe, but the variability in children's behavior suggests that further research with larger samples is needed to better understand the benefits of the ketamine-midazolam combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized clinical trial on the efficacy of intranasal or oral ketamine-midazolam combinations compared to oral midazolam for outpatient pediatric sedation. Sado-Filho, J., Viana, KA., Corrêa-Faria, P., et al.[2020]

A systematic review of 10 randomized controlled trials involving pediatric patients found no significant differences in the efficacy of intranasal ketamine compared to intranasal dexmedetomidine for sedation during procedures, indicating that neither medication was clearly superior for outcomes like parental separation or mask acceptance.

However, intranasal ketamine was associated with a higher incidence of nausea and vomiting, while intranasal dexmedetomidine led to more cases of bradycardia, suggesting that safety profiles may influence clinical choices between these two premedication options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of intranasal ketamine compared with intranasal dexmedetomidine as a premedication before general anesthesia in pediatric patients: a systematic review and meta-analysis of randomized controlled trials. Dwivedi, P., Patel, TK., Bajpai, V., et al.[2022]

In a study involving 45 uncooperative pediatric dental patients, intranasal ketamine provided a faster onset of sedation compared to midazolam and their combination, with a statistically significant difference (P < 0.01).

Ketamine achieved the highest overall success rate for sedation at 89%, compared to 84% for the combination of midazolam and ketamine, and 69% for midazolam alone, while all medications were found to be safe with no significant adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparative evaluation of intranasal midazolam, ketamine and their combination for sedation of young uncooperative pediatric dental patients: a triple blind randomized crossover trial. Bahetwar, SK., Pandey, RK., Saksena, AK., et al.[2019]

In a study involving 20 preschool children, nasal administration of s-ketamine resulted in lower peak plasma concentrations and longer absorption times compared to intravenous administration, indicating a slower onset of action for the nasal route.

Despite the variability in absorption rates, nasal s-ketamine did not significantly affect blood pressure or heart rate, suggesting it is a safe option for sedation in pediatric patients, although continuous monitoring is recommended due to the potential for rapid absorption in some cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

S-ketamine and s-norketamine plasma concentrations after nasal and i.v. administration in anesthetized children. Weber, F., Wulf, H., Gruber, M., et al.[2016]

In a study of 17,948 pediatric patients, the combination of intranasal dexmedetomidine and ketamine achieved a high sedation success rate of 93%, indicating it is an effective method for procedural sedation in children.

The incidence of adverse events was very low at 0.58%, with only 0.02% experiencing major adverse events, suggesting that this sedation method is safe for use in a clinical setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of 17 948 pediatric patients undergoing procedural sedation with a combination of intranasal dexmedetomidine and ketamine. Yang, F., Liu, Y., Yu, Q., et al.[2019]

This study will evaluate the efficacy and safety of an intranasal combination of dexmedetomidine and ketamine for sedation in children under 7 years old, comparing it to the commonly used oral chloral hydrate in a randomized controlled trial involving 136 participants.

The primary goal is to determine how quickly each method achieves adequate sedation within 15 minutes, along with assessing sedation duration, failure rates, and any adverse effects, which will help establish the best sedation practice for pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two-center randomized controlled trial comparing oral chloral hydrate and intranasal combination of dexmedetomidine and ketamine for procedural sedation in children: study protocol. Jang, YE., Joo, EY., Lee, JH., et al.[2023]

Intranasal midazolam (INM) was effective for sedation in 24 out of 26 children, but intravenous ketamine and midazolam (IVKM) provided quicker sedation onset by an average of 5.3 minutes, making it a more efficient option for emergency procedures.

Children receiving INM were discharged 19 minutes earlier than those receiving IVKM, but overall sedation scores were significantly better with IVKM, indicating it offers a more consistent and satisfactory sedation experience.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous ketamine plus midazolam is superior to intranasal midazolam for emergency paediatric procedural sedation. Acworth, JP., Purdie, D., Clark, RC.[2019]

Intranasal dexmedetomidine alone is as effective as a combination of dexmedetomidine and ketamine for sedating children during dental procedures, with similar levels of quiet behavior observed in both groups.

Using dexmedetomidine alone resulted in fewer adverse events and a faster recovery time compared to the combination with ketamine, making it a safer option for outpatient pediatric sedation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intranasal Dexmedetomidine Compared to a Combination of Intranasal Dexmedetomidine with Ketamine for Sedation of Children Requiring Dental Treatment: A Randomized Clinical Trial. Sado-Filho, J., Corrêa-Faria, P., Viana, KA., et al.[2021]

Intravenous (i.v.) ketamine can be safely administered by emergency physicians to children for procedures, with only minor adverse effects such as transient apnea and mild agitation observed in a study of 156 cases over 9 years.

The sedation characteristics of i.v. ketamine are comparable to those of intramuscular (i.m.) ketamine, indicating that both routes can be effectively used for pediatric sedation in emergency settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous ketamine for pediatric sedation in the emergency department: safety profile with 156 cases. Green, SM., Rothrock, SG., Harris, T., et al.[2022]

Oral transmucosal ketamine (OTK) was found to be an effective and well-accepted method for sedation in 25 children, facilitating procedures like intravenous line insertion.

OTK, administered as lollipops, slightly increased gastric volumes but did not alter gastric pH, indicating it is a safe preoperative medication for pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral transmucosal ketamine: an effective premedication in children. Cioacă, R., Canavea, I.[2019]

Intranasal (IN) ketamine is a safe and effective alternative for providing analgesia and anxiolysis in pediatric emergency department patients, with 100% provider comfort and high satisfaction scores (90 out of 100).

The use of IN ketamine resulted in a significantly shorter emergency department length of stay (mean 237.9 minutes) compared to traditional intravenous sedation methods (mean 332.4 minutes), while maintaining a low rate of minor adverse events (6%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of Intranasal Ketamine in Pediatric Patients in the Emergency Department. Guthrie, AM., Baum, RA., Carter, C., et al.[2023]

Intranasal dexmedetomidine (D) and esketamine (K) are both effective for moderate sedation in uncooperative pediatric dental patients, with a study involving 150 children aged 3-10 years.

Esketamine (0.5 mg/kg) and the highest dose of dexmedetomidine (2.0 µg/kg) provided faster sedation onset and lower pain scores compared to lower doses of dexmedetomidine, indicating their potential for better sedation management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison between dexmedetomidine and esketamine in pediatric dentistry surgery. Xin, N., Xu, H., Yue, C.[2022]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/33407719/

The intranasal dexmedetomidine plus ketamine for ... The Ketodex trial will provide evidence on the optimal dose for, and effectiveness of, IN ketodex as an alternative to IV ketamine providing sedation.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7789159/

The intranasal dexmedetomidine plus ketamine for procedural ... This analysis compares the effectiveness of IV ketamine and the optimal IN ketodex combination. The probability of adequate sedation with IV ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04195256

Intranasal Dexmedetomidine Plus Ketamine for Procedural ... Qiao et al. found that IN dexmedetomidine 2 mcg/kg and oral ketamine 3 mg/kg in children undergoing IV insertion was superior to both IN dexmedetomidine 2.5 mcg ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0735675721007130

Dexmedetomidine in combination with ketamine for ... DEX-KET for pediatric sedation results in better sedation outcomes than DEX or KET by shortening onset of sedation and recovery while maintaining hemodynamic ...

5. ijponline.biomedcentral.com ijponline.biomedcentral.com/articles/10.1186/s13052-021-01196-0

Intranasal dexmedetomidine and intranasal ketamine ... In this study the combination of intranasal ketamine and intranasal dexmedetomidine allowed for a significantly shorter sedation induction time ...

6. bmjopen.bmj.com bmjopen.bmj.com/content/10/12/e041319

Adaptive randomised controlled non-inferiority multicentre ... Preliminary evidence suggests that a combination of dexmedetomidine and ketamine may be superior than either agent alone.18 19 A combination of intranasal ...

7. d-nb.info d-nb.info/1256025771/34

Intranasal dexmedetomidine and intranasal ketamine ... In this study the combination of intranasal ketamine and intranasal dexmedetomidine allowed for a significantly shorter sedation induction time than the ...