Background & Aims
There is a high need for novel efficacious, rapid-acting, non-invasive, needle-free analgesics for the treatment of acute moderate to severe pain in children of all ages. both in the emergency room setting or for painful procedures. The aim of the present project is to develop CT001, a fixed combination of intranasal sufentanil and ketamine, as a well characterized treatment option for administration in a healthcare setting. The objective of the present study was to investigate the efficacy and safety of CT001, a combination of intranasal sufentanil and ketamine, and provide support for optimal dose levels for the full pediatric age span, with respect to plasma exposure, nasal bioavailability and tolerability, analgesic efficacy and safety aspects. This was done by comparing the efficacy of CT001 to its individual components and a placebo, integrating comprehensive pharmacokinetic/pharmacodynamic (PK/PD) modeling and simulation studies. The program is approved by EMA and FDA.
Methods
We utilized clinical data obtained from 5 clinical trials: one PK/PD and safety study in children with procedural pain (study 0201), one PK/PD and safety study in adults having undergone molar extraction, including CT001, and different doses of sufentanil and ketamine as monotherapy and placebo, (study 0205), one registry based safety and tolerability study in children in ambulatory care (study 0203), one nasal spray bioavailability study in adults (study 0204), and one PK and safety study in children with procedural pain (study 0206). Data on plasma exposure, bioavailability, and other PK measures, as well as safety assessments (adverse events and vital signs) were assessed to arrive at relevant final dosages to be used in pediatric patients. The modeling incorporated data from four of the above-mentioned clinical studies. The PK/PD modeling and simulation study was based on comprehensive data across demographics. Additional data on modeling methods will be shared on the poster
Results
Based on 4 clinical studies a unified adult/ pediatric PK/PD model was developed. Based on the model, CT001 is estimated to provide pain relief in children of 87%, (95% CI: 75%/93%) on the 0-10 Numeric Rating Scale (NRS), Corresponding values with only sufentanil exposure were 52% (34%/65%), and only ketamine exposure were 32% (95% CI: 12%/47%), but a 10% (95% CI: 1%/20%) increase for placebo. Data also confirms previous findings that the addition of a low dose of ketamine has an opioid sparing effect. Safety profiles across all studies demonstrated mild, transient side effects without severe adverse events, with a low incidence of nausea and no cases of respiratory depression or hypoxia, The data supports that CT001 is a safe treatment for acute pain management in children in a hospital-based setting, to be further confirmed in an extensive pediatric follow-up study.
The modeling may also indicate an age and weight differentiation in bioavailability, also supporting the differentiated dosing to be applied in upcoming trials.
Conclusions
The integration of PK/PD modelling provides a robust novel framework for understanding drug behavior across demographics. The modelling supports that CT001 has the potential to become a rapid-acting and needle-free effective contribution in the management of acute pain in pediatric patients in the ER and for procedural pain. The combination of a favorable safety profile and the intranasal spray device, with which it is being co-developed, ensuring adequate dosing with minimal risk of handling errors, also add to the future potential clinical benefit of this treatment option.
References
Fjendbo Galili?S, Nikolajsen?L, Papadomanolakis Pakis?N. Subanaesthetic single dose ketamine as an adjunct to opioid analgesics for acute pain management in the emergency department: a systematic review and meta-analysis. BMJ Open 2023;13:e066444. doi:10.1136/ bmjopen-2022-066444
Assouline B, Tramer MR, Kreienbühl L, Elia N. Benefit and harm of adding ketamine to an opioid in a patient-controlled analgesia device for the control of postoperative pain: systematic review and meta-analyses of randomized controlled trials with trial sequential analyses. Pain 2016;157:2854–2864 https://dx.doi.org/10.1097/j.pain.0000000000000705
Presenting Author
Marta Segerdahl
Poster Authors
Marta Segerdahl
MD, PhD
MS Medical Consulting
Lead Author
Mads U Werner
MD
DanTrials, Zelo Phase 1 Unit, Copenhagen University Hospitals–Bispebjerg Hospital, Denmark
Lead Author
Rik Schoemaker
PhD
Occams Coöperatie U.A.
Lead Author
Martin Juhl
PhD
Cessatech A/S
Lead Author
Topics
- Novel Experimental/Analytic Approaches/Tools