| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Healthy male or female participants scheduled for surgical removal of an impacted mandibular third molar, where bone removal is judged to be needed. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Healthy male or female participants scheduled for surgical removal of an impacted mandibular third molar, where bone removal is judged to be needed. |
|
| E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Dentistry [E06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10050327 |
| E.1.2 | Term | Dental surgery NOS |
| E.1.2 | System Organ Class | 100000004865 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
-To investigate the postoperative analgesic efficacy of intranasal
sufentanil, intranasal ketamine and intranasal CT001, in adults following impacted mandibular third molar extraction.
- To assess the relationship between analgesic efficacy and the plasma
concentrations of intranasal sufentanil, intranasal ketamine and intranasal
CT001. |
|
| E.2.2 | Secondary objectives of the trial |
-To investigate the dose-response relationship of intranasal sufentanil,
intranasal ketamine and intranasal CT001.
- To investigate the safety and tolerability of intranasal sufentanil, intranasal ketamine and intranasal CT001. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Healthy (The American Society of Anaesthesiologists’ Physical Classification System (ASA) I-II) male or female participants scheduled
for surgical removal of an impacted mandibular third molar, where bone removal is judged to be needed.
2. Ability to understand spoken and written Danish
3. Written informed consent for participation in the study
4. Age: > 18 and < 55 years
5. Body Mass index above (>)18.5 or below (<) 30.0 kg/m2
6. Physical examination, including blood pressure, pulse rate, ECG and laboratory assessment without clinically significant abnormalities. A
potential participant with measurements outside of the reference range for the population being studied may be included at the investigator´s
discretion provided the finding is unlikely to introduce additional risk factors, jeopardize study integrity, or to interfere with the study assessments or procedures.
7. A woman of childbearing potential is eligible to participate if she is not pregnant, nor breastfeeding, and agrees to follow the contraceptive guidance during the treatment period for at least 7 days after administration of study treatment
8. Prior to randomisation: Numeric Pain Rating Scale (NRS anchored by 0 = “no pain”, 10 = “worst pain imaginable”) ≥ 5 at rest within 4 hours after the administration of the last dose of local anaesthetic |
|
| E.4 | Principal exclusion criteria |
1. Current or history of any clinically significant disease or disorder, which, in the opinion of the investigator, may put the potential subject at risk when
participating in the study, or influence the potential subject’s ability to participate in the study or influence the study results.
2. Any clinically significant illness, medical/surgical procedure or trauma within 4 weeks of the administration of investigational product that is likely
to introduce additional risk factors, jeopardize study integrity, or to interfere with the study assessments or procedure
3. History of increased bleeding tendency
4. Clinically significant mental illness
5. Opioid Risk Tool score of >3
6. Pain Catastrophizing Scale score, total points >30
7. Hospital Anxiety and Depression Scale (HADS), points ≥11 for anxiety or
≥11 points for depression
8. Daily intake of analgesics
9. Daily use of tobacco, including snuff
10. History of alcohol or drug abuse or use of illicit drugs or positive screen for drugs of abuse at screening or on admission to the Clinic prior to the administration of the investigational medicinal product.
11. Use of prescription drugs within 14 days (including low-dose acetylsalicylic acid [<150 mg/day]) or over-the-counter drugs 24 hours
except paracetamol, which is allowed until 6 pm the day before surgery (intranasal medication 48 hours, ibuprofen max 400 mg/day) prior to the
first dose of study medication, unless it is the opinion of the Investigator that the medication will not interfere with the study procedures or
compromise the participant.
12. Any scheduled invasive treatment or medical/surgical procedure during the study period, except surgical removal of an impacted mandibular third
molar
13. Abnormal nasal cavity/airway such as: a. evidence of previous significant nasal disorder including
surgery, or dependence of inhaled drug b. current significant nasal congestion due to common cold
c. minimum air flow during the nasal passages (evaluated at the investigator’s discretion)
14. History or presence of hypersensitivity or allergy to sufentanil, ketamine, NSAIDs or local anaesthetics, a history of anaphylactic or anaphylactoid
reactions, or a history of other allergy that, in the opinion of the investigator, contraindicates the participation.
15. Positive COVID-19 test or clinical symptoms of COVID-19 (testing of potential participants will follow the health authorities’ guidelines and
current local guidelines)
16. Is currently participating in or has participated in an interventional clinical trial with an investigational compound or device within 30 days of signing the informed consent for this trial
17. Previous randomisation to treatment in the present study
18. Blood or plasma donation within 4 weeks prior to the dosing procedure visit (Visit 3 [Day 0]).
19. Chronic pain as judged by the investigator |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy:
• The sum of pain intensity differences (SPID) at 55 min (corresponding to the first dose) derived from pain intensity scores measured by the Numerical Rating Scale (NRS) (0-10, 0= no pain, 10= worst possible pain).
Concentration-effect relationship:
• Estimates of population pharmacokinetic (PK) parameters required to adequately describe the time profiles of ketamine, the time profiles of sufentanil, and an estimate of the potential change in PK of ketamine in the presence of sufentanil, and an estimate of the potential change in PK of sufentanil in the presence of ketamine. Population PK modelling is data driven and therefore the exact PK parameters cannot be pre-specified, but will describe the absorption, distribution, elimination, and potential interaction of the two compounds.
Estimates of population pharmacokinetic-pharmacodynamic (PK-PD)
parameters required to adequately describe the relationship between
the PK time profiles and the effect on pain intensity. Population PKPD
modelling is data driven and therefore the exact PK-PD
parameters cannot be pre-specified but will describe the impact of
changes in concentrations on the pain intensity time profiles. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The sum of pain intensity differences (SPID) at 55 min (corresponding to the first dose) derived from pain intensity scores measured on the Numerical Rating Scale (NRS) (0-10, 0= no pain, 10= worst pain imaginable)
PK-analyses are collected at baseline, and time points 5 (+ 2), 10 (+ 3), 15 (+ 3), 30 (+ 3), 55 (+ 4), 65 (+ 3), 80 (+ 3), 95 (+ 3), 110 (+ 3), 140 (+ 4), 180 (+ 4) min post-first-dose of IMP. |
|
| E.5.2 | Secondary end point(s) |
Key secondary variables:
• Maximum Pain intensity difference (PIDmax)
• “Time to meaningful relief” defined as the time when participants feel that the “pain relief becomes meaningful to them”. If meaningful relief is not achieved the participants’ onset time is censored with the maximum time of the study i.e. 180 min.
• The sum of pain intensity differences (SPID) at 30 min derived from pain intensity scores at rest measured by the NRS (0-10)
• Numbers of participants receiving rescue medication until 180 min post dose
• Responder/non-responder at 30 minutes after first dose: Two different responder criteria will be used:
- at least 30% reduction in pain intensity score (or mild pain (NRS 1-3)) compared to baseline
- at least 50% reduction in pain intensity scores (or mild pain (NRS 1-3))
• The sum of pain intensity differences (SPID) at 90 min (corresponding to the first and second dose) derived from pain intensity scores measured on NRS 0-10
Other secondary variables:
• “Time to first perceptible pain relief” defined as the time of the
administration of the first dose to the time when participants “first feel any pain relief”. If first perceptible relief is not achieved; the participants’ onset time will be censored with the maximum time of the study i.e. 180 min.
• Time to rescue medication
• Mean pain intensity difference (PID) from baseline at rest at measurement time points (5, 10, 15, 20, 30, 40, 55, 65, 70, 75, 90, 105, 120, 140, 160, and 180 min post dose)
• Mean pain intensity difference (PID) from baseline on jaw movement at measurement time points (16, 31, 56, 91, 121, 161, 181 min post dose)
• Ramsay sedation score (1= agitated, anxious, restless, 6= unarousable) (time points baseline, 4, 9, 14, 19, 29, 39, 54, 64, 69, 74, 89, 104, 119, 139, 159, and 179 min post dose)
- Median time to a request for rescue medication |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 16 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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