E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Healthy volunteers (n = 94) are included. The main study includes 14 subjects who have had an uncomplicated, impacted mandibular, third molar extraction 4-5 weeks prior to participation in the study. The sub-study includes 80 subjects who will receive a first degree heat injury. |
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E.1.1.1 | Medical condition in easily understood language |
Healthy volunteers (n = 94) including fourteen subjects who have had an uncomplicated, removal of a wisdom tooth 4-5 weeks prior to participation in the study. |
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E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Anesthesia and Analgesia [E03] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10049475 |
E.1.2 | Term | Chronic pain |
E.1.2 | System Organ Class | 100000004867 |
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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 |
The principal aim of the study is to investigate whether the administration of naloxone, a selective mu-opioid receptor (MOR) antagonist, can re-introduce pain (at rest, during mastication and during pressure-evoked condition) and hyperalgesia four to five weeks after unilateral, uncomplicated, impacted mandibular, third molar extraction (TME; n = 14). A three-step the target-controlled-infusion (TCI) model is employed. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives are assessments of: o Secondary hyperalgesia/allodynia area assessed by a polyamide monofilament at mandibular skin sites directly overlying surgical and contralateral side o Online Reaction Time o Hospital Anxiety and Depression Scale (HADS; only pre-infusion) o Pain Catastrophizing Scale (PCS; only pre-infusion) o Clinical Opiate Withdrawal Scale
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Thermal Injury; Sub-study (Protocol-HighNxTME_v1.4_ 16.11.2015) Naloxone-induced reinstatement of secondary hyperalgesia areas (SHA) one week after a first degree thermal injury (FTI) is studied in "hi-sensitizers" (HS) and "low-sensitizers" (LS), i.e., volunteers with large and small SHAs, respectively, two to three hours after the thermal injury. A preliminary FTI (n = 80) is used to separate volunteers into HS and LS, defined as the upper quartile (n = 20) and the lower quartile (n = 20), respectively, of SHAs. The primary objective is to ascertain the predictive value of the HS/LS-phenotype in predicting response to naloxone-induced reinstatement of secondary hyperalgesia.
Secondary objectives are: o Pain during BI (NRS) o Pin-prick pain thresholds assessed (PPT) by weighted-pin instruments at primary and secondary hyperalgesia areas o Online Reaction Time Hospital Anxiety and Depression Scale (HADS; only pre-FTI)
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E.3 | Principal inclusion criteria |
• Healthy male • Age above 18 yrs and below 65 yrs • Signed informed consent • Participants submitted to unilateral, primary, impacted, uncomplicated mandibular third molar extraction 4 weeks (+ 3 days) prior to examination Day 1 (main study). • Standardized surgical procedure (main study). • Urin-sample without traces of opioids (morphine, methadon, buprenorphine, codeine, tramadol, ketobemidone, oxycodone, hydromorphone, dextromethorphan) • ASA I-II • Body mass index (BMI): 18 < BMI < 30 kg/sq.m
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E.4 | Principal exclusion criteria |
• Participants, who cannot cooperate with the investigation • Participants, who have had previous surgery in the mandibular region (main study) • Participants with pain at rest > 3 (NRS [0: no pain; 10: worst perceivable pain]) • Activity-related pain in the surgical field > 5 (NRS) • Allergic reaction against morphine or other opioids (including naloxone), • Abuse of alcohol or drugs – according to investigator’s evaluation • Use of psychotropic drugs (exception of SSRI) • Neurologic or psychiatric disease • Chronic pain condition • Regular use of analgesic drugs • Nerve lesions in the assessment sites (e.g., after trauma, dental surgery) • Use of prescription drugs one week before the trial • Use of over-the-counter (OTC) drugs 48 hours before the trial • Scarring or tattoos in the examination areas |
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E.5 End points |
E.5.1 | Primary end point(s) |
(Abbreviations: BL = baseline; NX = naloxone; NRS = numerical rating scale; PL = placebo; TCI = during target-controlled-infusion): 1. a primary outcome based on a summed measure (SM) of resting pain (RP), masticatory pain (MP; (movement-related) and pressure-evoked pain (PM; pressure algometry [100 kPa]). NRS-SM = NRS-RP + NRS-MP + NRS-PM. 2. the summed pain intensities (SPIs) are calculated as: (BL-SPINX) and (TCI-SPINX), and, (BL-SPIPL) and (TCI-SPIPL), where (TCI-SPI) indicates SM-value at highest obtainable TCI-step (Fig. 2). 3. the summed pain intensity differences (SPIDs) are the differences: SPIDNX = (TCI-SPINX) – (BL-SPINX) and SPIDPL = (TCI-SPIPL) - (BL-SPIPL) 4. the primary endpoint is: ΔSPID = SPIDNX - SPIDPL (MIREDIF = 45%)
For the sub-study: 1. secondary hyperalgesia areas (SHAs) are measured at BL and during highest obtainable TCI-level 2. Differences are calculated: (TCI-SHANX – BL-SHANX) and (TCI-SHAPL - BLSHAPL) 3. the primary endpoint is: Δ SHA = (TCI-SHANX – BL-SHANX) - (TCI-SHAPL - BLSHAPL). MIREDIF is not possible to calculate due to the exploratory nature of the sub-study.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Summed measures (SM) of resting pain (RP), masticatory pain (MP; (movement-related) and pressure-evoked pain are assessed at Baseline (pre-infusion; 0 min); Step 1 (TCI-infusion1: 15 to 25 min); Step 2 (TCI-infusion 2: 39 to 49 min); Step 3 (TCI-infusion 3: 65 to 75 min).
For the sub-study: Assessments of SHAs at Baseline (pre-infusion; 0 min); Step 1 (TCI-infusion 1: 15 to 25 min); Step 2 (TCI-infusion 2: 39 to 49 min); Step 3 (TCI-infusion 3: 65 to 75 min).
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E.5.2 | Secondary end point(s) |
* Pressure pain thresholds (PPT) and secondary hyperalgesia/allodynia areas are assessed at Baseline (pre-infusion; 0 min); Step 1 (TCI-infusion1: 15 to 25 min); Step 2 (TCI-infusion 2: 39 to 49 min); Step 3 (TCI-infusion 3: 65 to 75 min). * Clinical Opiate Withdrawal Scale (COWS) and Online Reaction Time assessments are made at Baseline (pre-infusion; 0 min); Step 1 (TCI-infusion 1: 13 to 15 min); Step 2 (TCI-infusion 2: 37 to 39 min); Step 3 (TCI-infusion 3: 63 to 65 min). * Psychometrics (Hospital Anxiety and Depression Scale [HADS], Pain Catastrophizing Scale [PCS]) are only assessed at Baseline (pre-infusion; 0 min).
For the sub-study: * Pain during FTI (NRS; 0,1,2,3,4,5,6 and 7 min after thermal injury). * Pin-prick pain thresholds (PPT) assessed by weighted-pin instruments at primary and secondary hyperalgesia areas (0, 1, 2, 165 and 165-169 hrs (during TCI [time; 15 to 25 min; 44 to 4 min'; and 70 to 75 min]) after TFI. * Clinical Opiate Withdrawal Scale (COWS) and Online Reaction Time assessments are made at Baseline (pre-infusion; 0 min); Step 1 (TCI-infusion 1: 13 to 15 min); Step 2 (TCI-infusion 2: 37 to 39 min); Step 3 (TCI-infusion 3: 63 to 65 min). * Hospital Anxiety and Depression Scale (HADS; only pre-FTI) * Pain Catastrophizing Scale (PCS; only pre-FTI) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
* Pressure pain thresholds (PPT) and secondary hyperalgesia/allodynia areas are assessed at Baseline (pre-infusion; 0 min); Step 1 (TCI-infusion1: 15 to 25 min); Step 2 (TCI-infusion 2: 39 to 49 min); Step 3 (TCI-infusion 3: 65 to 75 min). * Clinical Opiate Withdrawal Scale (COWS) and Online Reaction Time assessments are made at Baseline (pre-infusion; 0 min); Step 1 (TCI-infusion 1: 13 to 15 min); Step 2 (TCI-infusion 2: 37 to 39 min); Step 3 (TCI-infusion 3: 63 to 65 min). * Psychometrics (Hospital Anxiety and Depression Scale [HADS], Pain Catastrophizing Scale [PCS]) are only assessed at Baseline (pre-infusion; 0 min).
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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 | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
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 | No |
E.8.1.6 | Cross over | Yes |
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 | 2 |
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 | Yes |
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
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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 | 1 |
E.8.9.1 | In the Member State concerned days | |