E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Surgical Procedures, Operative [E04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
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 movement and in pressure-evoked condition) and hyperalgesia six to eight weeks after unilateral, primary, open groin hernia repair with mesh-implantation (GHR). A three-step the target-controlled-infusion (TCI) model is employed. |
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E.2.2 | Secondary objectives of the trial |
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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 |
Pharmacokinetics of High-dose Target-controlled Naloxone Infusion. 2015-02-16 version 1.8 Since the pharmacokinetics of naloxone and its main-metabolite (naloxone-3-glucuronide), at the dose-levels used in this study (below or equals 3.5 mg/kg), are unknown, we have added a subset of volunteer participants in order to investigate the pharmacokinetic construct validity of the target-controlled-infusion (TCI) model. |
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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 inguinal, open groin hernia repair 6-8 weeks prior to study start. • Surgical procedure a.m. Lichtenstein. • 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/m2
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E.4 | Principal exclusion criteria |
• Participants, who do not speak or understand Danish • Participants, who cannot cooperate with the investigation • Participants, who have had previous surgery in the groin region • Participants with pain at rest > 3 (NRS) • 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 • Skin lesions or tattoos in the assessment areas • Nerve lesions in the assessment sites (e.g., after trauma, disc herniation, etc.) • Use of prescription drugs one week before the trial • Use of over-the-counter drugs 48 hours before the trial
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E.5 End points |
E.5.1 | Primary end point(s) |
(Abbreviations: BL = baseline; NRS = numerical rating scale (pain; 0 to 10); NX = naloxone; PL = placebo; TCI = during target-controlled-infusion): 1. The primary endpoint is based on a summated measure (SM) of resting pain (RP), movement-related pain (MP) and pressure evoked pain (PM). NRS(SM) = NRS(RP) + NRS(MP) + NRS(PM)
2. the summed pain intensities (SPIs) are calculated as: (BL-SPI[NX]) and (TCI-SPI[NX]), and, (BL-SPI[PL]) and (TCI-SPI[PL]), where (TCI-SPI) indicate SM-value at highest obtainable TCI-step (Fig. 2)
3. The summed pain intensity differences (SPIDs) are the differences: SPID[NX] = (TCI-SPI[NX]) – (BL-SPI[NX]) and SPID[PL] = (TCI-SPI[PL]) - (BL-SPI[PL])
4. The primary endpoint is SPIDs
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Baseline (pre-infusion; 0 min); Step 1 (TCI-infusion 1 [naloxone: 0.25 mg/kg]: 15 to 25 min); Step 2 (TCI-infusion 2 [naloxone: 0.75 mg/kg]: 39 to 49 min); Step 3 (TCI-infusion 3 [naloxone: 2.25 mg/kg]: 65 to 75 min). |
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E.5.2 | Secondary end point(s) |
Pressure pain thresholds (PPT) by algometry at the surgical site compared to the contralateral site, secondary hyperalgesia/allodynia areas at surgical site and contralateral site, psychometrics (Hospital Anxiety and Depression Scale [HADS], Pain Catastrophizing Scale [PCS]) and ratings by Clinical Opiate Withdrawal Scale (COWS).
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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 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).
Clinical Opiate Withdrawal Scale (COWS) 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]) and ratings by Clinical Opiate Withdrawal Scale (COWS) 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 | 6 |
E.8.9.1 | In the Member State concerned days | |