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] - Anesthesia and Analgesia [E03] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
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 pharmacokinetics of naloxone and its main-metabolites at the dose-levels used in this study (< 3.5 mg/kg), are unknown. We examine the pharmacokinetic construct validity of the target-controlled-infusion (TCI) model in volunteer participants. |
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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 |
Effect of High-dose Target-controlled Naloxone Infusion on Pain and Hyperalgesia in Patients following Groin-Hernia-Repair. A Randomized, Placebo-controlled, Double-blind Crossover Study. 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 35 yrs • Signed informed consent • Urin-sample without traces of opioids (morphine, methadon, buprenorphine, codeine, tramadol, ketobemidone, oxycodone, hydromorphone, dextro-methorphan) • American Society of Anesthesthesiologists' Physical Status score: ASA I • 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 with pain at rest > 3 (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 • 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) |
The primary endpoints are standard pharmacokinetic parameters. These pharmacokinetic analyses will be undertaken using NONMEM (7.3 ICON Development Solutions, Manchester, U.K. [property of UCSF, U.S.]). One-, two- and three-compartment models will be assessed to decide the best structural model and different error models for the unexplained residual variability will be tested. Between-subject variability will be assessed and covariates such as age and weight might be included in the model. Model selection decisions will be based on a number of different criteria, including a reduction in the objective function value produced by NONMEM, plots of predicted concentrations and visual predictive plots generated from simulations. The final model and pharmacokinetic parameters obtained from this study (high naloxone dose) will be compared with the model and pharmacokinetic parameters used for the simulations (low naloxone dose data) in order to verify the simulations done.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Blood-samples (BS) for pharmacokinetic (PK) analyses will be taken: * Baseline (preinfusion; 0 min) * Step 1 (TCI-infusion 1 [naloxone: 0.25 mg/kg; 0 to 25 min]: BS 17, 20 and 23 min) * Step 2 (TCI-infusion 2 [naloxone: 0.75 mg/kg; 25 to 50 min]: BS 41, 44 and 47 min) * Step 3 (TCI-infusion 3 [naloxone: 2.25 mg/kg; 50 to 75 min]): BS 67, 70 and 75 min) * Post-TCI-infusion (75 to 340 min): BS 76, 77, 78, 79, 80, 82, 86, 94, 110, 142, 206 and 334 min
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E.5.2 | Secondary end point(s) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | No |
E.8.2.3 | Other | No |
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 | |