| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Healthy volunteers (intended indication: pain) |
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| E.1.1.1 | Medical condition in easily understood language |
| Study in healthy volunteers to examine drug effects on biomarkers in experimental pain |
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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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10033371 |
| E.1.2 | Term | Pain |
| E.1.2 | System Organ Class | 10018065 - General disorders and administration site conditions |
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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 |
1. To test if the punctate evoked BOLD response in the posterior insula at 3 hours post-drug administration differs in pregabalin period as compared to the placebo period, at the sensitized leg.
2. To test if the resting state connectivity between SII and thalamus at 3 hours post-drug administration in the presence of sensitization differs in the pregabalin period as compared to the placebo period. |
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| E.2.2 | Secondary objectives of the trial |
1. To test if the punctate evoked BOLD response in the posterior insula at 1 hour post-drug administration differs in at least one analgesic treatment period as compared to the placebo period, at the sensitized leg.
2. To test if the resting state connectivity between SII and thalamus at 1 hour post-drug administration in the presence of sensitization differs in at least one analgesic treatment session as compared to the placebo session. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Provision of signed and dated informed consent form
Stated willingness to comply with all study procedures and regimens and availability for the duration of the study
Caucasian male or female subjects, aged 18 years to 45 years
Subjects must be in good health as determined by the medical history, physical and laboratory examinations and must not show any clinically significant deviations from reference ranges as determined by 12-lead electrocardiogram (ECG), vital signs (blood pressure, pulse rate and respiratory rate) and laboratory parameters (renal and hepatic function)
Body mass index >18 kg/m2 and < 30 kg/m2 with a minimum body weight of 45.0 kg and a maximum of 100kg (for men and women)
Ability to take oral medication
For female subjects of childbearing potential: use of highly effective contraception with a low failure rate defined as <1% per year for at least 1 month prior to screening and agreement to use such a method during study participation and for an additional 4 weeks after the end of study drug administration: -combined (estrogen and progestogen containing) hormonal contraception, -progestogen-only hormonal contraception associated with inhibition of ovulation, -an intra-uterine device (hormone-free), -an intra-uterine hormone releasing system (IUS). A woman of non-childbearing potential may be included if surgically sterile (i.e., after hysterectomy or bilateral oophorectomy) or post-menopausal for at least 2 years
Right hand dominance (assessed using the Edinburgh Handedness Inventory, and defined as a score ≥60) |
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| E.4 | Principal exclusion criteria |
Presence of any medical devices (e.g., cardiac pacemaker), implants or protheses unless it is beyond discussion that these will not put the subject’s safety during the study at risk and will not interfere with the results of the study
Known or suspected allergic reactions / hypersensitivity to components of lacosamide/Vimpat®.
Second- or third-degree atrioventricular (AV) block.
Known or suspected allergic reactions / hypersensitivity to components of pregabalin/Lyrica®.
Known or suspected allergic reactions / hypersensitivity to components of tapentadol / Palexia®.
Known contraindication for drugs with µ-opioid agonist activity, i.e., significant respiratory depression, acute or severe bronchial asthma or hypercapnia.
Present or suspected paralytic ileus.
Acute intoxication with alcohol, hypnotics, centrally acting analgesics, or psychotropic drugs.
Not willing or able to abstain from changes in physical exercise activities during the Study.
Any chronic pain condition or recent (i.e. within the preceding 2 years) history thereof.
Migraine (at least 1 attack in the last 24 months).
Recurrent headache or back pain on more than 5 days/month in the last 3 months.
Caffeine consumption of more than 8 servings of coffee, tea, or other caffeinated drinks per day. Each serving is approximately 120mg of caffeine.
Any relevant symptom of neurological dysfunction of the motor and sensory system that may interfere with the conduct of the study.
Clinically-evident psychiatric diseases (e.g. depression, anxiety).
History or symptoms of central nervous system disease or peripheral nerve lesions or dysfunction with sequelae that may impact the study assessments or that may deteriorate by one dose of a drug with anti-epileptic, noradrenergic or opioid activity.
Focused neurological examination showing signs of abnormality.
Active internal disease or sequelae of internal disease (e.g. diabetes mellitus, liver diseases, kidney diseases, cardiovascular diseases, hypo- or hyperthyroidism, hypertension etc.).
Diseases or conditions known to interfere with the distribution, metabolism, or excretion of drugs.
Clinically significant disease (e.g. medical history of infection with human immunodeficiency virus (HIV) Type 1 or Type 2, hepatitis B, or hepatitis C) or condition that may affect efficacy or safety assessments, or any other reasons which, in investigator´s opinion, may preclude the subject´s participation in the trial.
Not willing or able to abstain from alcohol from 48 hours prior to any study period and until the end of the study period.
Consumption of cannabis in the last 4 weeks prior to the study.
Evidence or history of alcohol or drug (opioids, amphetamines, benzodiazepines, cannabinoids) abuse (as defined by ICD-10 or DSM IV) including positive or missing drugs of abuse screen (urine drugs of abuse test). Consumption of more than 21 alcohol units per week for male subjects and more than 14 units per week for female subjects (1 alcohol unit = 1 beer [12 oz/355 mL] = 1 wine [5 oz/150 mL] = 1 liquor [1.5 oz/40 mL] = 0.75 oz/20 mL alcohol).
Habitually smoking more than 10 cigarettes, 2 cigars, or 2 pipes of tobacco per day within the last 6 months before enrollment in this trial.
Known or suspected of not being willing or able to comply with the requirements of the trial protocol or the instructions.
Inability to communicate meaningfully with the trial site staff (e.g. insufficient language skills).
Any person with direct involvement in the trial conduct; any person under the direct supervision of the investigator or dependent on the investigator.
Blood loss of 500 mL or more (e.g., owing to blood donation) within 3 months before enrollment in this trial.
Pregnancy, planned pregnancy or lactation.
Presence of dermatological conditions in the test areas of the study that would prevent the proper application of study procedures, such as electrodes for HFS, pinprick (dermatitis, psoriasis, contact eczema, local changes of the skin due to regularly playing volleyball etc.).
Failure to comply with local MR Centre MR screening form that assesses compatibility and safety for participating in an MR experiment at 3 Tesla.
Any other reason to exclude the subject according to judgment by the investigator |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoints are the evoked neural activity response in the posterior insula (first primary endpoint), and the functional connectivity between the thalamus and the secondary somato-sensory cortex (SII, second primary endpoint) in a centrally sensitized state, as measured by using BOLD signal at the second imaging time point (approx. 3h post dose). Here we use 2 functional neuroimaging signals using the BOLD signal. First one is the BOLD signal evoked by the pin-prick stimulus applied to the sensitized skin. The second is the BOLD signal obtained when the subjects are awake but resting. This resting BOLD signal will be used for assessing the functional connectivity between brain regions. The main outcome of interest is the comparison between pregabalin and placebo. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 3 hour post-drug administration |
|
| E.5.2 | Secondary end point(s) |
| Key secondary endpoints are defined like the two primary endpoints. However, here the defined time point is at the first imaging session, approx. 1h post dose. Other secondary endpoints are the changes from baseline (within period) in pin-prick ratings reported by the subjects when stimulating the hyperalgesic area of skin and the primary endpoints (i.e. evoked neural activity response in the posterior insula, and the functional connectivity between the thalamus and the secondary somato-sensory cortex in a centrally sensitized state, as measured by using pin-prick stimulus-evoked and resting BOLD signal) but for the comparison between tapentadol and placebo and between lacosamide and placebo. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
-1 hour post-drug administration
-changes from baseline within period |
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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 | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| The trial is meant to investigate the effects of lacosamide, pregabalin and tapentadol on biomarkers of pain processing observed by non-invasive functional magnetic resonance imaging (FMRI) of the brain. |
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| 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 | 4 |
| 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 | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 3 |
| 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
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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 | 2 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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