E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Nocebo effects on pain and itch |
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E.1.1.1 | Medical condition in easily understood language |
Nocebo effects on pain and itch (i.e., expectancy effects that contribute to the persistence or aggravation of pain and itch symptoms). |
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E.1.1.2 | Therapeutic area | Body processes [G] - Physical Phenomena [G01] |
MedDRA Classification |
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 primary objective is to test the role of NMDA receptor-dependent learning in an experimental model of conditioned nocebo effects on self-reported pain (sub-study 1) and itch (sub-study 2). Secondary objectives are to examine the role of NMDA manipulations and related neural correlates during the induction, evocation, and attenuation of nocebo effects using statistical learning models. We also aim to explore neural differences between control stimulations and nocebo-augmented pain and itch. Lastly, the moderating effects of psychological variables measured with questionnaires on the nocebo effect will also be explored. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives for both sub-studies are: 1. To examine neural activations during the induction of nocebo effects on pain or itch. Multivariate pattern analysis will be used to investigate differences in BOLD responses during the induction of nocebo effects and thereby classify participants into pharmacological treatment groups. 2. To examine neural activations during the evocation of nocebo effects on pain or itch. 3. To explore neural activations between the experience of pain and itch. 4. To explore neural activations between the experience of nocebo-augmented sensations and the experience of control sensory stimulations. 5. To predict the magnitude of induced nocebo effects on pain or itch, based on patterns of BOLD responses during the induction of nocebo effects. 6. To explore whether psychological characteristics of catastrophizing, anxiety, body vigilance, or attitudes towards medication influence the magnitude of conditioned nocebo effects on pain and itch. |
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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 |
This study is comprised of two parallel sub-studies: Sub-study 1, on pain: "Manipulating NMDA-dependent learning to alter nocebo effects on PAIN: A pharmacological fMRI study". In this sub-study we aim to additionally investigate neural correlates and the effect of NMDA receptor manipulations on the counterconditioning of nocebo effects on pain through counterconditioning. Sub-study 2, on itch: "Manipulating NMDA-dependent learning to alter nocebo effects on ITCH: A pharmacological fMRI study". In this sub-study we aim to additionally investigate neural correlates and the effect of NMDA receptor manipulations on the extinction of nocebo effects on itch. |
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E.3 | Principal inclusion criteria |
To be eligible, participants must meet all of the following criteria: 1. Between 18 and 35 years of age 2. Good understanding of spoken and written English 3. Native Dutch speaker |
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E.4 | Principal exclusion criteria |
A potential subject who meets any of the following exclusion criteria will be excluded from participation in this study: 1. History of serious or chronic medical or psychiatric conditions 2. History of chronic pain or itch conditions 3. Experiencing pain or itch on the day of testing 4. Currently using antihistamines, analgesic medication, or itch-reducing medication (in the 12 hours prior to testing) 5. Recent use of psychotropic drugs (including recreational drugs such as cannabis and psychotropic prescription-medication; in the past month) 6. Currently being (or intending to become) pregnant, or currently breastfeeding 7. Colour-blindness 8. Body Mass Index under 16 or over 30 9. Meeting any exclusion criteria for entering the MR scanner (e.g., permanent metal parts in the body) 10. Having a too high threshold for pain (where high pain cannot be induced with temperatures lower than 49.5 °C) or not responding to histamine (no itch response) |
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E.5 End points |
E.5.1 | Primary end point(s) |
The main study parameter is the magnitude of induced nocebo effects on self-reported pain and itch in the first evocation phase as compared between the pharmacological groups. The magnitude of the induced nocebo effects on pain and itch is measured as the difference between self-reported pain and itch on a Numeric Rating Scales between conditioned and control evocation trials in early trials of the first evocation phase. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
During the single experimental session, in early trials of the first evocation phase for each sub-study. |
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E.5.2 | Secondary end point(s) |
Secondary study endpoints for both sub-studies are: - The classification accuracy (into pharmacological groups), indicating that patterns of activation in the network of a priori ROIs form a model that can detect differences in neural activations during the induction of nocebo effects. - The classification accuracy (into pharmacological groups), indicating that patterns of activation in the network of a priori ROIs form a model that can detect differences in neural activations during the first evocation phase. - The classification accuracy, indicating that patterns of activation in the network of a priori ROIs form a model that can detect commonalities and differences in neural activations between the experience of pain and itch. - The classification accuracy, indicating that patterns of activation in the network of a priori ROIs form a model that can detect common neural activations between the experience of nocebo-augmented pain and nocebo-augmented itch, thereby indicating a signature of activations relevant to the manifestation of nocebo effects, independent from sensory input. - The prediction accuracy, indicating that patterns of activation in the network of a priori ROIs form a model that can predict the magnitude of induced nocebo effects based on patterns of activations during the induction of nocebo effects. - The moderation of the magnitude of induced nocebo effects in the first evocation phase by scores on the psychological questionnaires.
Secondary parameters for the pain sub-study only: - The magnitude of nocebo effects on pain present after nocebo attenuation, between the pharmacological groups, as measured in early trials of the second evocation phase relative to early trials of the first evocation phase. - The classification accuracy (into pharmacological groups) indicating that patterns of activation in the network of a priori ROIs form a model that can detect differences in neural activations during the attenuation of nocebo effects.
Secondary parameters for the itch sub-study only: - Differences in the time course of extinction of nocebo effects on itch, as measured during the evocation phase between the pharmacological groups. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
During the single experimental session. |
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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 | 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 | Yes |
E.6.13.1 | Other scope of the trial description |
Research into fundamental (neurobiological) mechanisms |
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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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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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 | Yes |
E.8.2.3.1 | Comparator description |
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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 | 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 | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |