| 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 |
| A syndrome with chronic widespread pain in muscles and tendons that is present for at least 3 months. |
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| E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutic techniques [E02] |
| 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 investigate if pharmacological conditioning with S-ketamine reduces pain sensitivity in patients with FMS. |
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| E.2.2 | Secondary objectives of the trial |
- To investigate whether pharmacological conditioning with S(+)-ketamine compared to pharmacological conditioning with placebo medication reduces clinical pain intensity in patients with FMS.
- To investigate whether pharmacological conditioning with S(+)-ketamine reduces subjective disease impact in patients with FMS.
- To investigate whether pharmacological conditioning with S(+)-ketamine reduces side effects by ketamine in patients with FMS. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Diagnosed with FMS by a rheumatologist
- Females
- Age between 18 and 75 years old
- Dutch speaking participants
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| E.4 | Principal exclusion criteria |
- A medical diagnosis other than fibromyalgia explaining the chronic pain symptoms.
- Presence of hypertension or any other severe cardiovascular co-morbidity (e.g., heart failure (NYHA III or IV), neuromuscular diseases, pulmonary obstructive & restrictive diseases, kidney failure (eGFR ≤ 60), liver diseases or epilepsy)
- Presence of any severe psychiatric disease not related to symptoms of FMS (e.g., schizophrenia, schizoaffective disorders, severe anxiety or depression (HADS > 15), bipolar disorder, dissociative personality disorder, or (previous) addiction to strong analgesics.
- Presence of any allergy for S(+)-ketamine, midazolam, ondansetron or flumazenil
- Long term use of medicine that is contra-indicated when administering S(+)-ketamine or midazolam: NMDA-receptor antagonists, parasympathomimetics (e.g., bronchodilators), thyroid hormones, vasopressin, CYP3A4 liver enzyme inhibitors (e.g., verapamil, diltiazem, or certain antibiotics), CYP3A4 liver enzyme inductors (e.g., rifampicin, carbamazepine, fenytoin), and strong opioids (e.g., morphine, fentanyl, heroin)
- Previous experience(s) with S(+)-ketamine in a medical setting or previous experience with recreational racemic Ketamine use.
- Use of painkillers different than usual dose of treatment on the day of experimentation.
- Use of alcohol or drugs 24 hours prior to the hospital visits
- Use of caffeine 12 hours prior to the hospital visits
- Body weight > 100kg or BMI >35
- Presence of pregnancy or lactation
- Presence of an ICD, pacemaker or implanted medication pump
- Presence of chronic pain at the local site of experimental pain stimuli or monitoring devices.
- Implanted materials in either arm (e.g., non-removable piercings)
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The main goal for this study is to assess changes in pain sensitivity due to pharmacological conditioning with S(+)-ketamine compared to pharmacological conditioning with (combined) placebo medication. Pain sensitivity is quantified in this study by investigating the presence three different Quantitative Sensory Testing (QST) modalities; pain pressure thresholds (PPT’s), pressure wind-up pain and aftersensations. The QSTs in this study are executed with pressure stimuli (in kg) applied with a handheld analogue algometer capable of delivering 10kg of force (Force Dial; Wagner Instruments, Greenwhich CT, USA, see also D6.3 Manual Algometer). Pressure pain stimuli seem to be the most adequate method of QST application in patients with FMS as they correlate better to their clinical pain then for example heat pain stimuli, correlate to their CNS hyperexcitability (by means of increased glutamate levels) and respond well to ketamine treatment. The pressure stimuli are applied to the thenar muscles of the dominant hand and ipsilateral tibialis anterior muscle. These muscle areas are preferred because they can accurately display any signs of pain sensitivity, have shown acceptable reliability, are known to be sensitive to ketamine treatment, and are also accessible during testing. PPT’s are the main parameter for this study. The main endpoint is a difference between PPT levels at baseline and directly post-intervention (at T = 60mins) between the study groups. The PPT’s are examined by applying three different pressure stimuli (kg force) at three adjacent areas on the hand and lower leg. The three pressure stimuli necessary to evoke pain are then averaged out to calculate a mean pressure threshold in Kg force. The mean pressure thresholds are subsequently averaged out for body location, as a minimum role for body location is expected. PPT’s are preferred as the main parameter in this study as they:
1) Are able to reliably demonstrate pain hypersensitivity (due to central or peripheral causes) in patients with FMS.
2) Can always be defined.
3) Have shown good to excellent reliability in healthy controls (ICC > 0.7) as well as in patients with FMS (ICC = 0.85).
4) Are increased by S(+)-ketamine administration. PPT’s therefore seem to be a valid way of testing the analgesic effect of S(+)-ketamine on altered pain sensitivity in patients with FMS.
Hence, PPT’s are chosen as the primary measurement method for studying the effects of conditioning S(+)-ketamine in CS pain in this study.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| PPT's are measured at baseline (T=0mins) and directly after the end of study intervention infusion (T = 60mins). |
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| E.5.2 | Secondary end point(s) |
The first secondary endpoint is the conditioned effects of S(+)-ketamine on wind-up pain measured as the change from baseline and compared to the conditioned effects in the placebo groups. The phenomenon of wind-up pain can be measured with temporal summation, a dynamic QST modality. Temporal summation is assessed by applying pressure pain at pain threshold level while asking participants to rate the 1st, 5th, and 10th stimulus on an NRS scale. A single temporal summation or wind-up pain score is then obtained by subtracting the 1st stimulus from the 10th (final) stimulus. The wind-up pain is assessed at two body locations: the hand and lower leg and the wind-up pain score will be averaged out for both locations as a minimal influence is expected. Reliability of pressure temporal summation was investigated in musculoskeletal trauma patients and was moderate to excellent (ICC range 0.69–0.91). Temporal summation is a valid measure for detecting signs of CS pain and is therefore used in this study.
The second secondary endpoint is the conditioned effects of S(+)-ketamine on aftersensations measured as the change from baseline and compared to the conditioned effects in the placebo groups. The aftersensations are obtained by asking a participant to rate late pain (in NRS) 15 seconds after the 10th summation stimulus on the hand and lower leg and subtracting this pain score from the 10th score of the summation sequence. Similar to the wind-up pain and pressure pain thresholds, the scores for aftersensation of the hand and lower leg will be averaged out.
The third secondary endpoint is going to be the influence of body location on the QST’s (temporal summation, PPT and aftersensations). Although expected to be minimal, the effects of (conditioned) S(+)-ketamine and/or midazolam on QST’s for different body locations will be controlled for.
The fourth secondary endpoint is going to be the change in clinical pain intensity from baseline to directly post-intervention as a result of the pharmacological conditioning with S(+)-ketamine compared to pharmacological conditioning with (combined) placebo medication. Clinical pain intensity is measured with a 11-point numeric rating scale (NRS) ranging from 0 (no pain) to 10 (worst pain imaginable).
The fifth secondary endpoint is extinction of pharmacological conditioning with S(+)-ketamine compared to pharmacological conditioning with (combined) placebo medication is studied by measuring wind-up pain, PPT’s, aftersensation and clinical pain intensity at T = 60mins (directly post-intervention), 75mins, 90mins, 120mins, and 180mins. A significant decrease in difference scores (i.e., a diminishing of the conditioned effect) is considered evidence for extinction.
The sixth secondary endpoint is the change in Fibromyalgia subjective disease impact from baseline after pharmacological conditioning with S(+)-ketamine, assessed with the Fibromyalgia Impact Questionnaire – Revised (FIQ-R). The FIQ-R consists of 3 domains with a total of 21-items: the physical function domain has 9 items, the overall impact domain has 2 items and the symptom domain has 10 items. All items are scored on a 11-point numeric rating scale from 0 to 10, with 10 being the worst. The total maximum scores is 100 (scores are summed up per domain and then multiplied by the respective weight of the domain).
The seventh secondary endpoint is the presence of adverse effects due to the use of either S(+)-ketamine or midazolam. Psychotomimetic side effects will be assessed with the Bowdle questionnaire. The Bowdle questionnaire evaluates three psychedelic ketamine effects, drug high and changes in internal and external perception, from 13 questions scored on a 100-mm VAS scale from zero (no effect) to 100 (maximum effect). Nausea and vomiting is assessed as being present or absent (yes or no). Sympathomimetic side effects (tachy or bradycardia, hypo or hypertension, hypoxemia, and hypo or hyperthermia) are studied by measuring the following vital parameters: heart pulse (beats/min), blood oxygen saturation (percentage), systolic and diastolic blood pressure (mmHg), breathing rate (breaths/min), and temperature (degrees Celsius). Monitoring vital parameters is done with a pressure monitoring device, pulse oximeter, and thermometer. Central nervous system side effects (e.g., sedation or agitation) are monitored with the Ramsay Sedation Scale (RSS). The RSS consists of a 6-item scale ranging from 1 (patient is agitated and anxious) to 6 (patient exhibits no response). The overall psychometric properties of the RSS are considered of moderate quality.
Alternative endpoints which will be assessed are demographic variables: age, sex, disease length, educational level, body weight, use of escape medication, current use of medicine, accuracy of blinding, and anxiety and depression with the HADS scale.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- The conditioned effects of S(+)-ketamine on PPT, AS and clinical pain intensity, and the Bowdle and RSS questionnaire will be assessed at T = 0, 30, 60, 75, 90, 120, and 180 mins.
- The FIQ-R is assessed before every experiment and after one week during the acquisition and evocation phase.
- Vital parameters are assessed after every 5 minutes during the intervention and after every 15 minutes during the testing. |
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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 | Yes |
| 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 | 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) | 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 | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | |
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