Chronic Neuropathic Pain
Conditions
Keywords
3, 4-methylenedioxymethamphetamine hydrochloride, Chronic Neuropathic Pain
Brief summary
This is a Health Canada regulated internal pilot study designed to assess the feasibility, tolerability, and preliminary efficacy of 3, 4-methylenedioxymethamphetamine hydrochloride capsules-AT for chronic neuropathic pain to inform a larger, fully powered multi-center study. This is an interventional, randomized, 2-arm parallel, triple blinded study. The total study duration is 2 years. Participants will receive preparatory psychotherapy session during week 2 and week 4 followed by a combined single dosing session with psychotherapy during week 6. Integrative psychotherapy will follow at weeks 6, 8, 12, and 16. Follow up for primary clinical endpoint at week 16; final follow up for secondary clinical endpoint at 16-weeks. Participants will be asked to complete adjunctive home psychotherapy in the form of online modules. Data collected will be entered in electronic case report form (REDCap Academic).
Detailed description
Primary objective: To demonstrate the feasibility of conducting the full EASE Pain trial by achieving targets in recruitment, data completion rate, blinding integrity, minimal serious drug-related adverse events, and by identifying barriers and facilitators to the full trial. Secondary objectives (full trial): To evaluate whether a 120 mg dose of oral 3,4-methylenedioxymethamphetamine with an optional 40mg supplementary dose leads to meaningful improvements in pain interference at 16-weeks in patients with moderate-to-severe chronic neuropathic pain compared to active-placebo, and assess changes in physical function, physical activity, emotional function, overall rating of improvement, and adverse events over 16 weeks. Study type: Intervention trial Allocation: Randomized Intervention model: 2-Arm Parallel Group Primary purpose: Feasibility Phase: Phase II Blinding: Triple blinded (patient- outcome assessor- and psychotherapist-blinded) Total study duration: 2 years Duration for each subject: 16 weeks. Preparatory psychotherapy from week 1 to 5; a single dosing session with psychotherapy at week 6 and integrative psychotherapy at weeks 7 to 16. Follow up for primary clinical endpoint and final follow up at week 16. Dosage regimen: Treatment arm: 3,4-methylenedioxymethamphetamine 120mg (3 x 40mg capsule) PO single dose plus psychological support; optional 40mg supplemental dose at 2hr mark if there are no tolerability issues reported, patient consents and lead physician deems appropriate. (Maximum dose 160mg) Placebo arm: Methylphenidate 30mg (3 x 10mg capsule) PO single dose plus psychological support; optional 10mg supplemental dose at 2hr mark if there are no tolerability issues reported, patient consents and lead physician deems appropriate. (Maximum dose of 40 mg) Treatment/ assessment visits: Week -1: Screening Week 1: Baseline data collection, psychotherapy workbook 1 (preparation) Week 2: Psychotherapy preparatory session 1 Week 3: Psychotherapy workbook 2 (preparation) Week 4: Psychotherapy preparation session 2 Week 5: Psychotherapy workbook 3 (preparation) Week 6: (Day 0): Randomization to drug and experimental session with in-person psychotherapy (Day 1) Psychotherapy integration session 1 Week7: Psychotherapy workbook 4 (integration). Questionnaire and AE follow up Week 8: Psychotherapy integration session 2 Week 9 to 11 Psychotherapy workbook 5 (integration) Week 10: Questionnaire and AE follow up Week 12: Psychotherapy integration session 3 Week 13 to 15: Psychotherapy workbook 6 (integration) Week 16: Psychotherapy integration session 4. Primary clinical end point (Questionnaires and Adverse Event (AE) follow up)
Interventions
Treatment arm: 3,4-Methylenedioxymethamphetamine 120mg (3 x 40mg capsule) PO single dose plus psychological support; optional 40mg supplemental dose at 2hr mark if there are no tolerability issues reported, patient consents and lead physician deems appropriate. (Maximum dose 160mg)
DRUGMethylphenidate
Placebo arm: Methylphenidate 30mg (3 x 10mg capsule) PO single dose plus psychological support; optional 10mg supplemental dose at 2hr mark if there are no tolerability issues reported, patient consents and lead physician deems appropriate. (Maximum dose of 40 mg)
Sponsors
Unity Health Toronto
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Intervention model description
Preparatory psychotherapy from week 1 to 5; a single dosing session with psychotherapy at week 6 and integrative psychotherapy at weeks 7 to 16. Follow up for primary clinical endpoint and final follow up at week 16.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Consenting adults 18 years and older. * Diagnosis of chronic neuropathic pain (greater than 3 months in duration) by a clinician with specialized training in chronic pain, confirmed with the standardized Leeds Assessment of Neuropathic Symptoms and Signs questionnaire. * Suffering from moderate-to-severe pain as defined by * Baseline Patient Reported Outcomes Measurement System - Pain Interference (PROMIS-PI) score of greater than or equal to 60 * An average pain intensity of greater than or equal to 5 on a 0-10 numeric rating scale,43 * Treatment-refractory pain as defined by a failure of ≥2 medications recommended in the Canadian consensus guidelines on the management of CNP to generate self-reported meaningful improvement in symptoms. * For participants of childbearing potential, use of a highly effective or double-barrier methods of contraception. Abstinence is acceptable if it is the preferred and usual lifestyle of the participant. * Sufficient English skills to participate in psychotherapy.
Exclusion criteria
* Past or current history of a psychotic disorder, mania, hypomania, bipolarity, current suicidal ideation, stimulant use disorder (i.e., cocaine, amphetamine, methamphetamine, MDMA, methylphenidate (Ritalin), etc , and any other substance use disorder within the past 12 months assessed by history and confirmed the Mini-International Neuropsychiatric Interview \[MINI\]. Other secondary psychiatric comorbidities (e.g., anxiety disorders, trauma related disorders, other personality disorders. etc.) will not be excluded * Participants with a history of suicide attempts are not excluded unless a significant risk of suicidal behavior is present at the time of screening as determined by the CRSS (Columbia suicide rating scale) * History of prior MDMA use (excluded to maintain blinding integrity) * Long QT syndrome, measured by an ECG with a QTc more than 450 ms for males, and 470 ms for females. * Presence of a relative or absolute contraindication to MDMA or Methylphenidate: * Pre-existing cardiovascular disorders evidenced in clinical records or disclosed on patient self-report, such as: uncontrolled hypertension (sustained blood pressure ≥160/100 mmHg), angina (ongoing angina at rest, recent hospitalization for acute coronary syndrome within the past 3 months, or a history of revascularization (e.g., stenting or bypass surgery) within the past 6 months), arterial occlusive disease; heart failure, hemodynamically significant congenital heart disease, cardiomyopathies, myocardial infarction (within the past 6 months), potentially life-threatening arrhythmias (new-onset within the last 3 months), arrhythmias causing hemodynamic instability (SBP \< 90 mm Hg), or requiring urgent intervention (e.g., atrial fibrillation with rapid ventricular response or ventricular tachycardia), channelopathies, aneurysmal vascular disease (e.g., thoracic and/or abdominal aorta, intracranial, and peripheral arterial vessels), advanced arteriosclerosis * Cerebrovascular conditions: acute stroke or recent history of intracerebral hemorrhage (ischemic or hemorrhagic stroke occurring within the past 6 months) * Conditions at risk of elevation of blood pressure and increase heart rate, such as glaucoma, tension, agitation, thyrotoxicosis, pheochromocytoma * Motor tics and/or family history or diagnosis of Tourette's syndrome * Moderate to severe chronic kidney disease or kidney failure, such as requiring dialysis, significant treatment adjustments for kidney function, or regular nephrologist follow-up) * Moderate to severe liver disease, such as cirrhosis, a history of significant jaundice unrelated to temporary illness, or any liver condition requiring regular monitoring by a specialist). * Current treatment with selective serotonin reuptake inhibitors (SSRI's) and serotonin-norepinephrine reuptake inhibitors (SNRI's), tricyclic antidepressants, serotonin 5-HT1 receptor agonists (triptans) and 5-HT3 receptor antagonist antiemetics (risk of Serotonin Syndrome) * Hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption (methylphenidate contains lactose) * Seizure disorders * Pregnancy, or breastfeeding * Known hypersensitivity to study drugs or any study drug excipients * Medications that interact with study drugs including: * Any lifetime history use of any stimulant medication (e.g., Adderall, Vyvanse, Ritalin) * Caffeine intake within 24 hours * Monoamine oxidase inhibitors (MAOI) within 14 days (e.g. phenelzine, moclobemide, isoniazid, linezolid, phenelzine, harmine) due to risk of hypertensive crisis * CYP2D6 substrates and modifiers (such as: buproprion, fluoxetine, paroxetine, duloxetine, mirabegron). * Adrenergic agents (e.g. clonidine) risk of sudden death * Vasopressor agents (ephedrine pseudoephedrine) * Coumarin anticoagulants (e.g., warfarin), * Anticonvulsants (e.g., phenobarbital, diphenylhydantoin, primidone) * Anti-psychotics and inhibitors of dopamine uptake (e.g. haloperidol, DOPA, tricyclic antidepressants) * Concomitant medication that could prolong ECG QT interval (e.g. ondansetron, risperidone, methadone) * Selective Serotonin Reuptake Inhibitors (citalopram, sertraline, fluvoxamine, escitalopram) * Selective Norepinephrine Uptake Inhibitors (e.g. venlafaxine, duloxetine); Serotonergic Drugs (e.g. dextromethorphan, fentanyl, St. John's Wort, tramadol, 5-hydroxytryptophan); serotonin 5-HT1 receptor agonists (triptans) and 5-HT3 receptor antagonist antiemetics due risk of Serotonin Syndrome which is a potentially life- threatening condition * Currently engaged in psychotherapy for CNP (other psychotherapy for non-CNP is allowed). * Any other clinically significant medical illness that, in the opinion of the investigator, may interfere with the interpretation of the study results or constitute a health risk for the participant if they take part in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The primary outcome of this pilot trial is to determine feasibility of a large-scale, multi-center trial. | 16 weeks | Average Monthly recruitment of \>1 participant per center means that the full trial should meet recruitment requirements within 12 months. |
| Secondary feasibility outcome | 16 weeks | Data completion rate (of primary clinical outcome)≥ 80% |
| Participant Retention | 16 weeks | Retention of ≥80% of participants at the reported primary outcome point of 16 weeks after the experimental session should minimize attrition bias in the definitive trial's primary outcome data (e.g. withdrawal due to side-effects) |
| Blinding | 16 weeks | Blinding Integrity (≤80% of participants in both arms correctly guess their treatment allocation (Note: 50% of participants would be expected to correctly guess treatment allocation due to chance alone) |
| Adverse Events | 16 weeks | ≤3 serious drug-related adverse events |
| Secondary Feasibility Outcome | 16 weeks | identification of patient, clinician and researcher-identified trial barriers using qualitative methods (e.g. interviews at the end of the study with participants who provides consent ) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Patient-Reported Outcomes Measurement Information System (PROMIS) pain Intensity, Pain Interference and Physical Function Scale | Week 1, Week 7, Week 11 and Week 16 | In the past 7 days patients to rate their pain on average- 0 scale-indicates No pain and 10 scale- indicates Worst imaginable pain |
| Patient Health Questionnaire (PHQ-9) | Week 1, Week 7, Week 11 and Week 16 | Over the last 2 weeks how often the patient has been bothered by daily activities on a scale of 0 to 3. 0 (Not at all) and 3 (Nearly every day) |
| Generalized Anxiety Disorder 7-Item (GAD-7) Questionnaire | Week 1, Week 7, Week 11 and Week 16 | Over the last 2 weeks, how often patients have been bothered by anxiety on a scale of 0 to 3. 0 equals Not at all and 3 equals Nearly every day |
| The Post traumatic Stress Disorder Checklist for Diagnostic and Statistical Manual for Mental Disorder-5 (PCL-5) | Week 1, Week 7, Week 11 and Week 16 | Over the past month, how patients were bothered by internal and external feelings like stress, negativity etc. This is measured on a scale of 0 (Not at all) to 4 (Extremely) |
| Health Questionnaire (EQ-5D-5L) | Week 1, Week 7, Week 11 and Week 16 | Patients to describe how their health is affected in terms of mobility, self-care, Usual activities like (work, study, family), Pain/Discomfort, Anxiety/Depression on a scale of 0( Worst health you can imagine) to 100 (Best health you can imagine) |
| The Patient Global Impression of Change Scale (PGIC) | Week 7, Week 11 and Week 16 | This questionnaire measures how the patient impression changed before being enrolled in the study. Measured in a scale of 1 (Very much Improved) to 7 ( Very Much Worse) |
| The Toronto Side Effect Scale (TSES) | Week 7, Week 11 and Week 16 | This questionnaire measures patient's symptoms in the last two weeks for Agitation, tremor, twitching etc in terms of frequency and Severity in a scale of 1 (Never) to 5 (Every day) |
| STAR-P | Week 7, Week 11 and Week 16 | This questionnaire measures patient's perception and attitude regarding the clinician on a scale of 0 (Never) to 4 (Always) |
| Subjective Drug Effects (VAS) | Week 6 | On a scale of 0 (Not at all) to 10 (Extremely) patients to describe their experience during intervention session regarding the subjective drug effects |
Countries
Canada
Contacts
CONTACTAkash Goel, MD,MPH,FRCPC
PRINCIPAL_INVESTIGATORAkash Goel, MD,MPH,FRCPC
Unity Health Toronto
Outcome results
None listed