Chronic Cluster Headache
Conditions
Keywords
Chronic cluster headache, Lysergic acid diethylamide
Brief summary
This study aims to investigate the efficacy and safety of LSD 25μg every 3 days for 3 weeks versus placebo in the treatment of chronic cluster headache (cCH). It is a 3-week double-blind placebo-controlled intervention study, preceded by a 4-week baseline observation period and followed by a 5-week post-treatment observation period. Primary objective: to evaluate the efficacy of LSD 25μg every 3 days for 3 weeks in cCH. Additional objectives: * To evaluate the safety of LSD 25μg every 3 days for 3 weeks in cCH. * To explore the exposure-response relationship of 25μg LSD in cCH. * To explore cost-effectiveness of treatment with LSD in cCH. * To evaluate the efficacy of LSD on health-related quality of life.
Detailed description
Treatment of cluster headache consists of acute remedies for attacks (mainly 100% O2, sumatriptan), transitional treatment for temporary frequency reduction (subcutaneous steroid injection at the greater occipital nerve (GON block), oral steroids or frovatriptan) and prolonged prophylaxis (e.g. verapamil, lithium, topiramate). Although the latter compounds have shown some efficacy in reducing the attack frequency, the evidence for their effect is weak. All current prophylactics are prescribed off-label and are limited in their utility due to associated side effects. Despite treatment, many (notably chronic) cluster headache patients continue suffering headache attacks. Invasive, expensive treatments like hypothalamic deep brain stimulation, occipital nerve stimulation and sphenopalatine ganglion stimulation are last resort options. Recently, a monoclonal antibody targeting calcitonin gene related peptide (CGRP) received FDA approval for episodic cluster headache, but was shown to be ineffective in cCH. Thus, there is a considerable unmet need for effective treatments that are better tolerated, safe and affordable. In this study, the investigators will assess the efficacy of prophylactic treatment with LSD in cCH. The evidence for the efficacy of LSD is limited, with the majority of data originating from case reports or uncontrolled and retrospective (internet) surveys. Nevertheless, these studies do provide indications that LSD may hold potential as a cluster headache prophylaxis. The primary objective of this randomized double-blind placebo-controlled trial is to compare the efficacy of LSD 25μg every 3 days for 3 weeks versus placebo in cCH. The investigators aim to show that, at the end of treatment, verum is more efficacious than placebo with comparable tolerability in an ambulatory setting. To explore the sustainability of benefit the investigators will also assess the (sustained) response at 5 weeks post-treatment (8 weeks postrandomization). If the study findings are positive, LSD should be further studied before use in routine clinical practice. Non-hallucinogenic low-dosed LSD may provide an alternative or adjunctive option for patients who do not respond to or cannot tolerate currently available treatments.
Interventions
DRUGLSD tartrate
LSD tartrate equivalent to 25 microgram LSD base
DRUGPlacebo
Placebo with equal appearance
Sponsors
ZonMw: The Netherlands Organisation for Health Research and Development
Canisius-Wilhelmina Hospital
Leiden University Medical Center
Radboud University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Study drug or placebo are similar in appearance, taste and smell
Intervention model description
3-week double-blind placebo-controlled intervention study, preceded by a 4-week baseline observation period and followed by 5 weeks post-treatment observation period.
Eligibility
Sex/Gender
ALL
Age
16 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* CCH according to the International Classification of Headache Disorders version 3 (ICHD-3) * At screening: stable weekly attack frequency in the 4 weeks prior to screening (assessed retrospectively), averaging at least 8 per week and each week within a 40% window around the average * At randomization: average of at least 8 attacks per week and no absence of attacks on more than two consecutive days during baseline
Exclusion criteria
* Use of excluded concomitant treatment at screening (lithium; other prophylactics if not on a stable dose for less than one month; steroids/GON block within 2 months before screening; sphenopalatinum block, neurostimulation (changed setting within 3 months before screening) or botulinum toxin within 3 months before screening) and during the double-blind phase * Use of LSD(-derivatives) (other than investigational drug), psilocybin, ketamine or cannabis within 3 months prior to screening and throughout the study * Lifetime and/or family history (first degree relatives) of psychotic or bipolar disorder, suicidal intention or attempt * A score of 6 or more on the 'Ervaringenlijst' (PQ-16) to exclude subclinical susceptibility to psychosis * Actual abuse of alcohol and/or recreational drugs * Lifetime history of cardiac valvular disease * History or evidence of cognitive disorder at screening * Positive urine drug screen at screening * Females: Pregnancy, lactation, no acceptable contraceptive use
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean change in weekly attack frequency, across treatments groups. | week 3 of treatment | In week 3 post-randomization, compared to the 4-week baseline average per week |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean change in weekly attack frequency across weeks 4-8 compared to the 4-week baseline and for each week separately. | week 8 post-randomization | — |
| 100% reduction (remission rate) in number of weekly attacks in the third treatment week, compared to the 4-week baseline, across treatment groups. | week 3 post-randomization | Rate of subjects with 100% reduction in weekly attack frequency compared to baseline |
| ≥50% reduction (50% responder rate) in number of weekly attacks in the third treatment week, compared to the 4-week baseline, across treatment groups. | week 3 post-randomization | Rate of subjects with more than 50% reduction in weekly attack frequency compared to baseline |
| ≥30% reduction (30% responder rate) in number of weekly attacks in the third treatment week, compared to the 4-week baseline, across treatment groups. | week 3 post-randomization | Rate of subjects with more than 30% reduction in weekly attack frequency compared to baseline |
| 100% reduction (remission rate) in number of weekly attacks across weeks 4-8 compared to the 4-week baseline and for each week separately. | week 8 post-randomization | Rate of subjects with 100% reduction in weekly attack frequency compared to baseline |
| ≥50% reduction (50% responder rate) in number of weekly attacks across weeks 4-8 compared to the 4-week baseline and for each week separately. | week 8 post-randomization | Rate of subjects with 50% reduction in weekly attack frequency compared to baseline |
| ≥30% reduction (30% responder rate) in number of weekly attacks across weeks 4-8 compared to the 4-week baseline and for each week separately. | week 8 post-randomization | Rate of subjects with 30% reduction in weekly attack frequency compared to baseline |
| Mean change in weekly attack frequency in the entire 3 week treatment period compared to the 4-week baseline. | week 3 post-randomization | — |
| Mean change in mean headache attack duration (minutes) per week, across treatment groups | week 3 post-randomization | In week 3 compared to the weekly average during 4-week baseline |
| Cost-effectiveness analysis (CEA) from a societal perspective comparing the LSD intervention with usual care. | Week 1, 3 and 8 | Healthcare use and productivity losses will be measured by patient questionnaires (iMCQ, and iPCQ) |
| Efficacy of treatment masking | Week 1 and 3 post-randomization | measured as perceived treatment assignment on a 5-point scale (likely verum/possibly verum/don't know/possibly placebo/likely placebo). |
| Mean change in mean headache attack severity (VAS 1-10), across treatment groups | week 3 post-randomization | In week 3 compared to the weekly average during 4-week baseline |
| Mean change in number of abortive medication use, across treatment groups | week 3 post-randomization | In week 3 compared to the weekly average during 4-week baseline |
| Failure of sustained response' | Weeks 4-8 post-randomization | Time to initiation of additional prophylactic treatment and/or GON-block during weeks 4-8, across treatment groups |
| Patient Global Impression of Change (PGIC) | Day 21 post-randomization | Patient Global Impression of Change at week 3 post-randomization; scale 0-7, higher scores representing better improvement |
| Health-related quality of life | weeks 3 and 8 | Change from baseline in EQ-5D-5L Visual Analogue Scale (VAS) at weeks 3 and 8. |
| Hospital Anxiety and Depression Score (HADS) | weeks 3 and 8. | Change from baseline in Hospital Anxiety and Depression Scale (HADS) at weeks 3 and 8. |
| Pharmacokinetic (PK)-pharmacodynamic (PD) modelling | Day 18 post-randomization | Plasma LSD concentrations on day 18 post-randomization frequency |
Other
| Measure | Time frame | Description |
|---|---|---|
| Alcohol consumption | during the entire 12-week duration of the study | Units of alcohol consumed during baseline, treatment and follow-up |
| PK-PD modelling | Week 1 and 3 | Correlation between individual pharmacokinetics of LSD and relative change of weekly attack frequency |
Countries
Netherlands
Contacts
Primary ContactJulia Jansen, MD
Outcome results
None listed