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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
65
LSD tartrate equivalent to 25 microgram LSD base
Placebo with equal appearance
Leiden University Medical Center (LUMC)
Leiden, Netherlands
RECRUITINGCanisius-Wilhelmina Ziekenhuis (CWZ)
Nijmegen, Netherlands
RECRUITINGMean change in weekly attack frequency, across treatments groups.
In week 3 post-randomization, compared to the 4-week baseline average per week
Time frame: week 3 of treatment
Mean change in weekly attack frequency across weeks 4-8 compared to the 4-week baseline and for each week separately.
Time frame: 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.
Rate of subjects with 100% reduction in weekly attack frequency compared to baseline
Time frame: week 3 post-randomization
≥50% reduction (50% responder rate) in number of weekly attacks in the third treatment week, compared to the 4-week baseline, across treatment groups.
Rate of subjects with more than 50% reduction in weekly attack frequency compared to baseline
Time frame: week 3 post-randomization
≥30% reduction (30% responder rate) in number of weekly attacks in the third treatment week, compared to the 4-week baseline, across treatment groups.
Rate of subjects with more than 30% reduction in weekly attack frequency compared to baseline
Time frame: week 3 post-randomization
100% reduction (remission rate) in number of weekly attacks across weeks 4-8 compared to the 4-week baseline and for each week separately.
Rate of subjects with 100% reduction in weekly attack frequency compared to baseline
Time frame: week 8 post-randomization
≥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.
Rate of subjects with 50% reduction in weekly attack frequency compared to baseline
Time frame: week 8 post-randomization
≥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.
Rate of subjects with 30% reduction in weekly attack frequency compared to baseline
Time frame: week 8 post-randomization
Mean change in weekly attack frequency in the entire 3 week treatment period compared to the 4-week baseline.
Time frame: week 3 post-randomization
Mean change in mean headache attack duration (minutes) per week, across treatment groups
In week 3 compared to the weekly average during 4-week baseline
Time frame: week 3 post-randomization
Mean change in mean headache attack duration (minutes) per week, across treatment groups
Across weeks 4-8 compared to the 4-week baseline and for each week separately.
Time frame: week 8 post-randomization
Mean change in mean headache attack severity (VAS 1-10), across treatment groups
In week 3 compared to the weekly average during 4-week baseline
Time frame: week 3 post-randomization
Mean change in mean headache attack severity (VAS 1-10), across treatment groups
Across weeks 4-8 compared to the 4-week baseline and for each week separately.
Time frame: week 8 post-randomization
Mean change in number of abortive medication use, across treatment groups
In week 3 compared to the weekly average during 4-week baseline
Time frame: week 3 post-randomization
Mean change in number of abortive medication use, across treatment groups
Across weeks 4-8 compared to the 4-week baseline
Time frame: week 8 post-randomization
Failure of sustained response'
Time to initiation of additional prophylactic treatment and/or GON-block during weeks 4-8, across treatment groups
Time frame: Weeks 4-8 post-randomization
Patient Global Impression of Change (PGIC)
Patient Global Impression of Change at week 3 post-randomization; scale 0-7, higher scores representing better improvement
Time frame: Day 21 post-randomization
Patient Global Impression of Change (PGIC)
Patient Global Impression of Change at week 8 post-randomization; scale 0-7, higher scores representing better improvement
Time frame: weeks 3 and 8
Health-related quality of life
Change from baseline in EQ-5D-5L Visual Analogue Scale (VAS) at weeks 3 and 8.
Time frame: weeks 3 and 8
Hospital Anxiety and Depression Score (HADS)
Change from baseline in Hospital Anxiety and Depression Scale (HADS) at weeks 3 and 8.
Time frame: weeks 3 and 8.
Pharmacokinetic (PK)-pharmacodynamic (PD) modelling
Plasma LSD concentrations on day 18 post-randomization frequency
Time frame: Day 18 post-randomization
Cost-effectiveness analysis (CEA) from a societal perspective comparing the LSD intervention with usual care.
Healthcare use and productivity losses will be measured by patient questionnaires (iMCQ, and iPCQ)
Time frame: Week 1, 3 and 8
Efficacy of treatment masking
measured as perceived treatment assignment on a 5-point scale (likely verum/possibly verum/don't know/possibly placebo/likely placebo).
Time frame: Week 1 and 3 post-randomization
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