Clinical trial NCT05477459: LSD to Improve Cluster Headache Impact Trial
Official title: Efficacy and Safety of Minidosing Lysergic Acid Diethylamide (LSD) for Chronic Cluster Headache: a Randomized Placebo-controlled Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Chronic Cluster Headache
Keywords: Chronic cluster headache
Lysergic acid diethylamide
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
Collaborators: name: ZonMw: The Netherlands Organisation for Health Research and Development
name: Canisius-Wilhelmina Hospital
name: Leiden University Medical Center
First posted: 2022-07-28
Enrollment: 65
Sex: ALL
Minimum age (years): 16
Maximum age (years): 75
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Mean change in weekly attack frequency, across treatments groups.
timeFrame: week 3 of treatment
Secondary outcomes:
measure: Mean change in weekly attack frequency across weeks 4-8 compared to the 4-week baseline and for each week separately.
timeFrame: week 8 post-randomization
measure: 100% reduction (remission rate) in number of weekly attacks in the third treatment week, compared to the 4-week baseline, across treatment groups.
timeFrame: week 3 post-randomization
measure: ≥50% reduction (50% responder rate) in number of weekly attacks in the third treatment week, compared to the 4-week baseline, across treatment groups.
timeFrame: week 3 post-randomization
measure: ≥30% reduction (30% responder rate) in number of weekly attacks in the third treatment week, compared to the 4-week baseline, across treatment groups.
timeFrame: week 3 post-randomization
measure: 100% reduction (remission rate) in number of weekly attacks across weeks 4-8 compared to the 4-week baseline and for each week separately.
timeFrame: week 8 post-randomization
measure: ≥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.
timeFrame: week 8 post-randomization
measure: ≥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.
timeFrame: week 8 post-randomization
measure: Mean change in weekly attack frequency in the entire 3 week treatment period compared to the 4-week baseline.
timeFrame: week 3 post-randomization
measure: Mean change in mean headache attack duration (minutes) per week, across treatment groups
timeFrame: week 3 post-randomization
measure: Mean change in mean headache attack duration (minutes) per week, across treatment groups
timeFrame: week 8 post-randomization
measure: Mean change in mean headache attack severity (VAS 1-10), across treatment groups
timeFrame: week 3 post-randomization
measure: Mean change in mean headache attack severity (VAS 1-10), across treatment groups
timeFrame: week 8 post-randomization
measure: Mean change in number of abortive medication use, across treatment groups
timeFrame: week 3 post-randomization
measure: Mean change in number of abortive medication use, across treatment groups
timeFrame: week 8 post-randomization
measure: Failure of sustained response'
timeFrame: Weeks 4-8 post-randomization
measure: Patient Global Impression of Change (PGIC)
timeFrame: Day 21 post-randomization
measure: Patient Global Impression of Change (PGIC)
timeFrame: weeks 3 and 8
measure: Health-related quality of life
timeFrame: weeks 3 and 8
measure: Hospital Anxiety and Depression Score (HADS)
timeFrame: weeks 3 and 8.
measure: Pharmacokinetic (PK)-pharmacodynamic (PD) modelling
timeFrame: Day 18 post-randomization
measure: Cost-effectiveness analysis (CEA) from a societal perspective comparing the LSD intervention with usual care.
timeFrame: Week 1, 3 and 8
measure: Efficacy of treatment masking
timeFrame: Week 1 and 3 post-randomization
Other outcomes:
measure: Alcohol consumption
timeFrame: during the entire 12-week duration of the study
measure: PK-PD modelling
timeFrame: Week 1 and 3
Locations:
city: Leiden
country: Netherlands
facility: Leiden University Medical Center (LUMC)
city: Nijmegen
country: Netherlands
facility: Canisius-Wilhelmina Ziekenhuis (CWZ)
Study officials:
affiliation: Radboud University Medical Center
name: Kees Kramers, Prof.
role: PRINCIPAL_INVESTIGATOR
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citation: de Coo IF, Naber WC, Wilbrink LA, Haan J, Ferrari MD, Fronczek R. Increased use of illicit drugs in a Dutch cluster headache population. Cephalalgia. 2019 Apr;39(5):626-634. doi: 10.1177/0333102418804160. Epub 2018 Oct 5.