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

Overview

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

• Drug LSD tartrate
  LSD tartrate equivalent to 25 microgram LSD base
• Drug Placebo
  Placebo with equal appearance

Primary outcome measures

• Mean change in weekly attack frequency, across treatments groups. [Time frame: week 3 of treatment]

Secondary outcome measures (12)

• 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. [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. [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. [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. [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. [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. [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 [Time frame: week 3 post-randomization]
• Mean change in mean headache attack duration (minutes) per week, across treatment groups [Time frame: week 8 post-randomization]
• Mean change in mean headache attack severity (VAS 1-10), across treatment groups [Time frame: week 3 post-randomization]
• Mean change in mean headache attack severity (VAS 1-10), across treatment groups [Time frame: week 8 post-randomization]

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Netherlands · 2 centers

• Leiden University Medical Center (LUMC) — Leiden
• Canisius-Wilhelmina Ziekenhuis (CWZ) — Nijmegen

Publications

• Hoffmann J, May A. Diagnosis, pathophysiology, and management of cluster headache. Lancet Neurol. 2018 Jan;17(1):75-83. doi: 10.1016/S1474-4422(17)30405-2. Epub 2017 Nov 23. PMID 29174963
• Rozen TD, Fishman RS. Cluster headache in the United States of America: demographics, clinical characteristics, triggers, suicidality, and personal burden. Headache. 2012 Jan;52(1):99-113. doi: 10.1111/j.1526-4610.2011.02028.x. Epub 2011 Nov 11. PMID 22077141
• Tepper SJ, Stillman MJ. Cluster headache: potential options for medically refractory patients (when all else fails). Headache. 2013 Jul-Aug;53(7):1183-90. doi: 10.1111/head.12148. Epub 2013 Jun 28. PMID 23808603
• McGeeney BE. Cannabinoids and hallucinogens for headache. Headache. 2013 Mar;53(3):447-58. doi: 10.1111/head.12025. Epub 2012 Dec 20. PMID 23278122
• Andersson M, Persson M, Kjellgren A. Psychoactive substances as a last resort-a qualitative study of self-treatment of migraine and cluster headaches. Harm Reduct J. 2017 Sep 5;14(1):60. doi: 10.1186/s12954-017-0186-6. PMID 28870224
• Sewell RA, Halpern JH, Pope HG Jr. Response of cluster headache to psilocybin and LSD. Neurology. 2006 Jun 27;66(12):1920-2. doi: 10.1212/01.wnl.0000219761.05466.43. PMID 16801660
• Schindler EA, Gottschalk CH, Weil MJ, Shapiro RE, Wright DA, Sewell RA. Indoleamine Hallucinogens in Cluster Headache: Results of the Clusterbusters Medication Use Survey. J Psychoactive Drugs. 2015 Nov-Dec;47(5):372-81. doi: 10.1080/02791072.2015.1107664. Epub 2015 Nov 23. PMID 26595349
• 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. PMID 30290701

Identifiers

NCT: NCT05477459 · 131-2022

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗