LSD to Improve Cluster Headache Impact Trial

Study Overview
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Brief Summary
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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 assess the effect of treatment with 25μg LSD on hypothalamic functional connectivity in patients with cCH, using resting state functional magnetic resonance imaging (rsMRI). To explore cost-effectiveness of treatment with LSD in cCH. To evaluate the efficacy of LSD on health-related quality of life.

Detailed Description
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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. The functional connectivity between the hypothalamus and other brain regions that are relevant in the psychophysiology of cluster headache has yet to be investigated in a placebo-controlled study. The implementation of pre- and post-treatment resting state functional MRI (rsMRI) in the placebo-controlled LICIT study presents a unique opportunity to verify the selectivity of previous fMRI findings pertaining to cluster headache, to further elucidate the potential involvement of the trigeminal cervical complex (TCC) in cluster headache pathophysiology, and to acquire a more profound comprehension of the neural regions and networks that are significant to the effector mechanism(s) of LSD in the context of cluster headache. This study can examine whether a change in the presumed cluster headache-specific brain regions and networks is related to the individual pharmacokinetics of LSD. Moreover, by correlating changes in functional connectivity with clinical outcome measures, the clinical relevance of these changes can be explored. By distinguishing between responders and non-responders, this study could be the first step in identifying an imaging biomarker as a predictor of treatment effect.

Official Title
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Efficacy and Safety of Minidosing Lysergic Acid Diethylamide (LSD) for Chronic Cluster Headache: a Randomized Placebo-controlled Study

Conditions
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Chronic Cluster Headache

Intervention / Treatment
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* Drug: LSD tartrate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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 (stimulator on) 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

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Verum<br>Lysergic diethylamide tartrate (equivalent to 25 microgram LSD base), one dose every 3 days for 3 weeks (totalling 7 vials) | Drug: LSD tartrate<br>* LSD tartrate equivalent to 25 microgram LSD base<br>* Other names: Lysergic acid diethylamide;|
| Placebo Comparator: Placebo<br>Placebo vial looking like verum vial, one vial every 3 days for 3 weeks (totalling 7 vials) | Drug: Placebo<br>* Placebo vials with equal appearance<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change in weekly attack frequency, across treatments groups. | In week 3 post-randomization, compared to the 4-week baseline average per week | week 3 of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Rate of subjects with 100% reduction in weekly attack frequency compared to baseline | 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 | 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 | 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 | 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 | 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 | week 8 post-randomization | 
| 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 | In week 3 compared to the weekly average during 4-week baseline | 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. | 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 | 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. | 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 | 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 | 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 | 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 | 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 | 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. | 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. | weeks 3 and 8. | 
| Pharmacokinetic (PK)-pharmacodynamic (PD) modelling | Plasma LSD concentrations on day 18 post-randomization frequency | 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) | 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). | Week 1 and 3 post-randomization | 
| Adapted Cluster Headache Quality of Life Questionnaire | Change from baseline in Adapted Cluster Headache Quality of Life Questionnaire (CHQ) at weeks 3 and 8 | weeks 3 and 8 post-randomization | 
| Change in functional connectivity between hypothalamus and diencephalo-mesencephalic structures | Change in functional connectivity between hypothalamus and diencephalo-mesencephalic structures on rsMRI, using a seed-based analysis, compared before and after a three-week treatment with 25µg LSD or placebo. | Day 1 and week 3 post randomization | 
| Change in functional connectivity between hypothalamus and TCC | Change in functional connectivity between hypothalamus and TCC on rsMRI, using a seed-based analysis, compared before and after a three-week treatment with 25µg LSD or placebo. | Day 1 and week 3 post randomization | 
| Resting state functional MRI correlates: hypothalamus and diencephalic-mesencephalic structures | Correlation between changes in functional connectivity between hypothalamus and diencephalo-mesencephalic structures on rsMRI and changes in weekly average number of cluster headache attacks, compared before and after a three-week treatment with 25µg LSD or placebo | Day 1 and week 3 post randomization | 
| Resting state functional MRI correlates: hypothalamus and TCC | Correlation between changes in functional connectivity between hypothalamus and TCC on rsMRI and changes in weekly average number of cluster headache attacks, compared before and after a three-week treatment with 25µg LSD or placebo. | Day 1 and week 3 post randomization | 
| Resting state functional MRI correlates in responders and non-responders: hypothalamus and diencephalic-mesencephalic structures | The difference in functional connectivity changes between the hypothalamus and diencephalic-mesencephalic structures on rsMRI in patients with cluster headache who achieved ≥30% reduction (30% responder rate) compared to those who achieved <30% reduction in the number of weekly attacks, for both verum and placebo. | Day 1 and week 3 post randomization | 
| Resting state functional MRI correlates in responders and non-responders: hypothalamus and TCC | The difference in functional connectivity changes between the hypothalamus and TCC on rsMRI in patients with cluster headache who achieved ≥30% reduction (30% responder rate) compared to those who achieved <30% reduction in the number of weekly attacks, for both verum and placebo. | Day 1 and week 3 post randomization |