We're building a better ClinicalTrials.gov. Check it out and tell us what you think!
Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Minidosing Lysergic Acid Diethylamide (LSD) for Chronic Cluster Headache

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05477459
Recruitment Status : Not yet recruiting
First Posted : July 28, 2022
Last Update Posted : August 1, 2022
Sponsor:
Collaborators:
ZonMw: The Netherlands Organisation for Health Research and Development
Radboud University Medical Center
Leiden University Medical Center
Information provided by (Responsible Party):
Wim Mulleners, Canisius-Wilhelmina Hospital

Tracking Information
First Submitted Date  ICMJE July 5, 2022
First Posted Date  ICMJE July 28, 2022
Last Update Posted Date August 1, 2022
Estimated Study Start Date  ICMJE May 2023
Estimated Primary Completion Date May 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 25, 2022)
Mean change in weekly attack frequency, across treatments groups. [ Time Frame: week 3 of treatment ]
In week 3 post-randomization, compared to the 4-week baseline average per week
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 25, 2022)
  • Mean change in weekly attack frequency across, treatments [ Time Frame: week 8 post-randomization ]
    In week 8 post-randomization, compared to the 4-week baseline average per week
  • 50% responder and remission rate in week 3, across treatment groups [ Time Frame: week 3 post-randomization ]
    Rate of subjects with more than 50% or 100% reduction in weekly attack frequency compared to baseline
  • 50% responder and remission rate in week 8, across treatment groups [ Time Frame: week 8 post-randomization ]
    Rate of subjects with more than 50% or 100% reduction in weekly attack frequency compared to baseline
  • Mean change in mean headache attack duration per week, across treatment groups [ Time Frame: week 3 post-randomization ]
    In week 3 compared to the weekly average during 4-week baseline
  • Mean change in mean headache attack duration per week, across treatment groups [ Time Frame: week 8 post-randomization ]
    In week 8 compared to the weekly average during 4-week baseline
  • Mean change in mean headache attack severity, across treatment groups [ Time Frame: week 3 post-randomization ]
    Weekly average peak pain intensity on visual analogue scale (VAS) (scale 0-10, 10 meaning worse outcome)) in week 3 compared to baseline (headache diary)
  • Mean change in mean headache attack severity, across treatment groups [ Time Frame: week 8 post-randomization ]
    Weekly average peak pain intensity on visual analogue scale (VAS) (scale 0-10. 10 meaning worse outcome) in week 8 compared to baseline (headache diary)
  • Mean change in number of abortive medication use, across treatment groups [ Time Frame: week 3 post-randomization ]
    In week 3 compared to the weekly average during 4-week baseline (headache diary)
  • Mean change in number of abortive medication use, across treatment groups [ Time Frame: week 8 post-randomization ]
    In week 8 compared to the weekly average during 4-week baseline (headache diary)
  • Rescue treatment [ Time Frame: Weeks 3-8 post-randomization ]
    Proportion of subjects who required additional prophylactic treatment in weeks 3-8, across treatments
  • Patient Global Impression of Change (PGIC) [ Time Frame: Day 21 post-randomization ]
    Patient Global Impression of Change at week 3 post-randomization; scale 0-7, higher scores representing better improvement
  • Patient Global Impression of Change (PGIC) [ Time Frame: Day 56 post-randomization ]
    Patient Global Impression of Change at week 8 post-randomization; scale 0-7, higher scores representing better improvement
  • EuroQoL EQ-5D-5L [ Time Frame: At randomization ]
    Assessment with the 5-level EuroQoL-5D (EQ-5D-5L), a standardized instrument developed by the EuroQol Group as a measure of health-related quality of life; represented as an index value 0-1 in addition to a total score that ranges from 0-100 (visual analog scale), higher scores indicating better health-related quality of life
  • EuroQoL EQ-5D-5L [ Time Frame: Week 3 post-randomization ]
    Assessment with the 5-level EuroQoL-5D (EQ-5D-5L), a standardized instrument developed by the EuroQol Group as a measure of health-related quality of life; represented as an index value 0-1 in addition to a total score that ranges from 0-100 (visual analog scale), higher scores indicating better health-related quality of life
  • EuroQoL EQ-5D-5L [ Time Frame: week 8 post-randomization ]
    Assessment with the 5-level EuroQoL-5D (EQ-5D-5L), a standardized instrument developed by the EuroQol Group as a measure of health-related quality of life; represented as an index value 0-1 in addition to a total score that ranges from 0-100 (visual analog scale), higher scores indicating better health-related quality of life
  • Hospital Anxiety and Depression Score (HADS) [ Time Frame: At randomization ]
    Assessment with the 14-item HADS, an instrument to measure anxiety (range 0-21) and depression (0-21)
  • Hospital Anxiety and Depression Score (HADS) [ Time Frame: Week 3 post-randomization ]
    Assessment with the 14-item HADS, an instrument to measure anxiety (range 0-21) and depression (0-21)
  • Hospital Anxiety and Depression Score (HADS) [ Time Frame: Week 8 post-randomization ]
    Assessment with the 14-item HADS, an instrument to measure anxiety (range 0-21) and depression (0-21)
  • Pharmacokinetic (PK)-pharmacodynamic (PD) modelling [ Time Frame: Day 18 post-randomization ]
    Plasma LSD concentrations on day 18 post-randomization frequency
  • Success of masking of intervention assignment [ Time Frame: 3 weeks ]
    Perceived treatment assignment on a 5-point scale (likely verum/possibly verum/don't know/possibly placebo/likely placebo)
  • Alcohol consumption [ Time Frame: 3 weeks post-randomization ]
    Units of alcohol consumed during treatment
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Minidosing Lysergic Acid Diethylamide (LSD) for Chronic Cluster Headache
Official Title  ICMJE Efficacy and Safety of Minidosing Lysergic Acid Diethylamide (LSD) for Chronic Cluster Headache: a Randomized Placebo-controlled Study
Brief Summary

Randomized double-blind placebo-controlled trial of LSD 25μg every 3 days for 3 weeks versus placebo, followed by a 5-week post-treatment observation of persistence of efficacy, in chronic cluster headache (CCH).

Main research objective

  1. To assess the efficacy and utility of a 3-week course of LSD 25μg for the relief of CCH

    Additional research objectives

  2. To explore the persistence of effect at 8 weeks post-randomization
  3. To assess the safety and tolerability of a 3-weeks treatment regimen
  4. To assess the cost-effectiveness
  5. To model the correlation of pharmacokinetic variables and pharmacodynamics effects
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. Moreover, all are used off-label, may have side effects and safety issues limiting their utility, and efficacy may not persist over time. 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, potentially through repeated administration of safe transitional treatments in the long-term control of disease activity.

In this study, the investigators will assess the efficacy of interval treatment with LSD in CCH. Formal evidence for the efficacy of LSD in cluster headache is currently lacking. However, several lines of circumstantial evidence provide strong indications that LSD may have potential for 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 response at 5 weeks post-treatment (8 weeks postrandomization).

If these expectations are realized, LSD might be positioned as a transitional treatment that may outlast currently available options and pave the way for studying repeated transitional treatment as a novel preventive strategy for long-lasting relief with improved tolerability. The hurdle of a listed substance needs to be conquered by many patients and health care professionals, though.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description:
Study drug or placebo will be provided in 1-ml ampoules and are similar in appearance, taste and smell
Primary Purpose: Treatment
Condition  ICMJE Chronic Cluster Headache
Intervention  ICMJE
  • Drug: LSD tartrate
    LSD tartrate equivalent to 25 microgram LSD base
    Other Name: Lysergic acid diethylamide
  • Drug: Placebo
    Placebo vials with equal appearance
Study Arms  ICMJE
  • Experimental: Verum
    Lysergic diethylamide tartrate (equivalent to 25 microgram LSD base), one dose every 3 days for 3 weeks (totalling 7 vials)
    Intervention: Drug: LSD tartrate
  • Placebo Comparator: Placebo
    Placebo vial looking like verum vial, one vial every 3 days for 3 weeks (totalling 7 vials)
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: July 25, 2022)
65
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 2025
Estimated Primary Completion Date May 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Wim Mulleners, MD PhD +31 24 3658765 ext 2344 w.mulleners@cwz.nl
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT05477459
Other Study ID Numbers  ICMJE 131-2022
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Individual patient data underlying publication, after deidentification, will be shared upon request to the correspondeing author
Supporting Materials: Study Protocol
Time Frame: 9-36 months after article publication
Access Criteria: For purpose of meta-analysis and approved by an independent review board
Current Responsible Party Wim Mulleners, Canisius-Wilhelmina Hospital
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Canisius-Wilhelmina Hospital
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE
  • ZonMw: The Netherlands Organisation for Health Research and Development
  • Radboud University Medical Center
  • Leiden University Medical Center
Investigators  ICMJE
Principal Investigator: Wim Mulleners, MD PhD Canisius-Wilhelmina Hospital
PRS Account Canisius-Wilhelmina Hospital
Verification Date July 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP