Chronic Cluster Headache Clinical Trial
— LICITOfficial title:
Efficacy and Safety of Minidosing Lysergic Acid Diethylamide (LSD) for Chronic Cluster Headache: a Randomized Placebo-controlled Study
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.
Status | Not yet recruiting |
Enrollment | 65 |
Est. completion date | August 2025 |
Est. primary completion date | July 2025 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 16 Years to 75 Years |
Eligibility | 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 |
Country | Name | City | State |
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n/a |
Lead Sponsor | Collaborator |
---|---|
Radboud University Medical Center | Canisius-Wilhelmina Hospital, Donders Centre for Cognitive Neuroimaging, Leiden University Medical Center, ZonMw: The Netherlands Organisation for Health Research and Development |
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Other | Alcohol consumption | Units of alcohol consumed during baseline, treatment and follow-up | during the entire 12-week duration of the study | |
Other | PK-PD modelling | Correlation between individual pharmacokinetics of LSD and relative change of weekly attack frequency | Week 1 and 3 | |
Other | PK-PDimaging modelling: hypothalamus and diencephalo-mesencephalic structures | Correlation between individual pharmacokinetics of LSD and changes in functional connectivity between hypothalamus and diencephalo-mesencephalic structures on rsMRI, compared before and after a three-week treatment with 25µg LSD | Week 1 and 3 | |
Other | PK-PDimaging modelling: hypothalamus and TCC | Correlation between individual pharmacokinetics of LSD and changes in functional connectivity between hypothalamus and TCC on rsMRI, compared before and after a three-week treatment with 25µg LSD | Week 1 and 3 | |
Other | Functional connectivity changes in resting state networks associated with pain | Mapping treatment-related changes in intrinsic functional connectivity in resting state networks that have been associated with pain, such as the salience network, using (independent component analyses; ICA). | Week 1 and 3 | |
Other | Other MRI measures | T1 structural scan
Diffusion tensor imaging (DTI): to investigate changes in white matter tracks and their possible contribution to functional imaging findings. |
Week 1 and 3 | |
Primary | 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 | 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 | ||
Secondary | 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 | |
Secondary | =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 | |
Secondary | =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 | |
Secondary | 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 | |
Secondary | =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 | |
Secondary | =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 | |
Secondary | Mean change in weekly attack frequency in the entire 3 week treatment period compared to the 4-week baseline. | week 3 post-randomization | ||
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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. | |
Secondary | Pharmacokinetic (PK)-pharmacodynamic (PD) modelling | Plasma LSD concentrations on day 18 post-randomization frequency | Day 18 post-randomization | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 |
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