- ICH GCP
- US-Register für klinische Studien
- Klinische Studie NCT07681869
Effects of Nimodipine on Alcohol Drinking
A Randomized Controlled Study on the Effects of Nimodipine on Alcohol Drinking Among Adults Who Are Heavy Alcohol Drinkers
Studienübersicht
Status
Bedingungen
Intervention / Behandlung
Detaillierte Beschreibung
Participants with AUD who drink heavily, will participate in a double-blind, placebo-controlled, cross-over design. At baseline, eligible participants will complete an MRI scan at the Yale MR center and MEG/EEG at the VA MIND Center. ADP Lab sessions will be conducted in the CNRU at the Connecticut Mental Health Center.
Nimodipine is rapidly absorbed after oral administration & peak concentrations are achieved within 0.5 to 1.5 hours. However, due to high first-pass metabolism, initial elimination is rapid (equivalent to a half-life of 1-2 hours); consequently, the bioavailability of nimodipine is approximately 13% after oral administration and there is a need for frequent dosing. The terminal elimination half-life of nimodipine is approximately 8 to 9 hours. In order to ensure adequate exposure and CNS bioavailability investigators will follow the administration schedule used in the Krupitsky trial*1. In this study 26 alcohol-dependent patients (who had not consumed alcohol for a month) received treatment with 90 mg dose of nimodipine (in the schedule portrayed below) prior to ketamine administration; results suggest that this dose of nimodipine reduced ketamine-induced psychosis, negative symptoms, euphoria and sedation as well as the perceived similarity of ketamine effects to alcohol. While the Krupitsky trial*1 did not report any adverse events following exposure to this dose investigators will closely monitor blood pressure and adverse events during the treatment period prior to the ADP 1 (vitals monitored at time of each dosing and again 30 minutes, 1 hour, and 2 hours after each dose).
Participants will receive either NIM or PLA in random order, during two sessions, separated by 3-5 washout days (to allow flexibility in scheduling). NIM/PLA will be provided at a dose of 90 mg/every 6 hours, over an 18-hour period (4 doses totaling 360mg), with the last dose administered approx. 1-2 hours prior to the start of the ADP period at 12 pm. MEG/EEG will be obtained 1-2 hours after the 3rd dose of NIM/PLA. During the two ADP sessions, participants will receive a priming dose of alcohol followed by a one-hour monitoring period. This will be followed by three one-hour self-administration periods; during each hour they will be able to choose between four drinks or monetary equivalents of these drinks (total of 12 drinks over three hours). ADP outcomes will include number of drinks consumed, alcohol craving, mood changes and alcohol effects, physiological measures (heart rate, blood pressure), as well as blood alcohol levels.
Participants will have 2 follow-up visits at 1-week and 1-month after the ADP session.
Studientyp
Einschreibung (Geschätzt)
Phase
- Phase 2
Kontakte und Standorte
Studienkontakt
- Name: Thomas Liss
- Telefonnummer: 2034447545
- E-Mail: thomas.liss@yale.edu
Studieren Sie die Kontaktsicherung
- Name: Nicholas Franco
- Telefonnummer: 2039745759
- E-Mail: nicholas.franco@yale.edu
Studienorte
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Connecticut
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New Haven, Connecticut, Vereinigte Staaten, 06519
- Yale University School of Medicine (Connecticut Mental Health Center)
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Teilnahmekriterien
Zulassungskriterien
Studienberechtigtes Alter
- Erwachsene
Akzeptiert gesunde Freiwillige
Beschreibung
Inclusion Criteria:
- Ages 21-50 (The lower limit is to avoid offering alcohol to individuals below the drinking age of 21. The upper age is determined by experience recruiting for our prior studies).
- Ability to read English at 6th grade level or higher.
- Meet DSM-V criteria for at least moderate AUD.
- Average weekly alcohol consumption of 30-70 standard drinks for men and 20-65 drinks for women. The lower limits are consistent with the lower sex-specific cut-offs defining high-risk drinking based on World Health Organization Risk Levels (WHO, 2000); the upper limits are designed to avoid recruiting participants whose drinking is likely to exceed the number of drinks available in the alcohol drinking paradigm (ADP).
Exclusion Criteria:
- Individuals who are seeking alcohol treatment or have been in alcohol treatment within the past 6 months.
- Meet current DSM-V criteria for substance use disorder, except for tobacco use disorder or mild cannabis use disorder.
- Positive urine drug screens at more than 1 baseline appointment for opiates, cocaine, benzodiazepines, and barbiturates.
- Psychotic or other severe psychiatric disorders as determined by clinical evaluation.
- Regular use of psychoactive drugs, except for individuals on a stable dose of an antidepressant for at least 2 months.
- Medical conditions that would contraindicate the consumption of alcohol or use of nimodipine including untreated or not adequately controlled hypertension or hypotension. Blood pressure at or below 100/65 will be exclusionary.
- Heart rate of less than 50 bpm.
- Clinically significant abnormalities in screening laboratories, including aspartate aminotransferase (AST) >3 times upper limit of normal (ULN); alanine aminotransferase (ALT) > 3 times ULN; total bilirubin >1.5 times ULN; serum creatinine >2.0 times ULN.
- Concurrent use of the following medications: CYP3A4 inhibitors and inducers, other calcium channel blockers, or other blood pressure lowering medications.
- Neurological trauma or disease, delirium, or hallucinations, or clinically significant or unstable medical conditions, including uncontrolled hypertension or diabetes, or significant cardiac, pulmonary, renal, hepatic, endocrine, or other systemic diseases, which in the opinion of the study physician and PI, may put the patient at risk because of participation in the study.
- Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar) scores of 8 or greater or a history of significant repeated alcohol withdrawals to reduce the likelihood of withdrawal symptomatology if subjects reduce their drinking.
- Women who are pregnant or nursing.
- Participants who refuse to use a reliable method of birth control from the time of first medication administration to 7 days after. These include oral contraceptives, contraceptive sponge, patch, double barrier (diaphragm/spermicidal or condom/spermicidal), intrauterine contraceptive system, etonogestrel implant, medroxyprogesterone acetate contraceptive injection, complete abstinence from sexual intercourse, hormonal vaginal contraceptive ring, surgical sterilization, or true abstinence.
- Subjects who report disliking spirits will be excluded because hard liquor will be provided during the ADP.
- Subjects who have taken any investigational drug within 4 weeks of the anticipated date of the first study dose.
- Individuals who report heavy drinking days in the 2 days prior to their intake appointment but have a negative ethyl glucuronide (EtG) test to rule out subjects who are misrepresenting their drinking history.
- Subjects who have donated blood within the past 6 weeks.
- Heart rate of less than 50 bpm.
- Subjects with a history or presence of cirrhosis.
- MRI contraindications including incompatible implants, other metal in body (e.g. pacemakers, shrapnel, metal implants) or claustrophobia.
Studienplan
Wie ist die Studie aufgebaut?
Designdetails
- Hauptzweck: Sonstiges
- Zuteilung: Zufällig
- Interventionsmodell: Crossover-Aufgabe
- Maskierung: Verdreifachen
Waffen und Interventionen
Teilnehmergruppe / Arm |
Intervention / Behandlung |
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Experimental: Nimodipine 1st / Placebo 2nd
Participants randomized to the Nimodipine 1st Arm will be administered Nimodipine prior to their 1st ADP session.
Then after a washout period, participants will take a matching placebo prior to the 2nd lab session.
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Nimodipine 90mg/dose or matching placebo will be administered every 6 hours for the duration of 18 hours (approx 6pm, 12am, 6am, 12pm).
In total, participants will receive a total of 4 doses totaling to 360mg.
Matching placebo will be administered on the same schedule as Nimodipine, every 6 hours for the duration of 18 hours (approx 6pm, 12am, 6am, 12pm).
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Experimental: Placebo 1st / Nimodipine 2nd
Participants randomized to the Placebo1st Arm will be administered matching placebo prior to their 1st ADP session.
Then after a washout period, participants will be administered Nimodipine prior to the 2nd lab session.
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Nimodipine 90mg/dose or matching placebo will be administered every 6 hours for the duration of 18 hours (approx 6pm, 12am, 6am, 12pm).
In total, participants will receive a total of 4 doses totaling to 360mg.
Matching placebo will be administered on the same schedule as Nimodipine, every 6 hours for the duration of 18 hours (approx 6pm, 12am, 6am, 12pm).
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Was misst die Studie?
Primäre Ergebnismessungen
Ergebnis Maßnahme |
Maßnahmenbeschreibung |
Zeitfenster |
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Number of drinks consumed
Zeitfenster: ADP Lab Session 1 (Day 1) and ADP Lab Session 2 (3-5 days later)
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Total number of drinks (out of 12) that were consumed during each of the two alcohol drinking paradigm (ADP) session.
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ADP Lab Session 1 (Day 1) and ADP Lab Session 2 (3-5 days later)
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Alcohol Craving using Yale Craving Scale
Zeitfenster: ADP Lab Session 1 (Day 1) and ADP Lab Session 2 (3-5 days later)
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Stimulation effect collected using the Biphasic Alcohol Effect Scale.
Brief Biphasic Alcohol Effects Scale-Stimulation subscale, measuring stimulation effects of alcohol on an 11-point rating scale from 0=Not at All to 10=Extremely, total scores ranging from 0 - 30, with higher measurements indicating higher stimulation.
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ADP Lab Session 1 (Day 1) and ADP Lab Session 2 (3-5 days later)
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Stimulation Effect
Zeitfenster: ADP Lab Session 1 (Day 1) and ADP Lab Session 2 (3-5 days later)
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Stimulation effect collected using the Biphasic Alcohol Effect Scale.
Brief Biphasic Alcohol Effects Scale-Stimulation subscale, measuring stimulation effects of alcohol on an 11-point rating scale from 0=Not at All to 10=Extremely, total scores ranging from 0 - 30, with higher measurements indicating higher stimulation.
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ADP Lab Session 1 (Day 1) and ADP Lab Session 2 (3-5 days later)
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Sedation Effect
Zeitfenster: ADP Lab Session 1 (Day 1) and ADP Lab Session 2 (3-5 days later)
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Stimulation effect collected using the Biphasic Alcohol Effect Scale.
Brief Biphasic Alcohol Effects Scale-Sedation subscale, measuring sedation effects of alcohol on Day 7, 6 items, 11-point rating scale from 0=Not at All to 10=Extremely, total scores ranging from 0 - 30, with higher measurements indicating higher sedation.
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ADP Lab Session 1 (Day 1) and ADP Lab Session 2 (3-5 days later)
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Sekundäre Ergebnismessungen
Ergebnis Maßnahme |
Maßnahmenbeschreibung |
Zeitfenster |
|---|---|---|
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Change in Systolic Blood Pressure
Zeitfenster: Medication dosing/ADP Lab Session 1 (Day 1) and medication dosing/ADP Lab Session 2 (3-5 days later)
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Mean change in systolic blood pressure in mmHg
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Medication dosing/ADP Lab Session 1 (Day 1) and medication dosing/ADP Lab Session 2 (3-5 days later)
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Change in Diastolic Blood Pressure
Zeitfenster: Medication dosing/ADP Lab Session 1 (Day 1) and medication dosing/ADP Lab Session 2 (3-5 days later)
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Mean change in diastolic blood pressure in mmHg
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Medication dosing/ADP Lab Session 1 (Day 1) and medication dosing/ADP Lab Session 2 (3-5 days later)
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Change in Heart Rate
Zeitfenster: Medication dosing/ADP Lab Session 1 (Day 1) and medication dosing/ADP Lab Session 2 (3-5 days later)
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Mean change in heart rate measured in beats per minute
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Medication dosing/ADP Lab Session 1 (Day 1) and medication dosing/ADP Lab Session 2 (3-5 days later)
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Andere Ergebnismessungen
Ergebnis Maßnahme |
Maßnahmenbeschreibung |
Zeitfenster |
|---|---|---|
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Changes in brain circuit hyperexcitation - Preprocessing and source analysis
Zeitfenster: Pre and Post 1st Medication dosing period (Day 1) and Pre and Post 2nd medication dosing period (3-5 days later)
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Magnetoencephalography/Electroencephalography (MEG/EEG) data will be preprocessed following a standard pipeline[13] including bandpass filtering (0.1-100 Hz), notch filtering (60Hz), and removal of artifacts with independent component analysis (ICA)[14-16].
For each subject, an MRI will be segmented using the FreeSurfer software suite and imported into the MEG/EEG data analysis toolbox for Matlab Brainstorm[17].
Data will be segmented into two-second epochs, and the time series will be obtained using maximum entropy on the mean (MEM)[10,11] on individual head models.
Reconstructed sources of subjects will be projected on the FSAverage atlas with FreeSurfer using a spherical representation of the cortex.
The Destrieux Atlas will be used to parcellate the cortex into regions of interest (ROIs) to be used to extract the time series of each ROI (ventromedial, medial and orbitofrontal).
MEG/EEG to be done before the 1st and after the 3rd dose of nimodipine at each lab session.
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Pre and Post 1st Medication dosing period (Day 1) and Pre and Post 2nd medication dosing period (3-5 days later)
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Changes in brain circuit hyperexcitation - Power Spectral Density (PSD) Exponent Estimation
Zeitfenster: Pre and Post 1st Medication dosing period (Day 1) and Pre and Post 2nd medication dosing period (3-5 days later)
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Magnetoencephalography/Electroencephalography (MEG/EEG) will be collected before the first dose and after the third dose of nimodipine at each of the 2 lab session days. The Python implementation of the specparam algorithm (https://github.com/fooof-tools)[2] will be used to estimate the exponent χ of the PSD power law (1⁄f^χ with χ>0 )[19,4,5]. For each subject, prefrontal cortex region of interest (ROI), and signal epoch, PSD will be calculated with Welch's method and fitted with the specparam algorithm in the 20-50Hz frequency range, as the exponent in this range has the strongest correlations with excitatory/inhibitory (E/I) ratio[2]. The resulting exponents and intercepts will be averaged across epochs, to obtain a single exponent and intercept estimate per ROI per subject. |
Pre and Post 1st Medication dosing period (Day 1) and Pre and Post 2nd medication dosing period (3-5 days later)
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Mitarbeiter und Ermittler
Sponsor
Ermittler
- Hauptermittler: Suchitra Krishnan-Sarin, Yale University School of Medicine, Dept of Psychiatry
Publikationen und hilfreiche Links
Allgemeine Veröffentlichungen
- Tadel F, Baillet S, Mosher JC, Pantazis D, Leahy RM. Brainstorm: a user-friendly application for MEG/EEG analysis. Comput Intell Neurosci. 2011;2011:879716. doi: 10.1155/2011/879716. Epub 2011 Apr 13.
- Donoghue T, Haller M, Peterson EJ, Varma P, Sebastian P, Gao R, Noto T, Lara AH, Wallis JD, Knight RT, Shestyuk A, Voytek B. Parameterizing neural power spectra into periodic and aperiodic components. Nat Neurosci. 2020 Dec;23(12):1655-1665. doi: 10.1038/s41593-020-00744-x. Epub 2020 Nov 23.
- Krupitsky EM, Burakov AM, Romanova TN, Grinenko NI, Grinenko AY, Fletcher J, Petrakis IL, Krystal JH. Attenuation of ketamine effects by nimodipine pretreatment in recovering ethanol dependent men: psychopharmacologic implications of the interaction of NMDA and L-type calcium channel antagonists. Neuropsychopharmacology. 2001 Dec;25(6):936-47. doi: 10.1016/S0893-133X(01)00346-3.
- Freeman WJ, Holmes MD, Burke BC, Vanhatalo S. Spatial spectra of scalp EEG and EMG from awake humans. Clin Neurophysiol. 2003 Jun;114(6):1053-68. doi: 10.1016/s1388-2457(03)00045-2.
- Freeman WJ, Rogers LJ, Holmes MD, Silbergeld DL. Spatial spectral analysis of human electrocorticograms including the alpha and gamma bands. J Neurosci Methods. 2000 Feb 15;95(2):111-21. doi: 10.1016/s0165-0270(99)00160-0.
- Chowdhury RA, Zerouali Y, Hedrich T, Heers M, Kobayashi E, Lina JM, Grova C. MEG-EEG Information Fusion and Electromagnetic Source Imaging: From Theory to Clinical Application in Epilepsy. Brain Topogr. 2015 Nov;28(6):785-812. doi: 10.1007/s10548-015-0437-3. Epub 2015 May 28.
- Chowdhury RA, Pellegrino G, Aydin U, Lina JM, Dubeau F, Kobayashi E, Grova C. Reproducibility of EEG-MEG fusion source analysis of interictal spikes: Relevance in presurgical evaluation of epilepsy. Hum Brain Mapp. 2018 Feb;39(2):880-901. doi: 10.1002/hbm.23889. Epub 2017 Nov 21.
- Cortes-Briones J, Skosnik PD, Mathalon D, Cahill J, Pittman B, Williams A, Sewell RA, Ranganathan M, Roach B, Ford J, D'Souza DC. Delta9-THC Disrupts Gamma (gamma)-Band Neural Oscillations in Humans. Neuropsychopharmacology. 2015 Aug;40(9):2124-34. doi: 10.1038/npp.2015.53. Epub 2015 Apr 24.
- De Clercq W, Vergult A, Vanrumste B, Van Paesschen W, Van Huffel S. Canonical correlation analysis applied to remove muscle artifacts from the electroencephalogram. IEEE Trans Biomed Eng. 2006 Dec;53(12 Pt 1):2583-7. doi: 10.1109/TBME.2006.879459.
- De Vos M, Ries S, Vanderperren K, Vanrumste B, Alario FX, Van Huffel S, Burle B. Removal of muscle artifacts from EEG recordings of spoken language production. Neuroinformatics. 2010 Jun;8(2):135-50. doi: 10.1007/s12021-010-9071-0.
- Gao R, Penzes P. Common mechanisms of excitatory and inhibitory imbalance in schizophrenia and autism spectrum disorders. Curr Mol Med. 2015;15(2):146-67. doi: 10.2174/1566524015666150303003028.
Studienaufzeichnungsdaten
Haupttermine studieren
Studienbeginn (Geschätzt)
Primärer Abschluss (Geschätzt)
Studienabschluss (Geschätzt)
Studienanmeldedaten
Zuerst eingereicht
Zuerst eingereicht, das die QC-Kriterien erfüllt hat
Zuerst gepostet (Tatsächlich)
Studienaufzeichnungsaktualisierungen
Letztes Update gepostet (Tatsächlich)
Letztes eingereichtes Update, das die QC-Kriterien erfüllt
Zuletzt verifiziert
Mehr Informationen
Begriffe im Zusammenhang mit dieser Studie
Zusätzliche relevante MeSH-Bedingungen
Andere Studien-ID-Nummern
- 2000038566_a
- 2P50AA012870-21 (US NIH Stipendium/Vertrag)
Plan für individuelle Teilnehmerdaten (IPD)
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Beschreibung des IPD-Plans
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