Effect of Intravenous Amantadine Sulphate on Disorders of Consciousness (DOC-AMSUL)

Effects of Intravenous Amantadine Sulphate on Brain Dynamics and Neurobehavioral Status in Patients With Disorders of Consciousness

Double-blind, placebo-controlled, crossover ("within subjects") study with an A-B-A-B treatment scheme to investigate the neuromodulatory effects of intravenous amantadine sulphate at a single daily dose of 200 mg in patients with disorders of consciousness (unresponsive wakefulness syndrome and minimally conscious state) by integrating traditional neurobehavioral assessment with spectral analysis of electrocortical activity derived from 64-channel electroencephalography (EEG) recordings.

Study Overview

• Status: Active, not recruiting
• Conditions: Consciousness Disorders; Electroencephalography; Amantadine
• Intervention / Treatment: Drug: Amantadine Sulfate

Detailed Description

Research hypothesis Intravenous amantadine sulphate treatment (200 mg) over five days improves consciousness, defined as an increase in CRS-r score of at least 3 points, and changes the band powers of the EEG in patients with disorder of consciousness admitted in a Neurorehabilitation Department.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Bolzano
    • Vipiteno, Bolzano, Italy, 39049
      • Hospital of Vipiteno

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

Adults with disorders of consciousness due to acquired brain injury classified according to international guidelines based on CRS-R evaluation as unresponsive wakefulness syndrome/vegetative state (UWS/VS) or minimally conscious state (MCS) either in the subacute or chronic stage

Exclusion Criteria:

• Age < 18 years
• History of epileptic seizures/status epilepticus
• Scalp defects
• pregnancy
• Severe uncompensated heart failure (NYHA IV)
• Atrioventricular block (AV block) second-degree and third-degree
• Known bradycardia (below 55 beats/minute)
• Known long QT interval (QTc according to Bazett > 420 ms
• History of serious ventricular arrhythmias
• Hypokalemia or hypomagnesemia
• Impaired renal function

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: amantadine sulphate and placebo with schema A-B-A-B; To obtain solid evidence of amantadine sulphate effects and their temporal dynamics, we conducted a double-blind, placebo-controlled, crossover ("within subjects") study with an A-B-A-B treatment scheme, in which "placebo" (A) and "amantadine sulphate" (B) intervention sessions alternated weekly in the same patient for a total of four weeks (A1-B1-A2-B2).

Drug: Amantadine Sulfate; intravenous amantadine sulphate at a single daily dose of 200 mg or physiological saline (0.9% NaCl solution); Other Names: physiological saline (0.9% NaCl solution)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
EEG band power alpha, beta, theta, delta	Change in each canonical band power of EEG induced by amantadine sulphate	days 14 and 28
Coma Recovery Scale-Revised (CRS-R)	Increase in the Coma Recovery Scale-Revised (CRS-R) score of at least 1 point. The CRS-R consists of 23 items divided into six subscales designed to assess: Auditory (AU), Visual (V), Motor (M), Oromotor/Verbal (O), Communication (C), and Arousal functions (AR). The total score ranges between 0 (worst) and 23 (best). The subscales are composed of hierarchically ordered items; the lowest items (0) represent reflexive activity, while the highest items (4,5,6,3,2,3 points for AU, V, M, O, C respectively) represent cognitively mediated behaviours. We adopted a cut-off score of 8 for distinguish UWS/VS (<8) from MCS (≥8) in patients induced by amantadine sulphate vs. placebo	days 14 and 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
"periodic" and "aperiodic" exponents of the average power spectral density	Change in "periodic" and "aperiodic" exponents of the average power spectral density vs. placebo and vs healthy controls	days 14 and 28

Collaborators and Investigators

• Sponsor: Azienda Sanitaria dell'Alto Adige
• Investigators: Principal Investigator: Viviana Versace, MD, Hospital of Vipiteno

Study record dates

Study Major Dates

• Study Start (Actual): September 15, 2018
• Primary Completion (Actual): January 10, 2024
• Study Completion (Estimated): September 30, 2024

Study Registration Dates

• First Submitted: May 15, 2024
• First Submitted That Met QC Criteria: May 30, 2024
• First Posted (Actual): June 5, 2024

Study Record Updates

• Last Update Posted (Actual): June 14, 2024
• Last Update Submitted That Met QC Criteria: June 13, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: EEG; DoC = Disorders of Consciousness; PSD = Power Spectral Density; Amantadine sulphate
• Additional Relevant MeSH Terms: Mental Disorders; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Neurocognitive Disorders; Consciousness Disorders; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Antiviral Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Dopamine Agents; Antiparkinson Agents; Anti-Dyskinesia Agents; Amantadine
• Other Study ID Numbers: 39049

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No