Clinical trial NCT05479032: Amantadine for Neuroenhancement in Acute Patients Study
Official title: Amantadine for Neuroenhancement in Acute Patients Study - A Prospective Pilot Proof of Concept Phase IIb Study in Intensive and Intermediate Care Unit Patients
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Disorder of Consciousness
Keywords: Amantadine
Neuroenhancement
Lead sponsor: University Hospital Tuebingen
Sponsor class: OTHER
First posted: 2022-07-28
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Introduction: Many patients on intermediate care (IMC) and intensive care units (ICU) suffer from reduced consciousness. In this situation, a treatment attempt with Amantadine is often undertaken. While clinicians report good results with this approach, the treatment is off-label and the scientific evidence limited.

Study design: Monocenter, phase IIb, proof of concept, open-label pilot study. Methods: 50 intensive care patients with reduced consciousness not otherwise explained will be treated with Amantadine for 5 days. Vigilance is checked before, during and after treatment (on discharge and after 3 months) using electroencephalography (EEG) and established clinical tests, for instance Glasgow Coma Scale (GCS), Glasgow Outcome Scale - Extended (GOS-E), Coma Recovery Scale Revised (CRS-R) and others.

Results: The primary endpoint "improvement of the GCS scale from screening to day 5 of at least 3 points" is analysed according to the Simon design. The secondary endpoints (GCS continuous scale, modified Rankins Scale (mRS), National Institute of Health Stroke Scale (NIHSS), GOS-E, CRS-R and Montreal Cognitive Assessment (MoCA) after 90 days, Richmond Agitation-Sedation Scale (RASS) and Intensive Care Delirium Screening Checklist (ICDSC) will be analysed by mixed models with time (categorically coded) as only factor including all measurements up to 3 months follow up.

Discussion: The investigators aim to shed light on an established clinical practice without sufficient scientific evidence. The investigators are aware that the power of our study is limited by design (no control group, no blinding). However, if successful, this study may be the basis for a randomized controlled trial in the future.


Eligibility criteria: Inclusion Criteria:

* Must be ≥ 18 years at the time of signing the informed consent.
* Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures or informed consent is signed
* As subject has per definition reduced consciousness and therefore is not in a position to provide written informed consent, inclusion of this patient is possible if the patient will give basic informed consent seven days after enrollment. Alternatively, the patient's relatives can give written informed consent.
* Able to adhere to the study visit schedule and other protocol requirements.
* Subject (male or female) is willing to use highly effective methods during treatment and for 4 days (male or female) after the end of treatment (adequate: combined hormonal contraception associated with inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner1, sexual abstinence2).

  1. Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of the WOCBP trial participant and that the vasectomized partner has received medical assessment of the surgical success
  2. In the context of this guidance sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject.
* All subjects must agree to refrain from donating blood while on study drug and for 28 days after discontinuation from this study treatment.
* All subjects must agree not to share medication.
* Reduced consciousness, defined as GCS \<8, not otherwise explained
* Inconspicuous EEG and ECG

Exclusion Criteria:

* Women during pregnancy and lactation.
* History of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal product.
* Participation in other clinical trials or observation period of competing trials.
* Age \< 18 years
* Reduced consciousness, otherwise sufficiently explained
* Delirium (Intensive Care Delirium Screening Checklist (ICDSC) \> 4 or \>5 in aphasic patients)
* History of epileptic seizures or status epilepticus
* Pre-existing cardial conditions (e.g. heart failure (NYHA IV), cardiomyopathy, myocarditis, arrythmia (patients with a QTc time increase of \>60ms or interval of \>480ms have to be excluded from treatment), simultaneous treatment with other QT time elongating drugs, hypo-magnesaemia or -kalemia)

Primary outcomes:
measure: Level of vigilance measured by change in the Glasgow Coma Scale (GCS); a patient is defined as responder if his/her score increases by at least 3 points.
timeFrame: Assessment will take place before treatment (baseline value) and after 120 hours after treatment begin.
Secondary outcomes:
measure: Change in vigilance reflected by change in the Richmond Agitation-Sedation Scale (RASS)
timeFrame: Assessment will take place before treatment (baseline value) and after 3 months.
measure: Change of vigilance measured by the Full Outline of UnResponsive (FOUR) score
timeFrame: Assessment will take place before treatment (baseline value) and after 3 months.
measure: Appearance of delirium measured by change in the Intensive Care Delirium Screening Checklist (ICDSC)
timeFrame: Assessment will take place before treatment (baseline value) and after 3 months.
measure: Change in symptoms measured by the National Institute of health Stroke Scale (NIHSS)
timeFrame: Assessment will take place before treatment (baseline value) and after 3 months.
measure: Change in symptoms measured by the modified Rankin Scale (mRS)
timeFrame: Assessment will take place before treatment (baseline value) and after 3 months.
measure: Change of vigilance measured by the Glasgow Outcome Scale - Extended (GOS-E)
timeFrame: Assessment will take place before treatment (baseline value) and after 3 months.
measure: Change of vigilance measured by the Coma Recovery Scale revised (CRS-R)
timeFrame: Assessment will take place before treatment (baseline value) and after 3 months.
measure: Change of vigilance measured by the Montreal Cognitive Assessment (MoCA)
timeFrame: Assessment will take place before treatment (baseline value) and after 3 months.
measure: Survival
timeFrame: Assessment will take place before treatment (baseline value) and after 3 months.
measure: Change of vigilance measured by EEG (ratio of fast and slow oscillations)
timeFrame: Assessment will take place before treatment (baseline value) and after 3 months.
measure: Clinical change measured by the therapists' questionnaire
timeFrame: Assessment will take place before treatment (baseline value) and after 3 months.
Other outcomes:
Locations:
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen
Study officials:
affiliation: University Hospital Tübingen, Deparment for Neurology and Stroke
name: Katharina Feil, attending physician
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital Tübingen, Deparment for Neurology and Stroke
name: Annerose Mengel, attending physician
role: PRINCIPAL_INVESTIGATOR
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