Stimulant Therapy Targeted to Individualized Connectivity Maps to Promote ReACTivation of Consciousness

Phase 1

Completed

• Conditions: Consciousness, Level Altered; Anoxic Brain Injury; Brain Injury Traumatic Severe (Diagnosis); Coma
• Interventions: Drug: Methylphenidate

• Registration Number: NCT03814356
• Lead Sponsor: Massachusetts General Hospital

Brief Summary

Phase 1 of the STIMPACT trial is an open label,dose-escalation,safety study of intravenous (IV) methylphenidate (MPH) therapy in patients with disorders of consciousness (DoC) caused by severe brain injuries. To be classified as having a DoC, a patient must be in a coma, vegetative state (VS), or minimally conscious state (MCS), as determined by behavioral assessment using the Coma Recovery Scale-Revised (CRS-R). Patients with DoC admitted to the intensive care unit (ICU) will be eligible for the study. A total of 10 patients with DoC will be enrolled in the Phase 1 study. Patients will receive escalating daily doses of IV MPH starting at 0.5 mg/kg, increasing stepwise to 1.0mg/kg and 2.0 mg/kg unless an adverse event (AE) necessitates dose de-escalation or a serious adverse event (SAE) necessitates that the patient stop participation in the study. Pharmacokinetics will be evaluated in selected patients with indwelling venous catheters or arterial catheters via serial serum measurements of MPH at each dose. The pharmacodynamic properties of IV MPH at each dose will be assessed by comparison of pre-versus post-dose EEG-based measures. The pharmacodynamic properties of the maximum tolerated dose will also be assessed by comparison of pre-versus post-dose resting state functional MRI (rs-fMRI) connectivity measures. Finally, we will test the association between structural connectivity of the ventral tegmental area (VTA), a dopaminergic brainstem nucleus that is believed to mediate MPH activation of the cerebral cortex, and EEG and rs-fMRI pharmacodynamic measures.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2019-01-15
• Study First Submitted QC: 2019-01-18
• Study First Posted: 2019-01-24
• Study Start: 2020-08-24
• Status Verified: 2024-04
• Primary Completion: 2024-04-01
• Study Completion: 2024-04-01
• Last Update Submitted: 2024-04-16
• Last Update Posted: 2024-04-17

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 10

Inclusion Criteria

1. Age ≥ 18 years
2. Severe, acute traumatic brain injury
3. Diagnosis of Coma, Vegetative State, or Minimally Conscious State

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Exclusion Criteria

1. Penetrating brain injury caused by a metallic missile/object (e.g. bullet)

2. Body metal contraindicating MRI

3. Prisoner or ward of the state

4. Neurological

   1. Bilateral dilated unresponsive pupils
   2. Intracranial hypertension (Intracranial Pressure [ICP] > 25 mmHg for > 5 min within past 24 hours with head-of-bed at standard clinical angle of 30-45 degrees)
   3. Intracranial bolt
   4. Status epilepticus or concern for post-ictal state

5. Cardiovascular

   1. Poorly controlled hypertension (SBP > 200 mmHg of DBP > 120mmHg for 30 minutes, despite anti-hypertensive therapy, within the past 24 hours)
   2. Coronary artery disease
   3. ST elevation myocardial infarction
   4. Acute coronary syndrome
   5. Hemodynamically significant dysrhythmia
   6. Congestive heart failure
   7. Cardiomyopathy (including Takotsubo cardiomyopathy)
   8. Other severe structural cardiac abnormalities

6. Renal

   a. Renal failure requiring renal replacement therapy (e.g. CVVH or HD)

7. Endocrine

   a. History of or clinical suspicion for thyrotoxicosis

8. Reproductive

   a. Pregnancy

9. Ophthalmologic

   a. History of glaucoma

10. Pharmacologic

    a. Monoamine oxidase inhibitor therapy within past 14 days

11. Other

    1. Any condition or finding that in the judgment of the PI or treating clinical team significantly increases the risk or significantly decreases the likelihood of a response to IV MPH

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
IV MPH	Methylphenidate	All patients will receive IV Methylphenidate (MPH). Patients will receive escalating daily doses of IV MPH starting at 0.5 mg/kg, increasing stepwise to 1.0mg/kg and 2.0 mg/kg unless an adverse event (AE) necessitates dose de-escalation or a serious adverse event (SAE) necessitates that the patient stop participation in the study.

Primary Outcome Measures

Name	Time	Method
Adverse Events	4 Days	The number of drug-related adverse events at each dose of IV MPH

Secondary Outcome Measures

Name	Time	Method
Maximal Serum Concentration	4 Days	The time to maximal serum concentration at each dose of IV MPH
Serum Half-life	4 Days	Serum half-life of IV MPH at each dose of IV MPH
Cerebral Cortical Connectivity as Measured by fMRI	4 Days	The effect of the maximum tolerated of IV MPH dose on brain connectivity, as measured by resting state fMRI
Cerebral Cortical Connectivity as Measured by EEG	4 Days	The effect of each of IV MPH dose on cerebral cortical connectivity, as measured by EEG

Trial Locations

Locations (1)

Massachusetts General Hospital; 🇺🇸 Boston, Massachusetts, United States