Stimulant Therapy Targeted to Individualized Connectivity Maps to Promote ReACTivation of Consciousness (STIMPACT)

Mass General Brigham

Status and phase: Active, not recruiting; Phase 1

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

Treatments: Drug: Methylphenidate

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT03814356

DP2HD101400 (U.S. NIH Grant/Contract)

140675

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 10 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

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

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

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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10 participants in 1 patient group

IV MPH

Experimental group

Description:

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.

Treatment:

Drug: Methylphenidate