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

Coma Clinical Trial

— STIMPACT  

Official title:

Stimulant Therapy Targeted to Individualized Connectivity Maps to Promote ReACTivation of Consciousness - A Phase 1 Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03814356
• Other study ID #: 140675
• Status: Completed
• Phase: Phase 1
• Start date: August 24, 2020
• Est. completion date: April 1, 2024

Study information

• Verified date: April 2024
• Source: Massachusetts General Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 10
• Est. completion date: April 1, 2024
• Est. primary completion date: April 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Anoxic Brain Injury
• Brain Injuries
• Brain Injuries, Traumatic
• Brain Injury Traumatic Severe (Diagnosis)
• Coma
• Consciousness Disorders
• Consciousness, Level Altered
• Wounds and Injuries

Intervention

Drug:
• Methylphenidate
IV MPH

Locations

Country	Name	City	State
United States	Massachusetts General Hospital	Boston	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Massachusetts General Hospital

Country where clinical trial is conducted

United States, 

References & Publications (1)

Edlow BL, Barra ME, Zhou DW, Foulkes AS, Snider SB, Threlkeld ZD, Chakravarty S, Kirsch JE, Chan ST, Meisler SL, Bleck TP, Fins JJ, Giacino JT, Hochberg LR, Solt K, Brown EN, Bodien YG. Personalized Connectome Mapping to Guide Targeted Therapy and Promote Recovery of Consciousness in the Intensive Care Unit. Neurocrit Care. 2020 Oct;33(2):364-375. doi: 10.1007/s12028-020-01062-7. Epub 2020 Aug 13. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Adverse Events	The number of drug-related adverse events at each dose of IV MPH	4 Days
Secondary	Maximal Serum Concentration	The time to maximal serum concentration at each dose of IV MPH	4 Days
Secondary	Serum Half-life	Serum half-life of IV MPH at each dose of IV MPH	4 Days
Secondary	Cerebral Cortical Connectivity as Measured by fMRI	The effect of the maximum tolerated of IV MPH dose on brain connectivity, as measured by resting state fMRI	4 Days
Secondary	Cerebral Cortical Connectivity as Measured by EEG	The effect of each of IV MPH dose on cerebral cortical connectivity, as measured by EEG	4 Days

External Links

•   Homepage of the Laboratory for NeuroImaging of Coma and Consciousness