Stimulant Therapy Targeted to Individualized Connectivity Maps to Promote ReACTivation of Consciousness
| Status: | Not yet recruiting |
|---|---|
| Conditions: | Hospital, Neurology, Psychiatric |
| Therapuetic Areas: | Neurology, Psychiatry / Psychology, Other |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 3/23/2019 |
| Start Date: | April 1, 2019 |
| End Date: | March 31, 2021 |
| Contact: | Brian L Edlow, MD |
| Email: | bedlow@mgh.harvard.edu |
| Phone: | 6176433956 |
Stimulant Therapy Targeted to Individualized Connectivity Maps to Promote ReACTivation of Consciousness - A Phase 1 Study
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.
(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.
Inclusion Criteria:
1. Age ≥ 18 years
2. Severe 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 a. Bilateral dilated unresponsive pupils b. Intracranial hypertension
(Intracranial Pressure [ICP] > 20 cmH2O for > 5 min within past 24 hours with head
of-bed at standard clinical angle of 30-45o) c. Intracranial bolt d. Status
epilepticus or concern for post-ictal state
5. Cardiovascular
1. Poorly controlled hypertension (SBP sustained > 180 mmHg for 30 minutes, despite
anti-hypertensive therapy, within the past 24 hours)
2. Coronary artery disease
3. Acute coronary syndrome Hemodynamically significant dysrhythmia
4. Congestive heart failure
5. Cardiomyopathy (including Takotsubo cardiomyopathy)
6. Other severe structural cardiac abnormalities
6. Renal
a. Renal failure requiring renal replacement therapy (e.g. CVVH or HD)
7. Endocrine a. Thyrotoxicosis
8. Reproductive
a. Pregnancy
9. Ophthalmologic
a. 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
We found this trial at
1
site
185 Cambridge Street
Boston, Massachusetts 02114
Boston, Massachusetts 02114
617-724-5200
Phone: 617-724-6352
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