Spinal Cord Injuries Clinical Trial
Official title:
Pilot Study of Mecamylamine for Autonomic Dysreflexia Prophylaxis
This is a preliminary study of the antihypertensive drug mecamylamine, used in the specific circumstance of hypertension caused by autonomic dysreflexia (AD), a condition that affects people with spinal cord injury (SCI). Initially, mild sensory stimulation of subjects' legs is used to intentionally provoke AD, as reflected by blood pressure elevation during such stimulation. In subsequent testing sessions, mecamylamine is given prior to sensory stimulation, to show the effect of the drug on preventing these AD-related blood pressure elevations.
In this one year pilot study we will enroll 3-5 people with SCI, and aim to develop a simple,
convenient BP cuff method to elicit AD (i.e., using a BP cuff applied to the leg as a mild
noxious stimulus), and then use that method to preliminarily evaluate the effects of the
antihypertensive drug mecamylamine on AD. Study participants will complete up to 5 research
visits, will undergo AD provocation using the leg cuff protocol, and will receive escalating
doses of mecamylamine, as needed and tolerated, in order to prevent AD:
After signing the informed consent form, at visit 1, subjects will complete an interview to
evaluate past medical history, an autonomic dysfunction questionnaire, a physical examination
(including an autonomic assessment and specialty SCI exam), vital signs measurement, and
baseline testing of the electrical activity of the heart (electrocardiography or ECG
testing).
At visit 2, subjects will complete a preparation procedure including: baseline vital signs
measurement, an interview to document all medications and/or supplements taken in the prior
24 hours, confirmation of completed bladder/bowel evacuation before the visit, confirmation
of no significant illness/injury since last visit, and documentation of any meals before the
visit. Next, the subject will be connected to an ECG monitor and a (second) BP cuff will be
applied to the arm (for measuring BP response to the leg cuff procedure). With the ECG and
arm cuff in place, s/he will undergo the AD provocation procedure: The BP cuff placed around
the leg just below the knee will be inflated for up to 10 minutes, as a means of providing
sensory stimulation to elicit AD. BP will be measured using the arm cuff every 2 minutes
during the leg cuff inflation, and periodically after the leg cuff is deflated, until BP and
heart rate are back to baseline values. Physical manifestations and symptoms of AD will be
recorded during the period of leg cuff inflation and thereafter, throughout recovery. This BP
cuff protocol will be repeated twice during the same visit, with trials separated by a
30-minute recovery period. The leg cuff will be deflated immediately if the blood
pressure-measuring cuff shows that systolic BP exceeds 180 mmHg, diastolic BP exceeds 100
mmHg, heart rate is less than 40 or greater than 100 beats per minute, adverse ECG changes
are evident, or symptoms are unacceptable to the subject. An established safety plan will be
followed in the event of a significant adverse reaction to the leg compression or study drug.
If the leg cuff inflation fails to elicit AD, then the subject will be dropped from the
study.
At visit 3, a similar visit preparation procedure will be completed as in visit 2. Three
hours prior to AD provocation testing with the leg cuff, subjects will receive 2.5 mg of
mecamylamine in tablet form, to try to prevent AD. Physical manifestations and symptoms of AD
will be recorded during the period of cuff inflation and thereafter, throughout recovery. The
leg cuff will be deflated after 10 minutes, or immediately as appropriate according to the
same criteria as listed for visit 2. After a 30-minute recovery, the leg cuff inflation will
be repeated once during the same session, to confirm whether or not 2.5 mg of mecamylamine
eliminates AD, or at least reduces the associated BP elevation, as well as the other
manifestations and symptoms. If the dose of 2.5 mg mecamylamine is effective, the subject
will not be asked to return for testing with a higher dose and study participation will end
with visit 3. If either trial of leg cuff inflation still elicits AD despite premedication
with 2.5 mg mecamylamine, then s/he will be scheduled to come back for visit 4.
At visit 4, the visit preparation will be completed as in visits 2 and 3. Three hours prior
to testing with the AD provocation procedure, 5 mg of mecamylamine will be given to the
participant to try to prevent AD, since the lower dose failed to do so. The same procedures
described above for visit 3 will be followed; subjects will again undergo 2 trials of AD
provocation with the leg squeezing procedure. If both are successful (i.e., no AD is
observed), the subject's participation in the study will end. If, despite premedication with
mecamylamine 5 mg, the subject still experiences AD, then s/he will be asked to return for
visit 5.
At visit 5, all the procedures as in visit 4 will be repeated, except that subjects will
receive 7.5 mg of mecamylamine. Regardless if the medication does not prevent AD, subjects
will not be scheduled to come for a follow up, as no further dose escalation will be
attempted.
If at visit 3, 4, or 5 a subject experiences symptomatic low blood pressure after taking
mecamylamine (manifest as dizziness, lightheadedness, or change in vision; this is considered
unlikely based on the published literature), s/he will be asked to drink several glasses of
cold water, and possibly to lay down for up to 30 minutes to try to alleviate those symptoms.
In the event symptomatic low blood pressure persists, the subject will be given 10 mg of
midodrine, a medication to elevate blood pressure. Midodrine would be expected to promptly
(in less than an hour) elevate blood pressure and alleviate those symptoms. Upon adequate
elevation of blood pressure to cause resolution of the symptoms, the subject will be
discharged from the study, because of the adverse effect of mecamylamine. If the midodrine 10
mg fails to resolve symptomatic low blood pressure, then further evaluation and treatment
will be provided as appropriate (e.g., intravenous fluids). The latter scenario is considered
to be extremely unlikely.
note - visits will be separated by no more than one month
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