Hypotension, Orthostatic
Conditions
Brief summary
The purpose of this clinical study is to evaluate the clinical effect of midodrine hydrochloride (ProAmatine®) compared to placebo in patients with orthostatic hypotension by measuring the time to onset of near syncopal symptoms and assessing several cardiovascular measurements, such as heart rate, blood pressure, and ECG, using the tilt table test.
Interventions
one dose, 10-30mg, given orally
DRUGPlacebo
Placebo
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
19 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* The male or female subjects must be 18 years of age or older and ambulatory. (Subjects must not require assistance with a walker or wheelchair to perform regular daily activities at all times.) * Women of childbearing potential must have a negative serum beta HCG pregnancy test at screening and baseline. * The subject has been diagnosed with symptomatic orthostatic hypotension due to Parkinson's disease, multiple system atrophy, pure autonomic failure or autonomic neuropathy (i.e. neurogenic orthostatic hypotension). * The subject manifests one of the following symptoms while standing or has a history of one of the following when not treated for orthostatic hypotension: dizziness, lightheadedness, feeling faint or feeling like they may black out. * The subject is willing and able to undergo the procedures required by this protocol including morning office visits, assessment completion, protocol compliance and participation in the wash-out period. * The subject has signed an Institutional-Review-Board approved written informed consent form prior to any study procedures taking place.
Exclusion criteria
* The subject is a pregnant or lactating female. * The subject has pre-existing sustained supine hypertension greater than 180 mm Hg systolic and 110 mm Hg diastolic. * The subject is taking medications such as vasodilators, pressors, diuretics, ACE inhibitors, angiotensin receptor blockers, beta-blockers, combined alpha and beta-blockers, MAOI's, herbals or specific mixed effect medications. * The Principal Investigator deems any laboratory test abnormality clinical significant. * The subject has a diagnosis of any of the following disorders at the time of screening: pheochromocytoma; cardiac conditions including: congestive heart failure within the previous 6 months, myocardial infarction within the previous 6 months, symptomatic coronary artery disease, history of ventricular tachycardia, or uncontrolled cardiac arrhythmias; thyrotoxicosis; uncontrolled diabetes mellitus (uncontrolled defined as a HgbA1c greater than or equal to 10%); history of cerebrovascular accident, transient ischemic attack (TIA) or symptomatic carotid artery stenosis within the previous 6 months; history of coagulopathies; pulmonary hypertension; severe psychiatric disorders; renal failure (Creatinine equal to or greater than 2 times the upper limit of normal) * The subject has a concurrent chronic or acute illness, disability, or other condition that might confound the results of the tests and/or measurements administered in this trial, or that might increase the risk to the subject.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Onset of Near-syncopal Symptoms During Tilt Table Testing | 1 hour post-dose | The tilt table test is a 10-minute assessment performed using a manual or automated tilt table in a specialized laboratory. Subjects were moved onto the horizontal table and secured to the table with straps to prevent injury. After an equilibration period of at least 10 minutes with the subject at rest, the test began and the head of the tilt table was elevated to a 70-degree angle over a period of up to 30 seconds. The head-up tilt table test in this study was conducted 1 hour after administration of the study medication. The endpoint was a confirmed report of a near-syncopal symptom(s) (of sufficient severity that caused the patient to ask that the tilt table be returned to the horizontal position). Symptoms of near syncope were defined as dizziness, lightheadedness, feeling faint, or feeling like the subject might black out. |
| Time to Onset of Near-syncopal Symptoms During Tilt Table Testing Analysis #2 | 1 hour post-dose | The tilt table test is a 10-minute assessment performed using a manual or automated tilt table in a specialized laboratory. Subjects were moved onto the horizontal table and secured to the table with straps to prevent injury. After an equilibration period of at least 10 minutes with the subject at rest, the test began and the head of the tilt table was elevated to a 70-degree angle over a period of up to 30 seconds. The head-up tilt table test in this study was conducted 1 hour after administration of the study medication. The endpoint was a confirmed report of a near- syncopal symptom(s) (of sufficient severity that caused the patient to ask that the tilt table be returned to the horizontal position). Symptoms of near syncope were defined as dizziness, lightheadedness, feeling faint, or feeling like the subject might black out. In this outcome measure, the data analyzed are the same as for Outcome Measure 1 but the summary data are presented as least squares mean (standard error). |
| Time to Onset of Near-syncopal Symptoms During Tilt Table Testing-Re-analysis With The Koch Procedure | 1 hour post-dose | The tilt table test is a 10-minute assessment performed using a manual or automated tilt table in a specialized laboratory. Subjects were moved onto the horizontal table and secured to the table with straps to prevent injury. After an equilibration period of at least 10 minutes with the subject at rest, the test began and the head of the tilt table was elevated to a 70-degree angle over a period of up to 30 seconds. The head-up tilt table test in this study was conducted 1 hour after administration of the study medication. The endpoint was a confirmed report of a near-syncopal symptom(s) (of sufficient severity that caused the patient to ask that the tilt table be returned to the horizontal position). Symptoms of near syncope were defined as dizziness, lightheadedness, feeling faint, or feeling like the subject might black out. The Koch procedure is a 3-step process to analyze results while utilizing the available information on magnitude of differences. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of The Effect of Treatment at 3 Hours Post-dose | 1 and 3 hours post-dose | Duration of effect was defined as the difference in time to onset of near-syncopal symptoms between the first and second tilt table test, conducted at 1 hour and 3 hours post-dose, respectively, at Treatment Visit 2 (time to onset at 3 hours minus time at 1 hour). The tilt table test is a 10-minute assessment performed using a manual or automated tilt table in a specialized laboratory. Subjects were moved onto the horizontal table and secured to the table with straps to prevent injury. After an equilibration period of at least 10 minutes with the subject at rest, the test began and the head of the tilt table was elevated to a 70-degree angle over a period of up to 30 seconds. The endpoint was a confirmed report of a near-syncopal symptom(s) (of sufficient severity that caused the patient to ask that the tilt table be returned to the horizontal position). Symptoms of near syncope were defined as dizziness, lightheadedness, feeling faint, or feeling like the subject might black out. |
| Total Score of the Orthostatic Hypotension Symptom Assessment (OHSA) | Approximately 1 hour post-dose | The OHSA measures the severity of six symptoms/symptom complexes associated with orthostatic hypotension. Subjects rated symptoms experienced during the tilt table test on an eleven-point scale from none to worst possible. The OHSA total score is the sum of six subscales, ranging from 0 (no symptoms) to 60 (worst possible symptoms). The OHSA was completed after the tilt table test was over, but was answered with reference to symptoms experienced during testing. The tilt table test is a 10-minute assessment performed using a manual or automated tilt table in a specialized laboratory. Subjects were moved onto the horizontal table and secured to the table with straps to prevent injury. After an equilibration period with the subject at rest, the test began and the head of the tilt table was elevated to a 70-degree angle over a period of up to 30 seconds. Symptoms of near syncope were defined as dizziness, lightheadedness, feeling faint, or feeling like the subject might black out. |
| Scores for 6 Items of The OHSA | Approximately 1 hour post-dose | The OHSA measures the severity of six symptoms/symptom complexes associated with OH: dizziness, lightheadedness, and feeling faint; problems with vision; weakness; fatigue; trouble concentrating; and head/neck discomfort. Subjects rated symptoms experienced during the tilt table test on an eleven-point scale from none to worst possible. Scores for each subscale range from 0 (no symptoms) to 10 (worst possible symptoms). The OHSA was completed after the tilt table test was over, but was answered with reference to symptoms experienced during testing. The tilt table test is a 10-minute assessment performed using a tilt table in a specialized laboratory. Subjects were moved onto the horizontal table and secured with straps to prevent injury. After an equilibration period with the subject at rest, the test began and the head of the tilt table was elevated to a 70-degree angle over 30 seconds. Symptoms of near syncope were defined as dizziness, lightheadedness, and feeling faint. |
| Number of Participants With Improvement of Clinician Clinician's Global Impression- Improvement (CGI-I) Scores After Tilt Table Test | 1 and 3 hours post-dose | The CGI-I instrument assesses the overall impression of the subject's orthostatic hypotension during the tilt table test by using a 7-point scale, with 1 being Very much improved; 2, Much improved; 3, Slightly improved; 4, No change; 5, Slightly worse; 6, Much worse; and 7, Very much worse. The clinician completed the CGI-I after each of the tilt table tests. A patient was assessed as Improved if the score was 1, 2, or 3. The tilt table test is a 10-minute assessment performed using a manual or automated tilt table in a specialized laboratory. Subjects were moved onto the horizontal table and secured to the table with straps to prevent injury. After an equilibration period of at least 10 minutes with the subject at rest, the test began and the head of the tilt table was elevated to a 70-degree angle over a period of up to 30 seconds. Symptoms of near syncope were defined as dizziness, lightheadedness, feeling faint, or feeling like the subject might black out. |
| Number of Participants With Improvement of Patient CGI-I Scores After Tilt Table Test | 1 and 3 hours post-dose | The CGI-I instrument assesses the overall impression of the subject's orthostatic hypotension during the tilt table test by using a 7-point scale, with 1 being Very much improved; 2, Much improved; 3, Slightly improved; 4, No change; 5, Slightly worse; 6, Much worse; and 7, Very much worse. The patient completed the CGI-I after each of the tilt table tests. A patient was assessed as Improved if the score was 1, 2, or 3. The tilt table test is a 10-minute assessment performed using a manual or automated tilt table in a specialized laboratory. Subjects were moved onto the horizontal table and secured to the table with straps to prevent injury. After an equilibration period of at least 10 minutes with the subject at rest, the test began and the head of the tilt table was elevated to a 70-degree angle over a period of up to 30 seconds. Symptoms of near syncope were defined as dizziness, lightheadedness, feeling faint, or feeling like the subject might black out. |
| Final Blood Pressure During Tilt Table Testing | 1 hour post-dose | Blood pressure was recorded just before tilt table testing and immediately after. Timed readings were stopped once a subject experienced near-syncopal symptoms, except for subjects for whom the table was returned to horizontal before 1 minute; for these subjects, a reading was made at 1 minute and was included in analyses. The tilt table test is a 10-minute assessment performed using a manual or automated tilt table in a specialized laboratory. Subjects were moved onto the horizontal table and secured to the table with straps to prevent injury. After an equilibration period of at least 10 minutes with the subject at rest, the test began and the head of the tilt table was elevated to a 70-degree angle over a period of up to 30 seconds. Symptoms of near syncope were defined as dizziness, lightheadedness, feeling faint, or feeling like the subject might black out. |
| Time to Onset of Near-syncopal Symptoms in The Per-protocol Population | 1 hour post-dose | The tilt table test is a 10-minute assessment performed using a manual or automated tilt table in a specialized laboratory. Subjects were moved onto the horizontal table and secured to the table with straps to prevent injury. After an equilibration period of at least 10 minutes with the subject at rest, the test began and the head of the tilt table was elevated to a 70-degree angle over a period of up to 30 seconds. The head-up tilt table test in this study was conducted 1 hour after administration of the study medication. The endpoint was a confirmed report of a near-syncopal symptom(s) (of sufficient severity that caused the patient to ask that the tilt table be returned to the horizontal position). Symptoms of near syncope were defined as dizziness, lightheadedness, feeling faint, or feeling like the subject might black out. |
| Diastolic Blood Pressure at 1 Minute and 10 Minutes Into The Tilt Table Test Conducted 1 and 3 Hours Post-dose at Treatment Visit 2 | 1 and 3 hours post-dose | Blood pressure was recorded just before tilt table testing, at each minute during tilt table testing, and immediately after. Timed readings were stopped once a subject experienced near-syncopal symptoms, except for subjects for whom the table was returned to horizontal before 1 minute; for these subjects, a reading was made at 1 minute and was included in analyses. The tilt table test is a 10-minute assessment performed using a manual or automated tilt table in a specialized laboratory. Subjects were moved onto the horizontal table and secured to the table with straps to prevent injury. After an equilibration period of at least 10 minutes with the subject at rest, the test began and the head of the tilt table was elevated to a 70-degree angle over a period of up to 30 seconds. Symptoms of near syncope were defined as dizziness, lightheadedness, feeling faint, or feeling like the subject might black out. |
| Heart Rate at 1 Minute and 10 Minutes Into The Tilt Table Test Conducted 1 and 3 Hours Post-dose at Treatment Visit 2 | 1 and 3 hours post-dose | Heart rate was recorded just before tilt table testing, at each minute during tilt table testing, and immediately after. Timed readings were stopped once a subject experienced near-syncopal symptoms, except for subjects for whom the table was returned to horizontal before 1 minute; for these subjects, a reading was made at 1 minute and was included in analyses. The tilt table test is a 10-minute assessment performed using a manual or automated tilt table in a specialized laboratory. Subjects were moved onto the horizontal table and secured to the table with straps to prevent injury. After an equilibration period of at least 10 minutes with the subject at rest, the test began and the head of the tilt table was elevated to a 70-degree angle over a period of up to 30 seconds. Symptoms of near syncope were defined as dizziness, lightheadedness, feeling faint, or feeling like the subject might black out. |
| Number of Participants With Shifts in Reference to Normal Range For Hematology Analytes at Discharge | Baseline to discharge | For hematology, blood samples (5.0mL) were taken at screening, study admission (if greater than 14 days since screening) and discharge/early termination. The following parameters were assessed: hemoglobin, hematocrit, red blood cells (RBC), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), white blood cell count - total and differential (WBC), and platelet count. A shift in reference to normal was either lower or higher at discharge. |
| Number of Participants With Shifts in Reference to Normal Range For Clinical Chemistry at Discharge | Baseline to discharge | For biochemistry, blood samples (10.0mL) were taken at screening, admission (if greater than 14 days since screening) and discharge/early termination. The following parameters were assessed: sodium, potassium, calcium, blood urea nitrogen (BUN)/Urea, creatinine, albumin, total protein and albumin/globulin (A/G) ratio, globulin, aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), total bilirubin, glucose, chloride, and creatine kinase. A shift in reference to normal was either lower or higher at discharge. |
| Number of Participants With Shifts in Reference to Normal Range For Urinalysis at Discharge | Baseline to discharge | For urinalysis, samples were taken at screening, study admission (if greater than 14 days since screening) and discharge/early termination): glucose, blood, protein, pH, specific gravity, leukocyte esterase, and microscopic examination. A shift in reference to normal was higher at discharge. |
| Systolic Blood Pressure at 1 Minute and 10 Minutes Into The Tilt Table Test Conducted 1 and 3 Hours Post-dose at Treatment Visit 2 | 1 and 3 hours post-dose | Blood pressure was recorded just before tilt table testing, at each minute during tilt table testing, and immediately after. Timed readings were stopped once a subject experienced near-syncopal symptoms, except for subjects for whom the table was returned to horizontal before 1 minute; for these subjects, a reading was made at 1 minute and was included in analyses. The tilt table test is a 10-minute assessment performed using a manual or automated tilt table in a specialized laboratory. Subjects were moved onto the horizontal table and secured to the table with straps to prevent injury. After an equilibration period of at least 10 minutes with the subject at rest, the test began and the head of the tilt table was elevated to a 70-degree angle over a period of up to 30 seconds. Symptoms of near syncope were defined as dizziness, lightheadedness, feeling faint, or feeling like the subject might black out. |
| Time to Onset of Near-syncopal Symptoms in The Per-protocol Population Analysis #2 | 1 hour post-dose | The tilt table test is a 10-minute assessment performed using a manual or automated tilt table in a specialized laboratory. Subjects were moved onto the horizontal table and secured to the table with straps to prevent injury. After an equilibration period of at least 10 minutes with the subject at rest, the test began and the head of the tilt table was elevated to a 70-degree angle over a period of up to 30 seconds. The head-up tilt table test in this study was conducted 1 hour after administration of the study medication. The endpoint was a confirmed report of a near- syncopal symptom(s) (of sufficient severity that caused the patient to ask that the tilt table be returned to the horizontal position). Symptoms of near syncope were defined as dizziness, lightheadedness, feeling faint, or feeling like the subject might black out. In this outcome measure, the data analyzed are the same as for Outcome Measure 4 but the summary data are presented as least squares mean (standard error). |
| Time to Near-syncopal Symptoms at Treatment Visit 1 | 1 hour post-dose | The tilt table test is a 10-minute assessment performed using a manual or automated tilt table in a specialized laboratory. Subjects were moved onto the horizontal table and secured to the table with straps to prevent injury. After an equilibration period of at least 10 minutes with the subject at rest, the test began and the head of the tilt table was elevated to a 70-degree angle over a period of up to 30 seconds. The head-up tilt table test in this study was conducted 1 hour after administration of the study medication. The endpoint was a confirmed report of a near-syncopal symptom(s) (of sufficient severity that caused the patient to ask that the tilt table be returned to the horizontal position). Symptoms of near syncope were defined as dizziness, lightheadedness, feeling faint, or feeling like the subject might black out. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Midodrine/Placebo Participants received a single oral dose of Midodrine HCl followed by matching Placebo the next day | 13 |
| Placebo/Midodrine Participants received matching Placebo followed by a single oral dose of Midodrine HCl the next day | 11 |
| Total | 24 |
Baseline characteristics
| Characteristic | Placebo/Midodrine | Total | Midodrine/Placebo |
|---|---|---|---|
| Age, Continuous | 60.8 years STANDARD_DEVIATION 12.91 | 60.0 years STANDARD_DEVIATION 15.46 | 59.4 years STANDARD_DEVIATION 17.84 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 24 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 21 Participants | 11 Participants |
| Sex: Female, Male Female | 5 Participants | 12 Participants | 7 Participants |
| Sex: Female, Male Male | 6 Participants | 12 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 13 | 2 / 11 |
| serious Total, serious adverse events | 1 / 13 | 0 / 11 |
Outcome results
Primary
Time to Onset of Near-syncopal Symptoms During Tilt Table Testing
The tilt table test is a 10-minute assessment performed using a manual or automated tilt table in a specialized laboratory. Subjects were moved onto the horizontal table and secured to the table with straps to prevent injury. After an equilibration period of at least 10 minutes with the subject at rest, the test began and the head of the tilt table was elevated to a 70-degree angle over a period of up to 30 seconds. The head-up tilt table test in this study was conducted 1 hour after administration of the study medication. The endpoint was a confirmed report of a near-syncopal symptom(s) (of sufficient severity that caused the patient to ask that the tilt table be returned to the horizontal position). Symptoms of near syncope were defined as dizziness, lightheadedness, feeling faint, or feeling like the subject might black out.
Time frame: 1 hour post-dose
Population: The Full Analysis Set (FAS), defined as subjects who were randomized, received at least one dose of study drug, and had at least one measurement of time to syncope during tilt table testing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Midodrine HCl | Time to Onset of Near-syncopal Symptoms During Tilt Table Testing | 551.3 seconds | Standard Deviation 115.63 |
| Placebo | Time to Onset of Near-syncopal Symptoms During Tilt Table Testing | 461.0 seconds | Standard Deviation 190.74 |
p-value: 0.146Sign test
Primary
Time to Onset of Near-syncopal Symptoms During Tilt Table Testing Analysis #2
The tilt table test is a 10-minute assessment performed using a manual or automated tilt table in a specialized laboratory. Subjects were moved onto the horizontal table and secured to the table with straps to prevent injury. After an equilibration period of at least 10 minutes with the subject at rest, the test began and the head of the tilt table was elevated to a 70-degree angle over a period of up to 30 seconds. The head-up tilt table test in this study was conducted 1 hour after administration of the study medication. The endpoint was a confirmed report of a near- syncopal symptom(s) (of sufficient severity that caused the patient to ask that the tilt table be returned to the horizontal position). Symptoms of near syncope were defined as dizziness, lightheadedness, feeling faint, or feeling like the subject might black out. In this outcome measure, the data analyzed are the same as for Outcome Measure 1 but the summary data are presented as least squares mean (standard error).
Time frame: 1 hour post-dose
Population: The FAS, defined as subjects who were randomized, received at least one dose of study drug, and had at least one measurement of time to syncope during tilt table testing.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Midodrine HCl | Time to Onset of Near-syncopal Symptoms During Tilt Table Testing Analysis #2 | 552.4 seconds | Standard Error 32.93 |
| Placebo | Time to Onset of Near-syncopal Symptoms During Tilt Table Testing Analysis #2 | 460.0 seconds | Standard Error 32.93 |
Comparison: Analysis of treatment differencep-value: 0.0296ANOVA
Primary
Time to Onset of Near-syncopal Symptoms During Tilt Table Testing-Re-analysis With The Koch Procedure
The tilt table test is a 10-minute assessment performed using a manual or automated tilt table in a specialized laboratory. Subjects were moved onto the horizontal table and secured to the table with straps to prevent injury. After an equilibration period of at least 10 minutes with the subject at rest, the test began and the head of the tilt table was elevated to a 70-degree angle over a period of up to 30 seconds. The head-up tilt table test in this study was conducted 1 hour after administration of the study medication. The endpoint was a confirmed report of a near-syncopal symptom(s) (of sufficient severity that caused the patient to ask that the tilt table be returned to the horizontal position). Symptoms of near syncope were defined as dizziness, lightheadedness, feeling faint, or feeling like the subject might black out. The Koch procedure is a 3-step process to analyze results while utilizing the available information on magnitude of differences.
Time frame: 1 hour post-dose
Population: The Full Analysis Set, defined as subjects who were randomized, received at least one dose of study drug, and had at least one measurement of time to syncope during tilt table testing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Midodrine HCl | Time to Onset of Near-syncopal Symptoms During Tilt Table Testing-Re-analysis With The Koch Procedure | 551.3 seconds | Standard Deviation 115.63 |
| Placebo | Time to Onset of Near-syncopal Symptoms During Tilt Table Testing-Re-analysis With The Koch Procedure | 461.0 seconds | Standard Deviation 190.74 |
Comparison: Analysis of treatmentp-value: 0.0342Signed Rank Test
Secondary
Diastolic Blood Pressure at 1 Minute and 10 Minutes Into The Tilt Table Test Conducted 1 and 3 Hours Post-dose at Treatment Visit 2
Blood pressure was recorded just before tilt table testing, at each minute during tilt table testing, and immediately after. Timed readings were stopped once a subject experienced near-syncopal symptoms, except for subjects for whom the table was returned to horizontal before 1 minute; for these subjects, a reading was made at 1 minute and was included in analyses. The tilt table test is a 10-minute assessment performed using a manual or automated tilt table in a specialized laboratory. Subjects were moved onto the horizontal table and secured to the table with straps to prevent injury. After an equilibration period of at least 10 minutes with the subject at rest, the test began and the head of the tilt table was elevated to a 70-degree angle over a period of up to 30 seconds. Symptoms of near syncope were defined as dizziness, lightheadedness, feeling faint, or feeling like the subject might black out.
Time frame: 1 and 3 hours post-dose
Population: The Full Analysis Set, defined as subjects who were randomized, received at least one dose of study drug, and had at least one measurement of time to syncope during tilt table testing.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Midodrine HCl | Diastolic Blood Pressure at 1 Minute and 10 Minutes Into The Tilt Table Test Conducted 1 and 3 Hours Post-dose at Treatment Visit 2 | At 1 minute 1 hour post-dose, n= 11, 12 | 81.5 mmHg | Standard Deviation 19.09 |
| Midodrine HCl | Diastolic Blood Pressure at 1 Minute and 10 Minutes Into The Tilt Table Test Conducted 1 and 3 Hours Post-dose at Treatment Visit 2 | At 10 minutes 1 hour post-dose, n= 10, 8 | 79.6 mmHg | Standard Deviation 16.18 |
| Midodrine HCl | Diastolic Blood Pressure at 1 Minute and 10 Minutes Into The Tilt Table Test Conducted 1 and 3 Hours Post-dose at Treatment Visit 2 | At 1 minute 3 hours post-dose, n= 11, 12 | 66.1 mmHg | Standard Deviation 9.66 |
| Midodrine HCl | Diastolic Blood Pressure at 1 Minute and 10 Minutes Into The Tilt Table Test Conducted 1 and 3 Hours Post-dose at Treatment Visit 2 | At 10 minutes 3 hours post-dose, n= 7, 6 | 69.3 mmHg | Standard Deviation 13.55 |
| Placebo | Diastolic Blood Pressure at 1 Minute and 10 Minutes Into The Tilt Table Test Conducted 1 and 3 Hours Post-dose at Treatment Visit 2 | At 10 minutes 3 hours post-dose, n= 7, 6 | 60.7 mmHg | Standard Deviation 14.69 |
| Placebo | Diastolic Blood Pressure at 1 Minute and 10 Minutes Into The Tilt Table Test Conducted 1 and 3 Hours Post-dose at Treatment Visit 2 | At 1 minute 1 hour post-dose, n= 11, 12 | 60.8 mmHg | Standard Deviation 13.99 |
| Placebo | Diastolic Blood Pressure at 1 Minute and 10 Minutes Into The Tilt Table Test Conducted 1 and 3 Hours Post-dose at Treatment Visit 2 | At 1 minute 3 hours post-dose, n= 11, 12 | 60.3 mmHg | Standard Deviation 18.53 |
| Placebo | Diastolic Blood Pressure at 1 Minute and 10 Minutes Into The Tilt Table Test Conducted 1 and 3 Hours Post-dose at Treatment Visit 2 | At 10 minutes 1 hour post-dose, n= 10, 8 | 64.9 mmHg | Standard Deviation 11.22 |
Secondary
Duration of The Effect of Treatment at 3 Hours Post-dose
Duration of effect was defined as the difference in time to onset of near-syncopal symptoms between the first and second tilt table test, conducted at 1 hour and 3 hours post-dose, respectively, at Treatment Visit 2 (time to onset at 3 hours minus time at 1 hour). The tilt table test is a 10-minute assessment performed using a manual or automated tilt table in a specialized laboratory. Subjects were moved onto the horizontal table and secured to the table with straps to prevent injury. After an equilibration period of at least 10 minutes with the subject at rest, the test began and the head of the tilt table was elevated to a 70-degree angle over a period of up to 30 seconds. The endpoint was a confirmed report of a near-syncopal symptom(s) (of sufficient severity that caused the patient to ask that the tilt table be returned to the horizontal position). Symptoms of near syncope were defined as dizziness, lightheadedness, feeling faint, or feeling like the subject might black out.
Time frame: 1 and 3 hours post-dose
Population: The Full Analysis Set, defined as subjects who were randomized, received at least one dose of study drug, and had at least one measurement of time to syncope during tilt table testing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Midodrine HCl | Duration of The Effect of Treatment at 3 Hours Post-dose | 45.1 seconds | Standard Deviation 94.03 |
| Placebo | Duration of The Effect of Treatment at 3 Hours Post-dose | 48.0 seconds | Standard Deviation 114.96 |
p-value: 0.9479t-test, 2 sided
Secondary
Final Blood Pressure During Tilt Table Testing
Blood pressure was recorded just before tilt table testing and immediately after. Timed readings were stopped once a subject experienced near-syncopal symptoms, except for subjects for whom the table was returned to horizontal before 1 minute; for these subjects, a reading was made at 1 minute and was included in analyses. The tilt table test is a 10-minute assessment performed using a manual or automated tilt table in a specialized laboratory. Subjects were moved onto the horizontal table and secured to the table with straps to prevent injury. After an equilibration period of at least 10 minutes with the subject at rest, the test began and the head of the tilt table was elevated to a 70-degree angle over a period of up to 30 seconds. Symptoms of near syncope were defined as dizziness, lightheadedness, feeling faint, or feeling like the subject might black out.
Time frame: 1 hour post-dose
Population: The Full Analysis Set, defined as subjects who were randomized, received at least one dose of study drug, and had at least one measurement of time to syncope during tilt table testing.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Midodrine HCl | Final Blood Pressure During Tilt Table Testing | Systolic Pressure | 106.5 mmHg | Standard Deviation 37.27 |
| Midodrine HCl | Final Blood Pressure During Tilt Table Testing | Diastolic Pressure | 70.6 mmHg | Standard Deviation 16.44 |
| Placebo | Final Blood Pressure During Tilt Table Testing | Systolic Pressure | 90.2 mmHg | Standard Deviation 24.17 |
| Placebo | Final Blood Pressure During Tilt Table Testing | Diastolic Pressure | 60.6 mmHg | Standard Deviation 15.04 |
Comparison: Final systolic pressure-Analysis of treatmentp-value: 0.0378ANOVA
Comparison: Final diastolic pressure-Analysis of treatmentp-value: 0.0108ANOVA
Secondary
Heart Rate at 1 Minute and 10 Minutes Into The Tilt Table Test Conducted 1 and 3 Hours Post-dose at Treatment Visit 2
Heart rate was recorded just before tilt table testing, at each minute during tilt table testing, and immediately after. Timed readings were stopped once a subject experienced near-syncopal symptoms, except for subjects for whom the table was returned to horizontal before 1 minute; for these subjects, a reading was made at 1 minute and was included in analyses. The tilt table test is a 10-minute assessment performed using a manual or automated tilt table in a specialized laboratory. Subjects were moved onto the horizontal table and secured to the table with straps to prevent injury. After an equilibration period of at least 10 minutes with the subject at rest, the test began and the head of the tilt table was elevated to a 70-degree angle over a period of up to 30 seconds. Symptoms of near syncope were defined as dizziness, lightheadedness, feeling faint, or feeling like the subject might black out.
Time frame: 1 and 3 hours post-dose
Population: The Full Analysis Set, defined as subjects who were randomized, received at least one dose of study drug, and had at least one measurement of time to syncope during tilt table testing.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Midodrine HCl | Heart Rate at 1 Minute and 10 Minutes Into The Tilt Table Test Conducted 1 and 3 Hours Post-dose at Treatment Visit 2 | At 1 minute 1 hour post-dose, n= 11, 13 | 77.6 beats per minute | Standard Deviation 13.93 |
| Midodrine HCl | Heart Rate at 1 Minute and 10 Minutes Into The Tilt Table Test Conducted 1 and 3 Hours Post-dose at Treatment Visit 2 | At 10 minutes 1 hour post-dose, n= 10, 8 | 77.7 beats per minute | Standard Deviation 16.08 |
| Midodrine HCl | Heart Rate at 1 Minute and 10 Minutes Into The Tilt Table Test Conducted 1 and 3 Hours Post-dose at Treatment Visit 2 | At 1 minute 3 hours post-dose, n= 11, 12 | 79.7 beats per minute | Standard Deviation 11.3 |
| Midodrine HCl | Heart Rate at 1 Minute and 10 Minutes Into The Tilt Table Test Conducted 1 and 3 Hours Post-dose at Treatment Visit 2 | At 10 minutes 3 hours post-dose, n= 8, 6 | 80.9 beats per minute | Standard Deviation 11.66 |
| Placebo | Heart Rate at 1 Minute and 10 Minutes Into The Tilt Table Test Conducted 1 and 3 Hours Post-dose at Treatment Visit 2 | At 10 minutes 3 hours post-dose, n= 8, 6 | 81.3 beats per minute | Standard Deviation 20.16 |
| Placebo | Heart Rate at 1 Minute and 10 Minutes Into The Tilt Table Test Conducted 1 and 3 Hours Post-dose at Treatment Visit 2 | At 1 minute 1 hour post-dose, n= 11, 13 | 80.5 beats per minute | Standard Deviation 14.07 |
| Placebo | Heart Rate at 1 Minute and 10 Minutes Into The Tilt Table Test Conducted 1 and 3 Hours Post-dose at Treatment Visit 2 | At 1 minute 3 hours post-dose, n= 11, 12 | 80.9 beats per minute | Standard Deviation 13.19 |
| Placebo | Heart Rate at 1 Minute and 10 Minutes Into The Tilt Table Test Conducted 1 and 3 Hours Post-dose at Treatment Visit 2 | At 10 minutes 1 hour post-dose, n= 10, 8 | 79.5 beats per minute | Standard Deviation 16.48 |
Secondary
Number of Participants With Improvement of Clinician Clinician's Global Impression- Improvement (CGI-I) Scores After Tilt Table Test
The CGI-I instrument assesses the overall impression of the subject's orthostatic hypotension during the tilt table test by using a 7-point scale, with 1 being Very much improved; 2, Much improved; 3, Slightly improved; 4, No change; 5, Slightly worse; 6, Much worse; and 7, Very much worse. The clinician completed the CGI-I after each of the tilt table tests. A patient was assessed as Improved if the score was 1, 2, or 3. The tilt table test is a 10-minute assessment performed using a manual or automated tilt table in a specialized laboratory. Subjects were moved onto the horizontal table and secured to the table with straps to prevent injury. After an equilibration period of at least 10 minutes with the subject at rest, the test began and the head of the tilt table was elevated to a 70-degree angle over a period of up to 30 seconds. Symptoms of near syncope were defined as dizziness, lightheadedness, feeling faint, or feeling like the subject might black out.
Time frame: 1 and 3 hours post-dose
Population: The Full Analysis Set, defined as subjects who were randomized, received at least one dose of study drug, and had at least one measurement of time to syncope during tilt table testing.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Midodrine HCl | Number of Participants With Improvement of Clinician Clinician's Global Impression- Improvement (CGI-I) Scores After Tilt Table Test | Treatment Visit 1- 1 hour post-dose, n=13, 11 | 4 participants |
| Midodrine HCl | Number of Participants With Improvement of Clinician Clinician's Global Impression- Improvement (CGI-I) Scores After Tilt Table Test | Treatment Visit 2- 1 hour post-dose, n=11, 13 | 6 participants |
| Midodrine HCl | Number of Participants With Improvement of Clinician Clinician's Global Impression- Improvement (CGI-I) Scores After Tilt Table Test | Treatment Visit 2- 3 hour post-dose, n= 11, 12 | 3 participants |
| Placebo | Number of Participants With Improvement of Clinician Clinician's Global Impression- Improvement (CGI-I) Scores After Tilt Table Test | Treatment Visit 1- 1 hour post-dose, n=13, 11 | 4 participants |
| Placebo | Number of Participants With Improvement of Clinician Clinician's Global Impression- Improvement (CGI-I) Scores After Tilt Table Test | Treatment Visit 2- 1 hour post-dose, n=11, 13 | 4 participants |
| Placebo | Number of Participants With Improvement of Clinician Clinician's Global Impression- Improvement (CGI-I) Scores After Tilt Table Test | Treatment Visit 2- 3 hour post-dose, n= 11, 12 | 5 participants |
Secondary
Number of Participants With Improvement of Patient CGI-I Scores After Tilt Table Test
The CGI-I instrument assesses the overall impression of the subject's orthostatic hypotension during the tilt table test by using a 7-point scale, with 1 being Very much improved; 2, Much improved; 3, Slightly improved; 4, No change; 5, Slightly worse; 6, Much worse; and 7, Very much worse. The patient completed the CGI-I after each of the tilt table tests. A patient was assessed as Improved if the score was 1, 2, or 3. The tilt table test is a 10-minute assessment performed using a manual or automated tilt table in a specialized laboratory. Subjects were moved onto the horizontal table and secured to the table with straps to prevent injury. After an equilibration period of at least 10 minutes with the subject at rest, the test began and the head of the tilt table was elevated to a 70-degree angle over a period of up to 30 seconds. Symptoms of near syncope were defined as dizziness, lightheadedness, feeling faint, or feeling like the subject might black out.
Time frame: 1 and 3 hours post-dose
Population: The Full Analysis Set, defined as subjects who were randomized, received at least one dose of study drug, and had at least one measurement of time to syncope during tilt table testing.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Midodrine HCl | Number of Participants With Improvement of Patient CGI-I Scores After Tilt Table Test | Treatment Visit 1-1 hour post-dose, n= 13, 11 | 3 participants |
| Midodrine HCl | Number of Participants With Improvement of Patient CGI-I Scores After Tilt Table Test | Treatment Visit 2-1 hour post-dose, n= 11, 13 | 5 participants |
| Midodrine HCl | Number of Participants With Improvement of Patient CGI-I Scores After Tilt Table Test | Treatment Visit 2-3 hour post-dose, n= 11, 12 | 3 participants |
| Placebo | Number of Participants With Improvement of Patient CGI-I Scores After Tilt Table Test | Treatment Visit 1-1 hour post-dose, n= 13, 11 | 2 participants |
| Placebo | Number of Participants With Improvement of Patient CGI-I Scores After Tilt Table Test | Treatment Visit 2-1 hour post-dose, n= 11, 13 | 3 participants |
| Placebo | Number of Participants With Improvement of Patient CGI-I Scores After Tilt Table Test | Treatment Visit 2-3 hour post-dose, n= 11, 12 | 3 participants |
Secondary
Number of Participants With Shifts in Reference to Normal Range For Clinical Chemistry at Discharge
For biochemistry, blood samples (10.0mL) were taken at screening, admission (if greater than 14 days since screening) and discharge/early termination. The following parameters were assessed: sodium, potassium, calcium, blood urea nitrogen (BUN)/Urea, creatinine, albumin, total protein and albumin/globulin (A/G) ratio, globulin, aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), total bilirubin, glucose, chloride, and creatine kinase. A shift in reference to normal was either lower or higher at discharge.
Time frame: Baseline to discharge
Population: The Safety population, defined as all subjects who received at least one dose of investigational product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Midodrine HCl | Number of Participants With Shifts in Reference to Normal Range For Clinical Chemistry at Discharge | Sodium | 0 participants |
| Midodrine HCl | Number of Participants With Shifts in Reference to Normal Range For Clinical Chemistry at Discharge | Potassium | 2 participants |
| Midodrine HCl | Number of Participants With Shifts in Reference to Normal Range For Clinical Chemistry at Discharge | Calcium | 1 participants |
| Midodrine HCl | Number of Participants With Shifts in Reference to Normal Range For Clinical Chemistry at Discharge | BUN/Urea | 0 participants |
| Midodrine HCl | Number of Participants With Shifts in Reference to Normal Range For Clinical Chemistry at Discharge | Creatinine | 1 participants |
| Midodrine HCl | Number of Participants With Shifts in Reference to Normal Range For Clinical Chemistry at Discharge | Albumin | 0 participants |
| Midodrine HCl | Number of Participants With Shifts in Reference to Normal Range For Clinical Chemistry at Discharge | Total protein and A/G ratio | 2 participants |
| Midodrine HCl | Number of Participants With Shifts in Reference to Normal Range For Clinical Chemistry at Discharge | Globulin | 0 participants |
| Midodrine HCl | Number of Participants With Shifts in Reference to Normal Range For Clinical Chemistry at Discharge | ALT | 0 participants |
| Midodrine HCl | Number of Participants With Shifts in Reference to Normal Range For Clinical Chemistry at Discharge | AST | 0 participants |
| Midodrine HCl | Number of Participants With Shifts in Reference to Normal Range For Clinical Chemistry at Discharge | ALP | 1 participants |
| Midodrine HCl | Number of Participants With Shifts in Reference to Normal Range For Clinical Chemistry at Discharge | GGT | 0 participants |
| Midodrine HCl | Number of Participants With Shifts in Reference to Normal Range For Clinical Chemistry at Discharge | Total bilirubin | 1 participants |
| Midodrine HCl | Number of Participants With Shifts in Reference to Normal Range For Clinical Chemistry at Discharge | Glucose | 6 participants |
| Midodrine HCl | Number of Participants With Shifts in Reference to Normal Range For Clinical Chemistry at Discharge | Chloride | 0 participants |
| Midodrine HCl | Number of Participants With Shifts in Reference to Normal Range For Clinical Chemistry at Discharge | Creatine kinase | 1 participants |
Secondary
Number of Participants With Shifts in Reference to Normal Range For Hematology Analytes at Discharge
For hematology, blood samples (5.0mL) were taken at screening, study admission (if greater than 14 days since screening) and discharge/early termination. The following parameters were assessed: hemoglobin, hematocrit, red blood cells (RBC), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), white blood cell count - total and differential (WBC), and platelet count. A shift in reference to normal was either lower or higher at discharge.
Time frame: Baseline to discharge
Population: The Safety population, defined as all subjects who received at least one dose of investigational product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Midodrine HCl | Number of Participants With Shifts in Reference to Normal Range For Hematology Analytes at Discharge | Hemoglobin | 1 participants |
| Midodrine HCl | Number of Participants With Shifts in Reference to Normal Range For Hematology Analytes at Discharge | Hematocrit | 0 participants |
| Midodrine HCl | Number of Participants With Shifts in Reference to Normal Range For Hematology Analytes at Discharge | RBC | 0 participants |
| Midodrine HCl | Number of Participants With Shifts in Reference to Normal Range For Hematology Analytes at Discharge | MCV | 0 participants |
| Midodrine HCl | Number of Participants With Shifts in Reference to Normal Range For Hematology Analytes at Discharge | MCH | 0 participants |
| Midodrine HCl | Number of Participants With Shifts in Reference to Normal Range For Hematology Analytes at Discharge | MCHC | 2 participants |
| Midodrine HCl | Number of Participants With Shifts in Reference to Normal Range For Hematology Analytes at Discharge | WBC | 1 participants |
| Midodrine HCl | Number of Participants With Shifts in Reference to Normal Range For Hematology Analytes at Discharge | Platelet count | 0 participants |
Secondary
Number of Participants With Shifts in Reference to Normal Range For Urinalysis at Discharge
For urinalysis, samples were taken at screening, study admission (if greater than 14 days since screening) and discharge/early termination): glucose, blood, protein, pH, specific gravity, leukocyte esterase, and microscopic examination. A shift in reference to normal was higher at discharge.
Time frame: Baseline to discharge
Population: The Safety population, defined as all subjects who received at least one dose of investigational product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Midodrine HCl | Number of Participants With Shifts in Reference to Normal Range For Urinalysis at Discharge | Glucose | 1 participants |
| Midodrine HCl | Number of Participants With Shifts in Reference to Normal Range For Urinalysis at Discharge | Blood | 2 participants |
| Midodrine HCl | Number of Participants With Shifts in Reference to Normal Range For Urinalysis at Discharge | Protein | 0 participants |
| Midodrine HCl | Number of Participants With Shifts in Reference to Normal Range For Urinalysis at Discharge | pH | 0 participants |
| Midodrine HCl | Number of Participants With Shifts in Reference to Normal Range For Urinalysis at Discharge | Specific gravity | 0 participants |
| Midodrine HCl | Number of Participants With Shifts in Reference to Normal Range For Urinalysis at Discharge | Leukocyte esterase | 2 participants |
| Midodrine HCl | Number of Participants With Shifts in Reference to Normal Range For Urinalysis at Discharge | Microscopic examination | 0 participants |
Secondary
Scores for 6 Items of The OHSA
The OHSA measures the severity of six symptoms/symptom complexes associated with OH: dizziness, lightheadedness, and feeling faint; problems with vision; weakness; fatigue; trouble concentrating; and head/neck discomfort. Subjects rated symptoms experienced during the tilt table test on an eleven-point scale from none to worst possible. Scores for each subscale range from 0 (no symptoms) to 10 (worst possible symptoms). The OHSA was completed after the tilt table test was over, but was answered with reference to symptoms experienced during testing. The tilt table test is a 10-minute assessment performed using a tilt table in a specialized laboratory. Subjects were moved onto the horizontal table and secured with straps to prevent injury. After an equilibration period with the subject at rest, the test began and the head of the tilt table was elevated to a 70-degree angle over 30 seconds. Symptoms of near syncope were defined as dizziness, lightheadedness, and feeling faint.
Time frame: Approximately 1 hour post-dose
Population: The Full Analysis Set, defined as subjects who were randomized, received at least one dose of study drug, and had at least one measurement of time to syncope during tilt table testing.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Midodrine HCl | Scores for 6 Items of The OHSA | Dizziness, Lightheadedness, and Feeling Faint | 3.4 scores on a scale | Standard Deviation 3.44 |
| Midodrine HCl | Scores for 6 Items of The OHSA | Problems with Vision | 1.5 scores on a scale | Standard Deviation 2.32 |
| Midodrine HCl | Scores for 6 Items of The OHSA | Weakness | 3.0 scores on a scale | Standard Deviation 3.13 |
| Midodrine HCl | Scores for 6 Items of The OHSA | Fatigue | 2.7 scores on a scale | Standard Deviation 3.22 |
| Midodrine HCl | Scores for 6 Items of The OHSA | Trouble Concentrating | 1.7 scores on a scale | Standard Deviation 2.04 |
| Midodrine HCl | Scores for 6 Items of The OHSA | Head/Neck Discomfort | 1.9 scores on a scale | Standard Deviation 2.52 |
| Placebo | Scores for 6 Items of The OHSA | Trouble Concentrating | 2.6 scores on a scale | Standard Deviation 3.13 |
| Placebo | Scores for 6 Items of The OHSA | Dizziness, Lightheadedness, and Feeling Faint | 4.7 scores on a scale | Standard Deviation 3.57 |
| Placebo | Scores for 6 Items of The OHSA | Fatigue | 3.5 scores on a scale | Standard Deviation 3.48 |
| Placebo | Scores for 6 Items of The OHSA | Problems with Vision | 2.7 scores on a scale | Standard Deviation 3.43 |
| Placebo | Scores for 6 Items of The OHSA | Head/Neck Discomfort | 2.1 scores on a scale | Standard Deviation 3.21 |
| Placebo | Scores for 6 Items of The OHSA | Weakness | 4.1 scores on a scale | Standard Deviation 3.17 |
Comparison: Item Dizziness, Lightheadedness, and Feeling Faint-Analysis of treatmentp-value: 0.0633ANOVA
Comparison: Item Problems with Vision-Analysis of treatmentp-value: 0.0191ANOVA
Comparison: Item Weakness-Analysis of treatmentp-value: 0.0727ANOVA
Comparison: Item Fatigue-Analysis of treatmentp-value: 0.282ANOVA
Comparison: Item Trouble Concentrating-Analysis of treatmentp-value: 0.088ANOVA
Comparison: Item Head/Neck Discomfort-Analysis of treatmentp-value: 0.6439ANOVA
Secondary
Systolic Blood Pressure at 1 Minute and 10 Minutes Into The Tilt Table Test Conducted 1 and 3 Hours Post-dose at Treatment Visit 2
Blood pressure was recorded just before tilt table testing, at each minute during tilt table testing, and immediately after. Timed readings were stopped once a subject experienced near-syncopal symptoms, except for subjects for whom the table was returned to horizontal before 1 minute; for these subjects, a reading was made at 1 minute and was included in analyses. The tilt table test is a 10-minute assessment performed using a manual or automated tilt table in a specialized laboratory. Subjects were moved onto the horizontal table and secured to the table with straps to prevent injury. After an equilibration period of at least 10 minutes with the subject at rest, the test began and the head of the tilt table was elevated to a 70-degree angle over a period of up to 30 seconds. Symptoms of near syncope were defined as dizziness, lightheadedness, feeling faint, or feeling like the subject might black out.
Time frame: 1 and 3 hours post-dose
Population: The Full Analysis Set, defined as subjects who were randomized, received at least one dose of study drug, and had at least one measurement of time to syncope during tilt table testing.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Midodrine HCl | Systolic Blood Pressure at 1 Minute and 10 Minutes Into The Tilt Table Test Conducted 1 and 3 Hours Post-dose at Treatment Visit 2 | At 1 minute 1 hour post-dose, n= 11, 13 | 142.2 mmHg | Standard Deviation 44.2 |
| Midodrine HCl | Systolic Blood Pressure at 1 Minute and 10 Minutes Into The Tilt Table Test Conducted 1 and 3 Hours Post-dose at Treatment Visit 2 | At 1 minute 3 hours post-dose, n= 11, 12 | 110.1 mmHg | Standard Deviation 19.06 |
| Midodrine HCl | Systolic Blood Pressure at 1 Minute and 10 Minutes Into The Tilt Table Test Conducted 1 and 3 Hours Post-dose at Treatment Visit 2 | At 10 minutes 1 hour post-dose, n= 10, 8 | 121.7 mmHg | Standard Deviation 37.57 |
| Midodrine HCl | Systolic Blood Pressure at 1 Minute and 10 Minutes Into The Tilt Table Test Conducted 1 and 3 Hours Post-dose at Treatment Visit 2 | At 10 minutes 3 hours post-dose, n= 7, 6 | 108.3 mmHg | Standard Deviation 30.48 |
| Placebo | Systolic Blood Pressure at 1 Minute and 10 Minutes Into The Tilt Table Test Conducted 1 and 3 Hours Post-dose at Treatment Visit 2 | At 10 minutes 3 hours post-dose, n= 7, 6 | 107.2 mmHg | Standard Deviation 19.32 |
| Placebo | Systolic Blood Pressure at 1 Minute and 10 Minutes Into The Tilt Table Test Conducted 1 and 3 Hours Post-dose at Treatment Visit 2 | At 1 minute 1 hour post-dose, n= 11, 13 | 97.3 mmHg | Standard Deviation 24.55 |
| Placebo | Systolic Blood Pressure at 1 Minute and 10 Minutes Into The Tilt Table Test Conducted 1 and 3 Hours Post-dose at Treatment Visit 2 | At 10 minutes 1 hour post-dose, n= 10, 8 | 102.9 mmHg | Standard Deviation 21.03 |
| Placebo | Systolic Blood Pressure at 1 Minute and 10 Minutes Into The Tilt Table Test Conducted 1 and 3 Hours Post-dose at Treatment Visit 2 | At 1 minute 3 hours post-dose, n= 11, 12 | 94.9 mmHg | Standard Deviation 31.36 |
Secondary
Time to Near-syncopal Symptoms at Treatment Visit 1
The tilt table test is a 10-minute assessment performed using a manual or automated tilt table in a specialized laboratory. Subjects were moved onto the horizontal table and secured to the table with straps to prevent injury. After an equilibration period of at least 10 minutes with the subject at rest, the test began and the head of the tilt table was elevated to a 70-degree angle over a period of up to 30 seconds. The head-up tilt table test in this study was conducted 1 hour after administration of the study medication. The endpoint was a confirmed report of a near-syncopal symptom(s) (of sufficient severity that caused the patient to ask that the tilt table be returned to the horizontal position). Symptoms of near syncope were defined as dizziness, lightheadedness, feeling faint, or feeling like the subject might black out.
Time frame: 1 hour post-dose
Population: The Full Analysis Set, defined as subjects who were randomized, received at least one dose of study drug, and had at least one measurement of time to syncope during tilt table testing.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Midodrine HCl | Time to Near-syncopal Symptoms at Treatment Visit 1 | 539.5 seconds | Standard Error 45.91 |
| Placebo | Time to Near-syncopal Symptoms at Treatment Visit 1 | 448.4 seconds | Standard Error 49.91 |
p-value: 0.1928ANOVA
Secondary
Time to Onset of Near-syncopal Symptoms in The Per-protocol Population
The tilt table test is a 10-minute assessment performed using a manual or automated tilt table in a specialized laboratory. Subjects were moved onto the horizontal table and secured to the table with straps to prevent injury. After an equilibration period of at least 10 minutes with the subject at rest, the test began and the head of the tilt table was elevated to a 70-degree angle over a period of up to 30 seconds. The head-up tilt table test in this study was conducted 1 hour after administration of the study medication. The endpoint was a confirmed report of a near-syncopal symptom(s) (of sufficient severity that caused the patient to ask that the tilt table be returned to the horizontal position). Symptoms of near syncope were defined as dizziness, lightheadedness, feeling faint, or feeling like the subject might black out.
Time frame: 1 hour post-dose
Population: The Per-protocol set, defined as participants in the Full Analysis Set who completed the study and were protocol compliant.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Midodrine HCl | Time to Onset of Near-syncopal Symptoms in The Per-protocol Population | 544.3 seconds | Standard Deviation 122.34 |
| Placebo | Time to Onset of Near-syncopal Symptoms in The Per-protocol Population | 447.9 seconds | Standard Deviation 199.31 |
p-value: 0.2266Sign test
Secondary
Time to Onset of Near-syncopal Symptoms in The Per-protocol Population Analysis #2
The tilt table test is a 10-minute assessment performed using a manual or automated tilt table in a specialized laboratory. Subjects were moved onto the horizontal table and secured to the table with straps to prevent injury. After an equilibration period of at least 10 minutes with the subject at rest, the test began and the head of the tilt table was elevated to a 70-degree angle over a period of up to 30 seconds. The head-up tilt table test in this study was conducted 1 hour after administration of the study medication. The endpoint was a confirmed report of a near- syncopal symptom(s) (of sufficient severity that caused the patient to ask that the tilt table be returned to the horizontal position). Symptoms of near syncope were defined as dizziness, lightheadedness, feeling faint, or feeling like the subject might black out. In this outcome measure, the data analyzed are the same as for Outcome Measure 4 but the summary data are presented as least squares mean (standard error).
Time frame: 1 hour post-dose
Population: The Per-protocol set, defined as participants in the Full Analysis Set who completed the study and were protocol compliant.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Midodrine HCl | Time to Onset of Near-syncopal Symptoms in The Per-protocol Population Analysis #2 | 545.1 seconds | Standard Error 36.9 |
| Placebo | Time to Onset of Near-syncopal Symptoms in The Per-protocol Population Analysis #2 | 447.2 seconds | Standard Error 36.9 |
Comparison: Analysis of treatment differencep-value: 0.0418ANOVA
Secondary
Total Score of the Orthostatic Hypotension Symptom Assessment (OHSA)
The OHSA measures the severity of six symptoms/symptom complexes associated with orthostatic hypotension. Subjects rated symptoms experienced during the tilt table test on an eleven-point scale from none to worst possible. The OHSA total score is the sum of six subscales, ranging from 0 (no symptoms) to 60 (worst possible symptoms). The OHSA was completed after the tilt table test was over, but was answered with reference to symptoms experienced during testing. The tilt table test is a 10-minute assessment performed using a manual or automated tilt table in a specialized laboratory. Subjects were moved onto the horizontal table and secured to the table with straps to prevent injury. After an equilibration period with the subject at rest, the test began and the head of the tilt table was elevated to a 70-degree angle over a period of up to 30 seconds. Symptoms of near syncope were defined as dizziness, lightheadedness, feeling faint, or feeling like the subject might black out.
Time frame: Approximately 1 hour post-dose
Population: The Full Analysis Set, defined as subjects who were randomized, received at least one dose of study drug, and had at least one measurement of time to syncope during tilt table testing.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Midodrine HCl | Total Score of the Orthostatic Hypotension Symptom Assessment (OHSA) | 13.7 scores on a scale | Standard Error 2.95 |
| Placebo | Total Score of the Orthostatic Hypotension Symptom Assessment (OHSA) | 19.4 scores on a scale | Standard Error 2.95 |
Comparison: Analysis of treatmentp-value: 0.059ANOVA