Orthostatic Hypotension
Conditions
Keywords
Symptomatic Orthostatic Hypotension
Brief summary
The purpose of this study is to determine whether midodrine works against the symptoms of orthostatic hypotension caused by being on a tilt table.
Detailed description
The efficacy of midodrine will be assessed in those subjects who have severe symptoms of orthostatic hypotension when not taking midodrine and are controlled when taking midodrine. The study will involve approximately 4 overnight stays.
Interventions
DRUGMidodrine HCl
dose at the subject's current dose level
DRUGPlacebo
single dose of matching 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
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male and female subjects must be 18 years of age or older and ambulatory. 2. Females of child-bearing potential (FOCP) must have a negative serum beta human chorionic gonadotropin (HCG) pregnancy test. 3. A documented history of severe Symptomatic Orthostatic Hypotension (SOH) that, in the judgment of the treating physician, has required treatment with midodrine HCl , and has been at a stable dose for at least 3 months. 4. The subject has manifested at least 1 of the following symptoms while standing or had a medical history of 1 of the following when not treated for orthostatic hypotension (OH): dizziness, lightheadedness, feeling faint, or feeling like they might black out.
Exclusion criteria
1. The subject is a pregnant or lactating female. 2. The subject has pre-existing sustained supine hypertension greater than 180mmHg systolic and 110mmHg diastolic BP or had these measurements at the Screening Visit. Sustained is defined as persistently greater at 2 separate measurements at least 5 minutes apart with the subject supine and at rest for the 5 minutes. 3. Subjects taking concomitant medications of interest are excluded unless those medications are reviewed and discussed with the Medical Monitor or Study Physician and documented prior to enrolling the subject. If agreement is reached between the Investigator and Sponsor for the subject to continue in the study, all allowed medications should be maintained at a constant dose throughout the study. 4. The Principal Investigator deems any clinical laboratory test (at the Screening Visit) abnormality to be clinically significant 5. The subject has participated in other studies of investigational drugs or devices within 30 days prior to enrollment in this study (other than Study SPD426-406). 6. Current or relevant history of physical or psychiatric illness, any medical disorder that may require treatment or make the subject unlikely to fully comply with the requirements of the study or complete the study, or any condition that presents undue risk from the investigational product or study procedures. 7. The subject has a concurrent chronic or acute illness, disability, or other condition (including significant unexpected laboratory or electrocardiogram \[ECG\] findings) that might confound the results of the tests and/or measurements administered in this study, or that might have increased the risk to the subject. 8. Known or suspected intolerance or hypersensitivity to the investigational product(s), closely-related compounds, or any of the stated ingredients. 9. Prior enrollment failure or randomization in this study. 10. History of alcohol abuse or other substance abuse within the last year.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Onset of Syncope/Near Syncope While on Tilt Table | 1 hour post-dose | After a 30-minute supine period, the table was tilted from 0-90º within 30 seconds and maintained in that position for 45 minutes or until endpoint. Subjects were monitored for near-syncopal symptoms (subject felt sufficiently dizzy, lightheaded, faint, or felt like they were about to black out and requested the table to be returned to horizontal). Such a report ended the test. Alternatively, if the investigator observed that the subject was about to lose consciousness, that also constituted an endpoint. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo First, Then Midodrine HCl (Randomized Phase) Placebo for first intervention on Day 2, then Midodrine hydrochloride dose at the subject's current dose level for the second intervention on Day 3. | 10 |
| Midodrine HCl First, Then Placebo (Randomized Phase) Midodrine hydrochloride dose at the subject's current dose level for the first intervention Day 2, then placebo for second intervention on Day 3. | 10 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Open-label Phase | Other | 4 | 0 | 0 |
| Randomized Phase (First Intervention) | Other | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo First, Then Midodrine HCl (Randomized Phase) | Midodrine HCl First, Then Placebo (Randomized Phase) | Total |
|---|---|---|---|
| Age, Continuous | 48.0 years STANDARD_DEVIATION 19.52 | 42.1 years STANDARD_DEVIATION 18.64 | 45.1 years STANDARD_DEVIATION 18.82 |
| Age, Customized 18 to 65 years, inclusive | 8 Participants | 8 Participants | 16 Participants |
| Age, Customized >= 66 years | 2 Participants | 2 Participants | 4 Participants |
| Region of Enrollment United States | 10 Participants | 10 Participants | 20 Participants |
| Sex: Female, Male Female | 8 Participants | 10 Participants | 18 Participants |
| Sex: Female, Male Male | 2 Participants | 0 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 24 | 1 / 20 | 1 / 20 |
| serious Total, serious adverse events | 0 / 24 | 0 / 20 | 0 / 20 |
Outcome results
Primary
Time to Onset of Syncope/Near Syncope While on Tilt Table
After a 30-minute supine period, the table was tilted from 0-90º within 30 seconds and maintained in that position for 45 minutes or until endpoint. Subjects were monitored for near-syncopal symptoms (subject felt sufficiently dizzy, lightheaded, faint, or felt like they were about to black out and requested the table to be returned to horizontal). Such a report ended the test. Alternatively, if the investigator observed that the subject was about to lose consciousness, that also constituted an endpoint.
Time frame: 1 hour post-dose
Population: The Full Analysis Set was defined as all randomized subjects who received at least 1 dose of randomized investigational product and who had at least 1 measurement of the time to onset of syncopal symptoms/near syncope during tilt-table testing.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Time to Onset of Syncope/Near Syncope While on Tilt Table | 1105.6 seconds | Standard Error 186.82 |
| Midodrine HCl | Time to Onset of Syncope/Near Syncope While on Tilt Table | 1626.6 seconds | Standard Error 186.82 |
p-value: 0.013195% CI: [124.2, 917.7]ANOVA