Symptomatic Orthostatic Hypotension
Conditions
Brief summary
To study the effect of midodrine against the symptoms of orthostatic hypotension
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 9 overnight stays.
Interventions
DRUGMidodrine HCl
dose at subject's current dose level
DRUGPlacebo
single dose of matching placebo
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
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 |
|---|---|---|
| Percent of Subjects Who Failed to Maintain a Response | 30 minutes post-dose on Day 16 | Failure to maintain a response was defined as any randomized subject that met both criterion 1 and criterion 2 below on Day 16: 1. The Orthostatic Hypotension Symptom Assessment (OHSA) Item 1 score increased by \>=4 points compared to baseline. OHSA Item 1 is a dizziness scale that is scored on a range from 0 (no dizziness) to 10 (severe dizziness). A lower score indicates less severe symptoms. 2. There was an increase in the number of syncopal/near syncopal events or severity of events within 15 minutes of standing compared to those observed at baseline. Syncope was defined as a loss of consciousness, and near syncope was defined as a feeling (e.g., dizziness, lightheadedness, feeling faint, feeling as though one would black out) that, without intervention, would lead to a loss of consciousness. |
Countries
Czechia, Poland, Slovakia, United States
Participant flow
Pre-assignment details
Subjects received the dose and frequency of Midodrine HCl that they had been receiving during their non-study treatment prior to enrolling in this study.
Participants by arm
| Arm | Count |
|---|---|
| Enrolled Population | 98 |
| Total | 98 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Part A (Open-label) | Other | 3 | 0 | 0 |
| Part B (Open-label) | Other | 1 | 0 | 0 |
| Part B (Open-label) | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Enrolled Population |
|---|---|
| Age, Continuous | 45.5 years STANDARD_DEVIATION 17.45 |
| Region of Enrollment Poland | 5 Participants |
| Region of Enrollment Slovakia | 3 Participants |
| Region of Enrollment United States | 90 Participants |
| Sex: Female, Male Female | 76 Participants |
| Sex: Female, Male Male | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 98 | 2 / 71 | 0 / 33 | 0 / 34 |
| serious Total, serious adverse events | 0 / 98 | 0 / 71 | 0 / 33 | 0 / 34 |
Outcome results
Primary
Percent of Subjects Who Failed to Maintain a Response
Failure to maintain a response was defined as any randomized subject that met both criterion 1 and criterion 2 below on Day 16: 1. The Orthostatic Hypotension Symptom Assessment (OHSA) Item 1 score increased by \>=4 points compared to baseline. OHSA Item 1 is a dizziness scale that is scored on a range from 0 (no dizziness) to 10 (severe dizziness). A lower score indicates less severe symptoms. 2. There was an increase in the number of syncopal/near syncopal events or severity of events within 15 minutes of standing compared to those observed at baseline. Syncope was defined as a loss of consciousness, and near syncope was defined as a feeling (e.g., dizziness, lightheadedness, feeling faint, feeling as though one would black out) that, without intervention, would lead to a loss of consciousness.
Time frame: 30 minutes post-dose on Day 16
Population: The Full Analysis Set was defined as all randomized subjects who received at least 1 dose of double-blind investigational product.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Midodrine HCl | Percent of Subjects Who Failed to Maintain a Response | 30.3 percentage of participants |
| Placebo | Percent of Subjects Who Failed to Maintain a Response | 44.1 percentage of participants |
p-value: 0.314595% CI: [-37.6, 9.8]Fisher Exact