Hypotension, Orthostatic
Conditions
Brief summary
We are seeking male and female patients to voluntarily take part in a clinical research study. Patients must be aged 18 or older and diagnosed with symptomatic orthostatic hypotension (low blood pressure while in the upright position) due to Parkinson's disease, multiple system atrophy, pure autonomic failure or autonomic neuropathies (i.e. neurogenic orthostatic hypotension). Symptoms of low blood pressure include dizziness, lightheadedness, changes in vision and generalized weakness upon standing. The main effect of the drug being studied is to increase blood pressure in the upright position so symptoms will decrease. The purpose of this clinical study is to further assess the clinical benefit of midodrine hydrochloride (ProAmatine®), an approved treatment for orthostatic hypotension. During the course of the study, participants will receive either ProAmatine® or a placebo. Assessments will be made using questionnaires that measure symptom and activity levels. Blood pressure in the lying down and standing positions will be measured at each visit.
Interventions
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* The male or female patient must be 18 years of age or older and ambulatory. * Female patients must be: without menses for at least 12 months prior to screening; surgically sterilized (bilateral tubal ligation or hysterectomy); or practicing adequate means of birth control. Adequate means of birth control is defined as the use of prescribed birth control pills, IUD, or hormonal injections from at least one month prior to screening. Double-barrier methods and abstinence are also acceptable forms of birth control. * The patient has been diagnosed with symptomatic orthostatic hypotension due to Parkinson's disease, multiple system atrophy, pure autonomic failure or autonomic neuropathies (i.e. neurogenic orthostatic hypotension). * The patient manifests at least 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 patient 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 patient signs an Institutional-Review-Board approved written Informed Consent form prior to any study procedures taking place.
Exclusion criteria
* The patient is pregnant or lactating female. * The patient has pre-existing sustained supine hypertension greater than 180 systolic and 110 diastolic mmHg. * The patient 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 clinically significant. * The patient 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 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 patient 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 patient.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Post-treatment Score For Item 1 of The Orthostatic Hypotension Symptom Assessment (OHSA) Scale | End of 2-week treatment period | Item 1 of the OHSA asked the patient to rate, using a 0-10 scale (0 meaning not bothered and 10 meaning the worst), his or her impression of the severity of dizziness, lightheadedness, feeling faint, or feeling like you might black out whenever he or she was standing and that improved when he or she sat or laid down. Higher scores indicate more severe disease. |
| Re-analysis of The Post-treatment Score For Item 1 of The OHSA Scale, Excluding Two Sites | End of 2-week treatment period | Item 1 of the OHSA asked the patient to rate, using a 0-10 scale (0 meaning not bothered and 10 meaning the worst), his or her impression of the severity of dizziness, lightheadedness, feeling faint, or feeling like you might black out whenever he or she was standing and that improved when he or she sat or laid down. Higher scores indicate more severe disease. |
| Post-treatment OHSA Item 1 Score of United States (US) Participants With Mild/Moderate Disease According to The Clinical Global Impressions-Severity (CGI-S) Scale | End of 2-week treatment period | Item 1 of the OHSA asked the patient to rate, using a 0-10 scale (0 meaning not bothered and 10 meaning the worst), his or her impression of the severity of dizziness, lightheadedness, feeling faint, or feeling like you might black out whenever he or she was standing and that improved when he or she sat or laid down. The results are reported by degree of severity according to the CGI-S scale, which uses 4 categories to describe disease severity: Mild, Moderate, Marked, and Severe. The Item 1 scores reported are grouped for participants with Mild or Moderate disease severity. Higher scores indicate more severe disease. |
| Post-treatment OHSA Item 1 Score of US Participants With Marked/Severe Disease According to The CGI-S Scale | End of 2-week treatment period | Item 1 of the OHSA asked the patient to rate, using a 0-10 scale (0 meaning not bothered and 10 meaning the worst), his or her impression of the severity of dizziness, lightheadedness, feeling faint, or feeling like you might black out whenever he or she was standing and that improved when he or she sat or laid down. The results are reported by degree of severity according to the CGI-S scale, which uses 4 categories to describe disease severity: Mild, Moderate, Marked, and Severe. The Item 1 scores reported are grouped for participants with Marked or Severe disease severity. Higher scores indicate more severe disease. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Participants Scored as Improved on The Clinician Version of The Clinical Global Impressions Improvement (CGI-I) Scale | From the time of titration until the end of treatment | The CGI-I is a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). Clinical Global Impressions ratings are completed with respect to neurogenic OH symptoms. A value of 0 was used if the investigator or patient assessment was not performed. The improved category is made up of patients who were evaluated as very much improved, much improved, or slightly improved for the classification of Overall Improvement. The CGI-I was completed at Visit 5 (Period 2) and Visit 6 (study completion). |
| Percent of Participants Scored as Improved on The Patient Version of The CGI-I Scale | From the time of titration until the end of treatment | The CGI-I is a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). Clinical Global Impressions ratings are completed with respect to neurogenic OH symptoms. A value of 0 was used if the investigator or patient assessment was not performed. The improved category is made up of patients who were evaluated as very much improved, much improved, or slightly improved for the classification of Overall Improvement. The CGI-I was completed at Visit 5 (Period 2) and Visit 6 (study completion). |
| Change From Baseline in Standing Blood Pressure (BP) | From the time of titration until the end of treatment | Standing BP was measured at Visit 5 (Period 2) and Visit 6 (study completion) and compared to measurements taken at Visit 3A (titration). Standing BP was measured 3 minutes after the patient rose from the supine position or as soon as the patient indicated they needed to sit down. If the patient indicated he or she needed to sit down, the BP measurement was taken while in the standing position, before the patient sat down. |
| Change From Baseline in Supine BP | From the time of titration until the end of treatment | Supine BP was measured at Visit 5 (Period 2) and Visit 6 (study completion) and compared to measurements taken at Visit 3A (titration). Supine BP was measured after the patient had been in the supine position for 5 minutes. |
| Change From Baseline in The OHSA Items 2 Through 6 Scores | From the time of titration until the end of treatment | Items 2 through 6 of the OHSA asked the patient to rate, using a 0-10 scale (0 meaning not bothered and 10 meaning the worst), his or her impression of the severity of the following symptoms whenever he or she was standing and that improved when he or she sat down or laid down: Item 2 addresses problems with vision (blurring, seeing spots, tunnel vision, etc); Item 3, weakness; Item 4, fatigue; Item 5, trouble concentrating; and Item 6, head or neck discomfort. Symptomatology was assessed at Visit 3A (titration), Visit 5 (Period 2), and Visit 6 (study completion). A negative change from baseline indicates that symptoms have improved. |
| Test Reliability of the Intent-to-Treat (ITT) Population | From the time of titration until the end of treatment | Item 1 of the OHSA, the OHSA composite score, and the OHDAS global daily activity score were analyzed for test-retest reliability as a measure of validity. Test-retest reliability is the Pearson product-moment correlation coefficient calculated between OHQ scores at Visit 3A (baseline measure) and OHQ scores at Visit 5 for the subjects who received Placebo during Randomization Period 1. |
| Responsiveness of the Intent-to-Treat (ITT) Population | From the time of titration until the end of treatment | Item 1 of the OHSA, the OHSA composite score, and the OHDAS global daily activity score were analyzed for responsiveness as a measure of validity. Assuming that subjects who received Placebo during Randomization Period 1 are stable between Visit 3A and Visit 5, and using them as the stable subjects, responsiveness was calculated as \[(OH CFB in Midodrine group)-(OH CFB in Placebo group)\]/(SD of OH CFB in Placebo group), where CFB is change from baseline, SD is the standard deviation of OH CFB of the stable subjects; the value reported is the quotient of this equation. |
| Convergent Validity of the Intent-to-Treat (ITT) Population | From the time of titration until the end of treatment | Item 1 of the OHSA and the OHSA composite score were analyzed for convergent validity with the CGI-I-Clinician scores. The change from baseline in the CGI-I scores are correlated with the OHSA Item 1 score change from baseline and the OHSA composite score change from baseline for the subjects in the ITT population. Values shown are Spearman correlation coefficients. |
| Change From Baseline in Short Form-36 (SF-36) Version 2 Health Survey Questionnaire Scores | From the time of titration until the end of treatment | The SF-36 consists of 36 items in eight domains: physical functioning, general health, role-physical, bodily pain, vitality, social functioning, role-emotional, and mental health. Version 2 references one week ago for some questions. Raw scale scores for the SF-36 were transformed to a 0-100 scale with a higher score indicating a better quality of life. A positive change from baseline indicates that symptoms have improved. The SF-36 was completed at Visit 5 (Period 2) and Visit 6 (study completion) and compared to the score from Visit 3A (titration). |
| Change From Baseline in The OHSA Composite Symptom Score | From the time of titration until the end of treatment | The OHSA composite symptom score was calculated by taking the average of the ratings for the symptoms present at Baseline. Participants were asked to rate symptoms by using a 0-10 scale (0 meaning not bothered and 10 meaning the worst). For subsequent visits, only those symptoms present at Baseline were scored. In this manner, a score was produced that represents the severity (and subsequent change in severity) of the patient's neurogenic OH symptoms, regardless of how many symptoms are presented at Baseline. Symptomatology was assessed at Visit 3A (titration), Visit 5 (Period 2), and Visit 6 (study completion). A negative change from baseline indicates that symptoms have improved. |
| Change From Baseline in The Orthostatic Hypotension Daily Activity Scale (OHDAS) Items 1 Through 4 Scores | From the time of titration until the end of treatment | The OHDAS had 4 items that asked the patient to give a graduated score from 0 (no limitation due to OH) to 10 (complete limitation due to OH). Item 1 addressed activities that required standing for a short time; Item 2, activities that required standing for a long time; Item 3, activities that required walking for a short time; and Item 4, activities that required walking for a long time. Symptomatology was assessed at Visit 3A (titration), Visit 5 (Period 2), and Visit 6 (study completion). A negative change from baseline indicates that symptoms have improved. |
| Change From Baseline in The Orthostatic Hypotension Global Daily Activity Score | From the time of titration until the end of treatment | The OHDAS global daily activity score was calculated as the average of all daily activity item scores. The OHDAS had 4 items that asked the patient to give a graduated score from 0 (no limitation due to OH) to 10 (complete limitation due to OH) to activities that required standing for a short time, standing for a long time, walking for a short time, walking for a long time. Symptomatology was assessed at Visit 3A (titration), Visit 5 (Period 2), and Visit 6 (study completion). A negative change from baseline indicates that symptoms have improved. |
Countries
United States
Participant flow
Pre-assignment details
Patients who completed the Titration Period were then randomized to receive either Midodrine/Placebo or Placebo/Midodrine during Treatment Periods 1 and 2. Some patients did not meet the criteria for randomization, had an AE, or withdrew from the study after completing the Titration Period prior to entering Treatment Period 1.
Participants by arm
| Arm | Count |
|---|---|
| Midodrine/Placebo Participants received their optimum dose of Midodrine HCl for 2 weeks, followed by 2 weeks of treatment with Placebo | 45 |
| Placebo/Midodrine Participants received Placebo for 2 weeks, followed by 2 weeks of treatment with their optimum dose of Midodrine HCl | 59 |
| Total | 104 |
Baseline characteristics
| Characteristic | Midodrine/Placebo | Placebo/Midodrine | Total |
|---|---|---|---|
| Age, Continuous | 62.0 years STANDARD_DEVIATION 14.22 | 62.2 years STANDARD_DEVIATION 14.43 | 62.2 years STANDARD_DEVIATION 14.27 |
| Sex: Female, Male Female | 23 Participants | 24 Participants | 47 Participants |
| Sex: Female, Male Male | 22 Participants | 35 Participants | 57 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 12 / 140 | 42 / 136 | 22 / 104 | 23 / 105 | 23 / 140 |
| serious Total, serious adverse events | 1 / 140 | 4 / 136 | 0 / 104 | 1 / 105 | 5 / 140 |
Outcome results
Primary
Post-treatment OHSA Item 1 Score of United States (US) Participants With Mild/Moderate Disease According to The Clinical Global Impressions-Severity (CGI-S) Scale
Item 1 of the OHSA asked the patient to rate, using a 0-10 scale (0 meaning not bothered and 10 meaning the worst), his or her impression of the severity of dizziness, lightheadedness, feeling faint, or feeling like you might black out whenever he or she was standing and that improved when he or she sat or laid down. The results are reported by degree of severity according to the CGI-S scale, which uses 4 categories to describe disease severity: Mild, Moderate, Marked, and Severe. The Item 1 scores reported are grouped for participants with Mild or Moderate disease severity. Higher scores indicate more severe disease.
Time frame: End of 2-week treatment period
Population: Randomized participants enrolled at any of the 28 US sites
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Midodrine HCl | Post-treatment OHSA Item 1 Score of United States (US) Participants With Mild/Moderate Disease According to The Clinical Global Impressions-Severity (CGI-S) Scale | 4.4 scores on a scale | Standard Deviation 2.97 |
| Placebo | Post-treatment OHSA Item 1 Score of United States (US) Participants With Mild/Moderate Disease According to The Clinical Global Impressions-Severity (CGI-S) Scale | 3.8 scores on a scale | Standard Deviation 2.63 |
Comparison: Analysis of US participants with mild or moderate disease severityp-value: 0.37ANOVA
Primary
Post-treatment OHSA Item 1 Score of US Participants With Marked/Severe Disease According to The CGI-S Scale
Item 1 of the OHSA asked the patient to rate, using a 0-10 scale (0 meaning not bothered and 10 meaning the worst), his or her impression of the severity of dizziness, lightheadedness, feeling faint, or feeling like you might black out whenever he or she was standing and that improved when he or she sat or laid down. The results are reported by degree of severity according to the CGI-S scale, which uses 4 categories to describe disease severity: Mild, Moderate, Marked, and Severe. The Item 1 scores reported are grouped for participants with Marked or Severe disease severity. Higher scores indicate more severe disease.
Time frame: End of 2-week treatment period
Population: Randomized participants enrolled at any of the 28 US sites
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Midodrine HCl | Post-treatment OHSA Item 1 Score of US Participants With Marked/Severe Disease According to The CGI-S Scale | 4.7 scores on a scale | Standard Deviation 2.9 |
| Placebo | Post-treatment OHSA Item 1 Score of US Participants With Marked/Severe Disease According to The CGI-S Scale | 6.1 scores on a scale | Standard Deviation 2.6 |
Comparison: Analysis of US participants with marked or severe disease severityp-value: 0.007ANOVA
Primary
Post-treatment Score For Item 1 of The Orthostatic Hypotension Symptom Assessment (OHSA) Scale
Item 1 of the OHSA asked the patient to rate, using a 0-10 scale (0 meaning not bothered and 10 meaning the worst), his or her impression of the severity of dizziness, lightheadedness, feeling faint, or feeling like you might black out whenever he or she was standing and that improved when he or she sat or laid down. Higher scores indicate more severe disease.
Time frame: End of 2-week treatment period
Population: Intent-to-Treat, defined as all patients who were randomly assigned to treatment in the study and have at least one post-randomization OHQ measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Midodrine HCl | Post-treatment Score For Item 1 of The Orthostatic Hypotension Symptom Assessment (OHSA) Scale | 4.1 scores on a scale | Standard Deviation 2.9 |
| Placebo | Post-treatment Score For Item 1 of The Orthostatic Hypotension Symptom Assessment (OHSA) Scale | 5.2 scores on a scale | Standard Deviation 2.7 |
p-value: <0.001ANOVA
Primary
Re-analysis of The Post-treatment Score For Item 1 of The OHSA Scale, Excluding Two Sites
Item 1 of the OHSA asked the patient to rate, using a 0-10 scale (0 meaning not bothered and 10 meaning the worst), his or her impression of the severity of dizziness, lightheadedness, feeling faint, or feeling like you might black out whenever he or she was standing and that improved when he or she sat or laid down. Higher scores indicate more severe disease.
Time frame: End of 2-week treatment period
Population: Intent-to-Treat, defined as all patients who were randomly assigned to treatment in the study and have at least one post-randomization OHQ measurement. Data for 2 sites were excluded from this re-analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Midodrine HCl | Re-analysis of The Post-treatment Score For Item 1 of The OHSA Scale, Excluding Two Sites | 4.3 scores on a scale | Standard Deviation 2.93 |
| Placebo | Re-analysis of The Post-treatment Score For Item 1 of The OHSA Scale, Excluding Two Sites | 5.1 scores on a scale | Standard Deviation 2.76 |
p-value: 0.011ANOVA
Secondary
Change From Baseline in Short Form-36 (SF-36) Version 2 Health Survey Questionnaire Scores
The SF-36 consists of 36 items in eight domains: physical functioning, general health, role-physical, bodily pain, vitality, social functioning, role-emotional, and mental health. Version 2 references one week ago for some questions. Raw scale scores for the SF-36 were transformed to a 0-100 scale with a higher score indicating a better quality of life. A positive change from baseline indicates that symptoms have improved. The SF-36 was completed at Visit 5 (Period 2) and Visit 6 (study completion) and compared to the score from Visit 3A (titration).
Time frame: From the time of titration until the end of treatment
Population: Intent-to-Treat, defined as all patients who were randomly assigned to treatment in the study and have at least one post-randomization OHQ measurement.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Midodrine HCl | Change From Baseline in Short Form-36 (SF-36) Version 2 Health Survey Questionnaire Scores | General Health | 1.97 scores on a scale | Standard Deviation 7.801 |
| Midodrine HCl | Change From Baseline in Short Form-36 (SF-36) Version 2 Health Survey Questionnaire Scores | Physical Functioning | 1.99 scores on a scale | Standard Deviation 8.255 |
| Placebo | Change From Baseline in Short Form-36 (SF-36) Version 2 Health Survey Questionnaire Scores | General Health | 1.59 scores on a scale | Standard Deviation 6.027 |
| Placebo | Change From Baseline in Short Form-36 (SF-36) Version 2 Health Survey Questionnaire Scores | Physical Functioning | 1.71 scores on a scale | Standard Deviation 8.034 |
Comparison: Analysis of general healthp-value: 0.569ANOVA
Comparison: Analysis of physical functioningp-value: 0.578ANOVA
Secondary
Change From Baseline in Standing Blood Pressure (BP)
Standing BP was measured at Visit 5 (Period 2) and Visit 6 (study completion) and compared to measurements taken at Visit 3A (titration). Standing BP was measured 3 minutes after the patient rose from the supine position or as soon as the patient indicated they needed to sit down. If the patient indicated he or she needed to sit down, the BP measurement was taken while in the standing position, before the patient sat down.
Time frame: From the time of titration until the end of treatment
Population: Intent-to-Treat, defined as all patients who were randomly assigned to treatment in the study and have at least one post-randomization OHQ measurement.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Midodrine HCl | Change From Baseline in Standing Blood Pressure (BP) | Systolic Pressure | 10.7 mmHg | Standard Deviation 21.68 |
| Midodrine HCl | Change From Baseline in Standing Blood Pressure (BP) | Diastolic Pressure | 5.9 mmHg | Standard Deviation 14.46 |
| Placebo | Change From Baseline in Standing Blood Pressure (BP) | Systolic Pressure | 2.8 mmHg | Standard Deviation 19.55 |
| Placebo | Change From Baseline in Standing Blood Pressure (BP) | Diastolic Pressure | 1.5 mmHg | Standard Deviation 13.03 |
Comparison: Analysis of standing systolic blood pressurep-value: 0.002ANOVA
Comparison: Analysis of standing diastolic blood pressurep-value: 0.01ANOVA
Secondary
Change From Baseline in Supine BP
Supine BP was measured at Visit 5 (Period 2) and Visit 6 (study completion) and compared to measurements taken at Visit 3A (titration). Supine BP was measured after the patient had been in the supine position for 5 minutes.
Time frame: From the time of titration until the end of treatment
Population: Intent-to-Treat, defined as all patients who were randomly assigned to treatment in the study and have at least one post-randomization OHQ measurement.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Midodrine HCl | Change From Baseline in Supine BP | Systolic Pressure | 7.6 mmHg | Standard Deviation 22.76 |
| Midodrine HCl | Change From Baseline in Supine BP | Diastolic Pressure | 3.4 mmHg | Standard Deviation 11.89 |
| Placebo | Change From Baseline in Supine BP | Systolic Pressure | -0.9 mmHg | Standard Deviation 15.74 |
| Placebo | Change From Baseline in Supine BP | Diastolic Pressure | 0.3 mmHg | Standard Deviation 10.35 |
Comparison: Analysis of supine systolic blood pressurep-value: <0.001ANOVA
Comparison: Analysis of supine diastolic blood pressurep-value: 0.002ANOVA
Secondary
Change From Baseline in The OHSA Composite Symptom Score
The OHSA composite symptom score was calculated by taking the average of the ratings for the symptoms present at Baseline. Participants were asked to rate symptoms by using a 0-10 scale (0 meaning not bothered and 10 meaning the worst). For subsequent visits, only those symptoms present at Baseline were scored. In this manner, a score was produced that represents the severity (and subsequent change in severity) of the patient's neurogenic OH symptoms, regardless of how many symptoms are presented at Baseline. Symptomatology was assessed at Visit 3A (titration), Visit 5 (Period 2), and Visit 6 (study completion). A negative change from baseline indicates that symptoms have improved.
Time frame: From the time of titration until the end of treatment
Population: Intent-to-Treat, defined as all patients who were randomly assigned to treatment in the study and have at least one post-randomization OHQ measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Midodrine HCl | Change From Baseline in The OHSA Composite Symptom Score | -1.3 scores on a scale | Standard Deviation 2.5 |
| Placebo | Change From Baseline in The OHSA Composite Symptom Score | -0.54 scores on a scale | Standard Deviation 1.952 |
p-value: 0.002ANOVA
Secondary
Change From Baseline in The OHSA Items 2 Through 6 Scores
Items 2 through 6 of the OHSA asked the patient to rate, using a 0-10 scale (0 meaning not bothered and 10 meaning the worst), his or her impression of the severity of the following symptoms whenever he or she was standing and that improved when he or she sat down or laid down: Item 2 addresses problems with vision (blurring, seeing spots, tunnel vision, etc); Item 3, weakness; Item 4, fatigue; Item 5, trouble concentrating; and Item 6, head or neck discomfort. Symptomatology was assessed at Visit 3A (titration), Visit 5 (Period 2), and Visit 6 (study completion). A negative change from baseline indicates that symptoms have improved.
Time frame: From the time of titration until the end of treatment
Population: Intent-to-Treat, defined as all patients who were randomly assigned to treatment in the study and have at least one post-randomization OHQ measurement.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Midodrine HCl | Change From Baseline in The OHSA Items 2 Through 6 Scores | Item 3, n=103, 103 | -1.3 scores on a scale | Standard Deviation 3.2 |
| Midodrine HCl | Change From Baseline in The OHSA Items 2 Through 6 Scores | Item 5, n=102, 102 | -0.4 scores on a scale | Standard Deviation 2.7 |
| Midodrine HCl | Change From Baseline in The OHSA Items 2 Through 6 Scores | Item 4, n=103, 103 | -1.2 scores on a scale | Standard Deviation 3.2 |
| Midodrine HCl | Change From Baseline in The OHSA Items 2 Through 6 Scores | Item 6, n=102, 102 | -0.8 scores on a scale | Standard Deviation 2.6 |
| Midodrine HCl | Change From Baseline in The OHSA Items 2 Through 6 Scores | Item 2, n= 103, 103 | -1.2 scores on a scale | Standard Deviation 2.5 |
| Placebo | Change From Baseline in The OHSA Items 2 Through 6 Scores | Item 6, n=102, 102 | -0.5 scores on a scale | Standard Deviation 2.1 |
| Placebo | Change From Baseline in The OHSA Items 2 Through 6 Scores | Item 2, n= 103, 103 | -0.2 scores on a scale | Standard Deviation 2.3 |
| Placebo | Change From Baseline in The OHSA Items 2 Through 6 Scores | Item 3, n=103, 103 | -0.4 scores on a scale | Standard Deviation 2.5 |
| Placebo | Change From Baseline in The OHSA Items 2 Through 6 Scores | Item 4, n=103, 103 | -0.4 scores on a scale | Standard Deviation 2.6 |
| Placebo | Change From Baseline in The OHSA Items 2 Through 6 Scores | Item 5, n=102, 102 | 0.0 scores on a scale | Standard Deviation 2.2 |
Comparison: Analysis of Item 2p-value: <0.001ANOVA
Comparison: Analysis of Item 3p-value: 0.002ANOVA
Comparison: Analysis of Item 4p-value: 0.004ANOVA
Comparison: Analysis of Item 5p-value: 0.026ANOVA
Comparison: Analysis of Item 6p-value: 0.226ANOVA
Secondary
Change From Baseline in The Orthostatic Hypotension Daily Activity Scale (OHDAS) Items 1 Through 4 Scores
The OHDAS had 4 items that asked the patient to give a graduated score from 0 (no limitation due to OH) to 10 (complete limitation due to OH). Item 1 addressed activities that required standing for a short time; Item 2, activities that required standing for a long time; Item 3, activities that required walking for a short time; and Item 4, activities that required walking for a long time. Symptomatology was assessed at Visit 3A (titration), Visit 5 (Period 2), and Visit 6 (study completion). A negative change from baseline indicates that symptoms have improved.
Time frame: From the time of titration until the end of treatment
Population: Intent-to-Treat, defined as all patients who were randomly assigned to treatment in the study and have at least one post-randomization OHQ measurement.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Midodrine HCl | Change From Baseline in The Orthostatic Hypotension Daily Activity Scale (OHDAS) Items 1 Through 4 Scores | Item 1, n=102, 101 | -1.1 scores on a scale | Standard Deviation 2.9 |
| Midodrine HCl | Change From Baseline in The Orthostatic Hypotension Daily Activity Scale (OHDAS) Items 1 Through 4 Scores | Item 2, n=98, 99 | -1.8 scores on a scale | Standard Deviation 3.14 |
| Midodrine HCl | Change From Baseline in The Orthostatic Hypotension Daily Activity Scale (OHDAS) Items 1 Through 4 Scores | Item 3, n=100, 101 | -1.1 scores on a scale | Standard Deviation 2.71 |
| Midodrine HCl | Change From Baseline in The Orthostatic Hypotension Daily Activity Scale (OHDAS) Items 1 Through 4 Scores | Item 4, n=89, 90 | -1.3 scores on a scale | Standard Deviation 3.31 |
| Placebo | Change From Baseline in The Orthostatic Hypotension Daily Activity Scale (OHDAS) Items 1 Through 4 Scores | Item 4, n=89, 90 | -0.5 scores on a scale | Standard Deviation 2.57 |
| Placebo | Change From Baseline in The Orthostatic Hypotension Daily Activity Scale (OHDAS) Items 1 Through 4 Scores | Item 1, n=102, 101 | -0.4 scores on a scale | Standard Deviation 1.95 |
| Placebo | Change From Baseline in The Orthostatic Hypotension Daily Activity Scale (OHDAS) Items 1 Through 4 Scores | Item 3, n=100, 101 | -0.2 scores on a scale | Standard Deviation 2.16 |
| Placebo | Change From Baseline in The Orthostatic Hypotension Daily Activity Scale (OHDAS) Items 1 Through 4 Scores | Item 2, n=98, 99 | -0.6 scores on a scale | Standard Deviation 2.41 |
Comparison: Analysis of Item 1p-value: <0.001ANOVA
Comparison: Analysis of Item 2p-value: <0.001ANOVA
Comparison: Analysis of Item 3p-value: <0.001ANOVA
Comparison: Analysis of Item 4p-value: 0.001ANOVA
Secondary
Change From Baseline in The Orthostatic Hypotension Global Daily Activity Score
The OHDAS global daily activity score was calculated as the average of all daily activity item scores. The OHDAS had 4 items that asked the patient to give a graduated score from 0 (no limitation due to OH) to 10 (complete limitation due to OH) to activities that required standing for a short time, standing for a long time, walking for a short time, walking for a long time. Symptomatology was assessed at Visit 3A (titration), Visit 5 (Period 2), and Visit 6 (study completion). A negative change from baseline indicates that symptoms have improved.
Time frame: From the time of titration until the end of treatment
Population: Intent-to-Treat, defined as all patients who were randomly assigned to treatment in the study and have at least one post-randomization OHQ measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Midodrine HCl | Change From Baseline in The Orthostatic Hypotension Global Daily Activity Score | -1.4 scores on a scale | Standard Deviation 2.6 |
| Placebo | Change From Baseline in The Orthostatic Hypotension Global Daily Activity Score | -0.4 scores on a scale | Standard Deviation 1.9 |
p-value: <0.001ANOVA
Secondary
Convergent Validity of the Intent-to-Treat (ITT) Population
Item 1 of the OHSA and the OHSA composite score were analyzed for convergent validity with the CGI-I-Clinician scores. The change from baseline in the CGI-I scores are correlated with the OHSA Item 1 score change from baseline and the OHSA composite score change from baseline for the subjects in the ITT population. Values shown are Spearman correlation coefficients.
Time frame: From the time of titration until the end of treatment
Population: Intent-to-Treat, defined as all patients who were randomly assigned to treatment in the study and have at least one post-randomization OHQ measurement.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Midodrine HCl | Convergent Validity of the Intent-to-Treat (ITT) Population | OHSA Item 1, n=103 | 0.36 correlation coefficient |
| Midodrine HCl | Convergent Validity of the Intent-to-Treat (ITT) Population | OHSA Composite Score, n=102 | 0.38 correlation coefficient |
Secondary
Percent of Participants Scored as Improved on The Clinician Version of The Clinical Global Impressions Improvement (CGI-I) Scale
The CGI-I is a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). Clinical Global Impressions ratings are completed with respect to neurogenic OH symptoms. A value of 0 was used if the investigator or patient assessment was not performed. The improved category is made up of patients who were evaluated as very much improved, much improved, or slightly improved for the classification of Overall Improvement. The CGI-I was completed at Visit 5 (Period 2) and Visit 6 (study completion).
Time frame: From the time of titration until the end of treatment
Population: Intent-to-Treat, defined as all patients who were randomly assigned to treatment in the study and have at least one post-randomization OHQ measurement.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Midodrine HCl | Percent of Participants Scored as Improved on The Clinician Version of The Clinical Global Impressions Improvement (CGI-I) Scale | 73.1 percent of participants |
| Placebo | Percent of Participants Scored as Improved on The Clinician Version of The Clinical Global Impressions Improvement (CGI-I) Scale | 45.2 percent of participants |
Secondary
Percent of Participants Scored as Improved on The Patient Version of The CGI-I Scale
The CGI-I is a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). Clinical Global Impressions ratings are completed with respect to neurogenic OH symptoms. A value of 0 was used if the investigator or patient assessment was not performed. The improved category is made up of patients who were evaluated as very much improved, much improved, or slightly improved for the classification of Overall Improvement. The CGI-I was completed at Visit 5 (Period 2) and Visit 6 (study completion).
Time frame: From the time of titration until the end of treatment
Population: Intent-to-Treat, defined as all patients who were randomly assigned to treatment in the study and have at least one post-randomization OHQ measurement.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Midodrine HCl | Percent of Participants Scored as Improved on The Patient Version of The CGI-I Scale | 62.5 percent of participants |
| Placebo | Percent of Participants Scored as Improved on The Patient Version of The CGI-I Scale | 50.0 percent of participants |
Secondary
Responsiveness of the Intent-to-Treat (ITT) Population
Item 1 of the OHSA, the OHSA composite score, and the OHDAS global daily activity score were analyzed for responsiveness as a measure of validity. Assuming that subjects who received Placebo during Randomization Period 1 are stable between Visit 3A and Visit 5, and using them as the stable subjects, responsiveness was calculated as \[(OH CFB in Midodrine group)-(OH CFB in Placebo group)\]/(SD of OH CFB in Placebo group), where CFB is change from baseline, SD is the standard deviation of OH CFB of the stable subjects; the value reported is the quotient of this equation.
Time frame: From the time of titration until the end of treatment
Population: Intent-to-Treat, defined as all patients who were randomly assigned to treatment in the study and have at least one post-randomization OHQ measurement.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Midodrine HCl | Responsiveness of the Intent-to-Treat (ITT) Population | OHSA Composite Score | -0.4014 quotient |
| Midodrine HCl | Responsiveness of the Intent-to-Treat (ITT) Population | OHSA Item 1 | -0.4099 quotient |
| Midodrine HCl | Responsiveness of the Intent-to-Treat (ITT) Population | OHDAS Global Daily Activity Score | -0.4903 quotient |
Secondary
Test Reliability of the Intent-to-Treat (ITT) Population
Item 1 of the OHSA, the OHSA composite score, and the OHDAS global daily activity score were analyzed for test-retest reliability as a measure of validity. Test-retest reliability is the Pearson product-moment correlation coefficient calculated between OHQ scores at Visit 3A (baseline measure) and OHQ scores at Visit 5 for the subjects who received Placebo during Randomization Period 1.
Time frame: From the time of titration until the end of treatment
Population: Intent-to-Treat, defined as all patients who were randomly assigned to treatment in the study and have at least one post-randomization OHQ measurement.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Midodrine HCl | Test Reliability of the Intent-to-Treat (ITT) Population | OHSA Item 1 | 0.53 correlation coefficient |
| Midodrine HCl | Test Reliability of the Intent-to-Treat (ITT) Population | OHSA Composite Score | 0.61 correlation coefficient |
| Midodrine HCl | Test Reliability of the Intent-to-Treat (ITT) Population | OHDAS Global Daily Activity Score | 0.66 correlation coefficient |