A Study for Patients With Neurogenic Orthostatic Hypotension

Phase 4

Completed

Conditions: Hypotension, Orthostatic

Registration Number: NCT00046475

Lead Sponsor: Shire

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 140

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Primary Outcome Measures

Name	Time	Method
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.
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.
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 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 Outcome Measures

Name	Time	Method
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 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.
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.
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).
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.
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 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).
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).
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.
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.

Trial Locations

Locations (15): North Alabama Neuroscience Research
🇺🇸
Huntsville, Alabama, United States
Dr. Harry Pepe & Associates, Inc.
🇺🇸
Miramar, Florida, United States
Suncoast Neuroscience Associates, Inc.
🇺🇸
Saint Petersburg, Florida, United States
Economou & Associates, LTD
🇺🇸
Chicago, Illinois, United States
Johns Hopkins Hospital
🇺🇸
Baltimore, Maryland, United States
Michigan Pain and Neurological Institute
🇺🇸
Ann Arbor, Michigan, United States
Dartmouth Hitchcock Medical Center
🇺🇸
Lebanon, New Hampshire, United States
NY Presbyterian Hospital
🇺🇸
New York, New York, United States
Medical College of Ohio
🇺🇸
Toledo, Ohio, United States
COR Clinical Research, LLC
🇺🇸
Oklahoma City, Oklahoma, United States
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North Alabama Neuroscience Research
🇺🇸Huntsville, Alabama, United States