Study to Assess the Benefit of Midodrine in the Treatment of Patients With Neurogenic Orthostatic Hypotension

This study has been completed.
Sponsor:
Information provided by:
Shire
ClinicalTrials.gov Identifier:
NCT00555880
First received: November 8, 2007
Last updated: May 5, 2015
Last verified: June 2010
  Purpose

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.


Condition Intervention Phase
Hypotension, Orthostatic
Drug: Midodrine hydrochloride
Drug: Placebo
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Multi-Center, Double-Blind, Randomized, Placebo-controlled, Crossover Study to Assess the Clinical Benefit of Midodrine Hydrochloride in Subjects With Moderate to Severe Neurogenic Orthostatic Hypotension

Resource links provided by NLM:


Further study details as provided by Shire:

Primary Outcome Measures:
  • Time to Onset of Near-syncopal Symptoms During Tilt Table Testing [ Time Frame: 1 hour post-dose ] [ Designated as safety issue: No ]
    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 [ Time Frame: 1 hour post-dose ] [ Designated as safety issue: No ]
    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 [ Time Frame: 1 hour post-dose ] [ Designated as safety issue: No ]
    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 Outcome Measures:
  • Time to Onset of Near-syncopal Symptoms in The Per-protocol Population [ Time Frame: 1 hour post-dose ] [ Designated as safety issue: No ]
    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 in The Per-protocol Population Analysis #2 [ Time Frame: 1 hour post-dose ] [ Designated as safety issue: No ]
    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 [ Time Frame: 1 hour post-dose ] [ Designated as safety issue: No ]
    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.

  • Duration of The Effect of Treatment at 3 Hours Post-dose [ Time Frame: 1 and 3 hours post-dose ] [ Designated as safety issue: No ]
    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) [ Time Frame: Approximately 1 hour post-dose ] [ Designated as safety issue: No ]
    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 [ Time Frame: Approximately 1 hour post-dose ] [ Designated as safety issue: No ]
    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 [ Time Frame: 1 and 3 hours post-dose ] [ Designated as safety issue: No ]
    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 [ Time Frame: 1 and 3 hours post-dose ] [ Designated as safety issue: No ]
    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 [ Time Frame: 1 hour post-dose ] [ Designated as safety issue: No ]
    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.

  • 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 [ Time Frame: 1 and 3 hours post-dose ] [ Designated as safety issue: No ]
    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.

  • 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 [ Time Frame: 1 and 3 hours post-dose ] [ Designated as safety issue: No ]
    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 [ Time Frame: 1 and 3 hours post-dose ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline to discharge ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline to discharge ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline to discharge ] [ Designated as safety issue: No ]
    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.


Enrollment: 24
Study Start Date: September 2004
Study Completion Date: March 2005
Arms Assigned Interventions
Experimental: 1 Drug: Midodrine hydrochloride
one dose, 10-30mg, given orally
Other Name: ProAmatine
Placebo Comparator: 2 Drug: Placebo
Placebo

  Eligibility

Ages Eligible for Study:   19 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00555880

Locations
United States, Indiana
Fort Wayne Neurological Center
Fort Wayne, Indiana, United States, 46805
United States, Massachusetts
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02215
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109
United States, Minnesota
Minnesota VA Medical Center
Minneapolis, Minnesota, United States, 55417
United States, Missouri
Forest Park Neurophysiology
Saint Louis, Missouri, United States, 63139
United States, New York
Mount Sinai Medical Center
New York, New York, United States, 10029
United States, North Carolina
Raleigh Neurology Associates
Raleigh, North Carolina, United States, 27607
United States, Ohio
University Hospitals of Cleveland
Cleveland, Ohio, United States, 44106
United States, South Carolina
Absher Neurology, PA
Greenville, South Carolina, United States, 29615
United States, Tennessee
Vanderbilt University
Nashville, Tennessee, United States, 37212
United States, Texas
Diabetes and Glandular Disease research Associates, PA
San Antonio, Texas, United States, 78229
Sponsors and Collaborators
Shire
Investigators
Principal Investigator: Richard Malamut, MD Crozer Chester Medical Center, Pennsylvania, USA
  More Information

Additional Information:
No publications provided

ClinicalTrials.gov Identifier: NCT00555880     History of Changes
Other Study ID Numbers: SPD426-404
Study First Received: November 8, 2007
Results First Received: April 13, 2015
Last Updated: May 5, 2015
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Hypotension
Hypotension, Orthostatic
Autonomic Nervous System Diseases
Cardiovascular Diseases
Nervous System Diseases
Orthostatic Intolerance
Primary Dysautonomias
Vascular Diseases
Midodrine
Adrenergic Agents
Adrenergic Agonists
Adrenergic alpha-1 Receptor Agonists
Adrenergic alpha-Agonists
Autonomic Agents
Cardiovascular Agents
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Sympathomimetics
Therapeutic Uses
Vasoconstrictor Agents

ClinicalTrials.gov processed this record on July 30, 2015