Autonomic Nervous System Diseases, Dopamine Beta-Hydroxylase Deficiency, Orthostatic Hypotension, Orthostatic Intolerance
Conditions
Keywords
autonomic nervous system diseases, blood pressure, congenital, orthostasis, catecholamines
Brief summary
The purpose of this study is to try different medications in patients with low blood pressure and other problems with their involuntary (autonomic) nervous system. The pharmacological trials in this study will perhaps lead to more effective treatment. The protocol includes single dose trials, dose-selection trials, 5-day trials and chronic (approximately 2 months) trials, although only dose-selection trials were consistently performed and have results presented.
Detailed description
We see many patients at the Autonomic Dysfunction Center who can be given a fairly definitive diagnosis, e.g., Orthostatic Intolerance, Pure Autonomic Failure, Multiple System Atrophy, and Baroreflex Failure. However, some patients present with a unique constellation of symptoms of autonomic dysfunction so that they do not fit into a diagnostic category. We hypothesize that a genetic cause exists in some of these patients. We further propose that our comprehensive evaluation of these patients will provide us with information on the pathophysiology of their condition and assist us in optimizing their treatment.
Interventions
Droxidopa administered in increasing dosages up to 300 mg
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Vanderbilt University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Although the study was designed as a potential trial of multiple medications, plus placebo, in actuality it served as a means of safely determining the optimal dose of Droxidopa for our patients with Dopamine beta-Hydroxylase Deficiency to take at home. Before each dose of Droxidopa, blood pressure and heart rate were measured for 30 minutes. At 60 or 120 minutes after dosing, blood pressure was also measured after 5 minutes of lying down and 5 minutes of sitting or standing. These measurements were used to calculate the orthostatic change in systolic blood pressure, the primary outcome.
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* patients with severe orthostatic hypotension and other autonomic symptoms who do not meet criteria for one of our standard diagnoses * non-smokers * drug-free * able to give informed consent * free of pulmonary, renal, hematopoietic, hepatic and cardiac disease
Exclusion criteria
* medications affecting the autonomic nervous system * any chronic illness (cardiac, pulmonary, endocrine, gastrointestinal, rheumatologic) * anemia (Hct \< 30) * women of childbearing age who are pregnant or nursing * smokers
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Systolic Blood Pressure With Standing | Up to 240 minutes post dose on Study Days 1, 2, 3 and 4. | The difference between upright and supine systolic blood pressures (dSBP; upright - supine) was calculated for each patient at 60-240 minutes after each dose of droxidopa. For each post-dose timepoint and study day, the average of up to three blood pressure readings per droxidopa dose was calculated. Dosing is individualized for each patient based upon how well the drug is tolerated and the degree of improvement in orthostatic vital signs and symptoms following drug administration. The dosages administered, as well as the number of timepoints and days, therefore, varied between patients. |
Countries
United States
Participant flow
Recruitment details
Eight patients with known or suspected dopamine beta-hydroxylase (DBH) deficiency were invited or referred for enrollment in this study.
Pre-assignment details
Although all 8 patients received droxidopa while in the study, data is not included for 2 patients who had previously been treated with this medication.
Participants by arm
| Arm | Count |
|---|---|
| Patients With Dopamine Beta-hydroxylase Deficiency Patients with known or suspected dopamine beta-hydroxylase deficiency were treated with droxidopa up to 300 mg three time daily. Supine and upright blood pressures were subsequently measured and the length of time the patients were able to stand was ascertained. | 6 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Physician Decision | 2 |
Baseline characteristics
| Characteristic | Patients With Dopamine Beta-hydroxylase Deficiency |
|---|---|
| Age, Continuous | 19 years STANDARD_DEVIATION 4.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 6 Participants |
| Region of Enrollment United States | 6 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 2 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 | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 |
Outcome results
Primary
Change in Systolic Blood Pressure With Standing
The difference between upright and supine systolic blood pressures (dSBP; upright - supine) was calculated for each patient at 60-240 minutes after each dose of droxidopa. For each post-dose timepoint and study day, the average of up to three blood pressure readings per droxidopa dose was calculated. Dosing is individualized for each patient based upon how well the drug is tolerated and the degree of improvement in orthostatic vital signs and symptoms following drug administration. The dosages administered, as well as the number of timepoints and days, therefore, varied between patients.
Time frame: Up to 240 minutes post dose on Study Days 1, 2, 3 and 4.
Population: Data is missing for 2 participants who had previously been treated with Droxidopa. In addition, since dosing was individualized for each patient, only those participants with data available at the specified timepoint were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Droxidopa 25 mg | Change in Systolic Blood Pressure With Standing | 240 minutes post-dose (Day 1) dSBP | -47 millimeters of mercury |
| Droxidopa 25 mg | Change in Systolic Blood Pressure With Standing | 60 minutes post-dose (Day 1) dSBP | -47 millimeters of mercury |
| Droxidopa 25 mg | Change in Systolic Blood Pressure With Standing | 120 minutes post-dose (Day 1) dSBP | -39.5 millimeters of mercury |
| Droxidopa 25 mg | Change in Systolic Blood Pressure With Standing | 180 minutes post-dose (Day 1) dSBP | -38 millimeters of mercury |
| Droxidopa 50 mg | Change in Systolic Blood Pressure With Standing | 120 minutes post-dose (Day 1) dSBP | -35.5 millimeters of mercury |
| Droxidopa 50 mg | Change in Systolic Blood Pressure With Standing | 180 minutes post-dose (Day 1) dSBP | -4 millimeters of mercury |
| Droxidopa 50 mg | Change in Systolic Blood Pressure With Standing | 60 minutes post-dose (Day 1) dSBP | -39 millimeters of mercury |
| Droxidopa 50 mg | Change in Systolic Blood Pressure With Standing | 240 minutes post-dose (Day 1) dSBP | -7 millimeters of mercury |
| Droxidopa 100 mg | Change in Systolic Blood Pressure With Standing | 60 minutes post-dose (Day 2) dSBP | -48 millimeters of mercury |
| Droxidopa 100 mg | Change in Systolic Blood Pressure With Standing | 120 minutes post-dose (Day 1) dSBP | -24 millimeters of mercury |
| Droxidopa 100 mg | Change in Systolic Blood Pressure With Standing | 120 minutes post-dose (Day 2) dSBP | -43.5 millimeters of mercury |
| Droxidopa 200 mg | Change in Systolic Blood Pressure With Standing | 120 minutes post-dose (Day 1) dSBP | -31 millimeters of mercury |
| Droxidopa 200 mg | Change in Systolic Blood Pressure With Standing | 60 minutes post-dose (Day 3) dSBP | -51 millimeters of mercury |
| Droxidopa 200 mg | Change in Systolic Blood Pressure With Standing | 120 minutes post-dose (Day 3) dSBP | -36.5 millimeters of mercury |
| Droxidopa 200 mg | Change in Systolic Blood Pressure With Standing | 120 minutes post-dose (Day 4) dSBP | -19 millimeters of mercury |
| Droxidopa 250 mg | Change in Systolic Blood Pressure With Standing | 60 minutes post-dose (Day 4) dSBP | -32.5 millimeters of mercury |
| Droxidopa 250 mg | Change in Systolic Blood Pressure With Standing | 120 minutes post-dose (Day 4) dSBP | -47 millimeters of mercury |
| Droxidopa 300 mg | Change in Systolic Blood Pressure With Standing | 120 minutes post-dose (Day 3) dSBP | -23 millimeters of mercury |
| Droxidopa 300 mg | Change in Systolic Blood Pressure With Standing | 60 minutes post-dose (Day 4) dSBP | -21 millimeters of mercury |
| Droxidopa 300 mg | Change in Systolic Blood Pressure With Standing | 60 minutes post-dose (Day 2) dSBP | -30 millimeters of mercury |
| Droxidopa 300 mg | Change in Systolic Blood Pressure With Standing | 120 minutes post-dose (Day 2) dSBP | -13 millimeters of mercury |
| Droxidopa 300 mg | Change in Systolic Blood Pressure With Standing | 60 minutes post-dose (Day 1) dSBP | -21 millimeters of mercury |