Neurogenic Orthostatic Hypotension
Conditions
Keywords
norepinephrine transporter inhibitors
Brief summary
Drug therapy for patients suffering from autonomic failure and neurogenic orthostatic hypotension are scarce and not effective. If left untreated, these patients have the highest risk of syncope, falls and fall-related injuries. The proposed study will determine the clinical benefit of a commercially available drug, atomoxetine, to reduce symptoms associated with neurogenic orthostatic hypotension in patients with autonomic failure.
Detailed description
Autonomic failure is a group of rare neurodegenerative disorders that primarily affect the autonomic nervous system. These patients develop neurogenic orthostatic hypotension (OH) because of impaired autonomic reflexes that control cardiovascular and neuro-humoral adaptation to upright posture. The treatment of neurogenic OH is challenging; the therapeutic options are scarce, and some patients are refractory to treatment. Atomoxetine is a selective norepinephrine transporter inhibitor that increases the availability of norepinephrine in the synapse by blocking its reuptake. Our preliminary data in sixty-five patients with primary autonomic failure and neurogenic OH showed that atomoxetine was more effective than midodrine, standard of care, in improving standing SBP (+7.5 mm Hg). Notably, only atomoxetine and not midodrine induced a significant reduction in OH-related symptoms (lightheadedness and dizziness) compared with placebo. In this proposal, we will test the hypothesis that prolonged administration of the norepinephrine transporter blocker, atomoxetine, improves OH-related symptoms and OH-impact on daily activities compared with placebo in autonomic failure patients. We propose a randomized, double-blind, placebo-controlled, 2x2 crossover study.
Interventions
DRUGAtomoxetine
norepinephrine transporter inhibitor
DRUGPlacebo
placebo
Sponsors
NYU Langone Health
Vanderbilt University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* 40 years old or older * Neurogenic Orthostatic Hypotension (defined by a reduction of ≥20 mmHg drop in SBP within 3 minutes of standing, associated with impaired autonomic reflexes as assessed by autonomic function tests.
Exclusion criteria
* Pregnancy or breastfeeding * Hypersensitivity to atomoxetine (severe allergic reaction, rash, urticaria, anaphylaxis) * Use of other norepinephrine transporter inhibitors such as Wellbutrin (Bupropion), Cymbalta (Duloxetine), Effexor (venlafaxine), Pristiq (desvenlafaxine), Savella (milnacipran) * Previous history (within 14 days prior to enrollment) and current use of monoamine oxidase inhibitors * Concomitant use of strong CYP2D6 inhibitors such as delavirdine, paroxetine, fluoxetine, quinidine * Pre-existing sustained severe hypertension (BP ≥ 140/80 mmhg in the sitting position) * Impaired hepatic function (aspartate amino transaminase \[AST\] and/or alanine amino transaminase \[ALT\] \>2 x upper limit of normal range) * Impaired renal function (serum creatinine equal or more than 1.6 mg/dl) * Myocardial infarction within 6 months prior to enrollment * Congestive heart failure (LV hypertrophy acceptable) * History of serious neurologic disease such as cerebral hemorrhage, or stroke * Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, unlikelihood of completing the study, and mental conditions rendering the subject unable to understand the nature, scope, and possible consequences of the study * Narrow-angle glaucoma
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in the OHQ (Orthostatic Hypotension Questionnaire) Composite Score | week 0 to week 4 | The Orthostatic Hypotension Questionnaire (OHQ) , patient-reported assessment tool consisting of the OH Symptom Assessment (OHSA), OH Daily Activity Scale (OHDAS). The composite score is composed of 10 individual items: 6 items measure specific symptoms , the Orthostatic Hypotension Symptom Assessment (OHSA), and 4 items measure the impact of those symptoms on a patient daily activities, the Orthostatic Hypotension Daily Activity Scale (OHDAS). This scales helps to measure the impact of orthostatic symptoms on daily. Scale is between 0-10: where 0 is minimum Orthostatic symptoms and 10 is the maximum / worse possible severity of the symptoms. All items are scored 0 through 10 (higher scores = more impact) and summed into the respective total scores. The OHSA and OHDAS subscales averaged to compute the OHQ composite score. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Blood Pressure | Baseline to 4 weeks | Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) (measured in mm of Hg) , is recorded after 10 mins of standing. The changes SBP and DBP are compared from baseline, post drug (4 weeks) |
| Change in Heart Rate (HR) | Baseline and at 4 weeks | HR is compared to baseline after 10 mins of standing. The difference increase in Heart rate from baseline, post drug at 4 weeks |
Countries
United States
Participant flow
Recruitment details
25 subjects completed study at Vanderbilt University Medical Center, Nashville 15 subjects were enrolled at NYU School of Medicine,Langone Medical Center.NY
Pre-assignment details
68 patients were screened, 20 subjects met exclusion criteria. 48 enrolled in the open-label, dose-optimization phase to identify Atomoxetine responders for eligibility to be randomized. 8 participants did not meet the response eligibility criteria, (Blood pressure too high (4), no response to drug (4) 40 patients randomized in the double-blind, placebo-controlled.
Participants by arm
| Arm | Count |
|---|---|
| All Participants All participants were randomized to receive all interventions. All participants received Atomoxetine and All participants received Placebo. Participants were randomized, double blinded, In Phase I (0-4 weeks), Day 0-Day 28, Day 0 is baseline: 50 % of participants got Atomoxetine (active drug) 50 % of participants got Placebo In Phase II Day 36 to Day 64. Participants were washed out of Phase I Participants who received Atomoxetine at phase 1, got Placebo in Phase II Participants who received Placebo at Phase 1, got Atomoxetine in Phase II | 40 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 67.9 years STANDARD_DEVIATION 8.1 |
| BMI (Body Mass Index) | 26.2 kg/m^2 STANDARD_DEVIATION 4.8 |
| Diagnosis 2 Multiple System Atrophy (MSA) | 18 Participants |
| Diagnosis 2 Non MSA (Parkinson disease or Pure autonomic failure | 22 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 40 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Height | 174.7 cm STANDARD_DEVIATION 9.9 |
| 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 | 40 Participants |
| Sex: Female, Male Female | 24 Participants |
| Sex: Female, Male Male | 16 Participants |
| To identify Atomoxetine Responders High Concentration responders -Atomoxetine 18mg | 10 Participants |
| To identify Atomoxetine Responders Low Concentration responders with Atomoxetine 10mg | 30 Participants |
| Weight | 80 Kg STANDARD_DEVIATION 18 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 48 | 0 / 40 | 1 / 40 |
| other Total, other adverse events | 1 / 48 | 13 / 40 | 13 / 40 |
| serious Total, serious adverse events | 0 / 48 | 1 / 40 | 2 / 40 |
Outcome results
Primary
Change in the OHQ (Orthostatic Hypotension Questionnaire) Composite Score
The Orthostatic Hypotension Questionnaire (OHQ) , patient-reported assessment tool consisting of the OH Symptom Assessment (OHSA), OH Daily Activity Scale (OHDAS). The composite score is composed of 10 individual items: 6 items measure specific symptoms , the Orthostatic Hypotension Symptom Assessment (OHSA), and 4 items measure the impact of those symptoms on a patient daily activities, the Orthostatic Hypotension Daily Activity Scale (OHDAS). This scales helps to measure the impact of orthostatic symptoms on daily. Scale is between 0-10: where 0 is minimum Orthostatic symptoms and 10 is the maximum / worse possible severity of the symptoms. All items are scored 0 through 10 (higher scores = more impact) and summed into the respective total scores. The OHSA and OHDAS subscales averaged to compute the OHQ composite score.
Time frame: week 0 to week 4
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in the OHQ (Orthostatic Hypotension Questionnaire) Composite Score | OHQ composite score at 4weeks | 3.35 Score on a scale | Standard Deviation 1.98 |
| Placebo | Change in the OHQ (Orthostatic Hypotension Questionnaire) Composite Score | Difference in OHQ composite score at 4 weeks | -0.58 Score on a scale | Standard Deviation 2.39 |
| Placebo | Change in the OHQ (Orthostatic Hypotension Questionnaire) Composite Score | OHQ composite score at Baseline | 4.61 Score on a scale | Standard Deviation 2.16 |
| Atomoxetin | Change in the OHQ (Orthostatic Hypotension Questionnaire) Composite Score | OHQ composite score at Baseline | 4.17 Score on a scale | Standard Deviation 2.29 |
| Atomoxetin | Change in the OHQ (Orthostatic Hypotension Questionnaire) Composite Score | OHQ composite score at 4weeks | 3.5 Score on a scale | Standard Deviation 2.25 |
| Atomoxetin | Change in the OHQ (Orthostatic Hypotension Questionnaire) Composite Score | Difference in OHQ composite score at 4 weeks | -0.5 Score on a scale | Standard Deviation 1.58 |
Secondary
Change in Blood Pressure
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) (measured in mm of Hg) , is recorded after 10 mins of standing. The changes SBP and DBP are compared from baseline, post drug (4 weeks)
Time frame: Baseline to 4 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in Blood Pressure | difference increase in SBP; post drug 4 weeks; standing for 10 mins | 3.88 mm of Hg | Standard Deviation 19.83 |
| Placebo | Change in Blood Pressure | DBP;post drug; standing 10 mins at 4 weeks | -3.06 mm of Hg | Standard Deviation 15.85 |
| Atomoxetin | Change in Blood Pressure | difference increase in SBP; post drug 4 weeks; standing for 10 mins | -2.44 mm of Hg | Standard Deviation 23.54 |
| Atomoxetin | Change in Blood Pressure | DBP;post drug; standing 10 mins at 4 weeks | -0.94 mm of Hg | Standard Deviation 15.6 |
Secondary
Change in Heart Rate (HR)
HR is compared to baseline after 10 mins of standing. The difference increase in Heart rate from baseline, post drug at 4 weeks
Time frame: Baseline and at 4 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Heart Rate (HR) | 79.12 Beats per minute | Standard Deviation 11.83 |
| Atomoxetin | Change in Heart Rate (HR) | 82.68 Beats per minute | Standard Deviation 14.58 |