Neurogenic Orthostatic HypotensionPhase 2NETAFNCT02784535
Norepinephrine Transporter Blockade, Autonomic Failure (NETAF)
A Phase 2 study testing Atomoxetine in people with Neurogenic Orthostatic Hypotension, run by Vanderbilt University Medical Center at 2 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 40 to 80 years
- Conditions the study is for
- Neurogenic Orthostatic Hypotension
- What is being tested?
- Atomoxetine
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 48 participants
- Where
- 2 sitesUnited States
- Study dates
- 29 Aug 2016to Jun 2023
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 40 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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)
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- 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
Trial locations and contacts
2 sites in 1 country.
United States2 sites
Vanderbilt University Medical Center
Nashville, Tennessee, 37232
Dysautonomic Center at NYU Langone Medical Center
New York, New York, 10016
About this study
Official title: Phase 2 Norepinephrine Transporter Blockade, Autonomic Failure IND117394 12/28/12
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.
Read the 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.
- Conditions
- Neurogenic Orthostatic Hypotension
- Being tested
- Atomoxetine, Placebo
- Keywords
- norepinephrine transporter inhibitors
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AtomoxetineDrug
Also called strattera
norepinephrine transporter inhibitor
PlaceboDrug
Also called non active medication
placebo
| Study group | Role | What they receive |
|---|---|---|
| placebo | Placebo comparator | placebo capsules Receives: Drug: Atomoxetine |
| atomoxetine | Active comparator | atomoxetine capsules 10 mg or 18 mg Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: week 0 to week 4
Secondary outcomes (2)
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)
Measured: Baseline to 4 weeks
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
Measured: Baseline and at 4 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 May 2016 (estimated)
- Study start29 Aug 2016
- Primary completion12 May 2021
- Study completionJun 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Neurogenic Orthostatic HypotensionStudies of the same condition, open and under way.
- More trials run by Vanderbilt University Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 48 participants (actual)
Sponsor and investigators
- Lead sponsor
- Vanderbilt University Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- NYU Langone Health
- Responsible party
- Principal investigator, Cyndya Shibao, MD, Vanderbilt University Medical Center
- Investigators
- Cyndya A Shibao, MD, Principal investigator, Vanderbilt University Medical CenterHoracio Kaufmann, MD, Principal investigator, NYU Langone Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02784535
- Sponsor's protocol ID
- 160415
- Acronym
- NETAF
- Status last verified
- Aug 2023
- First submitted
- 24 May 2016
- Last updated
- 13 Sep 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- No
Publications
Ramirez CE, Okamoto LE, Arnold AC, Gamboa A, Diedrich A, Choi L, Raj SR, Robertson D, Biaggioni I, Shibao CA. Efficacy of atomoxetine versus midodrine for the treatment of orthostatic hypotension in autonomic failure. Hypertension. 2014 Dec;64(6):1235-40. doi: 10.1161/HYPERTENSIONAHA.114.04225. Epub 2014 Sep 2.
PubMed 25185131Shibao C, Raj SR, Gamboa A, Diedrich A, Choi L, Black BK, Robertson D, Biaggioni I. Norepinephrine transporter blockade with atomoxetine induces hypertension in patients with impaired autonomic function. Hypertension. 2007 Jul;50(1):47-53. doi: 10.1161/HYPERTENSIONAHA.107.089961. Epub 2007 May 21.
PubMed 17515448
Study at a glance
From the registry record, last updated by the sponsor on 13 Sep 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase 2 Norepinephrine Transporter Blockade, Autonomic Failure IND117394 12/28/12
- ClinicalTrials.gov ID
- NCT02784535
- Acronym / sponsor ID
- NETAF / 160415
- Conditions
- Neurogenic Orthostatic Hypotension
- Keywords
- norepinephrine transporter inhibitors
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 48 participants (actual)
- Lead sponsor
- Vanderbilt University Medical CenterUniversity, hospital or other
- Collaborators
- NYU Langone Health
- Study start
- 29 Aug 2016 (actual)
- Primary completion
- 12 May 2021 (actual)
- Study completion
- Jun 2023 (actual)
- First posted
- 27 May 2016 (estimated)
- Results
- Posted 16 Sep 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| placebo | Placebo comparator | Drug: Atomoxetineplacebo capsules |
| atomoxetine | Active comparator | Drug: Placeboatomoxetine capsules 10 mg or 18 mg |
Who may qualify
- Ages
- 40 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- 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.
Key exclusion criteria (13 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AtomoxetineAlso: stratteranorepinephrine transporter inhibitor | Drug | placebo |
| PlaceboAlso: non active medicationplacebo | Drug | atomoxetine |
Primary outcome
Change in the OHQ (Orthostatic Hypotension Questionnaire) Composite Score
Time frame: 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.
2 secondary outcomes
Change in Blood Pressure
Time frame: Baseline to 4 weeks
Change in Heart Rate (HR)
Time frame: Baseline and at 4 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Sep 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 25185131Ramirez CE, Okamoto LE, Arnold AC, Gamboa A, Diedrich A, Choi L, Raj SR, Robertson D, Biaggioni I, Shibao CA. Efficacy of atomoxetine versus midodrine for the treatment of orthostatic hypotension in autonomic failure. Hypertension. 2014 Dec;64(6):1235-40. doi: 10.1161/HYPERTENSIONAHA.114.04225. Epub 2014 Sep 2.
- Background: PubMed 17515448Shibao C, Raj SR, Gamboa A, Diedrich A, Choi L, Black BK, Robertson D, Biaggioni I. Norepinephrine transporter blockade with atomoxetine induces hypertension in patients with impaired autonomic function. Hypertension. 2007 Jul;50(1):47-53. doi: 10.1161/HYPERTENSIONAHA.107.089961. Epub 2007 May 21.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Cyndya A Shibao, MD principal investigator
Vanderbilt University Medical Center
Horacio Kaufmann, MD principal investigator
NYU Langone Medical Center
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Atomoxetine in people with Neurogenic Orthostatic Hypotension, run by Vanderbilt University Medical Center at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 13 Sep 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 16 Sep 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in the OHQ (Orthostatic Hypotension Questionnaire) Composite Score (time frame: week 0 to week 4). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02784535, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Sep 2023.