Back to results

Norepinephrine Transporter Blockade, Autonomic Failure (NETAF) (NETAF)

Primary Purpose

Neurogenic Orthostatic Hypotension

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Atomoxetine

Placebo

About this trial

This is an interventional treatment trial for Neurogenic Orthostatic Hypotension focused on measuring norepinephrine transporter inhibitors

Eligibility Criteria

40 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Dysautonomic Center at NYU Langone Medical Center
Vanderbilt University Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Active Comparator

Arm Label

placebo

atomoxetine

Arm Description

placebo capsules

atomoxetine capsules 10 mg or 18 mg

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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)

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

Full Information

NCT ID

NCT02784535

First Posted

May 24, 2016

Last Updated

August 18, 2023

Sponsor

Vanderbilt University Medical Center

Collaborators

NYU Langone Health

1. Study Identification

Unique Protocol Identification Number

NCT02784535

Brief Title

Norepinephrine Transporter Blockade, Autonomic Failure (NETAF)

Acronym

NETAF

Official Title

Phase 2 Norepinephrine Transporter Blockade, Autonomic Failure IND117394 12/28/12

Study Type

Interventional

2. Study Status

Record Verification Date

August 2023

Overall Recruitment Status

Completed

Study Start Date

August 29, 2016 (Actual)

Primary Completion Date

May 12, 2021 (Actual)

Study Completion Date

June 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Vanderbilt University Medical Center

Collaborators

NYU Langone Health

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Neurogenic Orthostatic Hypotension

Keywords

norepinephrine transporter inhibitors

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Crossover Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

48 (Actual)

8. Arms, Groups, and Interventions

Arm Title

placebo

Arm Type

Placebo Comparator

Arm Description

placebo capsules

Arm Title

atomoxetine

Arm Type

Active Comparator

Arm Description

atomoxetine capsules 10 mg or 18 mg

Intervention Type

Drug

Intervention Name(s)

Atomoxetine

Other Intervention Name(s)

strattera

Intervention Description

norepinephrine transporter inhibitor

Intervention Type

Drug

Intervention Name(s)

Placebo

Other Intervention Name(s)

non active medication

Intervention Description

placebo

Primary Outcome Measure Information:

Title

Change in the OHQ (Orthostatic Hypotension Questionnaire) Composite Score

Description

Time Frame

week 0 to week 4

Secondary Outcome Measure Information:

Title

Change in Blood Pressure

Description

Time Frame

Baseline to 4 weeks

Title

Change in Heart Rate (HR)

Description

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

10. Eligibility

Sex

All

Minimum Age & Unit of Time

40 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Cyndya A Shibao, MD

Organizational Affiliation

Vanderbilt University Medical Center

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Horacio Kaufmann, MD

Organizational Affiliation

NYU Langone Medical Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

Dysautonomic Center at NYU Langone Medical Center

City

New York

State/Province

New York

ZIP/Postal Code

10016

Country

United States

Facility Name

Vanderbilt University Medical Center

City

Nashville

State/Province

Tennessee

ZIP/Postal Code

37232

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

25185131

Citation

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.

Results Reference

background

PubMed Identifier

17515448

Citation

Shibao 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.

Results Reference

background

Learn more about this trial

Norepinephrine Transporter Blockade, Autonomic Failure (NETAF)

We'll reach out to this number within 24 hrs