Clinical trial NCT03350659: Efficacy and Safety of Midodrine and Atomoxetine for Neurogenic OH
Official title: Efficacy and Safety of Midodrine and Atomoxetine Treatment in Patients With Neurogenic Orthostatic Hypotension : A Prospective Randomized Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Neurogenic Orthostatic Hypotension
Keywords: orthostatic hypotension
midodrine
atomoxetine
treatment
Lead sponsor: Seoul National University Hospital
Sponsor class: OTHER
Collaborators: name: Kyung Hee University Hospital at Gangdong
First posted: 2017-11-22
Enrollment: 50
Sex: ALL
Minimum age (years): 19
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, open-label clinical trial.
Primary purpose: TREATMENT

Brief summary: This was a randomized, open-label clinical trial. We will enroll patients with symptomatic neurogenic OH and randomize them to 1 of 2 treatments: (1) midodrine only, (2) atomoxetine only. We will follow up patients at 1 and 3 months after treatment. If the patients meet BP criteria for OH at 1 month, they will receive combination treatment with both midodrine and atomoxetin. The primary outcome measure is amelioration of questionnaire score evaluating OH-associated symptoms at 3 months. Secondary end-points were improvement in orthostatic blood pressure (BP) drop at 1 and 3 months.

Detailed description: Visit 1.

1. Enroll, baseline evaluation of the patients
2. Questionnaire

   * Evaluate orthostatic hypotension symptom: Orthostatic Hypotension Questionnaire (OHQ)
   * Quality of life: Korean version of Short-form 36
   * Depressive symptom: Korean version of Beck Depression Inventory(BDI)-2
3. Blood test (6cc): ELISA for alpha 1,2 and beta 1,2 adrenergic receptor antibody and nicotinic acetylcholine receptor antibody. Preserve sample for genetic testing.
4. Randomization: randomize patients to three group in 1:1 ratio (Midodrine 5mg/day single, Atomoxetine 18mg/day single)
5. Treatment education Visit 2. 1 month after treatment Orthostatic BP check/ check drug compliance and side effect/ Questionnaire If the patients meet BP criteria for OH, initiate combination treatment (Midodrine 5mg/day+Atomoxetine 18mg/day) Visit 3. 3 months after treatment Orthostatic BP check/ check drug compliance and side effect/ Questionnaire

Eligibility criteria: Inclusion Criteria:

* Age \>=19 patients who complained of dizziness
* Orthostatic hypotension after 3-minute standing (systolic blood pressure drop \>=20 or diastolic blood pressure drop \>=10

Exclusion Criteria:

* Drug-induced hypotension, if necessary, evaluate patient after discontinuing the causative drug for one month
* Heart failure or Chronic renal failure
* Severe supine hypertension (Systolic Blood Pressure \>180 or Diastolic Blood Pressure\>110mmHg)
* Pregnant women, breast-feeding
* Unable to perform questionnaire

Primary outcomes:
measure: Change of the Orthostatic Hypotension Associated Symptom Questionnaire (OH Questionnaire (OHQ)
timeFrame: after 3-month medical treatment
Secondary outcomes:
measure: Change in Orthostatic blood pressure Drop (mmHg)
timeFrame: after 3-month medical treatment
measure: Change of the Depression Score (Beck Depression Inventory-II )
timeFrame: after 3-month medical treatment
measure: Changes in Health-related Quality of Life
timeFrame: after 3-month medical treatment
Other outcomes:
Locations:
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
Study officials:
affiliation: Seoul National University Hospital
name: Chu Kon
role: PRINCIPAL_INVESTIGATOR
References:
citation: Consensus statement on the definition of orthostatic hypotension, pure autonomic failure, and multiple system atrophy. The Consensus Committee of the American Autonomic Society and the American Academy of Neurology. Neurology. 1996 May;46(5):1470. doi: 10.1212/wnl.46.5.1470. No abstract available.
citation: Smit AA, Halliwill JR, Low PA, Wieling W. Pathophysiological basis of orthostatic hypotension in autonomic failure. J Physiol. 1999 Aug 15;519 Pt 1(Pt 1):1-10. doi: 10.1111/j.1469-7793.1999.0001o.x.
citation: Hiitola P, Enlund H, Kettunen R, Sulkava R, Hartikainen S. Postural changes in blood pressure and the prevalence of orthostatic hypotension among home-dwelling elderly aged 75 years or older. J Hum Hypertens. 2009 Jan;23(1):33-9. doi: 10.1038/jhh.2008.81. Epub 2008 Jul 24.
citation: Hale GM, Valdes J, Brenner M. The Treatment of Primary Orthostatic Hypotension. Ann Pharmacother. 2017 May;51(5):417-428. doi: 10.1177/1060028016689264. Epub 2017 Jan 16.
citation: Low PA, Singer W. Management of neurogenic orthostatic hypotension: an update. Lancet Neurol. 2008 May;7(5):451-8. doi: 10.1016/S1474-4422(08)70088-7.
citation: Wright RA, Kaufmann HC, Perera R, Opfer-Gehrking TL, McElligott MA, Sheng KN, Low PA. A double-blind, dose-response study of midodrine in neurogenic orthostatic hypotension. Neurology. 1998 Jul;51(1):120-4. doi: 10.1212/wnl.51.1.120.
citation: Parsaik AK, Singh B, Altayar O, Mascarenhas SS, Singh SK, Erwin PJ, Murad MH. Midodrine for orthostatic hypotension: a systematic review and meta-analysis of clinical trials. J Gen Intern Med. 2013 Nov;28(11):1496-503. doi: 10.1007/s11606-013-2520-3. Epub 2013 Jun 18.
citation: Izcovich A, Gonzalez Malla C, Manzotti M, Catalano HN, Guyatt G. Midodrine for orthostatic hypotension and recurrent reflex syncope: A systematic review. Neurology. 2014 Sep 23;83(13):1170-7. doi: 10.1212/WNL.0000000000000815. Epub 2014 Aug 22.
citation: Byun JI, Moon J, Kim DY, Shin H, Sunwoo JS, Lim JA, Kim TJ, Lee WJ, Lee HS, Jun JS, Park KI, Lee ST, Jung KH, Jung KY, Lee SK, Chu K. Efficacy of single or combined midodrine and pyridostigmine in orthostatic hypotension. Neurology. 2017 Sep 5;89(10):1078-1086. doi: 10.1212/WNL.0000000000004340. Epub 2017 Aug 9.
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.
citation: Hale GM, Brenner M. Atomoxetine for Orthostatic Hypotension in an Elderly Patient Over 10 Weeks: A Case Report. Pharmacotherapy. 2015 Sep;35(9):e141-8. doi: 10.1002/phar.1635.