Treatment of Orthostatic Hypotension in Autonomic Failure

NCT00223691 | Completed Phase 1

• 2 other identifiers: 000814HL46681
• Study Type: interventional
• Target: 389
• Locations: 1 country
• Sites: 1

Brief Summary

The autonomic nervous system serves multiple regulatory functions in the body, including the regulation of blood pressure and heart rate, gut motility, sweating and sexual function. There are several diseases characterized by abnormal function of the autonomic nervous system. Medications can also alter autonomic function. Impairment of the autonomic nervous system by diseases or drugs may lead to several symptoms, including blood pressure problems (e.g., high blood pressure lying down and low blood pressure on standing), sweating abnormalities, constipation or diarrhea and sexual dysfunction. Because treatment options for these patients are limited. We propose to study patients autonomic failure and low blood pressure upon standing and determine the cause of their disease by history and examination and their response to autonomic testing which have already been standardized in our laboratory. Based on their possible cause, we will tests different medications that may alleviate their symptoms.

Conditions

Autonomic Failure; Orthostatic Hypotension

Keywords

orthostatic hypotension; autonomic failure

Outcome Measures

Primary Outcomes (1)

• Increase in seated systolic blood pressure 1-hr post drug compared to baseline.

  1.5-4 hours

Secondary Outcomes (1)

• Increase in standing time 1-hr post drug compared to baseline

  1.5-4 hours

Study Arms (2)

1: active intervention

EXPERIMENTAL

atomoxetine, pyridostigmine bromide, yohimbine, midodrine hcl, modafinil, octreotide, water intake, ranitidine hcl, diphenhydramine hydrochloride, tranylcypromine, ergotamine/ caffeine, celecoxib, pseudoephedrine, methylphenidate, indomethacin, ibuprofen, Oxymetazoline 0.05% nasal solution, acarbose, Rivastigmine tartrate, acetazolamide, carbidopa/levodopa, inflatable abdominal binder or bovril

Drug: Atomoxetine; Drug: Acarbose; Drug: Pyridostigmine Bromide; Drug: Yohimbine; Drug: Midodrine HCl; Drug: Modafinil; Drug: Octreotide; Other: water intake; Drug: Diphenhydramine Hydrochloride; Drug: Ranitidine HCL; Drug: Tranylcypromine; Drug: Ergotamine/ Caffeine; Drug: Celecoxib; Drug: Pseudoephedrine; Drug: Methylphenidate; Drug: Indomethacin; Drug: Ibuprofen; Drug: Oxymetazoline 0.05% nasal solution; Dietary Supplement: Bovril; Drug: Acetazolamide; Drug: Rivastigmine tartrate; Drug: Carbidopa/levodopa; Device: Inflatable abdominal binder

2: Placebo or sham device

PLACEBO COMPARATOR

placebo pill or inflatable abdominal binder (sham)

Drug: placebo; Device: inflatable abdominal binder (sham)

Interventions

Atomoxetine DRUG

10-50 mg, PO. Single dose. Alone or in combination with Yohimbine or Mestinon.

Also known as: Strattera

1: active intervention

Acarbose DRUG

25-100 mg, PO. Single dose.

Also known as: Precose

1: active intervention

Pyridostigmine Bromide DRUG

30 mg-180 mg PO. Single dose. Alone or in combination with Yohimbine or atomoxetine.

Also known as: Mestinon

1: active intervention

Yohimbine DRUG

2.7, 5.4 or 10.8 mg PO. Single dose. Alone or in combination with Atomoxetine or Pyridostigmine.

Also known as: Yocon

1: active intervention

Midodrine HCl DRUG

2.5, 5.0, 7.5, 10 mg PO. Single dose

Also known as: ProAmatine

1: active intervention

placebo DRUG

PO.Single dose.

2: Placebo or sham device

Modafinil DRUG

50-400 mg PO. Single dose

Also known as: Provigil

1: active intervention

Octreotide DRUG

5-50 µg, S.C. Single dose.

Also known as: Sandostatin

1: active intervention

water intake OTHER

Tap water 2 onz., 8 oz., 16 oz. PO, alone or in combination with any of the above medications. Single dose.

1: active intervention

Diphenhydramine Hydrochloride DRUG

12.5 mg-100 mg PO. Single dose. Alone or in combination with Ranitidine

Also known as: Benadryl

1: active intervention

Ranitidine HCL DRUG

150-300 mg PO. Single dose. Alone or in combination with Diphenhydramine.

Also known as: zantac

1: active intervention

Tranylcypromine DRUG

5 - 40 mg PO. Single dose

Also known as: Parnate

1: active intervention

Ergotamine/ Caffeine DRUG

Ergotamine: 1.0 mg PO. Single dose. Caffeine 100 mg PO.Single dose

Also known as: Cafergot

1: active intervention

Celecoxib DRUG

50-200 mg PO. Single dose

Also known as: Celebrex

1: active intervention

Pseudoephedrine DRUG

15, 30 or 60 mg, PO. Single dose.

Also known as: Sudafed

1: active intervention

Methylphenidate DRUG

5 or 10 mg PO. Single dose.

Also known as: Ritalin

1: active intervention

Indomethacin DRUG

25, 50 or 75 mg, PO. Singe dose.

Also known as: Indocin

1: active intervention

Ibuprofen DRUG

300, 600 or 900 mg, PO. Single dose.

Also known as: Advil, Motrin

1: active intervention

Oxymetazoline 0.05% nasal solution DRUG

1-2 sprays/ nostril. Single dose.

Also known as: Afrin

1: active intervention

Bovril DIETARY_SUPPLEMENT

6-10 g, PO. Single dose.

1: active intervention

Acetazolamide DRUG

125-1000 mg PO. Single dose. Alone or in combination with yohimbine or midodrine

Also known as: Diamox

1: active intervention

Rivastigmine tartrate DRUG

1.5-6 mg PO. Single dose.

Also known as: Exelon

1: active intervention

Carbidopa/levodopa DRUG

10mg/100mg or 25mg/100mg. 1-2 tab PO. Single dose. Alone or in combination with carbidopa (Lodosyn) 25-175 mg

Also known as: Sinemet, Lodosyn

1: active intervention

Inflatable abdominal binder DEVICE

External abdominal compression (20-40 mm Hg) with an inflatable abdominal binder applied after a pressor agent (e.g. midodrine, yohimbine).

Also known as: external abdominal compression

1: active intervention

inflatable abdominal binder (sham) DEVICE

External abdominal compression (5 mm Hg) with an inflatable abdominal binder applied after a pressor agent (e.g. midodrine, yohimbine).

Also known as: external abdominal compression (sham)

2: Placebo or sham device

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients referred for evaluation of their autonomic function
• Ages 18-85

You may not qualify if:

• Pregnancy

Sponsors & Collaborators

• Vanderbilt University: lead

Study Sites (1)

Vanderbilt University

Nashville, Tennessee, 37232, United States

Location

Related Publications (18)

• Shibao C, Okamoto L, Biaggioni I. Pharmacotherapy of autonomic failure. Pharmacol Ther. 2012 Jun;134(3):279-86. doi: 10.1016/j.pharmthera.2011.05.009. Epub 2011 Jun 12.

  PMID: 21664375 BACKGROUND

• Garland EM, Hooper WB, Robertson D. Pure autonomic failure. Handb Clin Neurol. 2013;117:243-57. doi: 10.1016/B978-0-444-53491-0.00020-1.

  PMID: 24095130 BACKGROUND

• Arnold AC, Biaggioni I. Management approaches to hypertension in autonomic failure. Curr Opin Nephrol Hypertens. 2012 Sep;21(5):481-5. doi: 10.1097/MNH.0b013e328356c52f.

  PMID: 22801444 BACKGROUND

• Jordan J, Shannon JR, Biaggioni I, Norman R, Black BK, Robertson D. Contrasting actions of pressor agents in severe autonomic failure. Am J Med. 1998 Aug;105(2):116-24. doi: 10.1016/s0002-9343(98)00193-4.

  PMID: 9727818 RESULT

• Shibao C, Gamboa A, Diedrich A, Biaggioni I. Management of hypertension in the setting of autonomic failure: a pathophysiological approach. Hypertension. 2005 Apr;45(4):469-76. doi: 10.1161/01.HYP.0000158835.94916.0c. Epub 2005 Feb 28.

  PMID: 15738343 RESULT

• Shibao C, Arzubiaga C, Roberts LJ 2nd, Raj S, Black B, Harris P, Biaggioni I. Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders. Hypertension. 2005 Mar;45(3):385-90. doi: 10.1161/01.HYP.0000158259.68614.40. Epub 2005 Feb 14.

  PMID: 15710782 RESULT

• Jordan J, Shannon JR, Diedrich A, Black B, Robertson D, Biaggioni I. Water potentiates the pressor effect of ephedra alkaloids. Circulation. 2004 Apr 20;109(15):1823-5. doi: 10.1161/01.CIR.0000126283.99195.37. Epub 2004 Apr 5.

  PMID: 15066944 RESULT

• Jacob G, Costa F, Biaggioni I. Spectrum of autonomic cardiovascular neuropathy in diabetes. Diabetes Care. 2003 Jul;26(7):2174-80. doi: 10.2337/diacare.26.7.2174.

  PMID: 12832331 RESULT

• Biaggioni I, Robertson RM. Hypertension in orthostatic hypotension and autonomic dysfunction. Cardiol Clin. 2002 May;20(2):291-301, vii. doi: 10.1016/s0733-8651(01)00005-4.

  PMID: 12119802 RESULT

• Jordan J, Biaggioni I. Diagnosis and treatment of supine hypertension in autonomic failure patients with orthostatic hypotension. J Clin Hypertens (Greenwich). 2002 Mar-Apr;4(2):139-45. doi: 10.1111/j.1524-6175.2001.00516.x.

  PMID: 11927799 RESULT

• Shannon JR, Diedrich A, Biaggioni I, Tank J, Robertson RM, Robertson D, Jordan J. Water drinking as a treatment for orthostatic syndromes. Am J Med. 2002 Apr 1;112(5):355-60. doi: 10.1016/s0002-9343(02)01025-2.

  PMID: 11904109 RESULT

• Jordan J, Shannon JR, Black BK, Ali Y, Farley M, Costa F, Diedrich A, Robertson RM, Biaggioni I, Robertson D. The pressor response to water drinking in humans : a sympathetic reflex? Circulation. 2000 Feb 8;101(5):504-9. doi: 10.1161/01.cir.101.5.504.

  PMID: 10662747 RESULT

• Shibao C, Gamboa A, Diedrich A, Dossett C, Choi L, Farley G, Biaggioni I. Acarbose, an alpha-glucosidase inhibitor, attenuates postprandial hypotension in autonomic failure. Hypertension. 2007 Jul;50(1):54-61. doi: 10.1161/HYPERTENSIONAHA.107.091355. Epub 2007 May 21.

  PMID: 17515447 RESULT

• 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.

  PMID: 17515448 RESULT

• Shibao C, Okamoto LE, Gamboa A, Yu C, Diedrich A, Raj SR, Robertson D, Biaggioni I. Comparative efficacy of yohimbine against pyridostigmine for the treatment of orthostatic hypotension in autonomic failure. Hypertension. 2010 Nov;56(5):847-51. doi: 10.1161/HYPERTENSIONAHA.110.154898. Epub 2010 Sep 13.

  PMID: 20837887 RESULT

• Okamoto LE, Shibao C, Gamboa A, Choi L, Diedrich A, Raj SR, Black BK, Robertson D, Biaggioni I. Synergistic effect of norepinephrine transporter blockade and alpha-2 antagonism on blood pressure in autonomic failure. Hypertension. 2012 Mar;59(3):650-6. doi: 10.1161/HYPERTENSIONAHA.111.184812. Epub 2012 Feb 6.

  PMID: 22311903 RESULT

• Okamoto LE, Walsh E, Diedrich A, Shibao CA, Gamboa A, Black BK, Paranjape SY, Muldowney JA 3rd, Habermann R, Peltier A, Tarpara K, Biaggioni I. Clinical Correlates of Efficacy of Pyridostigmine in the Treatment of Orthostatic Hypotension. Hypertension. 2025 Mar;82(3):489-497. doi: 10.1161/HYPERTENSIONAHA.124.24050. Epub 2024 Dec 27.

  PMID: 39727053 DERIVED

• Okamoto LE, Diedrich A, Baudenbacher FJ, Harder R, Whitfield JS, Iqbal F, Gamboa A, Shibao CA, Black BK, Raj SR, Robertson D, Biaggioni I. Efficacy of Servo-Controlled Splanchnic Venous Compression in the Treatment of Orthostatic Hypotension: A Randomized Comparison With Midodrine. Hypertension. 2016 Aug;68(2):418-26. doi: 10.1161/HYPERTENSIONAHA.116.07199. Epub 2016 Jun 6.

  PMID: 27271310 DERIVED

MeSH Terms

Conditions

Pure Autonomic Failure; Hypotension, Orthostatic

Interventions

Atomoxetine Hydrochloride; Acarbose; Pyridostigmine Bromide; Yohimbine; Midodrine; Modafinil; Octreotide; Drinking; Diphenhydramine; Ranitidine; Tranylcypromine; caffeine, ergotamine drug combination; Celecoxib; Pseudoephedrine; Methylphenidate; Indomethacin; Ibuprofen; Oxymetazoline; Acetazolamide; Rivastigmine; carbidopa, levodopa drug combination; Carbidopa

Condition Hierarchy (Ancestors)

Primary Dysautonomias; Autonomic Nervous System Diseases; Nervous System Diseases; Orthostatic Intolerance; Hypotension; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Propylamines; Amines; Organic Chemicals; Trisaccharides; Oligosaccharides; Polysaccharides; Carbohydrates; Pyridinium Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Ethanolamines; Amino Alcohols; Alcohols; Benzhydryl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Amino Acids, Peptides, and Proteins; Eating; Nutritional Physiological Phenomena; Diet, Food, and Nutrition; Physiological Phenomena; Digestive System Physiological Phenomena; Digestive System and Oral Physiological Phenomena; Ethylamines; Furans; Benzenesulfonamides; Sulfonamides; Amides; Sulfones; Sulfur Compounds; Pyrazoles; Azoles; Propanolamines; Propanols; Phenethylamines; Phenylacetates; Acids, Carbocyclic; Carboxylic Acids; Piperidines; Phenylpropionates; Imidazoles; Thiadiazoles; Thiazoles; Phenylcarbamates; Carbamates; Acids, Acyclic; Methyldopa; Dihydroxyphenylalanine; Catecholamines; Hydrazines; Catechols; Phenols

Study Officials

• Italo Biaggioni, MD

  Vanderbilt University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine and Pharmacology

Study Record Dates

• First Submitted: September 14, 2005
• First Posted: September 22, 2005
• Study Start: March 1, 2002
• Primary Completion: January 1, 2017
• Study Completion: January 1, 2017
• Last Updated: January 18, 2017

Record last verified: 2017-01

Locations

US (1)