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Orthostatic Dysregulation and Associated Gastrointestinal Dysfunction in Parkinson's Disease -Treatment

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ClinicalTrials.gov Identifier: NCT01993680
Recruitment Status : Completed
First Posted : November 25, 2013
Last Update Posted : January 25, 2021
Information provided by (Responsible Party):
Christian Baumann, University of Zurich

Brief Summary:

Disabling symptoms of blood pressure dysregulation, impaired swallowing and digestion are common amongst Parkinson's patients. So far the exact pathophysiology for this is not fully understood. There are results from pathological analyses that the autonomic nervous system is also affected by the accumulation of alpha-Synuclein and that this might even happen in very early stages of the disease process (Qualman et al., 1984; Wakabayashi et al., 1989; Wakabayashi et al., 1990; Bloch et al., 2006).

Blood pressure dysregulation is a common autonomic symptom in Parkinson's patients and treatment - currently most often achieved with Fludrocortisone - often leads to supine hypertension (Plaschke et al., 1998; Braune et al., 1999; Magerkurth et al., 2005).

There are studies in patients with autonomic failure that indicate that Pyridostigmine bromide might be an alternative treatment option without causing disabling supine hypertension (Singer et al., 2003; Sandroni et al., 2005; Singer et al., 2006; Yamamoto et al., 2006).

Delayed gastric emptying is also an autonomic symptom associated with Parkinson's disease. By the elevation of the cholinergic tone with Pyridostigmine bromide the investigators also expect to alleviate symptoms of delayed gastric emptying and obstipation, possibly even facilitating the uptake of dopaminergic medication through the gut (Sadjadpour, 1983; Bharucha et al., 2008).

Therefore the investigators designed a monocentric randomized, controlled, double blind, crossover phase II trial to show non-inferiority of the effect of pyridostigmine bromide vs. fludrocortisone on symptoms of autonomic dysregulation in Parkinson's disease.

Condition or disease Intervention/treatment Phase
Autonomic Disturbances in Parkinson's Disease Drug: Pyridostigmine bromide Drug: fludrocortisone Phase 2

Detailed Description:

In summary, investigators in recent years became more and more aware of the non-motor symptoms of PD and their impact on affected individuals. Therefore therapeutic strategies to ameliorate these symptoms are ever more needed. Sufficient clinical data for the treatment of symptoms of blood pressure dysregulation is still lacking. This study is aiming at closing this knowledge gap by comparing the efficacy and tolerability of a promising new agent, pyridostigmine bromide with the standard treatment, fludrocortisone.

The proposed target of pyridostigmine in this respect is at the autonomic ganglion in the efferent limb of the baroreflex. Via a reduction of acetylcholine breakdown the sympathetic ganglionic transmission increases upon orthostatic stress (Singer et al., 2006).

Via the same mechanism we aim to facilitate gastrooesophageal motility and gastric emptying: Both relaxation and contractibility of the oesophagus are known to be affected in PD patients as shown in a manometric study (Sung et al., 2010). Both relaxation and contractability are mainly influenced by nicotinergic and muscarinergic, cholinergic vagal efferents to the oesophagus (Chang et al., 2003). Via a reduction of acetylcholine breakdown we aim to increase the cholinergic tone and thereby normalize the reduced relaxation and contractibility.

We also intent to show that this faster gastric transit results in a faster absorption of Madopar into the bloodstream - we therefore will measure Levodopa and its metabolites during the first 60mins after ingestion of 125mg fast-release Madopar in serial venous blood samples via high-pressure liquid chromatography.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 18 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Monocentric Randomized, Controlled, Double Blind, Crossover Phase II Trial to Show Non-inferiority of the Effect of Pyridostigmine Bromide vs. Fludrocortisone on Symptoms of Autonomic Dysregulation in Parkinson's Disease
Study Start Date : June 2012
Actual Primary Completion Date : April 2015
Actual Study Completion Date : April 1, 2016

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Pyridostigmine bromide
14 days of active treatment followed by 21 days wash out
Drug: Pyridostigmine bromide

Drug doses during the trial:

Pyridostigmine bromide: 30mg p.o. 1-1-1 to 2-2-2 given for 14 days

Other Name: Mestinon

Active Comparator: fludrocortisone
14 days of fludrocortisone treatment; 21 days wash out
Drug: fludrocortisone
drug dose during the trial Fludrocortisone: 0,1mg p.o. 1-0-0 to 2-0-0 given for 14 days
Other Name: florinef

Primary Outcome Measures :
  1. Changes in diastolic blood pressure drop on Schellong manoeuvre [ Time Frame: 10min standing, 10 min supine ]
  2. Changes in half emptying time t50 on 13C-sodium octanoate breath test [ Time Frame: within 4h after test meal ]

Secondary Outcome Measures :
  1. Efficacy of Pyridostigmine bromide [ Time Frame: assess symptom severity for last 14 days ]
    central blood pressure, heart rate variability and pulse wave velocity

  2. Efficacy of Pyridostigmine bromide [ Time Frame: assess symptom severity for last 14 days ]
    Motor functions (UPDRS III), frequency and subjective quality of defecation, frequency and urgency of micturition, tremor severity (Whiget tremor scale);

  3. Safety & Tolerability of Pyridostigmine bromide [ Time Frame: assess symptom severity for last 14 days ]
    subjective assessment of sialorrhea, Hospital Anxiety and Depression Scale, Montreal Cognitive Assessment;

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Ages Eligible for Study:   50 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion criteria:

  • informed, written & formal consent for participation
  • male / female subjects, aged 50-80 years
  • PD patients (18 subjects with symptomatic orthostatic hypotension)

Exclusion criteria: - Antihypertensive treatment

  • medication influencing gastrointestinal motility for at least the elimination half life of the drug
  • medication interfering with blood-pressure regulation for at least the elimination half life of the drug
  • significant systemic illness
  • BMI <18 or >30kg/m2
  • symptoms or a history of GI disease or surgery
  • with any evidence of infectious disease
  • evidence or history of drug or alcohol abuse
  • diabetes mellitus

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01993680

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University Hospital Zurich, Division of Neurology
Zurich, ZH, Switzerland, 8091
Sponsors and Collaborators
Christian Baumann
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Principal Investigator: Christian Baumann, MD University Hospital Zurich, Division of Neurology
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Christian Baumann, Professor dr. med., University of Zurich
ClinicalTrials.gov Identifier: NCT01993680    
Other Study ID Numbers: KEK-ZH-NR. 2011-0358
First Posted: November 25, 2013    Key Record Dates
Last Update Posted: January 25, 2021
Last Verified: January 2021
Additional relevant MeSH terms:
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Parkinson Disease
Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
Pyridostigmine Bromide
Cholinesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cholinergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents