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

January 21, 2021 updated by: Christian Baumann

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

18

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Switzerland
    • ZH
      • Zurich, ZH, Switzerland, 8091
        • University Hospital Zurich, Division of Neurology

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

48 years to 78 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Double

Arms and Interventions

Participant Group / 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 Names:
  • 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 Names:
  • florinef

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Efficacy of Pyridostigmine bromide
Time Frame: assess symptom severity for last 14 days
central blood pressure, heart rate variability and pulse wave velocity
assess symptom severity for last 14 days
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);
assess symptom severity for last 14 days
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;
assess symptom severity for last 14 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Christian Baumann

Investigators

  • Principal Investigator: Christian Baumann, MD, University Hospital Zurich, Division of Neurology

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2012

Primary Completion (Actual)

April 1, 2015

Study Completion (Actual)

April 1, 2016

Study Registration Dates

First Submitted

April 27, 2012

First Submitted That Met QC Criteria

November 18, 2013

First Posted (Estimate)

November 25, 2013

Study Record Updates

Last Update Posted (Actual)

January 25, 2021

Last Update Submitted That Met QC Criteria

January 21, 2021

Last Verified

January 1, 2021

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • KEK-ZH-NR. 2011-0358

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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