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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

Tracking Information
First Submitted Date  ICMJE April 27, 2012
First Posted Date  ICMJE November 25, 2013
Last Update Posted Date January 25, 2021
Study Start Date  ICMJE June 2012
Actual Primary Completion Date April 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 18, 2013)
  • Changes in diastolic blood pressure drop on Schellong manoeuvre [ Time Frame: 10min standing, 10 min supine ]
  • Changes in half emptying time t50 on 13C-sodium octanoate breath test [ Time Frame: within 4h after test meal ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 18, 2013)
  • Efficacy of Pyridostigmine bromide [ Time Frame: assess symptom severity for last 14 days ]
    central blood pressure, heart rate variability and pulse wave velocity
  • 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);
  • 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;
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Orthostatic Dysregulation and Associated Gastrointestinal Dysfunction in Parkinson's Disease -Treatment
Official Title  ICMJE 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
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.

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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Autonomic Disturbances in Parkinson's Disease
Intervention  ICMJE
  • 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
  • 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
Study Arms  ICMJE
  • Experimental: Pyridostigmine bromide
    14 days of active treatment followed by 21 days wash out
    Intervention: Drug: Pyridostigmine bromide
  • Active Comparator: fludrocortisone
    14 days of fludrocortisone treatment; 21 days wash out
    Intervention: Drug: fludrocortisone
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 18, 2013)
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE April 1, 2016
Actual Primary Completion Date April 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 50 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Switzerland
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT01993680
Other Study ID Numbers  ICMJE KEK-ZH-NR. 2011-0358
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Christian Baumann, University of Zurich
Original Responsible Party University of Zurich
Current Study Sponsor  ICMJE Christian Baumann
Original Study Sponsor  ICMJE University of Zurich
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Christian Baumann, MD University Hospital Zurich, Division of Neurology
PRS Account University of Zurich
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP