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

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2013 by University of Zurich
Sponsor:
Information provided by (Responsible Party):
University of Zurich
ClinicalTrials.gov Identifier:
NCT01993680
First received: April 27, 2012
Last updated: November 25, 2013
Last verified: November 2013
  Purpose

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 Intervention Phase
Autonomic Disturbances in Parkinson`s Disease
Drug: Pyridostigmine bromide
Drug: fludrocortisone
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, 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

Resource links provided by NLM:


Further study details as provided by University of Zurich:

Primary Outcome Measures:
  • Changes in diastolic blood pressure drop on Schellong manoeuvre [ Time Frame: 10min standing, 10 min supine ] [ Designated as safety issue: No ]
  • Changes in half emptying time t50 on 13C-sodium octanoate breath test [ Time Frame: within 4h after test meal ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Efficacy of Pyridostigmine bromide [ Time Frame: assess symptom severity for last 14 days ] [ Designated as safety issue: No ]
    central blood pressure, heart rate variability and pulse wave velocity

  • Efficacy of Pyridostigmine bromide [ Time Frame: assess symptom severity for last 14 days ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: Yes ]
    subjective assessment of sialorrhea, Hospital Anxiety and Depression Scale, Montreal Cognitive Assessment;


Estimated Enrollment: 18
Study Start Date: June 2012
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   50 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01993680

Contacts
Contact: Sebastian Schreglmann, MD +41 (0)44 255 11 11 sebastian.schreglmann@usz.ch
Contact: Christian Baumann, MD christian.baumann@usz.ch

Locations
Switzerland
University Hospital Zurich, Division of Neurology Recruiting
Zurich, ZH, Switzerland, 8091
Sponsors and Collaborators
University of Zurich
Investigators
Principal Investigator: Christian Baumann, MD University Hospital Zurich, Division of Neurology
  More Information

Publications:
Responsible Party: University of Zurich
ClinicalTrials.gov Identifier: NCT01993680     History of Changes
Other Study ID Numbers: KEK-ZH-NR. 2011-0358
Study First Received: April 27, 2012
Last Updated: November 25, 2013
Health Authority: Switzerland: Swissmedic

Additional relevant MeSH terms:
Parkinson Disease
Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
Bromides
Fludrocortisone
Pyridostigmine Bromide
Anticonvulsants
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions
Anti-Inflammatory Agents
Cholinesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cholinergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on July 24, 2014