Completed

NCT Number: NCT01993680

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

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.

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Key information

Conditions

Autonomic Disturbances in Parkinson's Disease

Age range

50 year–80 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

University Hospital Zurich, Division of Neurology

Zurich, Canton of Zurich, 8091, Switzerland

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Pyridostigmine Bromide

Drug

Drug doses during the trial:

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

Other names: Mestinon

fludrocortisone

Drug

drug dose during the trial Fludrocortisone: 0,1mg p.o. 1-0-0 to 2-0-0 given for 14 days

Other names: florinef

Primary outcomes

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

Secondary outcomes

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;

Sponsors and collaborators

Lead sponsor

Christian Baumann

Other

Registry information

Official study 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

Important dates

Study start: 2012
Primary completion: 2015
Study completion: 2016
First posted: Nov 25, 2013
Registry last updated: Jan 25, 2021

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.