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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Autonomic Disturbances in Parkinson's Disease

Intervention / Treatment
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* Drug: Pyridostigmine bromide
* Drug: fludrocortisone


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pyridostigmine bromide<br>14 days of active treatment followed by 21 days wash out | Drug: Pyridostigmine bromide<br>* Drug doses during the trial: Pyridostigmine bromide: 30mg p.o. 1-1-1 to 2-2-2 given for 14 days<br>* Other names: Mestinon;|
| Active Comparator: fludrocortisone<br>14 days of fludrocortisone treatment; 21 days wash out | Drug: fludrocortisone<br>* drug dose during the trial Fludrocortisone: 0,1mg p.o. 1-0-0 to 2-0-0 given for 14 days<br>* Other names: florinef;|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of Pyridostigmine bromide | central blood pressure, heart rate variability and pulse wave velocity | assess symptom severity for last 14 days | 
| Efficacy of Pyridostigmine bromide | 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 | subjective assessment of sialorrhea, Hospital Anxiety and Depression Scale, Montreal Cognitive Assessment; | assess symptom severity for last 14 days |