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

• ClinicalTrials.gov Identifier: NCT01993680
• Recruitment Status: Completed
• First Posted: November 25, 2013
• Last Update Posted: January 25, 2021
• Sponsor: Christian Baumann
• Information provided by (Responsible Party): Christian Baumann, University of Zurich

Tracking Information

• First Submitted Date: April 27, 2012
• First Posted Date: November 25, 2013
• Last Update Posted Date: January 25, 2021
• Study Start Date: June 2012
• Actual Primary Completion Date: April 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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: Same as current

Current Secondary Outcome Measures (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: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Orthostatic Dysregulation and Associated Gastrointestinal Dysfunction in Parkinson's Disease -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

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: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Autonomic Disturbances in Parkinson's Disease

Intervention

• 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

• 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 *

• Singer W, Opfer-Gehrking TL, Nickander KK, Hines SM, Low PA. Acetylcholinesterase inhibition in patients with orthostatic intolerance. J Clin Neurophysiol. 2006 Oct;23(5):476-81. doi: 10.1097/01.wnp.0000229946.01494.4c.
• Sandroni P, Opfer-Gehrking TL, Singer W, Low PA. Pyridostigmine for treatment of neurogenic orthostatic hypotension [correction of hypertension]--a follow-up survey study. Clin Auton Res. 2005 Feb;15(1):51-3. doi: 10.1007/s10286-005-0225-3.
• Schreglmann SR, Buchele F, Sommerauer M, Epprecht L, Kagi G, Hagele-Link S, Gotze O, Zimmerli L, Waldvogel D, Baumann CR. Pyridostigmine bromide versus fludrocortisone in the treatment of orthostatic hypotension in Parkinson's disease - a randomized controlled trial. Eur J Neurol. 2017 Apr;24(4):545-551. doi: 10.1111/ene.13260. Epub 2017 Feb 22.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 18, 2013): 18
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: April 1, 2016
• Actual Primary Completion Date: April 2015 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 50 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Switzerland

Administrative Information

• NCT Number: NCT01993680
• Other Study ID Numbers: KEK-ZH-NR. 2011-0358
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Christian Baumann, University of Zurich
• Original Responsible Party: University of Zurich
• Current Study Sponsor: Christian Baumann
• Original Study Sponsor: University of Zurich
• Collaborators: Not Provided

Investigators

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

• PRS Account: University of Zurich
• Verification Date: January 2021