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

NCT ID: NCT01993680

Last Updated: 2021-01-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 18 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-06-30
• Study Completion Date: 2016-04-01

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.

Conditions

Autonomic Disturbances in Parkinson's Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Pyridostigmine bromide

14 days of active treatment followed by 21 days wash out

Group Type: EXPERIMENTAL

Pyridostigmine bromide

Intervention Type: DRUG

Drug doses during the trial:

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

fludrocortisone

14 days of fludrocortisone treatment; 21 days wash out

Group Type: ACTIVE_COMPARATOR

fludrocortisone

Intervention Type: DRUG

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

Interventions

Pyridostigmine bromide

Drug doses during the trial:

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

Intervention Type: DRUG

fludrocortisone

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

Intervention Type: DRUG

Other Intervention Names

Mestinon; florinef

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

• 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

• Minimum Eligible Age: 50 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Christian Baumann

OTHER

Sponsor Role: lead

Responsible Party

Christian Baumann

Professor dr. med.

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Christian Baumann, MD

Role: PRINCIPAL_INVESTIGATOR

University Hospital Zurich, Division of Neurology

Locations

University Hospital Zurich, Division of Neurology

Zurich, Canton of Zurich, Switzerland

Countries

Switzerland

References

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.

Reference Type: BACKGROUND

PMID: 17016160 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 15768203 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 28224720 (View on PubMed)

Other Identifiers

KEK-ZH-NR. 2011-0358

Identifier Type: -

Identifier Source: org_study_id