Autonomic Disturbances in Parkinson's DiseasePhase 2NCT01993680
Orthostatic Dysregulation and Associated Gastrointestinal Dysfunction in Parkinson's Disease -Treatment
A Phase 2 study testing Pyridostigmine bromide and fludrocortisone in people with Autonomic Disturbances in Parkinson's Disease, run by Christian Baumann at 1 site in Switzerland.
Trial 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. Read more about this study
- Who is it for?
- Ages 50 to 80 years
- Conditions the study is for
- Autonomic Disturbances in Parkinson's Disease
- What is being tested?
- Pyridostigmine bromide and fludrocortisone
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 18 participants
- Where
- 1 siteSwitzerland
- Study dates
- Jun 2012to 1 Apr 2016
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 50 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- informed, written \& formal consent for participation
- male / female subjects, aged 50-80 years
- PD patients (18 subjects with symptomatic orthostatic hypotension)
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
Switzerland1 site
University Hospital Zurich, Division of Neurology
Zurich, Canton of Zurich, 8091
About this study
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
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).
Read more
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.
Read the 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.
- Being tested
- Pyridostigmine bromide, fludrocortisone
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Pyridostigmine bromideDrug
Also called Mestinon
Drug doses during the trial:
Pyridostigmine bromide: 30mg p.o. 1-1-1 to 2-2-2 given for 14 days
fludrocortisoneDrug
Also called florinef
drug dose during the trial Fludrocortisone: 0,1mg p.o. 1-0-0 to 2-0-0 given for 14 days
| Study group | Role | What they receive |
|---|---|---|
| Pyridostigmine bromide | Experimental | 14 days of active treatment followed by 21 days wash out Receives: Drug: Pyridostigmine bromide |
| fludrocortisone | Active comparator | 14 days of fludrocortisone treatment; 21 days wash out Receives: Drug: fludrocortisone |
What is being measured
The primary outcome is the main question the study is designed to answer.
Changes in diastolic blood pressure drop on Schellong manoeuvre
Measured: 10min standing, 10 min supine
Changes in half emptying time t50 on 13C-sodium octanoate breath test
Measured: within 4h after test meal
Secondary outcomes (3)
Efficacy of Pyridostigmine bromide
central blood pressure, heart rate variability and pulse wave velocity
Measured: 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);
Measured: assess symptom severity for last 14 days
Safety & Tolerability of Pyridostigmine bromide
subjective assessment of sialorrhea, Hospital Anxiety and Depression Scale, Montreal Cognitive Assessment;
Measured: assess symptom severity for last 14 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Nov 2013 (estimated)
- Study startJun 2012
- Primary completionApr 2015
- Study completion1 Apr 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Autonomic Disturbances in Parkinson's DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 18 participants (actual)
Sponsor and investigators
- Lead sponsor
- Christian Baumann
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Christian Baumann, University of Zurich
- Investigators
- Christian Baumann, MD, Principal investigator, University Hospital Zurich, Division of Neurology
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01993680
- Sponsor's protocol ID
- KEK-ZH-NR. 2011-0358
- Status last verified
- Jan 2021
- First submitted
- 27 Apr 2012
- Last updated
- 25 Jan 2021
- Results posted
- No
- Data monitoring committee
- Yes
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.
PubMed 17016160Sandroni 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.
PubMed 15768203Schreglmann 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.
PubMed 28224720
Study at a glance
From the registry record, last updated by the sponsor on 25 Jan 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01993680
- Acronym / sponsor ID
- KEK-ZH-NR. 2011-0358
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 18 participants (actual)
- Lead sponsor
- Christian BaumannUniversity, hospital or other
- Study start
- Jun 2012
- Primary completion
- Apr 2015 (actual)
- Study completion
- 1 Apr 2016 (actual)
- First posted
- 25 Nov 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Pyridostigmine bromide | Experimental | Drug: Pyridostigmine bromide14 days of active treatment followed by 21 days wash out |
| fludrocortisone | Active comparator | Drug: fludrocortisone14 days of fludrocortisone treatment; 21 days wash out |
Who may qualify
- Ages
- 50 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- informed, written \& formal consent for participation
- male / female subjects, aged 50-80 years
- PD patients (18 subjects with symptomatic orthostatic hypotension)
Key exclusion criteria (8 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Pyridostigmine bromideAlso: MestinonDrug doses during the trial: Pyridostigmine bromide: 30mg p.o. 1-1-1 to 2-2-2 given for 14 days | Drug | Pyridostigmine bromide |
| fludrocortisoneAlso: florinefdrug dose during the trial Fludrocortisone: 0,1mg p.o. 1-0-0 to 2-0-0 given for 14 days | Drug | fludrocortisone |
Primary outcome
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
3 secondary outcomes
Efficacy of Pyridostigmine bromide
Time frame: assess symptom severity for last 14 days
Efficacy of Pyridostigmine bromide
Time frame: assess symptom severity for last 14 days
Safety & Tolerability of Pyridostigmine bromide
Time frame: assess symptom severity for last 14 days
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Jan 2021.
- Background: PubMed 17016160Singer 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.
- Background: PubMed 15768203Sandroni 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.
- Derived from this study: PubMed 28224720Schreglmann 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Christian Baumann, MD principal investigator
University Hospital Zurich, Division of Neurology
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Pyridostigmine bromide and fludrocortisone in people with Autonomic Disturbances in Parkinson's Disease, run by Christian Baumann at 1 site in Switzerland.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 25 Jan 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Switzerland. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Changes in diastolic blood pressure drop on Schellong manoeuvre (time frame: 10min standing, 10 min supine). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01993680, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Jan 2021.