Management of Parkinson's disease if levodopa is broken down prematurely

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Stichting Radboud University Medical Center

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

14 May 2025 → ongoing

Decision date (initial)

2024-12-16

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

EVER Neuro Pharma GmbH · MDL Fonds (Dutch Digestive Foundation) · Stichting Woelse Waard · Stichting Alkemade-Keuls · ParkinsonNL

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

Can symptom management of persons with Parkinson's disease who have increased activity of the levodopa-metabolizing enzyme aromatic L-amino acid decarboxylase (AADC), or who have increased abundance of bacteria that produce the levodopa-metabolizing enzymes tyrosine decarboxylase (TDC), aromatic amino acid aminotransferase (AAT) or aromatic amino acid lactate dehydrogenase (ALDH), be improved by either circumventing the enzymatic mechanisms (using the dopamine receptor agonist apomorphine), or an antibiotic intervention against enzyme-producing bacteria (rifaximin), or both?

Secondary objectives 7

1. Investigating efficacy of subcutaneous apomorphine in Parkinson's disease patients who have a (primary or secondary) resistance to levodopa treatment, in the presence of increased AADC activity or increased abundance of bacteria that produce levodopa-metabolizing enzymes
2. Investigating efficacy of subcutaneous apomorphine in Parkinson's disease patients who have a (primary or secondary) resistance to levodopa treatment, in the presence of inflammation of the intestinal lining (as demonstrated by elevated faecal calprotectin).
3. Investigating efficacy of subcutaneous apomorphine in Parkinson's disease patients who have a (primary or secondary) resistance to levodopa treatment, using measures of objective motor function.
4. Investigating improvement in levodopa response after an oral course of the non-absorbable antibiotic rifaximin, in Parkinson's disease patients with increased faecal abundance of bacteria that produce levodopa-metabolizing enzymes.
5. Investigating improvement in levodopa response after an oral course of the non-absorbable antibiotic rifaximin, in Parkinson's disease patients with increased faecal abundance of bacteria that produce levodopa-metabolizing enzymes and presence of inflammation of the intestinal lining, as evidenced by increased faecal calprotectin.
6. Reduction of faecal abundance of bacteria that produce levodopa-metabolizing enzymes after rifaximin treatment
7. Reduction of gastrointestinal symptoms after rifaximin treatment

Conditions and MedDRA coding

Parkinson's disease

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Subject is an adult, at least 25 years of age, of either sex
2. Subject lives in the Netherlands
3. Subject can read and understand Dutch
4. Subject has completed the ethics board-approved Informed Consent
5. Subject is willing, competent, and able to comply with all aspects of the protocol, including multiple occasions of not taking their PD medication during a 12-hour period, and biospecimen collection
6. Diagnosis of Parkinson’s disease (idiopathic parkinsonism) by a neurologist, according to accepted clinical criteria
7. Documented peripheral levodopa resistance
8. Serum AADC enzyme activity of >144 mU/L (in sample taken in medicated condition) AND/OR faecal abundance of levodopa-metabolizing bacteria of >90,000 fragments per million

Exclusion criteria 17

1. Significant doubt over the correctness of the diagnosis idiopathic Parkinson’s disease
2. Pregnancy or breastfeeding
3. Allergies to any of the investigational and non-investigational medications or constituents thereof
4. Documented severe and debilitating dyskinesias on levodopa, to such an extent that levodopa treatment was terminated
5. Contraindications to levodopa/benserazide
6. Present use of, or planned initiation during the study period of, advanced therapies (AT) for Parkinson’s disease including deep brain stimulation (DBS), continuous jejunal levodopa infusion (CJLI), continuous subcutaneous (fos)levodopa infusion (CSLI), apomorphine pen injections or continuous subcutaneous apomorphine infusion (CSAI)
7. Any antibiotic therapy during the study period and in the 12 months preceding it, unless participant only participates in apomorphine substudy and is selected for inclusion based solely upon AADC activity, not bacterial abundance
8. Present, or in the past 14 days, use of non-selective monoamine oxidase (MAO) inhibitors (including tranylcypromine) or dual use of a selective MAO-B inhibitor (including rasagiline, safinamide) and a selective MAO-A inhibitor (including moclobemide)
9. Present, or in the past 4 weeks, use of any probiotic preparations, unless participant only participates in apomorphine substudy and is selected for inclusion based solely upon AADC activity, not bacterial abundance
10. Atypical or genetic parkinsonism, or parkinsonism caused by a structural laesion of the brain
11. Levodopa-resistant tremor, unless the subtotal of the ‘OFF’ MDS-UPDRS III tremor scores (item 3.15-3.18) makes up less than 15% of the ‘OFF’ MDS-UPDRS III total sum score
12. Presence of dementia
13. Current presence of hallucinations or delusions, or history of developing hallucinations or delusions under dopaminergic therapy. Exception: hallucinations or delusions not currently present AND currently adequately treated with a cholinesterase inhibitor to prevent recurrence.
14. Fear of needles/injection
15. Co-morbidities that would hamper interpretation of parkinsonian disability, such as coincident musculoskeletal abnormalities
16. Not able to stand or walk without the assistance of another person (walking aids are not an exclusion criterion)
17. Presence of gastrointestinal disease associated with impaired drug absorption (e.g. coeliac disease)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Proportion of responders (defined as >30.0% decrease in MDS-UPDRS-III compared to pre-treatment), apomorphine versus levodopa
2. MDS-UPDRS-IIIΔOFF-ONΔposttreatment-pretreatment, rifaximin compared to placebo

Secondary endpoints 5

1. MDS-UPDRS IIIΔOFF-ON
2. Composite Clinical Motor Score (CCMS)
3. Modified Hoehn & Yahr scale
4. Global Rating of Change (GRC)
5. Modified GIDS-PD

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Comparator 1

Placebo 1

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Stichting Radboud University Medical Center

Sponsor organisation

Stichting Radboud University Medical Center

Address

Geert Grooteplein Zuid 10

City

Nijmegen

Postcode

6525 GA

Country

Netherlands

Scientific contact point

Organisation

Stichting Radboud University Medical Center

Contact name

Research Support Helpdesk

Public contact point

Organisation

Stichting Radboud University Medical Center

Contact name

Research Support Helpdesk

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 12 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications