An international trial of deferiprone in patients with Parkinson’s disease

• Register: EUCTR
• Last refreshed on: 13 October 2020
• Main ID: EUCTR2015-004344-19-GB
• Date of registration: 16/02/2016
• Prospective Registration: Yes
• Primary sponsor: ApoPharma
• Public title: An international trial of deferiprone in patients with Parkinson’s disease
• Scientific title: A Dose-Ranging Study of the Efficacy, Safety, and Pharmacokinetics of Deferiprone Delayed Release Tablets in Patients with Parkinson’s Disease - LA48-0215
• Date of first enrolment: 31/03/2016
• Target sample size: 140
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-004344-19
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Canada, France, Germany, United Kingdom

Contacts

• Name: John Connelly
• Affiliation: ApoPharma

• Name: John Connelly
• Affiliation: ApoPharma

Key inclusion & exclusion criteria

Inclusion criteria:
1. Male or female aged =18 to < 80 years

2. Body weight =60 kg but =100 kg

3. Parkinson’s disease diagnosed according to UK Parkinson’s Disease Society Brain Bank Clinical Diagnostic Criteria and based on the presence of at least two of the three cardinal features of the disease (rest tremor, bradykinesia, and rigidity). If rest tremor is not present, patient must have unilateral onset of symptoms.

4. Absolute neutrophil count (ANC) =1.5 x 109/L (=1.0 x 109/L for Black population) at screening

5. On a stable dose for at least 3 months prior to the screening visit of any of the following treatments at an L-dopa equivalent daily dose of up to 600 mg:
o Dopaminergic agonist alone
o L-dopa alone
o Combination therapy with dopaminergic agonist and L-dopa
o Rasagiline
o At an early stage of the disease, without motor fluctuations and/or L-dopa–induced dyskinesia
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 82
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 58

Exclusion criteria:
1. Diagnosis of Parkinson’s disease more than 3 years prior to screening visit

2. Hoehn and Yahr stage = 3

3. Atypical or secondary Parkinsonism without dopa-sensitivity (e.g., vascular parkinsonism, supranuclear palsy, multisystem atrophy)

4. Progressing Axis I psychiatric disorders (psychosis, hallucinations, compulsive disorders, substance addiction, bipolar disorder, severe depression, anxiety) as assessed in a semi-structured interview in accordance with the Diagnostic and Statistical Manual of Mental Disorders

5. Not stabilized in terms of the current antiparkinsonian therapeutic regimen: already requires dose adaptation and/or is likely to require any change in dopamine therapy over the duration of the trial

6. Current treatment with bromocriptine

7. Current treatment with any antiparkinsonian drug other than those listed in the inclusion criteria

8. Current treatment with coenzyme Q10 or idebenone. (Patients who are on these medications but stop taking them at least 2 weeks prior to baseline may be enrolled.)

9. Current use of a Deep Brain Stimulation (DBS) system. (Patients who previously had a DBS system but have had it removed may be enrolled.)


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Parkinson’s disease
MedDRA version: 20.0 Level: PT Classification code 10061536 Term: Parkinson's disease System Organ Class: 10029205 - Nervous system disorders

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Intervention(s)

Product Name: Deferiprone 600 mg delayed release tablet
Pharmaceutical Form: Modified-release tablet
INN or Proposed INN: DEFERIPRONE
CAS Number: 30652-11-0
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 600-
Pharmaceutical form of the placebo: Modified-release tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Main Objective: Primary objective is to evaluate the efficacy of four different dosages of deferiprone delayed release (deferiprone-DR) tablets in patients with Parkinson’s disease.

Primary end point(s): Primary efficacy criterion:
Change from baseline to Month 9 in the motor examination subscale (Part III) of the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS)

Timepoint(s) of evaluation of this end point: Efficacy assessments:
• The MDS-UPDRS and MoCA will be completed at baseline and Months 3, 6, and 9

Note: The MDS-UPDRS and MoCA are to be administered early in the morning, at approximately the same time (± 1 hour) at each visit, and by the same qualified investigator.

Secondary Objective: Secondary objectives are:
• To evaluate the safety and tolerability of deferiprone-DR tablets in patients with Parkinson’s disease
• To evaluate the pharmacokinetics of deferiprone-DR tablets in a subset of study participants
• To evaluate the relationship between the pharmacokinetics and pharmacodynamics of deferiprone-DR tablets

Exploratory objectives are:
• To determine whether the efficacy responses to deferiprone differ depending on the genotype of certain enzymes that are implicated in Parkinson’s disease
• To determine whether the efficacy responses to deferiprone are correlated with ceruloplasmin levels or ceruloplasmin ferroxidase activities

Secondary Outcome(s)

Secondary end point(s): Secondary efficacy criteria:
• Change from baseline to Month 9 in the following measures:
- Total score on the MDS-UPDRS
- Scores on the individual subscales Part I (non-motor experiences of daily living), Part II (motor experiences of daily living), and Part IV (motor complications) of the MDS-UPDRS
- Combined scores from Parts II and III of the MDS-UPDRS
- Overall cognitive function, as assessed by the Montreal Cognitive Assessment (MoCA) test
- Pharmacodynamics measures of the following oxidative stress biomarkers: total antioxidant status, lipid peroxidation (malondialdehyde), protein carbonyls, 8-OHdG, glutathione, superoxide dismutase
- Pharmacodynamics measures of the following inflammatory factor biomarkers: TNF alpha and IL-6
• Time elapsed until the need for rescue medication

Exploratory efficacy criteria:
Mechanism of action (MOA) biomarkers to evaluate the following:
• Whether specific genotypes of the following enzymes which play a role in Parkinson’s disease affect the potential disease-modifying action of deferiprone:
- D544E polymorphisms of the glycoprotein ceruloplasmin
- V158M polymorphisms of the enzyme catechol O-methyltransferase (the only analysis will be determination at baseline of the COMT genotype)
• Whether the degree of change from baseline in ceruloplasmin levels and ceruloplasmin ferroxidase activity is correlated with the efficacy of deferiprone

Safety Criteria:
• Adverse events (AEs): frequency, intensity, time to onset, duration, and relatedness to study drug
• Serious adverse events (SAEs): frequency, intensity, time to onset, duration, and relatedness to study drug
• Number of discontinuations due to AEs
• Laboratory measures (hematology, blood chemistry, and urinalysis)
• ECG
• Vital signs
• Physical examination
• Assessment of suicidality (based on the Columbia Suicide Severity Rating Scale)

Pharmacokinetics Criteria:
The following PK parameters will be determined for deferiprone and its 3-O-glucuronide metabolite in the subset of patients who undergo extensive PK sampling: Cmax, Tmax, AUC0-t, AUC0-8, ?Z and T½.
T½ and AUC0-8 will be determined only in patients in whom the log-linear terminal phase can be clearly defined.

Pharmacokinetics/Pharmacodynamics Criteria:
Possible relationships between pharmacokinetic findings and efficacy biomarkers and endpoints will be evaluated.

Timepoint(s) of evaluation of this end point: Efficacy assessments:
• Blood samples at baseline, Months 3, 6, and 9
• Urine samples at baseline, Months 3, 6, and 9

Safety assessments:
• Hematology: Screening and weekly up to Month 9
• Blood chemistry: Screening, Months 1, 2, 3, 4, 5, 6, and 9
• Urinalysis: Screening, Months 3, 6, and 9
• ECG: Screening and Month 9
• Vital signs: Each visit up to Month 9
• Physical examination: Screening, baseline, Months 2, 4, 6, and 9
• Assessment of suicidality: Baseline and each visit up to Month 9
• Adverse events: Throughout, baseline (post–Dose 1) to Month 10

Pharmacokinetics assessments:
Assay of deferiprone and its 3-O-glucuronide metabolite at:
•CSF samples: Month 3
•Sparse collection of blood samples: Baseline and Month 3
•Extensive collection of blood samples: Month 1

Secondary ID(s)

LA48-0215

Source(s) of Monetary Support

ApoPharma

Ethics review

Status: Approved
Approval date: 31/03/2016
Contact: