E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061536 |
E.1.2 | Term | Parkinson's disease |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Primary objective is to evaluate the efficacy of four different dosages of deferiprone delayed release (deferiprone-DR) tablets in patients with Parkinson’s disease. |
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E.2.2 | Secondary objectives of the trial |
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 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 |
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E.4 | Principal 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.) |
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E.5 End points |
E.5.1 | 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) |
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E.5.1.1 | 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. |
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E.5.2 | 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-∞, λZ and T½.
T½ and AUC0-∞ 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. |
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E.5.2.1 | 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 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 18 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
France |
Germany |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 29 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 29 |