Efficacy and Safety Study of Deferiprone in Patients With Pantothenate Kinase-associated Neurodegeneration (PKAN)

ApoPharma89 enrolled

Overview

A multi-center, placebo controlled, double-blind trial comparing the efficacy and safety of 18 months of treatment with deferiprone versus placebo in patients with PKAN. This investigator-initiated trial was funded by the European Commission's Seventh Framework Programme (FP7/2007-2013, HEALTH-F2-2011, grant agreement No. 277984) to the TIRCON consortium (Treat Iron-Related Childhood-Onset Neurodegeneration) and by the FDA Office of Orphan Products Development (OOPD) (Dr. Elliott Vichinsky).

This is a multi-center, double-blind, randomized, placebo-controlled, 18-month study in patients with PKAN aged 4 years and older. Participants are randomized in a 2:1 ratio to receive either deferiprone oral solution or placebo, twice a day for 18 months. Efficacy assessments, an MRI scan to measure iron levels in the globus pallidus, pharmacokinetic evaluations, and safety assessments are conducted at specified time points. Following completion of the trial, eligible patients are invited to enroll in an 18-month extension study, TIRCON2012V1-EXT, in which all participants receive deferiprone.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Pantothenate Kinase-Associated Neurodegeneration

Interventions

Deferiprone oral solutionDRUG

Deferiprone 80 mg/mL oral solution will be administered twice daily (b.i.d.) for 18 months. An initial dose of 5 mg/kg b.i.d. will be administered for 6 weeks. The dose will then be escalated to 10 mg/kg b.i.d. and finally to 15 mg/kg b.i.d.

PlaceboDRUG

A deferiprone matching placebo oral solution will be given twice daily for 18 months.

Eligibility

Sex: ALLMin age: 4 Years

Medical Language ↔ Plain English

Main Inclusion Criteria: * Males or females 4 years of age and older at screening visit; * Have PKAN, confirmed by genetic testing (supporting evidence required); * Barry-Albright Dystonia (BAD) total score ≥ 3 at the screening visit; * Patients who have Deep Brain Stimulation (DBS) systems or baclofen pumps in place will be eligible for the study, but they must have had a stable setting for at least two months prior to the screening visit and stimulation parameters / pump settings must remain stable for the duration of the trial: Main Exclusion Criteria: * Evidence of iron deficiency defined by Fe:TIBC ratio \<15%, or serum ferritin \<12 ng/mL; * Treatment with deferiprone in the past 12 months; * Previous failure of treatment with deferiprone, or previous discontinuation of treatment with deferiprone due to adverse events; * Conditions known to contraindicate the use of deferiprone (history of agranulocytosis or recurrent episodes of neutropenia); * A serious, unstable chronic illness not related to PKAN condition during the past 3 months before screening visit including but not limited to: hepatic, renal, gastro-enterologic, respiratory, cardiovascular, endocrinologic, neurologic or immunologic disease; * Evidence of abnormal liver or renal function (serum liver enzyme level(s) \> 3 times upper limit of normal at screening) or abnormal creatinine levels at screening visit; * Disorders associated with neutropenia (ANC \< 1.5 x 10\^9/L) or thrombocytopenia (platelet count \< 50 x 10\^9/L) in the 12 months preceding the initiation of the study medication. Exception: for patients whose neutropenia was attributed by the treating physician to episodes of infection or to drugs associated with a decline in the neutrophil count and in whom the ANC has fully recovered at the screening visit; * History of malignancy; Other protocol inclusion or exclusion criteria may apply.

Locations (4)

Children's Hospital & Research Center at Oakland

Oakland, California, United States

Klinikum der Universität München

Munich, Germany

Foundation Neurological Institute C. Besta

Milan, Italy

Newcastle University Institute of Human Genetics

Newcastle upon Tyne, United Kingdom

Outcomes

Primary Outcomes

Change in Score on Barry-Albright Dystonia Scale

The Barry-Albright Dystonia (BAD) scale rates severity of dystonia (sustained muscle contractions causing twisting and repetitive movements or abnormal postures) in 8 body regions. The individual scores are summed to provide a total score ranging from 0 to 32, with higher scores indicating greater severity. The co-primary endpoint in this study was the change from baseline to Month 18 in BAD total score.

Time frame: Baseline to 18 Months

Score on Patient Global Impression of Improvement at End of Study

The Patient Global Impression of Improvement (PGI-I) is a global index that assesses the response of a condition to a therapy by asking patients to rate their current state relative to their state at baseline. It consists of a 7-point rating scale, where 1=very much improved, 2= much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse.

Time frame: Month 18

Secondary Outcomes

Change in Score on Unified Parkinson's Disease Rating Scale

The Unified Parkinson's Disease Rating Scale (UPDRS) is the major rating scale used to assess severity of symptoms of Parkinson's disease, some of which are similar to those of PKAN. The UPDRS subscales used in this study were Part I: Mentation, Behavior and Mood, scored from 0 (best) to 16 (worst); Part II: Activities of Daily Living, scored from 0 (best) to 52 (worst); Part III: Motor Examination, scored from 0 (best) to 108 (worst); and Part VI: Schwab and England Activities of Daily Living Scale, scored from 0% (worst) to 100% (best).

Time frame: Baseline to 18 Months

Change in Score on Functional Independence Measure

The Functional Independence Measure (FIM) scale is used to assess physical and cognitive disability in three areas of daily living: self-care, mobility, and cognition. Within each area, items are scored according to the level of assistance required to perform that activity of daily living. A score of 1-2 indicates that the patient is completely dependent on a helper to perform the task, a score of 3-5 indicates that the patient is moderately dependent, and a score of 6-7 indicates that no help is required. The individual scores are summed to provide a global score from 18 (worst) to 126 (best).

Data from ClinicalTrials.gov

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