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

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ClinicalTrials.gov Identifier: NCT01741532
Recruitment Status : Completed
First Posted : December 5, 2012
Results First Posted : May 23, 2019
Last Update Posted : July 5, 2019
Sponsor:
Collaborator:
Food and Drug Administration (FDA)
Information provided by (Responsible Party):
ApoPharma

Tracking Information
First Submitted Date  ICMJE December 3, 2012
First Posted Date  ICMJE December 5, 2012
Results First Submitted Date  ICMJE May 1, 2019
Results First Posted Date  ICMJE May 23, 2019
Last Update Posted Date July 5, 2019
Actual Study Start Date  ICMJE December 13, 2012
Actual Primary Completion Date October 21, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 27, 2019)
  • Change in Score on Barry-Albright Dystonia Scale [ Time Frame: Baseline to 18 Months ]
    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.
  • Score on Patient Global Impression of Improvement at End of Study [ Time Frame: Month 18 ]
    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.
Original Primary Outcome Measures  ICMJE
 (submitted: December 3, 2012)
  • Change in severity of dystonia (using BAD scale) in patients with PKAN treated with deferiprone in comparison to placebo. [ Time Frame: 18 months ]
    The Barry-Albright Dystonia Scale (BAD) will be completed at baseline, months 6, 12 and 18 visits and will be assessed by central raters.
  • Change in patient's global impression of condition's improvement (using PGI-I) in patients with PKAN treated with deferiprone in comparison to placebo. [ Time Frame: 18 months ]
    Patient Global Impression of Improvement (PGI-I) will be completed at months 6, 12 and 18 visits.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 27, 2019)
  • Change in Score on Unified Parkinson's Disease Rating Scale [ Time Frame: Baseline to 18 Months ]
    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).
  • Change in Score on Functional Independence Measure [ Time Frame: Baseline to 18 Months ]
    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).
  • Change in Score on WeeFIM [ Time Frame: Baseline to 18 Months ]
    The WeeFIM is the pediatric version of the Functional Independence Measure scale, and 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).
  • Change in Score on Pediatric Quality of Life [ Time Frame: Baseline to 18 Months ]
    The Pediatric Quality of Life (PedsQL) questionnaire is used to measure functional health and well-being from the patient's point of view. Separate versions of the questionnaire are available for children, young adults aged 18-25 years, and adults older than 25 years. Patients are asked to indicate how they have felt over the past month, and the scores of the 23 questions are used to generate an overall score that ranges from 0 (worst) to 100 (best).
  • Change in Score on Pittsburgh Sleep Quality Index [ Time Frame: Baseline to 18 Months ]
    The Pittsburgh Sleep Quality Index (PSQI) is a self-rated questionnaire that assesses sleep quality and disturbances over a 1-month time interval. A total of 19 individual items are used to generate 7 "component" scores: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction, and a score is generated that ranges from 0 (best) to 21 (worst).
  • Change in Level of Brain Iron [ Time Frame: Baseline to 18 Months ]
    Neurodegeneration in patients with PKAN is associated with localized brain iron accumulation, with the highest amount of accumulation seen in the globus pallidus, one of the main areas for motor control. MRI R2* scans of this region were performed at baseline and Month 18 in a subset of patients who did not have a deep brain stimulation (DBS) device implanted, and for whom the use of anesthesia, if required, was deemed acceptable by the investigator.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 3, 2012)
  • Change in globus pallidus iron levels (using MRI T2*) in patients with PKAN treated with deferiprone in comparison to placebo. [ Time Frame: 18 months ]
    MRI T2* assessments will be completed at the baseline and month 18 visits.
  • Change in motor symptoms (using UPDRS) in patients with PKAN treated with deferiprone in comparison to placebo. [ Time Frame: 18 months ]
    Unified Parkinson's Disease Rating Scale (UPDRS) will be completed at the baseline, months 6, 12, and 18 visits.
  • Change in quality of life (PedsQL) in patients with PKAN treated with deferiprone in comparison to placebo. [ Time Frame: 18 months ]
    Pediatric Quality of Life Inventory (PedsQL) will be completed at the baseline, months 6, 12 and 18 visits.
  • Change in patient's quality of sleep (using PSQI) in patients with PKAN treated with deferiprone in comparison to placebo. [ Time Frame: 18 months ]
    Pittsburgh Sleep Quality Index (PSQI) will be completed at the baseline, months 6, 12 and 18 visits.
  • Change in the measure of functional independence (using WeeFIM or FIM) in patients with PKAN treated with deferiprone in comparison to placebo. [ Time Frame: 18 months ]
    WeeFIM or FIM will be completed at the baseline, months 6, 12 and 18 visits.
  • Safety and tolerability of deferiprone in patients with PKAN. [ Time Frame: 18 months ]
    Safety and tolerability will be assessed based on changes in: frequency of adverse events (AEs), frequency of serious adverse events (SAEs), discontinuation due to AEs, clinical laboratory tests (including hematology and biochemistry)and ECG from baseline to month 18.
  • Steady state pharmacokinetics (PK) of deferiprone and its 3-O-glucuronide metabolite. [ Time Frame: 12 hours at month 6 visit ]
    Pharmacokinetics steady state standard parameters will be assessed in a subset of up to 24 patients over a 12 hour dosing interval using individual serum concentration-time profiles of deferiprone and its 3-O-glucuronide metabolite.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy and Safety Study of Deferiprone in Patients With Pantothenate Kinase-associated Neurodegeneration (PKAN)
Official Title  ICMJE A Randomized, Double-blind, Placebo-controlled Trial of Deferiprone in Patients With Pantothenate Kinase-associated Neurodegeneration (PKAN)
Brief Summary

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).

Detailed Description 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  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
Placebo solution matched deferiprone oral solution in appearance, taste, and packaging
Primary Purpose: Treatment
Condition  ICMJE Pantothenate Kinase-Associated Neurodegeneration
Intervention  ICMJE
  • Drug: Deferiprone oral solution
    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.
    Other Names:
    • DFP
    • L1
  • Drug: Placebo
    A deferiprone matching placebo oral solution will be given twice daily for 18 months.
Study Arms  ICMJE
  • Experimental: Deferiprone
    Deferiprone 80 mg/mL oral solution
    Intervention: Drug: Deferiprone oral solution
  • Placebo Comparator: Placebo
    Matching placebo solution
    Intervention: Drug: Placebo
Publications * Klopstock T, Tricta F, Neumayr L, Karin I, Zorzi G, Fradette C, Kmieć T, Büchner B, Steele HE, Horvath R, Chinnery PF, Basu A, Küpper C, Neuhofer C, Kálmán B, Dušek P, Yapici Z, Wilson I, Zhao F, Zibordi F, Nardocci N, Aguilar C, Hayflick SJ, Spino M, Blamire AM, Hogarth P, Vichinsky E. Safety and efficacy of deferiprone for pantothenate kinase-associated neurodegeneration: a randomised, double-blind, controlled trial and an open-label extension study. Lancet Neurol. 2019 Jul;18(7):631-642. doi: 10.1016/S1474-4422(19)30142-5.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 30, 2015)
89
Original Estimated Enrollment  ICMJE
 (submitted: December 3, 2012)
90
Actual Study Completion Date  ICMJE January 11, 2017
Actual Primary Completion Date October 21, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 4 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Germany,   Italy,   United Kingdom,   United States
Removed Location Countries Poland
 
Administrative Information
NCT Number  ICMJE NCT01741532
Other Study ID Numbers  ICMJE TIRCON2012V1
1R01FD004103-01 ( U.S. FDA Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party ApoPharma
Study Sponsor  ICMJE ApoPharma
Collaborators  ICMJE Food and Drug Administration (FDA)
Investigators  ICMJE
Study Chair: Fernando Tricta, MD ApoPharma Inc.
Principal Investigator: Thomas Klopstock, MD Friedrich-Baur-Institute, Department of Neurology, University of Munich Ziemssenstr
Principal Investigator: Elliott Vichinsky, MD Children's Hospital & Research Center at Oakland Hematology/ Oncology, Pediatric Rehabilitation
PRS Account ApoPharma
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP