Pantothenate Kinase-Associated Neurodegeneration
Conditions
Keywords
Pantothenate Kinase-associated Neurodegeneration, PKAN, NBIA, Deferiprone, Ferriprox, Neurodegeneration with brain iron accumulation
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.
Interventions
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.
DRUGPlacebo
A deferiprone matching placebo oral solution will be given twice daily for 18 months.
Sponsors
Food and Drug Administration (FDA)
ApoPharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Placebo solution matched deferiprone oral solution in appearance, taste, and packaging
Eligibility
Sex/Gender
ALL
Age
4 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Score on Barry-Albright Dystonia Scale | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Score on WeeFIM | 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 | 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 Unified Parkinson's Disease Rating Scale | 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 Level of Brain Iron | 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. |
| Change in Score on Pittsburgh Sleep Quality Index | 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 Score on Functional Independence Measure | 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). |
Countries
Germany, Italy, United Kingdom, United States
Participant flow
Recruitment details
Patients were recruited at 4 study sites in Germany, Italy, the U.K., and the U.S.
Participants by arm
| Arm | Count |
|---|---|
| Deferiprone Deferiprone 80 mg/mL oral solution, 15 mg/kg b.i.d. for 18 months | 59 |
| Placebo Matching volume of placebo solution, twice daily for 18 months | 30 |
| Total | 89 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 0 |
| Overall Study | Medical event | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Sponsor decision | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
| Overall Study | Worsening of the disease | 3 | 1 |
Baseline characteristics
| Characteristic | Placebo | Total | Deferiprone |
|---|---|---|---|
| Age, Continuous | 19.2 years STANDARD_DEVIATION 12.5 | 20.2 years STANDARD_DEVIATION 11.3 | 20.8 years STANDARD_DEVIATION 10.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 7 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 28 Participants | 79 Participants | 51 Participants |
| Sex: Female, Male Female | 17 Participants | 42 Participants | 25 Participants |
| Sex: Female, Male Male | 13 Participants | 47 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 58 | 0 / 30 |
| other Total, other adverse events | 57 / 58 | 30 / 30 |
| serious Total, serious adverse events | 18 / 58 | 10 / 30 |
Outcome results
Primary
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
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Deferiprone | Change in Score on Barry-Albright Dystonia Scale | 2.48 score on a scale | Standard Error 0.63 |
| Placebo | Change in Score on Barry-Albright Dystonia Scale | 3.99 score on a scale | Standard Error 0.82 |
p-value: 0.0761Mixed Models Analysis
Primary
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
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Deferiprone | Score on Patient Global Impression of Improvement at End of Study | 4.55 score on a scale | Standard Error 0.3 |
| Placebo | Score on Patient Global Impression of Improvement at End of Study | 4.66 score on a scale | Standard Error 0.38 |
p-value: 0.7279Mixed Models Analysis
Secondary
Change in Level of Brain Iron
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.
Time frame: Baseline to 18 Months
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Deferiprone | Change in Level of Brain Iron | -36.1 Hz | Standard Error 3.11 |
| Placebo | Change in Level of Brain Iron | -0.50 Hz | Standard Error 3.97 |
p-value: 0Mixed Models Analysis
Secondary
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).
Time frame: Baseline to 18 Months
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Deferiprone | Change in Score on Functional Independence Measure | 5.40 score on a scale | Standard Error 2.36 |
| Placebo | Change in Score on Functional Independence Measure | 0.69 score on a scale | Standard Error 3.34 |
p-value: 0.1524Mixed Models Analysis
Secondary
Change in Score on Pediatric Quality of Life
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).
Time frame: Baseline to 18 Months
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Deferiprone | Change in Score on Pediatric Quality of Life | Parent proxy-report, total score | -4.90 score on a scale | Standard Error 3.99 |
| Deferiprone | Change in Score on Pediatric Quality of Life | Patient self-report, total score | 1.21 score on a scale | Standard Error 3.68 |
| Placebo | Change in Score on Pediatric Quality of Life | Patient self-report, total score | 1.34 score on a scale | Standard Error 4.49 |
| Placebo | Change in Score on Pediatric Quality of Life | Parent proxy-report, total score | -2.37 score on a scale | Standard Error 4.9 |
Comparison: Patient self-report, total scorep-value: 0.9759Mixed Models Analysis
Comparison: Parent proxy-report, total scorep-value: 0.5781Mixed Models Analysis
Secondary
Change in Score on Pittsburgh Sleep Quality Index
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).
Time frame: Baseline to 18 Months
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Deferiprone | Change in Score on Pittsburgh Sleep Quality Index | 0.48 score on a scale | Standard Error 0.61 |
| Placebo | Change in Score on Pittsburgh Sleep Quality Index | 0.14 score on a scale | Standard Error 0.8 |
p-value: 0.6323Mixed Models Analysis
Secondary
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
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Deferiprone | Change in Score on Unified Parkinson's Disease Rating Scale | UPDRS Part II | 1.09 score on a scale | Standard Error 1.19 |
| Deferiprone | Change in Score on Unified Parkinson's Disease Rating Scale | UPDRS Part I | -0.25 score on a scale | Standard Error 0.43 |
| Deferiprone | Change in Score on Unified Parkinson's Disease Rating Scale | UPDRS Part VI | -2.17 score on a scale | Standard Error 2.94 |
| Deferiprone | Change in Score on Unified Parkinson's Disease Rating Scale | UPDRS Part III | 5.38 score on a scale | Standard Error 2.2 |
| Placebo | Change in Score on Unified Parkinson's Disease Rating Scale | UPDRS Part VI | -7.66 score on a scale | Standard Error 3.85 |
| Placebo | Change in Score on Unified Parkinson's Disease Rating Scale | UPDRS Part II | 2.36 score on a scale | Standard Error 1.52 |
| Placebo | Change in Score on Unified Parkinson's Disease Rating Scale | UPDRS Part III | 2.06 score on a scale | Standard Error 2.79 |
| Placebo | Change in Score on Unified Parkinson's Disease Rating Scale | UPDRS Part I | -0.07 score on a scale | Standard Error 0.55 |
Comparison: Comparison of treatment groups on change in score on UPDRS Part Ip-value: 0.7228Mixed Models Analysis
Comparison: Comparison of treatment groups on change in score on UPDRS Part IIp-value: 0.3677Mixed Models Analysis
Comparison: Comparison of treatment groups on change in score on UPDRS Part IIIp-value: 0.2182Mixed Models Analysis
Comparison: Comparison of treatment groups on change in score on UPDRS Part VIp-value: 0.1749Mixed Models Analysis
Secondary
Change in Score on WeeFIM
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).
Time frame: Baseline to 18 Months
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Deferiprone | Change in Score on WeeFIM | 4.91 score on a scale | Standard Error 5.3 |
| Placebo | Change in Score on WeeFIM | -2.40 score on a scale | Standard Error 5.42 |
p-value: 0.2026Mixed Models Analysis