Pantothenate Kinase-Associated Neurodegeneration
Conditions
Keywords
PKAN
Brief summary
This study investigated whether fosmetpantotenate (RE-024), a phosphopantothenate replacement therapy, was safe and effective in treating participants with PKAN.
Interventions
DRUGFosmetpantotenate
Daily dosing
DRUGPlacebo
Daily dosing
Sponsors
Travere Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. The participant had a diagnosis of PKAN as indicated by confirmed mutations in the pantothenate kinase 2 gene. 2. The participant was male or female aged 6 to 65 years, inclusive. 3. The participant had a score of ≥ 6 on the PKAN-specific activities of daily living measure.
Exclusion criteria
1. The participant had required regular or intermittent invasive ventilatory support to maintain vital signs within 24 weeks prior to randomization. 2. The participant had a deep brain stimulation device implanted within 6 months prior to screening. 3. The participant had taken deferiprone within 30 days prior to screening. 4. The participant was unable to maintain stable doses of allowed concomitant medications for the first 24 weeks of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline In The Pantothenate Kinase-Associated Neurodegeneration-Activities of Daily Living (PKAN-ADL) Total Score To The End Of The 24-week Double-blind Period | Baseline (Day -1), Week 24 | Change from baseline to Week 24 activities of daily living was assessed on the PKAN-ADL scale based on the Unified Parkinson's Disease Rating Scale (UPDRS) Part II. The PKAN-ADL is a validated measure of the participant's ability to complete ADL that are impacted by the diffuse motor manifestations of PKAN. It consists of 12 items related to activities of daily living, including eating, dressing, and walking. Each item has responses ranging from 0-4, with a higher value indicating greater disability in the given activity. To compute the total score, responses are summed across the 12 items. The available range of total scores on the PKAN-ADL scale was from 0 (no ADL affected) to 48 (ADL highly affected). The reported least square mean (LSM) was adjusted for baseline score and age group from the Type III analysis. A decrease in score indicates improvement in symptoms. |
| Number Of Participants With At Least 1 (≥1) Treatment-emergent Adverse Event (TEAE) And Treatment-emergent Serious Adverse Event (TESAE) During The 24-week Double-blind Period | From Screening until end of Week 24 | An adverse event (AE) is any untoward medical occurrence associated with the use of the investigational product (IP; active or placebo) in a participant, without regard to possibility of causal relationship with IP. A serious adverse event (SAE) is an AE resulting in any of the following outcomes: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of death from AE); persistent or significant disability/incapacity; congenital anomaly/birth defect; other medically important serious medical events. The TEAEs in the double-blind period are defined as AEs that are new or are a worsening of an existing condition that begins from day of first dose of IP until day after last dose for double-blind treatment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change From Baseline In The UPDRS Part 3 (UPDRS-III) Total Score To The End Of The 24-week Double-blind Period | Baseline (Day -1), Week 24 | The UPDRS is a comprehensive assessment of the burden and severity of signs and symptoms of Parkinsonism captured via systematic interview and neurological examination. The UPDRS-III is a standardized neurological examination that evaluates the performance of movements commonly affected in Parkinson's disease, PKAN, and other movement disorders. Part III of the UPDRS consists of 27 items, which correspond to 14 domains related to motor abilities such as tremor, stability, and bradykinesia. Each item has responses ranging from 0-4. To compute the UPDRS-III total score, responses are summed across the 27 items, and accordingly, range from 0-108. For domain totals, responses are summed across all of the items in a given domain (when domain corresponds to multiple items). An increase in score indicates greater disability. The reported LSM was adjusted for baseline score and age group from the Type III analysis. |
Countries
Canada, Czechia, France, Germany, Italy, Norway, Poland, Spain, United States
Participant flow
Recruitment details
The study was conducted in Spain, United States, Canada, Czech Republic, France, Germany, Italy, Norway, and Poland from 17-July-2017 to 23-December-2019. A total of 91 participants were screened, of which 84 participants were randomized in the double blind period, and 78 participants completed the double-blind period.
Pre-assignment details
The study consisted of a screening period of up to 29 days. All assessments at screening were done as per the schedule of assessments.
Participants by arm
| Arm | Count |
|---|---|
| Fosmetpantotenate Double-blind Period: each randomized participant received an oral dose of fosmetpantotenate with dose escalation for Days 1 through 3, followed by the full dose TID from Day 4, based on the participant's age and weight at screening, for 24 weeks.
Open-label Period: all participants continued treatment with fosmetpantotenate according to the dose they were receiving at the end of the double-blind period. No dose escalation was required. | 41 |
| Placebo Double-blind Period: each randomized participant received an oral dose of placebo matched to fosmetpantotenate with dose escalation for Days 1 through 3, followed by the full dose TID from Day 4, based on the participant's age and weight at screening, for 24 weeks.
Open-label Period: all participants started treatment with fosmetpantotenate according to the placebo dose they were receiving at the end of the double-blind period. No dose escalation was required. | 43 |
| Total | 84 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double-blind | Death | 0 | 2 |
| Double-blind | Withdrawal by Subject | 0 | 4 |
| Open-label | Death | 1 | 0 |
| Open-label | Termination of the study by Sponsor | 39 | 37 |
| Open-label | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | Total | Fosmetpantotenate |
|---|---|---|---|
| Age, Continuous | 23.1 years STANDARD_DEVIATION 13.56 | 22.9 years STANDARD_DEVIATION 12.14 | 22.6 years STANDARD_DEVIATION 10.61 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 10 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 36 Participants | 64 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 10 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 4 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 9 Participants | 22 Participants | 13 Participants |
| Race (NIH/OMB) White | 28 Participants | 53 Participants | 25 Participants |
| Sex: Female, Male Female | 19 Participants | 39 Participants | 20 Participants |
| Sex: Female, Male Male | 24 Participants | 45 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 41 | 2 / 37 | 0 / 41 | 2 / 43 | 1 / 41 | 0 / 37 |
| other Total, other adverse events | 35 / 41 | 25 / 37 | 34 / 41 | 35 / 43 | 25 / 41 | 26 / 37 |
| serious Total, serious adverse events | 9 / 41 | 9 / 37 | 8 / 41 | 6 / 43 | 4 / 41 | 9 / 37 |
Outcome results
Primary
Change From Baseline In The Pantothenate Kinase-Associated Neurodegeneration-Activities of Daily Living (PKAN-ADL) Total Score To The End Of The 24-week Double-blind Period
Change from baseline to Week 24 activities of daily living was assessed on the PKAN-ADL scale based on the Unified Parkinson's Disease Rating Scale (UPDRS) Part II. The PKAN-ADL is a validated measure of the participant's ability to complete ADL that are impacted by the diffuse motor manifestations of PKAN. It consists of 12 items related to activities of daily living, including eating, dressing, and walking. Each item has responses ranging from 0-4, with a higher value indicating greater disability in the given activity. To compute the total score, responses are summed across the 12 items. The available range of total scores on the PKAN-ADL scale was from 0 (no ADL affected) to 48 (ADL highly affected). The reported least square mean (LSM) was adjusted for baseline score and age group from the Type III analysis. A decrease in score indicates improvement in symptoms.
Time frame: Baseline (Day -1), Week 24
Population: Double-blind Full Analysis Set: any participant who received at least 1 dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Fosmetpantotenate | Change From Baseline In The Pantothenate Kinase-Associated Neurodegeneration-Activities of Daily Living (PKAN-ADL) Total Score To The End Of The 24-week Double-blind Period | -1.3 units on a scale | Standard Error 0.56 |
| Placebo | Change From Baseline In The Pantothenate Kinase-Associated Neurodegeneration-Activities of Daily Living (PKAN-ADL) Total Score To The End Of The 24-week Double-blind Period | -1.3 units on a scale | Standard Error 0.58 |
p-value: =0.911595% CI: [-1.69, 1.51]Mixed Models Analysis
Primary
Number Of Participants With At Least 1 (≥1) Treatment-emergent Adverse Event (TEAE) And Treatment-emergent Serious Adverse Event (TESAE) During The 24-week Double-blind Period
An adverse event (AE) is any untoward medical occurrence associated with the use of the investigational product (IP; active or placebo) in a participant, without regard to possibility of causal relationship with IP. A serious adverse event (SAE) is an AE resulting in any of the following outcomes: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of death from AE); persistent or significant disability/incapacity; congenital anomaly/birth defect; other medically important serious medical events. The TEAEs in the double-blind period are defined as AEs that are new or are a worsening of an existing condition that begins from day of first dose of IP until day after last dose for double-blind treatment period.
Time frame: From Screening until end of Week 24
Population: Safety Population: any participant who received at least 1 dose of study drug during any period of the study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Fosmetpantotenate | Number Of Participants With At Least 1 (≥1) Treatment-emergent Adverse Event (TEAE) And Treatment-emergent Serious Adverse Event (TESAE) During The 24-week Double-blind Period | ≥1 TEAE | 34 Participants |
| Fosmetpantotenate | Number Of Participants With At Least 1 (≥1) Treatment-emergent Adverse Event (TEAE) And Treatment-emergent Serious Adverse Event (TESAE) During The 24-week Double-blind Period | ≥1 TESAE | 8 Participants |
| Placebo | Number Of Participants With At Least 1 (≥1) Treatment-emergent Adverse Event (TEAE) And Treatment-emergent Serious Adverse Event (TESAE) During The 24-week Double-blind Period | ≥1 TEAE | 35 Participants |
| Placebo | Number Of Participants With At Least 1 (≥1) Treatment-emergent Adverse Event (TEAE) And Treatment-emergent Serious Adverse Event (TESAE) During The 24-week Double-blind Period | ≥1 TESAE | 6 Participants |
Secondary
Absolute Change From Baseline In The UPDRS Part 3 (UPDRS-III) Total Score To The End Of The 24-week Double-blind Period
The UPDRS is a comprehensive assessment of the burden and severity of signs and symptoms of Parkinsonism captured via systematic interview and neurological examination. The UPDRS-III is a standardized neurological examination that evaluates the performance of movements commonly affected in Parkinson's disease, PKAN, and other movement disorders. Part III of the UPDRS consists of 27 items, which correspond to 14 domains related to motor abilities such as tremor, stability, and bradykinesia. Each item has responses ranging from 0-4. To compute the UPDRS-III total score, responses are summed across the 27 items, and accordingly, range from 0-108. For domain totals, responses are summed across all of the items in a given domain (when domain corresponds to multiple items). An increase in score indicates greater disability. The reported LSM was adjusted for baseline score and age group from the Type III analysis.
Time frame: Baseline (Day -1), Week 24
Population: Double-blind Full Analysis Set: any participant who received at least 1 dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fosmetpantotenate | Absolute Change From Baseline In The UPDRS Part 3 (UPDRS-III) Total Score To The End Of The 24-week Double-blind Period | 0.7 units on a scale | Standard Deviation 5.25 |
| Placebo | Absolute Change From Baseline In The UPDRS Part 3 (UPDRS-III) Total Score To The End Of The 24-week Double-blind Period | -1.0 units on a scale | Standard Deviation 6.81 |
p-value: =0.142195% CI: [-0.7, 4.78]Mixed Models Analysis