Pantothenate Kinase-Associated Neurodegeneration
Conditions
Keywords
Neurodegeneration with Brain Iron Accumulation, NBIA, PKAN
Brief summary
The purpose of this study is to learn more about how people with the condition pantothenate kinase-associated neurodegeneration (PKAN) respond to a specialized study product. We are hoping to find out if the study product is safe, what effects-good and bad-the study product causes, and whether the study product changes certain measures of disease in PKAN.
Interventions
OTHERCoA-Z
People with PKAN lack a chemical to process or metabolize a certain vitamin in the brain. CoA-Z is designed to bypass this metabolic defect that causes PKAN.
OTHERPlacebo
The placebo is a strawberry-flavored syrup that looks and tastes like CoA-Z but has no active CoA-Z in it.
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Washington State University
Oregon State University
Spoonbill Foundation
Spoonbill
Oregon Health and Science University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Masking was used for the initial 6-month randomized, double-blind phase, placebo-controlled.
Intervention model description
An initial 6-month, dose-ranging, parallel-group, randomized, double-blind, placebo-controlled phase is followed by an 18-month, single-dose, open-label phase--these arms met enrollment goals. A direct-to-open-label arm of the study was opened to allow for additional enrollment.
Eligibility
Sex/Gender
ALL
Age
3 Months to 89 Years
Healthy volunteers
No
Inclusion criteria
* Has a diagnosis of PKAN confirmed by: a) genetic testing confirming 2 pathogenic or likely pathogenic mutations, or (b) typical findings on exam and brain MR imaging with only one pathogenic mutation +/- a second likely pathogenic or VOUS in PANK2, or (c) typical findings on exam and brain MR imaging with a single likely pathogenic or VOUS in PANK2, or (d) be a symptomatic sibling of a proband subject meeting a, b or c. * Be between 3 months old and 89 years old. * Be able to take study product by mouth or feeding tube. * Be willing and able to complete study procedures / telephone visits / blood draws independently, OR have a caregiver / parent willing and able to assist with these tasks. * Be enrolled or willing to enroll in the PKANready natural history study (eIRB 10832). * Be resident in North America (US or Canada) for the duration of the trial.
Exclusion criteria
* Have had exposure to a putative PANK2 bypass therapeutic agent in the 30 days prior to screening. * Be concurrently enrolled in another interventional clinical trial. * Have concurrent medical or other condition expected to preclude completion of study procedures of confound the assessment of clinical and laboratory measures of safety.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Treatment-emergent Adverse Events Assessed Using CTCAE v4.0 | 6 months following first dose in double-blind phase | Safety will be measured using the number of treatment-emergent adverse events (both AE and SAE) by treatment arm. Counts are adjusted for number of prescription medications at baseline as a measure of baseline disease severity. |
| Number of Treatment-emergent Clinically Significant Laboratory Abnormalities on Complete Blood Count. | 6-month randomized, double-blind, placebo-controlled phase | Safety will be assessed by measuring the number of treatment-emergent clinically significant laboratory abnormalities on Complete Blood Count. Clinical significance will be determined by Medical Safety Monitor and Clinical Investigators. |
| Number of Treatment-emergent Clinically Significant Laboratory Abnormalities on Comprehensive Metabolic Profile. | 6-month randomized, double-blind, placebo-controlled phase | Safety will be assessed by measuring the number of treatment-emergent clinically significant laboratory abnormalities on Comprehensive Metabolic Profile by collection month. Clinical significance will be determined by Medical Safety Monitor and Clinical Investigators. |
| Number of Participants Retained in Each Arm. | 6 month randomized, double-blind, placebo-controlled period | Tolerability will be assessed by measuring the number of participants retained in each arm over the course of the study. |
| Mean Percent of Study Product Consumed. | 6-month randomized, double-blind, placebo-controlled phase | Tolerability will be assessed by adherence to the study product regimen arm at each follow-up time point. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| CoASY mRNA Expression | Up to 6 months after first dose | Average relative CoASY gene expression, measured as the ratio to baseline of 1 / (2\^\[COASY Ct - 18s Ct\]), where Ct = cycle time and 18s is a housekeeping gene. Values \>1 reflect higher expression. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CoA-Z dose 1 Double blind CoA-Z 20mg/m\^2 (Dose 1) Open label CoA-Z 15mg/m\^2 (Dose 2) | 15 |
| CoA-Z dose 2 Double blind CoA-Z 15mg/m\^2 (Dose 2) Open label CoA-Z 15mg/m\^2 (Dose 2) | 17 |
| CoA-Z dose 3 Double blind CoA-Z 5mg/m\^2 (Dose 3) Open label CoA-Z 15mg/m\^2 | 17 |
| Placebo Double blind CoA-Z Placebo Open label CoA-Z 15mg/m\^2 | 16 |
| Open Label Open-label Arm CoA-Z 15mg/m\^2 | 12 |
| Total | 77 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Double-Blind Period, initial 6 months | Death | 0 | 1 | 0 | 0 | 0 |
| Double-Blind Period, initial 6 months | Physician Decision | 0 | 0 | 0 | 1 | 0 |
| Open-Label Period, subsequent 18 months | Death | 3 | 2 | 2 | 0 | 1 |
| Open-Label Period, subsequent 18 months | Participation ended early due to shortage of study product (COVID 19 supply chain issue) | 2 | 4 | 2 | 2 | 0 |
| Open-Label Period, subsequent 18 months | Withdrawal by Subject | 2 | 1 | 2 | 0 | 1 |
Baseline characteristics
| Characteristic | CoA-Z dose 2 | CoA-Z dose 3 | Placebo | CoA-Z dose 1 | Open Label | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 8 Participants | 11 Participants | 8 Participants | 7 Participants | 10 Participants | 44 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants | 6 Participants | 8 Participants | 8 Participants | 2 Participants | 33 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 2 Participants | 4 Participants | 2 Participants | 5 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 15 Participants | 12 Participants | 13 Participants | 7 Participants | 59 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Mean number of baseline medications | 6.2 medications STANDARD_DEVIATION 5.4 | 5.1 medications STANDARD_DEVIATION 4 | 5.6 medications STANDARD_DEVIATION 4.5 | 7.7 medications STANDARD_DEVIATION 6.1 | 2.7 medications STANDARD_DEVIATION 3.2 | 6.1 medications STANDARD_DEVIATION 5 |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 0 Participants | 4 Participants | 0 Participants | 5 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized More than one race | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Other race | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 4 Participants | 5 Participants |
| Race/Ethnicity, Customized Unknown or not reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 15 Participants | 14 Participants | 15 Participants | 11 Participants | 6 Participants | 61 Participants |
| Sex: Female, Male Female | 5 Participants | 7 Participants | 5 Participants | 5 Participants | 6 Participants | 28 Participants |
| Sex: Female, Male Male | 12 Participants | 10 Participants | 11 Participants | 10 Participants | 6 Participants | 49 Participants |
| Type of pantothenate kinase-associated neurodegeneration (PKAN) Atypical PKAN | 8 Participants | 8 Participants | 8 Participants | 7 Participants | 8 Participants | 39 Participants |
| Type of pantothenate kinase-associated neurodegeneration (PKAN) Classic PKAN | 9 Participants | 9 Participants | 8 Participants | 8 Participants | 4 Participants | 38 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 | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 1 / 17 | 0 / 17 | 0 / 16 | 3 / 15 | 2 / 16 | 2 / 17 | 0 / 16 | 1 / 12 |
| other Total, other adverse events | 10 / 15 | 15 / 17 | 9 / 17 | 8 / 16 | 9 / 15 | 10 / 16 | 10 / 17 | 10 / 16 | 2 / 12 |
| serious Total, serious adverse events | 8 / 15 | 7 / 17 | 5 / 17 | 3 / 16 | 7 / 15 | 7 / 16 | 7 / 17 | 3 / 16 | 3 / 12 |
Outcome results
Primary
Mean Percent of Study Product Consumed.
Tolerability will be assessed by adherence to the study product regimen arm at each follow-up time point.
Time frame: 6-month randomized, double-blind, placebo-controlled phase
Population: Population of all subjects who returned partial or complete dosing diaries.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CoA-Z dose 1 | Mean Percent of Study Product Consumed. | 98.98 percent of doses taken | Standard Deviation 0.014 |
| CoA-Z dose 2 | Mean Percent of Study Product Consumed. | 99.25 percent of doses taken | Standard Deviation 0.009 |
| CoA-Z dose 3 | Mean Percent of Study Product Consumed. | 98.66 percent of doses taken | Standard Deviation 0.022 |
| Placebo | Mean Percent of Study Product Consumed. | 96.94 percent of doses taken | Standard Deviation 0.048 |
Primary
Number of Participants Retained in Each Arm.
Tolerability will be assessed by measuring the number of participants retained in each arm over the course of the study.
Time frame: 6 month randomized, double-blind, placebo-controlled period
Population: All participants who completed Screening, Informed Consent, and enrolled in the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CoA-Z dose 1 | Number of Participants Retained in Each Arm. | 15 Participants |
| CoA-Z dose 2 | Number of Participants Retained in Each Arm. | 16 Participants |
| CoA-Z dose 3 | Number of Participants Retained in Each Arm. | 17 Participants |
| Placebo | Number of Participants Retained in Each Arm. | 15 Participants |
Primary
Number of Treatment-emergent Adverse Events Assessed Using CTCAE v4.0
Safety will be measured using the number of treatment-emergent adverse events (both AE and SAE) by treatment arm. Counts are adjusted for number of prescription medications at baseline as a measure of baseline disease severity.
Time frame: 6 months following first dose in double-blind phase
Population: All randomized participants.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| CoA-Z dose 1 | Number of Treatment-emergent Adverse Events Assessed Using CTCAE v4.0 | 1.15 Events per person |
| CoA-Z dose 2 | Number of Treatment-emergent Adverse Events Assessed Using CTCAE v4.0 | 1.38 Events per person |
| CoA-Z dose 3 | Number of Treatment-emergent Adverse Events Assessed Using CTCAE v4.0 | 1.14 Events per person |
| Placebo | Number of Treatment-emergent Adverse Events Assessed Using CTCAE v4.0 | 0.86 Events per person |
Comparison: Mean counts of events per person were calculated from a negative binomial regression model with categorical coefficients for active dose levels, controlling for the baseline number of prescriptions. A joint test of the null hypothesis that the three regression parameters representing active treatment = 0 was done.p-value: 0.5Wald test after neg binomial regression
Primary
Number of Treatment-emergent Clinically Significant Laboratory Abnormalities on Complete Blood Count.
Safety will be assessed by measuring the number of treatment-emergent clinically significant laboratory abnormalities on Complete Blood Count. Clinical significance will be determined by Medical Safety Monitor and Clinical Investigators.
Time frame: 6-month randomized, double-blind, placebo-controlled phase
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CoA-Z dose 1 | Number of Treatment-emergent Clinically Significant Laboratory Abnormalities on Complete Blood Count. | 0 Abnormal CBC event |
| CoA-Z dose 2 | Number of Treatment-emergent Clinically Significant Laboratory Abnormalities on Complete Blood Count. | 1 Abnormal CBC event |
| CoA-Z dose 3 | Number of Treatment-emergent Clinically Significant Laboratory Abnormalities on Complete Blood Count. | 0 Abnormal CBC event |
| Placebo | Number of Treatment-emergent Clinically Significant Laboratory Abnormalities on Complete Blood Count. | 0 Abnormal CBC event |
Primary
Number of Treatment-emergent Clinically Significant Laboratory Abnormalities on Comprehensive Metabolic Profile.
Safety will be assessed by measuring the number of treatment-emergent clinically significant laboratory abnormalities on Comprehensive Metabolic Profile by collection month. Clinical significance will be determined by Medical Safety Monitor and Clinical Investigators.
Time frame: 6-month randomized, double-blind, placebo-controlled phase
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CoA-Z dose 1 | Number of Treatment-emergent Clinically Significant Laboratory Abnormalities on Comprehensive Metabolic Profile. | 1 Abnormal CMP event |
| CoA-Z dose 2 | Number of Treatment-emergent Clinically Significant Laboratory Abnormalities on Comprehensive Metabolic Profile. | 1 Abnormal CMP event |
| CoA-Z dose 3 | Number of Treatment-emergent Clinically Significant Laboratory Abnormalities on Comprehensive Metabolic Profile. | 0 Abnormal CMP event |
| Placebo | Number of Treatment-emergent Clinically Significant Laboratory Abnormalities on Comprehensive Metabolic Profile. | 0 Abnormal CMP event |
Secondary
CoASY mRNA Expression
Average relative CoASY gene expression, measured as the ratio to baseline of 1 / (2\^\[COASY Ct - 18s Ct\]), where Ct = cycle time and 18s is a housekeeping gene. Values \>1 reflect higher expression.
Time frame: Up to 6 months after first dose
Population: All randomized participants
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| CoA-Z dose 1 | CoASY mRNA Expression | 1 month +3 days after first dose | 1.31 Ratio to baseline |
| CoA-Z dose 1 | CoASY mRNA Expression | 6 months after first dose | 1.07 Ratio to baseline |
| CoA-Z dose 2 | CoASY mRNA Expression | 6 months after first dose | 0.97 Ratio to baseline |
| CoA-Z dose 2 | CoASY mRNA Expression | 1 month +3 days after first dose | 1.13 Ratio to baseline |
| CoA-Z dose 3 | CoASY mRNA Expression | 1 month +3 days after first dose | 1.04 Ratio to baseline |
| CoA-Z dose 3 | CoASY mRNA Expression | 6 months after first dose | 1.02 Ratio to baseline |
| Placebo | CoASY mRNA Expression | 1 month +3 days after first dose | 1.07 Ratio to baseline |
| Placebo | CoASY mRNA Expression | 6 months after first dose | 0.96 Ratio to baseline |
Comparison: Test that high \> med \> low \> placebo vs the null that all groups are equal at 1 month + 3 days after first dose. Adjusted for PKAN type (classical or atypical), because randomization was stratified on type, and time point.p-value: 0.105Linear contrast / test for trend
Comparison: Test that high \> med \> low \> placebo vs the null that all groups are equal at 6 months after first dose. PKAN type (classical or atypical) was included because randomization was stratified on type. The study hypothesis was that expression levels would not vary significantly at this time point.p-value: 0.55Linear contrast / test for trend