Juvenile Neuronal Ceroid Lipofuscinosis
Conditions
Keywords
Batten Disease
Brief summary
The primary objective of this trial is to establish the safety and tolerability of short-term (8 weeks) administration of mycophenolate mofetil in ambulatory children with JNCL. The secondary objective is to gather preliminary evidence of the short-term (8 week) impact of mycophenolate mofetil on clinically relevant features of JNCL as measured by the Unified Batten Disease Rating Scale (UBDRS), including motor features, seizures, behavior, cognitive and functional measures. Funding source-FDA Office of Orphan Product Development (OOPD).
Detailed description
Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) is a fatal disorder. Currently treatment is symptomatic. Thus, there is a real need to intervene and slow the progression of this disease. Preliminary data on genetic knock-down of the ability to mount an immune response in cln3-knockout mice is supportive of a strategy for treating JNCL with an immuno-suppressive agent. Many drugs with the ability to suppress the immune system are steroidal and deemed unsuitable for long-term administration to children. Mycophenolate mofetil (CellCept) is used as an immunosuppressive agent in allogenic transplants in pediatric patients and is therefore approved by the Food and Drug Administration (FDA) for pediatric use. The study design is a double-blind, randomized, 22-week cross-over study of mycophenolate mofetil vs. placebo. After a 4-week washout period, subjects will undergo blinded crossover from active study drug to placebo or from placebo to active study drug. Subjects and caregivers will be evaluated in person in the University of Rochester Batten Center (URBC) at screening/baseline, and at weeks 8, 12, and 20. In addition, subjects will be evaluated by their local clinician who is a formalized member of the research team. Such contacts will occur at Weeks 2, 4, 14, 16, and any unscheduled or early termination visits. There will also be regular telephone contact between the URBC and the local clinician. We have selected the dosage currently FDA approved for use in children being treated for prophylaxis of renal transplant rejection.
Interventions
DRUGMycophenolate mofetil
The liquid dosage will be individualized, contingent upon the subject's weight. Subjects will receive 50% of the target dose (300mg/m2/dose BID) during Week 0-Week 2, then increase to the full dose (600mg/m2/dose BID) in Week 3, continuing at this dose through Week 8. Additionally, due to the risk of gastrointestinal disturbance (hemorrhage, ulcer), children will also receive prophylactic Prilosec (Omeprazole) for the duration of the study, during both the mycophenolate and placebo arms.
DRUGLiquid Placebo
The dosage will be individualized, contingent upon the subject's weight. Subjects will receive 50% of the target dose (300mg/m2/dose BID) during Week 0-Week 2, then increase to the full dose (600mg/m2/dose BID) in Week 3, continuing at this dose through Week 8. Additionally, due to the risk of gastrointestinal disturbance (hemorrhage, ulcer), children will also receive prophylactic Prilosec (omeprazole) for the duration of the study, during both the mycophenolate and placebo arms.
Sponsors
Batten Disease Support and Research Assocation (BDSRA)
University of Rochester
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Years to 25 Years
Healthy volunteers
No
Inclusion criteria
* JNCL as determined by a characteristic clinical presentation and confirmatory genetic evidence. * Able to walk 10 feet without assistance beyond that required due to vision impairment. * Subjects with local treating clinician (pediatrician or neurologist) willing to conduct the trial according to the protocol, good clinical practice, and applicable regulations. * Subjects with a parent/legal guardian willing to accompany them to all study visits, oversee study drug compliance, and monitor and report to local treating clinician/investigator and the URBC investigative personnel any signs of adversity.
Exclusion criteria
* Inability to tolerate oral administration of medications * Concomitant medical condition, which, in the opinion of the local treating clinician, the parent(s)/guardian, or the URBC study investigator would place the child at greater than acceptable risk from: 1) travel by plane or car to the URBC on four occasions over the course of 22 weeks, 2) exposure to mycophenolate mofetil at protocol defined dosages for periods up to 8 weeks. * Anticipated inability of the child (on the part of the investigator, parent/guardian, or URBC study personnel) to comply with the rigors of the protocol.. * Use of disallowed concomitant medications. * Administration of immunosuppressive medications * History of any prior exposure to mycophenolate mofetil * History of hypersensitivity to mycophenolate mofetil, or any other component of the product * History of frank gastrointestinal hemorrhage, ulceration, or melena * White blood cell count \< 3000/μL, absolute neutrophil count (ANC) \< 1500/μL, hemoglobin \< 10g/dL, or thrombocytopenia \<100,000/μL. * Abnormal liver function (aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or bilirubin greater than 3 times the upper limit of normal) * Pregnancy or vulnerability to engage in sexual intercourse based on report of the parent/guardian, judgment of the local treating clinician/investigator or judgment of the URBC study personnel. * Positive Tuberculosis test * Immunizations not up to date for age according to Centers for Disease Control guidelines
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tolerability - Number of Participants Who Completed Each Arm on Assigned Study Drug Dose | Baseline to 8 weeks | The primary outcome measure is tolerability, defined as the completion of 8 weeks on the assigned dosage of study drug. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Unified Batten Disease Rating Scale Physical Subscale Change | Baseline to 8 weeks | The Unified Batten Disease Rating Scale (UBDRS) is a disease-specific clinical assessment. Motor impairment was measured by the physical subscale of the UBDRS with a range of 0-112 with zero indicating better outcome. The overall treatment effect was determined - mean difference in physical subscale change (Mycophenolate minus placebo periods) in outcome, adjusted for baseline value and period effects. |
| Unified Batten Disease Rating Scale Seizure Subscale Change | Baseline to 8 weeks | The Unified Batten Disease Rating Scale (UBDRS) is a disease-specific clinical assessment. Seizure severity was measured by the seizure subscale of the UBDRS with a range of 0-54 with zero indicating better outcome. The overall treatment effect was determined - mean difference in seizure subscale change (Mycophenolate minus placebo periods) in outcome, adjusted for baseline value and period effects. |
| Unified Batten Disease Rating Scale Behavior Subscale Change | Baseline to 8 weeks | The Unified Batten Disease Rating Scale (UBDRS) is a disease-specific clinical assessment. Mood and behavior severity was measured by the behavior subscale of the UBDRS with a range of 0-55 with zero indicating better outcome. The overall treatment effect was determined - mean difference in behavior subscale change (Mycophenolate minus placebo periods) in outcome, adjusted for baseline value and period effects. |
| Unified Batten Disease Rating Scale Capability Subscale Change | Baseline to 8 weeks | The Unified Batten Disease Rating Scale (UBDRS) is a disease-specific clinical assessment. Capability severity was measured by the capability subscale of the UBDRS with a range of 0-14 with higher scores indicating better outcome. The overall treatment effect was determined - mean difference in capability subscale change (Mycophenolate minus placebo periods) in outcome, adjusted for baseline value and period effects. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group A: Mycophenolate to Placebo Crossover Subjects received one treatment period (8 weeks) of mycophenolate, then, after a 4-week washout, received one treatment period (8 weeks) of placebo, in a blinded manner. | 10 |
| Group B: Placebo to Mycophenolate Crossover Subjects received one treatment period (8 weeks) of placebo, then, after a 4-week washout, received one treatment period (8 weeks) of mycophenolate, in a blinded manner. | 9 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Group A: Mycophenolate to Placebo Crossover | Group B: Placebo to Mycophenolate Crossover | Total |
|---|---|---|---|
| Age, Continuous | 10.50 years STANDARD_DEVIATION 5.99 | 14.78 years STANDARD_DEVIATION 2.44 | 12.53 years STANDARD_DEVIATION 5.04 |
| Race/Ethnicity, Customized Race More than one Race | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Race White/Caucasian | 9 Participants | 8 Participants | 17 Participants |
| Region of Enrollment United States | 10 participants | 9 participants | 19 participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 8 Participants | 7 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 14 / 19 | 17 / 19 |
| serious Total, serious adverse events | 1 / 19 | 0 / 19 |
Outcome results
Primary
Tolerability - Number of Participants Who Completed Each Arm on Assigned Study Drug Dose
The primary outcome measure is tolerability, defined as the completion of 8 weeks on the assigned dosage of study drug.
Time frame: Baseline to 8 weeks
Population: All subjects.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Mycophenolate | Tolerability - Number of Participants Who Completed Each Arm on Assigned Study Drug Dose | 17 Participants |
| Placebo | Tolerability - Number of Participants Who Completed Each Arm on Assigned Study Drug Dose | 19 Participants |
Comparison: The primary outcome variable was tolerability, defined as the proportion of subjects able to complete 8 weeks on the assigned treatment. Tolerability was compared among the treatment groups using Prescott's test. A 95% confidence interval was computed for the tolerability of mycophenolate, placebo, and their difference.p-value: 0.2195% CI: [-0.033, 0.243]Prescott's test
Secondary
Unified Batten Disease Rating Scale Behavior Subscale Change
The Unified Batten Disease Rating Scale (UBDRS) is a disease-specific clinical assessment. Mood and behavior severity was measured by the behavior subscale of the UBDRS with a range of 0-55 with zero indicating better outcome. The overall treatment effect was determined - mean difference in behavior subscale change (Mycophenolate minus placebo periods) in outcome, adjusted for baseline value and period effects.
Time frame: Baseline to 8 weeks
Population: All subjects who completed 8 weeks of the respective treatment arm assignment.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Mycophenolate | Unified Batten Disease Rating Scale Behavior Subscale Change | -1.28 units on a scale |
| Placebo | Unified Batten Disease Rating Scale Behavior Subscale Change | -0.37 units on a scale |
p-value: 0.98Prescott's test
Secondary
Unified Batten Disease Rating Scale Capability Subscale Change
The Unified Batten Disease Rating Scale (UBDRS) is a disease-specific clinical assessment. Capability severity was measured by the capability subscale of the UBDRS with a range of 0-14 with higher scores indicating better outcome. The overall treatment effect was determined - mean difference in capability subscale change (Mycophenolate minus placebo periods) in outcome, adjusted for baseline value and period effects.
Time frame: Baseline to 8 weeks
Population: All subjects who completed 8 weeks of the respective treatment arm assignment.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Mycophenolate | Unified Batten Disease Rating Scale Capability Subscale Change | 0.33 units on a scale |
| Placebo | Unified Batten Disease Rating Scale Capability Subscale Change | 0.47 units on a scale |
p-value: 0.26Wilcoxon (Mann-Whitney)
Secondary
Unified Batten Disease Rating Scale Physical Subscale Change
The Unified Batten Disease Rating Scale (UBDRS) is a disease-specific clinical assessment. Motor impairment was measured by the physical subscale of the UBDRS with a range of 0-112 with zero indicating better outcome. The overall treatment effect was determined - mean difference in physical subscale change (Mycophenolate minus placebo periods) in outcome, adjusted for baseline value and period effects.
Time frame: Baseline to 8 weeks
Population: All subjects who completed 8 weeks of the respective treatment arm assignment.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Mycophenolate | Unified Batten Disease Rating Scale Physical Subscale Change | -1.18 units on a scale |
| Placebo | Unified Batten Disease Rating Scale Physical Subscale Change | 2.17 units on a scale |
p-value: 0.7295% CI: [-4.67, 3.28]Prescott's test
Secondary
Unified Batten Disease Rating Scale Seizure Subscale Change
The Unified Batten Disease Rating Scale (UBDRS) is a disease-specific clinical assessment. Seizure severity was measured by the seizure subscale of the UBDRS with a range of 0-54 with zero indicating better outcome. The overall treatment effect was determined - mean difference in seizure subscale change (Mycophenolate minus placebo periods) in outcome, adjusted for baseline value and period effects.
Time frame: Baseline to 8 weeks
Population: All subjects who completed 8 weeks of the respective treatment arm assignment.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Mycophenolate | Unified Batten Disease Rating Scale Seizure Subscale Change | -0.24 units on a scale |
| Placebo | Unified Batten Disease Rating Scale Seizure Subscale Change | -1.44 units on a scale |
p-value: 0.78Prescott's test