JUMP: Cellcept for Treatment of Juvenile Neuronal Ceroid Lipofuscinosis

• Sponsor: University of Rochester (Other)
• Overall Status: Completed
• CT.gov ID: NCT01399047
• Collaborator: Batten Disease Support and Research Assocation (BDSRA) (Other)
• Enrollment: 19
• Location: 1
• Arms: 2
• Duration (Months): 52
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Juvenile Neuronal Ceroid Lipofuscinosis	Drug: Mycophenolate mofetil; Drug: Liquid Placebo	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 19 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Phase II, Randomized, Placebo Controlled Trial of the Safety and Tolerability of Mycophenolate in Children With Juvenile Neuronal Ceroid Lipofuscinosis
• Study Start Date: Jul 1, 2011
• Actual Primary Completion Date: Nov 1, 2015
• Actual Study Completion Date: Nov 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Mycophenolate Mofetil	Drug: Mycophenolate 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.; Other Names: Cellcept
Placebo Comparator: Placebo liquid	Drug: Liquid 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.

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years to 25 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Rochester	Rochester	New York	United States	14642

Sponsors and Collaborators

• University of Rochester
• Batten Disease Support and Research Assocation (BDSRA)

Investigators

• Principal Investigator: Erika F Augustine, MD, University of Rochester

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Erika Augustine, PI, University of Rochester
• ClinicalTrials.gov Identifier: NCT01399047
• Other Study ID Numbers: 3908
• First Posted: Jul 21, 2011
• Last Update Posted: May 21, 2019
• Last Verified: May 1, 2019

• Keywords provided by Erika Augustine, PI, University of Rochester: Batten Disease
• Additional relevant MeSH terms: Neuronal Ceroid-Lipofuscinoses; Mycophenolic Acid

Study Results

Participant Flow

Arm/Group Title	Group A: Mycophenolate to Placebo Crossover	Group B: Placebo to Mycophenolate Crossover
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	10	9
COMPLETED	10	8
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Group A: Mycophenolate to Placebo Crossover	Group B: Placebo to Mycophenolate Crossover	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	10	9	19
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	10.50 (5.99)	14.78 (2.44)	12.53 (5.04)
Sex: Female, Male (Count of Participants)
Female	2 20%	2 22.2%	4 21.1%
Male	8 80%	7 77.8%	15 78.9%
Race/Ethnicity, Customized (Count of Participants)
White/Caucasian	9 90%	8 88.9%	17 89.5%
More than one Race	1 10%	1 11.1%	2 10.5%
Region of Enrollment (participants) [Number]
United States	10 100%	9 100%	19 100%

Outcome Measures

1. Primary Outcome

Title	Tolerability - Number of Participants Who Completed Each Arm on Assigned Study Drug Dose
Description	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

Outcome Measure Data

Analysis Population Description

All subjects.

Arm/Group Title	Mycophenolate	Placebo
Arm/Group Description	Includes data from all subjects while on mycophenolate, regardless of treatment order.	Includes data from all subjects while on placebo, regardless of treatment order.
Measure Participants	19	19
Count of Participants [Participants]	17 170%	19 211.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mycophenolate, Placebo
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.21
	Comments
	Method	Prescott's test
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.105
	Confidence Interval	(2-Sided) 95%; -0.033 to 0.243
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mycophenolate was tolerated in 17/19 subjects (89.5%, 95% CI: 66.9% - 98.7%), while placebo was tolerated in 19/19 subjects (100%, 95% CI: 82.4% - 100%). The difference in tolerability rates was 10.5% (95% CI: -3.3% - 24.3%, p=0.21).

2. Secondary Outcome

Title	Unified Batten Disease Rating Scale Physical Subscale Change
Description	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

Outcome Measure Data

Analysis Population Description

All subjects who completed 8 weeks of the respective treatment arm assignment.

Arm/Group Title	Mycophenolate	Placebo
Arm/Group Description	All data from subjects while on mycophenolate, regardless of treatment order.	All data from subjects while on placebo, regardless of treatment order.
Measure Participants	17	18
Mean (95% Confidence Interval) [units on a scale]	-1.18	2.17

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mycophenolate, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.72
	Comments
	Method	Prescott's test
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.69
	Confidence Interval	(2-Sided) 95%; -4.67 to 3.28
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Unified Batten Disease Rating Scale Seizure Subscale Change
Description	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

Outcome Measure Data

Analysis Population Description

All subjects who completed 8 weeks of the respective treatment arm assignment.

Arm/Group Title	Mycophenolate	Placebo
Arm/Group Description	All data from subjects while on mycophenolate, regardless of treatment order.	All data from subjects while on placebo, regardless of treatment order.
Measure Participants	17	18
Mean (95% Confidence Interval) [units on a scale]	-0.24	-1.44

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mycophenolate
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.78
	Comments
	Method	Prescott's test
	Comments

4. Secondary Outcome

Title	Unified Batten Disease Rating Scale Behavior Subscale Change
Description	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

Outcome Measure Data

Analysis Population Description

All subjects who completed 8 weeks of the respective treatment arm assignment.

Arm/Group Title	Mycophenolate	Placebo
Arm/Group Description	All data from subjects while on mycophenolate, regardless of treatment order.	All data from subjects while on placebo, regardless of treatment order.
Measure Participants	17	18
Mean (95% Confidence Interval) [units on a scale]	-1.28	-0.37

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mycophenolate
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.98
	Comments
	Method	Prescott's test
	Comments

5. Secondary Outcome

Title	Unified Batten Disease Rating Scale Capability Subscale Change
Description	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

Outcome Measure Data

Analysis Population Description

All subjects who completed 8 weeks of the respective treatment arm assignment.

Arm/Group Title	Mycophenolate	Placebo
Arm/Group Description	All data from subjects while on mycophenolate, regardless of treatment order.	All data from subjects while on placebo, regardless of treatment order.
Measure Participants	17	18
Mean (95% Confidence Interval) [units on a scale]	0.33	0.47

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mycophenolate
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.26
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Adverse Event Reporting Description	Reporting of adverse events were sought at each encounter and were considered in the evaluation of each safety assessment (laboratory studies, electrophysiology).
Arm/Group Title	Mycophenolate		Placebo
Arm/Group Description	Includes data from all subjects while on mycophenolate, regardless of order.		Includes data from all subjects while on placebo, regardless of order.
All Cause Mortality
	Mycophenolate		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Mycophenolate		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/19 (5.3%)		0/19 (0%)
Metabolism and nutrition disorders
Hyperkalemia	1/19 (5.3%)	1	0/19 (0%)	0
Other (Not Including Serious) Adverse Events
	Mycophenolate		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/19 (73.7%)		17/19 (89.5%)
Cardiac disorders
ECG Abnormality	0/19 (0%)	0	1/19 (5.3%)	1
Ear and labyrinth disorders
Haemotympanum	1/19 (5.3%)	1	0/19 (0%)	0
Ear pain	0/19 (0%)	0	1/19 (5.3%)	1
Endocrine disorders
Weight decreased	1/19 (5.3%)	1	0/19 (0%)	0
Eye disorders
Photophobia	0/19 (0%)	0	1/19 (5.3%)	1
Gastrointestinal disorders
Vomiting	6/19 (31.6%)	8	2/19 (10.5%)	3
Diarrhea	3/19 (15.8%)	3	2/19 (10.5%)	2
Abdominal pain upper	1/19 (5.3%)	1	0/19 (0%)	0
Gastroesophageal reflux disease	1/19 (5.3%)	1	0/19 (0%)	0
Retching	1/19 (5.3%)	1	0/19 (0%)	0
Abdominal Discomfort	0/19 (0%)	0	1/19 (5.3%)	1
Abdominal Pain	0/19 (0%)	0	1/19 (5.3%)	1
General disorders
Oedema peripheral	0/19 (0%)	0	1/19 (5.3%)	1
Chest pain	1/19 (5.3%)	1	0/19 (0%)	0
Fatigue	1/19 (5.3%)	1	1/19 (5.3%)	1
Infections and infestations
Otitis media	1/19 (5.3%)	1	1/19 (5.3%)	1
Strep pharyngitis	1/19 (5.3%)	1	0/19 (0%)	0
Sinusitis	1/19 (5.3%)	1	1/19 (5.3%)	1
Upper Respiratory Infection	2/19 (10.5%)	2	0/19 (0%)	0
Conjunctivitis	0/19 (0%)	0	1/19 (5.3%)	1
Gingivitis	0/19 (0%)	0	1/19 (5.3%)	1
Ear Infection	0/19 (0%)	0	1/19 (5.3%)	1
Otitis externa	0/19 (0%)	0	1/19 (5.3%)	1
Investigations
Blood prolactin increased	1/19 (5.3%)	1	0/19 (0%)	0
Weight increased	2/19 (10.5%)	2	1/19 (5.3%)	1
Blood calcium decreased	0/19 (0%)	0	1/19 (5.3%)	1
Cardiac murmur	0/19 (0%)	0	1/19 (5.3%)	1
Electrocardiogram abnormality	0/19 (0%)	0	1/19 (5.3%)	1
Electrocardiogram T wave inversion	0/19 (0%)	0	1/19 (5.3%)	1
Protein urine present	0/19 (0%)	0	1/19 (5.3%)	1
Metabolism and nutrition disorders
Decreased appetite	0/19 (0%)	0	2/19 (10.5%)	2
Hypoglycemia	0/19 (0%)	0	1/19 (5.3%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	1/19 (5.3%)	1	0/19 (0%)	0
Muscle Stiffness	1/19 (5.3%)	1	0/19 (0%)	0
Muscle twitching	1/19 (5.3%)	1	0/19 (0%)	0
Back pain	0/19 (0%)	0	1/19 (5.3%)	1
Musculoskeletal pain	0/19 (0%)	0	1/19 (5.3%)	1
Pain in extremity	0/19 (0%)	0	1/19 (5.3%)	1
Nervous system disorders
Headache	3/19 (15.8%)	3	3/19 (15.8%)	3
Tremor	2/19 (10.5%)	2	0/19 (0%)	0
Dyskinesia	1/19 (5.3%)	1	1/19 (5.3%)	1
Insomnia	1/19 (5.3%)	1	1/19 (5.3%)	1
Aphasia	0/19 (0%)	0	1/19 (5.3%)	1
Convulsion	0/19 (0%)	0	1/19 (5.3%)	1
Disorientation	0/19 (0%)	0	1/19 (5.3%)	1
Dysarthria	0/19 (0%)	0	1/19 (5.3%)	1
Motor dysfunction	0/19 (0%)	0	2/19 (10.5%)	2
Movement disorder	0/19 (0%)	0	1/19 (5.3%)	1
Seizure	0/19 (0%)	0	1/19 (5.3%)	1
Speech disorder	0/19 (0%)	0	1/19 (5.3%)	1
Dizziness	1/19 (5.3%)	1	1/19 (5.3%)	1
Ataxia	2/19 (10.5%)	2	0/19 (0%)	0
Psychiatric disorders
Abnormal behavior	1/19 (5.3%)	1	1/19 (5.3%)	1
Mental status changes	1/19 (5.3%)	1	0/19 (0%)	0
Mood altered	1/19 (5.3%)	1	0/19 (0%)	0
Aggression	0/19 (0%)	0	2/19 (10.5%)	2
Anger	0/19 (0%)	0	1/19 (5.3%)	1
Anxiety	0/19 (0%)	0	2/19 (10.5%)	2
Confusional state	0/19 (0%)	0	1/19 (5.3%)	1
Irritability	0/19 (0%)	0	1/19 (5.3%)	1
Nightmare	0/19 (0%)	0	1/19 (5.3%)	1
Perseveration	0/19 (0%)	0	1/19 (5.3%)	1
Renal and urinary disorders
Haematuria	1/19 (5.3%)	1	0/19 (0%)	0
Urinary incontinence	0/19 (0%)	0	1/19 (5.3%)	1
Respiratory, thoracic and mediastinal disorders
Cough	3/19 (15.8%)	3	1/19 (5.3%)	1
Oropharyngeal pain	1/19 (5.3%)	1	2/19 (10.5%)	2
Rhinorrhea	0/19 (0%)	0	1/19 (5.3%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.