Trial Outcomes & Findings for Treatment of Sunflower Syndrome With ZX008 (Fenfluramine Hydrochloride) in Children and Young Adults (Ages 4-25). (NCT NCT03790137)
NCT ID: NCT03790137
Last Updated: 2024-11-06
Results Overview
The number of handwaving episodes (seizures) per day were recorded on a seizure diary by either the subject or the parent of the subject. One handwaving episode was defined as the period starting from when the hand first came up toward the face, until there was a brief pause in waving. Subjects and their caregivers were instructed to record the total number of handwaving episodes each day during a one month baseline, and during the 3 month treatment period. The baseline seizure frequency was calculated as an average of the reported handwaving episodes per day during the baseline period. This number was compared to the average episodes per day for the final month of the study (month 3 of treatment with fenfluramine) for each patient. The median percent change in frequency of handwaving episodes across all patients is reported below.
COMPLETED
PHASE3
20 participants
Month 3
2024-11-06
Participant Flow
After signing consent and enrolling in the study, all patients underwent a baseline echocardiogram, as well as baseline labs. If there were abnormal findings, patients were excluded from participation due to concerns of cardiac toxicity with fenfluramine.
Participant milestones
| Measure |
Treatment Group
The treatment group will include approximately 20 pediatric and young adult patients (ages 4-25 years) seen by Elizabeth A. Thiele, M.D., Ph.D. at MGH's Pediatric Epilepsy Clinic. Subjects will be treated on an outpatient basis and will not require hospital admission. The treatment group will undergo a one month baseline, and then will take the investigational new drug, fenfluramine, for at least 84 days (\~3 months). They will remain on treatment beyond the core study if fenfluramine is deemed effective and well-tolerated.
Fenfluramine: Fenfluramine will be supplied to the treatment group as an oral solution. Subjects will receive their daily dose of Fenfluramine in two doses (one in the morning and one in the evening). After a four week baseline, all subjects that meet enrollment criteria will enter a titration period. The starting dose will be 0.2 mg/kg/day for the first 14 days. The dose will be increased every 2 weeks as tolerated by 0.2 mg/kg/day, to a maximum dose of 0.7 mg/kg/day (total maximum dose: 26 mg/day). The subjects will remain on a maximum dose for the duration of the core study.
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Overall Study
STARTED
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20
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Overall Study
COMPLETED
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19
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Overall Study
NOT COMPLETED
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1
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Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
Race and Ethnicity were not collected from any participant.
Baseline characteristics by cohort
| Measure |
Treatment Group
n=20 Participants
The treatment group will include approximately 20 pediatric and young adult patients (ages 4-25 years) with Sunflower syndrome seen by Elizabeth A. Thiele, M.D., Ph.D. at MGH's Pediatric Epilepsy Clinic. Subjects will be treated on an outpatient basis and will not require hospital admission. The treatment group will receive the investigational new drug, Fenfluramine Hydrochloride during the core study and may proceed to an extension phase of the study if there is perceived benefit.
Fenfluramine Hydrochloride: Fenfluramine Hydrochloride will be supplied to the treatment group as an oral solution in a concentration of 2.5 mg/mL. Subjects will receive their daily dose of Fenfluramine Hydrochloride in two doses (one in the morning and one in the evening). After a four week baseline, subjects that meet enrollment criteria will enter a titration period. The starting dose will be 0.2 mg/kg/day for the first 14 days. The dose will be increased every 2 weeks as tolerated by 0.2 mg/kg/day, to a maximum dose of 0.7 mg/kg/day, or a total maximum dose of 26 mg/day. The subject will remain on a dose of 0.7 mg/kg/day, 26 mg/day, or maximum tolerated daily dose for the duration of the core study.
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Age, Continuous
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11.9 years
n=20 Participants
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Sex: Female, Male
Female
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15 Participants
n=20 Participants
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Sex: Female, Male
Male
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5 Participants
n=20 Participants
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Region of Enrollment
United States
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20 participants
n=20 Participants
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PRIMARY outcome
Timeframe: Month 3Population: One patient withdrew from the study 3 days after starting study medication. This patient developed a rash, which was not thought to be related to study medication. The patient chose not to challenge the drug at an allergists office, and instead withdrew from the study. The other 19 patients completed the core study, but only 17 provided analyzable seizure data.
The number of handwaving episodes (seizures) per day were recorded on a seizure diary by either the subject or the parent of the subject. One handwaving episode was defined as the period starting from when the hand first came up toward the face, until there was a brief pause in waving. Subjects and their caregivers were instructed to record the total number of handwaving episodes each day during a one month baseline, and during the 3 month treatment period. The baseline seizure frequency was calculated as an average of the reported handwaving episodes per day during the baseline period. This number was compared to the average episodes per day for the final month of the study (month 3 of treatment with fenfluramine) for each patient. The median percent change in frequency of handwaving episodes across all patients is reported below.
Outcome measures
| Measure |
Treatment Group
n=17 Participants
The treatment group will include approximately 20 pediatric and young adult patients (ages 4-25 years) with Sunflower syndrome.
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% Change in Frequency of Handwaving Episodes
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-66.2 % change in hand waving episodes
Interval -78.7 to -31.3
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PRIMARY outcome
Timeframe: Month 3Population: 10 of the 20 patients reported having a generalized tonic-clonic seizure at some point in their lives.
Daily seizure logs will be maintained by either the subject or the parent of the subject and used to calculate seizure frequency. Frequency of Generalized Tonic-clonic seizures was recorded as an average number of seizures/day. The average number of tonic-clonic seizures per day during the baseline period was compared to the average number of tonic-clonic seizures per day during the final month (month 3) for each patient that had experienced at least one tonic-clonic seizure in their lifetime.
Outcome measures
| Measure |
Treatment Group
n=10 Participants
The treatment group will include approximately 20 pediatric and young adult patients (ages 4-25 years) with Sunflower syndrome.
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Change in Frequency of Generalized Tonic-clonic Seizures
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0 tonic-clonic seizures/day
Interval 0.0 to 0.0
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SECONDARY outcome
Timeframe: Month 3Population: The investigators read and interpreted pre-drug and post-drug EEGs for the first 9 patients that completed the core study. The remaining 10 patients did not undergo EEGs as part of this study, due to safety concerns during the COVID-19 pandemic.
The investigators will read and interpret pre-drug (baseline) and post-drug EEGs (month 3 of core study) for the first 9 patients. The average number of spikes/hour across these patients will be reported for both pre- and post-treatment EEGs.
Outcome measures
| Measure |
Treatment Group
n=9 Participants
The treatment group will include approximately 20 pediatric and young adult patients (ages 4-25 years) with Sunflower syndrome.
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Change in Spike Frequency on EEG
Pre-Treatment
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73.9 spikes/hour
Interval 0.0 to 277.2
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Change in Spike Frequency on EEG
Post-Treatment
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50.4 spikes/hour
Interval 0.0 to 187.2
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SECONDARY outcome
Timeframe: Month 3Population: The investigators read and interpreted pre-drug and post-drug EEGs for the first 9 patients that completed the core study. The remaining 10 patients did not undergo EEGs as part of this study, due to safety concerns during the COVID-19 pandemic.
The investigators will read and interpret pre- (baseline) and post-treatment (month 3) EEGs. The number of patients that experienced a photoparoxysmal response during the EEGs will be reported.
Outcome measures
| Measure |
Treatment Group
n=9 Participants
The treatment group will include approximately 20 pediatric and young adult patients (ages 4-25 years) with Sunflower syndrome.
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Number of Patients That Experienced a Photoparoxysmal Response on EEG
Baseline EEG (pre-treatment)
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5 Participants
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Number of Patients That Experienced a Photoparoxysmal Response on EEG
Month 3 EEG (post-treatment)
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3 Participants
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SECONDARY outcome
Timeframe: Month 3 (~84 days after the first dose of fenfluramine.)Population: 9 of the first 10 patients completed the core study. The second 10 patients did not undergo neuropsychological testing as part of this study due to safety concerns during the COVID-19 pandemic.
The Weschler Abbreviated Scale of Intelligence (WASI-II subtests) will be administered to the first 10 patients at baseline and 84 days after the start of the first dose of study drug. Results of these cognitive tests will be compared between baseline and 84 days post initial dose. The WASI-II measures cognitive functioning through 2 subtests, vocabulary and matrix reasoning. The raw scores on these subtests are combined to give a composite full-scale IQ (FSIQ) that is scaled to an average of 100 and standard deviation of 15. Maximum raw scores for the subtests are as follows (higher values are considered better and minimum score on each is 0). Vocabulary: ages 7-11: 47 ages 12-14: 53 ages 15-25: 59 Matrix Reasoning: ages 6-8: 24 ages 9-25: 30
Outcome measures
| Measure |
Treatment Group
n=9 Participants
The treatment group will include approximately 20 pediatric and young adult patients (ages 4-25 years) with Sunflower syndrome.
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Changes in Cognitive Functioning Determined by the Weschler Abbreviated Scale of Intelligence (WASI-II Subtests)
Baseline
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97.89 score on a scale
Standard Deviation 13.53
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Changes in Cognitive Functioning Determined by the Weschler Abbreviated Scale of Intelligence (WASI-II Subtests)
Month 3
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106.22 score on a scale
Standard Deviation 11.64
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SECONDARY outcome
Timeframe: Month 3 (approximately 84 days after the first dose of fenfluramine)Population: 9 of the first 10 patients underwent neuropsychological testing as part of the core study. The remaining patients did not undergo this testing due to safety concerns during the COVID-19 pandemic.
The Weschler Intelligence Scale for Children (WISC-V) -Processing Speed subtests will be administered at baseline and 84 days after the start of the first dose of study drug (Month 3; visit 5). Results of these cognitive tests will be compared between baseline and 84 days post initial dose. Raw scores for the coding and symbol search subtests will be used to evaluate processing speed. The maximum raw scores are as follows (the minimum score is 0 and higher scores are considered better). Coding: ages 6-7: 65 ages 8-16: 119 Symbol search: ages 6-7: 45 ages 8-16: 60
Outcome measures
| Measure |
Treatment Group
n=9 Participants
The treatment group will include approximately 20 pediatric and young adult patients (ages 4-25 years) with Sunflower syndrome.
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Changes in Cognitive Functioning Determined by the Weschler Intelligence Scale for Children (WISC-V) -Processing Speed Subtests.
Baseline
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89.63 score on a scale
Standard Deviation 9.12
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Changes in Cognitive Functioning Determined by the Weschler Intelligence Scale for Children (WISC-V) -Processing Speed Subtests.
Month 3
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92.14 score on a scale
Standard Deviation 10.48
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SECONDARY outcome
Timeframe: Month 3 (approximately 84 days after first dose of fenfluramine)Population: 8 of the first 9 patients completed this testing as part of the core study. The remaining patients did not undergo this testing due to safety concerns during the COVID-19 pandemic.
The Quality of Life in Childhood Epilepsy Questionnaire will be administered at baseline, and 84 days after the first dose (Month 3; visit 5). This questionnaire assesses mood, social relationships, and behaviors. Results will be compared. The QOLCE assesses quality of life across 4 domains of functioning: cognitive, emotional, social and physical. Scores range from 0-100. Composite scores are calculated as a mean across all measures.
Outcome measures
| Measure |
Treatment Group
n=8 Participants
The treatment group will include approximately 20 pediatric and young adult patients (ages 4-25 years) with Sunflower syndrome.
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Changes in Quality of Life Determined by the Quality of Life in Childhood Epilepsy Questionnaire(QOLCE-16)
Baseline
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60.41 score on a scale
Standard Deviation 18.88
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Changes in Quality of Life Determined by the Quality of Life in Childhood Epilepsy Questionnaire(QOLCE-16)
Month 3
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60.76 score on a scale
Standard Deviation 17.48
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SECONDARY outcome
Timeframe: Month 3 (approximately 84 days after the first dose of fenfluramine)Population: 7 of the first 9 patients provided pre- and post-treatment responses to the BRIEF questionnaire. The remaining patients did not undergo this testing due to safety concerns during the COVID-19 pandemic.
The Behavioral Rating Inventory of Executive Function (BRIEF) questionnaire will be administered at baseline, and 84 days after the first dose of fenfluramine (Month 3; Visit 5). This questionnaire assesses executive function across 8 clinical scales: 1. Inhibit 2. Shift 3. Emotional Control 4. Initiate 5. Working Memory 6. Plan/Organize 7. Organization of Materials 8. Monitor Item level scores are rated on a 3 point Likert Scale from 1-3: 1. Never 2. Sometimes 3. Often The Global Executive Composite (GEC) score is the total score of all 8 clinical subscales. The item scores are summed for each scale and raw scores are converted to Tscores. The mean of the GEC score will be reported. T scores from 60 to 64 are considered mildly elevated. T scores from 65 to 69 are considered potentially clinically elevated. T scores at or above 70 are considered clinically elevated.
Outcome measures
| Measure |
Treatment Group
n=7 Participants
The treatment group will include approximately 20 pediatric and young adult patients (ages 4-25 years) with Sunflower syndrome.
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Changes in Executive Functioning Determined by The Behavioral Rating Inventory of Executive Function (BRIEF) Questionnaire.
Baseline Score
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61.29 T Score
Standard Deviation 13.62
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Changes in Executive Functioning Determined by The Behavioral Rating Inventory of Executive Function (BRIEF) Questionnaire.
Month 3 Score
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58.50 T Score
Standard Deviation 15.84
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SECONDARY outcome
Timeframe: Month 3 (approximately 84 days after first dose of fenfluramine)Population: 7 of the first 9 patients provided pre- and post-treatment responses to the Beck Self Report Inventory. The remaining patients did not undergo this testing due to safety concerns during the COVID-19 pandemic.
The Beck Self Report Inventory will be administered at baseline, and 84 days after the first dose (Month 3; Visit 5). This questionnaire assesses self-concept, depression, anxiety, anger and disruptive behavior through a 100-item self-report. The raw scores for subscales are calculated in the following manner: * Add scores from Items 1-20 for the total Beck Self Concept Inventory for Youth (BSCI-Y) score. * Add scores from Items 21-40 for the total Beck Anxiety Inventory for Youth (BAI-Y) score. * Add scores from Items 41-60 for the total Beck Depression Inventory for Youth (BDI-Y) score. * Add scores from Items 61-80 for the total Beck Anger Inventory for Youth (BANI-Y) score. * Add scores from Items 81-100 for the total Beck Disruptive Inventory for Youth (BDBI-Y) score. Raw scores will be translated into T-scores. T-scores for BYI are as follows: * 55 or less = average * 55-59 = mildly elevated * 60-69 = moderately elevated * 70+ = extremely elevated
Outcome measures
| Measure |
Treatment Group
n=7 Participants
The treatment group will include approximately 20 pediatric and young adult patients (ages 4-25 years) with Sunflower syndrome.
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Changes in Self-Concept Determined by The Beck Self Report Inventory.
Baseline Score
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44.43 T-Score
Standard Deviation 13.43
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Changes in Self-Concept Determined by The Beck Self Report Inventory.
Month 3 Score
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52.88 T-Score
Standard Deviation 14.23
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SECONDARY outcome
Timeframe: Month 3The Beck Self Report Inventory will be administered at baseline, and 84 days after the first dose (Month 3; Visit 5). This questionnaire assesses self-concept, depression, anxiety, anger and disruptive behavior through a 100-item self-report. The raw scores for subscales are calculated in the following manner: * Add scores from Items 1-20 for the total Beck Self Concept Inventory for Youth (BSCI-Y) score. * Add scores from Items 21-40 for the total Beck Anxiety Inventory for Youth (BAI-Y) score. * Add scores from Items 41-60 for the total Beck Depression Inventory for Youth (BDI-Y) score. * Add scores from Items 61-80 for the total Beck Anger Inventory for Youth (BANI-Y) score. * Add scores from Items 81-100 for the total Beck Disruptive Inventory for Youth (BDBI-Y) score. Raw scores will be translated into T-scores. T-scores for BYI are as follows: * 55 or less = average * 55-59 = mildly elevated * 60-69 = moderately elevated * 70+ = extremely elevated
Outcome measures
| Measure |
Treatment Group
n=7 Participants
The treatment group will include approximately 20 pediatric and young adult patients (ages 4-25 years) with Sunflower syndrome.
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Changes in Anxiety Determined by the Beck Self Report Inventory
Baseline Score
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47.29 T score
Standard Deviation 8.20
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Changes in Anxiety Determined by the Beck Self Report Inventory
Month 3 Score
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45.13 T score
Standard Deviation 5.91
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SECONDARY outcome
Timeframe: Month 3The Beck Self Report Inventory will be administered at baseline, and 84 days after the first dose (Month 3; Visit 5). This questionnaire assesses self-concept, depression, anxiety, anger and disruptive behavior through a 100-item self-report. The raw scores for subscales are calculated in the following manner: * Add scores from Items 1-20 for the total Beck Self Concept Inventory for Youth (BSCI-Y) score. * Add scores from Items 21-40 for the total Beck Anxiety Inventory for Youth (BAI-Y) score. * Add scores from Items 41-60 for the total Beck Depression Inventory for Youth (BDI-Y) score. * Add scores from Items 61-80 for the total Beck Anger Inventory for Youth (BANI-Y) score. * Add scores from Items 81-100 for the total Beck Disruptive Inventory for Youth (BDBI-Y) score. Raw scores will be translated into T-scores. T-scores for BYI are as follows: * 55 or less = average * 55-59 = mildly elevated * 60-69 = moderately elevated * 70+ = extremely elevated
Outcome measures
| Measure |
Treatment Group
n=7 Participants
The treatment group will include approximately 20 pediatric and young adult patients (ages 4-25 years) with Sunflower syndrome.
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Changes in Depression Determined by the Beck Self Report Inventory
Baseline Score
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49.29 T score
Standard Deviation 12.38
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Changes in Depression Determined by the Beck Self Report Inventory
Month 3 Score
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47.13 T score
Standard Deviation 11.72
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SECONDARY outcome
Timeframe: Month 3The Beck Self Report Inventory will be administered at baseline, and 84 days after the first dose (Month 3; Visit 5). This questionnaire assesses self-concept, depression, anxiety, anger and disruptive behavior through a 100-item self-report. The raw scores for subscales are calculated in the following manner: * Add scores from Items 1-20 for the total Beck Self Concept Inventory for Youth (BSCI-Y) score. * Add scores from Items 21-40 for the total Beck Anxiety Inventory for Youth (BAI-Y) score. * Add scores from Items 41-60 for the total Beck Depression Inventory for Youth (BDI-Y) score. * Add scores from Items 61-80 for the total Beck Anger Inventory for Youth (BANI-Y) score. * Add scores from Items 81-100 for the total Beck Disruptive Inventory for Youth (BDBI-Y) score. Raw scores will be translated into T-scores. T-scores for BYI are as follows: * 55 or less = average * 55-59 = mildly elevated * 60-69 = moderately elevated * 70+ = extremely elevated
Outcome measures
| Measure |
Treatment Group
n=7 Participants
The treatment group will include approximately 20 pediatric and young adult patients (ages 4-25 years) with Sunflower syndrome.
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Changes in Anger Determined by the Beck Self Report Inventory
Baseline Score
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45.00 T score
Standard Deviation 7.87
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Changes in Anger Determined by the Beck Self Report Inventory
Month 3 Score
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41.75 T score
Standard Deviation 5.52
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SECONDARY outcome
Timeframe: Month 3The Beck Self Report Inventory will be administered at baseline, and 84 days after the first dose (Month 3; Visit 5). This questionnaire assesses self-concept, depression, anxiety, anger and disruptive behavior through a 100-item self-report. The raw scores for subscales are calculated in the following manner: * Add scores from Items 1-20 for the total Beck Self Concept Inventory for Youth (BSCI-Y) score. * Add scores from Items 21-40 for the total Beck Anxiety Inventory for Youth (BAI-Y) score. * Add scores from Items 41-60 for the total Beck Depression Inventory for Youth (BDI-Y) score. * Add scores from Items 61-80 for the total Beck Anger Inventory for Youth (BANI-Y) score. * Add scores from Items 81-100 for the total Beck Disruptive Inventory for Youth (BDBI-Y) score. Raw scores will be translated into T-scores. T-scores for BYI are as follows: * 55 or less = average * 55-59 = mildly elevated * 60-69 = moderately elevated * 70+ = extremely elevated
Outcome measures
| Measure |
Treatment Group
n=7 Participants
The treatment group will include approximately 20 pediatric and young adult patients (ages 4-25 years) with Sunflower syndrome.
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Changes in Disruptive Behavior Determined by the Beck Self Report Inventory
Baseline Score
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44.14 T score
Standard Deviation 5.08
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Changes in Disruptive Behavior Determined by the Beck Self Report Inventory
Month 3 Score
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43.50 T score
Standard Deviation 5.76
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Adverse Events
Treatment Group
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
Treatment Group
n=19 participants at risk
The treatment group will include approximately 20 pediatric and young adult patients (ages 4-25 years) with Sunflower syndrome.
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|---|---|
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General disorders
Fatigue
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36.8%
7/19 • Adverse event data were collected between Baseline and Month 3 of the study (~84 days after the first dose of fenfluramine).
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General disorders
Reduced Appetite
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42.1%
8/19 • Adverse event data were collected between Baseline and Month 3 of the study (~84 days after the first dose of fenfluramine).
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General disorders
Nocturnal Enuresis
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10.5%
2/19 • Adverse event data were collected between Baseline and Month 3 of the study (~84 days after the first dose of fenfluramine).
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General disorders
Viral Illness
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21.1%
4/19 • Adverse event data were collected between Baseline and Month 3 of the study (~84 days after the first dose of fenfluramine).
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Gastrointestinal disorders
Diarrhea
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10.5%
2/19 • Adverse event data were collected between Baseline and Month 3 of the study (~84 days after the first dose of fenfluramine).
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General disorders
Shortness of Breath
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10.5%
2/19 • Adverse event data were collected between Baseline and Month 3 of the study (~84 days after the first dose of fenfluramine).
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General disorders
Chest Pain
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5.3%
1/19 • Adverse event data were collected between Baseline and Month 3 of the study (~84 days after the first dose of fenfluramine).
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General disorders
Seasonal Allergies
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10.5%
2/19 • Adverse event data were collected between Baseline and Month 3 of the study (~84 days after the first dose of fenfluramine).
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General disorders
Rhinorrhea
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5.3%
1/19 • Adverse event data were collected between Baseline and Month 3 of the study (~84 days after the first dose of fenfluramine).
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General disorders
irritability
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5.3%
1/19 • Adverse event data were collected between Baseline and Month 3 of the study (~84 days after the first dose of fenfluramine).
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General disorders
palilalia
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5.3%
1/19 • Adverse event data were collected between Baseline and Month 3 of the study (~84 days after the first dose of fenfluramine).
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General disorders
low serum calcium level
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5.3%
1/19 • Adverse event data were collected between Baseline and Month 3 of the study (~84 days after the first dose of fenfluramine).
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Skin and subcutaneous tissue disorders
acne exacerbation
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5.3%
1/19 • Adverse event data were collected between Baseline and Month 3 of the study (~84 days after the first dose of fenfluramine).
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General disorders
rash
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5.3%
1/19 • Adverse event data were collected between Baseline and Month 3 of the study (~84 days after the first dose of fenfluramine).
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Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place