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A study of the safety, tolerability and pharmacokinetics of NNZ-2591 and measures of efficacy in children and adolescents with Phelan-McDermid Syndrome.
The primary purpose of this study is to investigate the safety, tolerability and pharmacokinetics of treatment with NNZ-2591 oral solution in children and adolescents with Phelan-McDermid Syndrome. The secondary purpose is to investigate measures of efficacy. Subjects will receive treatment with NNZ-2591 oral solution (50 mg/mL) doses for a total of 13 weeks.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| NNZ-2591 | Experimental | NNZ-2591 oral solution (50mg/mL) to be administered twice daily dose for 13 weeks. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| NNZ-2591 | Drug | NNZ-2591 oral solution (50mg/mL) to be administered twice daily dose for 13 weeks. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Safety and Tolerability | To examine the incidence, severity and frequency of adverse events (AEs), including serious adverse events (SAEs) during treatment with NNZ-2591. | 13 weeks |
| Pharmacokinetic - Mean AUC24 | Approximately nine sparse pharmacokinetic (PK) samples were collected from each participant under steady-state conditions. These samples were taken at pre-dose, 1-3 hours post-dose, and/or 4-7 hours post-dose during Weeks 2, 6, and 13. The individual pharmacokinetic parameters for NNZ-2591, including half-life (t1/2) and area under the curve over 24 hours (AUC24), were derived using subject-level concentration-time profiles from the study population model. | Pre-dose, 1-3 h post-dose and/or 4-7 h post-dose at Weeks 2, 6 and 13. |
| Pharmacokinetic - t1/2 | Approximately nine sparse pharmacokinetic (PK) samples were collected from each participant under steady-state conditions. These samples were taken at pre-dose, 1-3 hours post-dose, and/or 4-7 hours post-dose during Weeks 2, 6, and 13. The individual pharmacokinetic parameters for NNZ-2591, including half-life (t1/2) and area under the curve over 24 hours (AUC24), were derived using subject-level concentration-time profiles from the study population model. | Pre-dose, 1-3 h post-dose and/or 4-7 h post-dose at Weeks 2, 6 and 13. |
| Measure | Description | Time Frame |
|---|---|---|
| CGI-I | Phelan-McDermid Syndrome-specific Clinical Global Impression of Improvement Scale (CGI-I) - Overall Improvement Score on a 7 point Likert scale (1-7) where lower scores are better. | CGI-I was assessed at Weeks 6, 13/EOT & 15. Overall improvement scores relate to Week 13/EOT visit. |
| CIC |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| James Shaw | Neuren Pharmaceuticals | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Rush University Medical Center | Chicago | Illinois | 60612 | United States | ||
| Massachusetts General Hospital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 41450730 | Derived | Neumeyer AM, Srivastava S, Holder JL, Milad MA, Squires L, Jones NE, Glass L, Berry-Kravis E. NNZ-2591 in Children and Adolescents With Phelan-McDermid Syndrome: Single-Group, Open-Label, Phase 2 Trial Results. Neurol Genet. 2025 Dec 23;12(1):e200338. doi: 10.1212/NXG.0000000000200338. eCollection 2026 Feb. |
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Following consent, participants underwent 4 weeks of screening for eligibility. If successful, participants were enrolled and commenced open-label active treatment.
Participants were recruited based on physician referral at 4 academic medical centers between August 2022 and June 2023. The first participant entered screening on 08 August 2022, and the last participant entered screening on 22 June 2023. Of 23 consented participants, 18 met eligibility criteria and were enrolled into the study. Enrolled participants received NNZ2591 12 mg/kg by liquid oral dose twice daily
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| ID | Title | Description |
|---|---|---|
| FG000 | NNZ-2591 | All enrolled participants |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Screening |
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| Treatment and Follow Up |
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Intention to treat
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| ID | Title | Description |
|---|---|---|
| BG000 | NNZ-2591 | All enrolled participants |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Safety and Tolerability | To examine the incidence, severity and frequency of adverse events (AEs), including serious adverse events (SAEs) during treatment with NNZ-2591. | Intention to treat population | Posted | Count of Participants | Participants | 13 weeks |
|
|
15 weeks for each participant starting on date of first dose
Once eligibility was confirmed, subjects were dosed at a starting dose of 4 mg/kg twice daily (BID). Doses were titrated to 8 mg/kg at week 2 and to 12 mg/kg at week 6. The mg/kg dosing was based on the subject's weight at baseline. Subjects received treatment with NNZ-2591 for a total of 13 weeks.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | NNZ-2591 | All enrolled participants | 0 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Gastroenteritis | Gastrointestinal disorders | MedDRA 25.1 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Constipation | Gastrointestinal disorders | MedDRA 25.1 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Chief Medical Officer | Neuren Pharmaceuticals | +61 (3) 9092 0480 | MedicalInformation@neurenpharma.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Oct 30, 2023 | Mar 5, 2025 | Prot_003.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Nov 6, 2023 | Mar 5, 2025 | SAP_004.pdf |
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| ID | Term |
|---|---|
| C536801 | Telomeric 22q13 Monosomy Syndrome |
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| ID | Term |
|---|---|
| C540261 | cyclo-L-glycyl-L-2-allylproline |
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Caregiver Impression of Improvement: Measured on a 7 point Likert scale (1-7) where lower scores are better. |
| CIC was assessed at Week13/EOT |
| CGI-S | Phelan-McDermid syndrome-specific Clinical Global Impression Scale-Severity (CGI-S) -Change from baseline on Overall Score. Based on a 7 point Likert scale (1-7) where a lower score is better. | Change in score assessed from baseline (visit 3, week 0) to visit 16 (week 13/EOT). |
| Top 3 Concerns | Caregiver Top 3 Concerns - Total Concerns Severity: Change from baseline. The range of scores was (0-30) for total concerns, with higher scores being worse | Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in overall improvement score. |
| MB-CDI | MacArthur-Bates Communicative Development Inventory (MB-CDI) - change from baseline. Range of scores was (0-792) with higher scores being better. | Change from baseline (visit 3, week 0) to visit 13/EOT (week 16). |
| ORCA | Observer-Reported Communication Ability (ORCA) - Change from baseline in Total Score. Range of Scores was (25.8-83.8) with higher scores being better | Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in Total Score. |
| ABC-2 | Aberrant Behavior Checklist-2 (ABC-2) - Total score: Change from baseline. Range of scores was (0-174) with higher scores being worse | Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in total score. |
| CSHQ | Child Sleep Habits Questionnaire (CSHQ) - Change from baseline in Total Score. Range of scores was (33-99) with higher scores being worse. | Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in total score. |
| GIHQ | Gastrointestinal Health Questionnaire (GIHQ) - Total Frequency Score: Change from Baseline. Range of scores was (0-212) with higher scores being worse. | Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in total frequency score. |
| VABS-3 | Vineland Adaptive Behavior Scales-3, Change from baseline in Composite Standard Score. Range of scores was (20-140) with higher scores being better. | Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in composite standard score. |
| QL-Disability | Quality of Life Inventory-Disability (QL-Disability) Overall Score - change from baseline. Range of scores was (0-100) with higher scores being better. | Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in overall score score. |
| ICND | Impact of Childhood Neurological Disability (ICND) - Change from baseline in overall quality of life rating. Range of (1- 6) for quality of life rating, with higher scores indicating greater impact. | Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in overall quality of life rating score. |
| PMS-DSRS | PMS Clinician Domain Specific Rating Scale - Change from baseline in overall severity score. Range of Scores Was (0-20) With Higher Scores Being Worse. | Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in overall severity score. |
| Behavior Problems Inventory - Short Form | Total Frequency Score - Change from Baseline. Range of scores was (0-4) for each of 30 behaviors, total range (0-120), with lower scores being better. | Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in total frequency score. |
| Boston |
| Massachusetts |
| 02114 |
| United States |
| Boston Children's Hospital | Boston | Massachusetts | 02115 | United States |
| Texas Children's Hospital | Houston | Texas | 77030 | United States |
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| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Count of Participants | Participants |
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| Height (cm) | Mean | Standard Deviation | cm |
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| Weight (kg) | Mean | Standard Deviation | kg |
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| BMI (kg/m^2) | Mean | Standard Deviation | kg/m^2 |
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| PMS Genotype | Count of Participants | Participants |
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| History of regression | Count of Participants | Participants |
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| Autism Mental Status Exam | The AMSE is an observational assessment that looks at 8 items of social, communicative and behavioral functioning in individuals with Autism Spectrum Disorder, with each item yielding a potential score of 0, 1 or 2, with range of 0-16. Higher scores indicate greater levels of impairment. | Mean | Standard Deviation | score on a scale |
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| Seizure Types | Only 2 participants recorded seizures at enrollment | Count of Participants | Participants |
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| Seizure Characteristics at baseline | Number | participants |
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| Stanford-Binet Intelligence Scale (NVIQ) Standard Score | The Stanford Binet Non Verbal IQ (NVIQ) is a normed combined score taken from the 5 non verbal subtests. The score represents an individuals performance on the 5 nonverbal subtests of the exam with a range of 40-160, with higher scores indicating greater non verbal intelligence. | Participants who could not be assessed on the Stanford-Binet Intelligence (SB-5) due to their developmental level were assessed using the Mullen Scales of Early Learning instead. | Mean | Standard Deviation | score on a scale |
|
| Stanford-Binet Intelligence Scale (NVIQ) z deviation score | The z deviation score measures how far an individual's performance deviates from the mean performance of the normative sample on a specific subtest or composite score. Formula: Z = (X-μ)/σ Where: Z: The z-score (z deviation score). X: The individual's raw or scaled score. μ: The mean score of the normative sample. σ: The standard deviation of the scores in the normative sample. A positive z-score indicates a score above the mean. A negative z-score indicates a score below the mean. | Participants who could not be assessed on the Stanford-Binet Intelligence (SB-5) due to their developmental level were assessed using the Mullen Scales of Early Learning instead. | Mean | Standard Deviation | score on a scale |
|
| Mullen Scales of Early Learning Non-Verbal Developmental Quotient Score | The Non-Verbal Developmental Quotient (NVDQ) on the Mullen Scales of Early Learning assesses a child's non-verbal cognitive abilities by combining t-scores from the two non-verbal subscales scores of the Mullen Scales:
5 Scores > 100 indicate higher non-verbal developmental abilities, while scores < 100 suggest potential delays. | Includes only participants who were unable to be assessed on the Stanford-Binet Intelligence (SB-5) due to their developmental level. | Mean | Standard Deviation | score on a scale |
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| Presence of co-morbid psychiatric disorders | Number | participants |
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| Primary | Pharmacokinetic - Mean AUC24 | Approximately nine sparse pharmacokinetic (PK) samples were collected from each participant under steady-state conditions. These samples were taken at pre-dose, 1-3 hours post-dose, and/or 4-7 hours post-dose during Weeks 2, 6, and 13. The individual pharmacokinetic parameters for NNZ-2591, including half-life (t1/2) and area under the curve over 24 hours (AUC24), were derived using subject-level concentration-time profiles from the study population model. | PK Population | Posted | Mean | Standard Deviation | µg.h/mL | Pre-dose, 1-3 h post-dose and/or 4-7 h post-dose at Weeks 2, 6 and 13. |
|
|
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| Primary | Pharmacokinetic - t1/2 | Approximately nine sparse pharmacokinetic (PK) samples were collected from each participant under steady-state conditions. These samples were taken at pre-dose, 1-3 hours post-dose, and/or 4-7 hours post-dose during Weeks 2, 6, and 13. The individual pharmacokinetic parameters for NNZ-2591, including half-life (t1/2) and area under the curve over 24 hours (AUC24), were derived using subject-level concentration-time profiles from the study population model. | All participants enrolled in this study who receive the study drug through to the morning dose of Week 2 (Visit 5) as a minimum, and who undergo PK sample collection at least one of the specified post-dose time point(s). | Posted | Mean | Standard Deviation | hours | Pre-dose, 1-3 h post-dose and/or 4-7 h post-dose at Weeks 2, 6 and 13. |
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| Secondary | CGI-I | Phelan-McDermid Syndrome-specific Clinical Global Impression of Improvement Scale (CGI-I) - Overall Improvement Score on a 7 point Likert scale (1-7) where lower scores are better. | Intention to treat | Posted | Mean | Standard Deviation | score on a scale | CGI-I was assessed at Weeks 6, 13/EOT & 15. Overall improvement scores relate to Week 13/EOT visit. |
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| Secondary | CIC | Caregiver Impression of Improvement: Measured on a 7 point Likert scale (1-7) where lower scores are better. | Intention to treat population | Posted | Mean | Standard Deviation | score on a scale | CIC was assessed at Week13/EOT |
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| Secondary | CGI-S | Phelan-McDermid syndrome-specific Clinical Global Impression Scale-Severity (CGI-S) -Change from baseline on Overall Score. Based on a 7 point Likert scale (1-7) where a lower score is better. | Intention to treat | Posted | Mean | Standard Deviation | score on a scale | Change in score assessed from baseline (visit 3, week 0) to visit 16 (week 13/EOT). |
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| Secondary | Top 3 Concerns | Caregiver Top 3 Concerns - Total Concerns Severity: Change from baseline. The range of scores was (0-30) for total concerns, with higher scores being worse | Intention to treat population | Posted | Mean | Standard Deviation | score on a scale | Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in overall improvement score. |
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| Secondary | MB-CDI | MacArthur-Bates Communicative Development Inventory (MB-CDI) - change from baseline. Range of scores was (0-792) with higher scores being better. | Intention to treat population | Posted | Mean | Standard Deviation | score on a scale | Change from baseline (visit 3, week 0) to visit 13/EOT (week 16). |
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| Secondary | ORCA | Observer-Reported Communication Ability (ORCA) - Change from baseline in Total Score. Range of Scores was (25.8-83.8) with higher scores being better | Intention to treat population | Posted | Mean | Standard Deviation | score on a scale | Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in Total Score. |
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| Secondary | ABC-2 | Aberrant Behavior Checklist-2 (ABC-2) - Total score: Change from baseline. Range of scores was (0-174) with higher scores being worse | Intention to treat population | Posted | Mean | Standard Deviation | score on a scale | Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in total score. |
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| Secondary | CSHQ | Child Sleep Habits Questionnaire (CSHQ) - Change from baseline in Total Score. Range of scores was (33-99) with higher scores being worse. | Intention to treat population | Posted | Mean | Standard Deviation | score on a scale | Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in total score. |
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| Secondary | GIHQ | Gastrointestinal Health Questionnaire (GIHQ) - Total Frequency Score: Change from Baseline. Range of scores was (0-212) with higher scores being worse. | Intention to treat population | Posted | Mean | Standard Deviation | score on a scale | Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in total frequency score. |
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| Secondary | VABS-3 | Vineland Adaptive Behavior Scales-3, Change from baseline in Composite Standard Score. Range of scores was (20-140) with higher scores being better. | Intention to treat population | Posted | Mean | Standard Deviation | score on a scale | Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in composite standard score. |
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| Secondary | QL-Disability | Quality of Life Inventory-Disability (QL-Disability) Overall Score - change from baseline. Range of scores was (0-100) with higher scores being better. | Intention to treat population | Posted | Mean | Standard Deviation | score on a scale | Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in overall score score. |
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| Secondary | ICND | Impact of Childhood Neurological Disability (ICND) - Change from baseline in overall quality of life rating. Range of (1- 6) for quality of life rating, with higher scores indicating greater impact. | Intention to treat population | Posted | Mean | Standard Deviation | score on a scale | Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in overall quality of life rating score. |
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| Secondary | PMS-DSRS | PMS Clinician Domain Specific Rating Scale - Change from baseline in overall severity score. Range of Scores Was (0-20) With Higher Scores Being Worse. | Intention to treat population | Posted | Mean | Standard Deviation | score on a scale | Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in overall severity score. |
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| Secondary | Behavior Problems Inventory - Short Form | Total Frequency Score - Change from Baseline. Range of scores was (0-4) for each of 30 behaviors, total range (0-120), with lower scores being better. | Intention to treat population | Posted | Mean | Standard Deviation | score on a scale | Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in total frequency score. |
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| 18 |
| 1 |
| 18 |
| 17 |
| 18 |
| Diarrhea | Gastrointestinal disorders | MedDRA 25.1 | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA 25.1 | Systematic Assessment |
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| Vomiting | Gastrointestinal disorders | MedDRA 25.1 | Systematic Assessment |
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| Fatigue | General disorders | MedDRA 25.1 | Systematic Assessment |
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| Pyrexia | General disorders | MedDRA 25.1 | Systematic Assessment |
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| Covid 19 | Infections and infestations | MedDRA 25.1 | Systematic Assessment |
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| Nasopharyngitis | Infections and infestations | MedDRA 25.1 | Systematic Assessment |
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| Otitis Media | Infections and infestations | MedDRA 25.1 | Systematic Assessment |
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| Decreased appetite | Metabolism and nutrition disorders | MedDRA 25.1 | Systematic Assessment |
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| Psychomotor Hyperactivity | Nervous system disorders | MedDRA 25.1 | Systematic Assessment |
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| Somnolence | Nervous system disorders | MedDRA 25.1 | Systematic Assessment |
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| Aggression | Psychiatric disorders | MedDRA 25.1 | Systematic Assessment |
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| Insomnia | Psychiatric disorders | MedDRA 25.1 | Systematic Assessment |
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| Rhinorrhea | Respiratory, thoracic and mediastinal disorders | MedDRA 25.1 | Systematic Assessment |
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