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| Clinical Trial Endpoint or Domain (full paper linked) | Recommended Primary Measure(s) or Key Points | Recommended Secondary/Exploratory Measure(s) |
Biomarkers | Clinical annotation | • Minimal clinical dataset (Table 2) |
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Standardization of sample collection | • Recommendations for sample collection and methodology
• Minimal sample annotations (Table 3) | • Optimal timing of sample collection (Table 2)
• Recommendations for analysis reproducibility (Table 4) |
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Cutaneous neurofibroma (cNF) | • Recommended sample collection for cNF trials
• Recommended annotation for cNF biopsy samples (Table 2) |
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Genotype-phenotype correlation | • NF1—suggested that individuals with mutations p.Met992del and p.Arg1809Cys not be included in natural history studies or clinical trials investigating plexiform neurofibromas
• NF2-SWN—genetic severity score |
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Cutaneous Neurofibroma (cNF) Outcomes | Core outcome domains | • Domains that should be measured in all cNF trials (Figure 3):
o Clinical assessment
– Anatomic location, change over time, cosmesis, number, pain, recurrence, visibility
o Daily life impact
– Health-related quality of life, psychological functioning, stigma
o Patient satisfaction
– Satisfaction with treatment, tolerability and adverse effects of treatments, treatment burden
o Perception of health
– Self-esteem, self-image |
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Measurement of cNF size | • General recommendations for measuring cNF |
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High-frequency ultrasound (HFUS) | • Linear measures (width and depth) for large and small cNF | • Recommended exploratory measure
o Sum of maximum depth or width |
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3D photography | • Measurement of surface area for large cNF (=5 mm)—preferred
• Linear measures for small cNF (<5 mm) | • Changes in appearance (coloration) of cNF
• Recommended exploratory measures
o Linear measurement (longest diameter)
o Measurement of volume
o Sum of surface area for all cNF |
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Digital calipers | • Longest diameter (linear measure)
• Digital calipers are not recommended for cNF <5 mm or for height measurements | • Recommended exploratory measure
o Sum of longest diameter |
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Functional Outcomes | Hearing | • Maximum word recognition score (WRS) (Table 2) | • Pure-tone average (PTA) |
Facial function | • Scaled Measurement of Improvement in Lip Excursion (SMILE) analysis
o Download FACEGRAM app (must be a member of the Sir Charles Bell Society) | • House-Brackmann scale |
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Muscle strength | • Handheld dynamometry (HHD) performed by a trained examiner using a well-defined protocol |
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Vision related to optic pathway gliomas | • Visual acuity (VA) using Teller Acuity Cards (TAC) | • HOTV testing once subjects are old enough to complete
• Assess optic disc for pallor, as this may affect the interpretation of VA over time
• Visual quality of life using the Children’s Visual Function Questionnaire (CVFQ) |
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Pulmonary function related to airway plexiform neurofibromas | • Extrathoracic/upper airway lesions (using oscillometry)
o Airway resistance at 10 Hz (R10)
• Intrathoracic/peripheral airway lesions (using spirometry)
o Preschool Children
– Forced expiratory volume in 0.75 seconds (FEV0.75)
o All others
– Forced expiratory volume in 1 second (FEV1) | • Extrathoracic/upper airway lesions (using oscillometry)
o Airway resistance at 5 or 20 Hz (R5, R20)
o Airway reactance at resonant frequency
o Airway reactance at 5, 10, and 20 Hz
• Intrathoracic/peripheral airway lesions (using spirometry)
o Forced vital capacity (FVC)
o Peak expiratory flow (PEF)
o Forced expiratory flows
• Possibly imaging, patient-reported, or quality of life measures |
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Sleep related to airway plexiform neurofibromas | • Apnea Hypopnea Index (AHI) | • Oxygen saturation and hypercapnia during sleep
• End-tidal CO2
• Arousal index |
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Neurocognitive Outcomes | Attention in school age children/adults and preschool age | • Performance measure of attention for school age children and adults
o Digit Span (DS) from the Wechsler scales (Wechsler Intelligence Scale for Children and Wechsler Adult Intelligence Scale)
• Behavioral problems associated with attention for school age children and adults
o Conners Parent Rating Scale-3 (Conners 3) for school age children
o Conners Adult ADHD Rating Scale (CAARS) for adults
• Behavioral problems associated with attention for preschool age children
o Attention Deficit Hyperactivity Disorder Rating Scale-Preschool (ADHD-RS-P) for preschool children
• Important points regarding measure choice | • Performance measure of attention for preschool age children
o NIH Toolbox tasks [Flanker, Dimension Change Card Sort (DCCS), List Sort Working Memory (LSWM)]
o Differential Ability Scales— 2nd edition (DAS-II) Recall of Digits Forward |
Social skills | • Broader social functioning and prosocial behaviors
o Social Skills Improvement System-Rating Scales (SSIS-RS)
• Problematic social behaviors associated with autism spectrum disorder (ASD)
o Social Responsiveness Scale, Second Edition (SRS-2) |
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Patient-Reported Outcomes | Appearance Distress | • FACE-Q Craniofacial Module Appearance Distress subscale |
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Hearing | • Self-Assessment of Communication (SAC) for adults ages 20 and older and the Self-Assessment of Communication–Adolescent (SAC-A)for children and adolescents ages 11-19 |
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Tinnitus | • Tinnitus Functional Index |
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Pain intensity | • Numerical Rating Scale (NRS-11) |
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Pain interference | • Pain Interference Index (PII) for children and adolescents
• Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Interference Scalefor adults |
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Physical functioning | • PROMIS Physical Functioning Scale |
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General quality of life | • Functional Assessment of Cancer Therapy–General (FACT-G) for adult-only medical trials
• World Health Organization Quality of Life–BREF (WHOQoL-BREF) for adult-only psychosocial trials
• Pediatric Quality of Life Inventory (PedsQL) Generic Core Scales (GCS) and Infant Scales for medical and psychosocial NF trials that enroll only children and adolescents or a wider age range from children through adults |
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NF1-specific quality of life | • Pediatric Quality of Life Inventory (PedsQL) NF1 module |
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NF2-SWN-specific quality of life | • NF2 Impact on Quality of Life (NFTI-QOL) for all NF2 clinical trials | • Recommended exploratory measure for NF2-SWN trials targeting vestibular schwannomas
o Penn Acoustic Neuroma Quality of Life (PANQoL) |
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Tumor Response | Benign tumor response (particularly plexiform neurofibromas and vestibular schwannomas) | • 3D volumetric response on MRI using a specific acquisition protocol (Table e-1) | • Evaluation for clinical benefit including patient-reported and functional outcomes |