REiNS International Collaboration

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)

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)

Cutaneous neurofibroma (cNF)

•    Recommended sample collection for cNF trials

•    Recommended annotation for cNF biopsy samples (Table 2)

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

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

Measurement of cNF size

•    General recommendations for measuring cNF

High-frequency ultrasound (HFUS)

•    Linear measures (width and depth) for large and small cNF

•    Recommended exploratory measure

o  Sum of maximum depth or width

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

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

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

Muscle strength

•    Handheld dynamometry (HHD) performed by a trained examiner using a well-defined protocol

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)

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 (FEV_0.75)

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

Sleep related to airway plexiform neurofibromas

•    Apnea Hypopnea Index (AHI)

•    Oxygen saturation and hypercapnia during sleep

•    End-tidal CO₂

•    Arousal index

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)

Patient-Reported Outcomes

Appearance Distress

•    FACE-Q Craniofacial Module Appearance Distress subscale

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

Tinnitus

•    Tinnitus Functional Index

Pain intensity

•    Numerical Rating Scale (NRS-11)

Pain interference

•    Pain Interference Index (PII) for children and adolescents

•    Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Interference Scalefor adults

Physical functioning

•    PROMIS Physical Functioning Scale

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

NF1-specific quality of life

•    Pediatric Quality of Life Inventory (PedsQL) NF1 module

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)

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