Development and Validation of Patient Reported Outcome (PRO) Measures for Individuals With Neurofibromatosis 1 (NF1) and Plexiform Neurofibromas (PNs)

Background:

- Neurofibromatosis 1 (NF1) is a genetic disease with multiple clinical manifestations,
including plexiform neurofibromas (PN) that can cause pain and may significantly impact
daily functioning and quality of life (QOL).

- Patient-reported outcomes (PROs) are useful in trials for conditions that are disabling
and chronic like NF1, where symptom reduction and improved functioning and QOL currently
are important treatment outcomes, which may occur with PN shrinkage.

- A critical step toward approval of drugs to treat PNs is to evaluate clinical benefit in
conjunction with a reduction in tumor volume as assessed by imaging endpoints.

- The FDA requests the use of PROs in NF1 clinical atrials, especially for assessing
changes in symptoms, such as pain.

- Currently, no valid PRO measures exist that are specific to the NF1 population to assess
PN pain, its functional impact on an individual s life, or overall physical functioning,
which may be affected by PNs.

Objectives:

- Phase 1: Qualitative Evaluation

---To evaluate current modifications and the need for any additional modifications to
existing measures of pain intensity (Numeric Rating Scale; NRS-11) and pain interference
(Pain Interference Index; PII) and select the most appropriate items to measure physical
functioning (PROMIS Physical Functioning; PROMIS-PF) in NF1 based on qualitative
feedback from patients with NF1, PNs and pain to use as endpoints in clinical trials for
individuals with NF1 and PNs.

- Phase 2: Evaluation of Psychometric Properties and Collection of Normative Data

- To evaluate final versions of the NRS-11, PII, and PROMIS-PF measures on
reliability, validity, sensitivity to change, and feasibility in individuals with
NF1 and PNs.

Eligibility:

Patients with documented NF1 either by NIH clinical criteria or molecularly-proven mutation
in the NF1 gene will be included in the study. Patients must have at least 1 plexiform
neurofibroma (PN) that is at least >3cm on physical exam or >3mL on volumetric MRI. Patients
must be at least 5 years of age and able to understand and speak English.

Design:

This protocol will be a limited site, multi-institutional research study to maximize our
ability to assess a large, diverse sample of individuals with NF1. NCI is the lead
institution and the three participating sites are Children s National Medical Center,
University of Chicago, and Cincinnati Children s Hospital.

This study will consist of 2 phases:

- Phase 1: Qualitative Evaluation

--The first phase involves evaluation of current modifications and the need for any
additional modification of the NRS-11 and the PII and evaluating the most appropriate
items from the PROMIS-PF item bank to use in the PROMIS-PF short form by conducting
focus groups and interviews with patients diagnosed with NF1 and PNs and parents of
children. We will conduct up to 24 focus groups across various age bands. We will
conduct up to four groups of 6-8 subjects for each age band (8-11 years; 12-14 years;
15-19 years [still in high school]; 18- 24 years [graduated from high school]; 25+
years; and parents of children with NF1). In lieu of focus groups with young children
(ages 5-7), we will conduct individual cognitive interviews. We will conduct up to 6
interviews for children ages 5, 6, and 7, resulting in up to 18 child cognitive
interviews; we will additionally conduct up to 6 cognitive interviews with parents of
children 5-7. This qualitative data will be evaluated and any necessary changes based on
patient responses, will be made to the NRS-11, PII, and PROMIS-PF. The measures will
then be converted into an electronic format that will have the same items and will have
the same question and answer format as the paper questionnaires. It will be administered
on an electronic tablet. We will then conduct up to 32 cognitive interviews across 3
broad age bands (8-12, 13-19, and 18+) up to 10 cognitive interviews with parents, and
up to 20 additional interviews across age bands if deemed necessary following
qualitative analysis for a maximum ceiling of 62 patients with a target of 42 cognitive
interviews to evaluate the measures. Based on these qualitative results these versions
will be updated if necessary to prepare for phase 2.

- Phase 2: Evaluation of Psychometric Properties and Collection of Normative Data

- The second phase will evaluate the final electronic versions of the NRS-11, the
PII, and the PROMIS-PF using a cross-sectional design to examine internal
consistency, construct validity, sensitivity to change, and to provide normative
data on the study measures for the NF1 population. It is our goal to recruit from
14 to 16 patients, with a target of 15 in each of 8 phase 2 age bands for an
approximate ceiling of 128 (target = 120) patients, 64 parents of children (target
= 60) 8+ and 16 parents of children ages 5-7 (target = 15). All patients and
parents will be asked to complete the measures two different times to examine
test-retest reliability or sensitivity to change. For the sensitivity to change
analysis, a subset of patients will be given the measure before and after starting
a new pain medication treatment (including new prescriptions and dose escalations)
or starting a new drug to reduce tumor size.

- INCLUSION CRITERIA:

- Documented NF1 either by NIH clinical criteria or molecularly-proven mutation in the
NF1 gene AND Greater than or equal to 1 plexiform neurofibroma in any location that is
either symptomatic or asymptomatic, and is defined by the following:

1. a neurofibroma that has grown along the length of a nerve and may involve
multiple fascicles and branches OR a spinal neurofibroma that involves two or
more levels with connection between the levels or extending laterally along the
nerve OR a skin thickness neurofibroma;

2. measures greater than or equal to 3cm on longest diameter by visual exam,
palpation or 2D MR imaging OR greater than or equal to 3mL by volumetric MR
imaging.

- Age greater than or equal to 5 years.

- Ability of subject or parent or guardian to understand and the willingness to sign a
written informed consent document.

- Participants must be able to understand and speak the English language.

- For phase 1 focus groups only, patients need to report experiencing PN related pain
recently with a minimum pain level of 3 on the current NRS-11 or report taking
prescription medication that reduces pain and experiencing PN related pain recently
with a minimum pain level of 1 on the current NRS-11.

- For phase 2, participants in the group evaluating sensitivity to change will need to
be starting a new pain medication regimen or increasing the dose of their existing
pain medication, or starting a drug to reduce PN size.

- Parent or Guardian Inclusion Criteria

- Parent or Guardian of participating subject

- Participants must be able to understand and speak the English language

EXCLUSION CRITERIA:

- Patients with severe cognitive or behavior impairments who, in the judgment of the
investigators, would not be able to cooperate with the study procedures will be
excluded.

- For phase 2, patients participating in the test-retest subgroup cannot be enrolled on
a clinical trial or cannot have started a new pain treatment regimen at their
appointment (e.g., medication, therapy, physical therapy, etc.)