Bevacizumab for Symptomatic Vestibular Schwannoma in Neurofibromatosis Type 2 (NF2)

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01207687
• Collaborator: (none)
• Enrollment: 14
• Locations: 3
• Arm: 1
• Duration (Months): 41
• Patients Per Site: 4.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

People who have neurofibromatosis type 2 (NF2) can have tumors that grow on the auditory nerves and cause hearing loss. These tumors are called vestibular schwannomas (VSs), or acoustic neuromas. People with NF2 can also get schwannomas in other parts of their body, as well as tumors called meningiomas and ependymomas. Because VSs can cause hearing loss, many people with NF2 will have treatment to preserve their hearing. This treatment usually involves surgery. Because surgery has risks and is not able to help everyone with VSs, other methods of treatment are being explored. One area of exploration is looking to see if there is a drug that can be taken that might prevent the VSs from growing larger and causing hearing loss or brainstem compression. This study is exploring whether a drug that is approved by the FDA and is currently used to treat other tumors might also work to treat VSs. Based on people who have taken this drug to treat VSs already, there is some reason to think that it might be helpful to certain people with NF2. People enrolled in this study will receive the drug one time every three weeks for one year by infusion. This study will follow subjects over the course of the year that the person is taking the drug and for six months after the drug is stopped. This study is recruiting people who have NF2 and are currently having symptoms of tinnitus, dizziness, and/or hearing loss from their VSs. If you have NF2 and are currently having symptoms caused by your VSs, you may be eligible to participate.

Condition or Disease	Intervention/Treatment	Phase
Vestibular Schwannoma; Neurofibromatosis Type 2	Biological: bevacizumab; Other: laboratory biomarker analysis; Procedure: quality-of-life assessment	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. The primary objective of this study is to determine the activity of bevacizumab for treatment of symptomatic vestibular schwannomas (VS) defined as progressive hearing loss in patients with neurofibromatosis type 2 (NF2) based on objective hearing response.

SECONDARY OJBECTIVES:

1. Determine the safety and tolerability of bevacizumab in this patient population on an every three week dosing schedule of 7.5mg/kg for 12 months of therapy.

2. Assess the rate of radiographic response (>= 20% reduction in volume). III. Determine the growth rate of VS using volumetric MRI analysis in comparison to 1-dimensional and 2-dimensional measurements.

3. Assess changes in function of the auditory system during bevacizumab treatment.

4. Assess the vascular permeability (Ktrans), relative cerebral blood volume/flow, mean transit time, and mean vessel diameter from perfusion-weighted MRI.

5. Assess the change in circulating endothelial cells, circulating progenitor cells, and plasma angiogenic proteins in subjects receiving bevacizumab treatment.

6. Observe the impact of bevacizumab on non-VS tumors in patients with NF2 via whole body MRI.

7. Explore hearing related QOL measures throughout treatment. IX. Explore the effect of treatment with bevacizumab on auditory function using distortion product optoacoustic emissions (DPOAE) (to be evaluated at NCI only).

OUTLINE:

Patients receive bevacizumab intravenously (IV) over 30-90 minutes once every 3 weeks. Courses repeat every 6 weeks for up to 48 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 3 and 6 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 2 Study of Bevacizumab in Children and Adults With Neurofibromatosis Type 2 and Symptomatic Vestibular Schwannoma
• Study Start Date: Oct 1, 2010
• Actual Primary Completion Date: Feb 1, 2013
• Actual Study Completion Date: Mar 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (bevacizumab) Patients receive bevacizumab IV over 30-90 minutes once every 3 weeks. Courses repeat every 6 weeks for up to 48 weeks in the absence of disease progression or unacceptable toxicity.	Biological: bevacizumab; Given IV; Other Names: anti-VEGF humanized monoclonal antibody anti-VEGF monoclonal antibody Avastin rhuMAb VEGF ; Other: laboratory biomarker analysis; Correlative studies; Procedure: quality-of-life assessment; Ancillary studies; Other Names: quality of life assessment

Outcome Measures

Primary Outcome Measures

1. Proportion of Patients With Hearing Response [Baseline to 12 months]

   A hearing response was defined as increased word recognition score above the 95% critical threshold that is maintained across two sequential evaluation time points. The word recognition score (WRS) is the percentage of phonetically-balanced, monosyllabic words that a patient can accurately repeat presented at either most comfortable level or most intelligible level.The proportion of patients with hearing response in the target ear was estimated using a binomial distribution along with 95% confidence intervals.

Secondary Outcome Measures

1. Incidence of Serious or Life Threatening Toxicities [Up to 6 months post-treatment]

   The number of patients with serious or life threatening toxicities (CTCAE grade 3 or above)

2. Radiographic Response [Baseline to 6 months post-treatment]

   The proportion of participants with radiographic response as measured by a >/= 20% reduction in tumor volume from baseline on MRI imaging will be estimated using a binomial distribution.

3. Median Percent Change in Target Vestibular Schwannoma Volume Using Volumetric MRI [Baseline to 12 months]

   The median percent change in the volume of the target vestibular schwannoma using volumetric MRI

4. Number of Participants With Changes in Function of the Auditory System [Baseline to 6 months post-treatment]

   The primary distortion product optoacoustic emissions (DPOAE) measurement will be treated non-parametrically (present or absent across time) DPOAE's will be considered present at the frequency of F2 when the distortion product is 6dB above the noise floor. Variables will be analyzed for differences using t-tests if the effects and sample sizes warrant, but this may not be advisable given the small numbers to be accrued.

5. Percent Change in Median Vascular Permeability (Ktrans) [Baseline to week 72]

   Correlation assessment were planned for imaging parameters and hearing response based on the estimated changes in Ktrans: a MRI measure of vascular permeability. Only 1/14 participants had complete Ktrans data that was amenable to analysis at baseline and week 72. Hence, these statistical analyses were not possible.

6. Quality of Life Assessed Using Health Survey Short Form-36 (SF-36) - Total Score [Baseline]

   The SF-36 is a patient reported outcome. SF-36 (v.1) was administered and was scored according to instructions found on the RAND website. The range of scores is 0 - 100, with a higher value indicating a more favorable health state. The total score is the median of the all the individual items.

7. Quality of Life Assessed Using Health Survey Short Form-36 (SF-36) - Component Scores [Baseline]

   The SF-36 is a patient reported outcome. SF-36 (v.1) was administered and was scored according to instructions found on the RAND website. The range of scores is 0 - 100, with a higher value indicating a more favorable health state. Scores are commonly reported as a physical component summary (PCS) and mental component summary (MCS). The PCS and MCS score have been transformed to the T-score metric, which has a mean of 50 and a standard deviation of 10 for the U.S. general population.

8. Quality of Life Assessed Using Health Survey Short Form-36 (SF-36) - Total Score [6 months]

   The SF-36 is a patient reported outcome. SF-36 (v.1) was administered and was scored according to instructions found on the RAND website. The range of scores is 1 - 100, with a higher value indicating a more favorable health state. The total score is the median of the all the individual items.

9. Quality of Life Assessed Using Health Survey Short Form-36 (SF-36) - Component Scores [6 months]

   The SF-36 is a patient reported outcome. SF-36 (v.1) was administered and was scored according to instructions found on the RAND website. The range of scores is 0 - 100, with a higher value indicating a more favorable health state. Scores are commonly reported as a physical component summary (PCS) and mental component summary (MCS). The PCS and MCS score have been transformed to the T-score metric, which has a mean of 50 and a standard deviation of 10 for the U.S. general population.

10. Quality of Life Assessed Using Health Survey Short Form-36 (SF-36) - Total Score [12 months]

    The SF-36 is a patient reported outcome. SF-36 (v.1) was administered and was scored according to instructions found on the RAND website. The range of scores is 0 - 100, with a higher value indicating a more favorable health state. The total score is the median of the all the individual items.

11. Quality of Life Assessed Using Health Survey Short Form-36 (SF-36) - Component Scores [12 months]

    The SF-36 is a patient reported outcome. SF-36 (v.1) was administered and was scored according to instructions found on the RAND website. The range of scores is 0 - 100, with a higher value indicating a more favorable health state. Scores are commonly reported as a physical component summary (PCS) and mental component summary (MCS). The PCS and MCS score have been transformed to the T-score metric, which has a mean of 50 and a standard deviation of 10 for the U.S. general population.

12. Quality of Life Assessed Using Health Survey Short Form-36 (SF-36) - Total Score [18 months]

    The SF-36 is a patient reported outcome. SF-36 (v.1) was administered and was scored according to instructions found on the RAND website. The range of scores is 0 - 100, with a higher value indicating a more favorable health state. The total score is the median of the all the individual items.

13. Quality of Life Assessed Using Health Survey Short Form-36 (SF-36) - Component Scores [18 months]

    The SF-36 is a patient reported outcome. SF-36 (v.1) was administered and was scored according to instructions found on the RAND website. The range of scores is 0 - 100, with a higher value indicating a more favorable health state. Scores are commonly reported as a physical component summary (PCS) and mental component summary (MCS). The PCS and MCS score have been transformed to the T-score metric, which has a mean of 50 and a standard deviation of 10 for the U.S. general population.

14. Quality of Life as Assessed by the Speech and Spatial Qualities Questionnaire (SSQ) [baseline]

    The SSQ is a 49 item patient-reported outcome with three subscales: speech understanding (14 questions), spatial location of sounds (17 questions), and the qualities of sounds (18 questions) as they appear to the patient with hearing impairment. Each response is recorded on an 11 point scale (0 - 10), with the anchor points "not at all" (= 0) and "perfectly" (=10). A higher score indicates better hearing. The median score is reported for each subscale. The minimum and maximum scores for the median of each subscale would be 0 and 10, respectively.

15. Quality of Life as Assessed by the Speech and Spatial Qualities Questionnaire (SSQ) [6 months]

    The SSQ is a 49 item patient-reported outcome with three subscales: speech understanding (14 questions), spatial location of sounds (17 questions), and the qualities of sounds (18 questions) as they appear to the patient with hearing impairment. Responses are recorded on a scale from 0 - 10, with the anchor points "not at all" (= 0) and "perfectly" (=10). A higher score indicates better hearing. The median score for each subscale is reported. The minimum and maximum scores for the median of each subscale would be 0 and 10, respectively.

16. Quality of Life as Assessed by the Speech and Spatial Qualities Questionnaire (SSQ) [12 months]

    The SSQ is a 49 item patient-reported outcome with three subscales: speech understanding (14 questions), spatial location of sounds (17 questions), and the qualities of sounds (18 questions) as they appear to the patient with hearing impairment. Responses are recorded on a scale from 0 - 10, with the anchor points "not at all" (= 0) and "perfectly" (=10). A higher score indicates better hearing. The median score for each subscale is reported. The minimum and maximum scores for the median of each subscale would be 0 and 10, respectively.

17. Quality of Life as Assessed by the Speech and Spatial Qualities Questionnaire (SSQ) [18 months]

    The SSQ is a 49 item patient-reported outcome with three subscales: speech understanding (14 questions), spatial location of sounds (17 questions), and the qualities of sounds (18 questions) as they appear to the patient with hearing impairment. Responses are recorded on a scale from 0 - 10, with the anchor points "not at all" (= 0) and "perfectly" (=10). A higher score indicates better hearing. The median score for each subscale is reported. The minimum and maximum scores for the median of each subscale would be 0 and 10, respectively.

18. Quality of Life Assessed by the Tinnitus Reaction Questionnaire (TRQ) [baseline]

    The TRQ is a 26 item patient reported outcome. It is scored using a 5 point Likert scale (0-4). The responses are summed, resulting in a range of 0 - 104 with higher scores indicating more distress related to tinnitus.

19. Quality of Life Assessed by the Tinnitus Reaction Questionnaire (TRQ) [6 months]

    The TRQ is a 26 item patient reported outcome. It is scored using a 5 point Likert scale (0-4). The responses are summed, resulting in a range of 0 - 104 with higher scores indicating more distress related to tinnitus.

20. Quality of Life Assessed by the Tinnitus Reaction Questionnaire (TRQ) [12 months]

    The TRQ is a 26 item patient reported outcome. It is scored using a 5 point Likert scale (0-4). The responses are summed, resulting in a range of 0 - 104 with higher scores indicating more distress related to tinnitus.

21. Quality of Life Assessed by the Tinnitus Reaction Questionnaire (TRQ) [18 months]

    The TRQ is a 26 item patient reported outcome. It is scored using a 5 point Likert scale (0-4). The responses are summed, resulting in a range of 0 - 104 with higher scores indicating more distress related to tinnitus.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must have a confirmed diagnosis of neurofibromatosis 2 by fulfilling National Institute of Health (NIH) criteria or Manchester criteria, or by detection of a causative mutation in the NF2 gene

• The NIH criteria (82) includes presence of:

• Bilateral vestibular schwannomas, OR

• First-degree relative with NF2 and EITHER unilateral eighth nerve mass OR two of the following: neurofibroma, meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity

• The Manchester criteria (101) includes presence of:

• Bilateral vestibular schwannomas, OR

• First-degree relative with NF2 and EITHER unilateral eighth nerve mass OR two of the following: neurofibroma, meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity, OR

• Unilateral vestibular schwannoma AND any two of: neurofibroma, meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity, OR

• Multiple meningiomas (two or more) AND unilateral vestibular schwannoma OR any two of: schwannoma, glioma, neurofibroma, cataract

• Patients must have measurable disease, defined as at least one VS >= 1.5 cm (on longest diameter) as measured by contrast-enhanced cranial MRI scan with fine cuts through the internal auditory canal (3 mm slices, no skip)

• Life expectancy of greater than 6 months

• ECOG performance status (Karnofsky >= 60% or Lansky Score >= 60)

• Patients must have normal organ and marrow function as defined below:

• Leukocytes >= 3,000/mcL

• Absolute neutrophil count >= 1,500/mcL

• Platelets >= 150,000/mcL or lower limit of institutional normal

• Total bilirubin =< 2 X institutional upper limit of normal

• AST(SGOT)/ALT(SGPT) =< 2.5 X institutional upper limit of normal

• Patients must have recovered from acute toxicity of prior treatment to grade 1 or less unless otherwise specified

• Patients must have a creatinine clearance or radioisotope GFR >= 60ml/min/1.73 m^2 or a normal serum creatinine based on age described in the table below:

• Age(years) =< 5: 0.8 mg/dL

• 5 < age (years) =< 10: 1.0 mg/dL

• 10 < age (years) =< 15: 1.2 mg/dL

• Age (years) > 15: 1.5 mg/dL

• Subjects must have a VS not amenable to surgery or have refused surgery due to high risk for permanent complications related to surgery (e.g. damage to lower cranial nerve function, facial palsy, risk for cerebrospinal fluid leak, etc.) as determined by a surgeon with experience in management of NF2 associated VS

• Subjects must have had a discussion of all available treatment options and their risks and benefits of these options including surgery, radiation therapy, observation, other clinical trials and expressed their preference for participation in this trial in the informed consent process

• The effects of bevacizumab on the developing human fetus at the recommended therapeutic dose are unknown; for this reason and because anti-angiogenic agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately

• Ability to understand and the willingness give written informed consent or assent

• Evidence of active disease, defined as progressive hearing loss (with decrease in word recognition score) related to VS (i.e., not due to prior interventions such as surgery or radiation) documented in the preceding 24 months with a word recognition score of < 90% in the target ear

• Proteinuria (including albuminuria) should be screened for by either urine analysis for urine protein creatinine (UPC) ratio or by urine dipstick; if the UPC ratio is greater than or equal to 0.5 or if urine dipstick shows 2+ proteinuria, 24-hour urine protein should be obtained and the level should be < 1000 mg for patient enrollment

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier

• Patients may not be receiving any other investigational agents

• Patients with nervous system tumors associated with NF2 (e.g., schwannomas, meningiomas, ependymomas, or gliomas) will not be excluded from this clinical trial as long as these tumors do not require treatment with radiation, surgery, or medical treatment at the time of enrollment on trial

• Patients with known hypersensitivity of Chinese hamster ovary cell products, other recombinant human antibodies, or compounds of similar chemical or biologic composition to bevacizumab

• Inability to tolerate periodic MRI scans or gadolinium contrast without general anesthesia

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements

• Clinically significant cardiovascular disease, such as:

• Inadequately controlled HTN (adult subjects: SBP > 160 mmHg and/or DBP > 90 mmHg despite antihypertensive medication, pediatric subjects: Requirement for antihypertensive treatment prior to enrollment, or diastolic blood pressure > 95th percentile for age)

• History of CVA within 12 months

• Myocardial infarction or unstable angina within 12 months

• New York heart association grade II or greater congestive heart failure

• Serious and inadequately controlled cardiac arrhythmia

• Significant vascular disease (e.g. aortic aneurysm, history of aortic dissection)

• Clinically significant peripheral vascular disease

• Pregnant women (positive pregnancy test) are excluded from this study because bevacizumab is an anti-angiogenic agent with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with bevacizumab, breastfeeding should be discontinued if the mother is treated with bevacizumab; both fertile men and women must agree to use adequate contraceptive measures during study therapy and for at least 6 months after the completion of bevacizumab therapy; abstinence is considered an adequate contraceptive measure

• In the event that a minor (age 12-17) who undergoes a pregnancy test as part of the screening process receives a positive result, they will be excluded from the study and their parent(s) of record will be notified of this result

• HIV-positive patients or cancer survivors are eligible for this study if they fulfill all other eligibility criteria

• Inability to perform volumetric measurement of target VS (e.g., due to the MRI artifact from auditory brainstem implant or due to presence of collision tumor (two or more tumors abutting each other) in the cerebellopontine angle); Note: questions about the ability to perform volumetric analysis on a baseline MRI scan should be directed to the study radiologist, Dr. Gregory Sorensen

• Concurrent use of anti-coagulant drugs (not including prophylactic doses), history of coagulopathy, or evidence of bleeding diathesis or coagulopathy

• Imaging (CT or MRI) evidence of newly identified hemorrhage (new within the last in the 6 months prior to enrollment), any history of symptomatic intracranial hemorrhage, or any history of spontaneous intracranial hemorrhage

• Serious or non-healing wound, ulcer or bone fracture

• History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months prior to day 1

• Invasive procedures defined as follows:

• Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to Day 1 therapy

• Brain biopsy within 28 days prior to day 1 of therapy (wounds must be fully healed from brain biopsies performed more than 28 days prior to day 1 of therapy)

• Anticipation of need for major surgical procedures during the course of the study

• Core biopsy within 7 days prior to D1 therapy

• Prior treatment with bevacizumab or other VEGF targeting therapies

• Personal history of autoimmune coagulopathy, including idiopathic thrombocytopenia purpura (ITP)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland	United States	21287
2	National Cancer Institute	Rockville	Maryland	United States	20850
3	Massachusetts General Hospital	Charlestown	Massachusetts	United States	02129

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Jaishri Blakeley, Johns Hopkins University/Sidney Kimmel Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01207687
• Other Study ID Numbers: NCI-2012-02987; NCI-2012-02987; J1002; NA_00034732; 8248; P30CA006973; NCT01204463
• First Posted: Sep 23, 2010
• Last Update Posted: Aug 27, 2018
• Last Verified: Jul 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Neurofibromatoses; Neurofibromatosis 1; Neurofibroma; Neurilemmoma; Neuroma, Acoustic; Neurofibromatosis 2; Bevacizumab; Antineoplastic Agents, Immunological; Antibodies; Immunoglobulins; Antibodies, Monoclonal

Study Results

Participant Flow

Arm/Group Title	Treatment (Bevacizumab) - All Participants
Arm/Group Description	Bevacizumab IV over 30-90 minutes once every 3 weeks. Courses repeat every 6 weeks for up to 48 weeks in the absence of disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	14
COMPLETED	12
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Treatment (Bevacizumab)
Arm/Group Description	People with NF2, not eligible for surgery with progressive vestibular schwannoma
Overall Participants	14
Age (Count of Participants)
<=18 years	2 14.3%
Between 18 and 65 years	11 78.6%
>=65 years	1 7.1%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	30.5
Sex: Female, Male (Count of Participants)
Female	10 71.4%
Male	4 28.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 7.1%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	11 78.6%
More than one race	0 0%
Unknown or Not Reported	2 14.3%
Region of Enrollment (Count of Participants)
United States	14 100%
Karnofsky performance status scale (units on a scale) [Median (Full Range) ]
Median (Full Range) [units on a scale]	80
word recognition score of target ear (units on a scale) [Median (Full Range) ]
Median (Full Range) [units on a scale]	60.5

Outcome Measures

1. Primary Outcome

Title	Proportion of Patients With Hearing Response
Description	A hearing response was defined as increased word recognition score above the 95% critical threshold that is maintained across two sequential evaluation time points. The word recognition score (WRS) is the percentage of phonetically-balanced, monosyllabic words that a patient can accurately repeat presented at either most comfortable level or most intelligible level.The proportion of patients with hearing response in the target ear was estimated using a binomial distribution along with 95% confidence intervals.
Time Frame	Baseline to 12 months

Outcome Measure Data

Analysis Population Description

All people who underwent treatment were analyzed. Two patients stopped treatment early. One due to toxicity at week 25 and one due to need for medical care not permitted while on treatment at week 49.

Arm/Group Title	Treatment (Bevacizumab) - All Participants	Treatment (Bevacizumab) - Pediatric Participants Only
Arm/Group Description	Patients who met all eligibility criteria underwent baseline evaluation and then received bevacizumab 7.5mg/kg IV once every 3 weeks for up to 48 weeks in the absence of disease progression or unacceptable toxicity. Hearing evaluation for word recognition score was evaluated every 12 weeks. Hearing response was defined as improvement beyond the 95% CI maintained across 2 timepoints.	All enrolled patients < 18 years of age received bevacizumab 7.5mg/kg IV once every 3 weeks for 12 months.
Measure Participants	14	2
Number (95% Confidence Interval) [Proportion with hearing response]	0.36	0.50

2. Secondary Outcome

Title	Incidence of Serious or Life Threatening Toxicities
Description	The number of patients with serious or life threatening toxicities (CTCAE grade 3 or above)
Time Frame	Up to 6 months post-treatment

Outcome Measure Data

Analysis Population Description

Participants evaluated for serious or life threatening toxicities

Arm/Group Title	Treatment (Bevacizumab) - All Participants	Treatment (Bevacizumab) - Pediatric Participants
Arm/Group Description	All enrolled patients received bevacizumab 7.5mg/kg IV once every 3 weeks for 12 months.	All enrolled patients < 18 years of age received bevacizumab 7.5mg/kg IV once every 3 weeks for 12 months.
Measure Participants	14	2
Count of Participants [Participants]	2 14.3%	0 NaN

3. Secondary Outcome

Title	Radiographic Response
Description	The proportion of participants with radiographic response as measured by a >/= 20% reduction in tumor volume from baseline on MRI imaging will be estimated using a binomial distribution.
Time Frame	Baseline to 6 months post-treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Bevacizumab) - All Participants	Treatment (Bevacizumab) - Pediatric Participants
Arm/Group Description	All enrolled participants received bevacizumab 7.5mg/kg IV once every 3 weeks for up to 12 months.	All enrolled patients < 18 years of age received bevacizumab 7.5mg/kg IV once every 3 weeks for 12 months.
Measure Participants	14	2
Number (95% Confidence Interval) [participants]	0.43 3.1%	0.50 NaN

4. Secondary Outcome

Title	Median Percent Change in Target Vestibular Schwannoma Volume Using Volumetric MRI
Description	The median percent change in the volume of the target vestibular schwannoma using volumetric MRI
Time Frame	Baseline to 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Bevacizumab) - All Participants	Treatment (Bevacizumab) - Pediatric Participants
Arm/Group Description	All enrolled participants received bevacizumab 7.5mg/kg IV once every 3 weeks for up to 12 months.	All enrolled patients < 18 years of age received bevacizumab 7.5mg/kg IV once every 3 weeks for 12 months.
Measure Participants	14	2
Median (Full Range) [percentage of change in tumor volume]	0.5	10.8

5. Secondary Outcome

Title	Number of Participants With Changes in Function of the Auditory System
Description	The primary distortion product optoacoustic emissions (DPOAE) measurement will be treated non-parametrically (present or absent across time) DPOAE's will be considered present at the frequency of F2 when the distortion product is 6dB above the noise floor. Variables will be analyzed for differences using t-tests if the effects and sample sizes warrant, but this may not be advisable given the small numbers to be accrued.
Time Frame	Baseline to 6 months post-treatment

Outcome Measure Data

Analysis Population Description

Distortion product optoacoustic emissions (DPOEs) were only obtained for participants at the NCI site; thus, data from 5 participants were analyzed.

Arm/Group Title	Treatment (Bevacizumab) - All Participants
Arm/Group Description	Bevacizumab IV over 30-90 minutes once every 3 weeks. Courses repeat every 6 weeks for up to 48 weeks in the absence of disease progression or unacceptable toxicity.
Measure Participants	5
Present	3 21.4%
Absent	2 14.3%

6. Secondary Outcome

Title	Percent Change in Median Vascular Permeability (Ktrans)
Description	Correlation assessment were planned for imaging parameters and hearing response based on the estimated changes in Ktrans: a MRI measure of vascular permeability. Only 1/14 participants had complete Ktrans data that was amenable to analysis at baseline and week 72. Hence, these statistical analyses were not possible.
Time Frame	Baseline to week 72

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Bevacizumab) - All Participants
Arm/Group Description	Bevacizumab IV over 30-90 minutes once every 3 weeks. Courses repeat every 6 weeks for up to 48 weeks in the absence of disease progression or unacceptable toxicity.
Measure Participants	1
Number [percent change in median Ktrans]	-20

7. Secondary Outcome

Title	Quality of Life Assessed Using Health Survey Short Form-36 (SF-36) - Total Score
Description	The SF-36 is a patient reported outcome. SF-36 (v.1) was administered and was scored according to instructions found on the RAND website. The range of scores is 0 - 100, with a higher value indicating a more favorable health state. The total score is the median of the all the individual items.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Bevacizumab) - All Participants
Arm/Group Description	Bevacizumab IV over 30-90 minutes once every 3 weeks. Courses repeat every 6 weeks for up to 48 weeks in the absence of disease progression or unacceptable toxicity.
Measure Participants	14
Median (Full Range) [units on a scale]	77.85

8. Secondary Outcome

Title	Quality of Life Assessed Using Health Survey Short Form-36 (SF-36) - Component Scores
Description	The SF-36 is a patient reported outcome. SF-36 (v.1) was administered and was scored according to instructions found on the RAND website. The range of scores is 0 - 100, with a higher value indicating a more favorable health state. Scores are commonly reported as a physical component summary (PCS) and mental component summary (MCS). The PCS and MCS score have been transformed to the T-score metric, which has a mean of 50 and a standard deviation of 10 for the U.S. general population.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Bevacizumab) - All Participants
Arm/Group Description	Bevacizumab IV over 30-90 minutes once every 3 weeks. Courses repeat every 6 weeks for up to 48 weeks in the absence of disease progression or unacceptable toxicity.
Measure Participants	14
Physical Component Summary (PCS)	50.67
Mental Component Summary	50.79

9. Secondary Outcome

Title	Quality of Life Assessed Using Health Survey Short Form-36 (SF-36) - Total Score
Description	The SF-36 is a patient reported outcome. SF-36 (v.1) was administered and was scored according to instructions found on the RAND website. The range of scores is 1 - 100, with a higher value indicating a more favorable health state. The total score is the median of the all the individual items.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

One participant was off study at this point secondary to an adverse event and did not complete the questionnaire. Hence, data from 13 of the 14 participants were available for analysis at this time point.

Arm/Group Title	Treatment (Bevacizumab) - All Participants
Arm/Group Description	Bevacizumab IV over 30-90 minutes once every 3 weeks. Courses repeat every 6 weeks for up to 48 weeks in the absence of disease progression or unacceptable toxicity.
Measure Participants	13
Median (Full Range) [units on a scale]	80.56

10. Secondary Outcome

Title	Quality of Life Assessed Using Health Survey Short Form-36 (SF-36) - Component Scores
Description	The SF-36 is a patient reported outcome. SF-36 (v.1) was administered and was scored according to instructions found on the RAND website. The range of scores is 0 - 100, with a higher value indicating a more favorable health state. Scores are commonly reported as a physical component summary (PCS) and mental component summary (MCS). The PCS and MCS score have been transformed to the T-score metric, which has a mean of 50 and a standard deviation of 10 for the U.S. general population.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

One participant was off study at this point secondary to an adverse event and did not complete the questionnaire. Hence, data from 13 of the 14 participants were available for analysis at this time point.

Arm/Group Title	Treatment (Bevacizumab) - All Participants
Arm/Group Description	Bevacizumab IV over 30-90 minutes once every 3 weeks. Courses repeat every 6 weeks for up to 48 weeks in the absence of disease progression or unacceptable toxicity.
Measure Participants	13
Physical Component Score (PCS)	52.23
Mental component Summary (MCS)	54.30

11. Secondary Outcome

Title	Quality of Life Assessed Using Health Survey Short Form-36 (SF-36) - Total Score
Description	The SF-36 is a patient reported outcome. SF-36 (v.1) was administered and was scored according to instructions found on the RAND website. The range of scores is 0 - 100, with a higher value indicating a more favorable health state. The total score is the median of the all the individual items.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

One participant was off study at this point secondary to an adverse event and did not complete the questionnaire. Hence, data from 13 of the 14 participants were available for analysis at this time point.

Arm/Group Title	Treatment (Bevacizumab) - All Participants
Arm/Group Description	Bevacizumab IV over 30-90 minutes once every 3 weeks. Courses repeat every 6 weeks for up to 48 weeks in the absence of disease progression or unacceptable toxicity.
Measure Participants	13
Median (Full Range) [units on a scale]	75.97

12. Secondary Outcome

Title	Quality of Life Assessed Using Health Survey Short Form-36 (SF-36) - Component Scores
Description	The SF-36 is a patient reported outcome. SF-36 (v.1) was administered and was scored according to instructions found on the RAND website. The range of scores is 0 - 100, with a higher value indicating a more favorable health state. Scores are commonly reported as a physical component summary (PCS) and mental component summary (MCS). The PCS and MCS score have been transformed to the T-score metric, which has a mean of 50 and a standard deviation of 10 for the U.S. general population.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

One participant was off study at this point secondary to an adverse event and did not complete the questionnaire. Hence, data from 13 of the 14 participants were available for analysis at this time point.

Arm/Group Title	Treatment (Bevacizumab) - All Participants
Arm/Group Description	Bevacizumab IV over 30-90 minutes once every 3 weeks. Courses repeat every 6 weeks for up to 48 weeks in the absence of disease progression or unacceptable toxicity.
Measure Participants	13
Physical Component Summary (PCS)	47.88
Mental Component Summary (MCS)	56.62

13. Secondary Outcome

Title	Quality of Life Assessed Using Health Survey Short Form-36 (SF-36) - Total Score
Description	The SF-36 is a patient reported outcome. SF-36 (v.1) was administered and was scored according to instructions found on the RAND website. The range of scores is 0 - 100, with a higher value indicating a more favorable health state. The total score is the median of the all the individual items.
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

One participant had withdrawn consent from the study and did not complete the questionnaire. Hence, data from 13 of the 14 participants were available for analysis at this time point.

Arm/Group Title	Treatment (Bevacizumab) - All Participants
Arm/Group Description	Bevacizumab IV over 30-90 minutes once every 3 weeks. Courses repeat every 6 weeks for up to 48 weeks in the absence of disease progression or unacceptable toxicity.
Measure Participants	13
Median (Full Range) [units on a scale]	75.28

14. Secondary Outcome

Title	Quality of Life Assessed Using Health Survey Short Form-36 (SF-36) - Component Scores
Description	The SF-36 is a patient reported outcome. SF-36 (v.1) was administered and was scored according to instructions found on the RAND website. The range of scores is 0 - 100, with a higher value indicating a more favorable health state. Scores are commonly reported as a physical component summary (PCS) and mental component summary (MCS). The PCS and MCS score have been transformed to the T-score metric, which has a mean of 50 and a standard deviation of 10 for the U.S. general population.
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

One participant had withdrawn consent from the study and did not complete the questionnaire. Hence, data from 13 of the 14 participants were available for analysis at this time point.

Arm/Group Title	Treatment (Bevacizumab) - All Participants
Arm/Group Description	Bevacizumab IV over 30-90 minutes once every 3 weeks. Courses repeat every 6 weeks for up to 48 weeks in the absence of disease progression or unacceptable toxicity.
Measure Participants	13
Physical Component Summary (PCS)	51.73
Mental Component Summary (MCS)	51.51

15. Secondary Outcome

Title	Quality of Life as Assessed by the Speech and Spatial Qualities Questionnaire (SSQ)
Description	The SSQ is a 49 item patient-reported outcome with three subscales: speech understanding (14 questions), spatial location of sounds (17 questions), and the qualities of sounds (18 questions) as they appear to the patient with hearing impairment. Each response is recorded on an 11 point scale (0 - 10), with the anchor points "not at all" (= 0) and "perfectly" (=10). A higher score indicates better hearing. The median score is reported for each subscale. The minimum and maximum scores for the median of each subscale would be 0 and 10, respectively.
Time Frame	baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Bevacizumab) - All Participants
Arm/Group Description	Bevacizumab IV over 30-90 minutes once every 3 weeks. Courses repeat every 6 weeks for up to 48 weeks in the absence of disease progression or unacceptable toxicity.
Measure Participants	14
Speech Understanding	3.2
Spatial Location of Sounds	3.2
Qualities of Sounds	4.7

16. Secondary Outcome

Title	Quality of Life as Assessed by the Speech and Spatial Qualities Questionnaire (SSQ)
Description	The SSQ is a 49 item patient-reported outcome with three subscales: speech understanding (14 questions), spatial location of sounds (17 questions), and the qualities of sounds (18 questions) as they appear to the patient with hearing impairment. Responses are recorded on a scale from 0 - 10, with the anchor points "not at all" (= 0) and "perfectly" (=10). A higher score indicates better hearing. The median score for each subscale is reported. The minimum and maximum scores for the median of each subscale would be 0 and 10, respectively.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

At this time point, one participant was off study due to adverse events and did not complete the questionnaire. Three participants did not complete the questionnaire at this time point. Hence, data from 10 participants were available for analysis.

Arm/Group Title	Treatment (Bevacizumab) - All Participants
Arm/Group Description	Bevacizumab IV over 30-90 minutes once every 3 weeks. Courses repeat every 6 weeks for up to 48 weeks in the absence of disease progression or unacceptable toxicity.
Measure Participants	10
Speech Understanding	4.2
Spatial Location of Sounds	4.0
Qualities of Sounds	6.8

17. Secondary Outcome

Title	Quality of Life as Assessed by the Speech and Spatial Qualities Questionnaire (SSQ)
Description	The SSQ is a 49 item patient-reported outcome with three subscales: speech understanding (14 questions), spatial location of sounds (17 questions), and the qualities of sounds (18 questions) as they appear to the patient with hearing impairment. Responses are recorded on a scale from 0 - 10, with the anchor points "not at all" (= 0) and "perfectly" (=10). A higher score indicates better hearing. The median score for each subscale is reported. The minimum and maximum scores for the median of each subscale would be 0 and 10, respectively.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

At this time point, one participant was off study due to an adverse event and did not complete the questionnaire. Hence, data from 13 of the 14 participants were available for analysis at this time point.

Arm/Group Title	Treatment (Bevacizumab) - All Participants
Arm/Group Description	Bevacizumab IV over 30-90 minutes once every 3 weeks. Courses repeat every 6 weeks for up to 48 weeks in the absence of disease progression or unacceptable toxicity.
Measure Participants	13
Speech Understanding	5.4
Spatial Location of Sounds	4.8
Qualities of Sounds	6.9

18. Secondary Outcome

Title	Quality of Life as Assessed by the Speech and Spatial Qualities Questionnaire (SSQ)
Description	The SSQ is a 49 item patient-reported outcome with three subscales: speech understanding (14 questions), spatial location of sounds (17 questions), and the qualities of sounds (18 questions) as they appear to the patient with hearing impairment. Responses are recorded on a scale from 0 - 10, with the anchor points "not at all" (= 0) and "perfectly" (=10). A higher score indicates better hearing. The median score for each subscale is reported. The minimum and maximum scores for the median of each subscale would be 0 and 10, respectively.
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

One participant had withdrawn consent from the study and did not complete the questionnaire. Hence, data from 13 of the 14 participants were available for analysis at this time point.

Arm/Group Title	Treatment (Bevacizumab) - All Participants
Arm/Group Description	Bevacizumab IV over 30-90 minutes once every 3 weeks. Courses repeat every 6 weeks for up to 48 weeks in the absence of disease progression or unacceptable toxicity.
Measure Participants	13
Speech Understanding	4.1
Spatial Location of Sounds	3.6
Qualities of Sounds	6.3

19. Secondary Outcome

Title	Quality of Life Assessed by the Tinnitus Reaction Questionnaire (TRQ)
Description	The TRQ is a 26 item patient reported outcome. It is scored using a 5 point Likert scale (0-4). The responses are summed, resulting in a range of 0 - 104 with higher scores indicating more distress related to tinnitus.
Time Frame	baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Bevacizumab) - All Participants
Arm/Group Description	Bevacizumab IV over 30-90 minutes once every 3 weeks. Courses repeat every 6 weeks for up to 48 weeks in the absence of disease progression or unacceptable toxicity.
Measure Participants	14
Median (Full Range) [units on a scale]	18

20. Secondary Outcome

Title	Quality of Life Assessed by the Tinnitus Reaction Questionnaire (TRQ)
Description	The TRQ is a 26 item patient reported outcome. It is scored using a 5 point Likert scale (0-4). The responses are summed, resulting in a range of 0 - 104 with higher scores indicating more distress related to tinnitus.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

At this time point, one participant was off study due to an adverse event and did not complete the questionnaire. One participant did not complete this questionnaire at this time point. Hence, data from 12 of the 14 participants were available for analysis at this time point.

Arm/Group Title	Treatment (Bevacizumab) - All Participants
Arm/Group Description	Bevacizumab IV over 30-90 minutes once every 3 weeks. Courses repeat every 6 weeks for up to 48 weeks in the absence of disease progression or unacceptable toxicity.
Measure Participants	12
Median (Full Range) [units on a scale]	18

21. Secondary Outcome

Title	Quality of Life Assessed by the Tinnitus Reaction Questionnaire (TRQ)
Description	The TRQ is a 26 item patient reported outcome. It is scored using a 5 point Likert scale (0-4). The responses are summed, resulting in a range of 0 - 104 with higher scores indicating more distress related to tinnitus.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

At this time point, one participant was off study due to an adverse event and did not complete the questionnaire. Hence, data from 13 of the 14 participants were available for analysis at this time point.

Arm/Group Title	Treatment (Bevacizumab) - All Participants
Arm/Group Description	Bevacizumab IV over 30-90 minutes once every 3 weeks. Courses repeat every 6 weeks for up to 48 weeks in the absence of disease progression or unacceptable toxicity.
Measure Participants	13
Median (Full Range) [units on a scale]	10

22. Secondary Outcome

Title	Quality of Life Assessed by the Tinnitus Reaction Questionnaire (TRQ)
Description	The TRQ is a 26 item patient reported outcome. It is scored using a 5 point Likert scale (0-4). The responses are summed, resulting in a range of 0 - 104 with higher scores indicating more distress related to tinnitus.
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

At this time point, one participant had withdrawn consent from the study and did not complete the questionnaire. Hence, data from 13 of the 14 participants were available for analysis at this time point.

Arm/Group Title	Treatment (Bevacizumab) - All Participants
Arm/Group Description	Bevacizumab IV over 30-90 minutes once every 3 weeks. Courses repeat every 6 weeks for up to 48 weeks in the absence of disease progression or unacceptable toxicity.
Measure Participants	13
Median (Full Range) [units on a scale]	23

Adverse Events

Time Frame	From first dose until 6 months off of drug or until resolution of all SAE to baseline, assessed up to 12 months
Adverse Event Reporting Description	definition is that used in clinicaltrials.gov
Arm/Group Title	Treatment (Bevacizumab) - All Participants		Treatment (Bevacizumab) - Pediatric Participants
Arm/Group Description	All enrolled participants received bevacizumab 7.5mg/kg IV once every 3 weeks for up to 12 months.		All enrolled patients < 18 years of age received bevacizumab 7.5mg/kg IV once every 3 weeks for 12 months.
All Cause Mortality
	Treatment (Bevacizumab) - All Participants		Treatment (Bevacizumab) - Pediatric Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/2 (0%)
Serious Adverse Events
	Treatment (Bevacizumab) - All Participants		Treatment (Bevacizumab) - Pediatric Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/14 (14.3%)		0/2 (0%)
Blood and lymphatic system disorders
Idiopathic thrombocytopenia purpura	1/14 (7.1%)	1	0/2 (0%)	0
Vascular disorders
Hypertension	1/14 (7.1%)	2	0/2 (0%)	0
Other (Not Including Serious) Adverse Events
	Treatment (Bevacizumab) - All Participants		Treatment (Bevacizumab) - Pediatric Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/14 (92.9%)		1/2 (50%)
Blood and lymphatic system disorders
Anemia	1/14 (7.1%)	1	0/2 (0%)	1
Hemolysis	1/14 (7.1%)	1	0/2 (0%)	1
Cardiac disorders
Palpitations	2/14 (14.3%)	2	0/2 (0%)	2
Ear and labyrinth disorders
Vertigo	1/14 (7.1%)	1	1/2 (50%)	1
Gastrointestinal disorders
Abdominal pain	2/14 (14.3%)	2	0/2 (0%)	2
Diarrhea	3/14 (21.4%)	3	1/2 (50%)	1
Dyspepsia	2/14 (14.3%)	2	0/2 (0%)	2
Hemorrhoidal hemorrhage	2/14 (14.3%)	2	0/2 (0%)	2
Mucositis oral	1/14 (7.1%)	1	0/2 (0%)	1
Nausea	4/14 (28.6%)	7	1/2 (50%)	1
Oral hemorrhage	2/14 (14.3%)	2	0/2 (0%)	2
Oral pain	1/14 (7.1%)	1	0/2 (0%)	1
Rectal hemorrhage	1/14 (7.1%)	1	0/2 (0%)	1
Vomiting	1/14 (7.1%)	1	0/2 (0%)	1
Weight loss	1/14 (7.1%)	1	0/2 (0%)	1
General disorders
Fatigue	9/14 (64.3%)	13	1/2 (50%)	2
Injury, poisoning and procedural complications
Bruising	2/14 (14.3%)	2	0/2 (0%)	2
Wound complication	1/14 (7.1%)	1	0/2 (0%)	1
Investigations
ALT increased	5/14 (35.7%)	8	0/2 (0%)	8
AST increase	4/14 (28.6%)	8	0/2 (0%)	8
CPK increase	1/14 (7.1%)	1	1/2 (50%)	1
Electrocardiogram with prolonged QTc	1/14 (7.1%)	1	1/2 (50%)	1
Increased blood bicarbonate	1/14 (7.1%)	1	0/2 (0%)	1
Platelet count decreased	1/14 (7.1%)	2	1/2 (50%)	2
Weight gain	1/14 (7.1%)	1	0/2 (0%)	1
Metabolism and nutrition disorders
Anorexia	1/14 (7.1%)	2	0/2 (0%)	2
Hyperglycemia	2/14 (14.3%)	4	0/2 (0%)	4
Hypermagnesemia	2/14 (14.3%)	3	1/2 (50%)	2
Nervous system disorders
Dizziness	1/14 (7.1%)	1	0/2 (0%)	1
Headache	1/14 (7.1%)	2	1/2 (50%)	2
Peripheral sensory neuropathy	1/14 (7.1%)	1	0/2 (0%)	1
Renal and urinary disorders
Hemoglobinuria	1/14 (7.1%)	1	1/2 (50%)	1
Proteinuria	2/14 (14.3%)	10	1/2 (50%)	6
Reproductive system and breast disorders
Irregular menstruation	2/7 (28.6%)	6	1/2 (50%)	4
Menorrhagia	1/7 (14.3%)	3	1/2 (50%)	1
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	1/14 (7.1%)	1	1/2 (50%)	1
Dyspnea	2/14 (14.3%)	2	1/2 (50%)	1
Epistaxis	7/14 (50%)	10	1/2 (50%)	1
Hoarseness	1/14 (7.1%)	1	1/2 (50%)	1
Nasal septum perforation	1/14 (7.1%)	1	0/2 (0%)	1
Sore throat	2/14 (14.3%)	4	1/2 (50%)	2
Voice alteration	1/14 (7.1%)	1	0/2 (0%)	1
Skin and subcutaneous tissue disorders
Dry skin	2/14 (14.3%)	2	1/2 (50%)	1
Vascular disorders
Hypomagnesemia	1/14 (7.1%)	1	0/2 (0%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.