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NCT02819479: LIBERTI

Low-dose Intra-arterial Bevacizumab for Edema and Radiation Necrosis Therapeutic Intervention (LIBERTI)

Completed Phase 2 Results posted Last updated 24 May 2022
What this trial tests

Phase 2 trial testing 25% Mannitol in Radiation Necrosis in 10 participants. Completed in 6 June 2019.

Timeline
23 November 2016
Primary endpoint
6 June 2019
6 June 2019

Quick facts

Lead sponsorNorton Healthcare
PhasePhase 2
StatusCompleted
Study typeINTERVENTIONAL
Allocationna
Designsingle group
Maskingnone
Primary purposetreatment
Enrollment10
Start date23 November 2016
Primary completion6 June 2019
Estimated completion6 June 2019
Sites2 locations across United States

Drugs / interventions tested

Conditions studied

Sponsor

Norton Healthcare — full company profile →

Who can join

18 and older, any sex, with Radiation Necrosis. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Change in Radiation Necrosis and Cerebral Edema After a Single Treatment of Low Dose Intra-arterial Avastin (Bevacizumab) Primary · Baseline (before treatment), and 3 months and 12 months after single dose intra-arterial Avastin (bevacizumab)

Imaging response to therapy will be quantitatively assessed on MRI using volumetric analysis. Regions of T2 and FLAIR prolongation above contralateral white matter will be calculated and quantified in cubic centimeters. Region of interest (ROI) will be created using a semi-automated, thresholding and region-growing technique. Enhancement of the lesion will be calculated using similar volumetric ROI analysis with a contrast threshold of 40% above background and measured in cubic centimeters.

Vol EDEMA at Baseline
GroupValue95% CI
Low-dose Intra-arterial Avastin (Bevacizumab)86.8± 95.9
Vol EDEMA at 3 months
GroupValue95% CI
Low-dose Intra-arterial Avastin (Bevacizumab)38.6± 37.5
Vol EDEMA at 12 months
GroupValue95% CI
Low-dose Intra-arterial Avastin (Bevacizumab)32.6± 33.7
Vol Radiation Necrosis at Baseline
GroupValue95% CI
Low-dose Intra-arterial Avastin (Bevacizumab)14.5± 12.1
Vol Radiation Necrosis at 3 months
GroupValue95% CI
Low-dose Intra-arterial Avastin (Bevacizumab)6.6± 7.5
Vol Radiation Necrosis at 12 months
GroupValue95% CI
Low-dose Intra-arterial Avastin (Bevacizumab)3.2± 3.3
Change in Headache Associated Morbidity Measured With MIDAS TOTAL SCORE After a Single Treatment of Low Dose Intra-arterial Avastin (Bevacizumab) Will be Measured. Secondary · Baseline (before treatment), and 6 weeks, 3 months, 6 months, 9 months, and 12 months after single dose intra-arterial Avastin (bevacizumab)

We will determine how severely headache affect the patient's life before and after treatment by performing the Migraine Disability Assessment (MIDAS) questionnaire. MIDAS TOTAL SCORE is the sum of Items 1 through 5. A Total Score of 0-5 signifies little or no disability, score of 6-10 signifies mild disability, score of 11-20 signifies moderate disability, and score of 21+ signifies severe disability. The theoretical maximum score would be 450.

MIDAS TOTAL at Baseline
GroupValue95% CI
Low-dose Intra-arterial Avastin (Bevacizumab)81.7± 110.1
MIDAS TOTAL at 6 weeks
GroupValue95% CI
Low-dose Intra-arterial Avastin (Bevacizumab)49.7± 66.6
MIDAS TOTAL at 3 months
GroupValue95% CI
Low-dose Intra-arterial Avastin (Bevacizumab)22.1± 30.3
MIDAS TOTAL at 6 months
GroupValue95% CI
Low-dose Intra-arterial Avastin (Bevacizumab)28.3± 46.2
MIDAS TOTAL at 9 months
GroupValue95% CI
Low-dose Intra-arterial Avastin (Bevacizumab)24.4± 33.7
MIDAS TOTAL at 12 months
GroupValue95% CI
Low-dose Intra-arterial Avastin (Bevacizumab)15.6± 26.5
Change in Headache Associated Morbidity Measured With MIDAS DAYS of HEADACHE After a Single Treatment of Low Dose Intra-arterial Avastin (Bevacizumab) Will be Measured. Secondary · Baseline (before treatment), and 6 weeks, 3 months, 6 months, 9 months, and 12 months after single dose intra-arterial Avastin (bevacizumab)

We will determine how severely headache affect the patient's life before and after treatment by performing the Migraine Disability Assessment (MIDAS) questionnaire. MIDAS DAYS of HEADACHE is Item 6 of the questionnaire which sums total number of days the patient had headache symptoms over the past 3 months regardless of headache severity or resultant disability. Min score of 0 days is the best possible score. Max Score of 90 days is worse possible score, meaning the patient experienced headache pain every day over past 3 months.

MIDAS DAYS of HEADACHE at Baseline
GroupValue95% CI
Low-dose Intra-arterial Avastin (Bevacizumab)33.3± 29.8
MIDAS DAYS of HEADACHE at 6 weeks
GroupValue95% CI
Low-dose Intra-arterial Avastin (Bevacizumab)25.8± 35.0
MIDAS DAYS of HEADACHE at 3 months
GroupValue95% CI
Low-dose Intra-arterial Avastin (Bevacizumab)9.0± 9.3
MIDAS DAYS of HEADACHE at 6 months
GroupValue95% CI
Low-dose Intra-arterial Avastin (Bevacizumab)14.6± 14.1
MIDAS DAYS of HEADACHE at 9 months
GroupValue95% CI
Low-dose Intra-arterial Avastin (Bevacizumab)12.4± 17.6
MIDAS DAYS of HEADACHE at 12 months
GroupValue95% CI
Low-dose Intra-arterial Avastin (Bevacizumab)11.5± 17.0
Change in Headache Associated Morbidity Measured With MIDAS PAIN LEVEL After a Single Treatment of Low Dose Intra-arterial Avastin (Bevacizumab) Will be Measured. Secondary · Baseline (before treatment), and 6 weeks, 3 months, 6 months, 9 months, and 12 months after single dose intra-arterial Avastin (bevacizumab)

We will determine how severely headache affect the patient's life before and after treatment by performing the Migraine Disability Assessment (MIDAS) questionnaire. MIDAS PAIN LEVEL is Item 7 which rates the 3-month average headache PAIN LEVEL on scale from 0 to 10 where 0 = no pain at all, and 10 = pain as bad as it can be.

MIDAS PAIN LEVEL at Baseline
GroupValue95% CI
Low-dose Intra-arterial Avastin (Bevacizumab)6.9± 2.2
MIDAS PAIN LEVEL at 6 weeks
GroupValue95% CI
Low-dose Intra-arterial Avastin (Bevacizumab)6.4± 1.8
MIDAS PAIN LEVEL at 3 months
GroupValue95% CI
Low-dose Intra-arterial Avastin (Bevacizumab)4.7± 2.9
MIDAS PAIN LEVEL at 6 months
GroupValue95% CI
Low-dose Intra-arterial Avastin (Bevacizumab)5.0± 2.9
MIDAS PAIN LEVEL at 9 months
GroupValue95% CI
Low-dose Intra-arterial Avastin (Bevacizumab)4.8± 3.0
MIDAS PAIN LEVEL at 12 months
GroupValue95% CI
Low-dose Intra-arterial Avastin (Bevacizumab)4.8± 3.5
Change in Headache Measured With Headache Impact Test (HIT-6) After a Single Treatment of Low Dose Intra-arterial Avastin (Bevacizumab) Secondary · Baseline (before treatment), and 6 weeks, 3 months, 6 months, 9 months, and 12 months after single dose intra-arterial Avastin (bevacizumab)

Quantitative change in headache will be assessed by performing the Headache Impact Test (HIT-6), which is a fixed-length 6-item questionnaire. The score for this questionnaire can range from 36 to 78, with 36 indicating minimum headache impact and the max score of 78 indicating worst possible headache impact.

Headache Impact Test-6, Baseline
GroupValue95% CI
Low-dose Intra-arterial Avastin (Bevacizumab)62.4± 7.5
Headache Impact Test-6, 6 Weeks
GroupValue95% CI
Low-dose Intra-arterial Avastin (Bevacizumab)54.5± 11.4
Headache Impact Test-6, 3 months
GroupValue95% CI
Low-dose Intra-arterial Avastin (Bevacizumab)52.3± 13.0
Headache Impact Test-6, 6 months
GroupValue95% CI
Low-dose Intra-arterial Avastin (Bevacizumab)53.3± 13.6
Headache Impact Test-6, 9 months
GroupValue95% CI
Low-dose Intra-arterial Avastin (Bevacizumab)53.2± 15.4
Headache Impact Test-6, 12 months
GroupValue95% CI
Low-dose Intra-arterial Avastin (Bevacizumab)52.1± 14.4
Change in Functional Status After a Single Treatment of Low Dose Intra-arterial Bevacizumab Secondary · Baseline (before treatment), Day 1, and at 3 months, and 12 months after single dose intra-arterial Avastin (bevacizumab)

Quantitative change in functional status will be assessed by performing Karnofsky Performance Status Scale (KPS). The KPS score can range from 0 to 100 where 0 is dead and 100 is fully alive and normal with no complaints and no evidence of disease.

Karnofsky at Baseline
GroupValue95% CI
Low-dose Intra-arterial Bevacizumab79.0± 9.9
Karnofsky at Day 1
GroupValue95% CI
Low-dose Intra-arterial Bevacizumab81.0± 7.4
Karnofsky at Month 3
GroupValue95% CI
Low-dose Intra-arterial Bevacizumab83.0± 11.6
Karnofsky at Month 12
GroupValue95% CI
Low-dose Intra-arterial Bevacizumab86.3± 7.4
Change in Steroid Usage After a Single Treatment of Low Dose Intra-arterial Avastin (Bevacizumab) Secondary · 12 months prior to single dose of IA bevacizumab; 12 months following single dose of IA bevacizumab

To assess the utility of intra-arterial (IA) bevacizumab treatment in allowing decreased steroid usage, total cumulative days of steroid usage were compared between the 12 months PRIOR TO and the 12 months IMMEDIATELY FOLLOWING IA bevacizumab. Days of steroid usage were tabulated via medical history and chart review at the baseline visit for the 12 months prior to IA bevacizumab and post-treatment on days 0 and 1, week 6, and months 3, 6, 9 and 12 for the 12 month total after IA bevacizumab treatment. Excluding topical steroid preparations, all days of enteral or parenteral steroid intake of a

12 months PRIOR to IA bevacizumab
GroupValue95% CI
Low-dose Intra-arterial Avastin (Bevacizumab)61.50 – 156.25
12 months AFTER IA bevacizumab
GroupValue95% CI
Low-dose Intra-arterial Avastin (Bevacizumab)13.00 – 87.25
Post-operative Neurocognitive Change After Intra-arterial Bevacizumab Secondary · Baseline (before bevacizumab), and 3 months and 12 months after single dose intra-arterial Avastin (bevacizumab)

In order to investigate post-operative changes in Neurocognitive performance after intra-arterial bevacizumab, patients who consented underwent formal neuropsychological battery testing. Sixteen subtests from the Neuropsychological Assessment Battery (Stern \& White, PAR Inc.) were chosen for brevity, sensitivity, and due to the wide range of available normative data (ages 18-97). For each subtest, T-score = 50 is the normative mean with SD = 10. Thus T-scores of 40-60 are within one standard deviation of the mean and are considered generally normal. Scores increasingly below 40 indicate decre

Digits Forward at Baseline
GroupValue95% CI
Low-dose Intra-arterial Bevacizumab41.1± 11.8
Digits Forward at 3 months
GroupValue95% CI
Low-dose Intra-arterial Bevacizumab44.1± 12.2
Digits Forward at 12 months
GroupValue95% CI
Low-dose Intra-arterial Bevacizumab42.3± 11.7
Digits Backward at Baseline
GroupValue95% CI
Low-dose Intra-arterial Bevacizumab44.9± 8.3
Digits Backward at 3 months
GroupValue95% CI
Low-dose Intra-arterial Bevacizumab44.9± 11.9
Digits Backward at 12 months
GroupValue95% CI
Low-dose Intra-arterial Bevacizumab40.3± 13.1
Numbers & Letters SPEED at Baseline
GroupValue95% CI
Low-dose Intra-arterial Bevacizumab38.2± 10.7
Numbers & Letters SPEED at 3 months
GroupValue95% CI
Low-dose Intra-arterial Bevacizumab36.7± 10.8

Adverse events — posted to ClinicalTrials.gov

Time frame: 1 year. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Low-dose Intra-arterial Bevacizumab
Serious: 6/10 (60%)
Deaths: 0/10

Serious adverse events (10 terms)

ReactionSystemLow-dose Intra-arterial Be…
SeizureNervous system disorders
Acute encephalopathyNervous system disorders
Double VisionNervous system disorders
Chest PainCardiac disorders
HeadacheNervous system disorders
DizzinessNervous system disorders
DysarthriaNervous system disorders
Left Lower Extremity HemiparesisNervous system disorders
Left Upper Extremity HemiparesisNervous system disorders
Cerebral EdemaNervous system disorders
Other adverse events (77 terms — click to expand)

ReactionSystemLow-dose Intra-arterial Be…
HeadacheNervous system disorders
Blurred visionEye disorders
FallGeneral disorders
Neck painMusculoskeletal and connective tissue disorders
NumbnessNervous system disorders
Leg crampsMusculoskeletal and connective tissue disorders
SeizuresNervous system disorders
Traumatic FallInjury, poisoning and procedural complications
VomitingGastrointestinal disorders
1st degree AV blockCardiac disorders
AcneSkin and subcutaneous tissue disorders
Altered Mental StatusNervous system disorders
AmnesiaNervous system disorders
AnxietyNervous system disorders
Asthma episodeRespiratory, thoracic and mediastinal disorders
Bilateral lower leg edemaVascular disorders
Cervical strainMusculoskeletal and connective tissue disorders
ConfusionNervous system disorders
Decreased appetiteGastrointestinal disorders
DehydrationGeneral disorders
DiplopiaEye disorders
Expressive aphasiaNervous system disorders
Fracture Left HandInjury, poisoning and procedural complications
Generalized AnxietyPsychiatric disorders
Generalized MalaiseGeneral disorders
hair lossSkin and subcutaneous tissue disorders
HallucinationsPsychiatric disorders
Head TraumaInjury, poisoning and procedural complications
HypercholesterolemiaGeneral disorders
HypersomniaNervous system disorders
HypertensionCardiac disorders
HypertriglyceridemiaGeneral disorders
Inability to focusEye disorders
Inability to focus attentionNervous system disorders
Incomplete Spontaneous AbortionPregnancy, puerperium and perinatal conditions
DizzinessNervous system disorders
Eye twitchesEye disorders
Homonymous HemianopiaEye disorders
Leg skin tear non-healing woundSkin and subcutaneous tissue disorders
Leg traumatic injuryInjury, poisoning and procedural complications

Most-reported serious reactions: Seizure, Acute encephalopathy, Double Vision, Chest Pain, Headache, Dizziness, Dysarthria, Left Lower Extremity Hemiparesis.

Data from ClinicalTrials.gov NCT02819479 adverse events section.

Sponsor's own description

To assess the overall safety and efficacy of intra-arterial (IA) bevacizumab for the treatment of radiation necrosis. A single 2.5 mg/kg dose of bevacizumab will be given intra-arterially after osmotic blood-brain-barrier disruption.

Publications & conference data

5 peer-reviewed publications reference this trial (live from Europe PMC):

  1. The Medical Management of Cerebral Edema: Past, Present, and Future Therapies.
    Halstead MR, Geocadin RG. · · 2019 · cited 56× · PMID 31512062 · DOI 10.1007/s13311-019-00779-4
  2. Blood-brain barrier opening by intracarotid artery hyperosmolar mannitol induces sterile inflammatory and innate immune responses.
    Burks SR, Kersch CN, Witko JA, Pagel MA, et al · · 2021 · cited 47× · PMID 33906946 · DOI 10.1073/pnas.2021915118
  3. Single low-dose targeted bevacizumab infusion in adult patients with steroid-refractory radiation necrosis of the brain: a phase II open-label prospective clinical trial.
    Dashti SR, Kadner RJ, Folley BS, Sheehan JP, et al · · 2022 · cited 16× · PMID 35426830 · DOI 10.3171/2022.2.jns212006
  4. Single-shot bevacizumab for cerebral radiation injury.
    Voss M, Wenger KJ, Fokas E, Forster MT, et al · · 2021 · cited 13× · PMID 33596839 · DOI 10.1186/s12883-021-02103-0
  5. Intra-arterial Bevacizumab in Adult Patients With Steroid-Refractory Cerebral Radiation Necrosis: An Observational Study of Clinical Indications and Outcomes.
    Shields LB, Kadner RJ, Ghiassi M, Shelburne CT, et al · · 2025 · cited 1× · PMID 40225447 · DOI 10.7759/cureus.80522

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