HYPOTHESES
HA: Among patients with MRONJ, after 12 months of treatment with PENTO, the area of
exposed bone in the PENTO group will be different than the area of exposed bone in the
standard therapy group.
H0: Among patients with MRONJ, after 12 months of treatment with PENTO, the area of
exposed bone in the PENTO group will equal the area of exposed bone in the standard
therapy group.
SPECIFIC AIMS
To determine if the PENTO regimen in addition to the standard of care treatment for MRONJ
significantly reduces the area of exposed bone compared to standard of care alone.
Standard of care is defined as the clinical guidelines of the 2014 AAOMS Position Paper
on Medication-Related Osteonecrosis of the Jaw (MRONJ)
Challenges: Identifying patients with Stage 1, 2, 3 MRONJ who will be compliant with
therapy and available for follow-up. Measuring greatest anterior-posterior and
superior-inferior dimensions to calculate area. Ensuring patient safety with interim
analyses and an appropriate stopping protocol.
Approach: The investigators will treat patients with Stage 1, 2, 3 MRONJ with either
PENTO as an adjunct to the standard of care or standard of care alone with placebo.
Impact: >6 million patients in the US are at risk for MRONJ. If proven to successfully
treat MRONJ, the trial would establish a non-operative treatment option for successful
management of MRONJ with potential for significant decreased morbidity for the patient.
SAMPLE
The sample will be derived from the population of patients who present to a participating
trial site for management of MRONJ during the trial's enrollment period. To be included
in the trial a patient must meet the criteria listed below. If a patient is excluded from
the trial the reason will be documented for the study's record as well as basic
demographic data, MRONJ staging, risk medications, indication for and use of
antiresorptive and antiangiogenic medications and area of exposed bone will be collected.
RANDOMIZATION
A stratified permuted-block randomization will be used to allocate patients to treatment.
This method ensures balanced allocations to achieve approximately the preset treatment
allocation ratio of 1:1 and avoids predictability of future assignments. Strata will be
constructed for the prognostic variables of initial MRONJ stage (1,2,3) and
antiresorptive therapy (bisphosphonate vs. denosumab/RANK-L inhibitor). Within each
strata, block sizes of 2 and 4 will be used to randomize patients to PENTO + standard of
care or to standard of care with placebo alone with randomization of treatment sequence
to meet the 1:1 allocation ratio within each block.
A computer-generated list of random allocations will be prepared for each strata. The
allocation sequence will be concealed from the researcher enrolling and assessing
participants in sequentially numbered, opaque, sealed and stapled envelopes.
Corresponding envelopes will be opened only after the enrolled participants complete
DATA MANAGEMENT AND ANALYSIS
The primary analysis of interest is the association between treatment group and area of
exposed bone. The primary analysis will be a repeated measures analysis of variance
(ANOVA) with one within subject (time) factor and one between subject (treatment) factor
will be completed for A = area based upon Dap and Dsi and geometric shape of the lesion.
If outcomes do not meet assumptions then non-parametric analogues will be used.
SAMPLE SIZE ESTIMATE
alpha = 0.05, beta = 0.10, Anticipated drop-out rate = 30%
A stratified permuted- block randomization will be used to allocate patients to
treatment. Intention to treat to include all subjects as randomized to treatment
(detailed on page 3 of the application). If a patient drops out or is withdrawn prior to
12-month treatment endpoint, the last observation carried forward (LOCF) will be included
in analysis. In addition, patients "as treated" (patient received incorrect treatment) or
"as protocol" (doesn't include patient dropouts or withdrawals) will be analyzed to
evaluate effectiveness of the treatment. To detect a relative change in primary outcome
≥20% with the above parameters, a minimum sample of 44 patients in each study arm is
required (total n=88).
The investigators deemed that an improvement of ≥20% by the intervention group compared
to the control group in decreased bone exposure to be clinically significant. There is no
consensus in the current literature on a clinically significant difference between the
control and treatment arms. However, if the study is powered for the outcomes expected
based on current literature, a difference of 50% between arms would only require 7
patients per arm. Therefore the investigators believe the study to be overpowered to
ensure the statistical analysis would remain significant if the suspected success of the
PENTO regimen is not true.
STOPPING RULES
Because this is an investigational use of pentoxifylline and the benefits of PENTO in
MRONJ are not presently established, interim analyses (p=.001) will be performed at 3 and
6 months. If the trial is stopped after an interim analysis for proven benefit, the trial
will be converted to an open trial and the patients will be followed for the entire
12-month treatment period, or until they achieve complete mucosal coverage.
Patient withdrawal from study criteria include:
A serious adverse event related to the trial medication.
Patient becomes pregnant.
Any relevant deterioration in the health of the subject (AEs, vital signs, ECG,
laboratory parameters).
Clinically relevant change in vital signs if technical failure
OVERSIGHT RESPONSIBILITIES
Oversight of the trial is provided by the Principal Investigator (PI) Dr. Dillon and Co-
Investigators (Co-I) Dr. Ruggiero, Dr. Morlandt, and Dr. Ward.
MONITORING PROCEDURES
Drs. Dillon, Ruggiero, Morlandt, and Ward assure that informed consent is obtained prior
to performing any research procedures, that all subjects meet eligibility criteria, and
that the study is conducted according to the IRB-approved research plan. Blinded study
data are accessible at all times for the PI and Co-investigators to review. All four
investigators will review study conduct including accrual, drop-outs, and protocol
deviations on a quarterly basis. In addition, the investigators will review adverse
events (AEs) individually real-time and in aggregate on a monthly basis. Last, the
investigators will review serious adverse events (SAEs), dose limiting toxicities, and
any other specific intervention complications in real-time. The PI ensures all protocol
deviations, AEs, and SAEs are reported to the FDA, DSMB and IRB according to the
applicable regulatory requirements.
COLLECTION AND REPORTING OF SAEs AND AEs
For this study, the following standard AE definitions are used:
Adverse event (AE): Any unfavorable and unintended sign (including an abnormal laboratory
finding), symptom or disease temporally associated with the use of a medical treatment or
procedure, regardless of whether it is considered related to the medical treatment or
procedure.
Serious Adverse Event: Any AE that results in any of the following outcomes:
AEs are graded according to the following scale:
Mild: An experience that is transient & requires no special treatment or
intervention.
Moderate: An experience that is alleviated with simple therapeutic treatments.
Severe: An experience that requires therapeutic intervention. The experience
interrupts usual daily activities.
The study uses the following AE attribution scale:
Not related: The AE is clearly not related to the study
Possibly related: An event that follows a reasonable temporal sequence from the
initiation of study procedures, but that could readily have been produced by a
number of other factors.
Related: The AE is clearly related to the study procedures.
SAEs and specific procedure-associated AEs are reported to the University of Washington
IRB and DSMB within 24 hours. In addition, all AEs are reported according to the
University of Washington IRB AE reporting guidelines.
MANAGEMENT OF RISKS TO SUBJECTS
Expected AEs associated with the Pentoxifylline and Tocopherol include: Dizziness,
headache, nausea, vomiting, indigestion, flushing, angina, palpitations,
hypersensitivity, itchiness, rash, hives, bleeding, hallucinations, arrhythmias, aseptic
meningitis
AE Management
If any unanticipated problems related to the research involving risks to subjects or
others happen during the course of this study (including SAEs) these will be reported to
the IRB in accordance with University of Washington Human Subjects Division (HSD)
protocols and the DSMB. AEs that are not serious but that are notable and could involve
risks to subjects will be summarized in narrative or other format and submitted to the
IRB and DSMB at the time of continuing review.
DATA SAFETY AND MONITORING (DSMB) ANALYSIS PLAN
The Analysis for safety (AEs) will be conducted at a minimum of 3 and 6 months. However,
depending upon recruitment the analysis of safety will be as follows when:
10, 20, 30, 40, 60, 80, 100 patients have completed 3 months of follow up.
Patient withdrawal criteria include:
A serious adverse event related to the trial medication.
Patient becomes pregnant.
Any relevant deterioration in the health of the subject (AEs, vital signs, ECG,
laboratory parameters).
Clinically relevant change in vital signs if technical failure can be excluded and
result is confirmed by at least 1 additional measurement.
PLAN FOR DATA MANAGEMENT
Compliance of regulatory documents and study data accuracy and completeness will be
maintained through an internal study team quality assurance process.
Confidentiality throughout the trial is maintained by the previously described
study-specific confidentiality procedures. DATA will be stored as de-identified on a
REDCap database which will be password protected and only accessible by study members.
INFORMED CONSENT/ETHICAL CONSIDERATIONS
Quality and integrity of the research will be ensured through data safety monitoring and
informed patient consent for participation. Enrollment will be done by the study
coordinator at each site not the participating surgeon. Other than the UW study
coordinator the other coordinators will be research students participating in the trial.
The research will be independent and impartial, and key study personnel directly involved
in patient care will be blinded to the treatment. Informed consents to be obtained from
patients will state the overall purpose of the study, alternatives to participation, and
any direct and indirect risks/benefits from participation. All patient literature and
consents will be written at an 8th grade reading level. The confidentiality and anonymity
of the research respondents and patient health information will be respected. IRB
approvals will be obtained at all study sites prior to beginning any research activities.
The individual study site IRBs will determine if it is appropriate to pursue an expanded
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