Pentoxifylline and Tocopherol (PENTO) in the Treatment of Medication-related Osteonecrosis of the Jaw (MRONJ)
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT03040778|
Recruitment Status : Enrolling by invitation
First Posted : February 2, 2017
Last Update Posted : May 5, 2020
|First Submitted Date ICMJE||January 30, 2017|
|First Posted Date ICMJE||February 2, 2017|
|Last Update Posted Date||May 5, 2020|
|Actual Study Start Date ICMJE||April 1, 2018|
|Estimated Primary Completion Date||January 2022 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Change in Bone exposure area (mm^2) [ Time Frame: 0 months, 1 month, 3 months, 6 months, 9 months, 12 months ]
The primary lesion's area of exposed bone will be estimated by measuring the greatest anterior-posterior and superior-inferior dimensions in millimeters (mm) of the site with the largest area of exposed bone present at the time of study enrollment. If there are multiple areas of exposed bone in a single patient, the site with the largest sum of linear anterior-posterior and superior-inferior dimensions will be included in the study.
|Original Primary Outcome Measures ICMJE||Same as current|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||Pentoxifylline and Tocopherol (PENTO) in the Treatment of Medication-related Osteonecrosis of the Jaw (MRONJ)|
|Official Title ICMJE||Pentoxifylline and Tocopherol (PENTO) in the Treatment of Medication-related Osteonecrosis of the Jaw (MRONJ): A Prospective, Randomized Controlled Trial to Evaluate a Novel Non-operative Treatment|
|Brief Summary||The overall purpose of this project is to answer the following clinical question: Among Medication-Related Osteonecrosis of the Jaw (MRONJ) patients, do those who are treated with the Pentoxifylline and Tocopherol (PENTO) regimen and standard of care, when compared to those treated with standard of care alone, have decreased areas of exposed bone after one year of treatment?|
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.
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)
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.
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.
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.
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:
Oversight of the trial is provided by the Principal Investigator (PI) Dr. Dillon and Co- Investigators (Co-I) Dr. Petrisor, Dr. Ruggiero, Dr. Morlandt, and Dr. Ward.
Drs. Dillon, Ruggiero, Petrisor, 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 five 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:
The study uses the following AE attribution scale:
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
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:
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 access Investigational
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Phase 3|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Primary Purpose: Treatment
|Study Arms ICMJE||
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Enrolling by invitation|
|Estimated Enrollment ICMJE
|Original Estimated Enrollment ICMJE||Same as current|
|Estimated Study Completion Date ICMJE||January 2023|
|Estimated Primary Completion Date||January 2022 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages ICMJE||18 Years to 90 Years (Adult, Older Adult)|
|Accepts Healthy Volunteers ICMJE||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT03040778|
|Other Study ID Numbers ICMJE||STUDY00004779|
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||
|IPD Sharing Statement ICMJE||
|Responsible Party||Jasjit Dillon, University of Washington|
|Study Sponsor ICMJE||University of Washington|
|PRS Account||University of Washington|
|Verification Date||May 2020|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP