The study will employ a 1:1 randomization between Arm 1 (consecutive daily irradiation) and Arm 2 (irradiation at two- to three-day intervals), based on the stratification factors described in the Design section. Random assignment of treatment groups is centrally managed by Tatsuya Kawai using the web-based system of Mujinwari (Iruka System Ltd., Tokyo, Japan) and is balanced with randomly permuted blocks. Tatsuya Kawai is a member of data managing team and is not involved in enrollment. The other co-investigators are responsible for enrollment. Interventions will be initiated within 14 days of randomization.
We use a randomized phase II screening design, with a two-sided α of 0.20 and a power of 80% as recommended for our current study . In a phase II screening design, the α level is set higher than the level of a phase III design (i.e., 0.05). Even if the phase II trial is positive (i.e., p < 0.20), that is not considered conclusive without a subsequent phase III trial. The results of the previous study of irradiation at intervals demonstrated a 1-year IC-LC of 93% . Assuming a 1-year IC-LC of 70% for Arm 1 (consecutive daily irradiation) and 90% for Arm 2 (irradiation at two- to three-day intervals) and a 1-year OS of 50% for target patients, with 80% power, alpha of 0.20, an 5% lost follow-up rate, accrual time of 4 years and a total trial time of 5 years, 70 patients will be required (35 in Arm 1 and 35 in Arm 2). The secretariat of the study will contact all co-investigators to facilitate enrollment regularly.
The intention-to-treat analyses will be performed, and patients will be analyzed in the groups to which they are assigned. The IC-LC rate will be calculated using the Kaplan-Meier method and differences will be compared using the stratified log-rank test. Only recurrence of initially treated sites will be treated as event and death will not be considered to be competing event. When enrolled patient dies, the data at the last follow up will be used to calculate the IC-LC rate. Cox proportional hazards multivariable regression analysis will be used to determine baseline factors predictive of primary endpoint.
The IC-PFS rate will be calculated using the Kaplan-Meier method and differences will be compared using the stratified log-rank test. Only development of initially treated sites and new BM will be treated as event and death will not be considered to be competing event. When enrolled patient dies, the data at the last follow up will be used to calculate the IC-PFS rate. The OS rate will be calculated using the Kaplan-Meier method and differences will be compared using the stratified log-rank test. OS was defined as the time from the date of randomization to death from any cause.
The rates of grade 2 or higher toxicity will be compared between groups using the Fisher’s Exact Test. The non-worsening of KPS and MMSE scores at 6- and 12-months post-enrollment will be measured with differences between groups tested using the Fisher’s Exact Test. When enrolled patient dies, the data at the last follow up will be used. For KPS, a decrease in KPS of ≥10% will be considered a decline in KPS and sensitivity analysis will be performed. For MMSE, a decrease in MMSE score of ≥3 points will be considered a decline in cognitive function and sensitivity analysis will be performed.
Interim analysis and monitoring
Because a small sample size is required in this study, interim analysis will not be conducted. However, the safety of this trial will be independently evaluated by the data monitoring committee (DMC) when 35 and 70 patients are accrued. Principal Investigator reports about progress of the clinical trial, data correction, toxicities, and protocol deviation and violation to the DMC. The DMC is composed by the Clinical Research Center of Nagoya City University and is independent from the clinical trial team. Here is the item for the monitoring.
A registration status
A consideration of eligibility for a patient enrolled in this study
Any serious adverse event associated with this SRT procedure occurs
A violation or deviation from this study protocol
A critical problem for a progress, safety, and reliability of this study
A compliance of an ethical guideline
Ethical considerations and institutional review board
The principal investigator obtained ethical approval and clinical trial authorization by competent authorities according to local laws and regulations. The written informed consent form provided to potential participants should be adhere to the ethical principles that have their origin in the Declaration of Helsinki and must be approved by IRB. The protocol including the case reporting form, the informed consent form, and any other written information to be given to potential participants was centrally reviewed and approved by the IRB of Nagoya City University Graduate School of Medical Sciences (approval number: 46-22-0004). All hospitals participating in this study will obtain IRB approval prior to local initiation.
Informed consent to participate will be obtained from all of the participants. The investigator should obtain written informed consent from each patient before starting any study procedures and treatment. The investigator should inform the patient, or the patient’s legally acceptable representative, of the potential risks, benefits, and all aspects of the study. In addition, the investigator should inform the patient that participation in the study is completely voluntary and that they can refuse voluntarily to enter the study or to withdraw from it at any time, for any reason. The informed consent must be signed and dated by all of the patients.
Subject discontinuation/ withdrawal
When patients discontinue participation in the study, the clinical and laboratory evaluations that would have been performed at the end of the study should be obtained. If a subject is removed because of an adverse event, they needed to be observed by the treating physician as long as deemed appropriate.
The personal information of study participants will be held in utmost secrecy. All study records will only identify the subject by initials and the study identification number assigned by data managing team. Access to proprietary information is only permitted for direct subject management and for those involved in monitoring the study. The names and personal information of study participants will not be opened in any study report. Akira Torii is a member of data managing team and has access to data of the case reporting form sent from investigators.
Protocol amendments and trial publication
Any protocol amendments, regarding eligibility criteria, outcomes, and analyses, must be enacted by the principal investigator. Protocol amendments will be reported to all participating hospitals, investigators, IRBs, and trial registries through the principal investigator. Any conference presentation or publication of results of the study will be led by the principal investigator within 1 year after completion of trial. The results will be submitted to a peer-reviewed journal and will be presented at domestic and international conferences. Authorship of the conference presentation and scholarly paper will be decided by the principal investigator with reference to general guideline regarding qualification for authorship.