Protocol for a randomized study of the efficacy of ibandronic acid plus eldecalcitol in patients with gastric cancer after gastrectomy: A comparative study of different routes of administration of ibandronic acid

Overall study design

This study was approved by the Japan Registry of Clinical Trials (jRCT), approval number jRCT1041200059, on November 6, 2021. The aim of this study is to evaluate the efficacy of different routes of ibandronic acid administration (oral tablets and intravenous injection) on bone mineral density, focusing on the digestive symptoms of patients after gastrectomy. The overall study flow chart is shown in Figure 1. This study protocol follows the SPIRIT guidelines.³⁰

Figure 1. Flow chart of the study protocol.

We are conducting this trial in accordance with the principles of the Declaration of Helsinki. The Nagoya City University Certified Review Board (CRB4200003) approved this study (deliberation number 2020B003, November 6, 2021). Written informed consent will be obtained from all trial participants by physicians in charge. Physicians and medical institutions involved in this research will cooperate with the monitoring procedure manual and carry out this study in compliance with clinical research methods, related notices, and good clinical practice.

To ensure compliance with the protocol treatment, the attending physicians will ask patients about the medication status at each visit and offer guidance if there is any negligence of medication. The attending physicians will confirm the status of compliance with this study.

Drugs

For patients in the investigational arm (group A), sodium ibandronate hydrate (Bonviva^® intravenous infusion 1 mg syringe; Chugai Pharmaceutical Co., Ltd., Tokyo, Japan) will be administered intravenously once a month with daily oral intake of eldecalcitol (Edirol^® Capsule 0.75 μg; Chugai Pharmaceutical Co., Ltd.). For patients in the control arm (Group B), sodium ibandronate hydrate (Bonviva Tablets 100 mg; Chugai Pharmaceutical Co., Ltd.) will be administered orally once a month with a sufficient amount of water (approximately 180 mL) upon waking, with daily oral administration of eldecalcitol. For patients with hypercalcemia (corrected Ca = 10.5 mg/dL or more) identified at the time of registration or administration period, eldecalcitol dose will be reduced to appropriately 0.5 μg daily. Concomitant therapy will be permitted, including palliative and supportive therapies, such as analgesics, antiemetic agents, and anti-vomiting agents, for any symptoms due to primary disease or any adverse events. Additionally, chemotherapy for gastric cancer will be permitted. The usage of bone modulators and calcium/vitamin D supplements will not be permitted.

Patients

We will recruit patients aged 45–85 years who underwent gastrectomy for gastric cancer and are at a risk of fragility fracture. The inclusion criteria will be as follows and all should be complied: i) patients who underwent total or partial gastrectomy for gastric cancer; ii) patients with existing vertebral fractures and/or femoral proximal fractures or with lumbar and/or proximal femur bone mineral density of less than 80% of the young adult mean (YAM); iii) patients with a relatively stable general condition (performance status [PS], 0–2); iv) patients aged ≥45 years and <85 years on the registration date; v) patients less than six months after gastrectomy; and vi) patients with their latest blood test (within 14 days before registration examination) complying with all of the following criteria: white blood cell count ≥ 1,500/μL; platelet count ≥ 100,000/μL; total bilirubin level ≤ 1.5 mg/dL; aspartate aminotransferase level ≤ 100 IU/L; alanine aminotransferase level ≤ 100 IU/L; serum creatinine level ≤ 1.5 mg/dL; and corrected Ca value < 10.5 mg/dL.

The exclusion criteria will be as follows and all should be complied: i) surgical resection extending to organs other than the stomach (e.g., esophagus and pancreas); ii) patients with long-term immobility and inability to sit or stand in an upright position; iii) pregnant or breastfeeding women; iv) patients with a history or high risk of osteonecrosis of the jaw; v) patients with a history of hypocalcemia; vi) patients with urolithiasis; vii) patients with a history of allergy to the drugs used in this study; viii) patients with distant metastasis (including ascites cytology positive patients) at the time of registration; ix) patients with anorexia; x) patients who are being treated for osteoporosis at the time of registration; xi) stenosis of the esophagus or achalasia; xii) history of the hypersensitivity to ibandronate; xiii) patients who have socioecomonic problems or are assumed not to be supportive to this study. The risk of osteonecrosis will be assessed by the examination of dentists based on the presence of chronic periodontitis, necessity of exodontia or poorly-fitting denture.¹⁴

Randomization

The patient registration center will randomly assign patients to one of two treatment groups. The target number of patients in each group is 35. A computer-generated random sequence, made by Clinical Research Management Center in Nagoya City University Hospital, will be used to allocate a total of 70 patients with no stratification to sequential identification. An independent allocation manager will be responsible for the allocation process, and the allocation list will be concealed an envelope until interventions are assigned.

Target outcomes

The primary outcome of this study is the change in lumbar bone mineral density. Bone mineral density will be measured based on the dual-energy X-ray absorptiometry (DEXA) method. Bone mineral density will be evaluated during the pre-observational period, 24 weeks after the start of medication, and at the time of final observation (52 weeks after the start of medication). In addition, the following secondary assessments will be performed: i) change in femur bone mineral density (if patients with the presence of osteophytes and osteoarthritis on the X-ray of spine, femur bone mineral density will be substituted for lumbar bone mineral density); ii) change in bone metabolism markers, including serum cross-linked C-telopeptide of type I collagen (CTX), tartrate-resistant acid phosphatase 5b (TRACP-5b), total type 1 amino-terminal propeptide (P1NP), and 25OH vitamin D concentration (ELISA method); iii) change in health-related QOL, evaluated using the EuroQol 5 Dimension (EQ-5D)¹⁵ at the start date of medication, 12 weeks after the start of medication, 24 weeks later, and at the time of final observation (after 52 weeks); iv) change in digestive symptoms, evaluated using the Gastrointestinal Symptom Rating Scale (GSRS)¹⁶ at the start date of medication, 12 weeks after the start of medication, 24 weeks later, and at the time of final observation (after 52 weeks); v) presence or absence of fracture events during the medicated period; and vi) medication compliance rate. A total of 13 ibandronic acid doses will be scheduled in both groups over 52 weeks. The actual number of medications/13 will be calculated as the medication compliance rate.

Schedule

In the pre-observation period, medical interviews will be conducted focusing on the patients’ backgrounds including sex, age, height, weight, menopausal age, current medication, medical history (presence or absence of past fractures), eating habits, intake of vitamin D or Ca supplements, drinking/smoking history, presence or absence of femoral fractures in their parents, the area of extension of gastrectomy and the length of the remaining stomach, reconstruction techniques after gastrectomy, surgical intervention (open/laparoscopy/robot-guide), presence or absence of gallbladder resection, and presence or absence of post-operative anticancer drugs. In addition, the mineral density of the lumbar spine and femur will be measured using the DEXA method. Spine radiography will be performed in two directions: front and side in a standing position around the 4th lumbar vertebra and the 9th thoracic vertebra. The alignment of the entire spine and the existing fracture will also be confirmed. After confirming the selection criteria using medical charts and blood tests, the physicians will obtain written informed consent from all trial participants.

On day one of the trial, vital signs, blood test results, bone metabolism markers (CTX, TRACP-5b, P1NP, and 25OH vitamin D concentrations (using ELISA)), and physical function (EQ-5D and GSRS) will be examined.

After the start of medication administration, the following will be recorded: vital signs; medication status; the presence of adverse events; presence or absence of new fracture events; blood tests (to determine whether patients comply with the same criteria from the inclusion periods); bone metabolic markers; improvement in physical function evaluation (EQ-5D and GSRS); and bone density measurement (lumbar spine and femur). Subsequently, medical checks for vital signs, compliance with medication, and the presence of adverse events will be performed at 4, 12, 24, and 52 weeks. After the discontinuation of drug administration, observation and investigation will be conducted up to 4 weeks after the date of the last administration of the research drug. If adverse events continue, follow-up and investigation will be continued until recovery from the adverse events (Table 1).

Table 1. Assessment and evaluation schedule.

Stages of the study	Screening and exam description	Registration	0 weeks	4 weeks	12 weeks	24 weeks	52 weeks	4 weeks after discontinuation or cessation of drug administration
Informed consent	○
Allocation to Group A and Group B		○
Patient backgrounda	○
Vital signs	○		○	●	●	●	●	●
Bone density measurement (lumbar spine, proximal femur)	○					●	●
X-ray of the spine	○						●
Blood testb	○		○		●	●	●
Bone metabolism markers			○		●	●	●
Administration of research drugs*
Checking the proper medication				●	●	●	●
EQ-5D, GSRS			○		●	●	●
Checking adverse eventsc

a Collection of information on drugs related to the efficacy or safety of the research drug.

b Hematological testing of white blood cell count, red blood cell count, hemoglobin, hematocrit, and platelet count. Testing of alkaline phosphatase, aspartate aminotransferase (glutamate oxalacetate transaminase), alanine aminotransferase (glutamic pyruvic transaminase), lactate dehydrogenase, γ-glutamyl transpeptidase, creatine kinase, total bilirubin, total protein, albumin, urea nitrogen, creatinine, amylase, sodium, potassium, crawl, calcium, and inorganic phosphorus levels, and estimated glomerular filtration rate to confirm the safety of the study.

c Adverse events are all unfavorable events regardless of a causal relationship with drugs.

* Delays in the administration of test and control drugs will be acceptable for up to two weeks. If delayed, the observation date will be changed according to the number of days.

Safety

To evaluate safety, adverse events considered to be related to the research medicine will be monitored. Digestive symptoms, abnormality of calcium concentrations will be checked carefully on medical checks. Dubious symptoms for osteonecrosis of the jaw or atypical femoral fracture will be targeted to the further evaluations. All serious adverse events will be reported from the start of drug administration to the end of the follow-up period, along with the relationship among the type, severity, treatment content, time of expression, and turning point. Adverse events will include all undesirable or unintended symptoms and signs (including abnormalities in laboratory tests). The adverse events will be grade based on the Common Terminology Criteria for Adverse Events version 5. Serious adverse event is defined as an adverse event that is fatal, life threatening, requires in-patient hospitalization or prolonged hospitalization, results in persistent or significant disability/incapacity or other significant medical hazards. Follow-up investigations will be performed until the disappearance of/or recovery from adverse events. All serious adverse events will be reported to the Certified Review Board by the physicians in charge. The investigators shall promptly and appropriately treat the subjects and record the adverse event, date of onset, severity, and outcome, as well as ascertain the causal relationship of the study drug.

Data collection methods

The data will be collected using a unified Case Report Form, which can be found as Extended data²⁹ and dissemination of the GSRS and EQ-5D charts.

Data management

All individuals involved in this research will properly handle the information of the research subjects and protect the personal information according to the “Act on the Protection of Personal Information.” The information of all patients involved in this study will be confidentially handled using the research specific identification code. Only the principal investigator (H.A.) will handle correspondence table between autonyms and anonyms. During the research, related information will be managed using a highly secured offline computer. Quality of the data will be checked during the data monitoring process.

Statistical analysis

Statistical analysis will be performed within six months after data collection and enrollment of the final research participant. As it is predicted that the number of events will not be sufficient to make an early cancellation decision in the middle of registration, an intermediate analysis will not be performed.

The effectiveness of the investigational drugs will be evaluated using the intent-to-treat analysis for all eligible patients. The full analysis set (FAS) will comprise the entire group excluding the following research subjects: patients who do not meet the inclusion criteria, those who meet the exclusion criteria, those who are never administered drugs, and those for whom data are not obtained after the start of research medication. In the FAS, the per-protocol set (PPS) will comprise the entire group excluding the following research subjects: those for whom data on the main evaluation items are not obtained 52 weeks after the start of medication or those with a medication compliance rate of less than 80%. The sample size calculation was based on a previous study,³ which reported that another bisphosphonate preparation (alendronate internal use) and eldecalcitol increased lumbar bone density by approximately 6% at 12 months after administration compared with an increase of approximately 3% with eldecalcitol alone. We expect the difference between the intravenous infusion and oral intake combined with eldecalcitol will show 1.5% higher lumbar bone mineral density at 52 weeks (set to half of the additional effect of alendronate in the above previous study). The number of patients required to detect this with statistical significance is estimated to be 29 in each group with standard deviation 2%, significance level 5% (bilateral sides), and power 80%. Therefore, the target number of patients in this study is 35 (70 patients in total) in each group with the expectation that several patients will drop out.

To analyze effectiveness in the FAS and PPS, the rate of change in the bone mineral density from before the start of treatment will be calculated with respect to the lumbar bone mineral density at 52 weeks, and a comparison between groups will be performed using a Student’s t-test. In addition, for the analyses of secondary evaluation items in the FAS and PPS, the rate of change from before the start of treatment will be calculated for bone metabolism markers (TRAPC5b, P1NP), femoral bone mineral density, and QOL (EQ-5D, GSRS) at 52 weeks using a Student’s t-test for comparison between groups. The frequency of fragile fracture events in each drug group will be calculated, and an intergroup comparison will be performed using a chi-square test.

Only the principal investigator (H.A.) will prepare a correspondence table of the research subject identification code set and only the principal investigator and biostatistician (H.H.) can access the final trial dataset.

Data monitoring

In this clinical study, an independent data monitoring officer (Y.G.) will be assigned. On-site monitoring will be conducted to confirm whether the study is carried out safely and according to the research plan and whether the data are collected reliably. Monitoring will be conducted before the start of the research, during the research (every three months), and at the end of the research. In addition, monitoring will be carried out at the time of registration and when a serious adverse event occurs.

Plans for dissemination

The results of this study will be published in peer-reviewed journals.

Study status

We are currently recruiting patients.

Underlying data

No data are associated with this article.

Extended data

Figshare: case report form.xlsx. https://doi.org/10.6084/m9.figshare.20217278.v3.²⁹