Effects of vitamin D supplementation on risks of delayed relapse or death in patients with cancer and especially in a subgroup of patients with p53-positive cancer: A double-blind, randomized, placebo-controlled, clinical trial (AMATERASU2 Trial)
Effects of vitamin D supplementation on risks of delayed relapse or death in patients with cancer and especially in a subgroup of patients with p53-positive cancer (AMATERASU2 Trial)
Urashima Mitsuyoshi
The Jikei University School of Medicine
3-25-8, Nishishimbashi,Minato-ku,Tokyo
+81-3-3433-1111
urashima@jikei.ac.jp
Wada Haruka
The Jikei University School of Medicine
3-25-8, Nishishimbashi,Minato-ku,Tokyo
+81-3-3433-1111
wada.haruka519@gmail.com
Recruiting
Jan. 01, 2022
Jan. 06, 2022
1240
Interventional
randomized controlled trial
double blind
placebo control
parallel assignment
prevention purpose
Target disease
I. Cancer types that are expected to be completely cured by surgery (including cases where metastasis can be resected) and have a certain frequency of death from all cancers: lung cancer, colon cancer, liver cancer, gastric cancer, breast cancer, esophageal tract Cancer, pancreatic cancer, head and neck cancer
II. Mainly includes stage I, II, III and some IV. On the other hand, it does not include carcinoma in situ.
Some IV; Include if radical cure = macroscopic resection even in stage IV: Include stage IVA for head and neck cancer, liver metastasis for colorectal cancer, etc. if remission is obtained.
Carcinoma in situ; Endoscopically resected by preoperative diagnosis of carcinoma in situ, but postoperative pathological diagnosis revealed that it was stage I or higher. If complementary surgery is required at this research facility due to referrals, etc., it will be included in the study. The endoscopy facility may be another hospital.
III. Histopathology is major
Lung cancer: invasive adenocarcinoma, squamous carcinoma, adenosquamous carcinoma
Colorectal cancer: Adenocarcinoma (including colorectal cancer but not small intestine cancer)
Liver cancer: Hepatocellular carcinoma
Pancreatic cancer: pancreatic ductal cancer (adenocarcinoma)
Gastric cancer: adenocarcinoma, esophagogastric junction adenocarcinoma (Siewert type III)
Breast cancer: Invasive breast cancer
Esophageal cancer: squamous epithelial cancer, esophagogastric junction adenocarcinoma (Siewert type I, II)
Head and neck cancer: pharyngeal cancer, hypopharyngeal cancer, laryngeal cancer, oral cavity cancer
Selection criteria
(1) Initial cancer patients who fall under the above target diseases (= if multiple cancers, recurrent cancers, invasive cancers occur at other sites and a series of treatments have been completed and less than 5 years have passed, all are excluded).
Invasive cancer: However, those with a history of carcinoma in situ within 5 years or multiple cancers in situ are included in the research target.
(2) Patients scheduled to undergo surgery at the Jikei University Hospital Surgery / Otorhinolaryngology, International Medical and Welfare University Hospital Surgery (biopsy may be performed at other medical facilities or other departments such as department of endoscopy).
(3)
a. Even if there is a history of invasive cancer that has developed in a different organ, the patient is included if a series of treatments has been completed and the patient has been in remission for at least 5 years.
b. Even if there is a history of invasive cancer that has developed in the same organ, the patient is included if a series of treatments has been completed and the patient has been in remission for at least 5 years.
c. If the history of cancer was carcinoma in situ, even if it has not been more than 5 years since the completion of a series of treatments, the patient is included in the trial.
(4) Even if a pathological sample for p53 staining evaluation cannot be obtained, it will be the subject of research (= This case is not included in the subgroup analysis, but is included in the overall analysis).
(5) The age of the day when the informed consent is received is 20 years of age and older as well as to 90 years of age and younger.However, if the principal investigator or the research coordinator determines that the consent ability is insufficient due to comorbidities such as dementia, or if a substitute person is required for consent, the research subject is excluded.
(6) Performance status (PS) is 0-2 based on ECOG standards.
i.e., Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours or even better.
Exclusion criteria: Postoperative pathological results were found, for example, carcinoma in situ, sarcoma, surgery could not remove all tumors macroscopically (Patients who are histologically positive for tumor tissue stump are not excluded). Even if the patient is provisionally registered once, he/she can be excluded if it is before the start of supplementation (= randomization = main registration).
(1) Exclude cases that have undergone surgery at medical facilities other than the Department of Surgery and Otorhinolaryngology, Jikei University Hospital, and Surgery, or International University of Health and Welfare Hospital for the cancer type to be studied.
However, the following cases are included in the research target.
a. When only biopsy is performed in other facilities or department of endoscopy.
b. Endoscopic submucosal dissection (ESD) was performed at other facilities or department of endoscopy, and since it was Stage I or higher, Department of Surgery and Otorhinolaryngology, Jikei University Hospital, and Surgery, or International University of Health and Welfare Hospital is requested a complementary operation.
(2)
a. If there is a history of invasive cancer in a different organ and has not completed a series of treatments for more than 5 years, the patient is excluded from the trial.
b. If there is a history of invasive cancer in the same organ and has not completed a series of treatments for more than 5 years, the patient is excluded from the trial.
(3) Double cancer status (eg, esophageal cancer and head and neck cancer were found at the same time). However, if the double cancer is carcinoma in situ, it is included in the target.
(4) Participating in other clinical trials such as JCOG study, and not permitting it to participate in other clinical trials (if permitted, it is the subject of this study).
(5) Cancer that develops at another site after enrollment in this study is not considered as an outcome, but as an adverse event. For example, if a person is enrolled in this study as patients with colorectal cancer but develops gastric cancer one year later, the incidence of gastric cancer is not an outcome but an adverse event. Even if gastric cancer recurs later, it is not included in the outcome unless colorectal cancer recurs. This case is also counted as an adverse event.
(6) If participants have hypercalcemia (serum calcium level is 10.5 mg / dl or more) either at the time of main registration or at the time of provisional registration.
(7) If you have been taking vitamin D supplements for 500 IU / day or more for the past year or more and do not want to stop and switch to test supplements (intention) or for medical reasons. However, it is not necessary to exclude the following cases, but it should be stated in the case report form.
a. Vitamin D supplements tolerate less than 500 IU / day, such as 400 IU / day per day. Microgram x 40 = IU (International Unit), Example: 10microgram = 400 IU
b. Include patients taking active form of vitamin D (1,25-vitamin D), bisphosphonate, and/or calcium to prevent and/or treat osteoporosis.
(8) Preoperative diagnosis and postoperative pathological diagnosis are different, and if the main tumor is sarcoma, hematological malignancies such as malignant lymphoma, or neuroendocrine tumor (including carcinoid syndrome), other rare cancers (shown in the target diseases).
(9) Exclude cases where carcinoma in situ is diagnosed in the pathological tissue (= cancer with a near zero possibility of recurrence).
(10) The tumor could not be completely removed by surgery (the tumor remained macroscopically and did not reach complete remission).
(11) The principal or other investigator of this trial judges that it would be difficult for a patient to participate in this study due to serious complications during a series of treatments such as surgery, adjuvant chemotherapy, and radiation therapy.
(12) Due to complications, swallowing function is impaired and oral intake was difficult, or gastrostomy was added.
(13) When the postoperative Performance status (PS) deteriorates to 3 or 4 according to the ECOG standard = Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours or even worse than that.
(14) Serious hepatic disorder, renal disorder (Glomerular Filtration Rate [GFR] estimated value or creatinine clearance less than 30 mL / min / 1.73 m2, etc.), cardiovascular disease [JCOG version CTCAE version 5.0 Grade 3])
(15) The principal or other investigator of this trial judges that participation in this research is inappropriate.For example, it corresponds to the case where the principal investigator or the research coordinator judges that the consent ability is insufficient due to a comorbidity such as dementia, or the case where a substitute person judges that consent is necessary.
Dosage, dose and duration of study supplements
Timing of start: Start blinded trial supplements from the first outpatient visit or in hospital after surgery. However, if the general condition is not good, such as strong nausea during postoperative chemotherapy, the attending physician may decide to delay the start of oral administration. However, the extension will be a maximum of 2 months from the date of surgery (the same day of the following month), and if it exceeds this, it will be excluded from the trial (= if it is excluded before the start of trial supplement [randomization], it is not a protocol violation).
Dosage and administration: Take 1 capsule once a day (at a timing that makes it easy to take in the morning or at night)
dose:
Vitamin D supplement: Vitamin D 2,000 IU / capsule
Placebo: Olive oil
Capsule material: Gelatin derived from fish, glycerin
Administration period: Administer until the end of the study, except when it becomes difficult to take the supplement. Even if it recurs, if the general condition is good, administration should be continued. When hypercalcemia or urinary stones occur and side effects of taking supplements are suspected, the oral administration can be temporarily suspended or terminated at the discretion of the attending physician.
cancer, p53-positive cancer
vitamin D
Neoplasms, Tumor Suppressor Protein p53
Vitamin D
Primary endpoint
Events that appeared earlier due to recurrence of the cancer 365 days and more after the start of oral study supplements or death due to all causes; recurrence / death less than 365 days after the start of oral study supplements is one of the secondary endpoints.
However, subjects who reach the following conditions within 365 days * after the start of oral administration are excluded from the analysis.
a. Withdrawal of consent (refusal to take trial supplements)
b. Difficulty taking trial supplements due to complications
c. Not taking 60% and more of trial supplements; Judgment is based on the number of capsules left after having the bottle brought.
d. Transfer hospitals
On the contrary, if it is 365 days or later after the start of oral administration, the above is included in the analysis; patients who did not take the test supplement sufficiently after 1 year are also analyzed as the distribution group [intention to treat (ITT) analysis].
Cancer that newly develops in another site after the start of the supplement is not included in the recurrence and is regarded as an "adverse event". If it is difficult to distinguish between recurrence and new cancer, the judgment of the research physician will be respected. This is because it is double-blind, and it is considered that the observation bias is unlikely to be mixed.
Secondary endpoints
(1) Recurrence in cancer patients, especially p53-positive cancer patients, 365 days after the start of the test supplement (competitive risk analysis is performed): Only recurrence, not including death.
(2) Death from all causes after 365 days after the start of the test supplement in cancer patients, especially p53-positive cancer patients: overall survival
(3) In cancer patients, especially p53-positive cancer patients, it is not delayed, but (a) recurrence / death from the start of the test supplement, (b) death due to all causes, and (c) recurrence only.
(4) In cancer patients, especially p53-positive cancer patients, (a) recurrence / death, (b) death due to all causes, and (c) recurrence only after 548 days (one and a half years) after the start of the test supplement.
(5) In cancer patients, especially p53-positive cancer patients, the event that appeared earlier due to recurrence 365 days after the start of the test supplement or death due to all causes (patients who did not take 60% or more after 1 year) Exclude and analyze [per protocol analysis]).
