Randomized, double-blind, placebo-controlled, parallel-group trial of sirolimus for tocilizumab-resistant idiopathic multicentric Castleman disease: Study protocol for clinical trial (SPIRIT Compliant)

JRCT ID: jRCT2071190029

Registered date:09/10/2019

Basic Information

• Recruitment status: Complete
• Health condition(s) or Problem(s) studied: idiopathic multicentric Castleman's disease
• Date of first enrollment: 25/05/2020
• Target sample size: 20
• Study type: Interventional

Intervention(s)

Treatment: Sirolimus 2 mg po once/day.
Control: Placebo given orally once daily

Outcome(s)

• Primary Outcome: CHAP score: presence or absence of a score decrease of 1 or greater from baseline at 16 weeks of study drug administration.

Secondary Outcome

(1) Hb (g/dL): change from baseline at 2, 4, 8, 12, 16, and discontinuation of study drug
(2) Alb (g/dL): change from baseline at 2, 4, 8, 12, 16, and discontinuation of study drug
(3) CRP (mg/dL): change from baseline at 2, 4, 8, 12, 16, and discontinuation of study drug
(4) Physician global assessment (Disease activity assessment, 100 mm VAS): change from baseline at 2, 4, 8,, 12, and 16 weeks after drug discontinuation
(5) Patient global assessment (Disease activity assessment, 100 mm VAS): change from baseline at 2, 4, 8, 12, 16, and discontinuation of study drug
(6) SF -36: change from baseline at 4, 8, 12, and 16 weeks, and drug discontinuation
(7) Lymph node changes in subjects with lymphadenopathy: change from baseline at 16 weeks of study drug initiation, change from baseline at the time of discontinuation, and change from baseline at 16 weeks of study drug initiation, at time of discontinuation, in the number of lymph nodes greater than or equal to 15 mm in diameter.
(8) CHAP score: change from baseline at 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, and drug discontinuation
(9) CHAP score minus CRP score: change from baseline at 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, and discontinuation of study drug.
(10) CR achieved in response to CDCN treatment: change from baseline at 16 weeks and discontinuation of study drug
(11) PR achievement in CDCN response assessment: change from baseline at 16 weeks and discontinuation of study drug
(12) safety
1 Adverse events (Incidence of adverse events, serious adverse events, and adverse reactions)
2 Laboratory tests (Hematology, blood chemistry, and urinalysis)
3 All medically important indicators (Physical findings, vital signs, imaging tests, 12 lead ECG, echocardiography, etc.)

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

Patients with idiopathic multicentric Castleman's disease who meet all of the following criteria are eligible for enrollment.
(1) Patients aged 18 or older at the time of obtaining consent; gender is not an issue
(2) Patients diagnosed with idiopathic multicentric Castleman's disease according to the criteria of the Ministry of Health, Labour and Welfare "Diagnostic Criteria and Classification of Severity for Designated Intractable/Rare Diseases"
(3) Patients who meet all of the following definitions of inadequate response
a. Tocilizumab (TCZ (genetic recombination)) or TCZ with corticosteroids (However, TCZ was continued for at least 8 weeks at the time of obtaining consent at the same dose. Adrenocortical steroids should be administered at the same dose for at least 4 weeks at the time of obtaining informed consent, and the dose of oral corticosteroids should be no more than 0.5 mg/kg/day of prednisolone.)
b. A CHAP score of at least one of CRP, Hb, or Alb
(4) Patients who have received a full explanation of the contents of the written explanation and other matters related to the clinical trial, understand the contents of the written explanation and obtain written consent of their free will to participate in the clinical trial. If the patient was younger than 20 years of age at the time of obtaining consent, written consent to participate in the clinical trial from the legally acceptable representative and written consent to participate in the clinical trial from the patient.

Exclude criteria

Patients with any of the following are excluded from the study.
(1)Patients with any of the following at the time of screening

2) Neutrophil count < 1,000/microL
3) Platelet count < 75000/microL
4) ALT exceeds 3.0 times the upper limit of normal
5) AST exceeds 3.0 times the upper limit of normal
6) Total bilirubin > 1.5 times baseline
7) ALP exceeds 2.5 times the upper limit of the reference value
8) Serum creatinine > 1.5 times the upper limit of normal and creatinine clearance < 50 mL/min
Estimated creatinine clearance using the Cockcroft-Gault formula. However, if there is an actual measurement, the actual measurement is used.
(2) Patients with uncontrolled dyslipidemia (Patients with a serum triglyceride level of > 500 mg/dL or an LDL cholesterol level of => 190 mg/dL who are receiving treatment for dyslipidemia)
(3) Patients with poorly controlled diabetes mellitus (Diabetic patients with fasting blood glucose < 130 mg/dL or HbA1c =< 8.0%, despite being treated for diabetes)
(4) Patients with a history of myocardial infarction, angina pectoris, or stroke associated with atherosclerosis
(5) Patients with an ECOG PS of 4
(6) Patients with concomitant or a history of idiopathic pulmonary fibrosis or drug-induced pulmonary disorder
(7) Patients with active tuberculosis (Patients undergoing prophylactic chemotherapy for LTBI may participate)
(8) Patients who have complicated infectious diseases within 4 weeks of the first administration of the investigational product and who are judged to be inappropriate by the investigator or sub-investigator
(9) Patients who were diagnosed with a malignancy within 5 years prior to the initial administration of the study drug. This excludes cases in which resection or no treatment was performed for more than 5 years before the first administration of the investigational product, cured skin cancer (Epithelial cell carcinoma or basal cell carcinoma), and cervical cancer.
(10) Patients with HBV, HCV, or HIV positive screening tests
A positive HBsAb test qualifies as negative HBV-DNA.
HCV antibody-positive patients are eligible only if they are HCV RNA-negative on polymerase chain reaction (PCR) testing
(11) Patients complicated by a serious illness who are judged by the investigator or sub-investigator to be inappropriate for the study
(12) Patients who have previously used an mTOR inhibitor that includes sirolimus (Sirolimus, everolimus, temsirolimus, etc. Except when contained in drug-eluting stents or external preparations)
(13) Patients with a history of hypersensitivity to any of the ingredients of the investigational product
(14) Patients who cannot use appropriate contraception during the study drug administration period or 12 weeks after the last treatment with the study drug (Men and women are women who may be pregnant.)
(15) Female patients during lactation or pregnancy
(16) Patients who underwent surgery (Surgery involving invasion of a body cavity or requiring a suture of three or more needles) within 8 weeks prior to the first dose of study drug
(17) Patients who received live vaccines within 6 weeks prior to the initial administration of the study drug
(18) Patients who received chemotherapy within 8 weeks prior to the first dose of study drug
(19) Patients who have used other investigational products or devices within 6 months prior to the initial administration of the investigational product
(20) Other patients deemed inappropriate by the investigator or sub-investigator

Related Information

• Primary Sponsor: Kawakami Atsushi
• Source(s) of Monetary Support: Japan Agency for Medical Research and Development