A randomised, double-blind, placebo-controlled phase III trial on the efficacy and safety of tocilizumab in patients with familial Mediterranean fever.

OBJECTIVES: To evaluate the efficacy and safety of tocilizumab (TCZ), an interleukin 6 receptor monoclonal antibody, in a subset of Japanese patients with familial Mediterranean fever (FMF). METHODS: We performed a double-blind, randomised, parallel-group trial, followed by an open-label extension trial, in patients with colchicine-resistant or -intolerant FMF (crFMF) (UMIN000028010). Patients were randomly assigned (1:1) to receive TCZ (162 mg every week) or placebo, administered subcutaneously, for 24 weeks. Rescue treatment was allowed if the rescue criteria were met. The primary endpoint was the number of fever attacks over the 24 weeks of treatment. Secondary endpoints included the frequency of accompanying symptoms during attacks, serum CRP and SAA values, and adverse events (AEs). The open-label extension study evaluated the long-term safety and efficacy of TCZ in patients who had completed the preceding study (UMIN000032557). RESULTS: We randomly assigned 23 patients to either TCZ (n=1) or placebo (n=12). The TCZ-placebo rate ratios were 0.691 (95% confidence intervals (CI), 0.189-2.531; p=0.577) for the fever attacks, based on the group rates per week. The recurrence of attacks was significantly lower in the TCZ group (hazard ratio = 0.457; 95% CI, 0.240-0.869). Fever attacks, accompanying symptoms, serum CRP and SAA values were controlled in most of the patients who received long-term TCZ. In these trials, the numbers and severity of AEs did not differ between groups. CONCLUSIONS: Although a primary endpoint was not met in the preceding trial, long-term administration of TCZ showed stable efficacy and safety for patients with crFMF.

An open-label continuation trial of tocilizumab for familial Mediterranean fever with colchicine ineffective or intolerance: Study protocol for investigator-initiated, multicenter, open-label trial.

BACKGROUND: Colchicine is the first-line treatment for familial Mediterranean fever (FMF), but secondary amyloidosis resulting from persistent inflammation is a concern in patients with colchicine-resistant or colchicine-intolerant FMF. Although tocilizumab (TCZ), which is a recombinant, humanized, anti-human interleukin 6 receptor monoclonal antibody, has been reported to prevent FMF attacks, the long-term safety and efficacy of TCZ on individuals with colchicine-resistant or colchicine-intolerant FMF have not been evaluated. METHODS/DESIGN: In this investigator-initiated, multicenter, open-label trial, the long-term safety of TCZ will be evaluated in patients participating in a placebo-controlled, randomized, double-blind, parallel-group trial on colchicine-resistant or colchicine-intolerant FMF. The study will be conducted in 9 centers in Japan. After the evaluation and examination for 24 weeks in the preceding study, this trial will be started promptly. The trial will be completed by the time the drug is approved for FMF treatment in Japan. The primary endpoint is the incidence of adverse events, and the secondary endpoints include the number of FMF attacks, number of occurrences of accompanying symptoms during attacks, serum C-reactive protein and amyloid A levels, general evaluation by a physician (100 mm visual analog scale [VAS]), general evaluation by a patient (100 mm VAS), and body temperature. DISCUSSION: The study is expected to obtain evidence regarding the long-term safety of TCZ as a potential new therapeutic agent for patients with colchicine-resistant or colchicine-intolerant FMF. TRIAL REGISTRATION: This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000037116) as UMIN000032557 on May 30 2018.

An open-label continuation trial of sirolimus for tocilizumab-refractory idiopathic multicentric Castleman disease: Study protocol for an investigator-initiated, multicenter, open-label trial (SPIRIT compliant).

BACKGROUND: Interleukin 6 (IL-6) inhibitors are the first-line treatment for idiopathic multicentric Castleman disease (iMCD); however, there is no established treatment for cases that are resistant to IL-6 inhibitors. Although sirolimus, a mammalian target of rapamycin inhibitor, has been suggested to be effective in patients with iMCD, the long-term safety and efficacy of sirolimus on individuals with IL-6 inhibitor-resistant iMCD have not been evaluated. METHODS/DESIGN: In this investigator-initiated, multicenter, open-label trial, the long-term safety of sirolimus will be evaluated in patients participating in a placebo-controlled, randomized, double-blind, parallel-group trial on tocilizumab (TCZ)-resistant iMCD. The study will be conducted in 7 centers in Japan. This trial will be promptly started after the evaluation and examination for 16 weeks in the preceding study. The trial will be completed by the time the drug is approved for iMCD treatment in Japan. The primary endpoint is the incidence of adverse events. The secondary endpoints include the following: the levels of hemoglobin, albumin, and C-reactive protein; change in CHAP score; physician global assessment (100-mm visual analog scale); patient global assessment (100-mm visual analog scale); and lymph node changes in subjects with lymphadenopathy. DISCUSSION: This clinical trial will provide evidence regarding the long-term safety of sirolimus as a potential novel therapeutic agent for patients with tocilizumab-resistant iMCD. TRIAL REGISTRATION NUMBER: jRCT2051200050.

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

BACKGROUND: Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder of unknown etiology with systemic symptoms that include fever, night sweats, weight loss, and fatigue. Although tocilizumab (TCZ), which is a recombinant, humanized, anti-human interleukin 6 receptor monoclonal antibody, has been recommended to treat patients with iMCD, 40% of patients with iMCD do not achieve complete remission with TCZ treatment. METHODS/DESIGN: In this phase II, investigator-initiated, multicenter, double-blind, randomized, parallel-group trial, the efficacy and safety of sirolimus will be compared with placebo in patients with TCZ-resistant iMCD. The study will be conducted in 8 centers in Japan. Participants (n = 20) will be randomly assigned to receive 2 mg of oral sirolimus (n = 10) or placebo (n = 10) once daily for 16 weeks. The primary endpoint is a decrease in CHAP score by ≥1 from baseline at 16 weeks. Secondary endpoints include levels of hemoglobin, albumin, and C-reactive protein; change in CHAP score; SF-36 Health Survey Questionnaire; physician global assessment (100 mm visual analog scale); patient global assessment (100 mm visual analog scale) at 2, 4, 8, 12, and 16 weeks; change in lymphadenopathy at 16 weeks; and pharmacodynamic assessment, including the measurement of whole blood sirolimus level. DISCUSSION: This clinical trial will provide evidence of efficacy and safety of sirolimus as a potential new therapeutic agent for patients with TCZ-resistant iMCD. TRIAL REGISTRATION: This study was registered with the Japan Registry of Clinical Trials as jRCT2071190029 on October 8, 2019.

Sponsor-based evaluation of the system for the execution of clinical trial at hospitals and related issues.

With the revision of the Good Clinical Practice (GCP) in 1997, the Clinical Trial Center was established at Saga University Hospital in 1999, where clinical research coordinators (CRC) of nurses and pharmacists have been carrying out support for clinical trials since June 2000. At present, two pharmacists, two nurses, and three clerical work assistants support the execution of clinical trials; however, in recent years the number of clinical trial commissions has been gradually decreasing. On this occasion, in order to carry out even higher quality and smoother clinical trials, we conducted a questionnaire targeting the sponsors of clinical trials (head monitors) to evaluate this hospital's system for the execution of clinical trials from the sponsor's standpoint. Moreover, for the purpose of comparison with the systems of other institutions, the same questionnaire was conducted on two other hospitals-the University of Occupational and Environmental Health, Japan and the Social Insurance Shimonoseki Kousei Hospital. The problems of the clinical trial execution in our team turned out lack of knowledge concerning GCP and our complex system from the result of the questionnaire.

Comparison of the efficacy and safety of tocilizumab for colchicine-resistant or colchicine-intolerant familial Mediterranean fever: study protocol for an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Familial Mediterranean fever (FMF) is an inherited disorder caused by a number of mutations of the Mediterranean fever (MEFV) gene, coding a protein named pyrin that acts as a major regulatory component of the inflammasome. The first-line drug for FMF treatment is colchicine, but 10% of patients with FMF do not respond well to colchicine. Although the efficacy of tocilizumab (TCZ), which is a recombinant, humanized, antihuman interleukin 6 (IL-6) receptor monoclonal antibody, has been reported to prevent FMF attacks, the effects of TCZ on individuals with colchicine-resistant or colchicine-intolerant FMF have not been evaluated in a randomized clinical trial. METHODS/DESIGN: In this phase III, investigator-initiated, multicenter, double-blind, randomized, parallel-group trial, the efficacy and safety of TCZ will be compared with placebo in patients with colchicine-resistant or colchicine-intolerant FMF. The study will be conducted in nine centers in Japan. Participants (n = 24) will be randomly assigned to receive 162 mg of TCZ (n = 12) or placebo (n = 12) administered subcutaneously once weekly for 24 weeks. Rescue treatment will be allowed if rescue criteria are met. A primary endpoint is the number of fever attacks until 24 weeks. Secondary endpoints include the number of occurrences of accompanying symptoms during attacks; the time until a fever attack occurs; the duration of fever attacks; serum C-reactive protein and serum amyloid A; 36-item Short Form Health Survey; general evaluation by a physician (100-mm visual analogue scale); body temperature; the percentage of subjects who achieve FMF 50 at 12 weeks and 24 weeks; and pharmacodynamic assessment, including the measurement of serum TCZ level and soluble IL-6 receptor. DISCUSSION: The study is expected to produce evidence regarding the efficacy of a potential new therapeutic agent, TCZ, in improving the clinical course and outcome for patients with colchicine-resistant or colchicine-intolerant FMF. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry, UMIN000028010 . Registered on 7 July 2017.