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Investigator Initiated Clinical Trial of Rituximab for Thrombotic Thrombocytopenic Purpura (Rituximab-TTP trial)

Investigator Initiated Clinical Trial of Rituximab for Thrombotic Thrombocytopenic Purpura

Seven patients who had at least one infusion of rituximab therapy were analyzed. A total of 36 AEs in five patients were observed. Of these, 11 events in four patients were classified as ADRs because the causal relationship of these events with rituximab was not completely ruled out by the investigator. There were seven infections, and one each of muscle spasticity, dyspnea, urticaria, and thrombocytopenia. All of these ADRs were mild or moderate apart from two events: one cytomegalovirus viremia and one septic shock, both of which were observed in the same patient. Although the patient who suffered nocardiosis did not fully recover, the remaining ADRs were all recovered or remitted at the last observation at week 4. There were no infusion reactions or withdrawals owing to severe AEs or treatment-related deaths.

Six patients were included in the FAS population to evaluate efficacy. All patients could have discontinued PE and showed improved clinical condition. The blood platelet counts increased in all patients after rituximab infusion and the median blood platelet counts were significantly increased at week 2 compared with baseline and remained at a clinically acceptable level. Five patients showed a marked increase of blood platelet counts (to >100*10^9/L) at week 4. Of these, two patients reached the target of efficacy endpoint, >150*10^9/L.

The clinical efficacy of rituximab for the treatment of refractory TTP was demonstrated, achieving clinically significant recovery of blood platelet counts and leading to PE cessation. Furthermore, rituximab was well tolerated with no safety concerns observed in this study and therefore is considered a useful therapeutic approach for Japanese TTP patients.

International Journal of Hematology, http://www.ncbi.nlm.nih.gov/pubmed/27188338

Yoshitaka Miyakawa

Saitama Medical University Hospital

38 Morohongo, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan

miyakawa@saitama-med.ac.jp

Kazuo Watanabe

CTD Inc.

3-3-2Tsukiji,Chuo-ku,Tokyo,140-0045,Japan

+81-3-6228-4105

watanabe@c-ctd.co.jp

COMPLETED

Jan. 20, 2014

Interventional

uncontrolled open-label multicenter study

open(masking not used)

No

2

Tentative registration
1)Definitive or suspected case of acquired TTP according to the Provisional Diagnostic Guideline of TTP of Study Group for Coagulation Disorders (MHLW).
-Definitive diagnosis: ADAMTS13 activity <5% and ADAMTS13 inhibitor positive, or presence of all of the 5 clinical symptoms(*) regardless of ADAMTS13 activity.
Suspected diagnosis: presence of thrombocytopenia and microangiopathic hemolytic anemia regardless of ADAMTS13 activity. * thrombocytopenia, microangiopathic hemolytic anemia, renal insufficiency, fever, fluctuating levels of neuropsychiatric symptoms.
2) 20 to 79 years old at the time of informed consent.
3) Written informed consent from the subject or legally acceptable representative

Registration
1) Patients with refractory or relapsed TTP who fulfill the criteria below.
-refractory TTP: fulfill one of the following conditions
i) Platelet count <50,000/microL after 5 procedures of plasma exchange.
ii) ADAMTS13 inhibitor level of 2 bethesda unit (BU)/mL or more at the time of tentative registration.
-relapsed TTP: relapse after at least 30 days from the previous episode.

Tentative registration
1) Secondary TTP associated with drug, hematopoietic stem cell transplantation, solid organ transplantation, collagen disease, malignancy, or pregnancy.
2) Congenital TTP (Upshaw-Shulman Syndrome) due to ADMTS 13 deficiency.
3) Presence of malignancy.
4) Severe hematological, neuropsychiatric, hepatic, pulmonary, endocrinological, immunological, or gastrointestinal conditions not related to TTP.
5) Previous exposure to rituximab.
6) Male patient who is not able to consent contraception during study period.
7) Female patient who is pregnant, lactating, or suspected of pregnancy. Female patient who wish to pregnant during study period.
8) Pariticipation in another registration clinical trial and administration of investigational drug during 12 weeks before informed consent.
9) Patients inadequate as the subject of the study judged by investigators.

Registration
1) Known HIV seropositive status.
2) Positive status of HBs antigen, HBs antibody, HBc antibody, or HCV antibody except for HBV seropositivity due to vaccination.

Both

Thrombotic Thrombocytopenic Purpura

Intervention type:DRUG Name of intervention:Rituximab Dose form / Japanese Medical Device Nomenclature:INJECTION Route of administration / Site of application:INTRAVENOUS DRIP Dose per administration:375 mg/m2 mg/m2 Dosing frequency / Frequency of use:QW 4 Planned duration of intervention:4 weeks Intended dose regimen:1st cycle Initiate infusion at a rate of 50 mg/hr. In the absence of adverse events such as allergic reaction or infusion reaction, increase infusion rate by 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr. Subsequent cycles If patients did not experience or experience grade 2 or less severe adverse events such as allergic reaction or infusion reaction during previous cycles, initiate infusion at a rate of 100 mg/hr and increase infusion rate by 100 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr. If patients experience grade 3 or more severe adverse events such as allergic reaction or infusion reaction during previous cycles, initiate infusion at a rate of 50 mg/hr and increase infusion rate by 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr. detailes of teratment arms: Comparative intervention name: Dose form / Japanese Medical Device Nomenclature: Route of administration / Site of application: Dose per administration: Dosing frequency / Frequency of use: Planned duration of intervention: Intended dose regimen:

Response rate at 4 weeks. Response is defined by fulfilling all the conditions below. 1) Normalization of platelet count 2) cessation of plasma exchange 3) Improvement of clinical symptoms

1) Peripheral blood B-cell count (CD20 positive cell, CD19 positive cell), peripheral blood T-cell count (CD3 positive cell)
2) Changes of platelet count from base line.
3) Normalization of platelet count: the rate of patients who achieved plate count of >=150,000/microL.
4) Cessation of plasma exchange: the rate of patients who achieved plate count of >=150,000/microL for 2 consecutive days and cessation of plasma exchange.
5) Improvement of clinical symptoms: improvement of anemia (Normalization of hemoglobin level or increase of hemoglobin level by 2 g/dL or more), Neuropsychiatric symptoms (Improvement of sum of GCS from base line).

Dec. 16, 2013