|E.1 Medical condition or disease under investigation
|Medical condition(s) being investigated
|Acquired thrombotic thrombocytopenic purpura
|Medical condition in easily understood language
|Diseases [C] - Blood and lymphatic diseases [C15]
|Condition being studied is a rare disease
|E.2 Objective of the trial
|Main objective of the trial
|We know that a fall in ADAMTS13 activity in remission can be a sign of upcoming TTP relapse. We plan to see if low dose rituximab is as effective as the standard dose in preventing TTP relapse by looking at the length of time until patients need to be treated again with ritiuximab or other immunosuppression
|Secondary objectives of the trial
|We will also look to see if low-dose rituximab is as effective as standard dose rituximab in:
• the time it takes for ADAMTS13 activity to normalise after rituximab
• how long ADAMTS13 stays normal after rituximab
• subsequent relapse rates of patients with a clinical TTP episode
• subsequent re-treatment rates of patients using rituximab or other immunosuppression
and also whether there is a difference in side effects between the 2 doses, either related to the infusion itself or other rituximab-related adverse effects.
|Trial contains a sub-study
|Principal inclusion criteria
|1. Male or female, age>18
2. Antibody-mediated TTP with at least one previous acute TTP episode
3. ADAMTS13 activity dropping to ≤15% documented on 2 separate occasions on different days, , with platelets>150 and no evidence of microangiopathic haemolytic anaemia and LDH <1.5 x upper limit normal
4. Females of childbearing potential and males agree to use an effective method of contraception from the time consent is signed for 12 months after treatment completion. Effective methods of contraception acceptable for this trial are oral, implanted or injected hormonal methods of contraception, IUD or IUS, and barrier methods of contraception
5. Females of childbearing potential have a negative pregnancy test within 7 days prior to being randomised. Participants are considered not of child bearing potential if they are surgically sterile (i.e. they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal
6. Willing and able to provide written informed consent.
7. Willing and able to comply with the trial protocol
|Principal exclusion criteria
|1. Females who are pregnant, planning pregnancy or breastfeeding
2. Concurrent and/or recent involvement in other research that is likely to interfere with the intervention within 3 months of study enrolment
3. Known allergies to rituximab
4. Patients currently undergoing plasma infusion/exchange
5. Patients on therapy with other immunosuppressive medication (except steroids)
6. Patients with a current acute severe infection or a history of recurring or chronic infections or underlying conditions which may further predispose patient to serious infection.
|E.5 End points
|Primary end point(s)
| The primary outcome will be time to re-treatment with rituximab/other immunosuppression measured in days from day of first rituximab infusion (D1)until D1 of any subsequent course of elective rituximab, or introduction of other immunosuppression initiated with the aim of preventing clinical relapse of TTP.
This will be analysed as a time-to-event variable.
|Secondary end point(s)
|Time to normalisation of ADAMTS13 activity–number of days from D1 of first rituximab infusion until ADAMTS13 activity returns to normal range; this is a time-to-event outcome.
Duration of ADAMTS13 response – number of days from normalisation of ADAMTS13 activity to ADAMTS13 activity dropping outside of remains in normal range; this is a time-to-event outcome.
Subsequent relapse rate with clinical TTP episode (%) – the proportion of patients who experience a clinical relapse of TTP during trial follow-up compared to patients who do not; this is a binary outcome.
Subsequent re-treatment rate with rituximab/other immunosuppression (%) – the proportion of patients who are retreated with rituximab or other immunosuppression, for the prevention of clinical relapse of TTP, during trial follow-up compared to patients who are not; this is a binary outcome.
Time to B cell depletion – number of days from D1 to CD19 count <0.005x109/L0.5% ; this is a time-to-event outcome .
Time to B cell return – number of days from D1 to CD19 count returning to normal range; this is a time-to-event outcome.
Infusion-related adverse effects
Delayed rituximab-related adverse effects eg serum sickness, abnormal LFTs, cytopenias, infections- not occurring during rituximab infusion
|E.6 and E.7 Scope of the trial
|Scope of the trial
|Trial type and phase
|Human pharmacology (Phase I)
|First administration to humans
|Other trial type description
|Therapeutic exploratory (Phase II)
|Therapeutic confirmatory (Phase III)
|Therapeutic use (Phase IV)
|E.8 Design of the trial
| Comparator of controlled trial
|Other medicinal product(s)
|Number of treatment arms in the trial
The trial involves single site in the Member State concerned
| The trial involves multiple sites in the Member State concerned
|Number of sites anticipated in Member State concerned
|The trial involves multiple Member States
|E.8.6 Trial involving sites outside the EEA
|Trial being conducted both within and outside the EEA
|Trial being conducted completely outside of the EEA
|Trial has a data monitoring committee
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|The end of trial is will be a database lock 2 months after the date of the last visit of the last participant to allow time to enter data, clean/check data.
|E.8.9 Initial estimate of the duration of the trial
|In the Member State concerned years
|In the Member State concerned months
|In the Member State concerned days
|In all countries concerned by the trial years
|In all countries concerned by the trial months