Prophylactic therapy with recombinant ADAMTS13 safe for congenital TTP

1. In this randomized controlled trial, among individuals with congenital thrombotic thrombocytopenic purpura (TTP), no patients in a prophylactic group that received recombinant ADAMTS13 had an acute TTP event, whereas one adverse event occurred in a patient who received prophylactic standard therapy. 

2. The most common TTP manifestation was thrombocytopenia.

Evidence Rating Level: 1 (Excellent)

Study Rundown: TTP is a rare thrombotic microangiopathy that results from a deficiency in the ADAMTS13. A phase three randomized control trial was initiated to assess the efficacy and safety of recombinant ADAMTS13 in patients with TTP. The participants were randomized in a 1:1 ratio into two cohorts. The first group was the prophylactic cohort, which received preventative treatment for TTP. In contrast, the second group was the on-demand cohort, which only received treatment after a TTP event. For the prophylactic group, the patients were treated either with ADAMTS13 or with standard therapy, thus allowing for comparison between the two methods. To best understand the effects of the therapy method, the study assessed observed acute TTP events in the prophylactic cohort as the primary outcome. the secondary outcomes included TTP manifestations. As there were substantial differences in the volume between the standard therapy and the recombinant ADAMTS13, the trial could not be blinded and was thus limited to an open-label design. Overall, therapy with recombinant ADAMTS13 was an effective and safe method to treat patients with congenital TTP. In the prophylactic group, the levels of ADAMTS13 reached approximately normal maximum activity, and low levels of disease-related events were reported.

Click here to read the study in the NEJM

In-Depth [randomized controlled trial]: A randomized control trial was conducted to assess the effects of recombinant ADAMTS13 on patients with TTP. Individuals were eligible to participate in the study if they were between the ages of 0 and 70 at the time of screening and had no serious side effects from standard therapy. Furthermore, patients were eligible for the prophylactic group if they had no signs of an acute TTP event at screening. On the other hand, patients were eligible for the on-demand group if they had an acute TTP event at screening. A total of 48 patients were randomized to receive either standard therapy or prophylaxis with recombinant ADAMTS13. While no acute TTP events occurred when administering recombinant ASAMTS13, one patient had an acute event with standard therapy while receiving prophylaxis. Of the possible TTP manifestations, thrombocytopenia was the most common (annualized event rate, 0.74 with recombinant ADAMTS13 and 1.73 with standard therapy). In the group receiving prophylactic ADAMTS13, 71% of participants experienced adverse events. Whereas in the group receiving standard therapy, a total of 84% experienced adverse events. Specifically examining adverse events that were considered to be related to the trial drug, they occurred in four patients (9%) in the prophylactic group and 21 patients (48%) in the on-demand group. None of the patients receiving ADAMTS13 interrupted or stopped the trial due to adverse events, whereas seven patients receiving standard therapy interrupted their treatment while 1 patient stopped it. Neutralizing antibodies were not found in patients in the intervention group that received the recombinant ADAMTS13. After the recombinant or standard therapy, the mean maximum ADAMTS13 activity was 101% and 19%, respectively.  In summary, recombinant ADAMTS13 was an effective and safe prophylactic treatment method for congenital TTP.

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