Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura

Scully. NEJM 2018; published online Jan 9, 2019.DOI:10.1056/NEJMoa1806311

Clinical Question

  • In patients with acquired thrombotic thrombocytopenic purpura, does caplacizumab compared with placebo,  reduce the time to normalisation of the platelet count?


  • Acquired thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy characterised by thrombocytopenia and haemolytic anaemia
  • Autoantibodies inhibit activity of the von-Willebrand factor-cleaving protease ADAMTS13 which leads to platelet consumption and microvascular thrombosis
  • Caplacizumab, an immunoglobulin fragment, targets the A1 domain of von Willebrand factor, preventing interaction with the platelet glycoprotein receptor and the subsequent microvascular thrombosis
  • The phase II TITAN study demonstrated a significantly reduced time to normalisation of platelet count in patients treated with caplacizumab compared with placebo


  • Double blind randomised controlled trial
  • Stratified according to baseline GCS
  • Followed up for 28 days post treatment period
  • Efficacy analyses conducted in the intention to treat population
  • Safety analyses conducted in per-protocol population (all patients who received at least 1 dose of caplacizumab or placebo)
  • Sample size calculation: 132 patient would give the trial
    • 80% power to detect a 40% reduction in the primary outcome, with a 5% significance level and a 10% dropout rate
    • 83% power to detect a 20% reduction in the first key secondary outcome with a 5% significance level
  • Industry sponsored
  • Registered on clinicaltrials.gov


  • 92 centres worldwide (Australia, USA, Europe)
  • Data collected November 2015 – April 2017


  • Inclusion criteria:
    • TTP diagnosed on the basis of clinical presentation
      • both thrombocytopenia and microangiopathic haemolytic anaemia with schistocytes seen on blood smear
    • Had received 1 plasma exchange treatment
    • Age >=18 years, and in some sites children aged 2-18 years were eligible
  • Exclusion criteria:
    • Congenital TTP
    • Suspected thrombotic microangiopathy that was not associated with TTP, such as haemolytic uraemic syndrome
  • 145 patients randomised
    • 1 patient withdrew consent prior to receiving study medication
    • 36 patients who had received at least 1 dose of study drug discontinued trial regimen (13 in the intervention group and 23 in the placebo group). The most common reasons for discontinuation were adverse events, withdrawal of consent, physician decision
  • Comparing baseline characteristics of intervention vs. placebo groups:
    • Age: 45 vs. 47
    • Recurrent TTP: 33% vs. 53%, p<0.05
      • consistent with more severe disease in intervention group as initial TTP episodes tend to be more severe at presentation than recurrent episodes
    • Median platelet count: 24,000 vs. 25,000
    • Median LDH: 449 vs. 403 U/l
    • Median creatinine: 77 vs. 82 umol/l
    • ADAMTS13 activity <10%: 81% vs. 89%
    • GCS <=12: 8% vs. 7%
    • Immunosuppressive therapy
      • Glucocorticoids: 96% vs. 97%
      • Rituximab: 39% vs. 48%
        • Started by trial day 3: 12% vs. 22%
      • Mycophenolate mofetil: 8% vs. 0%
      • Other: 8% vs. 4%
    • Immune globulin concentrate infusion: 6% vs. 0%


  • Caplacizumab
    • 10mg IV loading dose before the start of the 1st plasma exchange post randomisation
    • Subsequent 10mg doses given subcutaneously once daily until 30 days after last daily plasma exchange
    • Treatment could be extended for maximum of further 28 days, dependent on risk factors for recurrence of TTP


  • Placebo
    • Dosing schedule as per intervention group

Management common to both groups

  • Standard of care treatment for TTP
    • Daily plasma exchange
      • 1-1.5 * plasma volume, until at least 2 days after normalisation of the platelet count
    • Glucocorticoids
      • Prednisone or prednisolone at a dose of >=1mg/kg/day during daily plasma-exchange period and continuing for 1st week after the end of the daily plasma exchange period. Subsequent tapering of steroids at physician discretion with aim of stopping completely within 30 days after last plasma exchange
    • Other immunosuppressive therapy allowed in accordance with clinical practice at each site
    • If new decrease in the platelet count that necessitated the re-initiation of daily plasma exchange then patients switched to open-label caplacizumab


  • Primary outcome: Time from 1st administration of study drug to normalisation of platelet count (>150,000), with discontinuation of daily plasma exchange within 5 days thereafter – significantly reduced in the intervention group
    • At any given time point, patients in the intervention group were 1.55 times as likely to have a normalisation of the platelet count compared with placebo
    • Rate ratio 1.55; 95% C.I. 1.09-2.19, p=0.01
    • Time to normalisation of platelet count:
      • 25th centile: 1.75 vs. 1.94 days
      • 50th centile: 2.69 vs. 2.88 days
      • 75th centile: 2.95 vs. 4.50 days
  • Secondary outcomes:
    • 1st key secondary outcome: composite of TTP related death, recurrence of TTP, or a major thromboembolic event during the double blind treatment period – significantly reduced in the intervention group
      • 12% vs. 49%, p<0.001
    • TTP related death – no significant difference
      • 0% vs. 4%
    • Recurrence of TTP – significantly reduced in the intervention group
      • At any time: 12% vs. 38%, p<0.001
      • During double blind treatment protocol: 4% vs. 38%
      • All 6 patients who had a relapse after stopping caplacizumab had an ADAMTS13 activity level <10% when the caplacizumab was stopped
    • Major thromboembolic event – no significant difference
      • 8% vs. 8%
    • Refractory disease – no significant difference
      • 0% vs. 3%, p=0.06
    • In the intervention group significantly reduced:
      • Number of days of plasma exchange
        • 5.8 vs. 9.4 days
      • Length of ICU stay
        • 3.4 vs. 9.7 days
      • Length of hospital stay
        • 9.9 vs. 14.4 days
    • All cause mortality – no significant difference
      • 1% vs. 4%
    • Serious adverse events – significantly increased in the intervention group
      • Overall: 32% vs. 16%
      • Bleeding: 11% vs. 1%, most commonly epistaxis
      • Cardiac disorders: 6% vs. 1%

Authors’ Conclusions

  •  In patients with TTP, calpacizumab was associated with faster normalisation of the platelet count, a lower incidence of the composite of TTP related death, recurrence of TTP or a thromboembolic event during the treatment period


  • Randomised controlled trial
  • Multi-centre, multi-national
  • Double blinded
  • Use of matched placebo
  • Intention to treat analysis performed
  • Stratification by GCS to ensure equal balance in both groups
  • Appropriate statistical models used


  • Primary outcome is not patient orientated
  • The significant improvement in time to platelet count resolution was driven by differences seen in the 75th centile. There was no significant difference in the 25th and 50th centile groups
  • There was a large dropout rate, with 13 of those receiving the intervention, and 25 of those receiving placebo not completing treatment. It is possible that the twice-higher rate of dropout in the placebo group meant that these patients differed in some way from those in the intervention arm
  • 1st key secondary outcome is a composite outcome. This includes TTP related mortality rather than all cause mortality
  • Industry sponsored
  • Differences in baseline characteristics
  • The use of other immunosuppressive therapy was not standardized which may have led to differences in the rates of use between the two groups
  • Patients were only followed-up for 28 days so long-term data on the safety of caplacizumab was not investigated

The Bottom Line

  • In patients with acquired TTP, the use of caplacizumab compared with placebo significantly reduced the time to normalisation of platelet count. The difference was driven predominately by changes at the 75th centile with no significant differences at the 25th and 50th centiles
  •  The 1st key secondary outcome found that the composite of TTP related death, recurrence of TTP or major thromboembolic event was significantly reduced in the intervention group. This was predominantly due to a reduction in the recurrence rate of TTP. The duration of ICU and hospital stay as well as the number of cycles of plasma exchange were significantly reduced in the intervention group
  • The number of serious adverse events was significantly increased in the intervention group

External Links


Summary author: Dave Slessor
Summary date: 20th January 2019
Peer-review editor: Fraser Magee

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