TITAN
(2016)Objective
To evaluate the efficacy and safety of caplacizumab, an anti-von Willebrand factor Nanobody, in treating acquired thrombotic thrombocytopenic purpura (TTP)
Study Summary
• Fewer exacerbations occurred with caplacizumab (8% vs 28%)
• Bleeding events were more common with caplacizumab (54% vs 38%) but mostly mild
Intervention
Caplacizumab 10 mg daily subcutaneous injection vs placebo, given during plasma exchange and for 30 days after
Inclusion Criteria
Adults with acute acquired TTP, platelet count <100,000/mm³, no active bleeding, requiring plasma exchange
Study Design
Arms: Caplacizumab (n=36) vs Placebo (n=39)
Patients per Arm: 36 caplacizumab, 39 placebo
Outcome
• Secondary: Complete remission 81% vs 46%
• Safety: More bleeding with caplacizumab but generally mild
Bottom Line
Caplacizumab significantly reduced time to platelet recovery and decreased exacerbations in acquired TTP patients, but increased bleeding risk compared to placebo.
Major Points
- Phase 2 randomized controlled trial of caplacizumab vs placebo in acquired TTP
- Primary endpoint was time to confirmed platelet count normalization (≥150,000/mm³)
- Caplacizumab reduced median time to response by 39% (3.0 vs 4.9 days, P=0.005)
- Fewer exacerbations with caplacizumab (8% vs 28%)
- More bleeding events with caplacizumab (54% vs 38%) but mostly mild to moderate
- Study terminated early due to recruitment challenges, not safety concerns
Study Design
- Study Type
- Randomized, single-blind, placebo-controlled trial
- Randomization
- Yes
- Blinding
- Single-blind (investigators were aware of von Willebrand factor-ristocetin cofactor activity results)
- Sample Size
- 75
- Follow-up
- 12 months
- Centers
- 56
- Countries
- Multiple countries worldwide
Primary Outcome
Definition: Time to confirmed normalization of platelet count (≥150,000/mm³ confirmed at 48 hours with LDH ≤2x upper normal limit)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 4.9 days median (95% CI 3.2-6.6) | 3.0 days median (95% CI 2.7-3.9) | - (Event rate ratio 2.20 (1.28-3.78)) | 0.005 |
Limitations & Criticisms
- Study terminated early due to recruitment challenges, reducing statistical power
- Single-blind design due to necessity of monitoring von Willebrand factor activity
- Higher relapse rate in caplacizumab group during follow-up period
- Increased bleeding risk with caplacizumab treatment
- Small sample size (75 patients total)
Citation
N Engl J Med 2016;374:511-22