Abstract Number: PB0921
Meeting: ISTH 2020 Congress
Theme: Hemophilia and Rare Bleeding Disorders » Hemophilia - Clinical
Background: Primary results of PROPEL (NCT02585960) demonstrated clinical benefits of targeting elevated factor VIII (FVIII) troughs with rurioctocog alfa pegol (TAK-660, SHP660, BAX 855) prophylaxis with no change in safety profile.
Aims: Assess efficacy and target joint (TJ) resolution with pharmacokinetic (PK)-guided TAK-660 prophylaxis in a post-hoc analysis.
Methods: PROPEL study design was previously reported (Klamroth et al., RPTH 2019); ethics committees’ approval and patient informed consent obtained. Patients were randomized to PK-guided TAK-660 prophylaxis targeting FVIII troughs of 1-3% (reference) or 8-12% (elevated). TJ was defined as a joint with ≥4 bleeds during any consecutive 6 months. Outcomes evaluated: total annualized bleeding rate (ABR; all bleeds) according to patients’ TJ status at screening and TJ ABR (per-protocol analysis set; second 6 months completed, no significant protocol deviations); course of TJs in treated patients with ≥6-months’ observation (full analysis set; randomized, ≥1 prophylactic dose received).
Results: In patients with 0 (n=26) and ≥1 (n=69) TJs, respectively, mean total ABR point estimates (95% CI) were 2.6 (1.5-4.6) and 2.4 (1.6-3.5) in 1-3% arm and 1.5 (0.6-3.5) and 0.9 (0.5-1.6) in 8-12% arm (Table 1). Spontaneous and spontaneous joint ABRs were also lower in 8-12% versus 1-3% arm irrespective of TJ status; injury-related ABR was slightly higher in 8-12% arm with no TJs and lower with ≥1 TJ at screening. Mean TJ ABRs (both arms) decreased during 12-months’ treatment (Table 2). In 112/115 evaluable patients, TJs resolved in all but 1 patient per arm after 6 months’ prophylaxis.
Conclusions: Targeting 8-12% versus 1-3% FVIII troughs was associated with reduced bleeding into TJs, reduced ABR irrespective of baseline TJ status, and TJ resolution within the first 6 months in all but 1 patient per arm. Results show the clinical benefit of elevating FVIII troughs with TAK-660 for TJ resolution, an important consideration for joint health in hemophilia A.
| TJ status | Point estimate (95% CI)* of mean ABR | FVIII trough level 1-3% | FVIII trough level 8-12% |
| No TJs (1-3% arm, n=16; 8-12% arm, n=10) | Total ABR | 2.6 (1.5-4.6) | 1.5 (0.6-3.5) |
| Spontaneous ABR | 1.3 (0.6-2.5) | 0.1 (0.0-1.1) | |
| Spontaneous joint ABR | 1.2 (0.7-2.3) | 0.0 (NC) | |
| Injury-related ABR | 0.8 (0.3-2.2) | 1.0 (0.3-3.5) | |
| ≥1 TJ (1-3% arm, n=36; 8-12% arm, n=33) | Total ABR | 2.4 (1.6-3.5) | 0.9 (0.5-1.6) |
| Spontaneous ABR | 1.3 (0.7-2.3) | 0.5 (0.2-1.1) | |
| Spontaneous joint ABR | 1.2 (0.6-2.4) | 0.5 (0.2-1.3) | |
| Injury-related ABR | 1.1 (0.6-1.9) | 0.4 (0.2-1.0) | |
| ABR, annualized bleeding rate; FVIII, factor VIII; NC, not calculable due to no events in the 8-12% arm; TJ, target joint. *Point estimates and 95% CIs were obtained from a generalized linear model fitting a negative binomial distribution. | |||
[ABR by TJ status at screening: second 6-month study period in the per-protocol analysis set.]
| Study period | Parameter | FVIII trough level 1-3% (n=52) | FVIII trough level 8-12% (n=43) | |
| First 6 months | TJ ABR | Mean (SD) | 0.5 (1.4) | 0.7 (2.3) |
| Median (Q1-Q3) | 0.0 (0.0-0.0) | 0.0 (0.0-0.0) | ||
| Second 6 months | TJ ABR | Mean (SD) | 0.1 (0.6) | 0.2 (1.3) |
| Median (Q1-Q3) | 0.0 (0.0-0.0) | 0.0 (0.0-0.0) | ||
| ABR, annualized bleeding rate; FVIII, factor VIII; Q, quartile; TJ, target joint. | ||||
[ABR of TJ bleeds: first and second 6-month study periods in the per-protocol analysis set]
To cite this abstract in AMA style:
Collins P, Windyga J, Escobar M, Ibrahim HM, Lam JCM, Tangada SD, Engl W, Honauer I, Fernandez A, Lee H-, Klamroth R, Escuriola-Ettingshausen C. Efficacy and Target Joint Resolution with Pharmacokinetic-Guided Rurioctocog Alfa Pegol Prophylaxis Targeting Two Factor VIII trough Levels in Patients with Severe Hemophilia A: Post-Hoc Analysis of the Phase 3 PROPEL Trial [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/efficacy-and-target-joint-resolution-with-pharmacokinetic-guided-rurioctocog-alfa-pegol-prophylaxis-targeting-two-factor-viii-trough-levels-in-patients-with-severe-hemophilia-a-post-hoc-analysis-of-t/. Accessed November 30, 2023.« Back to ISTH 2020 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/efficacy-and-target-joint-resolution-with-pharmacokinetic-guided-rurioctocog-alfa-pegol-prophylaxis-targeting-two-factor-viii-trough-levels-in-patients-with-severe-hemophilia-a-post-hoc-analysis-of-t/