Session: 322. Hemophilia A and B: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Research, Clinical Research, Education, Patient-reported outcomes
Joint and muscle bleeds cause acute pain in persons with hemophilia (PwH). Assessment of pain by PwH and their providers is important in guiding the management of bleeding episodes (BEs), as the onset of acute pain often signals the start of joint or soft tissue BEs and the need for treatment. In addition, pain relief can indicate bleed resolution and motivate a decision to end treatment. Pain is a personal experience, and while no measurement tool can fully capture the change in pain during a therapeutic intervention, a visual analog scale (VAS) has been validated in certain age groups in hemophilia and used in several studies.
Eptacog beta is an FDA-approved recombinant activated FVII for the treatment and control of BEs in PwH A or B with inhibitors (PwHABI) ≥12 years of age using initial dose regimens (IDRs) of 75 or 225 µg/kg. The pivotal PERSEPT 1 trial (NCT02020369) included 27 male participants ≥12 years old who treated 468 BEs (465 mild/moderate and 3 severe BEs) with eptacog beta.
The objectives of this post hoc analysis are to (i) characterize changes in pain intensity through 24h following the initial eptacog beta infusion for BE treatment in adolescent and adult PwHABI (12 to <18 and ≥18 years of age, respectively) from PERSEPT 1, and (ii) determine the levels of pain reduction associated with a decision to end treatment, thus identifying decreases in pain that are clinically meaningful in the PwHABI care setting.
Methods
Adolescent and adult PwHABI in PERSEPT 1 were randomized to receive either 75 or 225 µg/kg eptacog beta followed by 75 µg/kg at prespecified intervals for BE treatment. Pain levels were evaluated by the participants or their caregiver at bleed onset and at predefined treatment evaluation timepoints using a 0 to 100 mm VAS (0 mm corresponding to no pain; 100 mm corresponding to worst possible pain). VAS pain score analysis was stratified by four age and IDR subgroups (adult/75 IDR, adult/225 IDR, adolescent/75 IDR, and adolescent/225 IDR). Depending on the baseline VAS pain score recorded at bleed onset, the analysis was stratified according to three VAS groups: lower range (baseline VAS score of 0-33 mm), middle range (34-66 mm), and upper range (67-100 mm). VAS scores at baseline and at the treatment evaluation timepoint immediately following the final eptacog beta infusion (i.e., when a decision to end treatment was made) were recorded for BEs in each of the three VAS groups.
Results
Five adolescents and 22 adults treated 252 BEs with the 75 IDR and 216 BEs with the 225 IDR. The mean (standard deviation; SD) baseline VAS pain scores for BEs in the four age/IDR subgroups varied from 26.5 (22.1) to 45.3 (25.2) mm. At 12h post-initial infusion of eptacog beta, mean (SD) VAS pain scores in these subgroups had dropped to values varying from 1.1 (5.4) to 11.2 (18.1) mm. At 24h, mean (SD) VAS pain scores across these four subgroups again decreased, dropping to values varying from 0.0 (0.0) to 3.8 (9.4) mm.
The number [percentage] of BEs in the lower, middle, and upper VAS range groups was 186 [39.7%], 183 [39.1%], and 87 [18.6%], respectively. Baseline VAS scores for 12 BEs [2.6%] were not recorded. Mean (SD) pain scores at timepoints corresponding to decisions to end treatment of BEs in the lower, middle, and upper VAS categories were 4.0 (8.3), 16.5 (14.6), and 20.3 (16.6) mm, respectively, with associated mean (SD) VAS score reductions from baseline of 10.4 (12.0), 33.9 (15.2), and 57.0 (17.9) mm, respectively. Although the absolute magnitude of pain score reductions increased with BE pain severity, on a percentage basis these reductions remained relatively constant (lower VAS range: 71% reduction; middle range: 68%; upper range: 74%). VAS score reductions across VAS categories in the adult group varied between 64-71%, while in the adolescent group the corresponding percent reductions were 87-98%.
Conclusions
Pain relief was observed at 12h after initial eptacog beta infusion for both IDRs and in both age groups, with further pain decreases observed at 24h. In addition, PwHABI with high baseline BE-related pain required larger declines in VAS score to achieve clinically meaningful pain relief than PwHABI experiencing mild BE pain. Our findings provide new benchmark measurements of clinically relevant pain relief in PwHABI. We propose that the reductions in pain observed in this study might be adopted as a possible endpoint for substantive effect when designing clinical trials of bypassing agents in PwHABI.
Disclosures: Kessler: CSL Behring: Other: Scientific advisory board; Novo Nordisk: Other: Scientific advisory board; Genentech: Other: Scientific advisory board, Research Funding; Octapharma: Other: Scientific advisory board, Research Funding; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Other: Scientific advisory board; Takeda: Other: Scientific advisory board. Castaman: Roche: Consultancy, Honoraria, Other: participant of advisory boards , Speakers Bureau; Bioviiix: Speakers Bureau; UniQure: Membership on an entity's Board of Directors or advisory committees, Other: participant of advisory boards ; Sobi: Honoraria, Other: participant of advisory boards , Speakers Bureau; Alexion: Other: participant of advisory boards ; Takeda: Honoraria, Other: participant of advisory boards, Speakers Bureau; BioMarin: Honoraria, Other: participant of advisory boards, Speakers Bureau; Bioverativ: Honoraria, Speakers Bureau; Grifols: Speakers Bureau; Grifols: Speakers Bureau; Bayer: Honoraria, Other: participant of advisory boards ; Werfen: Speakers Bureau; Kedrion: Speakers Bureau; CSL Behring: Honoraria, Other: participant of advisory boards ; LFB: Honoraria, Other: participant of advisory boards , Speakers Bureau; Novo Nordisk: Honoraria, Other: participant of advisory boards , Research Funding, Speakers Bureau; Pfizer: Honoraria, Other: participant of advisory boards . Hermans: LFB, CAF-DCF, Novo Nordisk and Roche: Consultancy; LFB, CAF-DCF, Novo Nordisk and Roche: Honoraria. Jimenez-Yuste: NovoNordisk: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sobi: Consultancy, Honoraria, Research Funding; Octapharma: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Grifols: Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; BioMarin: Consultancy, Honoraria; Spark: Consultancy, Honoraria. Mahlangu: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Spark: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; University of the Witwatersrand and NHLS: Current Employment; World Federation of Hemophilia: Speakers Bureau; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; International Society on Thrombosis and Haemostasis: Speakers Bureau; Biomarin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Miesbach: Bayer, Biotest, CSL Behring, LFB, Novo Nordisk, Octapharma, Pfizer, Takeda/Shire: Research Funding; Bayer, Biomarin, Biotest, CSL Behring, Chugai. LFB, Novo Nordisk, Octapharma, Pfizer, Roche,sobi, Takeda/Shire: Speakers Bureau; Bayer, Biomarin, Biotest, CSL Behring, Chugai. LFB, Novo Nordisk, Octapharma, Pfizer, Roche,sobi, Takeda/Shire: Honoraria; Bayer, Biomarin, Biotest, CSL Behring, Chugai, Freeline, LFB, Novo Nordisk, Octapharma, Pfizer, Regeneron, Roche, Sanofi, sobi, Takeda/Shire, uniQure: Consultancy. Oldenburg: Bayer, Biogen Idec, Biomarin, Biotest, Chugai, CSL Behring, Freeline, Grifols, LFB, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Spark Therapeutics, Swedish Orphan Biovitrum and Takeda: Honoraria, Other: reimbursed for attending symposia/congresses , Research Funding. Recht: Bayer: Research Funding; CSL Behring: Ended employment in the past 24 months, Research Funding; Genentech: Consultancy, Research Funding; Grifols: Research Funding; HEMA Biologics: Consultancy, Research Funding; LFB: Research Funding; Novo Nordisk: Consultancy, Research Funding; Octapharma: Research Funding; Pfizer: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Takeda: Research Funding; uniQure: Consultancy, Research Funding; Spark Therapeutics: Research Funding; Partners in Bleeding Disorders: Membership on an entity's Board of Directors or advisory committees. Wheeler: Sanofi-Aventis: Honoraria; Pfizer Inc: Honoraria; Novo Nordisk: Consultancy, Honoraria; HEMA Biologics: Honoraria; Bayer: Honoraria; UniQure: Honoraria; Octapharma: Honoraria, Research Funding; CSL Behring: Honoraria; Genentech: Honoraria; Takeda Pharmaceuticals: Honoraria; Vega Therapeutics, Inc.: Honoraria. Pipe: Siemens, YewSavin: Research Funding; Scientific Advisory Board GeneVentiv, Equilibra Bioscience: Membership on an entity's Board of Directors or advisory committees; Apcintex, ASC Therapeutics, Bayer, Be Bio, BioMarin, CSL Behring, HEMA Biologics, Freeline, LFB, Metagenomi, Novo Nordisk, Pfizer, Poseida Therapeutics, Precision Bioscience, Regeneron, Roche/Genentech, Sanofi, Takeda, Spark Therapeutics, UniQure: Consultancy.
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