Assignment Outcome measures to evaluate effectiveness of therapy - PowerPoint PPT Presentation

Assignment • Outcome measures to evaluate effectiveness of therapy • Treatment and control of bleeding in presence of inhibitors (including with novel therapies) • Inhibitor eradication strategies • Adherence to treatment

Domain 1: Treatment/control of bleeding • No suitable PhenX toolkit measure • Prior scoping in this area presented in a review article • Ossoli and Berntorp (2016) J Int Med • Looking at data extracted from national/int’l registries • Principles include measurement of frequency, location, cause and extent • Best example is HemoRec Registry out of Poland

HemoRec Registry • For each bleeding episode, patient characteristics, such as age and weight, were extracted together with background information about the bleed: re-bleed or new bleed (re-bleed was defined as a bleed in the same location within 48 h of cessation of the previous episode), nature of the bleed (spontaneous, traumatic, unknown), anatomical site of the bleed (joint, muscle, other, multiple sites), start time of the bleed, time of initiation of rFVIIa treatment, starting dose of rFVIIa, total number of doses administered and total dose.

HemoRec Registry publications 1.Economic evaluation of rFVIIa high initial dose compared to rFVIIa standard initial dose in patients with haemophilia with inhibitors using the Czech HemoRec registry. Salaj P, Kubes R, Cetkovsky P, Capova I, Penka M, Ovesná P, Mesterton J, Lindgren P. Thromb Res. 2014 Feb;133(2):162-7 2.Economic analysis of recombinant activated factor VII versus plasma-derived activated prothrombin complex concentrate in mild to moderate bleeds: haemophilia registry data from the Czech Republic. Salaj P, Penka M, Smejkal P, Geierova V, Ovesná P, Brabec P, Cetkovsky P, Kubes R, Mesterton J, Lindgren P. Thromb Res. 2012 May;129(5):e233-7. 3.Effect of rFVIIa dose and time to treatment on patients with haemophilia and inhibitors: analysis of HemoRec registry data from the Czech Republic. Salaj P, Brabec P, Penka M, Pohlreichova V, Smejkal P, Cetkovsky P, Dusek L, Hedner U. Haemophilia. 2009 May;15(3):752-9.

Specific examples in inhibitor clinical trials • DOSE studies - Novo Nordisk • Emicizumab clinical trial program – Roche/Genentech • Both generally follow bleeding definitions established by the ISTH subcommittee and used in recent non-inhibitor trials • Blanchette VS, Key NS, Ljung LR, et al. Definitions in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost 2014;12:1935−9. • Mahlangu J, Powell JS, Ragni MV, et al. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood 2014;123:317−25.

Definitions • Treated bleeds ⎯ if the bleed was treated with coagulation factors • All bleeds ⎯ irrespective of treatment with coagulation factors • Treated spontaneous bleeds ⎯ if the bleed occurred spontaneously and it was treated with coagulation factors • Treated joint bleeds ⎯ if the bleed qualified for joint bleed and it was treated with coagulation factors • Treated target joint bleeds ⎯ if the bleed qualified for joint bleed, occurred in target joint and it was treated with coagulation factors • 72-Hour Rule • Two bleeds of the same type (e.g., “joint,” “muscle,” or “other”) and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. The last treatment was defined as the last treatment associated with the bleed before a new bleed occurred, either in the same or in a different location.

ABR Statistical Considerations • number of bleeds analyzed using the negative binomial (NB) regression model with efficacy period as an offset in the model to account for the difference in follow-up times. Annualized Bleeding Rate estimated from the model and presented with 95% CI. • In addition to the model based approach, individual patient ABR may be calculated based on the formula: $%&'() *+ ',((-. /0( -%)123 (+415657 8()1*- • ABR = ´ 365.25 $%&'() *+ -67. -%)123 /0( (+415657 8()1*-

Issues that need to be discussed • Do we have different requirements for registry-based data vs within clinical trials? • Any reason to think that there is/should be unique bleed definitions for an inhibitor patient vs non-inhibitor or patient on traditional factor replacement vs non-factor therapies? • Are we ready to include radiological assessments (MSKUS) into bleeding measures • Bleed control (acute management) is different than joint outcomes (long term outcome), yet need to be harmonized in some way • Are we satisfied with HJHS for long term outcomes for the forseeable future?

Domain 2: Inhibitor Eradication • Traditional Primary Outcomes for ITI • Efficacy: inhibitor eradication, defined as: • Unmeasureable inhibitor • Normal factor VIII or IX recovery • Normal factor VIII or IX half-life • Safety evaluation: incidence of adverse events (such as musculoskeletal bleeding events, all bleeding events, administration site infections, severe allergic reactions, and nephrotic syndrome) • Secondary outcomes: • Joint outcomes • QoL • Cost and resource utlization

Measures Used • None in PhenX for Primary Outcomes • “Unmeasureable inhibitor” • Bethesda/Nijmegen modification < 0.6 BU Consider CDC testing algorithm including use of chromogenic methodology • • Especially important given incorporation of substitution therapy (ie. emicizumab) • “Normal recovery” • FVIII incremental recovery (IR) ≥1.3 IU/dL per IU/kg in 2 consecutive determinations representing 66% of the expected IR 2 IU/dL per IU/kg • “Normal half-life” • FVIII t 1/2 of > 6 hours (standard half-life) What is the rationale for a modified half-life threshold for extended half-life? • • Particular challenge in IR and half-life determinations with use of substitution therapy • With hemostatic rebalancing therapies, what impact reduced dosing? ie. recommendation of only 10 IU/kg of FVIII and 20 IU/kg FIX • DiMichele DM, Hoots WK, Pipe SW, Rivard GE, Santagostino E. International workshop on immune tolerance induction: consensus recommendations. Haemophilia 2007; 13(Suppl. 1): 1–22.

Success Definitions • Complete Success • Meets all 3 primary outcome measures • Partial success • Meets < 3 primary outcome measures • Failure • Does not meet criteria for complete or partial success * • Relapse Inhibitor recurrence as evidenced by change in any of the primary outcome measures • • All success definitions are time-dependent • Traditional time period of 33 months • What is a reasonable time-frame for determining success, especially in view of efficacy of non-factor therapies? • Time-frame for evaluation of relapse • 12 to 48 months in recent studies • Should this be extended considerably in era of non-factor therapies considering exposure to factor may be distributed over a significantly protracted time period? * ObsITI included criteria of “partial response”

References • Athale et al. Cochrane Database of Systematic Reviews 2014, Issue 4 • Hay, DiMichele et al. Blood . 2012; 119(6):1335-1344 • Kreuz et al. Haemophilia (2016), 22, 87–95 • DiMichele DM, Hoots WK, Pipe SW, Rivard GE, Santagostino E. International workshop on immune tolerance induction: consensus recommendations. Haemophilia 2007; 13(Suppl. 1): 1–22. • Jimenez-Yuste et al. Haemophilia (2016), 22, 859–865 • Holstein et al. Thrombosis Research 148 (2016) 38–44 • Ljung. British Journal of Haematology, 2018, 180, 501–510