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Children's Hospital of Michigan, Detroit, MI, USA; *University of California at Davis, Department of ...... Children's Hospital, Akron, OH, USA; J. Lusher, I. Warrier,.
Journal of Thrombosis and Haemostasis, 2: 574–583

ORIGINAL ARTICLE

Human recombinant DNA-derived antihemophilic factor in the treatment of previously untreated patients with hemophilia A: final report on a hallmark clinical investigation J. LUSHER, C. ABILDGAARD,* S. ARKIN,  P. M. MANNUCCI,à R. ZIMMERMANN,§ L. SCHWARTZ– and D . H U R S T – Children’s Hospital of Michigan, Detroit, MI, USA; *University of California at Davis, Department of Pediatrics, Sacramento, CA (ret.), USA;  Schneider Children’s Hospital, New Hyde Park, NY, USA; àAngelo Bianchi Bonomi Hemophilia and Thrombosis Center, IRCCS Maggiore Hospital and University of Milan, Milan, Italy; §Kurpfalzkrankenhaus Hospital and Hemophilia, Heidelberg, Germany; and –Bayer HealthCare, West Haven, CT, USA

To cite this article: Lusher J, Abildgaard C, Arkin S, Mannucci PM, Zimmermann R, Schwartz L, Hurst D. Human recombinant DNA-derived antihemophilic factor in the treatment of previously untreated patients with hemophilia A: final report on a hallmark clinical investigation. J Thromb Haemost 2004; 2: 574–83.

Summary. Background: Development of recombinant factor VIII (rFVIII) replacement therapy represents a milestone in the treatment of hemophilia A. Objective: The objective of this long-term, multicenter study was to assess the safety, efficacy and rate of inhibitor formation of rFVIII (Kogenate) in the treatment of hemophilia A in a group of previously untreated patients (PUPs). Patients and methods: Between January 1989 and October 1997, 102 evaluable patients (mean age 3.9 years) were treated with rFVIII as sole therapy for prophylaxis against bleeding or for hemorrhage. Patients with mild hemophilia were treated for ‡2 years, while those with moderate or severe hemophilia were treated for ‡5 years or 100 exposure days. Results: All patients responded well to therapy, so that 82% of bleeding episodes required a single infusion for treatment. Only four mild drug-related adverse events were recorded during the study for an overall rate of 0.03% (4/13 464 infusions). No viral seroconversions were observed. The inhibitor incidence in PUPs with severe hemophilia was 29% (19/65). Overall, inhibitory antibodies developed in 21 patients (20.6%). Inhibitor titers were low (0.6– 1.2 Bethesda Units (BU), laboratory evidence such as low recovery values, or clinical evidence such as poor response to therapy and/or need to provide additional infusions for followup therapy]. Inhibitor assays were performed locally at the investigator’s laboratory. The minimum value for a detectable inhibitor was originally defined as 1.2 BU, but based on the lower limit of detection of site laboratories, was lowered to 0.6 BU in June 1993. Two-thirds of the sites chose to employ a minimum value of 1.0 BU based on normal limits of detection at their institutions. Thus, 10 patients had Bethesda titers between 0.6 and 1.2 BU at enrollment prior to any FVIII treatment. The study was approved by the institutional review committees or ethics committees of all participating centers and was conducted according to the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use in Good Clinical Practice. Written informed consent was obtained from patients or their legal guardians at the time of study entry. Study design

The study design was an open-label, multicenter evaluation of the long-term efficacy and safety of recombinant factor VIII (Kogenate; Bayer HealthCare, Berkeley, CA, USA) when used as the sole mode of replacement therapy in PUPs with hemophilia A. Recombinant FVIII was used for all infusions required during the course of the study, whether as prophylaxis against bleeding, or as treatment for spontaneous or traumatic  2004 International Society on Thrombosis and Haemostasis

bleeding episodes. Dose and treatment regimens were determined by the participating investigator for each individual patient, and rFVIII was administered intravenously in the clinic, hospital or at home. The first infusion occurred in January 1989, and all evaluable patients continued in the study until 30 June 1995. After that date, patients with mild hemophilia (FVIII >5%) were discontinued from the study, after receiving at least 2 years of treatment. Patients with severe (baseline FVIII level mean normal + 3 SD ” 3 Mean normal + 2SD< test sample < mean normal + 3 SD ” 2 Mean normal+ 1SD< test sample< mean normal+ 2SD ” 1 Mean normal < test sample < mean normal + 1 SD ” 0 Test sample < mean normal ” ) 1 These ELISA assays as well as T4 (CD4)/T8 (CD8) cell counts were performed every 6 months; and starting in June 1993, viral screening tests were performed every 12 months. Viral screening included tests for HIV, hepatitis B, hepatitis C, Epstein–Barr, and cytomegalovirus. Immune tolerance induction

Patients who developed high-titer rFVIII inhibitors were treated under immune tolerance induction (ITI) regimens at the investigator’s discretion. In 1992, a separate ITI protocol was created, and high-titer inhibitor patients were routinely transferred to the protocol for immune tolerance treatment. Daily doses of rFVIII were determined according to titer at ITI study entry: 50 IU kg)1 for 1.5% IU)1 kg)1). After two additional weeks of treatment and a confirmatory inhibitor assay, these patients were tapered from ITI and returned to on-demand therapy. Partial tolerance was defined as inhibitor titer decrease of at least 50% accompanied by an increase in FVIII recovery to 0.5–1.5% IU)1 kg)1. Patients who showed partial tolerance were allowed to continue ITI therapy at double the previous dosage for another 24 weeks or until the inhibitor disappeared, whichever occurred first; thereafter, patients were tapered from ITI as described above. Failure to respond was defined as no evidence of developing tolerance during the initial 24 weeks or during a subsequent 12 weeks at double dosage. Patients were discontinued from the study if their inhibitor had not

disappeared after 36 weeks (failure to respond) or 48 weeks (partial tolerance). While enrolled in the ITI study, alternative therapy to control hemorrhage was permitted. Results Patient demographics

One hundred and six patients were enrolled, of whom 102 were valid for safety and efficacy. (Previous publications in abstract form prior to final compilation and approval of the study results have reported 101 patients.) Twenty-one patients (20.6%) had mild hemophilia, 16 (15.7%) had moderate hemophilia, and 65 (63.7%) had severe hemophilia. The mean age was 3.9 years (median 1.0 years) at enrollment, although patients with severe hemophilia were substantially younger compared with those with mild or moderate hemophilia (Table 1). Five patients were ‡ 18 years. Eighty patients were white, 21 were non-white (black, nine; hispanic, nine; other, three), and race information was not collected for one patient. Two patients had received minimal treatment prior to study entry (fresh frozen plasma at birth, one; cryoprecipitate at birth, one). Patients had baseline inhibitor titers below or at the lower limit of normal for the local laboratory. For 10 patients, baseline inhibitor ranged from 0.6 to 1.0 BU. Six of the 10 patients were enrolled at sites where the normal range cut-off was £1.0 and judged not to have an inhibitor. Three of the 10 patients, enrolled where a normal Bethesda titer was defined as 0.6–10 BU (severe, 8; moderate, 1). à>10 BU (severe, 11; moderate, 1).

baseline levels of 0.9 and 0.62 BU observed at the study site, had a level of 0.0 BU upon confirmatory testing of a duplicate plasma sample at the reference laboratory. Confirmatory tests at the reference laboratory could not always be conducted prior to enrollment. Of these 10 patients, one (patient 83) developed a low-titer inhibitor, and two (patients 129 and 166) developed high-titer inhibitors. The inhibitor assays in this study were conducted using the original Bethesda method before the Nijmegen modification of the Besthesda assay was developed. Publications by Verbruggen et al. [29] and Giles et al. [30] have demonstrated the limitations of the conventional Bethesda assay compared with the Nijmegen modification, particularly with regard to detecting low levels of FVIII inhibitor. This may have contributed to the variability in inhibitor titers observed in this study. Exposure to study drug

The 102 patients received a total of 13 464 infusions of rFVIII between January 1989 and October 1997, which comprised a total of 11.1 million IU. The mean number of infusions per patient was 132 (SD ¼ 172; range 1–753). Mean time on study was 4.2 years (SD ¼ 1.4; range 0.4–6.3). Patients with severe hemophilia tended to be on study longer than those patients with mild or moderate hemophilia (severe 4.4 years; mild/ moderate 3.9 years). The mean number of exposure days was 126 (SD ¼ 168, range 1–712). Seventy patients (69%) had >20 exposure days, including the 21 inhibitor patients (high titer 12; low titer nine). Of note, the nine patients with low-titer inhibitors had the longest time on study, the most exposure days, and the highest number of infusions compared with the other patient groups (Table 2).

withdrawn (n ¼ 4), and protocol violation (n ¼ 1). An additional four patients were enrolled but not included in the study (received another blood product soon after enrollment, three; non-compliance with prestudy screening, one). Efficacy

Infusions required for bleeding episodes Of the total 13 464 infusions of rFVIII administered on study, 6175 infusions were given for the treatment of 4451 new bleeding episodes (spontaneous new bleeds, 1432; bleeding from trauma, 3019). The majority of bleeding episodes (82%) required only a single treatment with rFVIII (Fig. 1). Over 93% of bleeding episodes required only one or two infusions. For those patients with severe hemophilia A, 83% of bleeding episodes were treated with one infusion and 94% were treated with only one or two infusions. The mean dose administered for treatment of bleeding episodes was 42.2 ± 23.9 IU kg)1. Patient response to treatment for bleeding episodes Response of patients treated with rFVIII for bleeding episodes was subjectively assessed by patients, parents, or guardians as Ô3Õ or

Withdrawals from study

Of the 102 safety- and efficacy-valid patients, 24 prematurely discontinued participation from the study as designed, including four who were enrolled in the ITI protocol. Causes of discontinuation were loss to follow-up (n ¼ 7), development of an inhibitor (n ¼ 7), non-compliance (n ¼ 5), consent  2004 International Society on Thrombosis and Haemostasis

Fig. 1. Infusions required for treatment of bleeding episodes. Bars depict percent of bleeding episodes treated with a given number of infusions. Total number of bleeding episodes is labeled above each bar.

578 J. Lusher et al Table 3 Adverse events by relationship to study drug and severity* Patient

Relationship to study drug

Severity

Symptom

Study day

Day of infusion?

102 105 115 182 82 129 81 125 82 129 82 125 182 182

Related Related Related Related Not related Not related Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown

Mild Mild Mild Mild Mild Mild Mild Mild Mild Mild Moderate Moderate Moderate Moderate

Urticaria (hives) Flushing Erythema at injection site Rash Wheezing Emesis (two occasions) Rash Rash Fever Fever (two occasions) Emesis Diarrhea Rash Fever

232 0 212 51 0 4 and 6 603 138 0 359 and 364 0 153 51 381

Yes Yes Yes No (+1) Yes Yes, Yes No ()1) Yes Yes Yes, No (+1) Yes No (+1) No (+1) Yes

*Development of inhibitors is not included.

Ô4Õ on a 0–4 scale (4 ¼ most successful) in 93.8% of treatments. This observation was consistent with the majority of bleeding episodes requiring only one or two infusions for control of hemostasis. Subjective assessment scale data were analyzed up to June 1992 only, as the data from this study and the study performed in previously treated patients [8] had established the efficacy of rFVIII at that time. FVIII recoveries Recovery studies were performed on 157 occasions in 38 of the 102 patients. Protocol-defined FVIII recoveries were waived if precluded by blood volume considerations, or if patients were treated outside the hemophilia treatment center. As the majority of patients were infants at study entry (age 0.6–10 BU) and 12 of 21 inhibitors (57.1%) were high titer (peak >10 BU). Two patients with moderate hemophilia developed inhibitors (low titer, 1; high titer, 1). Inhibitors (low titer, 7; high titer, 1) disappeared in eight patients receiving episodic treatment without any modification to their treatment regimen such as immune tolerance induction. Of the 21 patients who developed inhibitors, all but five high-titer patients continued treatment with rFVIII. The incidence of inhibitor formation was higher for black patients (4/9, 44%) than for hispanic (2/9, 22%), white (15/80, 19%), or other/missing patients (0/4, 0%). Blacks also had a greater incidence of high-titer inhibitors (4/9, 44%) compared with hispanic (1/9, 11%) or white patients (7/80, 9%). All inhibitors observed in black patients were high-titer inhibitors  2004 International Society on Thrombosis and Haemostasis

rFVIII for previously untreated patients 579 Table 4 Summary of patients with inhibitor formation

Patient

Severity (% FVIII)

Age first exposure (months)

Inhibitor levels (BU) Positive FH

66 70 110 119 126 129** 142 147 166** 171 184 45 106 109 61 65 79 83** 84 146 185

Severe (0%) Moderate (2%) Severe (