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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Clinical Trial Design with TPO Mimetics
  5. Effects of TPO Mimetics on Bleeding
  6. Concomitant and Rescue Medication Use
  7. Conclusions
  8. Acknowledgements
  9. References

Patients with ITP may have severe thrombocytopenia, putting them at risk for serious bleeding. ITP trials of new treatments must allow use of standard-of-care therapies to prevent serious bleeding. Thrombopoietin mimetic trials used platelet counts and rescue/concomitant medication use as endpoints. These trials were of insufficient size and duration to measure mortality or serious bleeding, which are infrequent with appropriate treatment. A recent Cochrane review criticized the thrombopoietin mimetic registrational trials for inadequately assessing bleeding and survival. We discuss how these endpoints are difficult to measure in clinical trials designed to improve platelet counts and minimize bleeding, in accordance with ethical trial design. Am. J. Hematol. 2012. © 2012 Wiley Periodicals, Inc.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Clinical Trial Design with TPO Mimetics
  5. Effects of TPO Mimetics on Bleeding
  6. Concomitant and Rescue Medication Use
  7. Conclusions
  8. Acknowledgements
  9. References

While ITP is generally a benign disease, the risk of mortality in affected patients is roughly twice that of the general population, particularly in patients who are older or who have more advanced disease with a history of bleeding [1–6]. Causes of death in ITP include severe bleeding, such as gastrointestinal and intracranial hemorrhage, post-splenectomy complications, and infections secondary to long-term immunosuppression from therapy. Infection and bleeding are the most frequently reported causes of death in ITP, with one study reporting death due to infection as being more common than death due to bleeding [2, 3]. Hospitalizations in adults with ITP are on average more costly, longer, and associated with higher mortality than hospitalizations within the US population as a whole [6].

In this article, we review the available bleeding and mortality data from clinical trials of the thrombopoietin (TPO) mimetics romiplostim and eltrombopag in immune thrombocytopenia (ITP). In the pivotal randomized trials of these agents, bleeding and mortality were reported as adverse events, but were not included as endpoints. We further discuss the problems with and appropriateness of determining bleeding and mortality endpoints in ITP clinical trials given the need to use rescue therapy for severe thrombocytopenia. It must be noted that no head-to-head comparative trials have been conducted with these two TPO mimetics; what follows is a description of the published data for each individual product. We also review data on use of rescue therapies and concomitant medications in these trials, as use of rescue therapy can confound analysis of bleeding and mortality outcomes in ITP trials.

Clinical Trial Design with TPO Mimetics

  1. Top of page
  2. Abstract
  3. Introduction
  4. Clinical Trial Design with TPO Mimetics
  5. Effects of TPO Mimetics on Bleeding
  6. Concomitant and Rescue Medication Use
  7. Conclusions
  8. Acknowledgements
  9. References

As ITP patients with severe thrombocytopenia are at high risk for serious bleeding, ethically, clinical trials of these patients must provide effective treatment to prevent bleeding, in accordance with ITP treatment guidelines [7–9]. In addition, medications such as corticosteroids, platelet transfusions, and intravenous immunoglobulin (IVIG), among others, may be introduced or increased in dose to effective levels during the conduct of clinical trials to “rescue” ITP patients from severe thrombocytopenia that places them at risk for serious or fatal bleeding. Because rescue medications are also expected to reduce the risk of severe bleeding events, the effects of a new ITP treatment on further reducing the risk of bleeding are difficult to assess, especially when the use of rescue medications is likely different across trial arms.

ITP treatments, including rescue medications, are expected to reduce the risk of bleeding; thus, severe bleeding events or death should occur infrequently in the context of appropriate treatment. Because ITP is a rare disease, it is not feasible to conduct clinical trials of sufficient size to measure events that occur infrequently. As the relationship between bleeding and thrombocytopenia in ITP has been well established [10, 11], durable increases in platelet counts to =50 × 109/L [7–9] have been accepted as an appropriate endpoint for hemostatic platelet counts for ITP patients. Regulatory agencies have thus required the use of durable platelet response as the primary endpoint for ITP clinical trials and as the basis for the regulatory approval of TPO mimetics [12, 13]. While bleeding was not prospectively defined as an efficacy endpoint in the TPO mimetic clinical trials, it was of clinical interest, and bleeding data were collected in adverse event reports. Examination of that bleeding data is useful in understanding the complexities of evaluating new ITP treatments, as well as the relationship between hemostatic platelet counts and the incidence of bleeding or death.

Effects of TPO Mimetics on Bleeding

  1. Top of page
  2. Abstract
  3. Introduction
  4. Clinical Trial Design with TPO Mimetics
  5. Effects of TPO Mimetics on Bleeding
  6. Concomitant and Rescue Medication Use
  7. Conclusions
  8. Acknowledgements
  9. References

Romiplostim

Romiplostim clinical trial data indicate a benefit in reducing more severe bleeding, as shown in the Phase 3 24-week placebo-controlled registration trials (Fig. 1) [14, 15]. Most bleeding adverse events of any severity occurred at platelet counts at or below 20 × 109/L, with no grade 2 or higher bleeding events reported at platelet counts above 50 × 109/L, and no grade 3 or higher events reported above 20 × 109/L. In a trial comparing romiplostim with standard-of-care treatment in nonsplenectomized patients, the romiplostim group had lower exposure-adjusted incidences of overall bleeding events (3.6 vs. 5.0/100 patient-years, P = 0.001) and bleeding events of grade 3 or higher (0.11vs. 0.33/100 patient-years, P = 0.02) [16].

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Figure 1. Incidence of bleeding adverse events by maximum severity in the phase 3 trials of romiplostim. (Reproduced from Ref. 15, with permission from John Wiley and Sons.)

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Eltrombopag

Bleeding data collected as adverse events in eltrombopag placebo-controlled trials and an open-label trial indicate that treatment with this TPO mimetic led to decreases in bleeding events as well [17–20]. Specifically, in a 6-month placebo-controlled trial, bleeding was significantly reduced with eltrombopag (P < 0.0001) [19]. In this same trial, clinically significant bleeding was seen in 33% of eltrombopag-treated patients and 53% of placebo-treated patients (Fig. 2). In the open-label trial of intermittent eltrombopag dosing, bleeding increased during periods when patients were off eltrombopag and then decreased again when patients were on therapy [20].

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Figure 2. Proportions of patients with clinically significant bleeding (WHO bleeding scale grades 2–4) in the 6-month placebo-controlled eltrombopag trial. (Reproduced from Ref. 19, with permission from Elsevier Limited.) [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

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Integrated analyses

The data from individual trials described above suggest that use of TPO mimetics leads to improvements in bleeding rates. In addition, the effect of these treatments on bleeding in larger numbers of patients has been examined in integrated analyses. Bleeding was analyzed in an integrated dataset of 13 romiplostim ITP clinical trials [14, 16, 21–29] with over 1,000 patient-years of data from 718 patients. When the bleeding data from several romiplostim trials were combined, rates of bleeding events of grade 3 severity or greater appeared to be reduced with romiplostim compared with placebo/standard of care, although this difference was not significant (Table I) [30].

Table I. Bleeding in Romiplostim Integrated Analysis
GradePlacebo/standard of care; N = 138, Pt-yr = 110.0Romiplostim; N = 653, Pt-yr = 921.5
Rate per 100 pt-yr (95% CI)EventsRate per 100 pt-yr (95% CI)Events
  1. Abbreviations: CI, confidence interval; N, number of patients; Pt-yr, patient-year.

  2. Adapted from Ref. 44 (obtained from the Hematologica/the Hematology Journal website http://www.haematologica.org), with permission from the Ferrata Storti Foundation, Pavia, Italy.

Any214 (187, 243)235193 (184, 202)1,779
≥248 (36, 63)5347 (43, 52)433
≥317 (10, 27)1911 (9, 14)103

A further analysis performed by the Cochrane collaboration [31] analyzed effects of TPO mimetics on bleeding and mortality. The review included over 800 patients from six trials of TPO mimetics [14, 16–19, 21] as identified by a literature search. These trials contained bleeding data; no randomized controlled trials were found that examined survival. Data from open-label extension trials were excluded. Five of the trials compared TPO mimetics with placebo (romiplostim: 100, eltrombopag: 299, and placebo: 175) and one compared romiplostim with medical standard of care (SOC) (romiplostim: 157; SOC: 77). The authors found that the rates of clinically relevant bleeding events (defined as grade III or IV, as defined by the World Health Organization) did not differ significantly between TPO mimetics and placebo (RR 0.48, 95% CI: 0.20–1.15) or TPO mimetics and SOC (RR 0.49, 95% CI: 0.15–1.63). However, differences were seen with secondary outcomes, such as an improved overall platelet response relative to placebo (RR 4.06, 95% CI: 2.93–5.63) and SOC (RR 1.81, 95% CI: 1.37–2.37) and a decrease in overall bleeding relative to placebo (RR 0.78, 95% CI: 0.68–0.89). Adverse events were found to be similar between trial arms. Based on the primary outcome findings, the authors concluded that there was no evidence supporting the efficacy of TPO receptor agonists in chronic ITP.

Bleeding as an endpoint

As described above, the ability of randomized ITP clinical trials to detect differences in bleeding rates is limited by the requirements of ethical clinical trial design. Therefore, it would be clinically unacceptable to restrict concomitant and rescue ITP medication use such that platelet counts would fall and more bleeding events would occur. Thus, it is not surprising that comprehensive analyses of the effects of treatment on bleeding do not show a significant difference between test agents and the comparator arms of these trials. Therefore, bleeding events, although clinically relevant, are paradoxically difficult endpoints to assess in ITP clinical trials.

Effects of TPO mimetics on mortality

As noted in the Cochrane review of TPO mimetics [31], mortality data are also not abundant for this relatively new class of agents. This is not surprising given that severe bleeding events are expected to be infrequent and do not always lead to death in this relatively benign hematologic condition. Furthermore, an impact on mortality is extremely difficult to measure in small prospective clinical trials of relatively short duration, in part, as mortality associated with man ITP treatments, including splenectomy, may occur years or even decades later. However, preliminary mortality data are available for both romiplostim and eltrombopag.

For romiplostim, a mortality meta-analysis [32] was performed of the two placebo-controlled trials [14], the standard-of-care comparator trial [16], and a subsequent open-label extension trial that enrolled patients from the three other trials [15, 24, 33]. In total, there were 238 patients, originally assigned to romiplostim (n = 187), placebo (n = 33), or standard of care (n = 18). A Cox regression model was used to estimate mortality rates. The authors of this combined analysis concluded that the mortality rate in patients treated with romiplostim was significantly lower than that in patients treated with placebo or standard of care (HR, 0.187; 95% CI, 0.048–0.931; P = 0.04), with the survival benefit maintained when data from the subsequent extension trial were included in the analysis (HR, 0.120; 95% CI, 0.035–0.410; P = 0.0007). Causes of death varied and included those related to the cardiovascular system (e.g., myocardial infarct and congestive cardiac failure), infection (e.g., pneumonia and meningitis), and cancer (e.g., hepatic, liver, and lung cancer).

Factors predicting increased mortality risk in a multiple Cox regression model included treatment with placebo or standard of care as compared with romiplostim (P < 0.0001), age = 65 years (P = 0.002), greater number of prior ITP treatments (P = 0.064), and concurrent baseline ITP treatment (P = 0.016). Examination of the relationship between bleeding and mortality showed a positive correlation between the grade of worst bleeding event and risk of death (P < 0.0001). There also was an association between mortality and the occurrence of a bleeding event with a worst grade of =2 (P = 0.0154), =3 (P = 0.0002), and =4 (P = 0.0002).

A mortality analysis was also performed with data from 494 patients receiving eltrombopag or placebo in five trials: three placebo-controlled and two open-label trials, one of which was an extension trial [34]. For placebo, there was one death over 35 patient-years, whereas for eltrombopag, there were seven deaths over 584.4 patient-years. As noted by the authors, the mortality rate with eltrombopag was lower relative to that in the literature [34]. The deaths with eltrombopag, which were attributed to cardiac/respiratory failure, pancreatic cancer, gastrointestinal hemorrhage, subarachnoid hemorrhage, pulmonary sepsis, and motor vehicle accident (one death was of unknown cause), were not considered to be related to eltrombopag.

Concomitant and Rescue Medication Use

  1. Top of page
  2. Abstract
  3. Introduction
  4. Clinical Trial Design with TPO Mimetics
  5. Effects of TPO Mimetics on Bleeding
  6. Concomitant and Rescue Medication Use
  7. Conclusions
  8. Acknowledgements
  9. References

While mortality data with TPO mimetics are not yet sufficient to allow meaningful evaluation and bleeding data are not necessarily appropriate endpoints to evaluate new ITP treatments because of concomitant and rescue ITP medication use, another endpoint can be used to measure TPO mimetic efficacy. The use of concomitant and rescue ITP medications would theoretically decrease with a new treatment, which effectively maintained hemostatic platelet counts and prevented bleeding. As these medications can be difficult for patients to tolerate and have many associated side effects, the ability to decrease use of these treatments is of significant clinical importance.

Romiplostim phase 3 clinical trials allowed unrestricted use of concomitant and rescue ITP medications [14, 16]. As rescue ITP medication use was anticipated to reduce the risk of serious bleeding, the proportion of patients needing rescue medication was a predefined secondary endpoint. Rescue medication use was reduced with romiplostim compared with placebo in both splenectomized patients (26.2 vs. 57.1%; P = 0.0175) and nonsplenectomized patients (17.1 vs. 61.9%; P = 0.0004). Concomitant ITP therapy was also reduced; 87% (20/23) of romiplostim-treated patients (8/11 nonsplenectomized; 12/12 splenectomized) reduced or discontinued concomitant therapy as compared with 38% (6/16) of placebo-treated patients (5/10 nonsplenectomized, 1/6 splenectomized). More details regarding the decreases in specific concomitant medications (i.e., IVIG and corticosteroids) are described elsewhere [35, 36]. In the trial comparing romiplostim with medical standard-of-care treatments, concomitant ITP treatments were needed in a much smaller proportion of patients in the romiplostim group (44%) than in the standard-of-care group (79%).

Eltrombopag clinical trials also allowed use of concomitant/rescue ITP medications [17, 18]. While data were not reported, the 6-week trials had as secondary endpoints the reduction of baseline ITP treatments and the use of rescue medications [17]. In the 6-month eltrombopag trial, concomitant medications, most frequently corticosteroids, were more likely to be reduced for eltrombopag-treated patients (37/63; 59%) than for placebo-treated patients (10/31; 32%; P = 0.016) [19]. Likewise, rescue treatment was less common with eltrombopag (24, 18%) as compared with placebo (25; 40%; P = 0.001).

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Clinical Trial Design with TPO Mimetics
  5. Effects of TPO Mimetics on Bleeding
  6. Concomitant and Rescue Medication Use
  7. Conclusions
  8. Acknowledgements
  9. References

The conduct of randomized trials of new treatments in ITP requires responsible and ethical clinical trial study design to minimize the risk of serious bleeding, thus necessitating the use of concomitant and rescue medication on study. Thus, serious bleeding events in a well-conducted ITP trial would not be predicted to occur frequently. Likewise, mortality is problematic to measure in the relatively rare and benign hematologic disorder for which many interventions may contribute to mortality years or decades later. These characteristics of ITP and ITP clinical trial design are important context information to keep in mind when interpreting the recent Cochrane Review, which had bleeding as its major endpoint. Trials of new treatments for ITP, such as the TPO mimetics, have used as an endpoint the maintenance of hemostatic platelet counts, with supporting data from demonstrated reductions in concomitant ITP or rescue medications, many of which are associated with significant morbidity. This approach has been endorsed by professional guidelines, which support the use of TPO mimetics as standard-of-care treatment for refractory ITP [8, 9]. Of note, these are relatively new agents, and data related to the long-term safety and benefits continue to be collected and evaluated. As clinical experience with this class of ITP treatments grows, additional data regarding their safety and impact on important outcomes, such as bleeding and mortality, and the role of increases in platelet counts to a hemostatic range and durability in contributing to these outcomes will allow comprehensive evaluation of these agents. In the meantime, although bleeding and mortality data are of clinical importance, the absence of such data should not preclude the use of platelet count endpoints in the development of new therapeutic agents for this uncommon and burdensome disease. We conclude that efficacy of experimental agents in ITP trials is best measured by platelet counts and reduction in use of concomitant and rescue ITP medications. This is in contrast with the conclusions of a recent Cochrane review focusing on bleeding outcomes, the measurements of which are confounded by the necessary use of prophylactic and rescue use of ITP medications in clinical trials.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Clinical Trial Design with TPO Mimetics
  5. Effects of TPO Mimetics on Bleeding
  6. Concomitant and Rescue Medication Use
  7. Conclusions
  8. Acknowledgements
  9. References

The authors would like to acknowledge medical writing provided by Susanna Mac, MD, PhD, an employee of Amgen Inc. The following are the authors' disclosures: Ivy Altomare has been a member of advisory boards and a speaker for Amgen Inc., Jeffrey Wasser has been a member of advisory boards and a speaker for Amgen Inc., and Vinod Pullarkat has been a speaker for Amgen Inc., and Glaxo Smith Kline and a member of advisory boards for Amgen Inc.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Clinical Trial Design with TPO Mimetics
  5. Effects of TPO Mimetics on Bleeding
  6. Concomitant and Rescue Medication Use
  7. Conclusions
  8. Acknowledgements
  9. References
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