Tolerability and safety of the intravenous immunoglobulin octagam^® 10% in patients with immune thrombocytopenia: a post-authorisation safety analysis of two non-interventional phase IV trials

ABSTRACT

Objectives: To provide detailed data on the tolerability and safety of octagam^® 10%, a ready-to-use intravenous immunoglobulin, in a subgroup of patients with immune thrombocytopenia (ITP) involved in an integrated analysis of post-authorisation safety surveillance (PASS) studies.

Methods: A subgroup analysis was conducted using data collected from two non-interventional studies that included patients with ITP treated with octagam^® 10%. Patients were observed and monitored for possible adverse drug reactions (ADRs) during or after administration of octagam^® 10%, with a particular focus on thromboembolic events (TEEs). ADRs were analysed at the case and event level.

Results: In this analysis of 112 patients receiving octagam^® 10% (mean dose 0.4 g/kg/infusion), there were five cases with at least one adverse drug reaction (ADR) associated with 626 infusions of octagam^® 10% (case incidence of 0.8% per infusion). ADRs were of mild or moderate severity. There were a total of 10 events, most commonly back pain (n = 3) and headache (n = 2). Nausea, dizziness and a sensation of heaviness were also reported. The remaining two events involved drug exposure during pregnancy. There were no TEEs or other serious ADRs.

Discussion: In this subgroup analysis of patients who received octagam^® 10% (manufactured using an amended process) in two PASS studies, the overall ADR rate was low, with ADRs occurring in only 0.8% of all infusions. No TEEs or other serious ADRs were reported.

Conclusions: Routine clinical use of octagam^® 10% was safe and well tolerated, with no unexpected safety issues, in patients with ITP. The two studies from which data were taken are registered with the International Standard Randomised Controlled Trial Number Registry, numbers ISRCTN58800347 and ISRCTN02245668.

KEYWORDS:

• Adverse drug reaction
• immune thrombocytopenia
• intravenous immunoglobulin
• octagam^®
• pooled analysis
• post-authorisation safety surveillance
• safety
• tolerability

Introduction

Immune thrombocytopenia (ITP) is an autoimmune disorder characterised by antibody-mediated destruction of platelets in the spleen and suppressed platelet production, which together lead to a reduced platelet count and an increased risk of bleeding [1–3]. ITP can occur in the absence of an underlying disease (primary ITP) or in association with other disorders (secondary ITP) [2,3]. The management of primary ITP is distinct from secondary ITP [2].

Intravenous immunoglobulin (IVIG) is a standard first-line treatment approach in patients with primary ITP or selected secondary forms of ITP [2–4]. IVIG can be used alone or together with corticosteroids [2–4]. Anti-RhD can be used as alternative to IVIG, but it is only suitable for Rh(D)-positive non-splenectomised patients, and care must be taken because of a risk of severe haemolysis [2–4]. The goal of ITP management is to provide a haemostatic platelet count while minimising treatment-related toxicity [2].

Octagam^® 10% (Octapharma AG, Lachen, Switzerland) is a sterile ready-to-use, sucrose-free liquid preparation of highly purified IVIG that is indicated in Europe as a replacement therapy in primary and secondary immunodeficiencies, and as an immunomodulatory therapy in a number of autoimmune conditions, including ITP [5]. In the U.S.A., octagam^® 10% is approved for the treatment of adults with chronic ITP to rapidly increase platelet counts to prevent or control bleeding [6]. Octagam^® 10% was originally approved in 2008 in Germany and other European countries. In 2011, octagam^® 10% and a less concentrated preparation of octagam^® 5% became available on the market with an amended manufacturing process [7].

In March 2014, an integrated safety analysis from four non-interventional post-authorisation safety surveillance (PASS) studies was conducted to evaluate the tolerability and safety of octagam^® 10% and 5% in various indications, most commonly secondary immunodeficiency, followed by primary immunodeficiency, ITP and other autoimmune disorders [7]. Here, we provide more detailed data on the tolerability and safety of octagam^® 10% in the subgroup of patients with ITP identified from the overall integrated safety analysis.

Methods

Study design and conduct

Data from four non-interventional, post-approval, multicentre PASS studies were collected and included in the overall safety analysis [7]. For all four studies, hospital in- and out-patients were included if their physicians prescribed them octagam^® (10% or 5%) for treatment of their medical condition. Data from the only two studies that included patients with ITP treated with octagam^® 10% are reported in this subgroup analysis.

The design of the two studies has been published elsewhere [7]. Briefly, Study 1 (registered with the International Standard Randomised Controlled Trial Number Registry at ISRCTN58800347), conducted in Germany, involved 1559 patients who received octagam^® 10% for any indication. The study started in September 2008 and was completed in December 2013. Data collection for this safety analysis includes data from June 2011 to November 2013. Study 2 (registered at ISRCTN02245668) is an ongoing study conducted in Austria, Canada, France, Spain and the U.K. in patients receiving octagam^® 10% or 5% for any indication. The study was started in August 2011 and aims to enrol at least 500 patients. Data collection for this safety analysis ended in March 2014, at which point a total of 158 patients were included.

Patients with ITP who were prescribed commercially available octagam^® 10% at the discretion of their treating physician were included in both studies. Octagam^® 10% contains 100 mg of human immunoglobulin G per millilitre of solution. Participating physicians decided on the length and dosage of octagam^® 10% treatment based on the severity of the disease and the patients’ clinical condition. Patients were observed and monitored for any possible adverse drug reactions (ADRs) associated with the administration of octagam^®, with a particular focus on thromboembolic events (TEEs).

If required by national regulations, the study protocol was reviewed and approved by each study site’s Independent Ethics Committee or Institutional Review Board before the start of the study (Study 2). If required by local regulatory authorities, patients provided written informed consent before entry into the study (Study 2).

Data collection and analysis

Data was collected for each patient by their physician using case report forms (CRFs). Paper CRFs were used for Study 1, and electronic CRFs were used for Study 2. The CRFs comprised four sections: patient baseline data; octagam^® treatment details; suspected ADRs and octagam^® efficacy assessment. Data from the separate studies were transferred into a central database.

All ADRs were handled as post-marketing safety data, so physicians recorded the details on separate individual case safety reports. An adverse drug reaction (ADR) was defined as any adverse or unintended response to octagam^®, meaning that a causal relationship between octagam^® and an adverse event could not be ruled out. Adverse events that were not considered to be related to treatment with octagam^® were not recorded. ADRs were classified according to the nature of the event (MedDRA preferred term), frequency, severity (mild, moderate and severe) and causal relation to octagam^® (definite, probable, possible or unlikely).

ADRs were analysed at the case level and at the event level. A ‘case’ comprised all ADRs that were related to a single octagam^® infusion. ADRs were reviewed on a case-by-case basis by an independent Data Monitoring Committee (DMC), with a particular focus on suspected TEEs. Cases not marked as TEEs were reviewed with the objective of detecting ‘hidden’ TEEs. The DMC also assessed ADRs for causality. A definite relationship involved an adverse event with a time from drug intake that made a causal relationship plausible, and that could not be explained by disease or other drug, and, if necessary, for which re-challenge was satisfactory. An unlikely relationship involved an adverse event that occurred with a time from drug intake that made a causal relationship improbable, but not impossible, and for which disease or other drugs could provide plausible explanations. In the case of unclear or implausible causality, the DMC made a final decision as to whether there was any likelihood of the adverse event being related to octagam^®.

Treatment efficacy was assessed using a Likert scale rating the influence of treatment on the course of the patients’ disease at the end of the observation period as ‘beneficial’, ‘unchanged’ or ‘unfavourable’.

Statistical analysis

All safety and efficacy analyses were descriptive. Continuous variables are presented as mean or median values. Categorical study variables are presented as absolute and relative frequencies. Statistical analyses were performed using the software package SAS release 9.3 (SAS Institute Inc., Cary, NC, U.S.A.).

Results

Patient and treatment characteristics

In Studies 1 and 2, a total of 961 patients received a total of 9556 infusions of octagam^® 10%. Within this group, there were 112 patients with ITP (51% female; mean age 59.7 years, range 21–92 years). Collectively, these patients received a total of 626 infusions of octagam^® 10% (mean dose 0.4 g/kg/infusion) administered over 297 courses (mean dose 0.9 g/kg/course; Table 1).

Table 1. Baseline demographics and treatment details of the subgroup of patients with ITP who received octagam^® 10% in post-authorisation safety studies.

Characteristic
Patients, n	112
Gender, n (%)
Male	55 (49.1%)
Female	57 (50.9%)
Mean age, years (range)	59.7 (21–92)
Total number of octagam^® 10% infusions	626
Median treatment interval, weeks (range)	3.2 (0.7–91.3)
Courses, n	297
Courses with >1 infusion, n (%)	124 (41.8)
Mean dose per infusion
g	26.5
g/kg of bodyweight	0.4
Mean dose per course, g/kg of bodyweight	0.9
Total octagam^® weight used, g	16,120

Note: ITP: immune thrombocytopenia.

Adverse drug reactions

In total, five cases with at least one ADR were reported in the subgroup of 112 patients with ITP who received 626 infusions of octagam^® 10%, resulting in an incidence of 0.8%. Available data showed that ADRs were considered mild or moderate in severity (Table 2).

Table 2. Number of ADR cases and events by MedDRA preferred term reported in the subgroup of 112 patients ITP who received octagam^® 10% in post-authorisation safety studies.

ADRs, n	Octagam^® infusions (n = 626)
Total cases^a	5
Mild	2
Moderate	2
Severe	0
No severity data	1
Total events	10
Nausea	1
Drug exposure during pregnancy	2
Back pain	3
Sensation of heaviness	1
Dizziness	1
Headache	2

Note: ITP: immune thrombocytopenia; MedDRA: Medical Dictionary for Regulatory Activities.

^aCases include all ADRs that were related to a single infusion.

The five ADRs comprised a total of 10 events, which were most commonly back pain (n = 3) and headache (n = 2; Table 2). Nausea, dizziness and a sensation of heaviness were also reported. The remaining two events were reports of drug exposure during pregnancy, without any adverse reaction. None of the patients with ITP who received octagam^® 10% had a TEE, acute renal failure, haemolytic anaemia or any other serious ADR (incidence 0.0%; exact binominal 95% confidence interval: 0.00–0.59%).

Efficacy

This PASS was designed to demonstrate that the modified octagam^® manufacturing process resulted in a safe product and was not powered to show efficacy. However, a total of 59 observation periods were assessed during octagam^® 10% treatment at mean intervals of 2.6 months. Of these assessments, physicians considered the clinical development since last observation period as improved in 55.9% and as not changed in 44.1%.

Discussion

In this subgroup analysis of 112 patients with ITP who collectively received 626 infusions of octagam^® 10% in two non-interventional PASS studies, the overall ADR rate was low, with ADRs occurring in only 0.8% of all infusions. ADRs were of mild-to-moderate severity, and resolved without sequelae. No TEEs or other serious ADRs were reported.

From the medical perspective, the case incidence is meaningful as it shows how often one infusion causes at least one ADR, but it is also useful to examine the nature of ADRs at an event level. In our subgroup analysis of patients with ITP treated with octagam^® 10%, the five reported patients with at least one ADR involved a total of 10 events, the most common of which were back pain and headache. Nausea and dizziness were also reported. Such events, together with other minor hypersensitivity reactions involving symptoms such as fevers and chills, are consistent with previously reported studies of octagam^® 10% [8], and other ready-to-use liquid preparations of IVIG 10% [9–11] and IVIG 5% [12–14] in patients with ITP. As was observed with the patients with ITP treated with octagam^® 10% in our subgroup analysis, ADRs associated with IVIG are generally transient and of mild-to-moderate severity [8–14].

The safety of octagam^® 10% has previously been evaluated at high doses and high infusion rates in a controlled clinical trial involving 116 patients with ITP [8]. Octagam^® 10% was administered at a dose of 1 g/kg per day on two consecutive days to a total of 2 g/kg, with a maximum infusion rate of 7.2 mL/kg/h. ADRs occurred in 55.2% of patients overall. Of note, the data presented here were generated in an uncontrolled, observational study with less monitoring and patient evaluations. The guideline-recommended dose of IVIG for ITP is a total cumulative dose of 2 g/kg body weight divided over either 2 days (1 g/kg/day) or 5 days (0.4 g/kg/day) [2–4], and most ADRs can be prevented or treated by slowing the infusion rate [15]. The frequency of ADRs in this study also compared favourably to the results of a previously reported PASS study investigating the safety of another ready-to-use IVIG 10% liquid preparation in the treatment of ITP, where the incidence of ADRs was 46% [9]. The incidence of ADRs in the current and previous PASS studies was well within the upper range of ADR rates reported for IVIG preparations [15].

Compared with octagam^® 5%, the more concentrated octagam^® 10% preparation enables the infusion of smaller volumes of IVIG to achieve the same maximum daily dose [8]. The preparations are expected to be equally safe and efficacious [8]. Indeed, the overall integrated PASS analysis showed that octagam^® 10% and octagam^® 5% were both safe and not associated with an increased incidence of TEEs [7]. Supplementary data from the overall analysis showed that, in patients with ITP, the ADR case incidence was comparably low with octagam^® 5% (0.1% per infusion) and octagam^® 10% (0.8% per infusion). The two products were both administered at a dose of 0.4 g/kg per infusion.

The overall analysis also showed that octagam^® 10% was safe in patients with ITP and in patients with primary or secondary immunodeficiency [7]. Supplementary data from the overall analysis showed that ADRs occurred least frequently in patients with ITP and most frequently in patients with secondary immunodeficiency (case incidence of 2.1%), despite these patients being treated at the lowest dose (mean 0.2 g/kg at a median maximum infusion rate of 3.3 mL/kg/h). Such observations suggest that the occurrence of ADRs is influenced by multiple factors, which may include IVIG infusion history, underlying disease and general condition of the patient, and is not solely related to dose or the rate of infusion [10,16,17].

TEEs, such as stroke, myocardial infarction, pulmonary embolism and deep vein thromboses, rarely occur with IVIG treatment [18,19]. IVIG can increase blood viscosity and impair blood flow, thereby increasing the risk of TEEs in patients with pre-existing risk factors, such as advanced age, immobilisation, diabetes mellitus, hypertension and a history of vascular disease or TEEs, so caution should be exercised when using IVIG products in such patients [18–20]. In patients at risk of TEEs, IVIG products should be administered at the minimum rate of infusion and dose practicable [17,20]. In our subgroup of 112 patients with ITP, there were no TEEs reported in association with 626 infusions of octagam^® 10%, with a mean dose of 0.4 g/kg per infusion.

Differences in the formulations, manufacturing processes, excipients, pH and other physicochemical properties of IVIG products may affect their safety [21–23]. For example, procoagulant substances in IVIG preparations, particularly FXIa, have been identified as a probable cause of IVIG-related TEEs [17,24,25]. All manufacturers of IVIG products are now required to identify steps in their manufacturing process that effectively remove procoagulant contaminants [17,25]. Acute renal failure and haemolytic anaemia are other serious but rare ADRs associated with IVIG that can be influenced by the physicochemical composition of the preparation: hyperosmolar IVIG formulations containing sucrose as a stabiliser appear to be disproportionately associated with renal dysfunction and acute renal failure [26], and IVIG-related haemolysis has been linked to anti-A and anti-B haemagglutinins in the preparation [27]. There were no cases of TEE, acute renal failure or haemolytic anaemia associated with octagam^® 10% in our patients with ITP.

In the current octagam^® 10% subgroup analysis, efficacy parameters such as platelet count and bleeding rates were not available due to the non-interventional and non-controlled nature of these studies. Physicians were only asked to assess the clinical appearance as improved, not changed or deteriorated roughly every 3 months. Therefore, these data cannot be compared with any interventional study of IVIG 10% in patients with ITP. Of the 59 observation period assessments in this study, an improvement was reported in 55.9% and no change in 44.1%. It was also less than the 71.9% response rate achieved with octagam^® 5% in patients with ITP seen in supplementary data from the overall analysis [7]. However, this may be explained by the fact that each of the 173 courses of octagam^® consisted of only one infusion, which is lower than the recommended two infusions that were administered in the controlled trials [10–12]; the mean dose per course (0.9 g/kg) was also lower than in pivotal controlled trials (1.0 g/kg per infusion and 2.0 g/kg per course) [10–12]. Furthermore, with regard to the duration of ITP (newly diagnosed or chronic) and treatment history (treatment-naïve or previous IVIG), variable populations of patients may have affected response to octagam^® 10% and 5% in the relevant PASS studies. Variable response criteria used by the treating physicians may also have influenced response rates. In general, although the integrated safety analysis benefitted from the increased statistical power of a pooled analysis, substantial variation between studies, owing to different study designs and study populations, must be taken into account when interpreting efficacy results.

Conclusions

The results of this subgroup analysis in patients with ITP indicate that routine clinical use of octagam^® 10% is safe and well tolerated, with no unexpected safety issues. Octagam^® 10% is not associated with a high incidence of TEEs in patients with ITP, but in patients with pre-existing risk factors for such events, physicians should use octagam^® 10% and other IVIG 10% preparations cautiously, opting for a slow, low-dose infusion.

Acknowledgements

The authors thank all participating investigators as well as Simone Boniface from Springer Healthcare Communications who drafted the outline of this manuscript and Joanne Dalton who wrote the first draft of this manuscript on behalf of Springer Healthcare Communications. This medical writing assistance was funded by Octapharma.

Disclosure Statement

No potential conflict of interest was reported by the authors.

Notes on contributors

Dr Wietek was employed by Octapharma at the time of study realization and has since left the company. Currently, Dr Wietek is acting as freelancer for Octapharma.

ORCID

Stefan Wietek http://orcid.org/0000-0002-8838-6707

Additional information

Funding

The subgroup analysis was funded by Octapharma, and data were obtained from studies that were funded by Octapharma.