Zanamivir aqueous solution in severe influenza: A global Compassionate Use Program, 2009–2019

Abstract Background Zanamivir is a neuraminidase inhibitor effective against influenza A and B viruses. In 2009, GlaxoSmithKline (GSK) began clinical development of intravenous (IV) zanamivir and initiated a global Compassionate Use Program (CUP) in response to the evolving H1N1 global pandemic. The goal of the CUP was to provide zanamivir to critically ill patients with limited treatment options. Methods Zanamivir was administered to patients with suspected or confirmed influenza infection who were not suitable for other approved antiviral treatments. Reporting of serious adverse events (SAEs) was mandatory and recorded in the GSK safety database. A master summary tracking sheet captured requests and patient characteristics. A case report form was available for detailing medical conditions, dosing, treatment duration, and clinical outcomes. Results In total, 4,033 requests were made for zanamivir treatment of hospitalized patients from 38 countries between 2009 and 2019; ≥95% patients received zanamivir via the IV route. Europe had the highest number of requests (n = 3,051) followed by North America (n = 713). At least 20 patients were aged ≤6 months, of whom 12 were born prematurely. The GSK safety database included 466 patients with ≥1 SAE, of whom 374 (80%) had a fatal outcome. Drug‐related SAEs were reported in 41 (11%) patients, including hepatic failure (n = 6 [2%]) and acute kidney injury (n = 5 [1%)]. Conclusions The CUP facilitated global access to zanamivir prior to product approval. No new safety concerns were identified in the CUP compared with IV zanamivir clinical studies.

endonuclease, is approved in the United States, EU, and Japan. 4,5 Neuraminidase inhibitors (oseltamivir, zanamivir, and peramivir) have antiviral activity against all influenza A and B subtypes and are effective in the treatment and prophylaxis of influenza. 6,7 Compared with oseltamivir and peramivir, zanamivir displays efficacy against the most common influenza A virus resistance mutation, H275Y. 8,9 In Zanamivir powder for inhalation (RELENZA, zanamivir, GSK, United Kingdom) has been approved for >20 years for the treatment and prophylaxis of influenza A and B in adults and children ≥5 years of age in over 50 countries, including the EU, Japan, and the United States. 10,11 The clinical development program investigated IV zanamivir in adult and pediatric patients (between 6 months and 18 years of age) hospitalized with influenza. [12][13][14] In 2019, GSK received marketing authorization for IV zanamivir in Europe for the treatment of complicated and potentially life-threatening influenza A or B virus infection in adult and pediatric (≥6 months of age) patients for influenza virus known or suspected to be resistant to antiinfluenza medicinal products other than zanamivir, and/or when other anti-viral medicinal products for treatment of influenza, including inhaled zanamivir, are not suitable for the individual patient. 10 The CUP was terminated following this marketing authorization.
Patient characteristics, zanamivir dosing information and safety data, including serious adverse events (SAEs), were collected from 2009 to 2019. This current report presents analysis of all available CUP data on zanamivir aqueous solution received up to January 31, 2020.

| CUP design and initiation
The CUP was administered via applicable country regulatory requirements, with the requesting physician considered the designated sponsor. A Physician Guidance Document was developed to support requests for IV and nebulized zanamivir on a compassionate use named-patient basis and provide guidance on dosing, administration, and patient eligibility. Similarly, the European Medicines Agency published a "Condition of Use" document to give guidance for IV zanamivir requests via Article 83. The CUP was referenced through governmental information sources, including public health influenza advice websites. 15 The CUP process is summarized in Figure S1 and in Methods S1.

| Dosing and administration
Recommendations for IV administration of zanamivir specified in the "Guidance for physicians" was 600 mg in a 30-min infusion, every 12 h, adjusted for age, weight (for pediatric patients), renal function, and renal replacement modality. Nebulized zanamivir was recommended at a dose of 25 mg, four times/day. The recommended duration of initial treatment was 5 days (Methods S1).

| Eligibility criteria
Patients were eligible if, hospitalized and severely ill with influenza infection and not responding to authorized antiviral medicinal products (e.g., oral oseltamivir or inhaled zanamivir), or for whom drug delivery by a route other than IV was not expected to be dependable or feasible, or if there was resistance to other antiviral agents and inhaled zanamivir was not suitable. 16

| Data collection
Baseline and follow-up data were summarized across three databases ( Table 1). The master summary tracking sheet (MSTS) provided information on patient demographics and overall medical condition, with a data cut-off of May 6, 2019. All SAEs were required to be reported to local ethics committees and regulatory authorities per regulatory agency requirements and were recorded in the GSK safety database. Data cut-off was extended to January 31, 2020, (beyond termination of IV zanamivir supplies in the CUP) to allow adequate time for additional safety reports and/or followup information.
A case report form (CRF) was provided to collect information on medical conditions, zanamivir dosing, treatment duration, and clinical outcomes (data cut-off: January 31, 2020). Completion and return of this form to the sponsor was encouraged but not mandatory for supply of aqueous zanamivir. Modifications made to the CRF template over the CUP minimized the collection of unusable data (Table S1).
The information collected in each data source is summarized in Table S2, with additional information regarding the databases in Methods S1.

| AE reporting
Adverse events (AEs) meeting the definition of a SAE in patients who received ≥1 dose of zanamivir from the time of the first dose until 14 days after treatment completion were required to be reported. Any SAEs reported after this time were included in the GSK safety data set. SAEs were summarized separately for the pediatric population. Further description of AE reporting is provided in Methods S1.

| Baseline characteristics
The 4,033 patients included in the CUP based on MSTS data had a mean age of 47.3 years (range: 0-98) ( Table 1) (Table 1). Based on the standalone evaluation of the MSTS for infants and neonates, at least 20 patients were aged ≤6 months, of whom 12 were born prematurely with a gestational age of 23-35 weeks. 17 The 877 patients (including 16 pregnant women) in the CRF database had a mean age of 44.5 years, with more than three quarters (n = 681 [77%]) having chronic underlying illnesses or risk factors, the most common being respiratory illness recorded in 320 (36%) patients (Table 3).

| Zanamivir formulation, dosages, and dosing duration
A summary of zanamivir treatment captured in the MSTS and CRF databases is provided in Table 4. The majority (≥95%) of patients received zanamivir via the IV route. Based on MSTS data, an additional treatment course (beyond the initial 5-day course) was requested for nearly 25% of patients (range: 1-75 days).

| Clinical outcomes recorded in the CRFs
Among the 877 patients in the CRF database, 30% (n = 267) recovered or their condition resolved, 36% (n = 320) had not recovered or

| Serious adverse events
Overall, 466 patients reported ≥1 SAE based on data included in the GSK safety database with a total of 839 SAEs recorded, with a higher proportion of males (n = 251; 54%) and over 80% (n = 384) reporting previous or ongoing medical conditions or interventions (  SAEs were reported in 54 pediatric patients (  Treating physician's discretion -64 (7) Decision by patient or proxy -10 (1)

| SAEs in patient subgroups
Other  Immunocompromised patients and young children have an increased likelihood to harbor viruses with reduced antiviral drug susceptibility. 21,22 This was observed in the CUP population, as a substantial number of patients had underlying respiratory illness and were immunocompromised. These factors could lead to an extended treatment duration per the Physician Guidance Document. 21 A second treatment course beyond 5 days was requested for almost a quarter of patients, and a third or fourth course for almost 5%. A pharmacokinetic study of IV zanamivir in hospitalized neonates and infants with influenza infection 23 and a pregnancy registry have been established to collect additional information from these high-risk groups. 24 IV zanamivir exposure in infants aged ≤6 months in the CUP, although limited, also supported the design of the post-registration pharmacokinetic and safety study described above (ClinicalTrials.gov: No new safety concerns or signals were identified for IV zanamivir, and the overall SAE profile of IV zanamivir was similar to that reported in the clinical development program. 13 (Figure S2A,B).
Data presented here complement data from the IV zanamivir development program 8,9,28 and phase II and III clinical trials. 13,14,25 The open-label, international, phase II trial in adult patients reported SAEs in 34% of patients and 14-and 28-day all-cause mortality rates of 13% and 17%. 13 In the phase II, open-label, multicenter study in children (≥6 months and <18 years of age), 32% experienced grade 3 or 4 AEs, and the mortality rate was 7%. 25 The phase III trials reported SAEs in 16% and 19% of patients in the IV zanamivir 300and 600-mg groups, respectively, and all-cause mortality rates of 7%. 14  The limitations of this analysis should be considered.

FUNDING INFORMATION
This analysis was funded by GlaxoSmithKline (GSK ID: 113375). Case report form processing and data management were provided by Parexel and PPD and were funded by GSK.

CONFLICTS OF INTEREST
Aditya Joshi, Irene Miller, Tharaka Jayabalan, Peter Zammit-Tabona, Amanda Peppercorn and Amanda Oliver are employees of and hold stocks/shares in GSK. Jie Wang-Jairaj was a former employee of GSK at the time of the CUP and holds stock/shares in GSK.

ETHICS APPROVAL STATEMENT
Ethics approvals were obtained in accordance with local regulations.

PATIENT CONSENT STATEMENT
Before IV zanamivir administration, the treating physician obtained informed consent from the patient or legal guardian. A separate form was provided by GSK to obtain consent to share medical information; the latter was distinct from consent to treatment and was not a prerequisite for supply of zanamivir.

PEER REVIEW
The peer review history for this article is available at https://publons. com/publon/10.1111/irv.12947.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available in the supplementary material of this article.