Time Savings with Rituximab Subcutaneous Injection versus Rituximab Intravenous Infusion: A Time and Motion Study in Eight Countries

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Abstract

Background

Rituximab is a standard treatment for non-Hodgkin lymphoma. The SABRINA trial (NCT01200758) showed that a subcutaneous (SC) rituximab formulation did not compromise efficacy or safety compared with intravenous (IV) infusion. We aimed to quantify active healthcare professional (HCP) time and patient chair time for rituximab SC and IV, including potential time savings.

Methods

This non-interventional time and motion study was run in eight countries and 30 day oncology units. Rituximab SC data were collected alongside the MabCute trial (NCT01461928); IV data were collected per routine real-world practice. Trained observers recorded active HCP time for pre-specified tasks (stopwatch) and chair time (time of day). A random intercept model was used to analyze active HCP time (by task and for all tasks combined) in the treatment room and drug preparation area, drug administration duration, chair time and patient treatment room time by country and/or across countries. Active HCP and chair time were extrapolated to a patient’s first year of treatment (11 rituximab sessions).

Results

Mean active HCP time was 35.0 and 23.7 minutes for IV and SC process, respectively (-32%, p <0.0001). By country, relative reduction in time was 27–58%. Absolute reduction in extrapolated active HCP time (first year of treatment) was 1.1–5.2 hours. Mean chair time was 262.1 minutes for IV, including 180.9 minutes infusion duration, vs. 67.3 minutes for SC, including 8.3 minutes SC injection administration (-74%, p <0.0001). By country, relative reduction was 53–91%. Absolute reduction in extrapolated chair time for the first year of treatment was 3.1–5.5 eight-hour days.

Conclusions

Compared with rituximab IV, rituximab SC was associated with reduced chair time and active HCP time. The latter could be invested in other activities, whereas the former may lead to more available appointments, reducing waiting lists and increasing the efficiency of day oncology units.

Trial Registration

ClinicalTrials.gov NCT01200758

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Most cited references 9

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Preference for subcutaneous or intravenous administration of trastuzumab in patients with HER2-positive early breast cancer (PrefHer): an open-label randomised study.

Xavier Pivot, Joseph Gligorov, Volkmar Müller … (2013)

Subcutaneous trastuzumab has shown non-inferior efficacy and a similar pharmacokinetic and safety profile when compared with intravenous trastuzumab in patients with HER2-positive early breast cancer. We assessed patient preference for either subcutaneous or intravenous trastuzumab in the international, randomised PrefHer study. Eligible patients were women aged 18 years or older with HER2-positive, histologically confirmed primary invasive breast adenocarcinoma, no evidence of residual, locally recurrent, or metastatic disease after completion of surgery and chemotherapy (neoadjuvant or adjuvant), an Eastern Cooperative Oncology Group performance status of 0 or 1, and a baseline left-ventricular ejection fraction of 55% or more before the first dose of trastuzumab. Radiotherapy or hormone therapy was allowed. Patients were randomised (randomly permuted blocks of four) to receive four cycles of 600 mg fixed-dose subcutaneous adjuvant trastuzumab via a single-use injection device or hand-held syringe followed by four cycles of standard intravenous trastuzumab, or the reverse sequence. Randomisation was stratified by de-novo versus non-de-novo use of intravenous trastuzumab. The primary endpoint was the proportion of patients indicating an overall preference for subcutaneous or intravenous trastuzumab, assessed by patient interview in the evaluable intention-to-treat (ITT) population (patients who completed both interviews and had at least one administration of both subcutaneous and intravenous trastuzumab). Data collection for PrefHer is ongoing. This study is registered with ClinicalTrials.gov, number NCT01401166. 124 patients were randomly allocated to receive subcutaneous followed by intravenous trastuzumab, and 124 to receive the reverse sequence. 117 patients in the subcutaneous first group and 119 in the intravenous first group were included in the evaluable ITT population. Subcutaneous trastuzumab via the single-use injection device was preferred by 216 patients (91·5%, 95% CI 87·2-94·7; p<0·0001). Only 16 patients preferred intravenous trastuzumab (6·8%, 3·9-10·8), and four had no preference (1·7%, 0·5-4·3). Clinician-reported adverse events occurred in 141 of 242 (58%) patients during the pooled subcutaneous periods and 105 of 241 (44%) patients during the pooled intravenous periods; seven (3%) and five (2%) were grade 3, no patients had a grade 4 or 5 event. The most common grade 3 adverse event was influenza (two [0·8%] patients). Patient preference and safety results from PrefHer, combined with the known non-inferior efficacy and pharmacokinetic and safety profile data, suggest that a fixed dose of 600 mg trastuzumab administered subcutaneously every 3 weeks is a validated, well tolerated treatment option for HER2-positive breast cancer, and is the preferred treatment of patients. Copyright © 2013 Elsevier Ltd. All rights reserved.

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Pharmacokinetics and safety of subcutaneous rituximab in follicular lymphoma (SABRINA): stage 1 analysis of a randomised phase 3 study.

Andrew Davies, Francesco Merli, Biljana Mihaljevic … (2014)

Intravenous rituximab is a mainstay of treatment for follicular lymphoma. A subcutaneous formulation that achieves equivalent rituximab serum concentrations might improve convenience and save health-care resources without sacrificing clinical activity. We aimed to assess pharmacokinetic non-inferiority of 3 week cycles of fixed-dose subcutaneous rituximab versus standard intravenous rituximab. In our two-stage, randomised, open-label, phase 3 trial, we enrolled patients with previously untreated grade 1-3a, CD20-positive follicular lymphoma at 67 centres in 23 countries. In stage 1, we randomly allocated patients 1:1 with the Pocock and Simon algorithm to intravenous rituximab (375 mg/m(2)) or fixed-dose subcutaneous rituximab (1400 mg), stratified by induction chemotherapy regimen (cyclophosphamide, doxorubicin, vincristine, prednisone or cyclophosphamide, vincristine, prednisone), Follicular Lymphoma International Prognostic Index score, and region. After randomisation, patients received one induction dose of intravenous rituximab in cycle 1 and then allocated treatment for cycles 2-8. Patients with a complete or partial response following induction therapy continued intravenous or subcutaneous rituximab as maintenance every 8 weeks. The primary endpoint was the ratio of observed rituximab serum trough concentrations (Ctrough) between groups at cycle 7 (before cycle 8 dosing) of induction treatment in a per-protocol population. Patients were analysed as treated for safety endpoints. Stage 2 follow-up is ongoing and is fully accrued. This study is registered with ClinicalTrials.gov, number NCT01200758. Between Feb 4, 2010, and Oct 21, 2011, we enrolled 127 patients. Pharmacokinetic data were available for 48 (75%) of 64 patients randomly allocated intravenous rituximab and 54 (86%) of 63 patients randomly allocated subcutaneous rituximab. Geometric mean Ctrough was 83·13 μg/mL in the intravenous group and 134·58 μg/mL in the subcutaneous group (ratio 1·62, 90% CI 1·36-1·94), showing non-inferiority of subcutaneous rituximab. 57 (88%) of 65 patients in the intravenous rituximab safety population had adverse events (30 [46%] grade ≥3), as did 57 (92%) of 62 patients in the subcutaneous rituximab safety population (29 [47%] grade ≥3). The most common grade 3 or worse adverse event in both groups was neutropenia (14 [22%] patients in the intravenous group and 16 [26%] patients in the subcutaneous group). Adverse events related to administration were mostly grade 1-2 and occurred in 21 (32%) patients in the intravenous group and 31 (50%) patients in the subcutaneous group. Stage 1 data show that the pharmacokinetic profile of subcutaneous rituximab was non-inferior to intravenous rituximab and was not associated with new safety concerns. Stage 2 will provide data for efficacy and safety of the subcutaneous administration. F Hoffmann-La Roche. Copyright © 2014 Elsevier Ltd. All rights reserved.

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A time and motion study of subcutaneous versus intravenous trastuzumab in patients with HER2‐positive early breast cancer

Erwin De Cock, Xavier Pivot, Nik Hauser … (2016)

Abstract Within PrefHer (NCT01401166), patients and healthcare professionals (HCPs) preferred subcutaneous (SC) over intravenous (IV) trastuzumab. We undertook a prospective, observational time and motion study to quantify patients’ time in infusion chairs and active HCP time in PrefHer. Patients with HER2‐positive early breast cancer received four adjuvant cycles of SC trastuzumab (600 mg fixed dose via SC single‐use injection device [SID, Cohort 1] or SC handheld syringe [HHS, Cohort 2]) then four cycles of standard IV trastuzumab or the reverse sequence. Generic case report forms for IV and SC management, both in the treatment room and the drug preparation area, were tailored to reflect center practices. Patient chair time and active HCP time were recorded. We compared pooled Cohort 1 + 2 IV with Cohort 1 SC SID and Cohort 2 SC HHS mean times across eight countries and individually within them utilizing a random intercept generalized linear mixed‐effects model. Per session, the SC SID saved a mean of 57 min of patient chair time versus IV (range across countries: 47–86; P < 0.0001); the SC HHS saved 55 min (40–81; P < 0.0001). Active HCP time was reduced by a mean of 13 min per session with the SC SID (range across countries: 4–16; P < 0.0001) and 17 min with the SC HHS (5–28; P < 0.0001) versus IV. SC trastuzumab, delivered via SID or HHS, saved patient chair and active HCP times versus IV infusion, supporting a transition to either SC method.

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Author and article information

Contributors

Ray Borrow: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 30 June 2016

Publication date Collection: 2016

Volume: 11

Issue: 6

Electronic Location Identifier: e0157957

Affiliations

[1 ]United Biosource Corporation, Barcelona, Spain

[2 ]United Biosource Corporation, London, United Kingdom

[3 ]United Biosource Corporation, Montreal, Canada

[4 ]Genentech Inc., South San Francisco, California, United States of America

[5 ]IRCSS AOU, San Martino, Italy

[6 ]F. Hoffmann-La Roche Ltd, Basel, Switzerland

Public Health England, UNITED KINGDOM

Author notes

Competing Interests: EDC, PK, MS, ST and AMC declare that they have no competing interests. CW is a current employee and holds share options at Genentech Inc. CN is a current employee and holds share options at F. Hoffmann-La Roche Ltd. TW is a former employee at F. Hoffmann-La Roche Ltd. F. Hoffmann-La Roche Ltd holds a patent relating to the content of the manuscript. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Conceived and designed the experiments: EDC CW CN. Performed the experiments: EDC PK MS ST CW. Analyzed the data: EDC PK MS ST AMC TW CW CN. Wrote the paper: EDC PK MS ST CW AMC CN TW. Preparation and approval of final manuscript: EDC PK MS ST CW AMC CN TW.

[¤]

Current address: German Cancer Research Centre (DKFZ), Heidelberg, Germany

* E-mail: erwin.decock@ 123456ubc.com

Article

Publisher ID: PONE-D-15-44081

DOI: 10.1371/journal.pone.0157957

PMC ID: 4928781

PubMed ID: 27362533

SO-VID: 3e6583cc-d7eb-44ac-a06a-17ee191bc015

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 5 November 2015

Date accepted : 6 June 2016

Page count

Figures: 7, Tables: 2, Pages: 16

Funding

Funded by: funder-id http://dx.doi.org/10.13039/100007013, F. Hoffman-La Roche;

Award Recipient : Erwin De Cock

This work was funded by F. Hoffmann-La Roche Ltd. F. Hoffmann-La Roche Ltd. provided support in the form of salaries for authors CW, CN and TW, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.

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Data Availability All relevant data are within the paper and its Supporting Information files.

Time Savings with Rituximab Subcutaneous Injection versus Rituximab Intravenous Infusion: A Time and Motion Study in Eight Countries

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Abstract

Background

Methods

Results

Conclusions

Trial Registration

Related collections

PLOS Climate

Most cited references 9

Preference for subcutaneous or intravenous administration of trastuzumab in patients with HER2-positive early breast cancer (PrefHer): an open-label randomised study.

Pharmacokinetics and safety of subcutaneous rituximab in follicular lymphoma (SABRINA): stage 1 analysis of a randomised phase 3 study.

A time and motion study of subcutaneous versus intravenous trastuzumab in patients with HER2‐positive early breast cancer

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