The atezolizumab-specific Roche DPM Module on the Kaiku Health DPM platform

The atezolizumab-specific Roche DPM Module will be used in this study across cohorts to collect data on preselected disease-specific and treatment-specific symptoms, aid self-triaging of symptom severity and support self-management of mild and moderate symptoms (figure 3). Depending on the patient’s indication, selected disease-related or treatment-related symptom questions, including a free-text symptom field, will be presented to the patient (online supplemental table 1). Relevant symptoms were selected based on the AE profile of the drug treatment and symptom profile of the disease. The selection was refined in a discussion process with physicians, nurses and patient groups. The coverage of symptoms experienced in clinical practice by patients and healthcare professionals was validated in a real-world evidence-based feasibility study.46 The Module should be used in accordance with the provided training and as indicated in the accompanying user guide.

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Figure 3

Overview of DPM tools. DPM, digital patient monitoring.

Participants will be invited every 7 days to report symptoms or can report symptoms ad hoc as needed. Notifications of symptom reports will be sent to the care team in order to prioritise review and management, based on the reported severity of the symptoms in line with the PROs version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE).47 For selected mild or moderate symptoms, specific educational material will be provided, including additional symptom severity assessment and symptom self-management instructions (based on The Symptom Navi Programme).48 49 Via a care team-user interface on the Kaiku Health DPM platform, the care team can track, across cohorts, participant symptom reports between clinical appointments, in order to facilitate clinical decision-making. The care team is also able to exchange messages with the participant.

The atezolizumab-specific Roche DPM Module and Kaiku Health DPM platform is mobile-enabled and accessible through a web browser or an application on devices such as personal computers, laptops, mobile phones and tablets. Participants using the atezolizumab-specific Roche DPM Module will receive access to the DPM module on their own personal devices (ie, not devices provided during the study) and training on its use at their baseline study visit. Kaiku Health is a Class IIa active medical device both under the Medical Devices Directive (according to Rule 10; current at time of writing) and under the Medical Devices Regulation (according to Rule 11).50 51

All participants across both study cohorts will report symptom interference and burden, health-related QoL and treatment satisfaction using the validated questionnaires described below.

Study setting and participant recruitment

Approximately 40 sites, initially across 10 countries, will enrol approximately 400 participants in Cohort A and 40 participants in Cohort B (figure 2). Participants will provide written informed consent in a face-to-face setting (examples of the informed consent forms are provided as online supplemental materials) and will be enrolled and randomised (if applicable) through an interactive web-based response system. Ethics committees reviewed the protocol, the patient informed consent forms (Cohort A and B), the Roche modules and their content and the additional patient-facing material shared within the DPM solution. The study received its first Ethics Committee approval in Spain in October 2022 (received: 3 October 2022; health authority approval: 12 December 2022). Enrolment of patients is expected from December 2022 onwards, for a period of 18 months.

Participants and study design

For all cohorts, participants must be aged ≥18 years old, have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0, 1 or 2, and have an email address, access to an internet-capable device (smartphone, tablet or personal computer) and access to an internet connection.

Key exclusion criteria for Cohorts A and B are: (1) any physical or cognitive condition preventing use of the Kaiku Health DPM platform; (2) lack of proficiency with any of the available Roche DPM Module language translations or presence of psychiatric/neurological disorders or any condition that may impact the participant’s ability to use the DPM platform; (3) current use of another DPM or electronic PRO tool for symptom management and/or reporting; (4) current participation in another interventional trial; (5) receiving an atezolizumab biosimilar or non-comparable biologic; and (6) history of other malignancy within 5 years prior to initiation of study treatment (excluding malignancies with a negligible risk of metastases or death).

Cohort A will investigate the impact of the atezolizumab-specific Roche DPM Module on health outcomes in participants prescribed locally approved anticancer regimens containing intravenous atezolizumab for metastatic NSCLC, extensive-stage SCLC or Child Pugh A unresectable hepatocellular carcinoma, according to Barcelona Clinic Liver Cancer staging.52 Participants in Cohort A must have a confirmed diagnosis from their treating physician for the relevant indication (via local laboratory or radiological report), have a life expectancy of ≥12 weeks and be systemic therapy-naïve (except for participants with EGFR-mutant or ALK-positive NSCLC who may have received prior systemic therapy with prior tyrosine kinase inhibitors). Participants receiving concomitant anticancer treatment not part of a locally approved combination at the time of starting intravenous atezolizumab will be excluded.

In Cohort A, participants will be randomised 1:1, through a permuted-block randomisation method to ensure a balanced assignment, to a locally approved, anticancer regimen containing intravenous atezolizumab and local standard-of-care support ± the atezolizumab-specific Roche DPM Module (table 1). Randomisation will be stratified by disease indication and baseline ECOG PS (0/1 vs 2). Following the study baseline visit to receive access to and training on the atezolizumab-specific Roche DPM Module, participants will return for visits per their routine anticancer treatment administration schedule. No extra visits are mandated by this protocol, but additional clinical visits may occur at the discretion of both the care team and participant, based on symptom reports via the DPM Module.

Cohort B will assess the feasibility of using the Roche DPM Module to support SC atezolizumab administration by a qualified healthcare professional at the participant’s home, as part of symptom management support in between treatment administration visits, in patients with programmed cell-death ligand 1 (PD-L1)-positive, early-stage NSCLC. Participants who have had a complete resection of histologically/cytologically confirmed Stage IIB–IIIB NSCLC (T3–N2 for stage IIIB per the Union for International Cancer Control/American Joint Commission on Cancer staging system),53 have locally confirmed PD-L1-positive tumours, and have completed adjuvant chemotherapy at 4–12 weeks prior to randomisation and are adequately recovered from this (per the investigator’s decision), are eligible. PD-L1-positive tumours are defined as PD-L1 expression on ≥1% of tumour cells, as documented through locally approved, pre-existing local testing of a representative tumour tissue specimen. The PD-L1 assay must be a health authority-approved assay (ie, adhering to local drug/device regulations) and performed per manufacturer’s recommendations and requirements. Participants with EGFR mutation-positive or ALK rearrangement-positive tumours, as determined by local testing, will be excluded from Cohort B.

In Cohort B, eligible participants will use the atezolizumab-specific Roche DPM Module and will receive three cycles of SC atezolizumab (1875 mg; Day 1 of each 21-day cycle) in the hospital setting, before receiving up to 13 cycles at home by a healthcare professional (ie, in the flexible care setting) (table 1). Participants will continue to receive SC atezolizumab until Cycle 16 or loss of clinical benefit. Monitoring of participants beyond the atezolizumab-specific Roche DPM Module is supported by vital sign assessment and collection of laboratory samples at every administration visit, phone/video calls to the clinic healthcare professional during or on the day before administration and participant hospital visits every 3 months. In addition to the standard 7-day interval for symptom reporting, participants in Cohort B are also invited to report symptoms on the day after administration.

Objectives and endpoints

In Cohort A, the primary efficacy endpoint is the mean difference in change of the participant-reported Total Symptom Interference Score from the MD Anderson Symptom Inventory (MDASI) Core Items at Week 12 from baseline (table 2).54 This will be measured in participants receiving a locally approved, anticancer regimen containing intravenous atezolizumab and local standard-of-care support ± the atezolizumab-specific Roche DPM Module. MDASI is a 19-item questionnaire to assess symptom burden defined as the sum of symptom severity and impact of symptoms (interference).54 Overall symptom distress is defined as the mean of the ratings of the interference questions in MDASI.54 This primary endpoint was selected based on multiple previous studies, some of which used MDASI, demonstrating the potential of DPM tools to significantly reduce overall symptom burden, severity and distress in patients with cancer, compared with the standard of care alone.29 40–45

Secondary efficacy endpoints include number of hospitalisations and cumulative days hospitalised due to serious AEs, number of unscheduled visits to the emergency room or clinical visits for symptom management, changes from baseline in global health status (GHS)/QoL score from the European Organisation for Research and Treatment of Cancer (EORTC) Item Library 6 (EORTC IL6) GHS/QoL (from the EORTC Quality of Life Questionnaire (QLQ-C30)),55 change from baseline in the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L)56 and change from baseline in the mean symptom severity score from the MDASI Core Items (table 2). The EORTC QLQ-C30 is a validated, reliable self-reported measure that will be used to assess GHS and QoL.55 57 The EuroQol EQ-5D-5L is a validated, self-reported health status questionnaire that will be used to calculate a health status utility score for use in health economic analyses. There are two components: a five-item health state profile and a Visual Analogue Scale.56

Participants will be assessed for the primary endpoint and health-related QoL data at baseline and every 6 weeks until Week 24, regardless of whether they have discontinued anticancer therapy or started a new line of therapy. Safety and tolerability, including incidence and severity of device-associated AEs and adverse device effects, and incidence, nature and severity of anticancer treatment-associated AEs, will also be assessed, graded according to the National Cancer Institute’s CTCAE V.5.0.58 Safety data related to anticancer treatment will continue to be collected for 90 days following the last dose of atezolizumab, and for 30 days following the last dose of an alternative cancer therapy that has started prior to the 24-week time point and where the patient has continued to be followed up beyond this time point. Safety data related to adverse device effects will continue to be collected for 30 days following study end. A number of exploratory efficacy endpoints will also be assessed in Cohort A, as detailed in table 2. After 24 weeks, participants will continue to be followed up until 18 months after randomisation for OS.

In Cohort B, the primary endpoint is the flexible care adoption rate at Cycle 6 in participants using the atezolizumab-specific Roche DPM Module and receiving an SC atezolizumab anticancer treatment regimen (table 2). Adoption is defined as a joint decision by the investigator and the participant to continue to receive SC atezolizumab at home rather than in the hospital setting; if a participant or investigator decides to terminate administration of SC atezolizumab at home before Cycle 6, but continue in the hospital setting, this will be classified as ‘not adopting’. Exploratory endpoints for Cohort B are detailed in table 2.

Data collection methods

An electronic case report form will be used by care teams to collect and report participant clinical data across all cohorts at each scheduled anticancer treatment visit and unscheduled study-related visits. Across cohorts, electronic PRO measures that collect symptom interference/burden and health-related QoL data (ie, MDASI, EORTC IL6, EQ-5D-5L) will be completed through an application separate to the DPM Module downloaded on an electronic device, or a web link. In both cohorts, safety data on the Module will also be collected.

Across both cohorts, the atezolizumab-specific Roche DPM Module will be used by participants to report symptoms and communicate with care teams. Participants will be required to report their symptoms as they occur and at least once weekly. Additional qualitative data may also be collected via interviews with the participants and/or care teams.

Statistical analysis

For Cohort A, the full analysis population will consist of all randomised participants, that is, the intention-to-treat population. The safety analysis population is defined as all participants who received at least one dose of the anticancer intravenous atezolizumab treatment regimen and/or used the atezolizumab-specific Roche DPM Module. All participants who were given access to the atezolizumab-specific Roche DPM Module will be included in the DPM arm.

Hypothesis tests will be two-sided (significance level: 5%). The focus of ORIGAMA is hypothesis testing, and the primary endpoint for Cohort A was used to determine the sample size of the study. A sample size of 400 randomised participants (200 participants per arm) provides 90% power to detect a difference between study arms in the mean change from baseline at Week 12 in the MDASI Total Interference Score of at least 8 points, assuming a two-sided 5% significance level and an SD of approximately 25 points. The assumption for mean change and SD is based on both the responsiveness of the MDASI Total Interference Score reported by Shi et al59 and analyses of historical data from pivotal trials of the GHS scale from EORTC QLQ-C30.57 In order to ensure that there is a representation of participants across the three indications included, enrolment will be capped for any one indication at 40% of the total sample size.

The clinical cut-off date for the primary analysis of Cohort A will take place when all randomised participants have been followed for ≥12 weeks, unless they withdraw from the study before this. If less than 50% of participants have been followed up for 12 months at the time of the primary analysis, an OS follow-up secondary analysis may take place. The study is not powered to demonstrate a statistically significant difference in OS.

For Cohort B, 40 participants will be enrolled. Since this cohort is exploratory, no sample size was calculated, and no formal hypothesis testing will be performed on the primary endpoint.

In Cohort B, the full analysis population will consist of all enrolled participants who completed three cycles of SC atezolizumab administered in the hospital setting. The safety analysis population is defined as all participants who received at least one dose of SC atezolizumab and/or used the atezolizumab-specific Roche DPM Module. The clinical cut-off date for the primary analysis will take place when all participants have completed 16 cycles, unless they withdraw from the study prior to this.

Across all cohorts assessing the same digital health solution, solution use (such as patient module adoption and adherence to weekly symptom reporting) and workflow efficiency data will be collected and analysed.

Study oversight and safety reporting

The study will be sponsored and managed by F. Hoffmann-La Roche Ltd. The sponsor will provide clinical operations management, data management and medical monitoring. The investigator is responsible for ensuring that all safety events are recorded on the electronic case report form and reported to the sponsor.

Patient and public involvement

Patients were systematically involved in the development and testing of the symptom self-management recommendations that are included in The Symptom Navi Programme.48 49 Via prior publications (eg, the first pilot study and the real-world evidence-based feasibility study),40 60 patients have been involved in the development of the atezolizumab-specific Roche symptom questionnaire and the Kaiku Health DPM tool.

Anne-Marie Baird is president of Lung Cancer Europe (LuCE), an umbrella patient organisation, and was involved in study concept and protocol development (since the first comprehensive protocol draft). Furthermore, she advised on patient-focused educational materials and study documents.

In collaboration with multiple stakeholders, research objectives and questions were developed with a focus on patient needs. The primary endpoint and several secondary endpoints are PROs using well validated measures. The impact or clinical utility of DPM for patients is the primary focus of this research.

It is planned that study findings will be discussed with patient representatives and presented at medical congresses and patient forums.

Ethics and dissemination

This study will be conducted in full conformance with the principles of the Declaration of Helsinki, and/or the applicable laws and regulations of the country in which the research is conducted, whichever affords the greater protection to the individual. The study received its first Ethics Committee approval in Spain in October 2022. The results of this study will be presented at national and/or international congresses and disseminated via publication in peer-reviewed journals.