Multicentre, double-blind, randomised, placebo-controlled study on the prophylactic use of naldemedine for opioid-induced nausea and vomiting in patients with cancer (POSEIDON study): a protocol paper

Abstract

Introduction

Opioid-induced nausea and vomiting (OINV) in patients with cancer imposes a substantial clinical burden and may compromise adherence to opioid therapy. Naldemedine, a peripheral μ-opioid receptor antagonist, is currently approved for the treatment of opioid-induced constipation. Recent evidence suggests similar benefits for the treatment of OINV. This study aims to evaluate the preventive effect of naldemedine on OINV in patients with cancer pain initiating opioid analgesics.

Methods and analysis

This multicentre, double-blind, randomised, placebo-controlled, parallel-group comparison trial will be conducted across 20 hospitals and clinics in Japan. An estimated 120 patients with cancer scheduled to initiate opioid analgesic therapy will be recruited and randomly assigned (1:1) to receive either naldemedine or placebo on day 1 (visit 1). From days 1 to 7, patients will receive blinded study medication concurrently with opioid analgesics and will be followed for 8 days. The primary endpoint will be the proportion of patients achieving a complete response (CR) on day 5, defined as no vomiting and no use of rescue antiemetics for up to 120 hours after initiation of opioid analgesics. Key secondary endpoints will include the proportion of patients achieving CR on days 1, 2, 3 and 7; changes in Numerical Rating Scale scores from baseline; duration of nausea; proportion of patients who experience vomiting; proportion of patients using rescue antiemetics and frequency of rescue antiemetic use. Additionally, the incidence of adverse events and serious adverse events will be recorded throughout the observation period.

Ethics and dissemination

This study has been reviewed and approved by the Hattori Clinic Certified Review Board (approval number: CRB3180027). Written informed consent will be obtained from all participating patients before study commencement. The results of the study will be presented at academic conferences in Japan or overseas and submitted for publication in a peer-reviewed journal.

Trial registration number

NCT07038551 and jRCTs031250128.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• This is a multicentre, double-blind, randomised, placebo-controlled trial specifically designed to evaluate the prophylactic effect of naldemedine on opioid-induced nausea and vomiting (OINV) in patients with cancer pain.

• Patients will be stratified by previously reported risk factors, such as age (<65 years vs ≥65 years), sex and type of opioid analgesic (strong vs weak), thereby enhancing the applicability of the study design to real-world clinical settings.

• In addition to OINV, the study will also assess the prophylactic effect of naldemedine on opioid-induced constipation.

• The sample size was calculated using data from a previous report that included patients with cancer pain initiating strong opioids; therefore, the incidence of OINV among patients prescribed weak opioid analgesics may be overestimated, which may lead to reduced sensitivity.

• The study population will include Japanese patients with cancer, which may limit the generalisability of the results to other populations.

Introduction

Opioid analgesics are recommended for managing moderate-to-severe cancer-related and non-cancer pain that is inadequately controlled with non-opioid analgesics.¹,³ However, due to the widespread peripheral distribution of opioid receptors, including in the gastrointestinal tract, patients may experience opioid-related adverse effects such as nausea, vomiting and constipation.^{4 5} These adverse effects can negatively impact adherence to opioid therapy and, consequently, impair quality of life (QoL).⁶,⁸

Opioid-induced nausea and vomiting (OINV) occurs due to the activation of μ-opioid receptors in the chemoreceptor trigger zone, which stimulates dopamine release and activates the vomiting centre.^{9 10} OINV typically develops during the initial administration of opioid analgesics or following dose escalation, contributing to a substantial clinical burden.^{11 12} Hence, implementing appropriate preventive measures is crucial in patients receiving opioid analgesics.

Evidence has shown the efficacy of prophylactic antiemetics in patients with cancer; however, their effectiveness in preventing OINV remains unclear.¹³,¹⁶ Additionally, randomised controlled trials comparing prophylactic antiemetics with placebo for the prevention of OINV in patients with cancer are limited.^{17 18}

Naldemedine, a peripheral μ-opioid receptor antagonist, is approved in the USA, the European Union and Japan for opioid-induced constipation.^{19 20} Clinical evidence has reported the safety and efficacy of naldemedine in patients using opioids for chronic non-cancer pain^{21 22} as well as for cancer-related pain.²³ Its effect on OINV has been reported in non-clinical studies using a ferret nausea and vomiting model, in which it suppressed morphine-induced OINV.²⁴ Moreover, in a clinical study involving patients with cancer, a significantly lower proportion of patients in the naldemedine group experienced vomiting at least once within 72 hours of initiating strong opioid analgesics compared with the placebo group.²⁵ Although these findings suggest a potential preventive effect of naldemedine on OINV, no clinical trials have been conducted with OINV as the primary endpoint. Therefore, further research using study designs specifically aimed at evaluating OINV is warranted. The present study aims to evaluate the prophylactic effect of naldemedine on OINV in patients with cancer pain initiating opioid analgesics.

Methods and analysis

Study design and settings

This multicentre, double-blind, randomised, placebo-controlled, parallel-group comparison study will be conducted across 20 hospitals and clinics in Japan. Among these, the International University of Health and Welfare Narita Hospital, Narita, Chiba, will serve as the lead facility. Other study centres are listed in online supplemental appendix 1.

Patient eligibility criteria

Patient eligibility criteria are summarised in table 1. Patients will be included in the study if they meet all the inclusion criteria and do not meet any of the exclusion criteria.

Table 1. Patient inclusion and exclusion criteria.

Criteria	Details
Inclusion criteria	Patients with cancer who are expected to initiate scheduled administration of opioid analgesics for cancer pain and to continue this regimen for ≥7 days.
	Patients aged ≥18 years at the time of providing informed consent.
	Patients who are able to ingest medication, food and beverages orally.
	Patients who are able to independently maintain records in a patient diary; if self-evaluation is possible, proxy recording by a representative of the patient is permitted.
	Patients unlikely to experience an acute change in general health status during the study period.
	Patients willing to provide written informed consent for participation in this study.
Exclusion criteria	Patients with opioid analgesic use within 28 days before the date of consent.
	Patients with a history of or current treatment with naldemedine.
	Patients experiencing nausea or vomiting of CTCAE grade ≥2 on the day of informed consent.
	Patients taking any of the following antiemetic medications within 7 days before the date of consent: metoclopramide, domperidone, histamine H1 receptor antagonists, phenothiazine antipsychotics (chlorpromazine, levomepromazine and prochlorperazine), haloperidol, atypical antipsychotics (perospirone, risperidone and olanzapine), serotonin 5-HT3 receptor antagonists (ondansetron, granisetron, ramosetron and palonosetron), corticosteroids (dexamethasone), scopolamine hydrobromide and NK-1 receptor antagonists (aprepitant, fosaprepitant and fosnetupitant).
	Patients who have undergone cancer chemotherapy that could potentially affect nausea and vomiting within 14 days before the date of consent, or who are scheduled to receive such treatment during the study period.
	Chemotherapy potentially affecting nausea and vomiting (including prophylactic medication) is defined as the first dose of irinotecan (CPT-11)-containing treatment regimens or other cancer chemotherapies considered likely to cause nausea and vomiting (including prophylactic medication). However, exceptions apply in the following cases: (1) patients scheduled for chemotherapy (including prophylactic medication) using the same regimen or the same medication at the same or lower dosage as the previous course, and who did not experience moderate or severe nausea and vomiting (CTCAE V.5.0 grade ≥2) during the previous course; (2) patients receiving daily treatment with oral anticancer agents (such as TS-1), provided that ≥7 days have elapsed from the start of oral administration to the time of consent and no moderate or severe nausea and vomiting (CTCAE V.5.0 grade ≥2) have occurred.
	Pregnant or breastfeeding patients.
	Patients with suspected hypersensitivity to opioid receptor antagonists such as naldemedine, naltrexone, methylnaltrexone or naloxone.
	Patients with contraindications listed in the package inserts for naldemedine and/or opioid analgesics (tramadol, morphine, oxycodone and hydromorphone).
	Patients who are participating in or scheduled to participate in clinical trials or other interventional studies.
	Patients with gastrointestinal obstruction or suspected obstruction, or a history of gastrointestinal obstruction with high risk of recurrence.
	Patients who have undergone surgeries or procedures impacting gastrointestinal function (eg, nerve block) or radiation therapy to the head, intestinal tract or pelvis within 14 days before the date of consent or those who are scheduled for such interventions during the study period.
	Patients with medical history or clinical findings indicating significant cardiovascular, respiratory, hepatic or renal dysfunction based on clinical laboratory values, ECG findings or physical examination and who are considered unsuitable for participation in this study.
	Patients with symptomatic intracranial disease (eg, brain metastasis or leptomeningeal disease).
	Patients with suspected dysfunction or impairment of the blood-brain barrier.
	Patients with an inability to understand the study and/or provide informed consent due to cognitive impairment or psychiatric disorders.
	Patients considered inappropriate for participation in this study by the principal investigator or subinvestigator based on concomitant therapy or medical findings.

CPT-11, irinotecan; CTCAE, Common Terminology Criteria for Adverse Events; ECG, electrocardiogram; 5-HT3, serotonin 5-hydroxytryptamine type 3; NK-1, neurokinin-1; TS-1, tegafur/gimeracil/oteracil.

Opioid analgesics included tramadol, morphine, oxycodone and hydromorphone. Specified antiemetic medications included metoclopramide, domperidone, histamine H1 receptor antagonists, phenothiazine antipsychotics including chlorpromazine, levomepromazine and prochlorperazine, haloperidol, atypical antipsychotics including perospirone, risperidone and olanzapine, serotonin 5-HT3 receptor antagonists including ondansetron, granisetron, ramosetron and palonosetron, corticosteroids including dexamethasone, scopolamine hydrobromide and NK-1 receptor antagonists including aprepitant, fosaprepitant and fosnetupitant. Chemotherapy considered likely to affect nausea and vomiting, including prophylactic medication, is described in the main text.

Withdrawal criteria

Enrolled patients meeting any of the following criteria will be withdrawn from the study by the principal investigator (PI) or subinvestigator, and appropriate care will be provided:

• Patient requests withdrawal from the study.

• The PI or subinvestigator determines that administration of prohibited concomitant medications is necessary (except when unavoidable to treat any adverse events [AEs]).

• Patient is found to have deviated from the inclusion criteria or meets any of the exclusion criteria.

• Discontinuation of follow-up visits by the patient.

• Occurrence of AEs making it undesirable to continue the study.

• Any other situation, in which the PI or subinvestigator considers continued participation inappropriate.

Randomisation and blinding

Eligible patients will be registered with the Japanese Organisation for Research and Treatment of Cancer (JORTC) data centre. Patients will be randomised in a 1:1 ratio to treatment groups using a centralised registration number provided by the data centre. Randomisation will be performed using the minimisation method, with stratification by age (<65 years vs ≥65 years), sex and type of opioid analgesic used (strong vs weak). Site will not be included as a randomisation factor or an adjustment factor in the analysis because this study aims to enrol 120 patients from 20 institutions, and the number of patients enrolled at each site is expected to vary, with some sites potentially enrolling only a small number of patients. The detailed study flow is shown in figure 1. As this will be a double-blind study, the information on allocation will be maintained as internal documentation within the data centre and will not be disclosed to the patients, PI, subinvestigators or research collaborators at participating medical institutions until unblinding.

Figure 1. Study flow. *By the minimisation method, stratified by age (<65 years vs ≥65 years), sex and type of opioid analgesic used (strong vs weak). JORTC, Japanese Organisation for Research and Treatment of Cancer.

Study visits and data collection

On the day of enrolment (visit 1), baseline assessments will be performed before the administration of opioid analgesics and the study drug. Regardless of the date of visit, the patient diary will be completed until day 8 (visit 2). If an adverse drug reaction or insufficient efficacy necessitates a clinical visit during the observation period, this will be performed as an unscheduled visit, which may also be conducted remotely via phone or virtual visit. The schedule of study visits, observations and assessments is summarised in table 2.

Table 2. Study visits, observations and assessments.

Visits	Visit 1*	Observation period			Unscheduled visit†
		Date of the first dose	Date of the last dose	Visit 2‡
Study day	Day 1		Day 7	Day 8
Allowed visit window				−1 to +3 days
Informed consent	X
Enrolment	X
Inclusion and exclusion criteria	X
Demographics/history	X
Initiation of opioid analgesics§		X
Opioid analgesics
Initiation of naldemedine/placebo§		X
Naldemedine/placebo
Physical examination¶	X			X	X
Concomitant medications/therapies	X			X	X
Nausea/vomiting record**
Bowel movement record**
Nausea score (NRS)**	X
Pain score (NRS)**	X
BFI	X			X††
Bowel satisfaction	X			X††
EORTC QLQ-C15-PAL	X			X††
Adverse events					X
Rescue medications, enemas and disimpaction**					X

Blue double arrow line indicates treatment/observation period.

X indicates study activity to be performed.

^*Baseline assessments at visit 1 will be performed before administration of opioid analgesics and the study drug.

^†If an adverse drug reaction or insufficient efficacy requires a clinical visit during the observation period, this will be performed at an unscheduled visit. Unscheduled visits may be performed remotely via a phone or virtual visit.

^‡If discontinuation occurs before visit 2, the same procedures as those specified for visit 2 will be performed on the date of discontinuation. If the patient is unable to return to the site within the acceptable window, the same procedures will be performed via a phone or virtual visit.

^§The date of the first dose of naldemedine and opioid analgesics is defined as the date of initiation of treatment (day 1). The date of initiation of treatment (day 1) will be the same day as visit 1. Participants will take the first doses of naldemedine and opioid analgesics at the same time. If it is difficult to take naldemedine and opioid analgesics at the same time, the drugs will be taken within 10 min of each other.

^¶Blood samples taken as necessary during physical examination and residual serum and stool samples will be retained.

^**Regardless of the date of visit, the patient diary will be completed until day 8.

^††BFI, bowel satisfaction and EORTC QLQ-C15-PAL will be assessed on day 8, based on the patient diary.

BFI, Bowel Function Index; EORTC QLQ-C15-PAL, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire – Core 15 – Palliative version; NRS, Numerical Rating Scale.

An electronic data capture (EDC) system will be used to collect data. Patient diaries, which include patient-reported outcomes, will be provided either in paper form or as electronic case report forms (eCRFs) and collected at each institution.

Study interventions

Once randomised to either the naldemedine or placebo group, patients will orally administer the study treatment in combination with an opioid analgesic after receiving instructions from the attending physician. The day of enrolment will be defined as visit 1, and the start of both the opioid analgesic and the study drug will be defined as day 1, coinciding with visit 1. Patients will be treated according to the schedule outlined in table 3.

Table 3. Treatment schedule.

Treatment group	Day 1	Days 2–7	From day 8 to completion of the observation period
Naldemedine group	Opioid analgesic+naldemedine	Opioid analgesic+naldemedine	Opioid analgesic
Placebo group	Opioid analgesic+placebo	Opioid analgesic+placebo	Opioid analgesic

On day 1, the first dose of the opioid analgesic and the study drug will be taken simultaneously. If simultaneous administration is not feasible, both drugs should be taken sequentially within 10 min. From days 1 to 7, patients will take the study drug orally once daily at the same time each day.

On day 1, the first dose of the blinded study drug and the opioid analgesic will be taken simultaneously. If simultaneous administration is not feasible, both drugs must be taken sequentially within 10 min. From days 1 to 7, the study drug will be administered once daily at the same time each day. Switching opioid analgesics will not be permitted during the observation period.

The starting dose of opioid analgesics must be at least the minimum dose specified in the package insert (tramadol: ≥100 mg/day; morphine: ≥15 mg/day; oxycodone: ≥10 mg/day and hydromorphone: ≥4 mg/day). No specific rules are defined for dose escalation and dose reduction.

Prohibited concomitant medications

From the time of consent acquisition until end of the observation period or discontinuation from the study, use of the following concomitant medications, including both prescription and over-the-counter drugs with equivalent effects, will be prohibited (except when their use is necessary to treat AEs):

• Scheduled administration of opioid receptor antagonists and agonists such as eptazocine, oxycodone, codeine, nalfurafine, nalmefene, naloxone, fentanyl, buprenorphine, pentazocine, morphine and levallorphan. However, over-the-counter products containing codeine are permitted.

• Scheduled administration of antiemetics or laxatives, or initiation of these medications after consent acquisition.

• Medications contraindicated for concomitant use, as listed in the package insert of the opioid analgesic.

Rescue medications

From the date of consent until the end of the observation period, patients may use the following rescue medications as needed after receiving instructions from the responsible physician or subinvestigator. The use and frequency of these medications will be recorded in the patient diary and reviewed at each visit.

• Antiemetics such as metoclopramide, domperidone, histamine H1 receptor antagonists, phenothiazine antipsychotics (chlorpromazine, levomepromazine and prochlorperazine), haloperidol, atypical antipsychotics (perospirone, risperidone and olanzapine), serotonin 5-HT3 receptor antagonists (ondansetron, granisetron, ramosetron and palonosetron), corticosteroids (dexamethasone) and scopolamine hydrobromide.

• Laxatives such as magnesium oxide, polyethylene glycol, lactulose, lubiprostone, linaclotide, elobixibat, macrogol, senna, sennoside, picosulfate, daikenchuto, daio-kanzoto and suppositories.

• Analgesics such as morphine, oxycodone, hydromorphone and tramadol.

• Enemas and manual disimpaction.

Study endpoints and assessments

The study endpoints and corresponding statistical analysis methods are summarised in table 4. The Bowel Movement Satisfaction Questionnaire is provided in online supplemental appendix 2.

Table 4. Study endpoints and statistical analysis methods.

Endpoint category	Endpoint
Primary efficacy endpoint	Proportion of patients who achieve CR on day 5 (CR5).* †
Secondary efficacy endpoints	The proportions of patients who achieve CR on day 1 (CR1), day 2 (CR2), day 3 (CR3) and day 7 (CR7).* †
	Changes from baseline in the average, minimum and maximum nausea NRS30 scores, and the average duration of nausea per day on days 1, 2, 3, 5 and 7 after initiation of opioid analgesic administration.* ‡
	The proportion of patients who experience vomiting at least once, the proportion of patients who use rescue antiemetics and the number of times rescue antiemetics are used within 24, 48, 72, 120 and 168 hours after initiation of opioid analgesic administration.* †
	The proportion of patients with ≥3 SBMs (excluding those occurring within 24 hours after administration of rescue laxatives or enemas), and the proportion of patients with ≥3 complete SBMs (defined as SBMs without a sense of incomplete evacuation) within the first 7 days after initiation of opioid analgesic administration.* †
	The proportion of patients with a sense of incomplete evacuation, proportion of patients with straining in ≥25% of bowel movements within the first 7 days after opioid analgesic initiation.* †
	The proportion of patients with ≥3 SBMs without straining, and proportion of patients with ≥3 SBMs without both a sense of incomplete evacuation and straining within the first 7 days after opioid analgesic initiation.* †
	The proportion of patients who use rescue laxatives or undergo enemas or manual disimpaction, and the frequency of their use within the first 7 days after opioid analgesic initiation.* † ‡
	The proportion of patients with a BFI score <28.831,* †, and the change from baseline in BFI score at visit 2. * ‡
	The proportion of patients selecting each option on the Bowel Movement Satisfaction Questionnaire at visit 2, and proportion of patients with worsened satisfaction from baseline.* †
	Change from baseline in the global QoL score and subscale assessments of the EORTC QLQ-C15-PAL32,34 at visit 2. * ‡ §
	Change from baseline in pain NRS scores on days 1, 2, 3, 5 and 7 after initiation of opioid analgesic administration.* ‡
Safety endpoints	Incidence of adverse events and serious adverse events during the observation period.¶
Exploratory endpoints	Proportion of patients who achieve CR5 in subgroups.**
	Risk analysis by baseline factors using CR3 and CR5.††

^*CR5 is defined as no vomiting and no use of rescue antiemetics for up to 120 hours after initiation of opioid analgesic administration. CR1, CR2, CR3 and CR7 are defined as no vomiting and no use of rescue antiemetics for up to 24, 48, 72 and 168 hours, respectively, after initiation of opioid analgesic administration. SBMs exclude those occurring within 24 hours after administration of rescue laxatives or enemas. Complete SBMs are defined as SBMs without a sense of incomplete evacuation.

^†Binary endpoints will be analysed using the same methodology as that used for the primary endpoint analysis.

^‡Continuous outcomes will be analysed using a two-sided two-sample t test, with point estimates and 95% CIs for mean values within each group and differences between groups.

^§Individual EORTC QLQ-C15-PAL item scores will also be analysed as ordinal categorical variables using the Mantel test.

^¶Safety endpoints will be summarised descriptively by treatment group.

^**Subgroup analyses will be conducted for CR5 using the same method as that used for the primary efficacy endpoint.

^††Risk analysis will be performed using CR3 or CR5 as the outcome variable and baseline factors as explanatory variables.

BFI, Bowel Function Index; CI, confidence interval; CR, complete response; EORTC QLQ-C15-PAL, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 15-Palliative; NRS, Numerical Rating Scale; QoL, quality of life; SBM, spontaneous bowel movement.

Drug supply

The study drug will be naldemedine tosilate 0.2 mg (Symproic 0.2 mg, provided by Shionogi & Co., Ltd.). Since naldemedine contains lactose as an excipient, the placebo will be prepared by encapsulating lactose only. The over-encapsulation of both treatment drugs will be performed (ProFiller1100 tabletop capsule filling machine [Lonza Corporation, Kanagawa, Japan]; Japan Pharmacopoeia DB capsule [double-blind capsule] 0.5 mL [7–6858-03, Kobayashi Capsule]) by the pharmacy department of the International University of Health and Welfare Narita Hospital, and blinding will be confirmed by JORTC.

Sample size

The sample size for this study was calculated based on our unpublished data. The incidence of OINV at 72 hours after starting a strong opioid analgesic in patients with cancer was 19% in the naldemedine group and 62% in the placebo group, which means a 69% relative risk reduction by naldemedine.

Since this study will include patients using weak opioid analgesics, the incidence of OINV in the placebo group is expected to be lower than that reported by Hamano et al.²⁵ The incidence of OINV in the placebo group was independently set at 44%, assuming a 1:1 ratio of patients receiving strong and weak opioid analgesics. Based on the relative risk reduction, the incidence of OINV in the naldemedine group was calculated at 14%. Assuming that inclusion of patients receiving weak opioid analgesics would reduce the difference between the groups, the incidence was set at 19%. Hence, the estimated CR5 value is 0.81 for the naldemedine group and 0.56 for the placebo group. Given an α level of 0.05 and a power of 0.8, power analysis determined that 54 patients per group would be required. Allowing for a dropout rate of 10%, the final sample size was adjusted to 60 patients per group, resulting in a total of 120 patients.

Statistical analysis

All analyses will be performed using Statistical Analysis System (SAS) V.9.4 or higher.

Handling of missing data

No imputation will be performed for missing values. The handling of ineligible and aberrant data will be discussed at case review meetings and other forums, and the data will be locked based on these discussions.

Efficacy analysis will be performed using the full analysis set, which will be based on the assigned group and include all patients who receive at least one dose of naldemedine or placebo and undergo at least one efficacy assessment. The safety analysis set will include all patients who receive at least one dose of naldemedine or placebo and will be analysed on an as-treated basis according to the treatment actually received.

Patient background characteristics and baseline data at visit 1 will be summarised for all enrolled patients, the full analysis set and the safety analysis set, by treatment group. Categorical variables will be summarised by frequency and proportion, while numerical variables will be summarised using descriptive statistics (number of cases, mean, SD, minimum, median and maximum) for each treatment group.

Efficacy analyses

The primary efficacy analyses will be performed for the full analysis set.

Analysis of the primary endpoint

The proportion of patients achieving CR5 will be compared between the naldemedine and placebo groups using a two-sided χ² test. Point estimates and 95% confidence intervals (CIs) will be calculated for CR5 within each group, as well as differences between groups. As a supplementary analysis, the common risk difference will be estimated using the Cochran-Mantel-Haenszel test adjusted for the allocation adjustment factors. Opioid doses will be summarised using oral morphine equivalent doses (OMEDs) to allow for a standardised assessment across different opioid analgesics. If sufficient data are available, post hoc exploratory analyses of OINV incidence according to OMED or type of opioid analgesic may be conducted.

Analysis of secondary endpoints

Binary variables will be analysed using the same methodology as that used for the primary endpoint analysis. Continuous outcomes, including changes from baseline in nausea NRS scores at visit 2, changes from baseline in pain NRS scores at visit 2, average duration of nausea per day, the number of times rescue antiemetics are used, the frequency of rescue laxative use, enema use and manual disimpaction, changes from baseline in BFI scores at visit 2, and changes from baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire – Core 15 – Palliative version (EORTC QLQ-C15-PAL) domain scores and individual item scores at visit 2, will be analysed using a two-sided two-sample t-test, with point estimates and 95% CIs for mean values within each group and differences between groups. Individual EORTC QLQ-C15-PAL item scores will also be analysed as ordinal categorical variables using the Mantel test. Formal normality testing will not be required as a prerequisite for these analyses; however, the distribution of continuous outcomes and potential outliers will be reviewed descriptively. If substantial deviations from the assumptions are observed, additional exploratory or sensitivity analyses may be considered.

Safety analyses

Safety analyses will be performed for the safety analysis set, which will be based on the actual treatments.

AEs will be graded using the Japan Clinical Oncology Group common criteria.²⁶ Counts and proportions will be summarised for all occurrences regardless of grade, as well as separately for Common Terminology Criteria for Adverse Events (CTCAE) grade ≤3 and grade ≥4 events. Aggregation will be performed for each AE.

Safety analyses will be conducted for all AEs reported in the eCRF that occur after the initial dose of the study drug. The number of AEs, deaths, other serious AEs and AEs leading to drug discontinuation will be summarised by treatment group. Proportions and corresponding 95% CIs will be calculated using the Clopper-Pearson method. The number of AE occurrences will also be reported.

Side effects will be summarised in the same manner as AEs.

Safety considerations

During the study period, physicians will monitor the health status of patients through examinations and tests on visit days, and by maintaining emergency contact with patients on non-visit days. If AEs occur, appropriate medical care will be provided, including discontinuation of the study drug or termination of the study, if necessary, to ensure the safety of the patients.

In the event of any disease or other health issues, safety information will be collected and reported to the PI, the study site managers and the Certified Review Board in accordance with the Clinical Research Act (including its implementation regulations and related notifications). Furthermore, the responsible (or designated) physician will report any AEs and diseases to Shionogi & Co., Ltd., in accordance with established safety reporting procedures.

If AEs occur, the responsible (or designated) physician will provide explanations to the patients, take appropriate measures, report to collaborators or monitoring personnel and follow the course of the event until recovery or remission, as far as possible. However, if it is medically determined that recovery is unlikely, observation as part of the study will be concluded after an explanation is provided to the patients.

Study oversight and management

Monitoring for this study will be outsourced to JORTC and Linical Co., Ltd. Monitoring will primarily be conducted through centralised review of data entered into the EDC system. If centralised monitoring identifies issues requiring further action, on-site monitoring will be performed, including verification of data against original records during facility visits. The responsible physician and the study site must provide monitoring personnel with direct access to study-related records on request.

Auditors will independently conduct document reviews and field investigations to ensure the reliability of the study and its documentation.

Data management and patient-reported outcomes

The EDC system used in this study is Viedoc (Viedoc Technologies AB), a web-based application that allows study sites and data centres to easily and securely collect, validate, transmit and analyse clinical trial data. Patient diaries will be provided in paper form and handed directly to patients for completion. Subsequently, designated personnel at each study site will enter the data into the EDC system. Before using the EDC system, the responsible (or designated) physician and study collaborators must review the ‘EDC Input Manual’ provided by the data centre, which explains the procedures and input guidelines. In accordance with this manual, information from enrolled patients will be entered into the EDC system based on original records, with the responsible (or designated) physician performing a final review and applying an electronic signature.

Ethics and dissemination

This study will be conducted in compliance with the ethical principles outlined in the Declaration of Helsinki (latest version), the Clinical Research Act (Act No. 16 of 2017), the Act on the Protection of Personal Information (Act No. 57 of 2003) and related notifications, as well as the implementation plan and study protocol. The study has been reviewed and approved by the Hattori Clinic Certified Review Board (approval number: CRB3180027). Written informed consent will be obtained from all participating patients before study commencement (online supplemental appendix 3). The results of the study will be presented at academic conferences in Japan or overseas and submitted for publication in a peer-reviewed journal.

Discussion

This study is proposed to assess the preventive effect on OINV when opioid analgesics and naldemedine are simultaneously initiated and co-administered for 5 days in patients with cancer pain. The primary endpoint of this study is CR5, defined as patients experiencing no vomiting and no use of rescue antiemetics for up to 120 hours after initiation of opioid analgesic administration.

So far, there are no universally accepted outcome measures for clinical trials assessing the efficacy of a medication in preventing OINV. Additionally, most indicators such as CTCAE and NRS are generally designed to reflect the severity of OINV. In the context of quantifying the occurrence of OINV, we believe that CR5 is aligning closely with the study objective. A study by Tsukuura et al used the CR5 rate (no vomiting and no use of rescue medication for nausea and vomiting during 120 hours) as the primary endpoint in a randomised, placebo-controlled, double-blind trial (POINT) that evaluated prophylactic treatment with prochlorperazine for oxycodone-induced nausea and vomiting among patients with cancer pain.¹⁷ In our study, given the simultaneous initiation and co-administration of naldemedine with opioid analgesics for 5 days, CR5 was considered an appropriate endpoint because the objective of our study is similar to that of the above study. Patients who may adversely impact the results of the primary endpoint—such as those who had used antiemetic drugs within 7 days before enrolment, had been prescribed opioid analgesics within 28 days or were undergoing chemotherapy that could cause nausea and vomiting—were excluded. However, the use of rescue antiemetics and laxatives was permitted to reduce patient burden. Additionally, several secondary endpoints, including CR1, CR2, CR3 and CR7, were included to provide interpretable findings.

An allocation simulation was conducted in advance to determine the number of factors that would allow appropriate randomisation within the sample size of this study. Moreover, based on risk factors reported by previous researchers,¹⁵²⁷,²⁹ a maximum of three allocation factors—age (<65 years vs ≥65 years), sex and type of opioid analgesic used (strong vs weak)—were selected in this study. The definition of elderly in Japan is ≥65 years; hence, the age categories were set according to this definition.

The sample size was calculated using data from a previous study that included patients with cancer initiating strong opioids²⁵; therefore, the incidence of OINV in patients prescribed weak opioid analgesics may be overestimated. Nonetheless, including patients prescribed weak opioids will improve the generalisability of the findings to routine clinical practice.

The study has some limitations, based on study methodology. The study will be conducted at multiple sites in Japan, which may limit the generalisability of the findings to other populations. CR rates were adopted as the primary endpoint of this study. The use of other measures may lead to different results, although this is unlikely because all secondary outcomes are expected to provide findings in the same direction. Although patients who used medications that could adversely impact the primary endpoint were excluded, the use of rescue antiemetics and laxatives was permitted to reduce patient burden. In addition, differences in cancer type, the cause and anatomical origin of pain requiring opioid therapy and opioid type may affect endpoint assessment; however, these factors are not planned to be collected in detail in this study. These factors should therefore be considered when interpreting the study findings, although post hoc exploratory analyses may be conducted if relevant data are available. Although the amount of codeine contained in over-the-counter medications available on the Japanese market is generally very small, the use of over-the-counter medications containing codeine may also affect the study endpoints and should be considered when interpreting the results.

Collectively, this will be the first study proposed to verify whether naldemedine can prevent OINV in Japanese patients with cancer pain initiating opioid analgesics. If this study demonstrates that, at opioid initiation, naldemedine is effective in reducing the incidence of OINV in patients with cancer, it can be expected that preventing OINV with naldemedine will facilitate more appropriate control of cancer pain by improving opioid adherence and QoL in patients, thereby reducing the burden on patients in Japan.

Trial status

Patient enrolment for this study is scheduled to begin in June 2025 and continue through February 2026. The observation period will extend from June 2025 (enrolment of the first patient) to March 2026 (last visit of the last patient).