Study Protocol for Feasibility Randomized,Placebo-Controlled Trial of Efficacy of Midazolam as the Second-Line Treatment for Dyspnea in Patients with Advanced Cancer

Abstract

Background:

Dyspnea is one of the most distressing symptoms in patients with advanced cancer. Although systemic opioids are recommended as first-line pharmacologic treatment, 30–50% of patients do not achieve adequate relief. Midazolam is often used for persistent dyspnea despite opioid administration; however, robust evidence supporting its efficacy as a second-line treatment remains limited.

Objectives:

To evaluate the feasibility of a randomized controlled trial assessing the efficacy and safety of continuous subcutaneous midazolam infusion as second-line treatment for persistent dyspnea despite morphine administration in hospitalized patients with advanced cancer.

Methods:

A protocol for a multicenter, randomized, double-blind, placebo-controlled feasibility trial (J-SUPPORT2201/JORTC-PAL22) is described. The trial is being conducted at nine sites in Japan.

Population:

Participants are hospitalized adult patients with advanced cancer who are not receiving active anticancer treatment and who experience dyspnea at rest (Integrated Palliative Care Outcome Scale dyspnea score ≥2) despite continuous morphine infusion.

Intervention/Control:

Protocol treatment includes standardized morphine escalation plus continuous subcutaneous infusion of midazolam (9 or 6 mg/day for vulnerable patients) or placebo for 24 hours.

Measurements:

The primary endpoint is feasibility, defined as completion of protocol treatment at 24 hours. Secondary endpoints include dyspnea intensity, anxiety, rescue morphine use, communication, adverse events, and 30-day survival.

Conclusions:

This feasibility trial will provide methodological insights and preliminary clinical data regarding midazolam as a second-line option for persistent dyspnea despite morphine infusion in patients with advanced cancer and help design future confirmatory trials.

Keywords

advanced cancer dyspnea midazolam morphine randomized controlled trial

Introduction

Dyspnea, defined as “a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity,” is a distressing symptom for both patients with advanced cancer and their families.¹ It is highly prevalent in this population and often intensifies as the disease progresses. Even in specialized palliative care settings, dyspnea frequently worsens over time, persists until death, and may become refractory to palliative treatments, sometimes necessitating palliative sedation.^2,3

In Japan, among hospitalized patients with advanced cancer receiving continuous opioid infusion for dyspnea within specialized palliative care services, median survival is 4–5 days.^4,5 This highlights the critical need for prompt and effective symptom management in this vulnerable population. International guidelines recommend opioids, such as morphine, as first-line pharmacologic treatment for dyspnea.^6–8 However, even with continuous opioid infusion, adequate symptom relief is not achieved in 30–50% of cases,^4,5 and no internationally established second-line treatment exists for persistent dyspnea despite opioid administration. According to international guidelines, benzodiazepines may be considered in such cases when dyspnea persists despite opioid treatment and nonpharmacological interventions, as anxiety and dyspnea often exacerbate each other.^6–8 Among benzodiazepines, midazolam exhibits multiple pharmacological actions, including anxiolytic, hypnotic, and sedative effects.⁹ Navigante et al. demonstrated that combination therapy with midazolam and morphine was significantly more effective than morphine monotherapy for alleviating terminal dyspnea.¹⁰ However, the study protocol involved a midazolam dose of 30 mg/day, which corresponds with that typically used for palliative sedation,^3,11,12 being higher than the dose commonly used for symptom control (≤10 mg/day).^11,13 Therefore, the applicability of this approach to routine palliative care practice remains unclear. The role of benzodiazepines in managing dyspnea in seriously ill patients remains a topic of ongoing debate. Some experts suggest that low-dose midazolam may serve as a viable second-line treatment for opioid-refractory dyspnea, particularly in the terminal phase, while others argue that benzodiazepines should be reserved for dyspnea associated with anxiety, indicating the presence of clinical equipoise.¹⁴ In clinical settings, palliative care physicians often initiate opioid monotherapy and consider adding low-dose midazolam (≤10 mg/day) as second-line treatment when dyspnea persists despite opioid titration or when further opioid escalation is limited by intolerable side effects, particularly in the terminal phase.^13,15 Although a multicenter cohort study indicated that continuous low-dose midazolam, used adjunctively with opioids, may be effective and safe for persistent terminal dyspnea, no randomized controlled trial has been conducted to confirm its effects.¹⁵

This study is a multicenter, double-blind, placebo-controlled, feasibility randomized trial designed to investigate the clinical efficacy of midazolam as a second-line treatment for dyspnea in hospitalized patients with advanced cancer. The results are expected to help with the design of future confirmatory trials and support the development of new therapeutic options for patients with dyspnea.

Aims

The primary aim is to evaluate the feasibility of conducting a randomized controlled trial to determine whether the addition of continuous low-dose subcutaneous midazolam infusion to morphine dose escalation provides superior symptom control compared with morphine dose escalation alone in hospitalized patients with advanced cancer who continue to experience dyspnea despite continuous morphine infusion. Secondary aims involve exploratory evaluations of treatment efficacy and safety.

Methods

Study design

This is a multicenter, double-blind, placebo-controlled, feasibility randomized trial designed to investigate the clinical efficacy of midazolam as second-line treatment for dyspnea at rest in hospitalized patients with advanced cancer (J-SUPPORT2201/JORTC-PAL22).^16,17 Figure 1 shows a flow diagram of the study procedures.

Study setting and patients

This trial is being conducted at nine sites across Japan, all of which have palliative care units or palliative care consultation teams, or both, staffed by palliative care physicians. Participants are hospitalized adult patients with advanced cancer who are not receiving active anticancer treatment and who experience dyspnea at rest, defined as a clinician-rated Integrated Palliative Care Outcome Scale (IPOS) dyspnea score ≥2, despite continuous morphine infusion. Eligible patients are identified through routine inpatient clinical practice at each site, including those admitted to palliative care units and those in general wards with involvement of palliative care consultation teams. All patients continue to receive specialist palliative care, including ongoing opioid infusion, and their clinical management is determined according to their individual clinical condition. The study period is scheduled from January 2024 to March 2027.

Eligibility and exclusion criteria

Patients with advanced cancer who experience dyspnea at rest are likely to show a gradual decline in consciousness and increasing communication difficulty, regardless of the presence or type of therapeutic intervention.² Given the high likelihood that such patients may be unable to fully comprehend the trial details at the time dyspnea worsens, a two-stage registration process will be employed in this study. To ensure patients receive a sufficient explanation and provide written informed consent, investigators will obtain initial consent during a relatively stable period (first-stage registration). For patients who subsequently meet the second-stage eligibility criteria (specifically, those with worsening dyspnea), their willingness to participate will be reconfirmed (second-stage registration). Detailed eligibility and exclusion criteria for each stage are summarized in Table 1.

Table 1.

Eligibility and Exclusion Criteria for First- and Second-Stage Registration

Eligibility criteria for first-stage registration	Exclusion criteria for first-stage registration
1. Patients with histologically, cytologically, or clinically confirmed advanced cancer. 2. Patients aged 18 years or older at the time of providing informed consent 3. Patients not receiving continuous infusion of benzodiazepines 4. Patients not undergoing anticancer treatment (i.e., no anticancer treatment within the previous two weeks, and no treatment planned in the near future) 5. Patients whose attending physician determines that they are likely to survive for more than three days from the time of first-stage registration 6. Patients without a scheduled transfer or discharge within three days 7. Patients without cognitive impairment who are capable of providing written informed consent for study participation	1. Severe renal impairment, defined as serum creatinine ≥2.1 mg/dL, based on the most recent blood test within two weeks prior to first-stage registration 2. Severe hepatic impairment, defined as AST ≥201 IU/L, ALT ≥201 IU/L, total bilirubin ≥2.0 mg/dL, or albumin <2.0 g/dL, based on the most recent blood test within two weeks prior to first-stage registration 3. Contraindications listed in the Midazolam Interview Form, including a history of hypersensitivity, acute angle-closure glaucoma, and myasthenia gravis 4. Patients requiring treatment with strong CYP3A4 inhibitors at the time of first-stage registration due to infectious diseases or active hepatitis B or hepatitis C infection 5. Pregnant or breastfeeding women, or women who may become pregnant and do not intend to use contraception during the study period 6. Any other condition that, in the judgment of the attending physician, renders the patient unsuitable for trial participation
Eligibility criteria for second-stage registration	Exclusion criteria for second-stage registration
1. Patients experiencing dyspnea at rest at the time of second-stage registration, with a clinician-rated IPOS score of 2 or higher (recall period: “now”) 2. Patients whose dyspnea persists after at least six hours of continuous morphine infusion and who meet one of the following dose conditions: a. Patients not receiving scheduled strong opioids prior to initiation of continuous infusion and receiving continuous morphine infusion ≥12 mg/day b. Patients receiving scheduled strong opioids prior to initiation of continuous infusion for dyspnea and receiving a continuous morphine infusion dose that has been increased by at least 20% from the initial dose 3. Patients not receiving continuous infusion of benzodiazepines 4. Patients who provided written informed consent for study participation at the time of first-stage registration	1. Patients undergoing treatment for dyspnea clearly caused by conditions unrelated to cancer 2. Patients scheduled to undergo interventions that may alter symptom severity within 24 hours of second-stage registration (e.g., thoracic drainage or current/planned use of NIPPV) 3. Patients who are completely unable to communicate, defined as a score of 3 on item 4 of the CCS 4. Patients exhibiting signs of imminent death, such as decreased responses to verbal/visual stimuli, apnea periods, respiration with mandibular movement, Cheyne–Stokes breathing, peripheral cyanosis, pulselessness of radial artery, drooping of nasolabial folds, hyperextension of neck, inability to close eyelids, grunting of vocal cords, or death rattle 5. Patients currently using strong CYP3A4 inhibitors 6. Patients in shock, in a coma, or with acute alcohol intoxication accompanied by vital sign suppression 7. Patients who have withdrawn consent for trial participation 8. Any other condition that, in the judgment of the attending physician, renders the patient unsuitable for trial participation

ALT, alanine aminotransferase; AST, aspartate aminotransferase; CCS, Communication Capacity Scale; IPOS, Integrated Palliative Care Outcome Scale; NIPPV, noninvasive positive pressure ventilation.

Recruitment strategy

Patients considered potentially eligible for the trial will be identified through routine inpatient clinical practice by investigators. Regular communication between the coordinating center and participating institutions, including investigator meetings and progress reports, will be implemented to ensure timely recruitment.

Treatment methods

As part of the protocol treatment, the existing continuous morphine infusion is escalated by one step. At the same time, continuous subcutaneous infusion of either midazolam (9 mg/day) or placebo (normal saline) is administered for 24 hours. The dose of 9 mg/day was selected based on prior clinical practice, guideline recommendations, and observational data supporting the use of low-dose midazolam (≤10 mg/day) for symptom control.^{8,11,13,15,18–20} This dose was chosen to balance potential efficacy and safety while minimizing the risk of excessive sedation that could affect outcome assessment. In addition, from the perspective of feasibility and future generalizability, a fixed dose of 9 mg/day was pragmatically selected, taking into account the practicality of administration using syringe pumps in routine clinical settings. For patients who are deemed clinically vulnerable, such as those aged 80 years or older, weighing less than 40 kg (measured or estimated), or with malnutrition, a reduced dose of 6 mg/day is permitted. The treatment schedule is outlined in Table 2.

Table 2.

Study Schedule

Assessment items	Within 14 days before first registration	First registration	Immediately before second registration	Second registration	Within 1 hour before protocol treatment initiation	Protocol treatment initiation	4 hours later	24 hours later	4 hours after discontinuation of protocol treatment	30 days after protocol treatment initiation
Patient background
Primary diagnosis	◯
Concomitant medications	◯		◯
Pathophysiology of dyspnea					◯
Registration
Patient registration		●		●
Protocol treatment
Study drug (Midazolam or saline)						◯
Increase in continuous opioid infusion						◯
Other palliative treatments besides protocol treatment
Dose of continuous opioid infusion			◯		◯		◯	◯	◯
Number of opioid rescue doses					◯		◯	◯	◯
Concomitant therapies^a					◯		◯	◯	◯
Physical findings
Laboratory data	◯
Vital signs BP, HR, RR, S_pO₂					◯		◯	◯	◯
Signs of impending death			◯ (late sign^b)		◯ (early sign^c)
Feasibility
Completion of study drug								◯
Dyspnea assessment
Dyspnea ESASr-J NRS (patient)					◯		◯	◯
Dyspnea ESASr-J NRS (clinician)					◯		◯	◯
Dyspnea IPOS (clinician)			◯		◯		◯	◯
RDOS					◯		◯	◯
PGI							◯	◯
Other symptoms
Anxiety ESASr-J NRS (patient)					◯		◯	◯
Anxiety IPOS (clinician)					◯		◯	◯
Pain IPOS (clinician)					◯		◯	◯
CCS item 4					◯		◯	◯
Modified RASS					◯		◯	◯
Concordance of desired dyspnea relief and communication level					◯		◯	◯
Achievement of treatment goals					◯		◯	◯
Adverse events
Somnolence, nausea, delirium, respiratory depression, hypotension, and so on					◯	◯
Outcome
Survival/Death							◯	◯	◯	◯

Other opioids, psychotropics, supplemental oxygen, airflow, and room temperature adjustment.

Early signs of imminent death: Palliative Performance Scale ≤20% and dysphagia of liquids.

Late signs of imminent death: Clinical signs such as decreased response to verbal or visual stimuli, apnea periods, respiration with mandibular movement, Cheyne–Stokes breathing, peripheral cyanosis, pulseless radial artery, drooping of the nasolabial folds, hyperextension of the neck, inability to close the eyelids, grunting, or death rattle.

BP, blood pressure; ESASr-J NRS, Edmonton Symptom Assessment System Revised Japanese Version—Numerical Rating Scale; HR, heart rate; PGI, Patient Global Impression; RASS, Richmond Agitation Sedation Scale; RDOS, Respiratory Distress Observation Scale; RR, respiratory rate; S_pO₂, peripheral capillary oxygen saturation.

Concomitant treatments

Concomitant treatments initiated before the start of protocol treatment, including corticosteroids, bronchodilators, anxiolytics, and respiratory rehabilitation, can be continued during the study period. Regarding oxygen therapy, the following rules are applied: For oxygen administered via a nasal cannula or mask, the delivery method and flow rate should remain unchanged for 24 hours after the initiation of protocol treatment, unless clinically required. Any modifications and their reasons must be documented in the electronic data capture (EDC) system (Viedoc Technologies AB, Uppsala, Sweden). High-flow nasal cannula oxygen therapy must not be newly initiated; if already in use, the oxygen concentration and flow rate should remain unchanged for 24 hours unless clinically necessary, with any changes documented. Noninvasive positive pressure ventilation must not be newly initiated or modified. During the 24-hour study period, the following concomitant treatments are prohibited: initiation, dose escalation, or modification of pharmacologic agents that may influence dyspnea relief (e.g., corticosteroids, bronchodilators, and benzodiazepines); initiation, dose escalation, or modification of agents potentially affecting blood pressure or respiratory rate (e.g., antihypertensives, diuretics, and benzodiazepines); initiation or modification of nonbenzodiazepine hypnotics; and initiation or modification of respiratory rehabilitation.

Criteria for discontinuation

Protocol treatment is discontinued if a protocol violation or ineligibility is identified, an adverse event (AE) occurs that makes continuation of the study drug inappropriate based on the judgment of investigators, the patient withdraws consent, the patient dies, or investigators determine that continuation of the study drug is inappropriate.

Endpoints

Outcome assessments at baseline (before initiation of protocol treatment), 4 and 24 hours after initiation, and 4 hours after discontinuation of protocol treatment will be conducted by blinded investigators.

Primary endpoint

The primary endpoint is the proportion of patients receiving the study drug 24 hours after initiation of protocol treatment. This timepoint was selected based on the following considerations: approximately 24 hours are required for plasma concentrations of midazolam to stabilize after the initiation of continuous infusion⁹; extending the observation period beyond several days increases the likelihood that outcome measures may be influenced by factors unrelated to protocol treatment, such as changes in the patient’s clinical condition^2,5; and a previous study demonstrated measurable effects by 24 hours.¹⁰

Secondary endpoints

Secondary endpoints will be used to assess treatment efficacy and safety at prespecified timepoints (Table 2), specifically at 4 and 24 hours after initiation of protocol treatment, 4 hours after discontinuation, and 30 days post-initiation. Details of the secondary endpoint items are shown in Table 3. Efficacy outcomes include dyspnea severity using the Numerical Rating Scale (NRS), IPOS, and Respiratory Distress Observation Scale (RDOS)^4,15,21–25 assessed at baseline and 4 and 24 hours after initiation. Additional efficacy outcomes include patient-reported global impression of change (PGI),²⁶communication ability assessed using item 4 of the Communication Capacity Scale (CCS),²⁷ trade-off classification based on dyspnea and communication status,^4,5,28 achievement of individualized treatment goals,²⁰ anxiety severity (NRS and IPOS), and pain severity (IPOS), and frequency of rescue parenteral morphine use will also be assessed according to the prespecified schedule outlined in Table 2. Safety outcomes include AEs and level of consciousness assessed by the modified Richmond Agitation-Sedation Scale (RASS).^29–32 Mortality and survival outcomes will also be evaluated. Given the limited prognosis of this population, 30-day outcomes are considered exploratory and are included to provide descriptive information.

Table 3.

Detailed Items of Secondary Endpoints

Secondary endpoint items

•

Severity of dyspnea assessed using NRS, clinician-rated IPOS, and RDOS.

•

Proportion of patients with dyspnea improvement, defined as ≥1-point decrease in NRS or IPOS score ≤1.

•

Patient-reported global impression of change, using the PGI scal

Efficacy of treatment:

Severity of anxiety, assessed using NRS and IPOS.

Frequency of rescue parenteral morphine doses administered for dyspnea.

Communication ability, assessed using item 4 of CCS.

Trade-off classification based on dyspnea and communication status: •

CR: IPOS = 0–1 and CCS item 4 = 0

•

PR: IPOS = 0–2 and CCS item 4 = 0–2, not meeting CR criteria

•

PD: IPOS = 3–4

•

UC: IPOS = 0–2 and CCS item 4 = 3

Achievement of individualized goals (consistent with patient-defined treatment goals).

Severity of pain, assessed using IPOS.

Feasibility of dyspnea assessment using NRS, including both patient-reported and proxy (clinician-assessment).

AEs, including somnolence, nausea, delirium, apnea, and hypotension, as well as level of consciousness assessed using the modified RASS, from the start of protocol treatment until four hours after its discontinuation.

10.

Mortality and survival outcomes were evaluated at 4 and 24 hours after the initiation of protocol treatment, 4 hours after discontinuation of protocol treatment, and at 30 days post-initiation.

AEs, adverse events; CR, complete relief; NRS, Numerical Rating Scale; PD, persistent dyspnea; PR, partial relief; UC, unable to communicate.

Safety assessments

An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product, and which does not necessarily have a causal relationship with this treatment.³³ AEs newly occurring or worsening after treatment initiation are defined as treatment-emergent adverse events (TEAEs). AEs are graded using the Japanese version of the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0²⁹ and assessed from treatment initiation until four hours after discontinuation. Prespecified safety events include death, somnolence, nausea, delirium, apnea, and hypotension.¹⁶ Other AEs are recorded if they are Grade ≥3 TEAEs, result in prolonged hospitalization, or are considered medically significant.

Sample size

Among patients who are registered and randomized, the completion rate is defined as the proportion who receive protocol treatment, escalation of the existing continuous morphine infusion by one step plus continuous subcutaneous infusion of midazolam or placebo, and continue it for 24 hours after initiation. The completion rate is to be set at 65% or higher. This estimate is based on data from a previous feasibility randomized controlled trial evaluating the effects of opioids on dyspnea.³⁴ To achieve a completion rate of 65% with a 95% confidence interval (CI) of ±20%, a total of 21 patients need to be enrolled.

Randomization

In this study, the EDC system is used for patient registration and allocation. Randomization is performed using the minimization method, with allocation factors including presence or absence of anxiety at the time of second-stage registration, severity of dyspnea (IPOS = 2 vs. IPOS ≧3), and prior use of regular strong opioids before the initiation of continuous opioid infusion for dyspnea and the participating institution. The timing of randomization is defined as the point at which the eligibility and exclusion criteria for second-stage registration are confirmed. The allocation sequence is not accessible to the investigators responsible for patient registration.

Blinding and unblinding procedures

Participants, care providers, investigators, and data analysts will remain blinded to treatment allocation throughout the study. Midazolam and placebo will be prepared in identical syringes by unblinded health care professionals to ensure an indistinguishable appearance and administration. Emergency unblinding will be permitted only when essential for ensuring participant safety, such as in the event of a serious AE or when knowledge of the allocated treatment is required for AE management. The decision for unblinding will be made by the coordinating investigator, in consultation with the Independent Data Monitoring Committee (IDMC) if necessary. The coordinating investigator will confirm the necessity of unblinding with the investigators before a decision is made. Final unblinding will occur after completion of all EDC entries and database lock, and will be conducted by the allocation manager.

Data collection and management

Study data will be collected at each site and entered into the EDC system. The data center will oversee data management, including quality control and central monitoring, and prepare regular reports for the principal investigator, site investigators, and IDMC. Outcome assessments will be conducted by trained investigators or clinical staff at each participating site. To ensure the quality and consistency of data collection, orientation and detailed training on the use of patient-reported and proxy measures have been provided to investigators at all participating sites, both on-site and via online sessions.

Confidentiality

Participants will be identified only by study-specific IDs. The correspondence table linking identities to study IDs will remain securely stored at each site, accessible only to the investigators, and will not be transferred to the data center. All study-related information will be stored securely, and electronic data will be protected within the EDC system, which has built-in security features and access controls. Data will be retained for the period required by regulations and then securely destroyed.

Statistical analysis

To assess feasibility, 95% CIs for the completion rate will be calculated using Wilson’s score method. Continuous variables, including dyspnea NRS at rest (patient-reported and clinician-rated), IPOS, RDOS, anxiety NRS (patient-reported), anxiety IPOS, and pain IPOS, will be analyzed at each time point, and changes from baseline will also be examined. Between-group comparisons will be performed using two-sided two-sample t-tests. Point estimates and 95% CIs for the mean difference between the two groups will be calculated. For binary outcomes, between-group comparisons will be conducted using chi-square tests. The following proportions will be compared: proportion of patients with ≥1-point improvement in dyspnea NRS (patient-reported and clinician-rated) and anxiety NRS (patient-reported) from the baseline at each timepoint^16,35,36; proportion of patients with IPOS scores of ≤1 for dyspnea, anxiety, and pain at each timepoint^4,23,28; and proportion of PGI for dyspnea rated as “slightly improved,” “improved,” or “very much improved” compared with the baseline.²⁶ Differences in proportions and their 95% CIs will also be calculated. All statistical tests will be two-sided, and p-values <0.05 will be considered significant. For safety evaluation, the frequency and incidence of AEs for each group will be calculated. A full statistical analysis plan will be written prior to data evaluation. No imputation of missing data will be performed; analyses will be based on observed cases only. For variables requiring two timepoints, only participants with both values available will be included. If necessary, supplementary analyses may be conducted, and the details of such sensitivity analyses will be prespecified in the statistical analysis plan. All analyses will be performed using SAS version 9.4 (SAS Institute, Cary, NC).

Trial Management

This trial is coordinated by Seirei Mikatahara General Hospital, with operational and data management support from the Japan Organization for Research and Treatment of Cancer (JORTC). The JORTC Data Center conducts data management, central monitoring, and statistical analyses. IDMC will oversee safety and trial conduct.

Central monitoring

Central monitoring will be performed via the EDC system to evaluate study progress, patient safety, and protocol adherence. On-site monitoring will be conducted only if deemed necessary.

Protocol amendments

Marked protocol amendments will be approved by the Clinical Research Review Board (CRB) and relevant ethics committees in accordance with the Japanese Clinical Trials Act and updated in Japan Registry of Clinical Trials (jRCT).¹⁶

Ancillary and post-trial care

Participants will receive all necessary medical care during the trial. In the event of a trial-related AE, appropriate medical treatment will be provided. Financial compensation will be offered only when there is a reasonable possibility of a causal relationship with trial participation, in accordance with the trial insurance policy. After completion of the 24-hour protocol treatment, the study drug is discontinued, while opioid infusion is continued and may be adjusted as clinically indicated. If dyspnea does not improve or worsens and the patient wishes, initiation of continuous subcutaneous midazolam is permitted as part of routine clinical care.

Dissemination policy

Results will be published in peer-reviewed journals and presented at scientific meetings in accordance with the International Committee of Medical Journal Editors authorship criteria.

Patient and public involvement

The study design was assessed based on feedback from patient advocacy groups, bereaved family members, and the general public through three face-to-face or online meetings. Their input on patient-centered outcomes, feasibility, and clarity of informed consent contributed to finalizing the protocol and patient information materials.

Discussion

This multicenter, double-blind, placebo-controlled feasibility randomized trial is designed to evaluate the feasibility and explore the preliminary efficacy and safety of continuous midazolam infusion as a second-line treatment for persistent dyspnea despite continuous morphine infusion in hospitalized patients with advanced cancer. Although opioids are recommended as a first-line pharmacologic treatment for dyspnea,^6–8 a substantial proportion of patients experience inadequate symptom relief,^4,5 and there is currently no internationally established second-line pharmacologic treatment for persistent dyspnea despite opioid administration.

A key strength of this study is its clinically relevant and methodologically rigorous design. In real-world palliative care practice, clinicians often consider adding low-dose midazolam when dyspnea persists despite opioid titration, or when further opioid escalation is limited by intolerable adverse effects.^11,13,15 This trial directly evaluates this widely used but insufficiently validated approach under rigorous conditions, including blinded allocation and placebo control. The protocol also incorporates several features to enhance feasibility and data completeness across the study population, including patients in the terminal phase. The two-stage registration and consent process is intended to respect patient autonomy by allowing informed consent to be obtained during a relatively stable period, with reconfirmation at the time of randomization. In addition, the protocol includes both patient-reported outcomes and proxy/observer assessments (e.g., NRS, IPOS, and RDOS), which may mitigate missing data due to declining communication ability.^4,15,21–25

Several limitations should be acknowledged. First, the study population is restricted to hospitalized patients with advanced cancer receiving continuous morphine infusion for dyspnea, which may limit generalizability to other settings or noncancer populations. Second, attrition due to rapid deterioration or death is expected and may influence feasibility outcomes and data availability.³⁷ Third, although the trial is double-blinded, the sedative effects of midazolam could potentially compromise blinding in some cases. Last, given that this is a feasibility trial, the sample size is not powered for definitive efficacy evaluation; therefore, efficacy-related findings should be interpreted as exploratory.

Despite these challenges, this feasibility trial is expected to provide important clinical and methodological insights regarding second-line pharmacologic treatment for persistent dyspnea despite opioid infusion. If the protocol is feasible and signals potential benefit without unacceptable AEs, the results will help with the design of future confirmatory trials and contribute to establishing evidence-based therapeutic options for cancer patients experiencing dyspnea.

Authors’ Contributions

S.M.: Lead author of the study protocol. M.M.: Principal investigator. All authors participated in the design of the study. S.O. and T.Y. designed the statistical analysis plan. All authors contributed to writing and revising the article critically, and all gave their approval for the final version to be published.

Footnotes

Acknowledgments

The authors thank Dr. Yasushi Goto, Dr. Teruhisa Azuma, Dr. Hiroto Ishiki, and Dr. Ayano Takeuchi for their contributions as members of IDMC, and Mr. Kota Kihara, Director of JORTC. As part of patient and public involvement, they are particularly grateful to patient advocacy groups, bereaved family members, and members of the general public for providing valuable advice and perspectives that informed the design of this study. The authors also acknowledge all those who contributed to this study, as follows: Naosuke Yokomichi, MD, PhD (Department of Palliative and Supportive Care, Seirei Mikatahara General Hospital); Kengo Imai, MD (Seirei Hospice, Seirei Mikatahara General Hospital); Toshihiro Yamauchi, MD (Seirei Hospice, Seirei Mikatahara General Hospital); Hideo Yamakawa, MD (Seirei Hospice, Seirei Mikatahara General Hospital); Naoya Ejiri, MD (Seirei Hospice, Seirei Mikatahara General Hospital); Yui Yamamura, MD (Seirei Hospice, Seirei Mikatahara General Hospital); Akemi Miyagi, BPharm (Department of Pharmacy, Seirei Mikatahara General Hospital); Yoshiaki Takashina, PhD (Department of Pharmacy, Seirei Mikatahara General Hospital); Masato Ishizuka, MPharm (Department of Pharmacy, Seirei Mikatahara General Hospital); Keisuke Kurihara, MPharm (Department of Pharmacy, Seirei Mikatahara General Hospital); Yumi Sakuma, MSN, CNS (Department of Nursing, Seirei Mikatahara General Hospital); Kanoko Hori, RN (Department of Nursing, Seirei Mikatahara General Hospital); Kaori Fukuta, RN (Department of Nursing, Seirei Mikatahara General Hospital); Emi Kiyohara, RN (Department of Nursing, Seirei Mikatahara General Hospital); Akihiro Tokoro, MD (Department of Psychosomatic Internal Medicine and Supportive and Palliative Care Team, NHO Kinki Chuo Chest Medical Center); Hitoshi Sumitani, MD (Department of Respiratory Medicine, NHO Kinki Chuo Chest Medical Center); Toshiya Maekura, MD (Department of Palliative Medicine, National Hospital Organization Osaka National Hospital); Daisuke Yamashita, MPharm (Department of Pharmacy, National Hospital Organization Osaka National Hospital); Keiji Muratsu, MPharm (Department of Pharmacy, National Hospital Organization Osaka National Hospital); Hidetoshi Hasegawa, MPharm (Department of Pharmacy, National Hospital Organization Osaka National Hospital); Maho Matsumoto, MPharm (Department of Pharmacy, National Hospital Organization Osaka National Hospital); Michiko Jotaki, MPharm (Department of Pharmacy, Daini Kyoritsu Hospital); Yoshiko Nishioka, MMS (Department of Pharmacy, Wakayama Medical University Hospital, Wakayama); and Akiko Uchigaki, MSN (Department of Nursing, Wakayama Medical University Hospital, Wakayama).

Disclaimer

The funders had no role in the study design and will have no role in data collection, analysis, or dissemination of study results.

Ethical Approval and Informed Consent Statement

The study protocol was approved by the CRB of Hamamatsu University School of Medicine and registered with the jRCT under the identifier jRCTs041230106; trial information was made publicly available on November 17, 2023. Written informed consent was obtained from all participants before enrollment.

Data Availability Statement

Any data relevant to this study will be made available upon reasonable request to the principal investigator after publication of the primary results.

Author Disclosure Statement

M.M. received lecture fees from Kyowa Kirin Co., Ltd., Daiichi Sankyo Co., Ltd, Hisamitsu Pharmaceutical Co., Inc., and Shionogi & Co., Ltd. T.Y. received grants and consulting fees from Daiichi Sankyo Co., Ltd. K.S. received lecture fees from Daiichi Sankyo Co., Ltd., Mundipharma K.K., Chugai Pharmaceutical Co., Ltd., and Mochida Pharmaceutical Co., Ltd. S.A. received consulting fees from Shionogi & Co., Ltd., Daiichi Sankyo Co., Ltd, and Hisamitsu Pharmaceutical Co., Inc. Y.M. received lecture fees from Hisamitsu Pharmaceutical Co., Inc., Takeda Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Shionogi & Co., Ltd., Teikoku Seiyaku Co., Ltd., Kyowa Kirin Co., Ltd., and Terumo Corporation. H.I. received grants from Eisai Co., Ltd., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., AstraZeneca plc, MSD K.K., Ono Pharmaceutical Co., Ltd., and Nipro; consulting fees from Mitsubishi Tanabe Pharma Corporation, AstraZeneca K.K., and Asahi Kasei Pharma Corporation; and lecture fees from Eisai Co., Ltd., Chugai Pharmaceutical Co., Ltd., Pfizer Inc., Kyowa Kirin Co., Ltd., Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co., Ltd., AstraZeneca K.K., MSD K.K., and Eli Lilly Japan K.K. T.Y. received lecture fees from Shionogi & Co., Ltd., Daiichi Sankyo Co., Ltd., Hisamitsu Pharmaceutical Co., Inc., and Fujimoto Pharmaceutical Corporation. The other authors declare no conflicts of interest.

Funding Information

This study is being supported by the Japanese Society for the Promotion of Science KAKENHI (JP 21K18288, JP 21H02829, and JP20K20618).

Abbreviations used

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