Randomized, placebo-controlled trial of efficacy of midazolam for breathlessness

JRCT ID: jRCTs041230106

Registered date:17/11/2023

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: Cancer
• Date of first enrollment: 13/02/2024
• Target sample size: 21
• Study type: Interventional
• Intervention(s): To increase the dose of continuous morphine infusion in one step, midazolam continuous subcutaneous infusion of 9 mg/day (6 mg/day is acceptable for patients who are considered vulnerable based on advanced age (over 80 years), underweight (measured or estimated 40 kg or less), undernutrition, etc.) or placebo for 24 hours.

Outcome(s)

• Primary Outcome: Percentage of patients receiving the study drug 24 hours after initiation of the protocol treatment (completion rate, feasibility)

Secondary Outcome

The following items 4 hours and 24 hours after the start of the protocol treatment.
1) Efficacy: Intensity of dyspnea (Numerical Rating Scale (NRS), Integrated Palliative care Outcome Scale (IPOS), Respiratory Distress Observation Scale (RDOS)), rate of improvement of dyspnea (NRS decreased by 1 or more, IPOS</=1), subjective assessment of efficacy (Patient Global Impression (PGI))
2) Intensity of anxiety (NRS, IPOS)
3) Number of rescue injections of morphine for dyspnea
4) Communication Capacity Scale (CCS), item 4
5) Trade-off scale based on intensity of dyspnea and communication (Complete relief (CR) if dyspnea IPOS = 0-1 and CCS item 4 = 0, Partial relief (PR) if IPOS 0-2, CCS item 4=0-2 and other than CR, Persistent dyspnea (PD) if IPOS = 3-4, and Unable to communicate (UC) if IPOS 0-2 and CCS item 4 = 3), matching the patient's goal (Individualized goal achievement)
6) Intensity of pain (IPOS)
7) Proportion of dyspnea that can be evaluated by NRS including patient-reported and medical-reported evaluations
8) Adverse events (somnolence, nausea, delirium, apnea, hypotension, etc.), consciousness level (modified Richmond Agitation-Sedation Scale (RASS)) (from the start of protocol treatment to 4 hours after discontinuation of the protocol treatment)
9) Outcomes 4 hours and 24 hours after starting the protocol treatment, 4 hours after stopping the protocol treatment, and 30 days after starting the protocol treatment

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

First Registration Eligibility Criteria
(It can be at any time from the admission to the second registration.) Specifically, the main triggers are when hospitalization, when dyspnea begins to occur, and when continuous morphine injection is started.)
1) Patients who have histologically, cytologically, or clinically advanced cancer (locally advanced or metastatic)
2) Patients who are 18 years of age or older at the time of obtaining consent
3) Patients who have not received continuous benzodiazepine infusion (regular administration of benzodiazepines and non-benzodiazepine hypnotic other than continuous infusion is acceptable)
4) Patients who have not received anti-cancer treatment (i.e., patients who have not received anti-cancer treatment in the last 2 weeks and patients who have not planned to receive anti-cancer treatment in the future)
5) Patients who are judged by the attending physician to be able to survive for more than 3 days from the time of primary enrollment
6) Patients who are not scheduled to be transferred or discharged within 3 days
7) Patients who do not have cognitive impairment and have obtained written consent to participate in this study
*In addition to the above, regarding patients outside of a palliative care unit, approval shoud be obtained from the patient's attending physician (a doctor who is mainly responsible for hospitalization, such as the doctor in charge of the primary medicine department). Prior to the start of the study, we will explain the study to clinical departments that request cooperation in the study registration.

Secondary Registration Eligibility Criteria
1) Patients who meet the eligibility criteria for the first registration and have resting dyspnea at the time of secondary registration (dyspnea at the time of the registration is >/=2 on IPOS based on medical personnel evaluation (recall period is "now"))
2) Patients with persistent dyspnea for resting dyspnea after 6 hours after initiation of continuous morphine injection:
- Patients who have not regularly used strong opioids are receiving at least 12 mg/day of continuous morphine infusion after initiation of continuous morphine injection for dyspnea
- Patients who regularly used strong opioids were given continuous morphine infusion for dyspnea and then at least 20% more than the amount at the beginning of continuous morphine infusion
3) Patients who have not received continuous benzodiazepine infusion (regular administration of benzodiazepines and non-benzodiazepine hypnotic other than continuous infusion is acceptable).
4) Patients who have obtained written consent to participate in this study (consent at the time of the first registration)

Exclude criteria

First Registration Exclusion Criteria
1) Severe renal dysfunction (serum creatinine >/= 2.1 mg/dL on the most recent blood test within 2 weeks prior to enrollment)
2) Severe hepatic dysfunction (AST>/=201 IU/L, ALT>/=201 IU/L, total bilirubin >/=2 mg/dL, or albumin<2 g/dL) on the most recent blood test within 2 weeks prior to enrollment
3) Patients with a history of hypersensitivity to midazolam
4) Patients with acute angle-closure glaucoma
5) Patients with myasthenia gravis
6) Patients with infectious diseases or other conditions that require the use of the following drugs*, which are strong inhibitors of CYP3A4, or who are infected with active hepatitis B virus (HBV) and hepatitis C virus (HCV) at the time of enrollment.
*HIV protease inhibitors (drugs containing ritonavir, saquinavir, indinavir, nelfinavir, atazanavir, fosamprenavir, darunavir), efovirenz, drugs containing cobicistat, ombitasvir, paritaprevir, ritonavir, azole antifungal agents (itraconazole, voriconazole), clarithromycin.
7) Pregnant women, nursing women, patients who may become pregnant and do not intend to use contraception during the study period
8) In addition, patients who have been judged by their attending physician to be inappropriate for participation in this study

Secondary Registration Exclusion Criteria
1) When therapeutic intervention is performed for dyspnea due to a condition that is clearly not directly related to cancer
2) Patients who are scheduled to receive an intervention that may cause a change in symptom intensity in a short period of time within 24 hours of enrollment (e.g., patients scheduled for chest drainage, patients who are using or plan to use non-invasive positive pressure ventilation)
3) Patients who cannot communicate at all (CCS, item 4=3)
4) Patients with signs of late death (no response to verbal stimuli, no response to visual stimuli, apnea for more than 10 seconds, mandibular breathing, Cheyne-Stokes breathing, cyanosis of the extremities, loss of radial artery pulse, drooping of nasolabial fold, neck hyperextension, inability to close the eyelids, groaning, death rattle, etc.)
5) Patients using the following drugs, which are strong inhibitors of CYP3A4: HIV protease inhibitors (drugs containing ritonavir, saquinavir, indinavir, nelfinavir, atazanavir, fosamprenavir, darunavir), efovirenz, drugs containing cobicistat, ombitasvir, palitaprevir, ritonavir, azole antifungal agents (itraconazole, voriconazole), clarithromycin.
6) Patients with shock, coma, and acute alcoholism with suppression of vital signs
7) When the patient or proxy requests withdrawal from participation in this study
8) Other patients who have been judged by their attending physician to be inappropriate for participation in this study

Related Information

• Primary Sponsor: Mori Masanori
• Secondary ID(s): J-SUPPORT2201,JORTC-PAL22