Subcutaneous Versus Intravenous Morphine When Switching From Oral to Parenteral Route in Palliative Cancer Patients (SIM)

The SIM-study: A Randomized Controlled Trial of Subcutaneous Versus Intravenous Morphine When Switching From Oral to Parenteral Route in Palliative Cancer Patients

The investigators aim to establish whether the intravenous or the subcutaneous route of administration has clinically significant advantages when parenteral administration of morphine is started with a combination of continuous infusion and bolus doses in palliative cancer patients.

Patients admitted to a Hospital palliative medicine unit with an indication for parenteral administration of morphine will be recruited.

The patients will have two similar infusion pumps with continuous infusion and bolus function. One infusion pump will be connected to an intravenous line, the other to a subcutaneous line. One pump contains morphine, one placebo. The primary endpoint is the time from initiation of infusion with titration to the final infusion rate that provides pain control is reached.

Study Overview

• Status: Recruiting
• Conditions: Pain Cancer
• Intervention / Treatment: Drug: Morphine

Detailed Description

Intravenous administration has theoretical advantages in more predictable pharmacokinetics and shorter time to maximum effect. Subcutaneous administration is less invasive, requires less specialized personnel and equipment, and probably poses a lower risk of complications than an intravenous line. Traditionally the subcutaneous route has been the recommended first choice for parenteral administration of opioids for palliative cancer patients.

The investigators aim to establish whether the intravenous or the subcutaneous route of administration has clinically significant advantages when parenteral administration of morphine is started with a combination of continuous infusion and bolus doses in palliative cancer patients.

Patients admitted to a Hospital palliative medicine unit with an indication for parenteral administration of morphine will be recruited.

The patients will have two similar infusion pumps with continuous infusion and bolus function. One infusion pump will be connected to an intravenous line, the other to a subcutaneous line. One pump contains morphine, one placebo. The primary endpoint is the time from initiation of infusion with titration to the final infusion rate that provides pain control is reached. Secondary endpoints are time from bolus administration to pain relief, comparison of Tmax, Cmax, and size of AUC0-60 after bolus doses, the number of bolus doses first 24 and 48 hours, and the number of patients reaching acceptable pain relief within 48 hours.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Olav Fredheim, MD PhD; Phone Number: +47 46808581; Email: olav.m.fredheim@ntnu.no
• Study Contact Backup: Name: Eva Gravdahl, MD; Phone Number: +47 40204004; Email: eva.gravdahl@ahus.no

Study Locations

• Norway
  • Lørenskog, Norway, 1478
    • Recruiting
    • Akershus University Hospital
    • Contact: Olav Fredheim, MD PHD; Phone Number: +4746808581; Email: olav.m.fredheim@ntnu.no
    • Contact: Eva Gravdahl, MD; Phone Number: +4740204004; Email: eva.gravdahl@ahus.no

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Unsatisfactory pain control despite titration of oral or transdermal opioids
• Planned discharge to home or nursing home

Exclusion Criteria:

• Estimated survival time <2 weeks
• A clear indication for either intravenous or subcutaneous administration
• Patient unable to report patient reported outcomes needed in the study due to language barriers or cognitive impairment
• Impossible to establish venous access

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intravenous morphine infusion; Morphine 10 mg/ml or morphine 20 mg/ml will be diluted with normal saline to 5 mg/ml or 10 mg/ml. Both active study medication and placebo will be prepared in 100 ml drug containers suitable for the infusion pump. The patient will have two similar infusion pumps. Morphine infusion connected to an i.v. line, placebo (normal saline) connected to a s.c line. Bolus dose will initially be equal to dose/hour. The nurse will administer bolus doses on both pumps (placebo and morphine pump) simultaneously. Patient reported pain intensity (NRS 0-10) and whether the bolus dose was initiated by the patient or the nurse will be recorded before each bolus dose. Bolus dose will be equally increased if/when the infusion rate is increased. If the bolus dose is ineffective, the bolus dose can be increased in steps of 0.1 ml until an effective dose is reached.	Drug: Morphine; Intravenous morphine infusion compared to subcutaneous morphine infusion; Other Names: Morphine hydrochloride trihydrate
Active Comparator: Subcutaneous morphine infusion; Morphine 10mg/ml or morphine 20 mg/ml will be diluted with normal saline to 5 mg/ml or 10 mg/ml. Both active study medication and placebo will be prepared in 100 ml drug containers suitable for the infusion pump. The patient will have two similar infusion pumps. Morphine infusion connected to a s.c. line, placebo (normal saline) connected to a i.v. line. Bolus dose will initially be equal to dose/hour. The nurse will administer bolus doses on both pumps (placebo and morphine pump) simultaneously. Patient reported pain intensity (NRS 0-10) and whether the bolus dose was initiated by the patient or the nurse will be recorded before each bolus dose. Bolus dose will be equally increased if/when the infusion rate is increased. If the bolus dose is ineffective, the bolus dose can be increased in steps of 0.1 ml until an effective dose is reached.	Drug: Morphine; Intravenous morphine infusion compared to subcutaneous morphine infusion; Other Names: Morphine hydrochloride trihydrate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time from initiation of i.v./s.c. morphine to stable infusion rate is reached	Time from initiation of i.v./s.c. morphine to stable infusion rate is reached	48 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients not reaching adequate pain relief.	Number of patients in each arm not reaching adequate pain relief within 48 hours.	48 hours
Number of bolus doses first 24 hours and 48 hours	Total number of bolus doses first 24 hours and 48 hours	24 and 48 hours
Time from bolus administration to clinically significant pain relief	Time from bolus administration to a reduction of minimum 2 on a 0-10 numeric rating scale.	60 minutes
Time to maximum plasma concentration (Tmax).	Time to maximum plasma concentration (Tmax) after bolus dose of morphine.	120 minutes
Maximum plasma concentration (Cmax).	Maximum plasma concentration (Cmax) after bolus dose of morphine	120 minutes
Area under the plasma concentration versus time curve (AUC).	Area under the plasma concentration versus time curve (AUC) after bolus administration of morphine.	120 minutes

Collaborators and Investigators

• Sponsor: University Hospital, Akershus
• Investigators: Principal Investigator: Olav Fredheim, MD PhD, University Hospital, Akershus

Study record dates

Study Major Dates

• Study Start (Actual): March 8, 2022
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): January 1, 2025

Study Registration Dates

• First Submitted: January 26, 2022
• First Submitted That Met QC Criteria: February 10, 2022
• First Posted (Actual): February 11, 2022

Study Record Updates

• Last Update Posted (Actual): December 26, 2023
• Last Update Submitted That Met QC Criteria: December 19, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Morphine
• Other Study ID Numbers: 2021/291056(REK)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No