Prevention of Opioid-induced Constipation in Patients With Advanced Cancer

NCT05216328 | Recruiting Phase 4 DMC

• 1 other identifier: 08440012010002
• Study Type: interventional
• Target: 330
• Locations: 1 country
• Sites: 13

Brief Summary

More than 70% of patients with cancer in the palliative phase have pain that often requires treatment with opioids (morphine-like agents). Constipation occurs in 59% of patients treated with opioids. Opioid-induced constipation (OIC) has consequences that range from daily discomfort with social insecurity and disability to intestinal obstruction. It leads to limitations in self-management, a reduced quality of life and a risk of the need for more care. In the guideline "Diagnosis and treatment of pain in patients with cancer" it is recommended to start preventively with an osmotic laxative such as macrogol/electrolytes or magnesium hydroxide when starting opioids. Macrogol/electrolytes has been proven to be effective for OIC, but is sometimes perceived by patients as unpleasant due to its taste. Magnesium hydroxide, which is less commonly prescribed for OIC, has a neutral taste. Although it is mentioned in the guideline, it is not studied for the treatment of OIC and also not officially registered for this. To support the advice of the guideline and to prove that a choice is possible, it is important to investigate whether there are differences in effectiveness and/or side effects between macrogol/electrolytes and magnesium hydroxide in the prevention of OIC. The aim of this study is to compare macrogol/electrolytes with magnesium hydroxide in the prevention of opioid-induced constipation in patients with cancer in the palliative (incurable) phase, who start opioids because of pain. The choice of laxative is determined by drawing lots (randomisation). After two weeks, its effect will be assessed and will be presented as the percentage of patients who have not developed constipation after starting opioids. If the laxative, as assigned by lot, is described as satisfactory by the patient, the patient can continue with the drug that the patient used, after the study through regular prescription. The investigators will ask the patients in the study about their satisfaction with the laxative used, any side effects and the degree of pain. Furthermore, the appeal to care for possible constipation will be examined. Because the best attainable quality of life in the palliative phase is the objective of all care, the investigators will also measure this perceived quality with a questionnaire in this study. The results of this study will lead to the best achievable prevention of opioid constipation in patients with cancer in the palliative phase.

Conditions

Constipation, Opioid-Induced

Keywords

Cancer; Palliative care; Cancer pain; Opioid-Induced Constipation; macrogol/electrolytes; magnesium hydroxide

Outcome Measures

Primary Outcomes (1)

• The percentage of patients with a score of <30 of the Bowel Function Index

  A clinician-administered patient-reported questionnaire to assess clinically significant constipation, validated in patients receiving opioids for chronic non-malignant pain and for malignant pain (Abramovitz 2013, Rentz 2009 and 2011). It consists of three questions, assessing ease of defecation, feeling of incomplete bowel evacuation and personal judgement of the patient regarding constipation, each during the last 7 days and each rated on a scale of 0 (best possible outcome) to 100 (worst possible outcome). A total score ≥30 (mean of the three separate scores) indicates clinically significant constipation. A change of the total score of \>12 is regarded as clinically meaningful. It has been used in a large observational study in cancer patients receiving opioids (Davies 2021) and in randomised trials of opioid antagonists for OIC (Ahmedzai 2012, Dupoiron 2017, Leng 2020, Poelaert 2015). It has been recommended as the assessment tool of choice for OIC (Argoff 2015, Farmer 2019).

  On day 14

Secondary Outcomes (6)

• The EQ5D

  On day 0 and day 14

• Rome IV criteria for opioid-induced constipation

  On day 0 and day 14

• Cancer pain score

  On day 0 and day 14

• Patient satisfaction with laxative

  On day 14

• Side effects of laxatives

  On day 14

Study Arms (2)

Macrogol/electrolytes

ACTIVE COMPARATOR

Macrogol/electrolytes is started at a dose of 1 sachet once a day orally, based on the current guideline 'Diagnosis and treatment of pain in patients with cancer' (www.pallialine.nl). The dose of macrogol/electrolytes may be increased to 2 sachets a day during the study period. The effect of laxatives will be judged after 14 days.

Drug: Macrogol Only Product in Oral Dose Form

Magnesium hydroxide

ACTIVE COMPARATOR

Magnesium hydroxide is started at a dose of 724 mg three times a day orally, based on the current guideline 'Diagnosis and treatment of pain in patients with cancer' (www.pallialine.nl). The dose of magnesium hydroxide may be increased to 1448 mg three times a day during the study period. The effect of laxatives will be judged after 14 days.

Drug: Magnesium hydroxide 724mg

Interventions

Macrogol Only Product in Oral Dose Form DRUG

Information already included in arm/group description.

Also known as: Macrogol/electrolytes

Macrogol/electrolytes

Magnesium hydroxide 724mg DRUG

Information already included in arm/group description.

Also known as: Magnesiumoxide

Magnesium hydroxide

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• In order to be eligible to participate in this study, a subject must meet all of the following criteria:
• Patients with metastatic cancer (≥18 years);
• Starting with slow release or transdermal opioids for pain;
• Able to complete a Dutch questionnaire. Previous treatment with opioids is allowed, if discontinued more than 4 weeks ago.

You may not qualify if:

• A potential subject who meets any of the following criteria will be excluded from participation in this study:
• Patients with contra-indications for laxatives
• Use of laxatives during the last four weeks
• Severely impaired renal function (serum creatinine \>180 umol/l)
• Estimated life expectancy \<3 months

Sponsors & Collaborators

• Amsterdam UMC, location VUmc: lead
• Leiden University Medical Center: collaborator
• University Medical Center Groningen: collaborator
• Radboud University Medical Center: collaborator
• Erasmus Medical Center: collaborator
• Spaarne Gasthuis: collaborator
• Rijnstate Hospital: collaborator
• Jeroen Bosch Ziekenhuis: collaborator
• Flevoziekenhuis: collaborator
• Martini Hospital Groningen: collaborator
• Haaglanden Medical Centre: collaborator
• UMC Utrecht: collaborator
• Groene Hart Ziekenhuis: collaborator
• Bernhoven Hospital: collaborator
• Isala: collaborator
• Antoni van Leeuwenhoekziekenhuis (AVL) Amsterdam: collaborator

Study Sites (13)

Flevoziekenhuis

Almere Stad, Flevoland, 1315 RA, Netherlands

RECRUITING

Rijnstate Ziekenhuis

Arnhem, Gelderland, 6815 AD, Netherlands

RECRUITING

Radboud university Medical center Nijmegen

Nijmegen, Gelderland, 6525 GA, Netherlands

RECRUITING

Jeroen Bosch Ziekenhuis

's-Hertogenbosch, North Brabant, 5223 GZ, Netherlands

RECRUITING

Amsterdam UMC, location VUmc

Amsterdam, North Holland, 1081 HV, Netherlands

RECRUITING

Spaarne Gasthuis

Hoofddorp, North Holland, 2134 TM, Netherlands

RECRUITING

Groene Hart Hospital

Gouda, South Holland, 2803 HH, Netherlands

RECRUITING

Leiden University Medical Center

Leiden, South Holland, 2333 ZA, Netherlands

RECRUITING

Erasmus Medical Center

Rotterdam, South Holland, 3015 GD, Netherlands

RECRUITING

Haaglanden Medical Centre

The Hague, South Holland, 2512 VA, Netherlands

RECRUITING

University Medical Center Groningen

Groningen, 9713 GZ, Netherlands

RECRUITING

Martini Hospital Groningen

Groningen, 9728 NT, Netherlands

RECRUITING

University Medical Center Utrecht

Utrecht, 3584 CX, Netherlands

RECRUITING

Related Publications (28)

• Abramowitz L, Beziaud N, Causse C, Chuberre B, Allaert FA, Perrot S. Further validation of the psychometric properties of the Bowel Function Index for evaluating opioid-induced constipation (OIC). J Med Econ. 2013 Dec;16(12):1434-41. doi: 10.3111/13696998.2013.851083. Epub 2013 Oct 24.

  PMID: 24102611 BACKGROUND

• Ahmedzai SH, Nauck F, Bar-Sela G, Bosse B, Leyendecker P, Hopp M. A randomized, double-blind, active-controlled, double-dummy, parallel-group study to determine the safety and efficacy of oxycodone/naloxone prolonged-release tablets in patients with moderate/severe, chronic cancer pain. Palliat Med. 2012 Jan;26(1):50-60. doi: 10.1177/0269216311418869. Epub 2011 Sep 21.

  PMID: 21937568 BACKGROUND

• Argoff CE, Brennan MJ, Camilleri M, Davies A, Fudin J, Galluzzi KE, Gudin J, Lembo A, Stanos SP, Webster LR. Consensus Recommendations on Initiating Prescription Therapies for Opioid-Induced Constipation. Pain Med. 2015 Dec;16(12):2324-37. doi: 10.1111/pme.12937. Epub 2015 Nov 19.

  PMID: 26582720 BACKGROUND

• Bell T, Annunziata K, Leslie JB. Opioid-induced constipation negatively impacts pain management, productivity, and health-related quality of life: findings from the National Health and Wellness Survey. J Opioid Manag. 2009 May-Jun;5(3):137-44. doi: 10.5055/jom.2009.0014.

  PMID: 19662923 BACKGROUND

• Christensen HN, Olsson U, From J, Breivik H. Opioid-induced constipation, use of laxatives, and health-related quality of life. Scand J Pain. 2016 Apr;11:104-110. doi: 10.1016/j.sjpain.2015.12.007. Epub 2016 Jan 25.

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• Davies A, Leach C, Butler C, Gregory A, Henshaw S, Minton O, Shorthose K, Batsari KM. Opioid-induced constipation in patients with cancer: a "real-world," multicentre, observational study of diagnostic criteria and clinical features. Pain. 2021 Jan;162(1):309-318. doi: 10.1097/j.pain.0000000000002024.

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  PMID: 22707180 BACKGROUND

• Drossman DA. Functional Gastrointestinal Disorders: History, Pathophysiology, Clinical Features and Rome IV. Gastroenterology. 2016 Feb 19:S0016-5085(16)00223-7. doi: 10.1053/j.gastro.2016.02.032. Online ahead of print.

  PMID: 27144617 BACKGROUND

• Dunlop W, Uhl R, Khan I, Taylor A, Barton G. Quality of life benefits and cost impact of prolonged release oxycodone/naloxone versus prolonged release oxycodone in patients with moderate-to-severe non-malignant pain and opioid-induced constipation: a UK cost-utility analysis. J Med Econ. 2012;15(3):564-75. doi: 10.3111/13696998.2012.665279. Epub 2012 Feb 23.

  PMID: 22313329 BACKGROUND

• Dupoiron D, Stachowiak A, Loewenstein O, Ellery A, Kremers W, Bosse B, Hopp M. A phase III randomized controlled study on the efficacy and improved bowel function of prolonged-release (PR) oxycodone-naloxone (up to 160/80 mg daily) vs oxycodone PR. Eur J Pain. 2017 Oct;21(9):1528-1537. doi: 10.1002/ejp.1054. Epub 2017 Jun 22.

  PMID: 28641363 BACKGROUND

• Farmer AD, Drewes AM, Chiarioni G, De Giorgio R, O'Brien T, Morlion B, Tack J. Pathophysiology and management of opioid-induced constipation: European expert consensus statement. United European Gastroenterol J. 2019 Feb;7(1):7-20. doi: 10.1177/2050640618818305. Epub 2018 Dec 14.

  PMID: 30788113 BACKGROUND

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  PMID: 9505981 BACKGROUND

• Ginex PK, Hanson BJ, LeFebvre KB, Lin Y, Moriarty KA, Maloney C, Vrabel M, Morgan RL. Management of Opioid-Induced and Non-Opioid-Related Constipation in Patients With Cancer: Systematic Review and Meta-Analysis. Oncol Nurs Forum. 2020 Nov 1;47(6):E211-E224. doi: 10.1188/20.ONF.E211-E224.

  PMID: 33063777 BACKGROUND

• Hawley P, MacKenzie H, Gobbo M. PEG vs. sennosides for opioid-induced constipation in cancer care. Support Care Cancer. 2020 Apr;28(4):1775-1782. doi: 10.1007/s00520-019-04944-5. Epub 2019 Jul 18.

  PMID: 31321524 BACKGROUND

• Head SJ, Kaul S, Bogers AJ, Kappetein AP. Non-inferiority study design: lessons to be learned from cardiovascular trials. Eur Heart J. 2012 Jun;33(11):1318-24. doi: 10.1093/eurheartj/ehs099. Epub 2012 May 7.

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• Hjalte F, Ragnarson Tennvall G, Welin KO, Westerling D. Treatment of Severe Pain and Opioid-induced Constipation: An Observational Study of Quality of Life, Resource Use, and Costs in Sweden. Pain Ther. 2016 Dec;5(2):227-236. doi: 10.1007/s40122-016-0059-9. Epub 2016 Nov 9.

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• Kistemaker KRJ, de Graeff A, Crul M, de Klerk G, van de Ven PM, van der Meulen MP, van Zuylen L, Steegers MAH. Magnesium hydroxide versus macrogol/electrolytes in the prevention of opioid-induced constipation in incurable cancer patients: study protocol for an open-label, randomized controlled trial (the OMAMA study). BMC Palliat Care. 2023 Mar 14;22(1):22. doi: 10.1186/s12904-023-01143-2.

  PMID: 36915062 DERIVED

Related Links

• guidelines palliative care
• The Dutch digital palliative care platform

MeSH Terms

Conditions

Opioid-Induced Constipation; Neoplasms; Cancer Pain

Interventions

Dosage Forms; Polyethylene Glycols; Electrolytes; Magnesium Hydroxide

Condition Hierarchy (Ancestors)

Constipation; Signs and Symptoms, Digestive; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Narcotic-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders; Pain; Neurologic Manifestations

Intervention Hierarchy (Ancestors)

Pharmaceutical Preparations; Technology, Pharmaceutical; Investigative Techniques; Ethylene Glycols; Glycols; Alcohols; Organic Chemicals; Polymers; Macromolecular Substances; Biomedical and Dental Materials; Manufactured Materials; Technology, Industry, and Agriculture; Inorganic Chemicals; Hydroxides; Alkalies; Anions; Ions; Magnesium Compounds

Study Officials

• Lia van Zuylen, Prof.dr.

  Amsterdam UMC, location VUmc

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Kay Kistemaker, MSc/MD

CONTACT

+31 6 50087799; k.kistemaker@amsterdamumc.nl

Lia van Zuylen, Prof. dr.

CONTACT

+3120 4445571; c.vanzuylen@amsterdamumc.nl

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr.

Study Record Dates

• First Submitted: January 19, 2022
• First Posted: January 31, 2022
• Study Start: December 2, 2022
• Primary Completion: December 1, 2025
• Study Completion: December 1, 2025
• Last Updated: November 22, 2024

Record last verified: 2024-11

Locations

NL (13)