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Naldemedine Improves Patient-Reported Outcomes of Opioid-Induced Constipation in Patients with Chronic Non-Cancer Pain in the COMPOSE Phase 3 Studies

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Naldemedine Improves Patient-Reported Outcomes of Opioid-Induced Constipation in Patients with Chronic Non-Cancer Pain in the COMPOSE Phase 3 Studies Journal of Pain Research Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH Naldemedine Improves Patient-Reported Outcomes of Opioid-Induced Constipation in Patients with Chronic Non-Cancer Pain in the COMPOSE Phase 3 Studies Michael Camilleri1 Objective: Opioid-induced constipation is among the most common side effects associated Martin Hale2 with opioid use in patients with chronic non-cancer pain, and it can have a significant Bart Morlion 3 negative impact on health-related quality of life (QOL). This analysis evaluated the effect Jan Tack4 of naldemedine 0.2 mg on patient-reported outcomes in three phase 3 clinical studies. Lynn Webster 5 Methods: COMPOSE-1 and COMPOSE-2 were identical randomized, double-blind, placebo- controlled, parallel-group studies of 12 weeks’ duration, allowing data to be integrated (n=1095). James Wild6 COMPOSE-3 was similar in design, but of 52 weeks’ duration (n=1241). Patients were adults 1Clinical Enteric Neuroscience with chronic non-cancer pain who had been treated with opioid analgesics for ≥3 months and Translational and Epidemiological Research (CENTER), Mayo Clinic, experiencing opioid-induced constipation. Patient-reported outcomes included Patient Rochester, MN, USA; 2Gold Coast Assessment of Constipation Symptoms (PAC-SYM; 12 questions assessed on a 5-point Likert Research, LLC, Plantation, FL, USA; scale), PAC-QOL (28 questions assessed on a 5-point Likert scale), and Subject Global 3Leuven Center for Algology and Pain Management, University Hospital Leuven, Satisfaction (measured on a 7-point Likert scale). The proportion of patients achieving a ≥1.5 University of Leuven, Leuven, Belgium; improvement in PAC-SYM and PAC-QOL was calculated. The correlation between change in 4 Translational Research Center for PAC-SYM and PAC-QOL scores and frequency of bowel movements was also explored. Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium; Results: The proportion of PAC-SYM and PAC-QOL responders was significantly higher 5PRA Health Sciences, Salt Lake City, UT, for naldemedine than for placebo at all assessed time points in COMPOSE-1/COMPOSE-2 USA; 6Upstate Clinical Research Associates, Williamsville, NY, USA (p<0.005 for both) and COMPOSE-3 (p<0.005 and p<0.0001, respectively). There was a statistically significant correlation between improvement in PAC-SYM/PAC-QOL and frequency of bowel movements at all time points (p≤0.0002). The majority of patients treated with naldemedine reported markedly or moderately improved satisfaction with con­ stipation and abdominal symptoms on the Subject Global Satisfaction questionnaire. Discussion: Naldemedine treatment was associated with a rapid and sustained clinically relevant improvement in patient-reported outcomes, indicating improvement in opioid- induced constipation-related symptoms and QOL. ClinicalTrials.gov Registration: NCT01965158, NCT01993940, NCT01965652. Keywords: gastrointestinal tract, minimal clinically important difference, mu opioid receptor, patient satisfaction, quality of life Correspondence: Michael Camilleri Clinical Enteric Neuroscience Translational and Epidemiological Plain Language Summary Research (CENTER), Mayo Clinic, 200 Opioid analgesic therapy is one treatment option for chronic moderate-to-severe cancer and First St. S.W., Charlton Building, Rm. 8-110, Rochester, MN, 55905, USA non-cancer pain in selected patients. However, treatment with opioids can result in opioid- Tel +1 507-266-2305 induced constipation, which is characterized by symptoms such as straining to pass a bowel Fax +1 507-538-5820 Email [email protected] movement, small or hard bowel movements, bloating, gas or flatulence, and abdominal pain. Journal of Pain Research 2021:14 2179–2189 2179 Received: 13 October 2020 © 2021 Camilleri et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms. Accepted: 16 June 2021 php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the Published: 16 July 2021 work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Camilleri et al Dovepress These symptoms can have a significant negative impact on an including OIC, by determining the minimal clinically individual’s quality of life. Naldemedine is approved in the important difference (MCID).7,12,13 United States, Japan, and the European Union for the treatment This analysis evaluates the effect of naldemedine on of opioid-induced constipation. This analysis determined whether PAC-SYM and PAC-QOL scores in three phase 3 clinical improvements in bowel movement frequency after treatment with studies in which naldemedine provided a significant naldemedine also improved health-related symptoms and quality improvement in the frequency of BMs over 12 weeks (in of life in non-cancer pain in 2336 patients with opioid-induced the COMPOSE-1 and COMPOSE-2 studies)14 and over 52 constipation based on an analysis of the COMPOSE-1, weeks (in COMPOSE-3).11 In COMPOSE-1 and COMPOSE-2, and COMPOSE-3 studies. The results showed COMPOSE-2, the proportion of patients who were respon­ that naldemedine treatment increased the frequency of bowel ders (defined as at least 3 spontaneous BMs [SBMs] per movements in patients with chronic non-cancer pain and, based week and an increase from baseline of at least 1 SBM per on patient questionnaires, improved health-related symptoms and week for ≥9 weeks of the 12-week treatment period and 3 quality of life. In addition, the results showed that the majority of of the last 4 weeks) was 47.6% and 52.5% with naldeme­ patients treated with naldemedine reported improved satisfaction with constipation and abdominal symptoms. dine, respectively, compared with 34.6% and 33.6%, respectively, with placebo.14 The longer-duration COMPOSE-3 study demonstrated that this improvement Introduction in OIC was sustained for 52 weeks with no apparent loss Opioid treatment can be effective for management of of efficacy.11 1 chronic non-cancer pain in select patients. However, the The objective of the current study was to determine use of opioids is associated with a number of significant whether the improvements in BM frequency after treat­ 2 adverse events, of which the most frequent is ment with naldemedine were clinically meaningful to 3 constipation. Opioid-induced constipation (OIC), charac­ patients when assessed by PAC-SYM and PAC-QOL, as terized by symptoms such as straining to pass a bowel well as by patient satisfaction with improvement in the movement (BM), small or hard BMs, bloating, gas or symptoms of OIC. flatulence, and abdominal pain,4 can have a significant negative impact on health-related quality of life (QOL).5 These symptoms can cause patients to skip or reduce Materials and Methods prescribed opioid doses, leading to inadequate pain relief Study Design and further decrements to QOL.4–6 The designs of COMPOSE-1, COMPOSE-2, and Patient-reported outcome (PRO) instruments are criti­ COMPOSE-3 have been described in detail cal for assessing the impact of disease and associated previously.11,14 All three studies were conducted in accor­ treatments on QOL; these instruments appraise the effects dance with the Declaration of Helsinki and all applicable of treatment as clinically meaningful to patients in accor­ local Good Clinical Practice guidelines and regulations. dance with regulatory requirements. In the case of patients All patients provided written informed consent. The with OIC, PRO instruments extend measurement of the Institutional Review Boards utilized in COMPOSE-1, -2, effects of treatment beyond improvements in the number and -3 are shown in Supplementary Table 1. of BMs over defined time periods. The Patient Assessment COMPOSE-1 and COMPOSE-2 were randomized, of Constipation Symptoms (PAC-SYM) and Patient double-blind, placebo-controlled, parallel-group, phase 3 Assessment of Constipation Quality of Life (PAC-QOL) studies of 12 weeks’ duration. For the purposes of this are validated PRO instruments that measure health-related analysis, data from these 2 identically designed studies symptoms and QOL related to constipation.7,8 The PAC- were integrated. Adults aged 18–80 years with chronic SYM has been validated specifically in the context of non-cancer pain who were treated with opioid analgesics OIC.9 These PRO instruments have been used in a range for ≥3 months, were experiencing OIC, and were either of studies, including clinical assessment of the peripherally not using laxatives or had agreed to discontinue laxative acting µ-opioid receptor antagonist naldemedine and the 5- use at the time of enrollment were randomized 1:1 to HT4 receptor agonist prucalopride in patients with naldemedine 0.2 mg or placebo once daily for 12 weeks. OIC.10,11 Importantly, a number of studies have estab­ Exclusion criteria included the presence of significant lished the clinical utility of these PROs in constipation, structural gastrointestinal abnormalities that might have 2180 https://doi.org/10.2147/JPR.S282738 Journal of Pain Research 2021:14 DovePress Powered by TCPDF (www.tcpdf.org) Dovepress Camilleri et al affected bowel transit, as well as other conditions or cir­ The SGS score was based on a 7-point scale, ranging cumstances not related to opioid use that might have from a score of 1 (markedly worsened) to 7 (markedly caused constipation. Patients who had no bowel movement improved). In the SGS evaluation, patients rated their for a period of 72 hours during screening and/or the treat­ degree of satisfaction with constipation and abdominal ment period could receive rescue laxatives; use of routine symptoms relative to the beginning of the study. This laxative regimens was not permitted in COMPOSE-1 and evaluation was administered at the end of the study COMPOSE-2.
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