Table 2.

Primary literature related to naldemedine or naloxegol for opioid-induced constipation in cancer patients.

Authors	Study Design	Medication Regimen	Inclusion Criteria	Outcomes Assessed	Results
Katakami N et al., J Clin Onc, June 2017, Japan [38]	Phase II b randomized double-blind placebo-controlled study	Naldemedine 1:1:1:1:1 assigned to either 0.1 mg, 0.2 mg, 0.4 mg, or placebo oral daily for 14 days	Adults 18 years or older with OIC and cancer, ECOG ≤ 2, on stable opioid regimen for ≥2 weeks	Primary: Change in spontaneous bowel movement frequency/week from baseline Secondary: -SBM responder rates -Change from baseline in frequency of SBM without straining -Complete SBM -Safety	-N = 227 (55–58/group) -Change in SBM frequency higher with all naldemedine doses vs. placebo (p < 0.05), as were SBM responder rates and change in complete SBM frequency -Change in SBM frequency without straining significantly improved with naldemedine 0.2 and 0.4 (but not 0.1) mg vs. placebo (at least p < 0.05).
					-Adverse events were more common with naldemedine (0.1 mg: 66.1%; 0.2 mg: 67.2%; 0.4 mg: 78.6%) than placebo (51.8%) -Most common adverse event: diarrhea
Katakami N et al., J Clin Onc, December 2017, Japan [39]	COMPOSE-4: randomized Phase III placebo-controlled double-blind study COMPOSE-5: open-label extension study	COMPOSE-4: 1:1 random assignment to Naldemedine 0.2 mg vs. placebo daily for 14 days COMPOSE-5: open-label 12-week extension	Adults 20 years or older with OIC and cancer, ECOG ≤ 2, on stable opioid regimen for ≥2 weeks	COMPOSE-4 Primary endpoint: Proportion of SBM responders (≥3 SBMs/week and increase ≥1 SBM/week from baseline) COMPOSE-5 primary end point: safety.	COMPOSE-4: N = 193 (97 naldemedine, 96 placebo); COMPOSE-5: N = 131 -Proportion of SBM responders naldemedine vs. placebo (71.1% [69 of 97 patients] vs 34.4% [33 of 96 patients]; p < 0.0001). -Greater change from baseline with naldemedine than with placebo in frequency of SBMs/week (5.16 v 1.54; p < 0.0001), SBMs with complete bowel evacuation/week (2.76 v 0.71; p < 0.0001), and SBMs without straining/week (3.85 v 1.17; p = 0.0005).
					-Treatment-emergent AEs: higher in patients treated with naldemedine than with placebo (44.3% [43 of 97 patients] v 26.0% [25 of 96 patients]; p = 0.01) -in COMPOSE-5, 105 (80.2%) of 131 of patients reported TEAEs. -Diarrhea was the most frequently reported TEAE in COMPOSE-4 (19.6% [19 of 97 patients on naldemedine] vs. 7.3% [seven of 96 patients] on placebo) and COMPOSE-5 (18.3% [24 of 131 patients] with naldemedine). -Naldemedine was not associated with opioid withdrawal and had no notable impact on opioid-mediated analgesia.
Katakami N et al., Ann Onc, 2018, Japan [40]	COMPOSE-4: randomized Phase III placebo-controlled double-blind study COMPOSE-5: open-label extension study	COMPOSE-4: 1:1 random assignment to Naldemedine 0.2 mg vs. placebo daily for 14 days COMPOSE-5: open-label 12-week extension study of Naldemedine 0.2 mg	Adults 20 years or older with OIC and cancer, ECOG ≤ 2, on stable opioid regimen for ≥2 weeks	Secondary endpoints: -proportion of complete SBM (CSBM) responders, SBM or CSBM responders by week -subjects with ≥1 SBM or CSBM within 24 h post-initial dose -Changes from baseline in frequency of SBMs or CSBMs/week assessed at weeks 1 and 2 -Time to first SBM or CSBM postinitial dose -QOL impact was evaluated by Patient Assessment of Constipation-Symptoms (PAC-SYM) and PAC-QOL questionnaires	-N = 193 for COMPOSE-4, N = 1341 for COMPOSE-5 -Improved bowel function for all secondary efficacy assessments versus placebo (all p ≤ 0.0002). -Median time to first SBM (4.7 h versus 26.6 h) and CSBM (24.0 h versus 218.5 h) post initial dose (all p < 0.0001). In COMPOSE-4, significant differences between groups were observed with the PAC-SYM stool domain (p = 0.045) and PAC-QOL dissatisfaction domain (p = 0.015). In COMPOSE-5, significant improvements from baseline were observed for overall and individual domain scores of PAC-SYM and PAC-QOL.
					-No discussion of AE/SE other than mentioning that naldemidine did not lead to any signs/symptoms of opioid withdrawal
Osaka I et al., Esmo Open 2019, Japan [41]	Subgroup analysis of pooled data from both Katakami 2017 studies	Naldemedine 0.2 mg vs. placebo	Adults 18 years or older with OIC and cancer, ECOG ≤ 2, on stable opioid regimen for ≥2 weeks	Proportions of SBM responders and patients with diarrhea. For patient subgroups with or without possible blood–brain barrier (BBB) disruptions, changes in Numerical Rating Scale (NRS) and Clinical Opioid Withdrawal Scale (COWS) scores.	-N = 307 (naldemedine: n = 155; placebo: n = 152) -73.5% SBM responders in naldemedine group versus 35.5% with placebo. -Significant increase in the proportion of SBM responders with naldemedine versus placebo (38.0% (95% CI 27.6% to 48.4%); p < 0.0001).
					-Changes from baseline in NRS and COWS scores were similar with naldemedine or placebo in patients with/without brain metastases -Higher proportions of SBM responders and patients who experienced diarrhea were observed with naldemedine versus placebo in all subgroups.
Takata K et al., Support Care Cancer 2022, Japan [42]	Non-interventional multi-center prospective post-marketing surveillance	Naldemedine 0.2 mg, for up to 12 weeks	Adult patients with opioid-induced constipation (OIC) and cancer pain	Safety & effectiveness	Effectiveness analysis set (N = 953): Improved frequency (75.0% and 83.2%) and condition of bowel movement (80.0% and 88.0%) at 2 and 12 weeks, respectively
					Safety analysis set (N = 1177), 145 ADRs occurred in 133 (11.3%) patients, diarrhea was the most frequent event (n = 107, 9.09%) but most cases of diarrhea were non-serious (98.1%). Most ADRs were non-serious (93.8%) and resolved within 2 weeks (75.9%).
Naya N, 2023, Cureus, Japan [43]	Non-interventional exploratory post hoc subgroup analysis of post-marketing surveillance, same dataset as [42]	naldemedine 0.2 mg, for up to 12 weeks	Adult patients with opioid-induced constipation (OIC) and cancer pain	Safety & effectiveness with subgroup analysis by: -age (≥75, <75 years) -ECOG performance status (PS 0–2, 3–4) -constipation severity (mild, moderate, severe) -brain metastasis (yes, no) -anticancer drug treatment (yes, no) -opioid at naldemedine initiation (fentanyl only, only strong opioids other than fentanyl, weak opioids only, other), -prior or concomitant use of laxative (only osmotic/saline laxatives, only stimulant laxatives, other, none)	-N = 1184 -Through week 2 to week 12, improvement rates in the frequency and condition of bowel movement among subgroups ranged from 63.6% to 89.7% and 67.6% to 94.9%, compared to 75.0% to 83.2% and 80.0% to 88.0% in the total population, respectively.
					Incidence of AE, including diarrhea, among subgroups ranged from 7.74% to 16.08% (diarrhea: 5.95% to 13.19%), compared to 11.30% (diarrhoea: 9.09%) in the total population.
Von Roenn JH et al., 2013, USA, published as poster only [32]	KODIAC-06, planned as a randomized, placebo-controlled, double-blind, multicenter, phase 3 trial	Naloxegol 12.5 or 25 mg	Adult cancer patients with OIC	-Efficacy	Study was closed early due to inability to enroll sufficient patients. No further details available, no response from author received by date of submission.
Bull J et al., J Pain Sym Man, 2019, USA [33]	Feasibility study, planned as 3-center randomized, placebo-controlled trial	Naloxegol 25 mg, with or without concomitant use of laxatives, (14 days of double-blind naloxegol vs. placebo followed by 14-day open-label naloxegol daily)	Adult advanced cancer patients aged ≥ 18 years, with life expectancy > 8 weeks, PPS ≥ 30, on at least 20 Morphine equivalents/d for >1 week, with OIC on laxatives	-Feasibility of a definitive trial for OIC in advanced cancer patients -Secondary outcomes: tolerability, safety, and efficacy.	Study closed early after 24 months due to inability to enroll sufficient patients: -An amount of 590 screened, 414 excluded for medical ineligibility, 140 patients/family declined, 24 other reasons ≥ only 12 patients participated. Of those, 7 became ineligible during the baseline/OIC confirmation period. Of the 5 randomized patients, 1 withdrew consent. Only 4 patients completed the study. No adverse events were reported related to the study drug.
Cobo Dols M et al., BMJ Support Palliat Care, 2020, Spain [44]	Non-interventional, 3-month follow-up observational cohortstudy	Naloxegol 12.5 or 25 mg, with or without concomitant use of laxatives	Adult cancer patients ≥ 18 years, on opioids for pain with OIC on laxatives, Karnofsky ≥ 50	-efficacy -quality of life	-N = 126 patients with mean age of 61.3 years, 6 patients withdrew (within first 30 days) -Number of days/week with complete SBMs increased significantly (p < 0.0001) from 2.4 to 4.6 on day 15, 4.7 after 1 month and 5 after 3 months. -Clinically relevant improvements (>0.5 points) in the PAC-QOL and PAC-SYM questionnaires (p < 0.0001) from 15 days of treatment. -Pain control significantly improved (p < 0.0001) during follow-up. -13.5% of patients (17/126) had some gastrointestinal AE, mostly of mild (62.5%) or moderate intensity (25%).
Lemaire A. et al., Supp Care Cancer, 2021, France [45]	Non-interventional “real life” outpatient multi-center, 4-week follow-up observational study	Naloxegol 12.5 or 25 mg, with or without concomitant use of laxatives	Adult cancer patients aged 18–70 years old with OIC on laxatives, any ECOG, on any opioid regimen	-Response rate to naloxegol at week 4 (primary criterion) -Evolution of quality of life using the Patient Assessment of Constipation Quality of Life (PAC-QOL) questionnaire -Safety	N = 124 cancer patients of which 79% had ECOG  ≤  2, metastatic stage, 80%. At inclusion, the median opioid dosage was 60 mg of oral morphine or equivalent. -At week 4, the response rate was 73.4% (95% CI [63.7–83.2%]), and 62.9% (95% CI [51.5–74.2%]) of patients had a clinically relevant change in quality of life (decrease in PAC-QOL score  ≥  0.5 point). -8% of patients had adverse events related to naloxegol (7% with gastrointestinal events; one serious diarrhea).
Davies A et. al., Cancers, 2022, 26 European countries [46]	Non-interventional, prospective “real world” singles arm open label multi-national 4-wek study	Naloxegol 12.5 or 25 mg (−50 mg), with or without concomitant use of laxatives	Adult cancer patients ≥ 18 years old who had been on opioids for at least 4 weeks and had OIC, any ECOG, on any opioid regimen. Colorectal cancer pts were excluded	-Safety,-defined as incidence of adverse events leading to study discontinuation -efficacy, -QoL	-N = 170 received at least one dose of naloxegol (=safety population) -Of 76 patients who completed both 4 weeks of treatment and 28 days of diary, 55 patients (72.4%, 95% CI 62.3–82.4%) responded to naloxegol treatment (i.e., had ≥3 SBMs/week and an increase of ≥1 SBM over baseline) -The Patient Assessment of Constipation—QoL Questionnaire total score and all its subscales improved from baseline to 4 weeks of follow up -N = 20 (11.8%, 95%CI 6.9–16.6) discontinued the study due to AE, and, of them, 12 (7.1%, 95%CI 3.2–10.9%) discontinued due to naloxegol-related AE industry-sponsored
Cobo Dols M et al., BMJ Support Palliat Care, 2023, Spain [47]	Non-interventional, 1-year prospective observational “real-world” study (continuation of Cobo 2020 study)	Naloxegol 12.5 or 25 mg, with or without concomitant laxative use	Adult cancer patients ≥ 18 years, on opioids for pain with OIC on laxatives, Karnofsky ≥ 50	Long-term efficacy, quality of life (QOL) and safety of naloxegol. Assessed by the patient assessment of constipation QOL questionnaire (PAC-QOL), the PAC symptoms (PAC-SYM), the response rate at day 15, and months 1-3-6-12, and global QOL (EuroQoL-5D-5L)	-N = 126 patients, mean age 61.5 years. 53 patients died during the study from their cancer. -PAC-SYM and PAC-QOL total score and all their dimensions improved from baseline (p < 0.0001). -At 12 months, 77.8% of patients responded to naloxegol. -Global QOL was conserved from baseline. 6 patients withdrew from the study due to AE (abdominal pain), in the first 15 days (3) or the first 30 days (3). -28 adverse reactions, mainly gastrointestinal were observed in 15.1% of patients (19/126), with 75% (21) classified as mild, 17.9% (5) as moderate and 7.1% (2) as severe; most adverse reactions (67.9%) appeared during the first 15 days of treatment.

OIC = opioid-induced constipation, SBM = spontaneous bowel movement, CBSM = complete spontaneous bowel movement, AE = adverse events, TEAE = treatment emergent adverse events, NRS = numerical rating scale, COWS = clinical opioid withdrawal scale, ECOG = Eastern Cooperative Oncology Group (assessment of functional status), PAC-SYM stool domain = patient assessment of constipation-symptoms, PAC-QOL dissatisfaction domain = patient assessment of constipation-quality of life, QoL = quality of life.