Naldemedin (1) – Rizmoic®

• Clinical trials
  • The COMPOSE 3 study is a double-blind, randomised, multicentre study comparing naldemedine with placebo over 52 weeks.
  • The KODIAC-08 trial is an open-label, randomised, multicentre trial comparing naloxegol with standard therapy over 52 weeks.

a) Adult patients with opioid-induced constipation who had previously been treated with a laxative

• For this patient population, the pharmaceutical manufacturer did not submit any study that would have been suitable for assessing the additional benefit of naldemedin compared with the appropriate comparator therapy.
• Overall, for adult patients with opioid-induced constipation who have previously been treated with a laxative, the additional benefit of naldemedin over the appropriate comparator therapy is not proven.

b) Adult patients with opioid-induced constipation for whom an over-the-counter laxative or a prescription-only medical device is no longer an option for the treatment of constipation

• In its dossier for the assessment of the additional benefit of naldemedin, the pharmaceutical manufacturer does not present any direct comparative studies against the appropriate comparator therapy, but rather an indirect comparison (naldemedin versus naloxegol via the bridge comparator ‘standard therapy’) based on the two RCTs COMPOSE 3 and KODIAC-08.
• However, the indirect comparison based on the aforementioned studies is not suitable for the present benefit assessment for the following reasons.
• The KODIAC-08 study, which was taken into account by the pharmaceutical manufacturer, is a long-term safety study that only records results for endpoints relating to adverse events. A risk-benefit comparison based on this study is therefore not possible.
• Furthermore, the study populations included in the two studies are not sufficiently similar. In the KODIAC-08 study, the study population only partially corresponds to the authorised therapeutic indication for naldemedine, as prior treatment with laxatives was not a requirement for inclusion in the study.
• Furthermore, in both studies, the proportion of patients who are no longer eligible for treatment with an additional laxative is unclear.
• Nor is the bridge comparator – standard therapy – for the indirect comparison sufficiently similar in the two studies, as in the COMPOSE 3 study, unlike in the KODIAC-08 study, no newly defined laxative therapy was used as standard therapy at the start of the study.
• Overall, an additional benefit of naldemedine is not proven for adult patients with opioid-induced constipation for whom an over-the-counter laxative or a prescription-only medical device is no longer an option for the treatment of constipation.
• Overall assessment / Conclusion
  • The pharmaceutical manufacturer has not provided any relevant data in the dossier for the assessment of the additional benefit of naldemedin compared with the appropriate comparator therapy for adult patients with opioid-induced constipation who have previously been treated with a laxative.
  • The G-BA considers the indirect comparisons presented for adult patients with opioid-induced constipation, for whom an over-the-counter laxative or a prescription-only medical device for the treatment of constipation is no longer an option, as generally unsuitable for deriving patient-relevant effects regarding the additional benefit of naldemedine.
  • The additional benefit compared with the appropriate comparator therapy is therefore, for adult patients with opioid-induced constipation – specifically, adult patients who have previously been treated with a laxative and for whom an over-the-counter laxative or a prescription-only medical device for the treatment of constipation is no longer an option – there is no proof that this is an effective treatment.

Courtesy translation only, please refer to the German original.