omatic congestive heart failure, or had any other overt CV disease were excluded from the clinical studies. In a thorough QT/QTc study, as defined by the ICH E14 Guideline, there were no clinically important changes in HR, RR, QT, PR or QRS intervals or T wave morphology observed. In addition, no safety and tolerability concerns were identified in this study up to the highest dose given (150 mg). According to the ICH E14 Guideline, this is considered a definitively negative thorough QT/QTc study. Patients with moderate or severe hepatic insufficiency (Child's-Pugh Class B or C) were excluded from the Phase III studies (Kodiac 4 and 5). Therefore, naloxegol has not been studied in OIC patients with moderate or severe hepatic impairment. Both studies were powered and stratified so that at least 50% of patients randomized to each treatment arm met baseline criteria to be categorized as a laxative inadequate responder (LIR).
Definition of laxative inadequate responder
To qualify as LIR, in the two weeks prior to first study visit patients had to have reported concurrent OIC symptoms of at least moderate severity while taking at least one laxative class for a minimum of four days during the pre-study period.
Efficacy in the patient population targeted in this SmPC
Response over 12 weeks in the LIR group
Efficacy and durability of effect were measured in the primary end-point as response over the 12-week treatment period to naloxegol as defined by ≥ 3 SBMs per week and a change from baseline of ≥ 1 SBM per week for at least 9 out of the 12 study weeks and 3 out of the last 4 weeks. The first of three multiplicity protected secondary endpoints was the 12-week responder rate in the LIR subgroup.
There was a statistically significant difference for the 25 mg dose versus placebo for the LIR subgroup responder rate in Kodiac 4 (p=0.002) and Kodiac 5 (p=0.014). Under multiplicity testing procedure, statistical significance for the 12.5 mg treatment group versus placebo in the LIR subgroup was observed in Kodiac 4 (p=0.028) but not in Kodiac 5 (p=0.074). In Kodiac 4, response rates in the placebo, 12.5 mg and 25 mg groups in the LIR subgroup were 28.8%, 42.6% and 48.7%, while in Kodiac 5, the corresponding response rates were 31.4, 42.4% and 46.8%. In the pooled data from Kodiac 4 and Kodiac 5, responder rates in the LIR subgroup were 30.1% for placebo, 42.5% for the 12.5 mg dose, and 47.7% for the 25 mg dose, with the relative risk (95% CI) for treatment effect versus placebo of 1.410(1.106, 1.797) and 1.584(1.253, 2.001) for the 12.5 mg and 25 mg groups, respectively.
Response over 12 weeks in patients with an inadequate response to at least two classes of laxative
Response to naloxegol over 12 weeks was tested in the sub-group of patients with inadequate response to at least two laxative classes, approximately 20% of the patients randomized. In a pooled analysis of Kodiac 4 and Kodiac 5 (90, 88 and 99 patients in the placebo, 12.5 mg and 25 mg groups respectively), higher response rates in this population was observed for the 25 mg dose group compared with placebo (p=0.040). The responder rates in this population were placebo 30.0%, 12.5 mg 44.3% and 25 mg 44.4%.
Time to first spontaneous bowel movement
The time to first SBM in the LIR subgroup after taking the first dose was shorter for the 25 mg dose as compared to placebo in Kodiac 4 (p<0.001) and Kodiac 5 (p=0.002). The 12.5 mg dose in the LIR subgroup also demonstrated shorter time to first post-dose SBM as compared to placebo in Kodiac 4 (p=0.002) and Kodi |
