ac 5 (p<0.001). In Kodiac 4, placebo, 12.5 mg and 25 mg dose had median time to first post dose SBM of 43.4, 20.6, and 5.4 hours, respectively. In Kodiac 5 the corresponding times to first post dose SBM were 38.2, 12.8, and 18.1 hours, respectively.
Mean number of days per week with at least one SBM
There was an increase in the mean number of days per week with at least one SBM in the LIR subgroup for the 25 mg dose in Kodiak 4 and Kodiac 5 (p<0.001 in both studies) and also for the 12.5 mg dose (p=0.006 in both studies).
OIC symptom improvement
The 25 mg dose in the LIR subgroup improved rectal straining (Kodiac 4 p=0.043, Kodiac 5 p<0.001). Stool consistency in the LIR subgroup as measured by the Bristol stool scale improved in Kodiac 5 versus placebo (p<0.001) but not in Kodiac 4 (p=0.156). The 25 mg dose in the LIR subgroup increased mean days per week compared with placebo with at least 1 complete spontaneous bowel movement (CSBM) in both studies (Kodiac 4 p=0.002, Kodiac 5 p<0.001).
Symptom responder end-point
A “symptom responder” was defined as meeting both the 12-week responder criteria and demonstrating improvement in pre-specified OIC symptoms and no deterioration in symptoms. In the LIR subgroup, the 25 mg dose increased the symptom responder rates in both studies as compared to placebo (Kodiac 4 p=0.001, Kodiac 5 p=0.005). The LIR subgroup symptom responder rates in Kodiac 4 for placebo, 12.5 mg and 25 mg arms were 24.6%, 36.5% and 45.3% and the symptom responder rates in Kodiac 5 were 25.6%, 33.6% and 42.7%.
Patient assessment of constipation symptoms (PAC-SYM) questionnaire
Naloxegol 25 mg dose in the LIR subgroup resulted in a greater improvement (change from baseline) of patient assessment of constipation symptoms (PAC-SYM) total scores compared with placebo in both studies at 12 weeks (Kodiac 4 p=0.023, Kodiac 5 p=0.002). The 12.5 mg dose in the LIR subgroup also resulted in greater improvement in total PAC SYM at week 12 compared with placebo in both studies (p= 0.020 and p=0.001 respectively). Naloxegol 25 mg dose, compared with placebo, also resulted in greater improvement (change from baseline) of week 12 PAC-SYM rectal domain scores in both studies (p=0.004 and p<0.001, Kodiac 4 and 5, respectively) and for the stool domain scores in Kodiac 4 (p=0.031) and Kodiac 5 (p<0.001). There was no relevant impact on abdominal symptoms in either study (p=0.256 and p=0.916, Kodiac 4 and 5, respectively).
Potential for interference with opioid-mediated analgesia
There were no clinically relevant differences between naloxegol 12.5 mg, 25 mg, and placebo in average pain intensity, daily opioid dose or in opioid withdrawal scores over the 12-week study.
In the 12-week studies (Kodiac 4 and 5), the frequency of back pain AEs was 4.3% for naloxegol 25 mg versus 2.0% for placebo, and the frequency of extremity pain AEs was 2.2% for naloxegol 25 mg, versus 0.7% for placebo. In a long-term safety study (Kodiac 8), the frequency of AE reports of back pain was 8.9% for naloxegol 25 mg versus 8.8% for usual care. For extremity pain, the rate for naloxegol 25 mg was 3.5% versus 3.3% for usual care.
Safety and tolerability over an extended 12-week period
Kodiac 7 was a 12-week safety extension that allowed for patients from Kodiac 4 to continue the same blinded treatment from Kodiac 4 for an additional 12 weeks (placebo, naloxegol 12.5 mg or 25 mg daily). The primary objective was to compare safety and tolerability among the three treatment groups for an additi |
