Naloxegol US PMR CV Safety.

The primary objective is to assess the overall risk of major adverse cardiovascular events
(MACE) among naloxegol-treated patients compared to that among patients on prescription
non-peripherally acting mu-opioid antagonist (PAMORA) opioid induced constipation (OIC)
treatment. The corresponding analysis is of a new-user cohort study that captures the
occurrence of MACE in persons receiving naloxegol or comparison medications. The study takes
place in actual-use settings in the US in which existing electronic data captures patient
diagnoses, health care, and treatment. The occurrence of MACE in naloxegol-treated patients
will be compared to the occurrence of MACE in medically-similar new users of other
prescription-only treatments for OIC in the same settings, with both naloxegol-treated and
comparison medication-treated patients being followed for as long as they continue on
therapy.

In further pursuit of the primary objective, there will be a self-controlled study that
follows all members of the new-user cohorts, including both new naloxegol users and new users
of comparator products, for as long as data are available as the patients may go on or off
treatment. A self-controlled study offers a complementary approach to the statistical control
for the possible confounding effects of personal characteristics. Using the same data
sources, this self-controlled design follows individuals from the time they finish their
first course of treatment as new users for as long as the study continues. Patient treatment
statuses are continuously updated since the treatment choices exercised by patients and their
caregivers create extended periods of study time on and off naloxegol and possibly on and off
other therapies for OIC. Comparisons of the occurrence of MACE occur within individuals and
so are unaffected by differences between individuals, as in a crossover trial.

The first secondary objective is to assess the potential confounding effects of lifestyle
risk factors on relative risk of MACE among naloxegol-treated patients compared with that
among patients on other prescription non-PAMORA OIC treatment. The corresponding analysis is
of a case-control study nested within the primary study population. All of the MACE "cases"
will be matched to other members of the cohorts ("controls"). In cases and controls, the
outpatient medical record will be abstracted for information on lifestyle risk factors. The
case-control analysis will provide information on the presence and effect of lifestyle
confounding factors that may be identifiable only by chart review.

Further secondary analyses will investigate the relative risks analyzed under an
intent-to-treat paradigm over fixed time periods of membership in the naloxegol and
comparator cohorts, relative risks for specific components of MACE, relative risks associated
with new oral PAMORA agents other than naloxegol (non-naloxegol oral PAMORAs [NNPAMORAs])
that may come onto the US market during the course of the study, and an exploration of the
possible variations in risk associated with variations in the dose and timing of naloxegol
dispensing in the case-control study.

Inclusion Criteria:

1. Patient receives a new dispensing of naloxegol, lubiprostone/linaclotide, or an oral
NNPAMORA. A new dispensing is one that occurs with no dispensing for the same drug
having occurred in the preceding 182 days. A patient only qualifies once under this
criterion for any drug.

2. Patients 18 years of age or older at the index date

3. Continuous availability of data for at least 183 days immediately before and including
the index date

4. 90 days of opioid dispensed in the 183 days before and including the index date of
which at least 30 days of opioid dispensed at at least 30 MEQ/day in the 60 days
before and including index date

5. Current users of a dispensed opioid, meaning that the interval between index study
drug dispensing and at least 1 prior opioid dispensing is less than the days supply
associated with the opioid dispensing

Exclusion Criteria:

1. Any medical care associated with a diagnosis of cancer in the 183 days before and
including the index date; a diagnosis of cancer for this purpose is any diagnostic
code of International Classification of Diseases, 9th revision (ICD-9) in the range
140-208 "Malignant neoplasms …" or of the 10th revision (ICD-10) in the range C00-C96,
"Malignant neoplasms"

2. Dispensing of methylnaltrexone for subcutaneous injection in the 183 days before and
including the index date

3. Indication in the electronic records of the occurrence of MACE in the 183 days before
and including the index date; see Section 9.3.2 "MACE" for screening criteria