A phase 2, double-blind, randomized, placebo

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PAIN 154 (2013) 1542–1550
www.elsevier.com/locate/pain
A phase 2, double-blind, randomized, placebo-controlled,
dose-escalation study to evaluate the efﬁcacy, safety, and tolerability
of naloxegol in patients with opioid-induced constipation
Lynn Webster a,⇑, Sunita Dhar b,1, Michael Eldon c, Lorianne Masuoka d,1, Jaakko Lappalainen e,
Mark Sostek e
a
CRI Lifetree Research, Salt Lake City, UT, USA
Genentech Inc., San Francisco, CA, USA
c
Nektar Therapeutics, San Francisco, CA, USA
d
Oakland, CA, USA
e
AstraZeneca Pharmaceuticals, Wilmington, DE, USA
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Keywords:
Naloxegol
NKTR-118
Naloxol
Naloxone
Opioid
Constipation
Naloxegol (previously known as NKTR-118) is a peripherally acting l-opioid receptor antagonist engineered using polymer conjugate technology in development as an oral, once-daily agent for the treatment of opioid-induced constipation (OIC). Eligible patients with OIC (n = 207), deﬁned as <3
spontaneous bowel movements (SBMs) per week with accompanying symptoms, on a stable opioid regimen of 30–1000 mg/day morphine equivalents for P2 weeks were randomized to receive 4 weeks of
double-blind placebo or naloxegol (5, 25, or 50 mg) once daily in sequential cohorts after a 1-week placebo run-in. The primary end point, median change from baseline in SBMs per week after week 1 of drug
administration, was statistically signiﬁcant for the 25- and 50-mg naloxegol cohorts vs placebo (2.9 vs 1.0
[P = 0.0020] and 3.3 vs 0.5 [P = 0.0001], respectively). The increase in SBMs vs placebo was maintained
over 4 weeks for naloxegol 25 mg (3.0 vs 0.8 [P = 0.0022]) and 50 mg (3.5 vs 1.0 [P < 0.0001]). Naloxegol
was generally well tolerated across all dosages. The most frequent adverse events (AEs) were abdominal
pain, diarrhea, and nausea. Most AEs at 5 and 25 mg/day were mild and transient. Similar AEs occurred
with increased frequency and severity in the 50-mg cohort. There was no evidence of a statistically signiﬁcant increase from baseline in pain, opioid use for the 25- and 50-mg cohorts, or centrally mediated
opioid withdrawal signs and/or symptoms with naloxegol. These data demonstrate that once-daily oral
naloxegol improves the frequency of SBMs compared with placebo and is generally well tolerated in this
population of patients with OIC.
Ó 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
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Article history:
Received 21 December 2012
Received in revised form 4 April 2013
Accepted 9 April 2013
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Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
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1. Introduction
Opioids are effective analgesics for treating moderate to severe
pain, but their use is often limited by adverse effects. Gastrointestinal (GI) side effects are among the most troublesome in terms of
frequency and severity [5]. Examples include abdominal cramping,
bloating, nausea, vomiting, dyspepsia, and constipation [4,9,10].
Up to 60% of patients experience opioid-induced constipation
⇑ Corresponding author. Address: CRI Lifetree Research, 3838 South 700 East,
Suite 202, Salt Lake City, UT 84106, USA. Tel.: +1 801 892 5140; fax: +1 801 261
3341.
E-mail addresses: [email protected], [email protected]
(L. Webster).
1
These authors are former employees of Nektar Therapeutics, San Francisco, CA,
USA.
(OIC), to which patients rarely develop tolerance [9,10] and which
can lead them to reduce or abandon opioid therapy [5].
OIC is believed to result primarily from agonist stimulation of
l-opioid receptors in the enteric nervous system, leading to decreased gastric motility and emptying, diminished intestinal secretions, and decreased motility in the small and large intestine
[5,9,10]. Common treatment involves the use of laxatives (eg, stool
softeners, stimulants, osmotic agents, combination agents, and/or
bulking agents) together with nonpharmacologic strategies such
as increased dietary ﬁber, ﬂuid intake, and exercise [9]. However,
many patients do not experience adequate symptom relief, because currently available therapies do not address the underlying
pathophysiology of OIC [5,6,11].
Opioid antagonists represent a possible alternative to laxatives
for the treatment of OIC [5]. However, in the absence of properties
0304-3959/$36.00 Ó 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.pain.2013.04.024
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L. Webster et al. / PAIN 154 (2013) 1542–1550
2.1. Patients
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Men and nonpregnant, nonbreastfeeding women who were 18
years of age or older were eligible for this study. Patients must
have been receiving a stable oral opioid regimen of 30 to
1000 mg/day oral morphine equivalent doses to treat nonmalignant or cancer-related pain for at least 2 weeks before screening,
with no change in dose anticipated for the duration of the study.
Eligible patients were stratiﬁed as low opioid baseline group
(30–100 daily morphine equivalent units [MEU]) and high opioid
baseline group (>100–1000 daily MEU). Documentation of OIC, deﬁned as 65 SBMs during the 2-week run-in period (which corresponds with <3 SBMs per week), was required. Patients were
required to have self-reported OIC (<3 SBMs per week) and at least
one of the following signs and symptoms at the initial screening
visit and during the 2-week run-in period: hard/lumpy stools,
straining, or sensation of incomplete evacuation/anorectal obstruction. Patients also had to be willing to stop the use of all laxatives
and other bowel regimens throughout the 2-week run-in period
and the 5-week treatment period.
Patients with evidence of renal or hepatic disease were excluded if they had serum creatinine >2 upper limit of normal
(ULN), serum alanine transaminase or aspartate transaminase >3 ULN, serum bilirubin >2.5 ULN, or cirrhosis. Patients
with ischemic heart disease or other medical conditions that
would unduly increase risk to the patient or affect the interpretation of study data were excluded, as were patients with a life
expectancy <6 months. A history of GI hemorrhage related to GI
pathology or fecal incontinence, irritable bowel syndrome, inﬂammatory bowel disease, intestinal obstruction, or other active GI
disorder associated with diarrhea, intermittent loose stools, or
constipation prohibited study eligibility. Patients using manual
maneuvers to induce a bowel movement were not eligible for
study enrollment.
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2. Methods
SBM had not occurred in a 72-hour period since the previous bowel
movement. In addition, patients entered the following data on a
daily basis in an electronic diary: bowel movements, pain scores,
unscheduled use of opioid medications for pain, and bisacodyl rescue use (if needed). Only patients with conﬁrmed OIC and who
continued to fulﬁll all the entry criteria were randomized and entered a 1-week single-blind placebo run-in period followed by a
4-week double-blind treatment period with naloxegol or placebo.
The placebo run-in period was included to establish baseline pain
control and allow assessment of placebo effect.
The study was planned to include 4 sequential dose cohorts of
naloxegol once daily (5 mg [cohort 1], 25 mg [cohort 2], 50 mg
[cohort 3], and 100 mg [cohort 4]), with 54 patients randomized
in a 1:1 ratio of active:placebo within each cohort. Randomization
was stratiﬁed to low (30–100 MEU/day) and high (>100–1000
MEU/day) MEU daily opioid dose based on the patient’s total daily
opioid dose at baseline using an Interactive Voice Response
System. Dose escalations would occur only after a thorough analysis of aggregate safety data from the current cohort, including pain
progression, possible opioid withdrawal signs and/or symptoms,
daily opioid use, and reported adverse events.
Study medication, consisting of a 4% oral solution of naloxegol
or placebo, was prepared by the unblinded study pharmacist and
dispensed to the patient in a blinded manner via preﬁlled syringes
at the time of a patient’s clinic visit. The study medication was then
self-administered by the patient orally via 1-mL (5- and 25-mg
cohorts) or 3-mL (50-mg cohort) syringes once daily at least 1 hour
before breakfast. Total volumes of each dose of study medication
were 0.125 mL, 0.625 mL, and 1.25 mL for the 5-, 25-, and 50-mg
cohorts, respectively. Patients and all study personnel were
blinded except for the site monitor responsible for monitoring drug
accountability and the site pharmacist and/or designated staff who
prepared the study medication.
All study participants provided written informed consent before
initiation of any study procedures. The protocol, amendments, and
all study-related material were approved by an institutional review board. The study was conducted in accordance with good
clinical practice and ethical principles as described in guidelines
of the International Conference of Harmonisation, the United
States Code of Federal Regulations, and the Declaration of Helsinki.
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restricting blood–brain barrier penetration, opioid antagonists can
generate central effects leading to inadequate pain control and/or
central opioid withdrawal signs and/or symptoms [7]. Administration of selective, peripherally acting l-opioid receptor antagonists
represents a rational and targeted approach to reducing the adverse GI effects of opioid therapy without reversing the centrally
mediated analgesic effects essential for maintaining adequate pain
control [5].
Naloxegol (previously known as NKTR-118) is a polymer conjugate of the opioid antagonist naloxone in clinical development as a
once-daily oral treatment for OIC [1,12]. It was speciﬁcally designed as a peripheral opioid antagonist of l-opioid receptors outside of the central nervous system, incorporating a polyethylene
glycol moiety that limits its capacity to cross the blood–brain barrier [1–3]. This randomized, double-blind, placebo-controlled,
phase 2, dose-escalation study evaluated the efﬁcacy and safety
of 3 dose levels of oral naloxegol with regard to the frequency of
spontaneous bowel movements (SBMs) in patients with OIC.
2.2. Study design
This was an international, multicenter, randomized, doubleblind, placebo-controlled, dose-escalation phase 2 study
(NCT00600119). Following an initial 10-day screening period, eligible patients underwent an additional 2-week run-in period to conﬁrm diagnosis of OIC (Fig. 1). During this period, patients were
required to discontinue use of all laxatives and other bowel regimens. Bisacodyl was the only rescue medication allowed if an
2.3. Assessments
The primary efﬁcacy end point was change in SBMs/week from
baseline to the end of week 1 of the double-blind treatment period.
An SBM was deﬁned as a bowel movement that occurred without
the use of a rescue laxative within the previous 24 hours. Baseline
SBMs per week were determined during the 2-week run-in period.
The number and timing of bowel movements was recorded daily
using electronic diary devices.
Secondary efﬁcacy end points included change from baseline in
SBMs per week for each of weeks 2, 3, and 4 of the double-blind
treatment period; change from baseline in SBMs per week across
the 4-week double-blind treatment period; and time from ﬁrst
dose of study drug to ﬁrst laxation. Patients also completed the
Patient Assessment of Constipation-Symptom Questionnaire
(PAC-SYM), Patient Assessment of Constipation-Quality of Life
Questionnaire (PAC-QoL), and Short Form Health Survey (SF-36)
at the investigator site on day 1 of the double-blind treatment
period before the ﬁrst dose of study drug, on day 1 of week 2 of
double-blind treatment, and at the end of double-blind treatment.
The PAC-SYM includes 12 items in 3 domains: abdominal symptoms, rectal symptoms, and stool symptoms. Each item was scored
on a 5-point scale from 0 = absence of symptoms to 4 = very severe.
The PAC-QoL has 28 items that are included in 4 subscales:
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≤10 Days
Initial
Screening
14 Days
Run-In to
Confirm OIC
(<3 SBMs/wk)
7 Days
29 Days
Single-Blind
Placebo
Run-In
Double-Blind
Naloxegol
14 ± 2 Days
Follow-Up
Single-Blind
Placebo
Run-In
Double-Blind
Placebo
Randomization
Fig. 1. Study ﬂow chart. OIC, opioid-induced constipation; SBM, spontaneous bowel movement.
2.4. Statistical analyses
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A sample size of 27 patients in each treatment group of the
3 cohorts would have 80% power to detect a difference of P2.5
SBMs per week between naloxegol and placebo, assuming an SD
of 3.5 SBMs per week with a 0.10 2-sided signiﬁcance level using
a Mann-Whitney test. Efﬁcacy analyses were based on the modiﬁed intent-to-treat (MITT) population, which included all randomized patients who received at least one dose of double-blind
treatment and had evaluable data for baseline and the end of week
1 of the double-blind treatment period. The Wilcoxon rank-sum
test was used to compare treatment groups within each cohort.
A 2-sided signiﬁcance level of 5% was applied for all statistical
comparisons. The PAC-SYM, PAC-QoL, and SF-36 total and subscale
scores were summarized for each visit and a Wilcoxon rank-sum
test was used to compare treatment groups.
Safety data were summarized descriptively for all randomized
patients who received at least one dose of study drug (SAS Version
9.1.3; SAS Institute Inc, Cary, NC, USA). PK parameters were determined by noncompartmental analysis using WinNonlin (Professional Version 5.2; Pharsight Corporation, Mountain View, CA, USA).
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physical discomfort, worries/concerns, psychosocial discomfort,
and satisfaction, and each item was scored from 0 to 4.
Blood samples were obtained from a subset of patients on days 1
(predose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, and 24 hours after ﬁrst
dose), 7 (predose), 14 (predose), and 28 (predose and 0.5, 1, 1.5, 2, 3,
4, 5, 6, 8, 12, 18, 24, 36, and 48 hours after last dose) of the
double-blind treatment period for evaluation of the following pharmacokinetic (PK) parameters: maximum plasma concentration of
naloxegol (Cmax), time to Cmax (tmax), area under the plasma concentration-time curve (AUC0–24), and elimination half-life (t1/2).
Safety was assessed by review of reported adverse events, treatment-emergent adverse events, serious adverse events, and study
discontinuations due to adverse events. The severity of adverse
events was categorized using the World Health Organization Common Toxicity Criteria. All adverse events were coded according to
the Medical Dictionary for Regulatory Activities version 9.0. Pain
intensity was assessed daily by the patient using the 11-point
numerical rating scale (NRS), with recordings for both the daily average pain rating and maximum pain rating over the last 24 hours. Patients also recorded total daily opioid usage (regularly scheduled
opioid therapy plus dosage of rescue therapy for breakthrough pain)
in the electronic diary for assessment of daily opioid requirement.
Opioid withdrawal signs and symptoms were measured 3 times during the study using the clinician-administered Clinical Opiate Withdrawal Scale (COWS), an 11-item clinician-administered sign rating
scale. COWS was completed at the beginning of the placebo run-in
period, 2 hours after the ﬁrst dose of study drug, and 3 days after
the ﬁrst dose of study drug. Based on the total score, withdrawal
signs are considered mild (score of 5–12), moderate (score of
13–24), moderately severe (score of 25–36), or severe (score >36).
Additional assessments occurred if the patient experienced and
communicated symptoms suggestive of opioid withdrawal. Opioid
withdrawal events were classiﬁed as moderate-to-severe opiate
withdrawal (MSOW) if the patient had either a COWS score P13
associated with a clinically signiﬁcant increase of the COWS score
from baseline, or patient-reported symptoms of opioid withdrawal
in the absence of a concomitant COWS evaluation that the investigator felt would have met a COWS score of P13.
A dose escalation safety committee (DESC), comprising 3 physicians and a biostatistician who were otherwise uninvolved in the
study, was responsible for data review. The DESC focused on speciﬁc
adverse events of interest that were identiﬁed within the protocol. In
particular, the DESC reviewed events that qualiﬁed for clinically relevant pain progression, MSOWs, and all treatment-related adverse
events that led to study drug discontinuation and early termination
from the study. Based on this, the DESC provided recommendation of
whether or not to proceed to the next dose level.
Clinical laboratory evaluations included hematology, serum
chemistry, urinalysis, electrocardiogram, vital signs, and physical
examination. Blood samples were collected at the start of the double-blind treatment period and at the follow-up visit.
3. Results
3.1. Patients
The study was conducted at 54 clinical sites in 4 countries
(United States, Germany, Romania, Canada) from January 2008 to
March 2009. Of 208 patients randomized, 207 were included in
the safety population; one patient who was randomized in error
was excluded from the study (Fig. 2). After randomization,
32 (15.4%) patients discontinued treatment during the doubleblind treatment period. Reasons for withdrawal during the
double-blind treatment period included adverse events (n = 15;
46.9%), subject withdrew consent (n = 6; 18.8%), investigator or
sponsor decision (n = 4; 12.6%), inclusion/exclusion criteria not
met (n = 2; 6.3%), and lost to follow-up (n = 1; 3.1%). The majority
of patients who discontinued study treatment because of adverse
events (most common adverse events were GI complaints such
as diarrhea, nausea, and abdominal pain) received naloxegol
50 mg (n = 10; 71.4%); 8 of these patients (80%) were also in the
high-baseline opioid stratum (>100–1000 MEU/day).
The DESC did not identify any safety concerns at completion of
the 5-mg cohort and 25-mg cohort, thereby recommending
evaluation of 50 mg in cohort 3. However, following review of 8 adverse events of special interest and the aggregate safety data from
patients in the 50-mg cohort, the DESC recommended against dose
escalation to 100 mg (cohort 4), as GI intolerability would likely
lead to a signiﬁcant number of patients terminating from treatment early. To determine if further dose cohorts were required,
the sponsor decided to perform a preliminary analysis of the
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Screening
Initial: N = 267
OIC: n = 235
Randomized
n = 208*
Cohort 2 (25 mg)
Placebo run-in
n = 60
Cohort 1 (5 mg)
Placebo run-in
n = 71
Discontinued, n = 5
Adverse event, n = 1
Lost to follow-up, n = 1
Sponsor decision, n = 1
Criteria not met, n = 1
MSOW, n = 1†
Discontinued, n = 2
Withdrew consent,
n=1
Adverse event, n = 1
Completed
n = 72
Low, n = 32
High, n = 40
Naloxegol
n = 35
Low, n = 14
High, n = 21
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Completed
n = 27
Low, n = 13
High, n = 14
Completed
n = 28
Low, n = 11
High, n = 17
Discontinued, n = 5
Adverse event, n = 1
Investigator decision,
n=2
Withdrew consent,
n=2
Discontinued, n = 3
Adverse event, n = 1
Criteria not met, n = 1
Sponsor decision, n = 1
Placebo
n = 27
Low, n = 13
High, n = 14
Naloxegol
n = 30
Low, n = 12
High, n = 18
Completed
n = 27
Low, n = 8
High, n = 19
Cohort 3 (50 mg)
Placebo run-in
n = 76
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Completed
n = 28
Low, n = 12
High, n = 16
Placebo
n = 32
Low, n = 11
High, n = 21
Completed
n = 57
Low, n = 25
High, n = 32
Discontinued, n = 0
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Naloxegol
n = 33
Low, n = 13
High, n = 20
Discontinued, n = 6
Withdrew consent, n = 3
Criteria not met, n = 1
Lost to follow-up, n = 1
Other, n = 1
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Completed
n = 65
Low, n = 24
High, n = 41
Not randomized
n = 59
Completed
n = 21
Low, n = 11
High, n = 10
Discontinued, n = 14
Withdrew consent,
n=3
Adverse event, n = 10
Other, n = 1
Discontinued, n = 4
Adverse event, n = 1
Sponsor decision, n = 1
Other, n = 2
Placebo
n = 37
Low, n = 18
High, n = 19
Completed
n=31
Low, n = 16
High, n = 15
Discontinued, n = 6
Adverse event, n = 2
Sponsor decision, n = 1
Criteria not met, n = 1
Other, n = 2
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Fig. 2. Patient disposition. ⁄One patient was randomized in error and subsequently excluded. OIC, opioid-induced constipation; MSOW, moderate-to-severe opiate
withdrawal. Initially reported as a possible event of opioid withdrawal but did not qualify as MSOW event.
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primary end point. Based on this analysis, the 25-mg dose was
identiﬁed as a safe and tolerable dose appropriate for phase 3 testing. In addition, it was decided to end the study after completion of
the 50-mg cohort.
The MITT population included 185 patients with a mean age of
49.7 years, and the majority (62%) were women (Table 1). Slightly
more patients were enrolled in the high-baseline opioid stratum
(n = 107; 58%) compared with the low-baseline opioid stratum
(n = 78; 42%). Mean body mass index ranged from 29.6 to
33.7 kg/m2 across groups.
3.2. Efﬁcacy
The median change from baseline to week 1 of the double-blind
treatment period in SBMs per week (primary end point) for each
cohort is shown in Fig. 3. In the 5-mg dose group, there was no statistical difference in change from baseline in SBMs per week at
week 1 compared with placebo (1.5 vs 1.2; P = 0.7781). Patients
treated with 25 mg of naloxegol had a statistically signiﬁcantly
greater change from baseline in SBMs per week at week 1 compared with placebo (2.9 vs 1.0; P = 0.0020). Similarly, patients treated with 50 mg of naloxegol had a statistically signiﬁcantly greater
change from baseline in SBMs per week vs placebo (3.3 vs 0.5;
P = 0.0001).
Signiﬁcant changes from baseline in SBMs were observed with
naloxegol vs placebo throughout weeks 2 through 4 of the
double-blind treatment period. The median change from baseline
in SBMs per week was statistically signiﬁcantly greater for the
50 mg of naloxegol dose group vs placebo at all time points during
weeks 2, 3, and 4 of double-blind treatment and for 25 mg of
naloxegol vs placebo at all time points except week 2 (Fig. 4).
The median change from baseline in SBMs per week across the
4-week double-blind treatment period was also statistically significant for both 25 mg of naloxegol (3.0 vs 0.8; P = 0.0022) and 50 mg
of naloxegol (3.5 vs 1.0; P < 0.0001) compared with placebo (Fig. 5),
but was not statistically signiﬁcant for the 5-mg dose of naloxegol
(1.3 vs 1.3; P = 0.5118).
Efﬁcacy results were generally consistent for the stratiﬁcation
groups based on opioid dose at baseline. For patients in the lowbaseline opioid stratum (30–100 MEU), the median change in SBMs
per week at week 1 of the double-blind treatment period was
0.8 for 5 mg of naloxegol (n = 13) compared with 2.0 for placebo
(n = 13; P = 0.1509), 3.3 for 25 mg of naloxegol (n = 13) compared
with 0.8 for placebo (n = 12) (P = 0.0295), and 2.5 for 50 mg of naloxegol (n = 16) compared with 0.5 for placebo (n = 19) (P = 0.0541).
For patients in the high-baseline opioid stratum (100–1000 MEU),
median changes in SBMs per week at week 1 were 2.0 for 5 mg
naloxegol (n = 18) compared with 1.0 for placebo (n = 18)
(P = 0.1448), 2.4 for 25 mg naloxegol (n = 16) compared with 1.3
for placebo (n = 15) (P = 0.0394), and 5.3 for 50 mg naloxegol
(n = 14) compared with 0.3 for placebo (n = 18) (P = 0.0019). Across
the 4-week double-blind treatment period, changes in SBMs per
week for naloxegol compared with placebo were statistically
signiﬁcant for naloxegol 25 and 50 mg in both baseline opioid dose
strata. For the low-baseline opioid stratum, 25 mg of naloxegol
increased SBMs per week to 3.4, compared with 1.0 for placebo
(P = 0.0487), and 50 mg of naloxegol increased SBMs per week to
3.2, compared with 0.8 for placebo (P = 0.0024). Changes in SBMs
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Table 1
Demographic and baseline characteristics (MITT population).
Characteristic
Cohort 1
Cohort 2
Cohort 3
Total
Placebo
(n = 31)
Naloxegol 5 mg
(n = 31)
Placebo
(n = 27)
Naloxegol 25 mg
(n = 29)
Placebo
(n = 37)
Naloxegol 50 mg
(n = 30)
n = 185
Age (years), Mean ± SD
47.5 ± 12.0
50.3 ± 13.1
51.0 ± 13.2
51.8 ± 11.4
48.4 ± 10.2
49.6 ± 11.0
49.7 ± 11.7
Sex, n (%)
Male
Female
Height (cm), Mean ± SD
Weight (kg), Mean ± SD
BMI (kg/m2), Mean ± SD
12 (38.7)
19 (61.3)
167.4 ± 9.6
89.1 ± 24.3
31.9 (8.87)
12 (38.7)
19 (61.3)
169.9 ± 7.9
87.9 ± 21.1
30.6 (7.54)
9 (33.3)
18 (66.7)
169.3 ± 9.1
84.9 ± 21.3
29.6 (7.05)
14 (48.3)
15 (51.7)
172.0 ± 10.7
91.6 ± 20.1
30.9 (5.67)
14 (37.8)
23 (62.2)
170.4 ± 10.1
87.0 ± 22.5
29.9 (6.85)
9 (30.0)
21 (70.0)
166.5 ± 8.7
93.5 ± 26.3
33.7 (8.87)
70 (37.8)
115 (62.2)
169.3 ± 9.5
89.0 ± 22.6
31.1 (7.59)
10 (32.3)
21 (67.7)
1.6 ± 0.9
12 (38.7)
19 (61.3)
1.8 ± 1.0
13 (48.1)
14 (51.9)
1.2 ± 0.9
12 (41.4)
17 (58.6)
1.4 ± 0.9
18 (48.6)
19 (51.4)
1.3 ± 0.9
13 (43.3)
17 (56.7)
1.6 ± 0.7
78 (42.2)
107 (57.8)
Opioid stratum, n (%)
6 100 MEU
>100 MEU
Baseline SBMs/week,
Mean ± SD
P =0.7781
P =0.0020
P =0.0001
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4.0
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n=37 n=30
50 mg
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n=31 n=31
n=27 n=29
5 mg
25 mg
Naloxegol Dose Cohort
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1.0
0.0
5-mg cohort, 0.8 vs 1.3 (P = 0.0557) for the 25-mg cohort, and 0.8 vs
1.4 (P = 0.1405) for the 50-mg cohort. Patients in the 25-mg cohort
experienced statistically signiﬁcantly lower PAC-QoL mean scores
for physical discomfort, satisfaction, and total score at week 2
(P 6 0.0130), and satisfaction and total score at week 4
(P 6 0.0253). Median total PAC-QoL scores at last observation carried forward were 1.4 vs 1.4 (P = 0.5799), 1.1 vs 1.7 (P = 0.0262),
and 1.3 vs 1.7 (P = 0.0599), respectively, for the 5-, 25-, and 50-mg
cohorts. Patients in the 25-mg cohort experienced statistically signiﬁcant (P < 0.05) improvement in physical functioning, mental
health, social functioning, and vitality as measured by the SF-36 vs
placebo at various time points during double-blind treatment, and
higher median scores compared to the placebo group.
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5.0
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Median Change in SBMS/Week From Baseline to
End of Week 1
BMI, body mass index; MITT, modiﬁed intent-to-treat population (n = 185) includes all randomized patients who received at least 1 dose of double-blind study treatment, had
a baseline value, and evaluable data at week 1 of the double-blind study period; MEU, morphine equivalent units; SBMs, spontaneous bowel movements.
Co
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Fig. 3. Median change in SBMs per week from baseline to end of week 1 of doubleblind treatment (MITT population). MITT, modiﬁed intent-to-treat; SBM, spontaneous bowel movement.
per week across the 4-week double-blind treatment period for 5
mg of naloxegol was 1.2, compared with 2.3 for placebo
(P = 0.1764). For the high-baseline opioid stratum, changes in SBMs
per week for naloxegol vs placebo were 1.7 vs 1.1 (P = 0.0774) for
the 5-mg cohort, 2.9 vs 0.7 (P = 0.0320) for the 25-mg cohort,
and 3.5 vs 1.0 (P = 0.0002) for the 50-mg cohort.
Median time to ﬁrst laxation was statistically signiﬁcantly
shorter with naloxegol than placebo in the 25-mg cohort (6.6 h
[95% conﬁdence interval (CI) 2.2–24.3] vs 48.6 h [95% CI
22.6–71.3] ; P = 0.0012) and 50-mg cohort (2.9 h 95% [CI 1.1–6.0]
vs 44.9 h [95% CI 19.9–76.6]; P = 0.0016), but not statistically
different in the 5-mg cohort (6.2 h [95% CI 3.5–46.9] vs 28.2 h
[95% CI 19.7–48.9]; P = 0.6324). Within 6 hours of naloxegol
administration, 50% of patients in the 5- and 25-mg cohorts and
68.4% of patients in the 50-mg cohort had an SBM based on
Kaplan-Meier estimates.
Patients in the 25-mg cohort experienced statistically signiﬁcantly lower PAC-SYM mean scores for rectal symptoms at week 2
(P = 0.0496), stool symptoms at weeks 2 and 4 (P 6 0.0335), and total score at week 2 (P = 0.0163) compared with placebo. Patients in
the 50-mg cohort experienced statistically signiﬁcantly lower
PAC-SYM mean scores for rectal symptoms at week 4 (P = 0.0116)
compared with placebo. Median total PAC-SYM scores at last observation carried forward vs placebo were 1.0 vs 1.0 (P = 0.8734) for the
3.3. Pharmacokinetics
Plasma naloxegol PK parameters were estimated for 5 patients
in the 5-mg cohort, 12 patients in the 25-mg cohort, and 5 patients
in the 50-mg cohort. Mean naloxegol Cmax and AUC0–24 were similar within cohorts at day 1 and day 28 of treatment (Table 2), indicating no clinically relevant accumulation of the drug during the
course of active treatment. Cmax and AUC0–24 values increased in
proportion to administered dose, and t1/2 values were similar
across dose levels. These ﬁndings show that naloxegol exhibits
dose-proportional PK in patients with OIC that are consistent with
preclinical and phase I studies (Table 2) [3,8]. There were no differences in PK characteristics between males and females, and
naloxegol clearance and volume of distribution were independent
of patient body weight, age, and serum creatinine.
3.4. Safety and tolerability
Across all dose cohorts, patients had a mean of 19.6 to 28.3 days
of exposure to study medication. For patients receiving 5 mg or
25 mg of naloxegol, there were no major differences in the frequency or type of reported treatment-emergent adverse events
compared with those receiving placebo (Table 3). In the 50-mg cohort, the incidence of treatment-emergent adverse events was
higher in patients who received naloxegol compared with those
who received placebo. Most adverse events were mild or moderate
in severity. The most frequently reported treatment-emergent adverse events were GI complaints and included abdominal pain,
diarrhea, and nausea (Table 3). Similarly, the most frequently
occurring treatment-emergent adverse events considered by the
investigator to be related to study medication were GI symptoms,
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L. Webster et al. / PAIN 154 (2013) 1542–1550
Median Change in SBMS/Week From Baseline
A
6.0
Placebo
5 mg naloxegol
5.0
4.0
3.0
2.0
1.0
0.0
DB week 2
DB week 3
DB week 4
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Placebo
25 mg naloxegol
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5.0
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4.0
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3.0
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or
2.0
0.0
aa
1.0
DB week 1
DB week 2
DB week 3
DB week 4
Median Change in SBMS/Week From Baseline
Co
Placebo run-in
C
DB week 1
6.0
pi
B
Median Change in SBMS/Week From Baseline
Placebo run-in
6.0
Placebo
50 mg naloxegol
5.0
4.0
3.0
2.0
1.0
0.0
Placebo run-in
DB week 1
DB week 2
DB week 3
DB week 4
Fig. 4. Time course of median change from baseline in SBMs per week in the (A) 5-mg cohort, (B) 25-mg cohort, and (C) 50-mg cohort (MITT population). DB, double-blind
treatment period; MITT, modiﬁed intent-to-treat; SBM, spontaneous bowel movement.
and these adverse events increased with increasing naloxegol dose
from 13 (39.4%) in the 5-mg cohort to 14 (46.7%) in the 25-mg
cohort and to 21 (60.0%) in the 50-mg cohort. Hyperhidrosis
occurred in 4 (12.1%) patients receiving 5 mg of naloxegol, 2
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Median Change in SBMS/Week From Baseline for
Weeks 1– 4
1548
5.0
P =0.5118
P =0.0022
P <0.0001
n=27 n=28
25 mg
n=35 n=24
50 mg
4.0
3.0
2.0
1.0
0.0
n=27 n=29
5 mg
Naloxegol Dose Cohort
pi
Table 2
Pharmacokinetic parameters of naloxegol (PK population).
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(6.7%) patients receiving 25 mg naloxegol, and 3 (8.6%) patients
receiving 50 mg of naloxegol. Among patients who reported adverse events in the GI disorders system organ class, the median onset times (naloxegol vs placebo) were 2 vs 16 days in the 5-mg
cohort, 2 vs 10 days in the 25-mg cohort, and 1 vs 15 days in the
50-mg cohort. Treatment-emergent adverse events led to study
discontinuation of 3 patients in the 5-mg cohort (placebo, 2; naloxegol, 1), 3 patients in the 25-mg cohort (placebo, 0; naloxegol,
3), and 14 patients in the 50-mg cohort (placebo, 3; naloxegol,
11). In the 50-mg cohort, 7 cases of premature study discontinuation due to treatment-emergent adverse events were considered
possibly or probably related to study medication and included
abdominal pain, diarrhea, nausea, vomiting, and abdominal
cramping.
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Fig. 5. Median change in SBMs per week from baseline for the aggregate of weeks 1
to 4 of double-blind treatment (MITT population). MITT, modiﬁed intent-to-treat;
SBM, spontaneous bowel movement.
Overall, severe adverse events (grade 3) occurred in 4 patients
in the 5-mg cohort (placebo, 2; naloxegol, 2), 6 patients in the
25-mg cohort (placebo, 3; naloxegol, 3), and 6 patients in the
50-mg cohort (placebo, 1; naloxegol, 5). The majority of severe
adverse events were GI disorders; for patients treated with naloxegol, grade 3 severe GI adverse events occurred in 1 of 2 patients in
the 5-mg cohort, 3 of 3 patients in the 25-mg cohort, and 4 of 5 patients in the 50-mg cohort. One patient receiving 25 mg of
naloxegol experienced a life-threatening adverse event (grade 4;
pulmonary embolism), which subsequently resulted in death. This
adverse event was deemed unrelated to study medication based on
the patient’s medical history of recurrent deep vein thrombosis. No
other deaths were reported during the study. Five patients experienced a total of 7 serious adverse events; 4 occurred in a naloxegol
group and 3 in the placebo group. Of these, only upper abdominal
cramping in a patient treated with 50 mg of naloxegol was considered by investigators to be related to study treatment.
Daily opioid usage remained steady from baseline throughout
the double-blind treatment and was similar between all naloxegol
groups and placebo (Supplementary Fig. 1). There were no statistically signiﬁcant changes from baseline for mean daily opioid dose
for the 25- or 50-mg cohort. Mean NRS scores remained consistent
from baseline to week 4 of double-blind treatment for all 3 cohorts,
and no statistically signiﬁcant differences vs placebo were observed (Supplementary Fig. 2). Similar consistent results between
treatment groups were obtained for mean NRS scores when patients were stratiﬁed by baseline opioid dose.
No statistically signiﬁcant differences in median COWS total
score were observed between placebo and naloxegol in the
5- and 25-mg cohorts at any time point. A statistically signiﬁcant
difference was observed in median COWS total score in the
50-mg cohort at day 1 of week 1 of double-blind treatment
compared to placebo (1.0 vs 0.0; P = 0.0069). A post hoc analysis
identiﬁed a statistically signiﬁcant difference in the GI component
of the total COWS score for day 1 of the double-blind treatment
Cohort 1 Naloxegol 5 mg
Cohort 2 Naloxegol 25 mg
Cohort 3 Naloxegol 50 mg
PK parameter, mean (CV%)
Day 1 (n = 5)
Day 28 (n = 4)
Day 1 (n = 12)
Day 28 (n = 9)
Day 1 (n = 5)
Day 28 (n = 4)
tmax, hr
Cmax, ng/mL
AUC0–24, hr ng/mL
t1/2, hr
1.7 (84.7)
9.1 (52.2)
34.0 (48.8)
NC
1.5 (81.7)
8.0 (49.2)
39.0 (23.1)
17.4 (8.3)
1.5 (61.1)
70.6 (42.3)
327.7 (47.7)
NC
1.4 (43.9)
81.1 (45.7)
334.8 (51.4)
14.1 (4.9)
1.5 (91.3)
123.7 (36.3)
426.8 (22.1)
NC
1.6 (101.7)
100.0 (41.9)
403.6 (36.7)
20.3 (10.3)
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Dose
CV%, coefﬁcient of variation expressed as percent of the mean; PK, pharmacokinetic; NC, not calculated on Day 1.
Table 3
Overall incidence of treatment-emergent adverse events and gastrointestinal (GI) adverse events in at least 5% of patients in any treatment group (safety population).
Patients, n (%)
Cohort 1
Cohort 2
Cohort 3
Placebo
Naloxegol 5 mg
Placebo
Naloxegol 25 mg
Placebo
Naloxegol 50 mg
Any AEs
P1 treatment-emergent AE
23 (71.9)
25 (75.8)
19 (70.4)
22 (73.3)
21 (56.8)
30 (85.7)
GI AEs
P1 treatment-emergent AE
Diarrhea
Nausea
Upper abdominal pain
Abdominal pain
Dyspepsia
Vomiting
Flatulence
GERD
Abdominal distention
11 (34.4)
5 (15.6)
1 (3.1)
0
1 (3.1)
1 (3.1)
2 (6.3)
2 (6.3)
1 (3.1)
2 (6.3)
15 (45.5)
5 (15.2)
5 (15.2)
6 (18.2)
1 (3.0)
1 (3.0)
0
3 (9.1)
4 (12.1)
2 (6.1)
13 (48.1)
1 (3.7)
5 (18.5)
1 (3.7)
2 (7.4)
4 (14.8)
1 (3.7)
2 (7.4)
1 (3.7)
1 (3.7)
16 (53.3)
4 (13.3)
4 (13.3)
3 (10.0)
9 (30.0)
3 (10.0)
4 (13.3)
2 (6.7)
0
0
10 (27.0)
2 (5.4)
3 (8.1)
2 (5.4)
0
2 (5.4)
2 (5.4)
0
1 (2.7)
0
24 (68.6)
11 (31.4)
7 (20.0)
10 (28.6)
6 (17.1)
2 (5.7)
4 (11.4)
3 (8.6)
1 (2.9)
1 (2.9)
AE, adverse event; GI, gastrointestinal; GERD, gastroesophageal reﬂux disease.
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Conﬂict of interest
da
Results from this study demonstrate that oral naloxegol
effectively treated OIC as measured by a clinically meaningful
and statistically signiﬁcant increase in the number of weekly SBMs.
Effects on SBMs were dose dependent over the range of naloxegol
5 to 50 mg. The mean increase from baseline in SBMs per week was
statistically signiﬁcant at all time points throughout the 4 weeks of
double-blind treatment for 50 mg of naloxegol and all time points
except week 2 for 25 mg of naloxegol, indicating a durable effect.
Similarly, the median time to ﬁrst laxation was statistically
signiﬁcantly shorter for patients receiving 25 mg or 50 mg of
naloxegol compared with placebo. The increase in SBMs per week
from weeks 1 to 4 was also signiﬁcant in both the high- and lowbaseline opioid strata. These beneﬁts with regard to OIC were not
associated with reversal or reduction of opioid-mediated analgesia
(ie, no shift in NRS score or increase in opiate use), nor with opioid
withdrawal (number of MSOW events and total COWS score).
There were no statistically signiﬁcant differences in change from
baseline for mean daily opioid use vs placebo for the 25- and
50-mg cohorts. Naloxegol was generally well tolerated across the
dosages tested, with GI adverse events being most common.
The observed dose dependence of naloxegol efﬁcacy was consistent with the results of PK analyses that showed dose-proportional steady-state plasma concentrations and total exposures
(AUC0–24). Naloxegol was rapidly absorbed, and the t1/2 was similar
across all dose levels. There were no relevant differences observed
in PK characteristics between males and females, and clearance
and volume of distribution of naloxegol were independent of body
weight, age, and serum creatinine. These ﬁndings are consistent
with preclinical and phase I data [3,8] and conﬁrm that, in this
study, naloxegol had predictable PK, potentially allowing for a
once-daily, oral-dosage regimen.
Patients treated with 25 mg naloxegol reported lower median
total scores on the patient-reported PAC-QoL questionnaire than
patients taking placebo. This group also reported statistically signiﬁcant improvement in SF-36 scale scores for physical functioning, mental health, social functioning, and vitality at various time
points during double-blind treatment compared with patients
receiving placebo, whereas differences between the 5-mg and
50-mg dose groups and placebo were not signiﬁcant. The absence
of a required minimum baseline score for the PAC-SYM or PAC-QoL
in this study, and the relatively low observed baseline scores, may
have made it difﬁcult to demonstrate improvement on these measures. Additional studies sufﬁciently powered and requiring a minimum level of symptoms at baseline may provide more meaningful
information on the effect of naloxegol on patient assessment of
outcomes and quality of life.
Results of this phase 2 study show that naloxegol increased
SBM frequency without interfering with the centrally mediated
analgesic effect of opioids or inducing signs and/or symptoms of
opioid withdrawal in patients with OIC. Moreover, naloxegol was
generally well tolerated, the most common adverse events being
abdominal pain, diarrhea, and nausea, which were more frequent
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4. Discussion
in the 50-mg cohort compared with the other cohorts. Most GI adverse events had onset within the ﬁrst week and resolved within
7 days, likely due to increased bowel function following a prolonged period of decreased activity. The DESC recommended
against dose escalation to 100 mg, as GI intolerability would likely
lead to a signiﬁcant number of patients terminating from treatment early. Following preliminary unblinded review of the study
data to determine if additional dose cohorts were required, it
was revealed that naloxegol at a once-daily dose of 25 mg was generally well tolerated and statistically signiﬁcantly increased SBMs
after 1 week of treatment. The 25-mg dose was therefore selected
to be further investigated in phase 3 studies.
While there appears to be a dose relationship for both efﬁcacy
and safety end points, this study was not speciﬁcally designed to
make statistical conclusions regarding dose response. Additional
studies are needed to conﬁrm the efﬁcacy of naloxegol by including a larger and more diverse population. Longer-term data are also
needed to conﬁrm the safety and tolerability of naloxegol with prolonged administration, as would be the case in the setting of
chronic opioid use.
In conclusion, naloxegol, at oral doses of 25 and 50 mg once daily, increased the frequency of SBMs in patients with OIC with consistent effects over 4 weeks, without interfering with the centrally
mediated analgesic effect of opioids in patients receiving a wide
range of stable opioid doses. The drug was generally well tolerated,
with mild GI symptoms the most common adverse events in this
study.
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period for the 50-mg cohort between naloxegol and placebo
(P = 0.0384; Wilcoxon rank-sum test). When the GI component
score was excluded from the total COWS score, no difference
between placebo and naloxegol was found at this time point, indicating a lack of effect on the components of COWS that reﬂect central nervous system withdrawal. No documented case of MSOW
(with COWS score P13) occurred in any patient receiving
naloxegol.
No clinically relevant changes in serum chemistry, urinalysis,
hematology, or electrocardiogram ﬁndings were observed.
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Writing and editing assistance was funded by AstraZeneca
Pharmaceuticals. M.E. is an employee of Nektar Therapeutics. J.L.
and M.S. are employees of AstraZeneca Pharmaceuticals. S.D. and
L.M. are former employees of Nektar Therapeutics.
Acknowledgements
The authors acknowledge Emily Xu for the programming of
study data and Hema Gowda, PharmD, from Scientiﬁc Connexions,
Newtown, PA, USA for writing and editing assistance.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.pain.2013.04.024.
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