The new england journal of medicine
`n engl j med 375;2 nejm.org July 14, 2016134
`From Indiana University School of Medi -
`cine–South Bend, South Bend (R.M.N.);
`Al
`liance Statistics and Data Center, Mayo
`Clinic (R.Q., H.L.), and Mayo Clinic (K.J.R.,
`J.M.L., C.L.L.), Rochester, MN; Sanford
`NCORP (National Cancer Institute Com -
`munity Oncology Research Program) of
`th
`e North Central Plains, Sioux Falls, SD
`(S.F.P.); Illinois Cancer Care–Peoria, Peo-
`ria (M.B.); Gundersen Lutheran Medical
`Ce
`nter, La Crosse, WI (L.D.); and Delaware–
`Christiana Care NCORP, Newark, DE (D.B.).
`Address reprint requests to Dr. Navari at
`4518 Crown Point Ln., Mount Olive, AL
`35117, or at rmnavari@ gmail . com.
`N Engl J Med 2016;375:134-42.
`DOI: 10.1056/NEJMoa1515725
`Copyright © 2016 Massachusetts Medical Society.
`BACKGROUND
`We examined the efficacy of olanzapine for the prevention of nausea and vomiting in
`patients receiving highly emetogenic chemotherapy.
`METHODS
`In a randomized, double-blind, phase 3 trial, we compared olanzapine with placebo,
`in combination with dexamethasone, aprepitant or fosaprepitant, and a 5-hydroxy-
`tryptamine type 3–receptor antagonist, in patients with no previous chemotherapy
`who were receiving cisplatin (≥70 mg per square meter of body-surface area) or
`cyclophosphamide–doxorubicin. The doses of the three concomitant drugs admin-
`istered before and after chemotherapy were similar in the two groups. The two
`groups received either 10 mg of olanzapine orally or matching placebo daily on
`days 1 through 4. Nausea prevention was the primary end point; a complete response
`(no emesis and no use of rescue medication) was a secondary end point.
`RESULTS
`In the analysis, we included 380 patients who could be evaluated (192 assigned to
`olanzapine, and 188 to placebo). The proportion of patients with no chemotherapy-
`induced nausea was significantly greater with olanzapine than with placebo in the
`first 24 hours after chemotherapy (74% vs. 45%, P = 0.002), the period from 25 to
`120 hours after chemotherapy (42% vs. 25%, P = 0.002), and the overall 120-hour
`period (37% vs. 22%, P = 0.002). The complete-response rate was also significantly
`increased with olanzapine during the three periods: 86% versus 65% (P<0.001),
`67% versus 52% (P = 0.007), and 64% versus 41% (P<0.001), respectively. Although
`there were no grade 5 toxic effects, some patients receiving olanzapine had increased
`sedation (severe in 5%) on day 2.
`CONCLUSIONS
`Olanzapine, as compared with placebo, significantly improved nausea prevention,
`as well as the complete-response rate, among previously untreated patients who were
`receiving highly emetogenic chemotherapy. (Funded by the National Cancer Institute;
`ClinicalTrials.gov number, NCT02116530.)
`ABSTRACT
`Olanzapine for the Prevention of
`Chemotherapy-Induced Nausea and Vomiting
`Rudolph M. Navari, M.D., Rui Qin, Ph.D., Kathryn J. Ruddy, M.D.,
`Heshan Liu, Ph.D., Steven F. Powell, M.D., Madhuri Bajaj, M.D.,
`Leah Dietrich, M.D., David Biggs, M.D., Jacqueline M. Lafky, M.S.,
`and Charles L. Loprinzi, M.D.
`Original Article
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`HELSINN EXHIBIT 2039
`Azurity Pharmaceuticals, Inc. v. Helsinn Healthcare S.A.
`IPR2025-00945
`Page 1 of 9
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`n engl j med 375;2 nejm.org July 14, 2016 135
`Olanzapine for Chemotherapy-Induced Nausea
`C
`hemotherapy-induced nausea and
`vomiting are associated with a significant
`deterioration in quality of life and are per-
`ceived by patients as major adverse effects of can-
`cer treatment.
`1 The use of 5-hydroxytryptamine
`type 3 (5-HT3) receptor antagonists,2 dexameth-
`asone,2 and neurokinin-1 (NK1) receptor antago-
`nists3-9 has significantly improved the control of
`this troublesome side effect. International guide-
`lines10-12 recommend combinations of these agents
`to prevent chemotherapy-induced nausea and vom-
`iting in patients receiving moderately or highly
`emetogenic chemotherapy. Nonetheless, nausea
`remains a major problem for many patients.
`1,2
`Olanzapine is approved by the Food and Drug
`Administration (FDA) as an antipsychotic agent
`that blocks multiple neurotransmitters: dopamine
`at D
`1, D2, D3, and D4 receptors; serotonin at 5-HT
`type 2a, 5-HT type 2c (5-HT2c), 5-HT3, and 5-HT
`type 6 receptors; catecholamines at alpha1-adren-
`ergic receptors; acetylcholine at muscarinic recep-
`tors; and histamine at H1 receptors in the central
`nervous system.8,9,13 Side effects may include mild
`short-term sedation,13-15 as well as weight gain and
`an increased risk of diabetes mellitus with pro -
`longed use (>6 months).15-17 The activity of olan-
`zapine at multiple receptors, particularly the D2,
`5-HT2c, and 5-HT3 receptors, which may be in -
`volved in nausea and vomiting, suggests that it
`might have clinically significant antiemetic prop-
`erties.
`A single-institution phase 3 trial showed that
`olanzapine, when combined with a single dose of
`dexamethasone and a single dose of palonosetron,
`an HT
`3-receptor blocker, was effective in control-
`ling early and longer-term nausea and vomiting in
`patients receiving highly emetogenic chemothera-
`py.
`18 Additional single-institution phase 3 studies
`have shown that olanzapine combined with stan-
`dard antiemetic agents improves control of nausea
`and vomiting in patients receiving moderately or
`highly emetogenic chemotherapy.
`19,20 A recent re-
`view, however, pointed to possible methodologic
`issues in these single-institution studies and called
`for well-planned, randomized, double-blind, multi-
`center studies to evaluate the role of olanzapine in
`the prevention of chemotherapy-induced nausea
`and vomiting.
`21
`The primary objective of the current trial was
`to evaluate olanzapine, as compared with placebo,
`for the control of nausea in patients receiving
`highly emetogenic chemotherapy, with nausea
`prevention assessed during three periods: 0 to 24
`hours, 25 to 120 hours, and 0 to 120 hours after
`chemotherapy. Secondary objectives were to com-
`pare the two study groups for the number of pa-
`tients with a complete response (no emesis and no
`rescue therapy) in the three periods, as well as to
`evaluate potential toxic effects of olanzapine.
`Methods
`Eligibility Criteria
`Patients 18 years of age or older with malignant
`disease who had not received previous chemo -
`therapy were eligible for enrollment in the study if
`they were scheduled to receive highly emetogenic
`chemotherapy (either cisplatin at a dose ≥70 mg
`per square meter of body-surface area, with or
`without other chemotherapeutic agents, or doxo-
`rubicin at a dose of 60 mg per square meter plus
`cyclophosphamide at a dose of 600 mg per square
`meter) and had a European Cooperative Oncology
`Group (ECOG) performance status of 0, 1, or 2
`(on a 5-point scale, with 0 indicating no symptoms
`and higher numbers indicating increasing dis -
`ability). Additional eligibility criteria were a serum
`creatinine level of 2.0 mg per deciliter (177 μmol
`per liter) or less, an aspartate or alanine amino-
`transferase level that was no more than 3 times the
`upper limit of the normal range, and an absolute
`neutrophil count of at least 1500 per cubic milli-
`meter; no nausea or vomiting in the 24 hours be-
`fore enrollment; no severe cognitive compromise;
`no known history of central nervous system dis-
`ease (e.g., brain metastases or a seizure disorder);
`no treatment with another antipsychotic agent
`such as risperidone, quetiapine, clozapine, a pheno-
`thiazine, or a butyrophenone within 30 days before
`enrollment or plans for such treatment during the
`study period; no long-term use of a phenothiazine
`as an antipsychotic agent (patients could receive
`prochlorperazine and other phenothiazines as
`rescue antiemetic therapy); no concurrent use of
`amifostine; no concurrent abdominal radiotherapy;
`no concurrent use of quinolone antibiotic therapy;
`no chronic alcoholism; no known hypersensitivity
`to olanzapine; no known cardiac arrhythmia, un-
`controlled congestive heart failure, or acute myo-
`cardial infarction within the previous 6 months;
`and no history of uncontrolled diabetes mellitus.
`Because of the teratogenic potential of the
`therapy used in this trial, women of childbearing
`age had to have a negative result of a pregnancy
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`Page 2 of 9
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`n engl j med 375;2 nejm.org July 14, 2016136
`The new england journal of medicine
`test performed within 7 days before enrollment.
`They also had to agree to use appropriate birth
`control throughout their participation in the study.
`Study Design and Oversight
`Patients were assigned to a study group with the
`use of the Pocock and Simon dynamic randomiza-
`tion procedure, which balances the marginal dis-
`tributions of the stratification factors between
`study groups. The stratification factors were sex,
`chemotherapy regimen (cisplatin-containing regi-
`men vs. anthracycline plus cyclophosphamide), and
`the specific 5-HT
`3–receptor antagonist used (palo-
`nosetron, ondansetron, or granisetron). The pa-
`tients and the medical professionals who cared for
`them were unaware of the assigned study regimen.
`The patients were assessed for only one chemo-
`therapy cycle. Rescue therapy of the treating inves-
`tigator’s choice was permitted for nausea, emesis,
`or retching, depending on the clinical circum -
`stances.
`All patients gave written informed consent. The
`study was approved by the institutional review
`board at each participating site and was indepen-
`dently monitored by the Alliance Data and Safety
`Monitoring Board. Data collection and analyses
`were conducted by the Alliance Statistics and Data
`Center. Data quality was ensured by a review of
`data performed by the Alliance Statistics and Data
`Center and by the study chairperson (the first au-
`thor) according to Alliance policies. The authors
`vouch for the accuracy and completeness of the
`data and analysis and for adherence to the study
`protocol, available with the full text of this article
`at NEJM.org.
`Treatment Regimen
`All participants received a 5-HT 3–receptor an-
`tagonist (palonosetron intravenously at a dose of
`0.25 mg, granisetron intravenously at a dose of
`1 mg or orally at a dose of 2 mg, or ondansetron
`intravenously or orally at a dose of 8 mg, with the
`specific agent chosen by the primary clinician) on
`day 1 of chemotherapy, dexamethasone (12 mg
`orally on day 1, and 8 mg orally on days 2, 3,
`and 4), and an NK
`1-receptor antagonist on day 1.
`In addition, patients received olanzapine (10 mg
`per day orally) or a matching placebo on days 1
`through 4. The NK
`1-receptor antagonist was intra-
`venous fosaprepitant (150 mg on day 1) or oral
`aprepitant (125 mg on day 1, and 80 mg on days 2
`and 3). The doses of the 5-HT
`3–receptor antago-
`nists, dexamethasone, and aprepitant used in the
`study are the standard doses recommended by
`various international guidelines for antiemetic
`agents.
`10-12 The dose of olanzapine was chosen on
`Figure 1. Patients Who Underwent Randomization, Started the Study, and Were Included in the Primary Analysis.
`401 Patients underwent randomization
`202 Were assigned to receive olanzapine 199 Were assigned to receive placebo
`10 Were excluded
`8 Withdrew
`2 Had major violations
`11 Were excluded
`10 Withdrew
`1 Had a major violation
`6 Were excluded owing to
`a lack of nausea data
`5 Were excluded owing to
`a lack of nausea data
`192 Started the study
`186 Were included in primary analysis 183 Were included in primary analysis
`188 Started the study
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`n engl j med 375;2 nejm.org July 14, 2016 137
`Olanzapine for Chemotherapy-Induced Nausea
`the basis of previous studies.2,18,19,22 In a phase 1
`trial of olanzapine as a prophylactic antiemetic
`agent, Passik et al.22 determined that 10 mg per
`day for 4 days was a dose associated with no toxic
`effects except minimal sedation. In a phase 2 trial,
`Navari et al.
`23 used a loading dose of olanzapine
`(administered daily for 2 days before chemother-
`apy) but subsequently determined that a loading
`dose was not necessary.
`18
`Study Visits and Assessment Procedures
`In the prestudy period, all pertinent demographic
`characteristics and medical data were recorded.
`Patients were asked to complete daily records of
`episodes of vomiting or retching (number and
`time) and the use of rescue therapy from the first
`day of chemotherapy (day 1) through day 5. Pa-
`tients were also asked to record daily levels of
`nausea according to a visual-analogue scale
`24 rang-
`Characteristic
`Olanzapine
`(N = 192)
`Placebo
`(N = 188)
`Total
`(N = 380)
`Age — yr
`Median 58.0 56.0 57.0
`Range 29.0–86.0 28.0–89.0 28.0–89.0
`Race or ethnic group — no. (%)†
`White 172 (89.6) 171 (91.0) 343 (90.3)
`Black 9 (4.7) 9 (4.8) 18 (4.7)
`Asian 5 (2.6) 4 (2.1) 9 (2.4)
`American Indian or Alaska Native 3 (1.6) 1 (0.5) 4 (1.1)
`Not assessed 3 (1.6) 3 (1.6) 6 (1.6)
`Sex — no. (%)
`Female 139 (72.4) 136 (72.3) 275 (72.4)
`Male 53 (27.6) 52 (27.7) 105 (27.6)
`5-HT3–receptor antagonist — no. (%)
`Palonosetron 145 (75.5) 143 (76.1) 288 (75.8)
`Ondansetron 46 (24.0) 44 (23.4) 90 (23.7)
`Granisetron 1 (0.5) 1 (0.5) 2 (0.5)
`Chemotherapy regimen — no. (%)
`Cisplatin-containing regimen 71 (37.0) 65 (34.6) 136 (35.8)
`Anthracycline and cyclophosphamide 121 (63.0) 123 (65.4) 244 (64.2)
`ECOG performance status — no. (%)‡
`0 149 (77.6) 144 (76.6) 293 (77.1)
`1 40 (20.8) 41 (21.8) 81 (21.3)
`2 2 (1.0) 3 (1.6) 5 (1.3)
`Not assessed 1 (0.5) 0 1 (0.3)
`Primary site of disease — no. (%)
`Breast 120 (62.5) 122 (64.9) 242 (63.7)
`Lung 27 (14.1) 22 (11.7) 49 (12.9)
`Other 45 (23.4) 44 (23.4) 89 (23.4)
`* The Wilcoxon test was used to compare age between the two study groups, and Fisher’s exact test was used for com-
`parisons of the other characteristics. There were no significant between-group differences. Percentages may not total
`100 because of rounding. 5-HT
`3 denotes 5-hydroxytryptamine type 3.
`† Race or ethnic group was self-reported.
`‡ The European Cooperative Oncology Group (ECOG) performance status is measured on a 5-point scale, with 0 indicat-
`ing no symptoms and higher numbers indicating increasing disability.
`Table 1. Baseline Demographic and Clinical Characteristics of the Study Patients.*
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`n engl j med 375;2 nejm.org July 14, 2016138
`The new england journal of medicine
`ing from 0 (“no nausea at all”) to 10 (“nausea as
`bad as it can be”). A study nurse contacted each
`patient daily on days 2 through 5 to ask about
`toxic effects and remind the patient to complete
`forms. Adverse events were graded according to
`the terminology and grading categories defined
`in the National Cancer Institute’s Common Ter-
`minology Criteria for Adverse Events, version 4.0.
`In addition, every day for 5 days, patients rated
`undesired sedation and undesired increase in ap-
`petite on numerical scales (with scores ranging
`from 0 to 10, with higher scores indicating greater
`sedation or appetite increase).
`Outcomes
`The primary end point, no nausea, was defined as
`a response of 0 on the visual-analogue scale for
`nausea during the overall assessment period (0 to
`120 hours), the early assessment period (0 to 24
`hours), and the later assessment period (25 to 120
`hours). The proportion of patients with no nausea
`was compared between treatment groups sequen-
`tially: first for the overall period and then for the
`early and later periods concurrently. This hierar-
`chical order was chosen because we considered
`relief for the overall period to be most important
`and relief in the early and later periods to be of
`equal secondary importance.
`Secondary end points included a complete re-
`sponse (no emetic episodes and no use of rescue
`medication). A complete response was determined
`on the basis of the patients’ daily records during
`the overall, early, and later assessment periods and
`reported adverse events.
`Statistical Analysis
`A group sequential design with an interim analy-
`sis for superiority and futility was adopted for
`this trial. The interim analysis was to be conducted
`when 50% of patients had been enrolled and had
`completed their daily assessments of nausea and
`vomiting. We used the Lan–DeMets family
`25 of
`alpha- and beta-spending functions correspond-
`ing to the O’Brien–Fleming boundary to control
`for overall type I and type II error rates. At the
`interim analysis, a P value greater than 0.003 and
`less than 0.844 indicated that the trial would
`continue.
`For the primary end point, we used chi-square
`tests to compare the proportion of patients with
`no nausea between treatment groups sequentially,
`first for the overall period, and then for the early
`and later periods together. A serial Simes gatekeep-
`ing procedure
`25 for the interim and final analyses
`was used to maintain the overall significance level
`at the level specified by the Lan–DeMets alpha-
`spending function. Logistic models were used to
`incorporate stratification factors, baseline scores,
`and other characteristics of the patients. The pri-
`mary analysis did not include missing data because
`of the small number of patients with missing data
`for the primary end point, but a sensitivity analy-
`sis was performed to evaluate the robustness of
`the primary analysis.
`Variable
`Olanzapine
`(N = 192)
`Placebo
`(N = 188)
`Total
`(N = 380) P Value*
`Adjusted
`P Value†
`number/total number (percent)
`0–24 hr after chemotherapy
`No nausea 135/183 (73.8) 82/181 (45.3) 217/364 (59.6) <0.001 0.002
`Nausea 48/183 (26.2) 99/181 (54.7) 147/364 (40.4)
`25–120 hr after chemotherapy
`No nausea 75/177 (42.4) 45/177 (25.4) 120/354 (33.9) 0.001 0.002
`Nausea 102/177 (57.6) 132/177 (74.6) 234/354 (66.1)
`0–120 hr after chemotherapy
`No nausea 66/177 (37.3) 39/178 (21.9) 105/355 (29.6) 0.002 0.002
`Nausea 111/177 (62.7) 139/178 (78.1) 250/355 (70.4)
`* P values were calculated with the use of the chi-square test.
`† P values were calculated according to the Simes gatekeeping procedure.
`Table 2. Primary End Point According to Study Group.
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`n engl j med 375;2 nejm.org July 14, 2016 139
`Olanzapine for Chemotherapy-Induced Nausea
`The modified intention-to-treat principle26 was
`applied for the primary analysis of efficacy in the
`population of patients who could be evaluated.
`This population was defined as all patients meet-
`ing the eligibility criteria who did not withdraw
`from the study before receiving treatment and
`had no major protocol violations (see the Supple-
`mentary Appendix, available at NEJM.org).
`A previous study
`18 showed that the proportion
`of patients not receiving olanzapine who were free
`of nausea during the overall assessment period
`was about 40%. Considering that a 17.5% increase
`in this proportion would be a clinically meaning-
`ful effect size, we calculated that we would need to
`enroll 332 patients (166 per group) to achieve 90%
`power to detect this effect size at the 5% signifi-
`cance level, using a two-sided chi-square test for
`a fixed sample size. We increased the sample size
`to 338 patients (169 per group) after adding an
`interim analysis for superiority and futility. The
`sample size calculation and simulation for oper-
`ating characteristics of the group sequential design
`were conducted with the use of East software, ver-
`sion 5.4 (Cytel).
`Analyses of secondary end points were explor-
`atory in nature, and reported P values for these
`analyses have therefore not been adjusted for
`multiple comparisons. Growth-curve models were
`used for repeated measures of symptoms and sec-
`ondary end points.
`Results
`Study Patients
`Figure 1 (and Fig. S1 in the Supplementary Appen-
`dix) shows the distribution and randomization
`of the study patients. A total of 401 patients at
`46 academic or community practice institutions
`in the United States were randomly assigned to a
`study group between August 2014 and March 2015;
`380 patients (192 assigned to olanzapine and 188
`assigned to placebo) began the study.
`Demographic and clinical characteristics are
`presented in Table 1 for the 380 patients who be-
`gan the study and who did not have major proto-
`col violations. There were no significant differ -
`ences between the olanzapine and placebo groups
`in terms of age, race, sex, 5-HT
`3–receptor inhibi-
`tor received, chemotherapy regimen administered,
`ECOG performance status, or primary site of dis-
`ease. In each group, a majority of the patients were
`women and a majority received chemotherapy
`consisting of doxorubicin plus cyclophosphamide.
`The distribution of institutions was balanced be-
`tween the study groups.
`Efficacy
`An interim analysis was performed in February
`2015, after primary end-point data had been re-
`corded for 50% of the patients on the basis of
`their daily assessments of nausea and vomiting.
`Complete Response
`Olanzapine
`(N = 192)
`Placebo
`(N = 188)
`Total
`(N = 380) Odds Ratio† P Value‡
`Adjusted
`P Value§
`number/total number (percent)
`0–24 hr after chemotherapy 0.30
`No 26/182 (14.3) 64/181(35.4) 90/363 (24.8)
`Yes 156/182 (85.7) 117/181 (64.6) 273/363 (75.2) <0.001 <0.001
`25–120 hr after chemotherapy 0.55
`No 54/163 (33.1) 80/168 (47.6) 134/331 (40.5)
`Yes 109/163 (66.9) 88/168 (52.4) 197/331 (59.5) 0.007 0.007
`0–120 hr after chemotherapy 0.39
`No 59/162 (36.4) 101/170 (59.4) 160/332 (48.2)
`Yes 103/162 (63.6) 69/170 (40.6) 172/332 (51.8) <0.001 <0.001
`* A complete response (a secondary end point) was defined as no emesis and no use of rescue medication.
`† Odds ratios are for emesis or the use of rescue medication (i.e., lack of complete response) in the olanzapine group as compared with the
`placebo group.
`‡ P values were calculated with the use of the chi-square test.
`§ P values were calculated according to the Simes gatekeeping procedure.
`Table 3. Complete Response According to Study Group.*
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`n engl j med 375;2 nejm.org July 14, 2016140
`The new england journal of medicine
`A P value of 0.3599 for the chi-square test com-
`paring the two study groups with respect to the
`proportion of patients who had no nausea during
`the overall assessment period indicated that we
`should continue enrolling patients according to
`the group sequential design. At the final analysis,
`the proportion of patients who had no nausea (the
`primary end point) was significantly greater in
`the olanzapine group than in the placebo group
`in each of the three assessment periods: early pe-
`riod, 74% vs. 45% (P = 0.002); later period, 42% vs.
`25% (P = 0.002); and overall period, 37% vs. 22%
`(P = 0.002) (Table 2). When all the patients with
`missing data were considered to have had nausea,
`the results were similar, with P values of less than
`0.004 for the early, later, and overall periods.
`Likewise, there were significant differences be-
`tween the olanzapine and placebo groups with
`respect to freedom from clinically significant
`nausea — that is, a nausea score of less than 3 on
`a scale from 0 to 10, as defined in previous re -
`ports.
`1,2,6,27-29 The proportion of patients receiv -
`ing olanzapine who had no clinically significant
`nausea was 87%, versus 70% of those receiving
`placebo, in the early period (P = 0.001), 72% versus
`55% in the later period (P = 0.001), and 67% versus
`49% in the overall period (P = 0.001).
`The proportion of patients with a complete
`response was significantly higher in the olan -
`zapine group than in the placebo group in all
`three assessment periods. During the early, later,
`and overall periods, the proportions were 86%
`vs. 65% (P<0.001), 67% vs. 52% (P = 0.007), and
`64% vs. 41% (P<0.001), respectively (Table 3).
`Adverse Events
`There were two grade 3 adverse events (fatigue
`and hyperglycemia) in the olanzapine group and
`two grade 3 adverse events (abdominal pain and
`diarrhea) in the placebo group. There were three
`grade 4 adverse events (two of which were hema-
`tologic) in the olanzapine group and no grade 4
`adverse events in the placebo group. No grade 5
`adverse events were reported in the study. None
`of the grade 3 or 4 adverse events were attrib -
`uted to olanzapine by the attending clinician.
`Figure 2A shows that patients receiving olan-
`zapine, as compared with those receiving placebo,
`had significantly increased sedation (severe in 5%)
`on day 2 as compared with baseline. The sedation
`resolved on days 3, 4, and 5, even though patients
`continued to receive olanzapine on days 3 and 4.
`No patient discontinued the study because of un-
`desired sedation. Figure 2B shows that there were
`no significant differences between the olanzapine
`and placebo groups with respect to undesired in-
`crease in appetite on days 2 through 5 after che-
`motherapy as compared with baseline.
`Discussion
`This large, randomized, double-blind, placebo-
`controlled, phase 3 trial showed that it is more
`Figure 2. Ratings of Undesired Sedation and Undesired Increase in Appetite
`in the Olanzapine and Placebo Groups.
`Patients were asked to record daily levels of undesired sedation and unde -
`sired increase in appetite using a visual-analogue scale ranging from 0 (none)
`to 10 (“as bad as it can be”). The mean scores for undesired sedation (Pan -
`el A) and undesired increase in appetite (Panel B) are shown for 5 days af -
`ter chemotherapy. I bars indicate standard errors.
`Mean/uni0020Score
`3
`2
`1
`0
`Baseline 2 3 4 5 6
`Day
`B Undesired/uni0020Increase/uni0020in/uni0020Appetite
`A Undesired/uni0020Sedation
`No./uni0020at/uni0020Risk
`Olanzapine
`Placebo
`190
`188
`181
`181
`182
`180
`179
`179
`179
`173
`175
`174
`Mean/uni0020Score
`3
`2
`1
`6
`5
`4
`6
`5
`4
`7
`7
`10
`9
`8
`10
`9
`8
`0
`Baseline 2 3 4 5 6
`3
`2
`1
`0
`Baseline 2 3 4 5 6
`3
`2
`1
`0
`Baseline 2 3 4 5 6
`Day
`No./uni0020at/uni0020Risk
`Olanzapine
`Placebo
`190
`187
`183
`181
`182
`180
`179
`179
`179
`174
`176
`174
`Placebo
`Olanzapine
`Placebo
`Olanzapine
`The New England Journal of Medicine is produced by NEJM Group, a division of the Massachusetts Medical Society.
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`n engl j med 375;2 nejm.org July 14, 2016 141
`Olanzapine for Chemotherapy-Induced Nausea
`effective to combine olanzapine than placebo with
`an NK1-receptor antagonist, a 5-HT3–receptor an-
`tagonist, and dexamethasone for the prevention of
`nausea and vomiting in patients who have not
`received previous chemotherapy but are currently
`receiving highly emetogenic chemotherapy. Patients
`who received olanzapine were more likely than
`those who received placebo to be free of nausea
`and emesis in the early, later, and overall assess-
`ment periods.
`The benefit of olanzapine in controlling nausea
`and emesis has been suggested in other phase 3
`trials.
`19,20 These trials showed that when olanzap-
`ine was added to guideline-directed prophylactic
`agents, nausea and emesis were significantly re-
`duced. The efficacy of olanzapine for nausea con-
`trol contrasts with the findings in clinical trials
`of NK
`1-receptor antagonists. Although these agents
`(aprepitant, fosaprepitant, netupitant, and rolapi-
`tant) significantly controlled early and later emesis
`in patients receiving moderately or highly emeto-
`genic chemotherapy they appear to have been less
`effective in controlling nausea.
`1-7,18
`In our study, patients who received olanzapine
`had more drowsiness on day 2 than at baseline,
`but for the most part, this symptom abated on
`days 3, 4, and 5, despite continued administration
`of oral olanzapine on days 3 and 4, suggesting that
`the patients adapted to the sedative effect of olan-
`zapine. Undesired increase in appetite was not seen
`in the current trial. There were no serious adverse
`events related to olanzapine, and no patient dis-
`continued olanzapine because of toxic effects. In
`view of the temporary drowsiness reported in this
`trial and previous reports of temporary drowsi -
`ness,
`13-15 more detailed information on drowsiness
`ratings, as well as the use of a lower dose of
`olanzapine (5 mg), could be explored in future
`trials.
`A limitation of our study is that we evaluated
`only one dose level of olanzapine. Lower or higher
`doses may have an effect on efficacy, toxic effects,
`or both. In addition, the study did not address the
`efficacy of olanzapine for multiple chemotherapy
`cycles. These issues should be considered in future
`clinical trials. In conclusion, our study showed
`that olanzapine combined with an NK
`1-receptor
`antagonist, a 5-HT3–receptor antagonist, and dexa-
`methasone is more effective than placebo com -
`bined with these agents for the prevention of
`nausea and vomiting in patients with no previous
`chemotherapy who are receiving highly emeto -
`genic chemotherapy.
`The content of this article is solely the responsibility of the
`authors and does not necessarily represent the official views of
`the National Institutes of Health.
`Supported by grants from the National Cancer Institute
`(UG1CA189823, U10CA180790, UG1CA189830, UG1CA189825,
`U
`G1CA189956, CA035269, and 5UG1CA189819).
`Disclosure forms provided by the authors are available with
`the full text of this article at NEJM.org.
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