`Dr. Reddy's Laboratories, Ltd., et al. v. Helsinn Healthcare S.A.
`Trial PGR2016-00007
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`Page 2 Of 9
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`DTX-0047-0003
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`Page 2 of 9
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`PERGAMON
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`This material may be protected by Copyright law (Title 17 U.S. Code)
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`i
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`European Journal of Cancer 37 (2001) 23984404
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`European
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`Journal of
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`www .ejconline.com
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`Randomised comparison of ondansetron plus dexamethasone
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`with dexamethasone alone for the control of delayed
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`cisplatin—induced emesis
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`H. Tsul<ada*, T. Hirose, A. Yokoyama, Y. Kurita
`Depczrtment ofIntemal Men'1'cine, Niigata Cancer Center Hospital, 2-15-3 Kuwagis/zz‘-c/10, Niigata, 951-8566, Japan
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`Received 6 February 2001; received in revised form l2 July 2001; accepted 12 September 2001
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`._._....._.-...-.-..aau.aw—w.—.---
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`Abstract
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`The role of 5-hy[li.‘OKytl'y]I)t21I11ll1€3 (HT3) antagonists in the treatment of delayed emesis is still controversial. To evaluate whether
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`5—HT3 antagonists can add to the efficacy of corticosteroids in controlling delayed emesis, we performed a randomised, prospective,
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`open study comparing ondansetron plus dexamethasone with dexamethasone alone in cisplatin—treated patients, 149 cisplatin-naive
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`patients with lung cancer received at least 60 mg/m2 of cisplatin and were treated with dexamethasone 32 ‘mg intravenously (iv)
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`and granisetron 3 mg i..v. on day 1. Patients were randomly assigned to receive either dexamethasone 16 mg i.v. alone (arm A) or
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`dexamethasone plus ondansetron 8 mg daily (arm B) on days 24. None of the efficacy variables related to control of delayed emesis
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`differed significantly between the two arms. In conclusion, there does not appear to be stiificieiit evidence to support the prolonged
`use of 5—l-IT3 receptor antagonists after 24 h of cisplatin-containing chemotherapy. © 2001 Elsevier Science Ltd. All rights reserved.
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`Keyword.s'.' Delayed emesis; Antiemetics; Cisplatin; Ondansetron; Dexamethasone; 5-HT3—recepto1‘ antagonists
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`1. Introduction
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`Nausea and emesis are among the most distressing
`adverse effects of cancer chemotherapy. The control of
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`nausea and cmcsis has a remarkable effect on the
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`patient’s quality of life and willingness to complete their
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`course of treatment.
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`Acute emesis after cisplatin administration has been
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`widely studied, and following the introduction of
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`5-hydroxytryptamineg (5-HT3)
`receptor antagonists,
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`significant advances have been made. in its control [I-4].
`Furthermore, large multicentre randomised trials have
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`the combination of a 5-HT3 receptor
`shown that
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`antagonist plusza corticosteroid is significantly more
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`effective than a 5-HT3 antagonist alone. In these trials,
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`the combination of a 5-HT3 receptor antagonist plus a
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`corticosteroid has been shown to yield an approximately
`75% (range 58-96%) complete control rate of acute
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`emesis after a high-dose eisplatin—based regimen [5—9].
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`* Corresponding author. Tel.: + 81-25-266-5111; fax: + 81-25-233-
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`3849.
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`E-mail add/‘es.r.' htsukada@niigata-cc.niigata.niigata.jp
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`(II. Tsukada).
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`However, the success achieved in the prevention of
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`acute emesis has not been extended to the control of the
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`delayed cmcsis induced by cisplatin. Delayed emesis,
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`although less intense than acute emesis, is still a major
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`problem for many patients, and its incidence varies, but
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`can be as high as 80% [l0,l 1]. Since the neuropharmaco-
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`logical mechanism of delayed emesis is not well under-
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`stood, preven-tion of this problem has been based on
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`empirical results [12]. In the clinical practice guidelines
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`developed by the American Society of Clinical Oncol-
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`ogy (ASCO), a corticosteroid plus metoclopramide -or a
`5—HT3 antagonist is recommended for the prevention of
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`delayed emesis [12]. Although the combination of corti-
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`costeroid and metocloprznnide has been shown to be
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`superior to placebo, and also to dexamethasone alone
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`[ll,l3], it is controversial whether continuation of a 5-
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`HT3 antagonist after acute control of emesis prevents
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`the development or reduces the frequency of delayed
`emesis [l4—20,23].
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`To evaluate the role of a 5—HT3 antagonist, in parti-
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`cular oral ondansetron,
`in the prevention of delayed
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`ernesis, we planned a single-institution randomised,
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`prospective, open study comparing ondansetron plus
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`0959-8049/Ol/$ - see front matter © 2001 Elsevler Science Ltd. All rights reserved.
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`PII: SO959—8049(0l)00326-4
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`in
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`Page 3 of 9
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`DTX-0047-0004
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`Page 3 of 9
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`H. Tsukada et al. / European Journal of Cancer 37 (2001) 2398-2404
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`2399
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`dexamethasone with dexamethasone alone in cisplatin-
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`treated patients,‘
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`2. Patients and methods
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`2.]. Patient selection
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`Eligibility criteria included pathologically—ccnfirmed
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`lung cancer, age between 15. and 80 years, performance
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`status of 3 or less according to the Eastern Cooperative
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`Oncology Group (ECOG)
`scale and chemotherapy
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`including cisplatin at a dose of at
`least 60 mg/m2.
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`Patients meeting any of the following criteria were
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`excluded: primary brain tumour or symptomatic brain
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`metastases, prior treatment with cisplatin, presence of
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`nausea and/or vomiting before the cisplatin treatment,
`current use of corticosteroids, recent changes in the
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`doses of major tranquilisers or sleeping pills habitually
`used, clinically significant gastrointestinal disease, or
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`evidence of severe uncontrollable diabetes. Written
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`informed consent was obtained from all patients, and
`the study-was approved by the Institutional Review
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`Board of our hospital.
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`2 .2. Treatment protocol
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`Patients were randomly assigned to receive either
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`dexamethasone alone (arm A) or dexamethasone plus
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`ondansetron (arm B). All the patients received cisplatin
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`treatment (60 or 80 mg/m2) only on the first day (day 1)
`of treatment, either alone or in combination with other
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`chemotherapeutic agents. On days 2-4, either no
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`chemotherapy or only agents with low emetogenicity
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`were administered. On day 1, patients received prophy-
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`lactic treatment with granisetron 3 mg intravenously
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`(i.v.) and dexamethasone 32 mg i.v. in four separate
`doses (8 mg each). Then patients assigned to treatment
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`arm A received dexamethasone 8 mg iv. twice daily on
`days 2-4. The treatment for arm B consisted of oral
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`ondansctron 8 mg daily in the morning on days 2-4, in
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`addition to dexamethasone at the same dose and on the
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`same schedule as arm A. If more than two episodes of
`severe nausea or vomiting were observed, patients
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`received a standard dose of metoclopramide (10 mg per
`body i.v. or intramuscularly) or domperidone (60 mg
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`per body suppository). Requirement of any other
`antiemetic treatment necessitated withdrawal from the
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`study;
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`2.3. Assessment ofejficacy
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`The protocol-specified primary end-points were com-
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`plete control of emesis (CCE), defined as no emetic epi-
`' Ksodcs, no use of rescue medication, and no missing data
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`during the 4-day period; complete control of nausea
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`(CCN), defined as no nausea, no use of rescue medica-
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`tion, and no missing data during the 4-day period; and
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`total control of emesis (TCE), defined as no vomiting;
`no nausea, no use of rescue medication, and no missing
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`data during the 4-day period.
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`immediately after
`randomisation (baseline period)
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`and at the end of each day (days 1-4), all patients were
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`asked to complete a daily diary. These diaries consisted
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`of the number of emetic episodes, the intensity of nau-
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`sea,
`their assessment of global satisfaction with the
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`antiemetic treatment, and general mood at that time.
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`Since all the patients were inpatients over the 4-day
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`study period, monitoring by direct observation and
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`interview was also used. Anemetic episode was defined
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`as any episode of vomiting or dry retching. .
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`The patients assessed the intensity of nausea accord-
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`ing to a graded scale: none, mild (did not interfere with
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`normal daily life), moderate (interfered with normal
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`daily life) and severe (bedridden due to nausea).
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`Patient’s global satisfaction with antiemetic treatment
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`was assessed using the visual analogue scale (VAS). The
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`patient was asked to place a mark on a 100-mm line
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`where 100 mm was ‘not at all satisfied’ and 0 mm was
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`‘totally satisfied’.
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`Each patient reported subjective assessment of general
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`mood day-by-day using a five-point face scale from
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`“QOL assessment of cancer patients receiving chemo-
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`therapy” reported by Kurihara and colleagues [30].
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`We plotted the daily VAS score and daily face scale
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`score on a time curve for each patient. The VAS and
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`face scale profiles were then evaluated on the basis of
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`area under curve (AUC) over the 4-day period calcu-
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`lated by trapezoidal summation, and the difference
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`between the baseline score and worst score during the
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`study period.
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`2.4. Assessment ofscgfetiy
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`All adverse events were documented throughout the
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`study period. Vital signs were recorded before and after
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`the administration of the antiemetic or cytostatic ther-
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`apy. Routine haematological and biochemical tests were
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`performed at
`the same times. The severity of each
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`adverse event and its relationship to the study treatment
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`was assessed by the investigator.
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`'2.5. Statistical analysis
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`The sample size was calculated assuming that 40% of
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`patients assigned to arm A, and at least 65% of the
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`patients of arm B would achieve total control of emesis.
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`With type 1 and 2 errors of 5 and 20%, respectively, it
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`was calculated that 61 patients should be included in
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`each arm. To ensure there would be at least 61 patients
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`assessable for analysis, we decided to include 70 patients
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`in each arm.
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`Page 4 of 9
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`DTX-0047-0005
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`Page 4 of 9
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`2400
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`‘ii
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`H. Tsukadu at (11. / European Journal of Cancer 37 (2001) 2398-2404
`
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`Recruited or accrued patients
`(n=149)
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`sidered significant. Received standard Intervention
`
`3. Results
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`3.]. Patients’ characteristics
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`A total of 149 patients entered the study, and 141
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`patients were evaluated for eflicacy according to the
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`intention-to-treat principle. 8 were lost to follow-up and
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`excluded from the analysis (Fig. 1). Toxicity was also
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`evaluated in these 141 patients. Of the assessable and
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`eligible patients, 70 received dexamethasone alone (arm
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`A) and 71 received ondansetron plus dexamcthasone
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`(arm B) as a maintenance treatment. Treatment groups
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`were well balanced for sex, age, daily alcohol consump-
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`tion, performance status and for cisplatin dose (Table 1).
`
`Received test Intervention
`as allocated
`as allocated
`
`
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`(I1-=73)
`(n=7G)
`
`Did not receive standard
`
` Did not receive test
`intervention as allocated
`Intervention as allocated
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`(n=0)
`(n=0l
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`Followed-up (n=73)
`
`Followedup (n=76)
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`Withdrawn (n=3)
`Intervention lnetieotive (n=0)
`Last to ioliow-up (n=0)
`
`Other (n:-.0)
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`Withdrawn (n=5)
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`Intervention lnellectlva (n=0)
`Lost to ioliow-up (n=5)
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`Other (n=D)
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` Completed trial (n—~70)
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`Completed trial (n=T1)
`
`Fig. 1. ‘Flow chart of the progress of patients through the trial (adap-
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`ted from Ref. [29]).
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`3.2. Control of acute emesis (day 1)
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`Analysis of nausea and emesis was performed sepa-
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`rately for day 1 (acute emesis) and for each day, from
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`day 2 to day -4, considering the overall results between
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`days 2 and 4 as an evaluation of delayed emesis.
`Fisher’s Exact test was used to evaluate the balance of
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`prognostic factors between the two groups, and to
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`examine differences in eflicacy and the incidence of
`
`Overall, complete control of emesis was observed in
`
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`93% and control of nausea was observed in 82% of
`
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`patients. Between the two randomised groups, no sig-
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`nificant differences were observed in the complete con-
`trol of vomiting (arm A versus arm B; 93% versus
`
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`’93%),'of nausea (84% versus 80%), or of both nausea
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`and vomiting (84% versus 79%). Mean number of
`
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`emetic episodes (0.1 versus 0.1), mean score of maximum
`
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`intensity of nausea (0.2 versus 0.3), and the number of
`
`NS
`
`NS
`
`NS
`
`NS
`
`
`
`V
`
`NS
`
`
`NS
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`
`NS
`
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`
`
`1
`
`71
`
`53/13
`
`
`63 (2(F72)
`
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`21/46
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`66/5
`
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`
`14
`57
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`25/46
`
`
`42/29
`
`
`Table 1
`
`Patients’ characteristics
`
`
`
`
`_
`
`Number of patients
`
`
`
`
`
`70
`
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`
`55/15
`
`65 (40-74)
`
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`Sex: male/female
`
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`
`
`Median age (years) (range)
`Habitual alcohol intake"
`
`
`
`No/Yes
`
`Performance status (ECOG)
`
`
`0-1/2—3
`
`Cisplatin dose (mg/mi)
`
`
`
`< 80
`
`
`
`> 30
`Histological type
`
`
`SCLC/NSCLC
`16/54
`
`Clinical stage
`
`
`I-III/IV
`
`
`
`
`28/37
`
`
`
`63/7
`
`
`
`13
`57
`
`
`
`
`
`
`44/26
`
`
`Dexamethasone alone
`
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`Ondansetron plus dexamethasone
`
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`P value
`
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`SCLC, small cell lung cancer; NSCLC, non-small cell lung cancer; ECOG, Eastern Co-operative Oncology Group; NS, non significant.
`“ , there are missing data in some categories.
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`Page 5 of 9
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`DTX-0047-0006
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`
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`adverse events. Mann—Whitney’s U-test was performed
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`to compare treatment groups with respect to intensity of
`
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`nausea, global satisfaction with antiemetic treatments,
`and ‘number of emetic episodes. All P values refer to
`
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`two-tailed tests, and P values less than 0.05 were con-
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`Fiandornised patients
`
`Not randomised (n=O)
`Reasons (give all violation
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`of inclusion criteria)
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`Page 5 of 9
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`
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`'
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`
`87% 86°/o
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`(l.96
`
`-74% 75%
`
`“fl
`
`(a) 100
`
`"
`
`
`
`
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`
`
`P=0.97
`84% 84%
`
`30
`
`
`
`H. Tsu/cada er al. /European Journal of Cancer 37 (2001) 2398-2404
`
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`0.81
`90% 89%
`
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`
`
`2401
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`
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`(b) 100
`
`
`
`
` 30
`
`
`
`P=0.76
`0.67
`
`6 0-95 67% 70%
`
`69% 66%
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`
`0.94
`
`54% 55%
`
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`
`60
`
`40
`
`Percent
`
`
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`
`20
`
`
`
`Percent
`
`60
`
`40
`
`20
`
`Day 2
`Day 3
`
`
`
`Days 2-4
`Day 4
`
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`
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`
`
`Days 2-4
`
`
`
`
`i,
`
`;
`
`-.-I:--‘1-;1-:~
`
`El ArmA - ArmB
`
`
`
`Fig. 2. Percentages of complete control of delayed (a) ernesis and (b) nausea.
`
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`patients receiving rescue medication (54 versus 55) were
`nearly identical in the two groups.
`
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`
`
`3 .3 . Comm] of delayed emesis
`
`
`
`
`
`
`The percentages of CCE or CCN on a daily basis over
`
`
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`days 2-4 are shown in Fig. 2. None of the pairwise
`
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`treatment comparisons of efficacy revealed a statistically
`
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`
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`significant difference. We also found no significant dif-
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`
`
`fcrence between the two arms in either total number of
`
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`
`
`vomiting episodes per patient during days 2-4
`
`
`
`
`(P=0.8716) or worst grade of nausea intensity duri11g
`
`
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`
`
`
`days 24 (P = 0.9474).
`
`
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`
`
`
`As shown in Fig. 3a, TCE rates for the entire study
`
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`period (days 2-4) were approximately 50%. TCE rates on
`
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`the individual days and over days 2-4 in the two compar-
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`able arms did not differ significantly. Irrespective of the
`
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`anticmctic treatment received, TCE was achieved in 70
`
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`of 115 patients (61%) who did not suffer from emesis on
`
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`day 1 and in 2 of 26 patients (8%) who suffered from
`
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`
`
`emesis on day 1. This difference was highly significant
`
`
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`
`
`
`
`(P<0.000l). In the subgroup of patients who did not
`
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`
`
`sufler from either vomiting or nausea on day 1, there
`
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`
`
`
`
`
`were no significant differences in the TCE rates (Fig. 3c).
`
`
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`
`
`TCE rates of those who suffered from emesis on day 1
`
`
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`
`
`were also similar in the two treatment groups (Fig. 3b).
`
`
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`
`
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`
`
`(b) 100
`
`
`
`
`
`
`
`80
`E so
`8
`
`3 4°
`
`20
`o
`
`
`(0) 100
`an
`
`E 60
`8
`E 40
`20
`
`
`
`(a) 100
`
`
`
`
`30
`
`
`'P=0.52
`
`69% 63%
`
`
`
`0.68
`
`66% 69%
`
`
`
`
`66% 65%
`0-91
`
`
`
`0.67
`
`53% 49%
`
`
`
`
`
`E 6°
`8
`
`ii.’
`
`40
`
`20
`
`0
`
`
`Day 2
`
`
`Day 3
`
`
`Day 2
`
`
`Day 3
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`Fig. 3. Total control rates over days 24 for delayed emesis among (a) total population, (b) the patients who suffered from emesis on day l and
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`(c) the patients who did not suffer from emesis on day l.
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`|:| Arm A - Arm B
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`Page 6 of 9
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`DTX-0047-0007
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`Page 6 of 9
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`2402
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`H. Tsu/coda et al. /European Journal of Cancer 37 (2001) 23984404
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`5
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`Face scale
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`Baseline
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`Day 1
`Day 2
`Day 3
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`Baseline Day 1
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`Fig. 4. Visual analogue scale (VAS) and face scale score profile over the study period. Open circles indicate each scale score profile for the patients
`assigned to arm A and closed circles indicate those for the patients assigned to arm B.
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`3.4. Patienzs’ global satisfaction
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`Profiles of the mean daily VAS and face scale scores
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`are shown in Fig. 4. Error bars represent the standard
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`errors. 28 patients were excluded from these analyses
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`because the investigators failed to deliver
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`tionnaires to 21 of them and because 7 patients stopped
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`filling out the questionnaires halfway through the study
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`period.
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`There was no difference between the groups in the
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`proportion of patients excluded. No statistically sig-
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`nificant differences were recorded between the groups in
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`the VAS or face scale score on any one of days 2—4.
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`Table 2
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`Adverse events (days 24)
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`Dexaincthasone Ondausetron plus
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`Pvalue
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`When we calculated the AUC over the 4-day period and
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`these two scales during the study period, no significant
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`differences were found between the two arms (Fig. 4),
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`3.5. Safety
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`No severe or unexpected adverse events were repor-
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`ted. Adverse events of grade 3 or 4 were also not
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`reported. Adverse events of grade 1 or 2 occurred in 34
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`(49%) of the 70 patients for arm A and in 46 (§5,%) of
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`71 for arm B (P=0.06). Epigastric pain, constipation,
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`asthenia, heartburn, and insomnia occurred with greater
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`frequency with arm B (8, 23, 27, 6 and l7 %, respec-
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`tively) compared with arm A *(l, 21, 21,
`1 and 9%,
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`respectively). However, there were no significant differ-
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`ences in the rates of each adverse event from days 2 to 4
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`between the two treatment groups (Table 2).
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`Number of patients 70
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`71
`NS
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`Number (%) of patients suffering adverse event
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`9 (13)
`4 (6)
`NS
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`771 (1)
`6 (8)
`NS
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`9 (13)
`7 (10)
`NS
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`IO (14)
`7 (10)
`NS
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`15 (21)
`16 (23)
`NS
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`15 (21)
`19 (27)
`NS
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`1 (1)
`4 (6)
`NS
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`6 (9)
`12 (17)
`NS
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`4 (6)
`4 (6)
`NS
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`36 (51)
`25 (35)
`NS
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`Adverse effects“
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`Headache
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`Epigastric pain
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`Rush
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`Abdominal gas
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`Constipation
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`Asthcnia
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`Heartburn
`Insomnia
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`I-Iot flashes
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`None
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`NS, non significant.
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`“ All events were grade 1 or 2.
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`4. Discussion
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`The combination of a corticosteroid plus a 5-HT3
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`antagonist is one of the recommended regimens for cis-
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`platin-induced delayed emesis in the ASCO Clinical
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`practice guidelines [12]. Several randomised trials have
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`shown that the addition of corticosteroids to 5-HT3
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`antagonists
`significantly improved the
`control of
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`delayed emcsis [16,21—23].
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`However, there was very limited data on the efficacy
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`of dexamethasone alone without 5—HT3 antagonists as
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`background therapy [24]. None of the trials comparing
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`Page 7 of 9
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`DTX-0047-0008
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`Page 7 of 9
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`H. Tsukada at al. / European Journal ofCzmcer 37 (2001) 2398-2404
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`2403
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`the combination of corticosteroid plus a 5—HT3 antago-
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`nist with corticosteroids alone determined the benefit of
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`adding 5-HT3 antagonist to corticosteroids in the con-
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`trol of delayed emesis [l8—20]. These studies employed
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`granisetron or tropisetron as a 5—HT3-receptor antagonist.
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`Although the majority of multiple, randomised stud-
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`ies have demonstrated that the four currently available
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