Helsinn Healthcare Exhibit 2052
`Dr. Reddy's Laboratories, Ltd., et al. v. Helsinn Healthcare S.A.
`Trial PGR2016-00008
`
`Page 1 of 10
`
`

`
`PALO—99—O3
`
`Confidemia! and Proprietary Infermatinn
`
`Helsfinn Healthcare SA
`
`L
`
`0002
`
`APPROVALISIGNATURE PAGE
`
`Heisinrz Heafithcare SA
`23.0. Box 357
`6915 F‘amhéo—Noranco
`Switzerland
`
`Project Manager
`
`2351 7-
`U
`J‘
`'
`4 ((3 M ‘L’
`
`-
`,,
`X
`‘ ‘g‘/{E9 ‘§*“"'/5
`
`-
`
`Aéberm Macciocchi. MD MFPM
`
`Date
`
`Signature
`
`Statistician
`Cecflia Moresino, MS:
`
`.13 5%
`Date
`
`-~
`
`6. ‘La
`Signatures
`
`mw
`
`
`
`
`
`
`
`reunn5_03. 19.07 02
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`P395 2 DI 250
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`HELSNOO37849
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`Page2 of 10
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`Page 2 of 10
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`

`
`PAi.O—99-O3
`
`Confidentiai and Proprietary Enmrmafion
`
`Heésinn Heaflhcare SA
`
`a
`
`0003
`
`
`
`APPROVALISIGNATURE PAC-3-E
`
`Kendle GmbH 8: C0 GM! KC5
`
`Stefan—Ge0rge--Ring 6
`81929 Munich
`
`Germany
`
`Giobai Project Manager
`Hildegard van Bergen, PhD
`
`(3 . 6”}. YOU?
`Date
`
`I
`I
`'- I. Q K. K] 3/
`Signature
`
`Data Manager
`
`Kerstin Honig-Bfium
`
`.
`
`I 94 ’
`
`1
`
`" 59’?
`
`,
`
`= V‘
`
`r"".
`
`I”
`
`{Z62
`
`\
`
`Date
`
`Signature
`
`
`
`Statistician
`Sabine Kiederle, MSC
`
`4’ 3 . 07! ,’Z©0?L
`Date
`
`S
`$Ignature
`
`Medical \-‘\Iri'tee*
`
`Patricia Bflnz, Phi)
`
`IA» E01
`
`Date
`
`/jsI
`
`‘w.E';...u
`
`Sgnature
`
`repuflbwfll, 15-! 0102
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`Page 3 013350
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`

`
`P/3\L.O—99—03
`
`Confidential and Proprietary information
`
`0
`l-ielsinn Healthcare SA
`
`0004
`
`
`
`SYNOPSES
`Name of Sponsorlcompany:
`
`lndividuai Study Table
`
`T
`1 (For National Authority Use only}
`
`Z
`
`Helsinn Healthcare SA
`
`Referring to Part
`
`of the Dossier _
`
`Votume:
`
`Page:
`
`
`
`
`
`
`
`
`
`_ Name of Active ingredient;
`
`__..
`.
`.
`.
`:
`= '
`.
`;Titte of the study: A doL:ble«blind clinical study to compare single IV doses of goalonosetron 0.25 mg
`or 0.75 mg, and ondansetron 32 mg 1V, in the prevention of moderately emetogenio
`' ohemotherapy—induced nausea and vomiting.
`- Investigators: Principal co-ordinating investigator for Germany: Prof. Christian Peschel. MD, principal
`‘co-ordinatmg investigator for ltaly: Roberto Labiance, MD.
`Study Centers: There were 58 active centers, 16 centers in Germany, 10 in ltaly, 2 in the United
`. Kingdom, 7 in The Netherlands (which were pooled together to 9 centers with the centers in the
`g United Kingdom) and 23 centers in Russia (subdivided by region in 2 centers in Arkhangelsk. 10
`Z centers ilvloscow and 11 in St. Petersbrg).
`itin ernce) Not applicable _
`7
`7
`f Study period (years): t .17 years
`I Phase of ctevelopmet: lll
`
`3 {first patient in): 0'l August 2000
`
`
`mm
`(last ptiet out): 02 October 2001
`Primary Objective: To compare the efficacy of single lV doses of palonosetron 0.25 mg or 0.75 mg.
`to ondansetron 32 mg iv in preventing moderately emeiogenic CINV.
`Secondary Objectives: To evaluate the safety and toierability of palonosetron and its relative safety
`in comparison with ondansetron. To evaluate the effect of antivemetic controi with palonosetron or
`odansetron on t quality or’ life of patients receiving moderately emetogenic chemotherapy.
`Methodology: This was a multicenter, phase lit, randomized. baianced, controlled, double-blind,
`double—dummy, parallel, stratified, and active comparator study.
`I Number of patients:
`Pianned:
`587 patients (189 per group, 180 evaiuaole patients per group)
`‘
`Enrolled:
`571 patients
`Analyzed
`Safety cohort:
`
`582 patients
`Palonosctron 0.25 mg: 187
`Pelonosetron 0.75 mg: 188
`Onctansetron 32 mg: 187
`563 patients
`Palonosetron 0.25 mg: 189
`Paionosetron 0.75 mg: 189
`Ondansetron 32 mg; 185
`517‘ patients
`Palonosetron 0.25 mg: 172
`Paionosetron 0.75 mg: 174
`
`.
`
`ITT cohort:
`
`PP cohort:
`
`mgmndansetron 32 mg: 171
`
`___u________
`
`
`
`repnr15_C3, 19.0102
`
`Page 4 Df 25:]
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`Page 4 of 10
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`Page 4 of 10
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`

`
`PALO—99—O3
`
`Confidential and Proprietary information
`
`L.
`Helsinn Healthcare SA
`
`0005
`
`
`individual Study Table
`or National Authrity Use
`Referring to Part
`of the Dossier
`
`7
`7
`Synopsis ctlnued 7
`Name of Sponsor/Cornpany:
`Hetsinn Healthcare SA
`
`Volu me:
`
`Name of Active lngreint: I
`
`I Page:
`
`‘ Main criteria for diagnosis and inctusiorr: Male or female, 218 years of age; histologically or
`cyiologicaliy confirmed malignant disease; naive or nonwnaive to chemotherapy, Karnofsky index
`2 50%; scheduled to receive a singie dose of at least i otthe following agents administered on Study
`' Day 1: any close of carboplatin, epirubicin, idaruinicin, itosiamide, irinotecan, or mitoxantrone; or
`rnethotrexate > 250 rnglmg; or cyciophospharnide < 1,500 mglrnz; doxorubicin > 25 mg/m2; or cispiatin
`s 50 mg/M2 (to be administered over‘1 to 4 hours). The administration of the major chemotherapeutic
`agent (which was the most ernetogenic agent according to classification of Hesketh, et a1.. The
`Oncologist ‘I999; 4:191-196) on Study Day 1 should not extend beyond 4 hours.
`Main criteria for exclusion: Inability to understand or cooperate with the study procedures; received
`any investigational drugs within 30 days before study entry; received any drug with ootentiai anti-
`. emetic efficacy within 24 hours of the start of treatment or were scheduled to receive until Day 5 of the
`
`study including 5-HT3 receptor antagonists, metoclopramide, phenothiazirre anti-emetics (including
`thiethylperazlne
`and
`oerohenazine),
`scopolamine,
`diphenhydrasnine,
`Z prochlorperazine,
`chlorphenirarnine rnaleate, trirnethobenzarnide, all tzienzodiazepines except ternazepam or ‘triazolarn
`
`tetrahydrocannabinoi, or nabiione, any
`clroperidol,
`used once nightiy for sleep. heloperidoi,
`corticosteroid including dexarnethasone, nydrocortisone. methyiprednisolone, prednisone (excluding
`topical or inhaled preparations); enrolled in a previous study with palonosetron (RS—25259 of Syntax); :
`had a seizure disorder requiring enticonvulsant medication unless clinicaily stable and tree of seizure
`activity; experienced any vomiting, retching; or NCI Common Toxicity Criteria grade 2 or 3 nausea in
`the 24 hours preceding chemotherapy; had ongoing vomiting from any organic etiology; experienced :
`i nausea (moderate to severe) or vomiting ‘toliowing any previous chemotherapy; scheduled to receive
`any dose of nitrogen rnLrstard(s), dacarbazine (DTlC} or streptozotocin; or
`lomustine (GCNU)
`>60 rnglmz, or carmustine {BCNEJ) >250 mglmz or any other chemotherapeutic agent with an I
`ernetogenicity level 5 according to the Hesketh et al. classification; or were scheduled to receive any
`chemotherapeutic agent with an errietogenicity levei 3 or higher during Days 2 to 6 of the Study; had a
`known contraindication to t3—l—i“i3 receptor antagonists; or were scheduled to receive radiotherapy of
`upper abdomen or cranium during Days 2 to 6.
`= Test product: Palonoaetron
`Dose: 0.25 mg, 0.75 mg
`2 Batch number: 0.25 mg: 'i73'f'32l, HPAOO3, 0.75 mg: ‘l?’3?33l, HPBOOZ
`(30 seconds ooius}
`
`Mode of administration: intravenous
`Duration of treatment: single dose
`
`
`
`
`
`YEDUI-I5¥B3 1‘3J.77 DZ
`
`Page 5 of 2.50
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`Page 5 of 10
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`

`
`PALO-99-O3
`
`Confidential and Proprietary Information
`
`i...
`Helsinri l-iealthcare SA
`
`0006
`
`
`
`Synopsis continued
`Name of Sponsor/Company:
`I-telsinn Healthcare SA
`
`iridividoai Study Table
`, Referring to Part
`of the Dossier
`
`{For National Authority Use oniy)
`
`Name 0 inished Podut:
`
`K
`
`Voiurne:
`
`1 Page:
`
`: Name ofAciv ingredient:
`9 Paloostron l-tCl
`E Reterence therapy: Ondansetron
`Dose: 32 mg
`Batch number: 8181373, 8'i6’i88A
`
`so adiitrtion: inravenous (15 Entries iv infuion)
`Duration of treatment: single dose
`Criteria for evaluation:
`
`_
`
`_ Primary Criterion: Complete response (defined as no emetic episode and no rescue medication}
`during the first 2!: hours after administration of chemotherapy.
`1 Secondary Criteria: Complete response (no emetic episode and no rescue medication) daily for the
`5 24 to 120 hour intervai, for cumulative time periods and for the overall 0 to 120 hour interval. complete
`control (defined as those patients who had a complete response and no more than rniid nausea),
`i number of emetic episodes, time to first emetic episode, time of administration and need for rescue
`medication, time to treatment failure, severity of nausea measured by the Likert Scale, patient global
`satisfaction with anti-emetic therapy (VAS), quality of life questionnaires (FLiE}.
`Safety: Adverse events, vital signs, physical examination, clinical iaboratory parameters, 12—iead
`_
`Hotter rnonirig or a slce paent atio.
`_
`__
`Statistical methods: The primary efftcacy variable was the proportion of patients considered to have
`achieved a complete response during the first 24 hours after administration of chemotherapy. The
`analysis based on the i‘i"i' cohort was considered as primary anatysis. To demonstrate the non-
`interiority of at ieast '1 dose of paionosetron to ondansetron, the lower bound of the 97.5% confidence
`intervals (CI) for the difference {palonosetron minus ondansetron) between the proportion of patients
`with a complete response (CR) during the first 24 hours after administration of chemotherapy was
`calculated and compared to ‘die pre-set threshold (-15% difference). Moreover, to investigate the
`equivalence of the 2 palonosetron doses with respect to CR (0 to 24 hours) the bound of the two—sided
`95% Ci of the difference between the proportions of CR (0 to 24) were compared to the pre-set
`threshold (:15%). The validation/study sensitivity was assessed by comparing CR (0 to 24 h) of the
`3 active control ondansetron with modeled historicat placebo results and modeled historicat ondansetron
`= results from the literature. Complete response at further time points was anaiyzed using the same
`statistical methods as for the primary efficacy parameter. Complete control and the proportion of
`Q patients receiving rescue medication were anaiyzed using the Chi-square test. Furthermore, Poisson
`regression analysis was performed for the emetic episodes taking into account if rescue medication
`was administered. Quatity of tits, number of emetic episodes, severity of nausea and patient giobai
`satisfaction were compared between the treatment groups using the Kruskal—Waltis test or the
`Wiicxon test. 7
`
`‘
`
`
`
`
`
`reporl.5_D3, ‘l9.C'F.E12
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`Page 6 0? 250
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`Page 6 of 10
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`

`
`PAi_O—99-O3
`
`Confidential and Proprietary lnionnation
`
`l-ielsinn Healthcare SA
`
`0007
`
`
`
`Synopsis continued
`Name of Sponsor/Company:
`i-telsinn Heatthcare SA
`
`
`_ tndlviduai Study Table
`For National Authority Use only)
`' Fieterring to Part
`of the Dossier
`
`E
`
`Name of Finished Product:
`
`Voturne:
`
`Page:
`
`
`
`Name of Active ingredient:
`_
`7
`7
`F-‘slonosetron HQ!
`Statistical methods (continued): Differences between the treatment groups regarding time to first
`emetic episode, time to first administration of rescue medication and time to treatment faiiure were
`analyzed using Kapian-Meier estimates and a Log-Rank test.
`i incidences for adverse events were calcuiated overali, by category, by body system and by preferred
`term. In addition, 95% Cl were provided for the overall incidence and for the inctdence by category of
`adverse events in each treatment group. Changes in laboratory values with respect to toxicity grades
`were investigated for each time point within each group using Wiicoxon matched pairs signed rank
`test. Ail other afety paraeers were anaiyzed descriptlveiy.
`Summary
`Efficacy resuits:
`_ The proportion of patients who achieved a complete response and the results from the statistics! I
`. analysis of the primary etficacy parameter complete response rate during the first 24 hours after
`Chemotherapy are displayed in Table '1. whereas in Table 2 the 97.5% Cls of the difference in CR rate
`éot each dose of palonosetron versus ondansetron are depicted.
`:
`
`
`
`Table 1: Patients with a complete response rates during the first 24 hours after chemotherapy
`(tTT cohort, N = 563)
`Time period
`Palonosetron 0.75 mg
`Palonosetron 0.25 mg
`
`
`{hours}
`{N=139)
`(N=189)
`
`N
`%
`N
`%
`|o—24
`
`153
`
`31.0
`
`H
`
`139
`
`73.5
`
`Ondansetrcn 32 mg
`{N=i85)
`N
`°/u
`
`mt
`
`68.6
`
`Table 2: The 97.5% confidence interval for the difference in complete response rates during the
`Irst 24 hours after chemotherapy between the palonosetron groups and the onctansetron group
`(ITT cohort, N = 563)
`
`Palonosetron 0.25 mg
`
`Palonosetron 0.75 mg
`
`
`
`minus ondanaetron mn1g'W__________
`
`
`E18“; 2.%]
`9725., Cl
`The lower limit of the 97.5% confidence interval for the ctitierence in complete response rates during
`the first 24 hours after chemotherapy was above -15% (preset threshold) for both comparisons of
`palonosetron to ondansetron 32 mg. “therefore.
`the nominferiority of both palonosetron doses to
`ondansetrcn 32 mg was demonstrated for the prevention of moderately emetogenic chemotherapy-
`induced nausea and vomiting. Furthermore,
`the lower iirnit of the 97.5% confidence intervai of the
`comparison paionosetron 0.25 mg with ondansetron was above zero,
`indicating superior complete
`response rates in the patonosetron 0.25 mg group compared to the ondansetron group. The resutts
`I from the PF cohort were consistent with the WT analysis.
`
`
`
`
`
`___minus ondansetron 32 mg
`_ [-6.1% 15.9%]
`
`
`
`
`
`reporisos. ‘lE‘.C7.02
`
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`

`
`PALO-99-03
`
`Confidential and Proprietary information
`
`L.-
`Helsinn Healthcare SA
`
`0008
`
`Synopsis Continued
` Name of Sponsor/Company:
`(For National Authority Use ohiy)
`; Individual Study Tools
`Helsinn l-ieelthcere SA
`Referring to Part
`of the Dossier
`
`
`
`
`
`A subgroup analysis by chemotherapeutic history showed in naive patients a trend towards higher
`Complete response rates and complete eoritrot rates. Furthermore, naive patients tended to have tees
`
`
`neuea, a higher patient giobal satisfactionandigher quality of tits scores than non-naive patits.
`
`
`
`repori5_oa. 19.97.02
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`
`
`Nam of Fiished Product:
` Name of Active ingredient:
`
`Volume:
`
`N Page;
`
`Paionostr l-iCt
`Efficacy resuits (continued):
`Non-inferiority of both palonosetron doses to ondensetron with regard to compiete response for
`delayed emesis was atso shown for aii additional
`time periods during this study. Superiority of
`paionosetron 0.25 mg compared to ondansetron with regard to complete response was shown on
`Study Days 1, 2, 3, and 4 and during each curnuietive time period.
`Pairwise testing revealed differences between palonosetron 0.25 mg and ondansetron in favor of
`patonosetron 0.25 mg for complete control during ail time periods {p < 0.050, Chi-square test) except
`for Study Days 1 and 5, number of emetic episodes on Study Days 1, 2, 3 and the time period 0 to 120
`‘ hours (:3 < 0.050, Witcoxon test), time to ‘fii"5t emetic episode (p < 0.001,
`i.og—Ranl-2 test), severity of
`nausea on Study Days 2, 3 and 4 (p < 0.050, Wilooxon test), time to treatment failure (p < 0.001, Log-
`Rank test), patient global satisfaction on Study Day 3 (p = 0.015, Wilcoxon test) and the total score for
`qnaiity of life within 24 to 96 hours (p ==0.014, Wiicoxon test). Furthermore,
`tnetter efficacy was
`obsewed for palonosetron 0.75 mg Compared to ondansetron for complete control on Study Days 3
`and 4 (p < 0.050, Chi-square test} as well as severity of nausea on Study Days 4 end 5 (p < 0.050,
`Wilooxon test).
`Superiority of paionosetron 0.25 mg to paionosetron 0.75 mg was demonstrated for complete
`response retes on Study Day 2 and during the time periods 0 to 48 hours, 0 to 72 hours, 0 to 96 hours
`and 0 to 120 hours because the upper limit of the confidence iritervais for the difference in complete
`response rates was below zero. in addition, differences in favor ot palonosetron 0.25 mg were seen
`between the 2 palonosetron groups for complete control on Study Day 2 (p = 0.010) and during the
`time periods 0 to 48 hours (p: 0.010) and 0 to 72 hours (p = 0.046, Chi-square test), number of
`emetic episodes on Study Day 2 (p = 0.003) and during the time period 0 to 120 hours (p = 0.036,
`Wiicoxon test), time to first emetic episode (p = 0.031, Log—F?.ank test), severity of nausea on Study
`Day 2 (p = 0.049) and time to treatment failure (p = 0.028, Log-Rank test).
`A subgroup analysis by gender showed in mate patients a trend towards higher complete response
`rates, higher complete control rates, less nausea, longer time to treatment failure, Eonger time to first
`emetic episode, less rescue medication, higher patient global satisfaction and higher quality of life
`scores for nausea compared to female patients. A better efficacy of both paionosetron doses
`compared to ondensetron was observed for most etfioecy parameter in mate and female patients.
`Furthermore, a consistent
`treatment group difference was found in female patients with the
`peionosetron 0.25 mg dose showing better efficacy than the palonosetron 0.75 mg dose and
`ondansetron 32 mg.
`
`Page 8 of 10
`
`

`
`PALO—99~03
`
`Confidential and Proprietary information
`
`-.... D009
`Helsinn Healthcare SA
`
`Ssis continued
`Name of Sponsor/Company:
`individual Study Table
`j (For Nationai Authority Use oniy)
`
`Helsinn Healthcare SA
`Referring to Part
`of the Dossier
`
`
`
`. Name finished Product
`
`Voiurne:
`
`
`
`
`
`
`Name of Active ingredient:
`
`Page:
`
`,,
`.
`_
`.
`.
`.
`.
`Pa‘°°5‘3t‘"°“ HG‘
`
`‘ Overall, better complete response rates were found in Arkhangelsk and St. Petersburg.
`The validity of the study was shown by better cornpiete response rates of ondansetron compared to
`modeied historical placebo and by similar complete response rates of ondansetron and modeled
`I historical ondansetron. Furthermore, the validity of deita used in this study was confirmed.
`Safety resuits:
`The percentage of patients with adverse events during the study was comparable in the treatment
`groups. in the palonosetron 0.25 mg group 114 patients (61.0%) experienced 273 adverse events, in
`the palonosetron 0.75 mg group 125 patients (56.5%) group had 275 adverse events and 120 patients
`(64.2%) in the ondansetron 32 mg group experienced 294 adverse events. Patients most frequently
`reported adverse events such as lymphopenia (palonoseiron 0.25 mg: 14.4%, paionosetron 0.75 mg:
`12.2%, ondansetron: 10.7%). leucopenia (palonosetron 0.25 mg: 12.8%, palonosetron 0.75 mg: 11.2%,
`ondansetron: 11.2%), often reported in patients receiving chemotherapy, and headache (paionosetron
`O.25rng: 10.2%, paionosetron 0.75rng: 12.2%. ondansetron: 15.0%) in the treatment groups. Most
`adverse events were of mild intensity (range of 80.8% to 64.6%).
`3 Of ail adverse events, 40 adverse events in 30 patients (18.0%) in the palonosetron 025 mg group, 45
`‘ adverse events in 30 patients (16.0%) oi the palonosetron 0.75 mg group and 50 adverse events in 26
`patients (13.9%) of the ondansetron 32 mg group were considered treatment related (definite, possibie,
`probable or unknown relationship to the study medication). Withdrawals due to adverse events were
`‘ rare in this study. One patient (0.5%) withdrew from the palonosetron 0.75 mg group due to clehiiity and ‘
`
`
`1 patient
`(0.5%)
`from the ondansetron group withdrew because of puimonary embolism, blood
`
`
`carbonate decreased and hyperbiiirubinemia. Two patients died in the palonosetron 0.75 mg group
`
`
`(patient no. 3145: atelectasls, pleural effusion and pneumonia; patients no. 1263: diabetic ketoacidosis).
`
`
`One death was reported in the ondansetron group (patient no. 3328: pulmonary embolism). in addition,
`
`
`, 1 death (patient no. 3219: progression of gastric cancer) was reported after database closure.
`
`
`= Therefore.
`included in the study database. None of the deaths was .
`the patients death was not
`
`
`: considered to be reiated to the study medication.
`
`
`‘ There were no safety concerns associated with results of laboratory parameters. vital signs, ECG
`
`j_ redig. and l-tolte
`rnasurddrig the study.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`remns_o3, 19.07.-32
`
`Page 9 of 250
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`

`
`PALO—99—O3
`
`Confidential and Proprietary Information
`
`L,- U010
`Helsinn Heelthoare SA
`
`yopsis continued
`Name of Soonsorlcompany:
`
`
`
`3 Helsinrt ttealthcare SA
`
`individuai Study Table
`Referring to Part
`of the Dossier
`
`I (For National Authority Use only)
`
`g Nam ishedro " Voiume:
`
`
`
`
`
`
`Page:
`
`
`
`
`
`; Name of Active Ingredient:
`Psonetm HG‘
`__
`.
`..
`I Conclusions:
`In this study, nonminferiority or’ the 2 doses of oaionoseti-on (0.25 mg and 0.75 mg} to oriciansetron
`32 mg was demonstrated for the complete response rate during the first 24 hours after chemotherapy,
`the primary efticacy parameter. Furthermore, non~inferiority of both paionoeetron groups compared to
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`ondansetron was also shown for most secondary efflcacy parameters and paionosetron 0.25 mg was
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`-shown to be superior to ondansetrori with regard to most of these secondary effioaoy parameters. Thus,
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`oalonosetron 0.25 mg showed a better efficacy profile over oradansetron during the delayed phase of
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`I nausea and vomiting. The rate of patients with adverse events was comparatznie in the treatment groups
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`and showed a similar pattern. There were no safety concerns associated with results of laboratory
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`parameters, vital signs and ECG recordings and Hotter monitoring measured during the study.
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`Date of report: 19 July 2002
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`r(+p0r|5_[=3, 19.07 02
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`t3’age 1{) 91' 250
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`HIGHLY CONFIDENTIAL - OUTSIDE COUNSEL EYES ONLY
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`HELSNOO37857
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