Weigle OS. Pharmacological therapy of obesity: past, present, and future. J Clin Endocrinol Metab.
`2003 Jun;88(6):2462-9. Review. No abstract available.
`
`Hundal RS, lnzucchi SE. Metformin: new understandings, new uses. Drugs. 2003;63(18):1879-94.
`Review.
`
`Bloomgarden, Z. Metformin. Diabetes Care 18: 1078-80, 1995.
`
`Campbell I. The obesity epidemic: can we turn the tide? BMJ 22-4, 2003.
`
`McNulty SJ, Ur E. Williams G; Multicenter Sibutramine Study Group. A randomized trial of
`sibutramine in the management of obese type 2 diabetic patients treated with metformin. Diabetes
`Care. 2003 Jan;26(1): 125-31.
`
`Love-Osborne K, Sheeder J, Zeitler P. Addition of metformin to a lifestyle modification program in
`adolescents with insulin resistance. J Pediatr. 2008 Jun; 152(6):817-22. Epub 2008 Mar 19.
`
`Gonzalez-Ortiz M. Martinez-Abundis E. Mora-Martinez JM, Grover-Paez F. Renal handling of uric
`acid assessed by means of pharmacological tests in obese women. Diabetes Nutr Metab. 2001
`Aug;14(4): 189-94.
`
`Clement K, Ferre P. Genetics and the pathophysiology of obesity. Pediatr Res. 2003 May;53(5):721
`-5. Epub 2003 Mar 5. Review.
`
`Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence and trends in obesity among US
`adults. 1999-2000. JAMA. 2002 Oct 9;288(14):1723-7.
`
`Lozano Castaneda 0. Adipocitoquinas. Rev Endocr Nutr. 10: 147-50, 2002.
`
`Karnehed N, Rasmussen F. Hemmingsson T. Tynelius P. Obesity and attained education: cohort
`study of more than 700,000 Swedish men. Obesity (Silver Spring). 2006 Aug;14(8):1421-8.
`
`Hensrud DO, Klein S. Extreme obesity: a new medical crisis in the United States. Mayo Clin Proc.
`2006 Oct;81(10 Suppi):S5-10. Review.
`
`Laboratories Silanes S.A. de C.V. (Jorge Gonzalez Canudas)
`Responsible Party:
`ClinicaiTrials.gov Identifier: NCT00941382 History of Changes
`OB Sil-02
`Other Study 10 Numbers:
`Study First Received:
`July 14, 2009
`July 15, 2009
`Last Updated:
`Mexico: Federal Commission for Sanitary Risks Protection
`Health Authority:
`
`Keywords provided by Laboratories Silanes S.A. de C.V.:
`sibutramine
`metformin
`obesity
`
`Additional relevant MeSH terms:
`Obesity
`Overnutrition
`Nutrition Disorders
`Overweight
`Body Weight
`Signs and Symptoms
`Metformin
`Sibutramine
`Hypoglycemic Agents
`
`Physiological Effects of Drugs
`Pharmacologic Actions
`Appetite Depressants
`Anti-Obesity Agents
`Central Nervous System Agents
`Therapeutic Uses
`Antidepressive Agents
`Psychotropic Drugs
`
`ClinicaiTrials.gov processed this record on September 09, 2010
`
`Contact Help Desk
`Lister Hill National Center for Biomedical Communications, U.S. National Library of Medicine,
`U.S. National Institutes of Health. U.S. Department of Health & Human Services,
`USA.gov, Copyright, Privacy, Accessibility, Freedom of Information Act
`
`Ex. 2007-0401
`
`

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`Ex. 2007-0402
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`
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`
`Study Of ComP.arative Effects Of Oral Clonidine Vs Oral
`Diazepam Pre-Medication On The Extent And Duration Of
`Sensory Blockade In Patients Undergoing Vaginal
`Hysterectomy Under Spinal Anaesthesia.
`
`Internet Journal of Anesthesiology, 2009 by Namrata Toshniwal, Alka Halbe, Hemlatha lyyer
`
`Clonidine stimulates alpha 2 adrenergic inhibitory neurons in medullary vasomotor centre which decreases sympathetic
`outflow. Decreased sympathetic nervous system activity is manifested as decreases in systemic blood pressure, heart rate
`and cardiac output. Our results show that there was significant difference in the time of onset of anaesthesia, which
`coincides with the study done by Herbhej singh, George, Y .Gaines and Paul .F.White, in which they concluded that oral
`Clonidine shortened the onset time of tetracaine's sensory block & prolonged the duration of sensory & motor block. There
`are more studies, which also show that oral clonidine premedication prolong the sensory as well as motor blockade from
`Lignocaine & Tetracaine spinal anaesthesia. The antinociceptive effect produced by the orally administered 2- adrenergic
`agonist is mainly caused by direct spinal activation due to spread of the drug via the systemic circulation into the spinal
`cord. Neuraxial Clonidine inhibits spinal substance P release and nociceptive neuron firing produced by noxious stimuli.
`Clonidine modifies function of K channels in the CNS causing cell membrane hyperpolarization which decreases
`anaesthetic requirements.
`
`Keywords: Spinal anesthesia; Clonidine; Analgesia
`
`Introduction
`
`Clonidine stimulates alpha 2 adrenergic inhibitory neurons in medullary vasomotor centre which decreases sympathetic
`outflow. Decreased sympathetic nervous system activity is manifested as decreases in systemic blood pressure, heart rate
`and cardiac output. Our results show that there was significant difference in the time of onset of anaesthesia, which
`coincides with the study done by Herbhej singh, George, Y .Gaines and Paul .F. White, in which they concluded that oral
`Clonidine shortened the onset time of tetracaine's sensory block & prolonged the duration of sensory & motor block. There
`are more studies, which also show that oral clonidine premedication prolong the sensory as well as motor blockade from
`Lignocaine & Tetracaine spinal anaesthesia. The antinociceptive effect produced by the orally administered 2- adrenergic
`agonist is mainly caused by direct spinal activation due to spread of the drug via the systemic circulation into the spinal
`cord. Neuraxial Clonidine inhibits spinal substance P release and nociceptive neuron firing produced by noxious stimuli.
`Clonidine modifies function of K channels in the CNS causing cell membrane hyperpolarization which decreases
`anaesthetic requirements.
`
`METHODS
`
`After obtaining approval from institutional ethics committee and written informed consent from all patients, this prospective
`and randomized study was carried out in 60 ASA grade I and II patients scheduled for vaginal hysterectomy in Dept of
`Anesthesiology, TNMC and Nair Hospital, Mumbai
`
`All Patients were assessed on the previous day of the surgery and patient satisfying the inclusion criteria were included in
`the study.
`
`Procedure, its complications and alternative methods were explained to the patient in his own language and patients
`consent was taken.
`
`Criteria for inclusion:
`
`1. Age: 18-60 yrs
`
`2. Weight: 40-70kg
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`3. ASA: Grade I & II
`
`4. Concious Co - operative patient
`
`Criteria for exclusion:
`
`1. Consent not available
`
`2. Age <18 or >60 yrs
`
`3. Weight < 40 or > 70 kg
`
`4. ASA grade Ill, IV, & V
`
`5. Any contra- indication to spinal anaesthesia (Absolute or relative)
`
`6. Non -
`
`co operative patient
`
`7. Patients who are on antihypertensive or any sedative or on any antipsychotic drugs.
`
`Base line record of pulse rate (by cardioscope), Blood pressure (by sphygmomanometer and NIBP)), Spo[sub 2] (by pulse
`oximetry) and respiratory rate were taken as Tbase.
`
`In our study groups age and also physical parameters like weight and height were comparable among the two groups.
`There was no significant difference in preoperative parameters like pulse rate, respiratory rate and mean arterial pressure
`between the two groups.
`
`The patients were randomly divided in two groups- Group C & Group D of 30 each. Patient in Group C received Clonidine 4
`-5mcg/kg oral premedication and patients in Group D received Diazepam 0.20-0.25mg/kg oral premedication 90 minutes
`before spinal anaesthesia.
`
`Blinding was done by packing the three tablets of 1 OOmcg each of clonidine and three tablets of 5mg each of Diazepam in
`silver foil, subsequently the packets were placed in small plastic pouches and were numbered randomly as per computer
`generated number. Person dispensed the drug and person observed did not know the content of the packet. Decoding of
`packets was done at the end of the study.
`
`After preloading, under all aseptic precautions with patient in sitting position, spinal anaesthesia was given with 23 G
`Quincke needle in L3-4 interspace with 2.5 cc of 0.5 % Bupivacaine and 25mcg Fentanyl. Patient was made to sit for 2
`minutes after subarachnoid block and then made supine. Onset, duration, height of sensory block, time taken to reach
`highest level, and the time taken for two segment regression, time taken for four segment regression and the time when
`patient asks for analgesia were monitored and noted sensory blocked were evaluated by pinprick sensation.
`
`Onset of anaesthesia was considered as appearance of analgesia at L 1.
`
`Duration of analgesia was considered as the time between onset and the time when patient asked for analgesia.
`
`After operation patient were observed till sensory level weaned upto L 1 and patient remained in the Gynaec recovery till
`patient received first dose of analgesia and that time was noted.
`
`Results
`
`The mean age in Group C was 50.93 years with standard deviation of 5.343 years and that in Group D was 50.93 years
`with standard deviation of 4.877 years. The groups were comparable according to age, weight and height.
`
`Mean arterial pressure (MAP) was significantly lower in Group Cas compared to Group D. Similar trends in falling Mean
`and Diastolic blood pressure are seen as with systolic blood pressure and the results were significant with lower blood
`pressure with Clonidine as compared to Diazepam.
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`According to above Table no 3, there was significant difference in time for onset of anaesthesia for Groups C and D. The
`mean time for onset of anaesthesia for Group C was 6.73 min with standard deviation of 2.392min and that for Group D
`was 8.50 min with standard deviation of 2.432 min. (p value 0.006). Our results demonstrate that there was significant
`difference in time for onset of anaesthesia for Groups C & D.
`
`There was also a significant difference in time taken to reach highest sensory level in Group C and D. The mean time taken
`to reach highest level for Group C was 18.97min with standard deviation of 6.239min and that for Group D was 24.40 min
`with standard deviation of 6.026min. (p value 0.001 ).
`
`The mean time taken for two segment regressions in Group C was 103.87 min with standard deviation of 12.754 min and
`that with Group D was 90.53 mins with standard deviation of 17.419 min. (p value 0.001)
`
`The mean time taken forfour segment regressions in Group C was 140.67 min with standard deviation of 27.753 min and
`that with Group D was 122.83 min with standard deviation of 24.589 min. (p value 0.001)
`
`The mean time when patient asks for analgesia in Group C was 286.67 with standard deviation of 79.017min and that with
`Group D was 114.30 min with standard deviation of 15.234 min.The difference was significant. ( p value 0.001)
`
`The time for surgery with Group C was95.00 with standard deviation of 6.823 min and that for Group D was 96.17 min with
`standard deviation of 7 .391. The difference was non-significicant. (p value 0.528)
`
`Discussion
`
`Clonidine is rapidly absorbed after oral administration. Peak plasma concentration is rapidly achieved in 60-90 mins is
`highly lipid soluble, easily crosses blood -brain barrier and therefore may interact with alpha -adrenergic receptors at spinal
`and supraspinal sites within the central nervous system.ln addition previous studies suggest that clonidine may also affect
`peripheral sensory nerves as a sole agent or in combination with local anaesthetics.
`
`Clonidine has been demonstrated to inhibit neurotransmission in both A-delta and C nerve fiber which are theorized to
`mediate pin-prick, surgical pain. Finally Clonidine has been demonstrated to potentiate inhibitory effects of local
`anaesthetics on C fiber activity. Therefore Clonidine may exert its effects within the central nervous system at peripheral
`nerve roots by potentiation of effects of local anaesthetics.
`
`We have compared our results with previous study which also showed the same results.[1][2][3][4][5][6]. The primary
`mechanism of Clonidine analgesia is via a non -opoid spinal action on central alpha 2 adrenergic receptor in the dorsal horn
`of spinal cord.
`
`The analgesic an effect of clonidine is mediated by the same central alpha2 adrenoreceptors that mediated its hypotensive
`effects. Clonidine added to local anaesthetics enhances the effects of local anaesthetics on C fiber action potentials.
`
`We have also studies showing that prolongation of sensory anaesthesia when clonidine and fentanyl was combined was
`solely due to clonidine[1].
`
`Our results showed that premedication with 4-5gm/ kg oral clonidine premedication prolongs the duration of sensory
`blockade by Bupivacaine and Fentanyl spinal anaesthesia as compared to that of 0.20-0.25mg/kg Diazepam oral
`premedication, and this results agree with the study done in 1992, by Kouechi Ota, Akiyoshi Namiki, Yoshihito Ujike & lkuko
`Takahashi 3 . They concluded that prolongation of tetracaine sensory analgesia may be produced by premedication with
`oral clonidine premedication may have a distinct advantage because of its capacity to prolong sensory blockade & its
`potent sedating properties.
`
`We added fentanyl to bupivacaine to determine its effect on anesthesia quality, and sensory block. The administration of
`intrathecal opioids may provide benefits in augmenting sensory level, but also carries a risk of respiratory depression but
`we had taken care of it by watching respiratory rate and saturation.
`
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`Our results showed that there was significant difference in the time of onset of anaesthesia, which coincides with the study
`done by Herbhej singh, George, Y .Gaines and Paul .F. White[1], in which they concluded that oral clonidine shortened the
`onset time of tetracaine's sensory block & prolonged the duration of sensory & motor block.
`
`There are more studies, which also show that oral clonidine premedication prolong the sensory as well as motor blockade
`from Lignocaine & Tetracaine spinal anaesthesia. The antinociceptive effect produced by the orally administered 2-
`adrenergic agonist is mainly caused by direct spinal activation due to spread of the drug via the systemic circulation into the
`spinal cord. Neuraxial Clonidine inhibits spinal substance P release and nociceptive neuron firing produced by noxious
`stimuli. Clonidine modifies function of K channels in the CNS causing cell membrane hyperpolarization which decreases
`anaesthetic requirements.
`
`The dose of clonidine (4-5gm/ kg) & time Interval (90min before spinal anaesthesia) were decided according to previous
`studies regarding safety of clonidine premedication in elderly & dose response studies of oral clonidine for tetracaine spinal
`anaesthesia.
`
`Thus in the end as per results from our comparative study of effect of oral clonidine versus oral diazepam premedication on
`sensory blockade by intrathecal bupivacaine 0.5%(2.5ml) and fentanyl 25mcg, showed that clonidine hastens the onset of
`action, and reduces the time taken to reach highest sensory levei.Cionidine also prolongs the total duration of sensory
`block by increasing the time for 2 and 4 segment sensory regression, also there was significant extension of analgesia.
`
`Although few incidences of hypotension, bradycardia, nausea, vomiting and pruritus (Diazepam) were noted with both the
`groups, the difference was not statistically significant.
`
`Endnotes
`
`1. Harbhej singh ,Geoge Y.Gaines and Paul white, Effects of oral clonidine and intrathecal clonidine on tetracaine spinal
`block.Anesth Analg 1994;79;1113-6 (s)
`
`2. Gaumann ,Brunet Jirounek, Clonidine enhances the effects of lidocaine on C fibre action potentiai.Anesth Analg
`1992;719-25 (s)
`
`3. Ota K,Namiki A,Ujike Y,et ai,Prolongation of tetracaine spinal anesthesia by oral clonidine Anesth Analg 1992;75 ;262-4
`(s)
`
`4. Belzarena SD ,Clinical effects of intrathecally administered fentanyl in patients undergoing cesarean section.Anesth
`Analg 1992;74;653-7 (s)
`
`5. Filos KS ,Goudas LC,Patoroni O,Polyzou V .Intrathecal clonidine as a sole analgesic for pain relief after cesarean
`section.Anesthesiology 1992;77;267-74 (s)
`
`6. Koichi OTA,Akiyoshi Namiki ,Yoshihito Ujike,and lkuko Takahashi, Prolongation of tetracaine spinal anesthesia by oral
`clonidine.Anesth Analg 1992;75;262-4 (s)
`
`PHOTO (BLACK & WHITE): Table 1: Comparison of Mean Age, Weight and Height
`
`PHOTO (BLACK & WHITE): Table 2: Comparison of various pre-operative variables
`
`PHOTO (BLACK & WHITE): Table 3: Comparison of various sensory block related parameters
`
`Citation:
`
`N. Toshniwal, A. Halbe & H. lyyer: Study Of Comparative Effects Of Oral Clonidine Vs Oral Diazepam Pre-Medication On
`The Extent And Duration Of Sensory Blockade In Patients Undergoing Vaginal Hysterectomy Under Spinal Anaesthesia .
`The Internet Journal of Anesthesiology. 2009 Volume 19 Number 2
`
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`
`Ex. 2007-0406
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`Page 5 of 5
`
`_PF _
`
`_ PO_ Correspondence Address Dr Namrata Toshniwal101, D Block Pimpleshwar Coop Ho So Mahadev Palav Marg
`Curry Road (W), Mumbai 400013 E mail [drnbt_30@rediffmail.com] Ph 09869048418
`
`Lexile Reading Level: 1620
`
`http://www.britannica.com/bps/additionalcontent/18/41575551/Study-Of-Comparative-Eff... 9114/2010
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`Ex. 2007-0407
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`
`Pazopanib Plus Lapatinib Compared To Lapatinib Alone In Subjects With Inflammatory ... Page 1 of 6
`
`A service Df the U.S. National Institutes Df Health
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`la.gov
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`Home Search Study Topics Glossary
`Search
`
`_j Full Text View
`
`Tabular View
`
`No Study Results Posted
`
`Related Studies
`
`Pazopanib Plus lapatinib Compared To lapatinib Alone In Subjects With
`Inflammatory Breast Cancer
`
`This study is currently recruiting participants.
`Verified by GlaxoSmithKiine, July 2010
`
`First Received: November 9, 2007 Last Updated: July 8, 2010 History of Changes
`
`Sponsor: GlaxoSmithKiine
`
`Information provided by: GlaxoSmithKiine
`
`ClinicaiTrials.gov Identifier: NCT00558103
`
`• Purpose
`
`The double blind part of the study is being conducted to compare the efficacy and safety of pazopanib in
`combination with lapatinib with that of lapatinib alone in subjects with inflammatory breast cancer whose
`tumors overexpress the ErbB2 protein. There is also an Open-label pazopanib arm to this study designed to
`test whether pazopanib given alone and lapatinib given alone would be safe and effective to treat patients
`with inflammatory breast cancer.
`
`Condition
`
`Intervention
`
`Inflammatory Breast Cancer
`
`Drug: lapatinib (Tykerb)
`Drug: pazopanib (GW786034)
`Drug: Pazopanib
`
`Phase
`
`Phase Ill
`
`Study Type:
`Study Design:
`
`I nterventional
`Allocation: Randomized
`Endpoint Classification: Safety/Efficacy Study
`Intervention Model: Parallel Assignment
`Masking: Double Blind (Subject, Investigator)
`Primary Purpose: Treatment
`
`Official Title:
`
`A Randomized, Multicenter, Phase Ill Study Comparing the Combination of Pazopanib and
`Lapatinib Versus Lapatinib Monotherapy in Patients With ErbB2 Over-expressing
`Inflammatory Breast Cancer
`
`Resource links provided by NLM:
`
`Genetics Home Reference related topics: breast cancer
`
`MedlinePius related topics: Breast Cancer Cancer
`
`Drug Information available for: Lapatinib Lapatinib Ditosylate Pazopanib
`
`U.S. FDA Resources
`
`Further study details as provided by GlaxoSmithKiine:
`
`http://clinicaltlials.gov/ct2/show/NCT005581 03
`
`9/14/2010
`
`Ex. 2007-0408
`
`

`
`Pazopanib Plus Lapatinib Compared To Lapatinib Alone In Subjects With Inflammatory ... Page 2 of 6
`
`Primary Outcome Measures:
`• Progression-free survival at anytime. [Time Frame: on going ]
`
`Secondary Outcome Measures:
`o Overall Response Rate (ORR)Overall survival (OS)Safety and tolerabilityHealth Status
`Assessments [ Time Frame: on going ]
`
`Estimated Enrollment:
`360
`Study Start Date:
`December 2007
`Estimated Study Completion Date:
`June 2012
`Estimated Primary Completion Date: June 2012 (Final data collection date for primary
`outcome measure)
`
`Assigned
`Interventions
`
`Drug: lapatinib
`(Tykerb)
`comparator
`Drug: pazopanib
`(GW786034)
`comparator
`
`Drug: Pazopanib
`Pazopanib
`monotherapy
`
`Arms
`
`arm 1: Active Comparator
`
`Pazopanib Open-label: Active Comparator
`Pazopanib alone arm incorporated into study VEG108838
`{lapatinib + pazopanib vs. lapatinib monotherapy in patients
`with recurrent Her2+ IBC).
`
`Eligibility
`
`Ages Eligible for Study:
`Genders Eligible for Study:
`Accepts Healthy Volunteers:
`
`18 Years and older
`Female
`No
`
`Criteria
`
`Inclusion criteria:
`
`Specific information regarding warnings, precautions, contraindications, adverse events, and other
`pertinent information on the investigational product that may impact patient eligibility is provided in
`the pazopanib IB and lapatinib prescribing information (or the lapatinib I B).
`
`For Cohort 1 of this study, eligible patients met inclusion criteria outlined in the original version of
`the protocol and protocol amendment 1.
`
`For Cohort 2 of this study, eligible patients must meet all of the following criteria:
`• Patients must have evaluable Inflammatory Breast Cancer {IBC) substantiated by all of the
`following prior to randomization:
`• History of invasive breast cancer documented by a biopsy and accompanying pathology
`report
`o Current photographs* (global view and close-up views of all skin lesions) submitted at
`screening demonstrating unequivocal evidence of IBC as determined by either the medical
`monitor alone or in consulation with one or more of the study Principal Investigators.
`• All patients must have photography at screening. Canfield Scientific Inc. will provide
`centralized monitoring, tracking, and collection of patients' photographs throughout the
`study. Screening photographs must be uploaded to the Canfield Scientific Inc website and
`approved by Canfield Scientific Inc, as the central photography vendor. The photographs,
`along with the completed Inflammatory Breast Cancer Skin Assessment Tool (IBSAT), must
`be reviewed and approved by GSK before a patient can be randomized. Sites should allow a
`
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`
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`
`Pazopanib Plus Lapatinib Compared To Lapatinib Alone In Subjects With Inflammatory ... Page 3 of 6
`
`minimum of 3 business days for this process. Sites submitting quality photographs and
`IBSATs on a regular basis will receive an exemption from this requirement for future
`patients.
`o Patients with secondary IBC are eligible.
`o Measurable lesions (cutaneous or radiographic) may be in the field of prior standard or
`palliative radiation therapy; however, there must be at least a 4 week period between the last
`radiation treatment and the baseline scan documenting disease status for the lesion to be
`measurable. If the irradiated lesion is the only site of disease, documented progression of
`the irradiated lesion is required.
`• Disease progression or relapse following treatment for invasive breast cancer, which must
`have included a chemotherapy regimen. In regions where trastuzumab is available with no
`barriers to access*, patients must have received prior trastuzumab in addition to
`chemotherapy in order to be eligible. *(Barriers to access may include financial
`considerations.)
`• Unequivocal ErbB2 overexpressing breast cancer, defined as 3+ staining by
`immunohistochemistry (IHC), or 2+ staining by IHC in conjunction with ErbB2 gene
`amplification by FISH/CISH, or ErbB2 gene amplification by FISH/CISH alone (in subjects
`whose tumor blocks were not assessed by IHC). ErbB2 gene amplification is defined by: >
`six (6) ErbB2 gene copies/nucleus for test systems without an internal control probe or an
`ErbB2/CEP 17 ratio of more than 2.2.
`
`Sites must submit a copy of the laboratory report demonstrating unequivocal ErbB2
`overexpression, if testing performed at a local laboratory, with the screening worksheet. Archived
`tumor must be provided for all patients for ErbB2 FISH testing by the central laboratory. Patients
`will remain on study based on local ErbB2 expression results. If archived tumor is not available, a
`biopsy must be obtained at screening and sent to TMD Laboratoraties for ErbB2 FISH testing.
`
`- Patients must provide written informed consent prior to performance of study-specific procedures
`or assessments, and must be willing to comply with treatment and follow up. Procedures conducted
`as part of the patient's routine clinical management (e.g., blood count, imaging study) and obtained
`prior to signing of informed consent may be utilized for screening or baseline purposes provided
`these procedures are conducted as specified in the protocol.
`
`Note: Informed consent may be obtained prior to the protocol-specified screening window (i.e. Day
`-14 to Day -1).
`o Females age ~ 18 years, except in Tunisia. In Tunisia, patients must be ~ 20 years to be
`eligible for this study.
`• Adequate organ function as defined below:
`• System (Laboratory Values)
`• Hematologic:Absolute neutrophil count (ANC)(~ 1.5 X 1 OA9fl)Hemoglobin1 (~9 g/dl)Piatelets
`(~1 00 X 1 OA9fl)lnternational normalized ratio (INR)(:5 1.2 X upper limit of normal (ULN))
`Partial thromboplastin time (PTT)(:51.2 X ULN)
`• Hepatic:Total bilirubin2 (:5 1.5 X upper limit of normal (ULN))AST and AL T(:5 2.5 X ULN)
`o Renai:Serum Creatinine (:5 1.5 mg/dl)Or, if serum creatinine >1.5 mg/dl,
`• Calculated creatinine clearance(~50 ml!min)
`o Urine Protein to Creatinine Ratio( <1)
`• Patients may not have had a transfusion within 7 days of screening assessment.
`• Exception: Patients with elevated bilirubin levels due to Gilberts syndrome are eligible.
`o Cardiac ejection fraction within the institutional range of normal as measured by
`echocardiogram. MUGA scans will be accepted in cases where an echocardiogram cannot
`be performed or is inconclusive or where MUGA scans are the accepted standard. Patients
`with known history of uncontrolled or symptomatic angina, arrhythmias, or congestive heart
`failure are not eligible.
`• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
`• A female is eligible to enter and participate in this study if she is of:
`
`Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any
`female who has had:
`• A hysterectomy
`o A bilateral oophorectomy (ovariectomy)
`
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`• A bilateral tubal ligation
`• Is post-menopausal
`• Patients not using hormone replacement therapy (HRT) must have experienced total
`cessation of menses for;:: 1 year and be greater than 45 years in age, OR, in questionable
`cases, have a follicle stimulating hormone (FSH) value >40 miU/mL and an estradiol value<
`40pg/ml (<140 pmoi/L).
`
`Patients must discontinue HRT prior to study enrollment due to the potential for inhibition of CYP
`enzymes that metabolize estrogens and progestins (See Section 8). For most forms of HRT, at
`least 2-4 weeks must elapse between the cessation of HRT and determination of menopausal
`status; length of this interval depends on the type and dosage of HRT. If a female patient is
`determined not to be post-menopausal, they must use adequate contraception, as defined
`immediately below.
`
`Childbearing potential, including any female who has had a negative serum pregnancy test within 2
`weeks prior to the first dose of study treatment, preferably as close to the first dose as possible, has
`used adequate contraception since the pregnancy test and agrees to use adequate contraception
`as described below. GSK acceptable contraceptive methods, when used consistently and in
`accordance with both the product label and the instructions of the physician, are as follow:
`o An intrauterine device with a documented failure rate of less than 1% per year.
`• Vasectomized partner who is sterile prior to the female patient's entry and is the sole sexual
`partner for that female.
`• Complete abstinence from sexual intercourse for 14 days before exposure to investigational
`product, through the dosing period, and for at least 21 days after the last dose of
`investigational product.
`o Double-barrier contraception (condom with spermicidal jelly, foam suppository, or film;
`diaphragm with spermicide; or male condom and diaphragm with spermicide).
`
`Note: Oral contraceptives are not reliable due to potential drug drug interactions.
`
`Female patients who are lactating should discontinue nursing prior to the first dose of
`investigational product and should refrain from nursing throughout the treatment period and for 14
`days following the last dose of investigational product.
`
`- French patients: In France, a patient will be eligible for inclusion in this study only if either affiliated
`to or a beneficiary of a social security category.
`
`Exclusion Criteria:
`• Patients meeting any of the following criteria must not be enrolled in the study:
`o Treatment in the 14 days prior to randomization with any cancer therapy (tumor
`embolization, chemotherapy, immunotherapy, biological therapy, or hormonal therapy) or
`treatment with mitomycin within 6 weeks prior to randomization. Such treatment may not be
`resumed or begun after study entry. Note: Patients receiving LH-RH analogue therapy prior
`to the study may continue to receive LH-RH analogues for the duration of study participation.
`Bisphosphonates are permitted if started prior to Day 1.
`o Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 and/or that is
`progressing in severity (with the exception of alopecia).
`• Prior lapatinib therapy or other Her2/ErbB2 targeted therapy (except trastuzumab).
`• Prior therapy with an anti-VEGF antibody or other VEGF/VEGF-R targeted therapy.
`o Use of an investigational agent, including an investigational anti-cancer agent, within 28
`days or 5 half-lives, whichever is longer, prior to the first dose of investigational product.
`• Use of any prohibited medication within the timeframes listed in Section 8.1.3
`• History of another malignancy.
`• Note: Subjects who have had another malignancy and have been disease-free for 5 years,
`or subjects with a history of completely resected non-melanomatous skin carcinoma or
`successfully treated in situ carcinoma are eligible. If subject previously had breast cancer, it
`must have been HER2+ with either 3+ overexpression by IHC or unequivocal HER2 gene
`amplification by FISH or CISH.
`o History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal
`carcinomatosis, except for individuals who have previously-treated CNS metastases, are
`asymptomatic, and have had no requirement for steroids or anti-seizure medication for 2
`
`http://clinicaltrials.gov/ct2/show/NCT005581 03
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`9/14/2010
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`Ex. 2007-0411
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`months prior to first dose of study drug. Screening with CNS imaging studies (computed
`tomography [CT] or magnetic resonance imaging [MRI]) is required only if clinically indicated
`or if the subject has a history of CNS metastases.
`• Clinically significant gastrointestinal abnormalities that may increase the risk for Gl bleeding
`including, but not limited to:
`• Active peptic ulcer disease
`• Known intraluminal metastatic lesion/s with suspected bleeding
`• Inflammatory bowel disease
`• Ulcerative colitis, or other gastrointestinal conditions with increased risk of perforation
`• History of abdominal fistula, gastrointestinal perforation, or intra abdominal abscess within
`28 days prior to beginning study treatment.
`• Clinically significant gastrointestinal abnormalities that may affect absorption of
`investigational product including, but limited to:
`• Malabsorption syndrome
`• Major resection of the stomach or small bowel.
`• Presence of uncontrolled infection.
`• Prolongation of corrected QT interval (QTc) > 480 msecs.
`• History of any one or more of the following cardiovascular conditions within the past 6
`months:
`• Cardiac angioplasty or stenting
`• Myocardial infarction
`• Unstable angina
`• Arterial thrombosis
`• Symptomatic peripheral vascular disease
`• Class Ill or IV conge