:::::::l
`
`related, most commonly injection site thrombosis and pyrexia, which were
`reported as drug-related events in <2% of patients in both drug exposure groups.
`In this SOC drug-related events of severe intensity were reported in 2/265 (<l%)
`patients in the daptomycin group and included pyrexia and weakness. The only
`drug-related event
`in the SOC Infections and Infestations reported in >1°/o of
`patients was fungal vaginosis, which was reported as drug-related in 5/265 (1.9%)
`of patients in both the daptomycin and comparator groups. The only severe drug-
`related event in this SOC was a fungal skin infection reported in one patient
`(<l%) in the daptomycin group. Drug-related events in the SOC Skin and
`Subcutaneous Tissue Disorders were reported more frequently in the comparator
`group (19/265; 7.2%) than in the daptomycin group (4/265; 1.5%). Drug-related
`pruritus and dermatitis were reported in 2 to 3% of patients in the comparator
`group and in 1% of patients in the daptomycin group. Only one patient in each
`treatment group (<1% each) experienced a drug-related event within the
`Respiratory System Disorders SOC. Drug-related dyspnea of moderate intensity
`was reported in one patient in the daptomycin group and drug-related dySpnea of
`moderate intensity and epistaxis of severe intensity were reported in one patient in
`the comparator group. Musculoskeletal, connective tissue and bone disorders
`assessed as drug-related were noted in 3/265 (1.1%) patients in the daptomycin
`group. Two of these drug-related events, arthralgia aggravated in one patient and
`myalgia in another were assessed by the investigator as Severe in intensity. Drug-
`related events within the Metabolism and Nutrition Disorders SOC were reported
`in approximately 1% of patients in both drug exposure groups. Less than 1% of
`patients in the daptomycin group and 1.9% of patients in the comparator group
`experienced drug-related vascular disorders. One patient in the comparator group
`experienced hypotension of severe intensity that was assessed as possibly drug
`related.
`
`58
`
`

`

`Table 37: Treatment—Emergent Drug-Related AEs Occurring in 21% of
`Patients by System Organ Class and Preferred Term in Study DAP-SST—
`9801 (Po-ulation: Safety
`'
`ystem O'rgan Class
`'referred Term
`
`
`.m—
`N = 265
`N = 265
`—
`
`_
`
`_——-
`
`
`
`
`
`
`
`onsliation
`
`'
`
`I 0056 Stools
`
`
`
`
`Investtations
`
`
`I'lood Creatine Phos-hokinase'lncreased
`
`
`lood Creatinine Increased
`I
`iver Function Tests NOS Abnormal
`
`
`
`I-lood Alkaline Phoshatase increased
`
`
`
`
`
`rexia
`1'
`'
`In ection Site Phleb1t1s
`
`
`
` 4 1.5%
`
`3 1-1%
`
`19 7.2%
`
`30.1%)
`
`6 2.3%
`
`
`
`
`
`
`‘
`
`"-
`
`
`
`
`
`
`
`
`
`
`
`
`
`kin 8.- Subcutaneous Tissue Disorders
`
`ruritus NOS
`
`II ennatitis NOS
`
`Infections and infestations
`
`
`’aeinosis Funeal NOS
`
`
`
`‘ervous Svstem Disorders
`Ilizziness Excl Vertigo
`
`
`
`
`
`
`
`’ascular Disorders
`
`
`
`
`
`.lood and L\m hat1c S\ stern D1sorders
`
`1usculoskeletal, Connective Tissue and Bone
`
`Io isorders
`
`
`
`
`
`
`
`3 (1.1%) —
`
`
`3 (1.1%
`
`
`
`Adverse events leading to discontinuation of treatment - Study DAP-SST-9801
`A total of 21 patients were discontinued from study treatment due to AEs,
`including 9/265 (3.4%) patients in the daptomycin group and 12/265 (4.5%)
`patients in the comparator group. The events leading to discontinuation were
`reported as possibly or probably related to study treatment for 4/265 (1.5%)
`patients in the daptomycin group and 9/265 (3.4%) patients in the comparator
`group.
`In the daptomycin group, the SAEs that resulted in discontinuation of
`study treatment and were assessed as drug-related included hypersensitivity
`reaction, anemia and thrombocytopenia, worsening of abdominal and joint pain in
`_ .H .,
`__ .—_. .r
`
`59
`
`

`

`l::::::::l
`
`In the comparator
`a patient with sickle cell disease, and elevated serum CPK.
`group, SAEs that resulted in discontinuation of study treatment and were assessed
`as drug-related included nausea, vomiting and rigors; elevated vancomycin levels
`andprun'tic rash; drug fever; hypersensitivity reaction with elevations in ALT and
`AST; rash; nausea and vomiting; drug rash; peripheral swelling; and urticaria.
`
`0
`
`Medical Officer Comment
`The Medical Officer reviewed the CRFs and patient narratives of all patients in
`study DAP-SST-9801 who discontinued study drug treatment due to AEs. As
`described below under "Serious adverse events ”, the Medical Oflicer believes that
`one of the patients (0070100041) with two AEs assessed by the investigator as
`possibly related are actually not related to study drug treatment (abdominal pain
`and arthralgias in a patient with sickle cell crisis).
`The A55 resulting in
`discontinuation of study drug treatment are consistent with the known AE profile
`of the drugs. The Medical Oflicer agrees with the other assessments of causality
`in both the comparator and daptomycin groups with the following two exceptions:
`0
`Patient 0118100050 was a 78 year old male treated with vancomycin for 3
`days for a wound infection of the left great
`toe.
`Study medication was
`discontinued due to severe nausea and vomiting. Deep swab of the wound
`grew multiple Gram-positive and Gram-negative organisms,
`including
`methicillin-sensitive S. aureus (MSSA). The investigator assessed the nausea
`and vomiting as not related to study drug; the Medical Officer considers it to
`be possibly related.
`Patient 0l63100041 was a 43 year old female who received one dose of
`vancomycin for a wound infection ofthe right ankle which grew (methicillin-
`resistant S. aureus (MRSA). She developed urticaria after the first dose of
`vancomycin, and the study was discontinued. The investigator considered the
`urticaria to be possibly relatedto study drug. However, the patient received a
`' course of vancomycin therapy after the study was discontinued without further
`urticaria; therefore, the Medical Officer considers this A13 to be not related to
`study drug.
`_
`The following patient who was discontinued from the study due to A55 in the
`daptomycin arm of study DAP-SST-9801 is presented to demonstrate a severe
`allergic reaction to daptomycin.
`0
`Patient 0053100064 was a 40 year old female with a post-operative MSSA
`infection of the left hip who received 5 doses of daptomycin. After the fourth
`dose she developed an allergic reaction cansisting of fever, chills, and
`shortness of breath. She received the fifth dose of daptomycin the following
`day; at the end of the infusion, she developed tachycardia, fever to 106°F, and
`hypoxia, and the study drug was discontinued. The investigator considered
`this AE to be probably related to study drug treatment, and the Medical
`Officer agrees.
`
`l
`
`60.
`
`

`

`l::—:::l
`
`Serious adverse events - Study DAP-SST-980]
`Table 38 below presents treatment-emergent SAEs by MedDRA SOC. A total of
`64 patients, 32/265 (12.1%) in each drug exposure group, experienced I or more
`SAEs. There was no difference between the drug exposure groups for the overall
`incidence of any SAE. The only SAEs with reported incidence of31% of patients
`were cellulitis. and urosepsis, occurring in 4/265 (1.5%) patients and 3/265 (1.1%)
`patients, respectively, in the daptomycin group. All other serious events were
`reported in <1% of patients in both drug exposure groups.
`Four patients,
`including 2/265 (<1%) patients in each arm, experienced serious drug-related
`events. These included a hypersensitivity reaction and diarrhea (aggravated) in the
`daptomycin group; and hypersensitivity reaction and pruritic rash in the
`comparator group. For about one—third of the patients who experienced SAEs, at
`least one SAE started while on treatment. For approximately one-half of the
`patients in each drug exposure group who experienced SAEs, all SAE(s) started
`more than five days after the end of treatment.
`
`Table 38: Treatment-Emergent SAEs by System Organ Class in Study
`DAP-SST-9801: Safetv Po n ulation
`
`ystem Organ Class
`"referred Term
`
`
`
`
`
`
`
`
`
`
`Com . arator
`
`
`
`.
`
`
`
`
`——--_
`-—--__
`
`
`
`2 (<1%
`2 <1%)
`1 (<1%)
`1 (<1%
`1 <1%)
`2 (<1%)
`
`1 <1%
`
`2 <1%)
`1 (<1%)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`astrointestinal Disorders
`
`skin & Subcutaneous Tissue Disorders
`mmune Svstem Disorders
`
`- 4etabolism and Nutrition Disorders
`
`I ervous S Istem Disorders
`I eoplasms Benign and Malignant (including Cysts and
`
`"0] ‘05
`
`urgical and Medical Procedures
`eneral Disorders’Administration Site Conditions
`
`
`I' anal and Urina Disorders
`
`
`1' esirato ', Thoracic and Mediastinal Disorders
`Mood and L
`nhatic S 'stem Disorders __--
`
`
`
`on enital and Familial/Genetic Disorders m“
`
`
`
`
`Medical Oflicer Comment
`The Medical Officer reviewed the CRFs and patient narratives of all patients with
`SAEs. Most of the serious events in the daptomycin arm appeared to be related to
`the patient’s underlying illness or the presenting illness.
`The investigator
`considered that three SAES were possibly related and two AEs were probably
`related to stuab' drug in the daptomycin arm. Farty-two SAEs were reported by the
`investigator in '32 patients. The Medical Oflicer agrees with these assessments
`with the exception of two SAE’s in one patient (0070100041) with a sickle cell
`crisis;
`the investigator deemed abdominal pain and arthralgias to be possibly
`
`61
`
`

`

`related to daptomycin, and the Medical Officer considers them to be unrelated.
`One additional patient had an SAE that the Medical Oflicer considers to be
`possibly related to daptomycin, while the investigator assessed the SAE as
`unrelated; a briefsummary of this case follows.
`0
`Patient 0002100045 was a 66 year old male treated with daptomycin for four
`days
`for an abdominal wall wound infection caused by Streptococcus
`constellatus and Streptococcus intermedius.
`Serum creatinine rose from a
`baseline of2.4 mg/dL to 7.1 mg/dL on le. Since no other etiology is evident
`for the patient's worsening renal insufficiency, the Medical Officer considers
`this SAE to be possibly related to study drug treatment.
`
`Deaths- Study DAP-SST—9801
`A total of 8/265 (3.0%) patients died during study DAP-SST-9801, including
`2/265 (<l%) patients in the daptomycin group and 6/265 (2. 3%) patients in the
`comparator group. None of the deaths were judged to be related to study
`treatment. Table 39 presents a list of the 8 patients who died. Six of eight (75%)
`patients were male and 6/8 (75%) patients were >70 years old at study entry. The
`primary site of infection was a wound infection in 6/8 (75%) patients; infected
`ulcer (not diabetic) and diabetic ulcer infection occurred in one patient each. All '
`8 of these patients who died had complicating medical conditions, including 4/8
`(50%) with DIM. One daptomycin-treated patient died of deep venous thrombosis
`(DVT) and pulmonary embolism, and one died of progressive lung cancer. One
`comparator-treated patient died of progression of underlying cancer; two died of
`underlying cardio- or ccrebrovascular conditions; and one died of worsening of
`pre-existing anemia. Two comparator-treated patients died of sepsis more than 3
`weeks post-treatment. The duration of study treatment in these 8 patients ranged
`from 4 to 10 days. Five patients died 3 to 62 days afier successfully completing
`therapy. One patient was on d4 of study treatment at the time of death; one patient
`had discontinued treatment on d4 due to an AB not associated with the death and
`
`died 15 days later; and one patient had discontinued treatment due to clinical
`failure, was switched to non—study medication, and died 22 days later.
`
`Medical Officer Comment
`The Medical Oflicer reviewed the CRFs and patient narratives of all patient
`deaths in this study. The sponsor concluded that the caus es ofdeath in these eight
`patients who died during study DAP-SST-9801appeared to be directly related to
`pre-existing underlying conditions, and the Medical Oflicer agrees. No death in
`either group appeared to be directly related to daptomycin or comparator. Of
`note, however,
`is the fact that in some instances, documentation of the ultimate
`cause of death was not included with the submission. Two of these deaths fall in
`to this category: Patient 0204100080 in the comparator group died of severe
`anemia (admission hemoglobin = 4 g/dL) predating study drug administration,
`but no cause for the anemia is given. Patient 0104100041 died ofprogressive
`lung cancer on d3 0P, but no information is given regarding the terminal event.
`
`62
`
`

`

`'Iable 39: Patients who Died'In__Study_DAP-SSR980]
`
`wccnder Age
`
`0072l00044 M
`
`Medical History
`
`Diagnosis
`
`SIRS Daysof Day
`
`(YIN)
`
`Cause of Death
`
`Hypertension, CAD.
`PVD. GI bleed,
`/p decompression
`laminectomy
`
`'
`
`'
`
`_
`..aurcus
`
`Bilateral LE DVT,
`Pulmonary embolism;
`spiration; acute
`respiratory failure
`
`
`
`
`
`Complicating
`Infection
`
`
`
`
`:
`
`.
`
`I
`
`.
`
`tl04l0004l M
`
`Lung cancer.COPD,
`Ibdominal aortic
`
`Infected
`Ulcer (not
`
`.aureus
`
`0P
`
`Progressive lung
`anccr
`
`-'Ineurysm
`
`l_iabetic)
`
`E. acca/is
`
`oneisol-ztedProgresslon of
`
`tll8100050 M
`
`78
`
`I m homa
`
`Infection
`
`Infection
`
`l24100002 F
`
`‘
`
`'
`tl24l0004l M
`
` ypertension.
`
`PVD, obesity
`Diabetes. l’VD. CHF,
`
`ngina
`
`OPD
`--. ‘,HF hypertension,
`.uureus
`
`ypertension,
`.faecalir
`
`VA. CAD. CH F,
`
`
`
`
`
`'
` .aga/acliae
`
`2P
`Exacerbation of
`
`Diabetic
`
`
`Ulcer
`
`l5P
`
`
`
`l m homa
`‘ercbrovascular
`'
`
`t204l00080 M
`
`ncmia (llet: ll%; Wound
`H _:b 4 _/dL
`Infection
`
`.aurcus
`
`orscning of
`ncmia
`
`Relationship
`to study
`medication
`
`Not related
`
`Not related
`
`ot related
`
`Not related
`
`63
`
`

`

`Study DAP-SST-9901
`Demographics
`Table 40 presents a summary ofthe demographic characteristics for the patients in
`the daptomycin and comparator arms for study DAP-SST-9901.
`The two
`treatment groups were well balanced with regard to
`all demographic
`characteristics. The majority of the patients in both treatment groups were male
`(>54%) and Caucasian (350%). The mean age of the patients was 47.9 years in
`the daptomycin arm and 48.6 years in the comparator arm; approximately 20% of
`patients in both arms were 365 years old at study entry.
`
`_ Table 40: Demographic Characteristics in Study DAP-SST-9901 (Population:
`lTT
`
`
`_
`
`N=270
`
`N=292
`
`lean : SEM
`linimum, Maximum
`1l’eiht k_
`Mean 1’ SEM
`linimum, Maximum
`ender N, %
`
`47.9 i 1.05
`18, 87
`
`'
`
`73.5 i 1.20
`40. 165
`
`'
`
`120 (44.4%
`150 (55.6%
`
`
`
`40, 130
`
`132 (45.2%
`160 54.8%)
`
`146 (50.0%
`91 (31.2%
`2 (0.7%
`53 (18.2%)
`'Bascd on ANOVA fixed effects model with factor for treatment group for continuous variables and Chi-square test for
`categorical variables.
`
`of 562 treated
`The distribution of patients by country/region is as follows:
`patients, 303 were enrolled in South Africa, 237 in Europe/Asia, and 22 in
`Australia.
`
`Disposition - Study DAP-SST—9901
`Table 41 below presents a summary of patient disposition during study DAP-
`SST-9901. A total of 571 patients were randomized to study treatment; 277 were
`randomized to receive daptomycin and 294 were randomized to receive
`comparator: vancomycin, flucloxacillin, oxacillin, or cloxacillin as designated by
`the investigator prior to randomization. Nine ofthe 571 randomized patients were
`discontinued from the study prior to receiving any study treatment. Among the
`562 patients who received at least one dose of study drug, 270 were randomized
`to the daptomycin arm and 292 to the comparator arm. One patient was
`randomized to receive daptomycin but was administered only comparator as study
`medication.
`In all safety analyses, data for this misrandomized patient are
`included in the comparator drug group.
`
`

`

`11::
`
`Therefore, there were 562 patients in the Safety population: 269 who received at
`least one dose of daptomycin, and 293 who received only comparator agents as
`study medication. Among the 293 patients in the comparator group, 149 received
`cloxacillin as study drug, 64 received vancomycin, 59 received oxacillin, 19
`received 'flucloxacillin, and 2 received both vancomycin and flucloxacillin. Over
`90% of patients in both treatment groups completed intravenous treatment as
`planned. There were no differences between the arms in the proportion of patients
`who discontinued intravenous drug therapy prematurely or in the reasons for
`discontinuation. Of the 269 daptomycin-treated patients, 18 (6.7%) discontinued
`prematurely as did 13 (4.4%) of the 293 comparator-treated patients. The most
`common reason for premature discontinuation in both arms was adverse event in
`7/277 (2.6%) patients
`in the daptomycin arm and 5/294 (1.7%) patients in the
`comparator
`arm. There were no patients
`in study DAP-SST-9901 who
`discontinued study medication due to an elevation in serum CPK.
`
`Table 41: Patient Dis uosition in Study DAP-SST-9901
`o - ulation
`andomized
`andomized But Not Treated
`
`
`
`Intent-to-Treat Po ulation (as randomized
`__-__
`afet P0-ulation (as treated
`omitted fiera-
`l'rematurel , Discontinued Theta
`~dverse Event
`.1inical (S 'motomatic Failure
`aliem s Decision
`romeoI Violation
`I 05! to Followu-
`
`)
`
`‘
`
`' One patient (0410100063) was randomized to receive daptomycin but was adminismred comparator drug in cnot. In this
`table. data for this patient are included in the daptomycin column for the randomized and HT populations but in the
`comparator column for all other populations.
`: One patient (0401 100057) is incorrectly included in Table 14.3.5.1 as discontinued due to an adverse evendother; skin
`allergy): this patient is also included in this table.
`
`Overall adverse events - Study DAP-SST-990]
`the table also
`Table 42 presents treatment-emergent ABS by MedDRA SOC;
`includes those preferred terms that were reported in 31% of patients in either
`treatment arm.
`There was no difference between the arms for the overall
`
`incidence of any AB. A total of 103/269 (38.3%) patients in the daptomycin
`group and 100/293 (34.1%) patients in the comparator group reported at least one
`AE during the study. The majority of events were assessed as unrelated to
`treatment by the investigators. There were no differences between the two arms
`in the incidence "of all AEs reported within any MedDRA SOC. AEs were most
`commonly reported in the Gastrointestinal Disorders SOC, with 30/269 (11.2%)
`and 25/293 (8.5%) of patients
`in the daptomycin and comparator arms,
`respectively, reporting at least one AE within this system. Fewer than 10% of
`patients in either arm experienced events in all other SOCs. The most frequently
`reported AE by preferred term was headache occurring in 19 patients overall
`
`65
`
`

`

`:::::3
`
`including 11/2269 (4.1%) patients in the daptomycin arm and 8/293 (2.7%)
`patients in the comparator arm. Other events reported in 2 to 4% of patients in
`either arm included constipation, nausea, injection site thrombosis, injection site
`phlebitis, increased CPK, insomnia, diarrhea, and dermatitis.
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`66
`
`

`

`::
`
`Table 42: Treatment-Emergent ABS by System Organ Class Including the
`
`Daptomycin
`N = 269
`
`Most Commonly Reported Events (21% of Patients) in Study DAP-SST-990l
`(Potulation: Safety
`Comparator
`ystem Organ Class
`N = 293
`'referred Term
`100 (34.1%)
`otal Number of Patients with AEs
`25 (8.5%)
`astrointestinal Disorders
`m__-—-—
`_m——
`Iliarrhea NOS
`7 2.6%) --—
`’omitin NOS
`——-—
`
`'
`.
`1 MW --—
`eneral Disorders/Administration Site Conditions
`24 (8.9%)
`27 (9.2%)
`
`
`95% Cl
`
`
`
`- _—_
`IniecIion Site Thrombosis
`In‘ection She Phlebitis —-_-—
`I__——
`[I__——
`
`
`
`-_--—
`----—
`---__
`-_‘-—
`-—.--
`
`
`
`nfection NOS
`
`esis NOS
`
`I__-—
`n—_----—
`1 <1%) —-—
`
`‘ervous Svstem Disorders
`1 eadache NOS
`
`Insomnia NEC
`
`I'lzziness (excl VeniO)
`
`kin 8.- Subcutaneous Tissue Disorders
`
`_——-—
`'ascular Disorders
`12 4.1%)
`
`—---—
`—-—-_
`—--——
`
`
`
`\ oolvcemia NOS
`lusculoskeletal, Connective Tissue and Bone
`II isorders
`
`r
`
`1 <1%) --—
`7 (2.6%)
`5 (1.7%)
`(-3.3, 1.5)
`
`I: load and Lym ohatic System Disorders
`
`5 (1.9%
`5 19% ——
`3 (1.1%) —-—
`3 (1.1%) _-—
`' Two sided 95%C1 around difference in proportions ofAEs (comparator daptomycin) using normal approximationto the
`binomial, calculated at the body system level only if reponed in 22% of patients.
`
`6 \l
`
`

`

`Medical Oflicer Comment
`AEs reported by SOC which occurred more commonly in the daptomycin arm
`included Investigations (6. 7% and 3.4% in the daptomycin arm and comparator
`- arm, respectively) and the preferred term blood CPK increased. Also higher in
`the daptomycin arm were the SOC Skin & Subcutaneous Tissue Disorders (6.3%
`and 4.4% in the daptomycin and comparator arms, respectively); the preferred
`term dermatitis was more common in the daptomycin arm (2.6%) versus
`comparator arm (<1 %).
`There was a slightly higher incidence in the SOC
`Musculoslreletal, Connective Tissue and Bone Disorders (7/269 [2.6%] in the
`daptomycin arm versus 5/293 [1.7%] in the comparator arm). These AEs are
`consistent with the known adverse event profile ofdaptomycin.
`
`Adverse events by intensity - Study DAP—SST—9901
`A total of 208 unique treatment-emergent AEs were reported in the daptomycin
`arm. The majority of these events were mild (113/208; 54.3%) or moderate
`(65/208; 21.3%) in intensity. A total of 30/208 events (14.4%) reported in 26/269
`(9.7%) were judged to be severe in intensity by the investigator.
`1n the
`comparator group, a total of 190 unique treatment-emergent AEs were reported
`including 119 (62.6%) that were assessed as mild and 52 (27.4%) that were
`moderate in intensity. Nineteen events (10.0% of 190) reported in 13 patients
`(4.4% of 293 patients) were judged to be severe in intensity. AEs of severe
`intensity with incidence of 31% within each SOC and by preferred term are
`displayed in Table 43. The'majon'ty of SAEs were reported in < 1% of patients in
`both the daptomycin and comparator groups. The only severe event with
`incidence 31% was sepsis NOS, which was reported in 3/269 (1.1%) patients in
`the daptomycin group and none of the patients in the comparator group. None of
`these reports of sepsis were judged to be drug-related by the investigators. Only 4
`patients,
`including 3 (1.1%) in the daptomycin group and one (<1%) in the
`comparator group, experienced events that were assessed as both severe in
`intensity and as possibly or probably related to study treatment. Three such events
`occurred in the daptomycin group:
`elevation in lactate dehydrogenase (LDH),
`elevation in eosinophil count, and hypotension. Elevation of serum CPK was the
`drug-related event of severe intensity in the comparator group. Laboratory
`abnormalities will be discussed further in the "Laboratory Assays" section.
`
`AWE/SR3 1135,
`ON attitiiiitttM
`
`68
`
`

`

`Table 43: Treatment-Emergent AES of Severe Intensity Occurring in 21% of
`Patients by System Organ Class and Preferred Term in Study DAP-SST-
`9901 Poulation: Safety
`ystem Oigan Class
`
`Daptomt cm
`N = 269
`
`Comparator
`N = 293
`
`
`
`
`26 (9.7%
`13 4.4%)
`i)
`6(2.2°/
`5 1.7%
`
`
`7 2.6%)
`2 0.7%
`3 1.1% __
`
`4 15%)
`1 0 3%
`
`
`3 (1.1%
`2 (0.7%
`ardiac Disorders
`kin & Subcutaneous Tissue Disorders
`3 1.1%
`l 0.3%)
`
`
`
`.
`Infections and lnfestations
`
`
`
`
`
`
`
`
`-
`
`Adverse events by subgroups - Study DAP-SST-9901
`Table 44 below presents the overall incidence of any treatment-emergent AEs for
`subgroups defined by demographic characteristic. There were no differences
`between the treatment arms for the overall
`incidence of any AF. or for the
`incidence of ABS within any SOC for any subgroup.
`
`Table 44: Incidence ofAdverse Events by Demographic Characteristics in
`
`Studv DAP—SST-9901 Poulation: Safetv
`
`Demographic
`Patients with AB in Sub_rou N %
`
`
`Characteristic
`II a utomvcin N = 269
`om arator N = 293
`
`
`(-12.8, 8.4
`
`(~18.7, 5.3
`
`
`53/150 (35.3%
`
`53/160 (33.1%
`
`95% 0'
`
`
`
`.
`79/216(36.6%
`78/236 33.1%
`24/53 (45.3%)
`22/57 (38.6%)
`
`
`
`
`
`
`
`-16.3,6.6
`56/147 38.1%
`58/135 (43.0%
`(-20.2. 5.4)
`22/91 24.2%
`30/95 (31.6%)
`(-l8.5, 21.6
`22/55 (40.0%
`15/39 (38.5%
`Two sided 95% Cl around difference in proportions ofAEs (comparator daptomycin) using normal approximation to the
`binomial, calculated at the body system level only if reported in22% ofpatients.
`
`-12.3,5.3
`(-25.1, 11.7)
`
`
`
`
`
`
`
`Medical Oflicer Comment
`The incidence ofAEs appears to be somewhat higher in females (42. 0%) versus
`males (35.3%) in the daptomycin group. Females also had more AEs in the
`daptomycin arm (42.0%) than in the comparator arm (35.3%). This pattern is
`opposite that seen in stuabz DAP-SST-9801, in which males had a higher AE rate
`than females andfemales had a higher AE rate in the comparator arm. Lastly, in
`the daptomycin arm, more AEs were reported in patients 3 65 years of age than
`in those < 65 years ofage, consistent with the results in study DAP—SST-9801 .
`
`Drug related adverse events — Study DAP-SST-990l
`Drug-related AEs with an incidence.of>1% within each SOC and preferred term
`are included in Table 45 below. There were no differences between the two arms
`
`in the incidence of drug-related AEs reported within any SOC. The majority of
`a: v,
`
`69
`
`\
`
`r"\
`
`

`

`gastrointestinal disorders 'were not considered related to study treatment. The only
`drug-related gastrointestinal disorder with a reported incidence of >l% was
`nausea, which was reported in 3/269 (1.1%) of patients in the daptomycin group
`and 4/293 (1.4%) of patients in the comparator group. Approximately 3% of
`patients in both arms experienced AB in the General Disorders/Administration
`Site Conditions SOC that were assessed as drug-related, primarily injection site
`thrombosis and phlebitis. These AEs were reported as drug-related in < 2% of
`patients in both drug arms. Only one event within the Infection and Infestation
`SOC was considered related to study treatment; a candidal infection was reported
`in one patient in the comparator group. One patient in each arm had a severe
`elevation in serum CPK reported as an A13 in the Investigations SOC; assessed as
`unrelated to treatment in the daptomycin arm and probably related to treatment in
`the comparator group. Less than 1% of patients in either arm experienced AEs
`within the Nervous System Disorders SOC that were judged to be drug-related.
`The majority of skin and subcutaneous tissue disorders were not considered to be
`drug-related. Drug-related dermatitis was reported in 4/269 (1.5%) patients and
`1/293 (<1%) patient
`in the daptomycin and comparator groups, respectively.
`Less than 1% of patients in both arms experienced drug-related vascular
`disorders. One patient in the daptomycin group experienced hypotension of
`severe intensity that was assessed as possibly drug related. Less than 1% of
`patients in both arms experienced drug-related events within the Metabolism and
`Nutrition Disorders SOC.
`Individual preferred term events considered to be drug
`related within the Musculoskeletal, connective tissue and bone disorders or
`
`Cardiac disorders SOCs were reported in < 1% of patients in both arms.
`
`'
`
`Table 45: Treatment-Emergent Drug-Related AEs Occurring in 21% of
`Patients by System Organ Class and Preferred Term in Study DAP-SST-
`9901 (Po-ulation: Safety
`
`
`system Organ Class
`
`
`29(9.9%
`30(11.2%)
`10(3.4%
`70.6%)
`
`2t<1%)
`5 1.7%
`
`
`2 (<1%
`In'ection Site Phlebitis
`
`
`.
`loom
`
`
`
`
`Daptomycin
`N = 269
`
`Comparator
`N = 293
`
`
`
`
`
`
`
`‘ lanine Aminotransferase Increased
`
`519%)
`_ 31.1%
`
`5
`
`l.
`
`
`
`
`
`
`
`«1.4%
`
`,—.\_
`
`Adverse events leading to discontinuation of treatment - Study DAP-SST-9901
`A total of 11 patients were discontinued from study treatment due to AEs,
`including 6/269 (2.2%) patients in the daptomycin group and 5/293 (1.7%)
`patients in the comparator group. The events leading to discontinuation were
`reported as possibly or probably related to study treatment for 3/269 (1.1%)
`_--_--
`
`70
`
`

`

`In
`patients'in the daptomycin group and 2/293 (<1%) in the comparator group.
`the daptomycin group, 2/269 patients were discontinued from treatment due to
`drug-related rash. One other patient in the daptomycin group experienced two
`febrile reactions thought to be drug—related, and the patient was discontinued from
`the study. Three patients in the daptomycin group were discontinued from study
`treatment due to unrelated events including diagnosis of osteomyelitis, sepsis, and
`pulmonary embolism. 1n the comparator group, 2/293 patients were discontinued
`from treatment due to drug-related rash. Three patients in the comparator group
`were discontinued from study treatment due to unrelated events including stroke,
`necrotizing fascitis, pulmonary edema, and bronchopneumonia.
`
`Medical Oflicer Comment
`The narratives and CRFs of all patients discontinuing study drug were reviewed
`by the Medical Officer. -. The Medical Oficer agrees with the investigator's
`assessment of causality. It is of interest that two of the patients in the. daptomycin
`arm had elevations of CPK during their hospital course. Patient 0304100063 had
`elevation of serum CPK to a maximum of 527 U/L on le which resolved by
`d26P; he did receive intramuscular injections during his hospital stay. Patient
`0409100054 was discontinuedfrom the study medication due to sepsis; she had
`an elevation of serum CPK to a maximum of 1038 U/L on d2P after 3 doses of
`daptomycin, but no follow-up serum CPK was obtained. The Medical Oflicer
`considers these elevations in serum CPK to be possibly related to study drug, but
`the elevations may also be attributable to intramuscular injections and sepsis,
`respectively.
`
`Serious adverse events - Study DAP-SST-9901
`Table 46 below presents treatment—emergent SAEs by MedDRA SOC and
`includes all events that were reported in 31% of patients in either drug exposure
`group. A total of 43 patients experienced one or more SAEs. There was no
`difference between the arms in the overall
`incidence of any SAE. A total of
`26/269 (9.7%) of patients in the daptomycin arm and 17/293 (5.8%) in the
`comparator group experienced SAEs during the study. The only SAE with a
`reported incidence of 31% of patients was cellulitis occurring in 3/269 (1.1%)
`patients in the daptomycin arm and none of the patients in the comparator arm.
`All other serious events were reported in < 1% of patients in both arms. Only one
`SAE, eosinophilia, in the daptomycin arm, was assessed as possibly related to
`study treatment. The majority of reported SAEs were assessed as severe in
`intensity including 17/36 (47.2%) SAEs reported in the 26 patients with SAEs in
`the daptomycin group and 10/19 (52.6%) SAEs reported in the 17 patients in the
`comparator group who experienced serious events. For about half the patients in
`each drug exposure group who experienced SAEs, at least one SAE started while
`on treatment. For one-third of the patients in each drug exposure group, their
`SAE(s) started 5 to 21 days after the end of treatment. By the sponsor's analysis,
`there was no difference in SAEs between arms in the demographic subgroups of
`sex, age, and race.
`
`71
`
`

`

`::
`
`Table 46: Treatment-Emergent SAEs by System Organ Class Including the
`Most Commonly Reported Events (21% of Patients) in Study DAP-SST-9901
`(Po ulation: Safetv
`.
`ystem Organ Class
`Preferred Term
`otal Number of Patients with SAES
`
`
`
`95% Cl
`
`
`
`Infections and 1nfestations
`
`ellulitis
`
`ascular Disorders
`
`ardiac Disorders
`
`kin & Subcutaneous Tissue Disorders
`
`
`
`eneral Disorders/Administration Site
`
`
`onditions
`
`
`
`Two sided 95% Cl around difference in proponions ofAEs (comparator daptomycin) \Lsrng normal approximation to the
`binomial, calculated at the body system level only ifreported in 22% of patients.
`
`
`
`Daptomycin
`N = 269
`26 9.7%
`
`Comparator
`N = 293
`~8.3. 0.6
`17 5.8%
`(-3.7, 1.8
`7 2.4%
`9 (3.3%
`3 (1.1%) —
`3 1.1%)
`6 (2.0%
`(-l.l, 3.0
`3 1.1%
`2 < 1%
`3 1.1%)
`2 < 1%
`4 (1.5%)
`
`
`
`Medical Oflicer Comment
`it appears that there were higher number of
`Although the numbers are small,
`unique treatment emergent SAEs in women in the daptomycin arm (24/119;
`20.2%) than in the comparator arm (5/133; 3.8%).
`This difference between
`treatment arms in females appeared to be present in all SOCs.
`
`The Medical Oflicer reviewed the narratives and CRFs for all patients in the
`daptomycin and comparator arms who had SAEs reported. The Medical Officer
`agrees with the assessment of relationship to study drug as given by the
`investigator; most SAES appeared to be related to the patient's underlying illness.
`
`Deaths - Study DAP-SST-9901
`A total of 8 patients died during study DAP—SST-990l, including 6/269 (2.2%)
`patients in the daptomycin group and 2/293 (<1%) in the comparator group. None
`of the deaths were judged by the investigator to be related to study treatment.
`Table 47 below presents a listing of the eight patients who died; Six patients were
`male. The primary site of infection was a diabetic ulcer in 4/8 (50%) patients;
`with wound infection, abscess, infected ulcer (not diabetic), and other infection
`occurring in one of each of the other 4 patients. Four of the patients were
`reported as discontinuing treatment due to the death (or AE associated with
`
`death); all had received 5 6 days of treatment. Three patients had successfully
`
`completed therapy; two on the day prior to death and one 10 days before. One
`patient was judged a treatment fai