CLINICAL REVIEW
`
`Clinical Review Section
`
`MO comments:
`In the daptomycin arm, cure rates were higher in patients with abscesses
`while cure rates were lower in patients with infected ulcer (non—diabetic)
`compared to the comparator arm. In patients with abscesses, incision and
`drainage itselfcan be curative. Patients with non-diabetic ulcers included
`patients with venous ulcers, and decubitus ulcers, both of which are
`associated with decreased tissue perfusion. This may accountfor the
`lower Cure rates seen in the daptomycin arm. Patients with history of
`diabetes had slightly lower cure rates compared to those without history
`ofdiabetes in the comparator arm; no diflerence was seen in the
`daptomycin arm.
`
`F. Oral sm‘tch
`
`Clinical success rates by treatment group were also compared for those
`patients who did and did not have oral switch therapy. Among patients in
`the MITT population who received only intravenous therapy, the clinical
`success rates were 67.0% (128/191) and 66.5% (125/188) for daptomycin
`and the comparator groups, respectively. Among the 46 patients in the
`MlTl‘ population who were switched to oral therapy, the clinical success
`rates were 66.7% (12/18) in the daptomycin group and 70.0% (17/24) in
`the comparator group.
`
`Table 39: SDCO by oral switch status (Population: MITT)
`
`“—
`128 (67.0%
`125 (66.5%
`80 (41.9%
`71 (37.8%
`48 (25.1%)
`54 (28.7%)
`
`ur
`
`linical
`1 m - rovement
`
`
`
`I ailure
`nable to
`I valuate
`
`43 (22 5%
`20 (10.5%)
`
`63 (33.5%
`41 21.8%
`22 (11.7%)
`
`“—
`12 667%
`17 70.8%
`
`m 11 611%
`linical
`1 (5 6%)
`I-mrovement
`
`6 33.3%)
`linical Failure
`flm-' 402.2%
`nable to
`2 (1 1.1%)
`I valuate
`Source: Table 14.2.1.23 .
`
`14 53.3%
`3 (12.5%)
`
`7 29.2%
`6 25.0%
`l (4.2%)
`
`-—. “u.
`-— -—.,
`
`Page 87'
`
`

`

`I
`
`CLINICAL REVIEW
`
`Clinical Review Section
`
`I
`
`MO Comments:
`
`Only a small number ofpatients were switched to oral therapy consistent
`with this primarily being an iii-patient study. Review ofa random sample
`ofcase reportforms had identified that several investigators made errors
`in the timing ofstudy visits relative to switch to oral antibiotics. However,
`for eflicacy analyses the sponsor only utilized the appropriate visit
`windowfor .TOC visit after oral medications were stopped The overall
`eflicacy analyses were thus not aflected.
`
`F. Concomitant procedures
`
`Patients with surgical procedures (debridement, curettage, incision and
`drainage etc) were flagged. Results ofan analysis separating patients into
`those who did and did not have these procedures are provided in table 40.
`
`Table 40: SDCO by concomitant surgical procedures
`(Population: lTT)
`
`
`
`95% CJ.
`
`(-23.6%, 8.2%)
`(-4.9%.16.0%
`
`Concomitant
`Procedures
`
`‘=264
`49/75 (65.3%)
`116/189 (61.4%)
`
`Comparator
`(N=266
`57/78 (73.1%)
`105/188 (55.9%)
`
`RESULTS (Study 990])
`
`Disposition of Patients
`
`A total of 571 patients were randomized, 277 to receive daptomycin and
`294 to receive comparator. Nine randomized patients discontinued prior to
`receiving any study treatment. Of 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 subject (0410100063) who was
`randomized to receive daptomycin but received comparator was
`considered misrandomized. In all efficacy analyses data for this subject
`are tabulated as randomized i.e., in the daptomycin arm and in all safety
`analyses as treated i.e. in the comparator arm.
`'
`
`Ofthe 293 patients treated with comparator drugs, 227 (77.5%) received
`semisynthetic penicillins (149 received cloxacillin, 59 received oxacillin,
`19 received flucloxacillin), 64 (21.8%) received vancomycin and two
`received vancomycin in combination with flucloxacillin.
`
`Comments:
`
`Unlike in study 980], semisynthetic penicillins were more commonly used
`as comparator agents rather than vancomycin, reflecting local antibiotic
`use patterns-andprevalence ofantibiotic resistant strains. For susceptible
`-. “v
`
`Page 88
`
`

`

`I
`
`CLINICAL REVIEW
`
`Clinical Review Section
`
`I
`
`organisms including methicillin-susceptible S. aureus, bactericidal activity
`ofsemisynthetic penicillins is superior to that ofvancomycin. This may
`have contributed to the lower cure rates in the comparator arm in stuafi»
`9801 compared to 9901.
`
`Over 90% of patients in'both treatment groups completed i.v. treatment as
`planned. The number of premature discontinuations were 18 (6.7%) and
`13 (4.4%) in the daptomycin and comparator arms respectively. The most
`common reason for premature discontinuation in both treatment arms was
`adverse event (2.6% and 1.7% in the daptomycin and comparator arms,
`respectively). No patients discontinued study medication due to elevation
`in CPK. Table 39 presents a summary of subject disposition during the
`study.
`'
`
`Table 41 (Sponsor Table 10-1): Subject Disposition
`
`Da . tomvcin
`Com 0 arator
`
`
`
`
`
`-_-—
`269 (100.0%
`293 (100.0%
`
`
`
`
`
`
`Po-ulation
`omleled Theta
`Premature] Discontinued Thera
`Adverse Event
`Clinical Failure
`
`Sub ecI'S Decision
`
`
`Prolocol Violation
`
`
`Lost 10 FDIIOW-U -
`
`2 07%
`
`
`
`
`
`
`
`
`
`
`
`
`
`Protocol Deviations
`
`Eligibility Deviations
`One or more eligibility deviations were reported for 32 (l 1.9%) patients in
`the daptomycin arm and 47 (16.1%) in the comparator arm. The most
`commonly reported deviation was serum CPK >50% above upper limit of
`normal (ULN) at baseline and was reported in 7.0% and 7.5% ofpatients
`in the daptomycin and comparator arms reSpectively. Elevations in CPK
`were generally considered to reflect prior trauma to the tissue at the
`primary site of infection, surgical incision and debridement, and
`intramuscular injections. All other deviations were reported in 52% of
`patients in either treatment group. Table 42 tabulates deviations that were
`reported in two or more patients.
`
`Page 89
`
`

`

`
`
`Clinical Review Section
`
`Table 42 (Sponsor Table 10-2): Eligibility deviations reported in Z 2
`patients (Intent-to-Treat)
`
` Deviation
`
`
`PK >50% above ULN
`
`
`
`D -rays not obtained at baseline for infections proximal to
`uone
`
`Daptomycin Comparator
`N = 270
`N = 292
`l9 7 0%
`22 7.5%
`
`
`
`3 (1.1%)
`
`6 (2.1%)
`
`
`
`pecimen available for Gram stain, culture and susceptibility
`est within 48 hr
`
`3 (1.1%)
`
`5 (1.7%)
`
`II id not have diagnosis of Gram positive skin infection with
`om-licatin_ factor
`
`
`
`4 (1.5%)
`
`3 (1.0%)
`
`
`
`
`
`
`
`we sets of blood cultures not obtained within 48 hours prior
`0 first dose
`
`
`alculated creatinine clearance < 30 mL/min or serum
`
`
`
`
`- e <18 or > 85 ears 18 to 65 for South African sites
`
`
`
`I ulti le infected ulcers at distant sites
`
`
`
`
`
`
`
`3 (1.1%)
`
`2 (0.7%)
`
`1 (0.4%)
`
`4 (1.4%)
`
`1 0.4%
`2 0.7%
`
`2 0.7%
`0 0.0%
`
`Two patients were discontinued from the study due to protocol violations.
`Subject 0310100054 was discontinued afier receiving 4 doses of
`daptomycin when the baseline wound culture was reported as yielding
`only Gram-negative rods. Subject 0401100061 was discontinued after
`receiving one dose of daptomycin when it was noted that the subject was
`also receiving flucloxacillin in' error.
`
`M0 Comments:
`
`Most protocol violations were ofa minor nature and were similar in the
`two arms. They are unlikely to impact assessment ofdrug efficacy.
`Enrollment ofpatients with elevated CPK could impact safety
`assessments.
`
`Data Sets Analyzed
`
`The ITT population includes all patients who received at least one dose of
`study treatment. The MITT population represents all ITT patients who had
`an infecting Gram positive pathogen isolated at baseline. In the
`comparator arm, 87.3% of patients were included in the MITT population
`compared to 78.9% in the daptomycin arm.
`
`The CE population includes approximately 90% of patients in both
`treatment arms. Fourteen (5.2%) patients in the daptomycin arm and 20
`(6.8%) in the comparator arm were excluded from the CE population by
`the sponsor as no evaluation was conducted during the TOC window.
`Twelve (4.4%) patients in the daptomycin arm and 10 (3.4%) in the
`comparator mm were excluded from the CE population because they
`received potentially effective non-study antibiotics either prior to
`treatment or post-baseline for reasons other than therapeutic failure. Seven
`
`Page 90
`
`

`

`l
`
`CLINICAL REVIEW
`
`Clinical Review Section
`
`I
`
`patients in the daptomycin arm and eight patients in the comparator arm
`were excluded from the CE population as they received an inadequate
`duration of treatment or < 80% of expected dose.
`
`The ME population comprises all patients in the CE population who had
`an infecting Gram positive pathogen isolated at baseline, ~73% and ~79%
`of ITT patients in the daptomycin and comparator arms respectively were
`included in the ME population. Table 43 presents the patient populations
`used for efficacy analysis.
`'
`
`Table 43 (Sponsor Table 11-1): Patient populations for efficacy
`analyses
`-
`
`Poulafion
`
`
`
`I odifiedlntent-to-Treat
`r oBaselinePatho-en
`
`linicall Evaluable
`
`
`I or Clinical] Evaluable
`
`
`
`No Evaluation in the Test-of-Cure Wind0w
`
`
`Dosing Com-Nance
`
`
`Post-baseline Effective Antibiotic
`
`
`
`Prior Efi'ective Antibiotic
`
`
`
`Misrandomized
`lCIOblOlOElCEIll Evaluable
`I
`I olMicrobiolo-icall Evaluable
`
`57 mm»
`245 90.7%
`
`262 89.7%
`
`4 (1.5%)
`3 1.1%
`
`l (0.4%
`196 72.6%
`74 (27.4%
`
`3 (l 0%
`3 10%
`
`0 00%
`23] (791%
`61 (20.9%
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Demographic and Other Baseline Characteristics
`Demographic Characteristics
`The two treatment groups were well balanced with regard to all
`demographic characteristics. Majority ofpatients was male and Caucasian.
`Mean age of patients was 47.9 years in the daptomycin group and 48.6
`years in the comparator group. Approximately 20% of patients in both
`treatment groups were 265 years of age at study entry. Table 44 presents a
`summary of the demographic characteristics.
`
`Page 91 ,
`
`

`

`I
`
`CLINICAL REVIEW
`
`Clinical Review Section
`
`I
`
`Table 44 (Sponsor Table 11-2): Demographic Characteristics
`
`p-value
`
`
`
`
`
`‘
`
`
`
`
`
`
`new ——I
`
`
`Characteristic
`
`
`
`
`
`
`DaptomV cm
`Comparator
`N = 270
`N = 292
`_—— 0-628
`Mean-1: SEM
`47 9+ 1.05
`48.6+098
`18, 87
`17,—85
`—
`em) —— 0623
`Mean i SEM
`73 5 :t l 20
`72.7 + 1.02
`40 I65
`40. 130
`swarm —— 0856
`Female
`120 (44 4%
`132 45 2%
`'
`Male
`150 55 6%
`I60 54.8%
`
`Black
`
`MO Comments:
`
`Patients in this study were younger, with a mean age of~48 years
`compared to ~55 years in study 9801. This is partly due to the fact that the
`upper limit for enrollment was 65 years in South Africa. Only 110/562
`(19.6%) patients were 2 65 years in this study compared to
`168/51 7(32.5%) in study 980]. The percentage of blacks was higher in
`this study reflecting differences in the study population.
`
`Ofthe 562 treated patients, 303 (53.9%) were enrolled in South Africa,
`237 (42.2 %) in Europe/Asia, and 22 (3.9 %) in Australia. The distribution
`of patients by country and by treatment group is displayed in the following
`table.
`
`4.0/2
`'
`0,5493 7,9,
`09/0,”:liq,
`
`._ a—_,
`
`Page 92
`
`

`

`CLINICAL REVIEW
`
`Clinical Review Section
`
`Table 45: Patient enrollment by country (Population: ITT)
`
` n
`
`Source: Table 14.1.2
`
`MO Comments:
`
`Sites in South Africa enrolled more than half the patients in this study.
`Five of these South African study sites had also enrolled ~18% ofpatients
`in study 980]. No patients, however, participated in both studies. The
`sponsor performed sensitivity analyses to evaluate the impact of these
`centers on the overall outcome. Results of those analyses and that of the
`FDA will be discussed later in the review.
`
`Baseline Disease Characteristics
`
`Primary Diagnosis
`
`The distribution of diagnoses was similar in both treatment arms. Wound
`infection was the most common diagnosis reported; 102 (37.8%) in the
`daptomycin arm and 108 (37.0%) in the comparator ann. Sponsor
`reviewed the 107 patients designated as having "other" infections, 67 had
`specific diagnoses, primarily wound infections or abscesses. All of the
`remaining 40 infections had complicating factors; 10 required adjunctive
`surgery, 11 were in patients with significant co~morbidity (e.g., diabetes),
`and 19 were assessed as complicated by the investigator (e.g., involved
`deeper tissues). Table 46 summarizes the primary diagnoses reported by
`the investigators at study entry. The sponsor-determined final diagnosis is
`shown in Table 47.
`~
`
`Page 93
`
`n n
`
`n-5
`
`62
`
`

`

`
`
`CLINICAL REVIEW
`
`Clinical Review Section
`
`Table 46 (Sponsor Table 11-3): Investigator’s Primary Diagnosis
`(Population: ITT)
`
`
`
`Either Infection
`
`Infected Ulcer (non-diabetic
`nfected Diabetic Ulcer
`
`
`
`
`Daptomycin
`N = 270
`102 37 8%
`
`Comparator
`N = 292
`108 37.0%
`
`P-_\'alue
`
`0.781
`
`56 (20.7%
`
`51 (17.5%)
`
`.
`
`
`
`
`Table 47 (Sponsor Table 11-4): Sponsor—Determined Final Diagnosis
`(Population: ITT)
`
`
`
`
`
`
`Primary Diagnosis
`
`
`'ound Infection
`Ia'or Abscess
`
`Infected Ulcer (non-diabetic)
` 3 F?'3. rt: 0. 9. D,0‘9; B S OO-1
`'
`Other Infection
`
`
`N = 270
`
`115 (42.6%)
`78 (28.9%)
`34 (12.6%)
`23
`8.5%
`20( 7.4%)
`
`Comparator
`N = 292
`
`122 (41.8%
`79 (27.1%)
`40 (13.7%)
`31 10.6%
`20( 6.8%
`
`
`
`
`MO Comments:
`
`Compared to study 9801, proportion ofpatients with abscesses was higher
`in this study and the proportion ofpatients with diabetic ulcers was
`smaller. Patients with abscesses will have higher cure rates compared to.
`patients with other complicated skin infections as an incision and
`drainage procedure in of itselfcan be curative thus skewing the overall
`cure rates.
`
`Stratification by diagnosis of infected diabetic ulcer
`At the time of randomization, 28 (10.4%) patients in the daptomycin arm
`were assigned to the diabetic ulcer stratum by the investigator compared to
`39 patients (13.4%) in the comparator arm. The sponsor reviewed the
`primary diagnosis and the description of the infection for each patient and
`compared these data with the stratum assigned by the study site at the time
`of randomization. In the daptomycin arm five patients stratified as having
`diabetic ulcer had a primary diagnosis other than diabetic ulcer. In the
`comparator group, 10 patients stratified as having diabetic ulcer had other
`infections and two patients with a primary diagnosis of diabetic ulcer were
`not assigned to that stratum. The sponsor performed analyses using either
`stratum or final diagnosis and found no difference in the efficacy results.
`
`MO Comments:
`
`Similar to study 980/, few patients with infected diabetic ulcers were
`enrolled and errors in classification of diabetic ulcer infection also
`occurred in this study. Sponsor and FDA analyses based on
`randomizationstrata will be presented in this review.
`.. “fl.
`
`Page 94
`
`

`

`
`
`CLINICAL REVIEW
`
`Clinical Review Section
`
`Baseline pathogens
`The distribution of pathogens was similar in both treatment groups. The
`most common pathogen was S. aureus, which was isolated from 70% and
`67.8% of patients in the daptomycin and comparator arms respectively.
`Spyogenes and Sagalacn'ae were isolated from ~35% of patients in both
`groups. Dual infection with both S. aureus and B -hemolytic streptococci
`was present in 20.7% of the MlTT population. Table 48 presents the
`infecting Gram positive pathogens isolated from the primary site of
`infection at the baseline evaluation.
`
`L
`
`Table 48 (Sponsor Table 11~5): lnfecting Gram positive pathogens at
`baseline (MITT)
`
`
`
`
`
`
`
`
`
`
`
`merococcus faecah's
`Other emerococci
`
`
`ram ositive anaerobes 8 3.l°/o
`
`N = 213
`
`N = 255
`
`
`
`
`
`
`
`
`
`
`Signs and symptoms of infection
`At the baseline visit, moderate to severe tenderness, erythema, edema and
`purulent drainage were present in the majority of patients in both
`treatment groups. Localized pain, swelling, and redness were present in
`97% or more of all patients. The proportion of patients reported to have
`fever at baseline was higher in the comparator group than in the
`daptomycin group (57% vs. 45%, respectively, p = 0.004). The recorded
`mean oral temperatures at baseline, however, were similar between the
`two arms (374°C, daptomycin, 375°C, comparator).
`
`Severity of infection
`Patients were characterized as having severe infection at baseline if they
`met one or more of the following criteria:
`'
`— fulfilled the definition for Systemic Inflammatory Response Syndrome
`(SIRS) by having 2 or more of the following findings: temperature
`>38° C or < 36° C; heart rate >90 beats/minute; respiration rate >20
`breaths lminute; or WBC >12 x 10 3 /L or < 4 x 103 /L or >10% bands)
`— had positive blood cultures at baseline;
`
`- were evaluated as having Severe tenderness or severe erythema.
`
`l’age 95
`
`

`

`I
`
`CLINICAL REVIEW
`
`Clinical Review Section
`
`1
`
`A total of 181 (67%) patients in the daptomycin treatment group and 177
`(60.6%) in the comparator group were classified as having severe
`infection. Approximately one third of the patients in each treatment group
`had SIRS. Bacteremia was diagnosed at baseline in six patients in each
`treatment group.
`
`Comments:
`
`In stuaj' 980], patients were considered.to have severe infections ifthey
`fulfilled definition ofSIRS or had a positive blood culture at baseline, or if
`the investigator assessed at least 3 of8 physical signs at the primary site
`of infection as severe. In this study however, presence ofsevere tenderness
`or severe erythema was sufficient to classifi’ an infection as severe. So, it
`is not surprising that although patients in study 9801 were sicker, the
`proportion ofpatients with severe infections was slightly lower than in
`study 9901. The number of bacteremic patients was similar to that seen in
`study 980].
`
`_ Baseline medical history, vital signs, and physical examination
`There were :no statistically significant differences between the treatment
`groups in the history of co-morbid illnesses, including diabetes, peripheral
`vascular disease, or irnmunocomprornise. A history of diabetes was
`reported in 18.5% and 23.3% of patients and a history of peripheral
`vascular disease was reported in 1 1.9% and 15.8%,'in the daptomycin and
`comparator arms respectively. Most patients in both treatment groups
`(~97%) were not immunocomprornised. More patients in the daptomycin
`arm were chronically bedridden compared to the comparator arm (2.6%
`vs. 0.3%, p = 0.024). There were no statistically significant differences
`between the treatment groups for any vital signs assessments at baseline.
`
`MO comments:
`
`In study 980], a history ofdiabetes was reported by >40% ofsubjects in
`both treatment arms which is much higher'than that reported in this study.
`Similarly, a history ofperipheral vascular disease was also more common
`in study 9801. Both these conditions can have a significant effect on
`wound healing and hence aflect clinical success rates.
`
`Baseline laboratory evaluations
`Mean white blood cell count was 11.4 x 10 3 /pL in the daptomycin arm
`and 12.] x 10 3 IpL in the comparator arm. Mean neutrophil percentage
`was 70.2% in the daptomycin arm and 72.4% in the comparator arm (p =
`0.031). There was no difference between treatment groups in absolute
`neutrophil count or other hematology parameters. There were no
`statistically significant differences between the treatment groups for any
`clinical chemistry assessments at baseline. Mean CPK at baseline was
`172.5 U/L (SEM 25.14) and 158.9 U/L (SEM 15.57) in the daptomycin
`
`Page 96
`
`

`

`.
`
`CLINICAL REVIEW -
`
`Clinical Review Section
`
`and comparator groups, respectively (p: 0.638), with a range of 18- 3702
`U/L in the daptomycin arm and 19-2410 in the comparator arm.
`
`Measurements oftreatment compliance
`Study Treatment
`Majority of patients received study treatment for 7 to 14 days, including
`230 (78.8%) patients in the comparator arm and 214 (79.3%) in the
`daptomycin arm. Only 8 patients, including one in the daptomycin
`treatment group and 7 in the comparator group, received treatment for >14
`days.
`
`Table 49 (Sponsor Table 12-1): Summary of duration of exposure
`(Safety population)
`
`
`
`Duration of IV therapy
`Daptomy cin
`Comparator
`N= 269
`N= 293
`
`
`
`
`54(20.1%
`56 i9.1%
`214(79. 6%
`230 78. 5%
`
`
`mm 704%)
`
`Seven patients (4 in the daptomycin arm and 3 in the comparator arm)
`were < 80% compliant with expected dosing. Switch to oral therapy was
`significantly more frequent among patients in the comparator arm (37/292;
`12.7%) than in the daptomycin arm (20/270; 7.4%). The primary reasons
`for switch to oral therapy were clinical improvement and patient request.
`
`MO Comments:
`
`In comparison to study 980] where ~ 15% ofpatients in each treatment
`arm received treatment for greater than 14 days, only eight patients in this
`study received treatment for > 14 days. The needfor prolonged therapy in
`a greater proportion ofpatients in study 9801 is consistent with the
`diflerences in patient characteristics in the two studies.
`
`Dosing regimens
`Patients with creatinine clearance between 30- 70 ml/min were to receive a
`
`modified dosing regimen for daptomycin (loading dose 4mg/kg, followed
`by 3mg/kg q 36 hrs). However, based on data subsequently submitted by
`the sponsor, it was noted that, only 9/35 (25.7%) patients with creatinine
`clearance between 30-70 ml/min actually received a modified regimen.
`These results are summarized in the table 50.
`
`a. k..-
`
`Page 97
`
`

`

`I
`
`CLINICAL REVIEW
`
`Clinical Review Section
`
`1
`
`Table 50: Dosing in renal insufficiency
`
`' Creatinine Clearance
`
`= mein
`
`‘includes 1 patient with CrCL < 30m1/min
`
`Concomitant antibiotic therapy and concurrent procedures
`Fifteen patients (5.6%) in the daptomycin group and 12 (4.1%) in the
`comparator group received effective non-study antibiotic for lack of
`efffrcacy and were considered clinical failures. Twelve patients (4.4%) in
`the daptomycin group and 10 (3.4%) in the comparator group were
`excluded from the CE population as they were administered potentially
`effective antibiotics for >2 days either prior to enrollment or post-baseline
`for reasons other than lack of efficacy.
`Overall, 46 patients (17%) in the daptomycin arm and 65 (22.3%) in the
`comparator arm received either aztreonam or metronidazole or both during
`the study.
`A total of 53 (19.6%) patients in the daptomycin arm and 58 (19.9%) in
`the comparator group underwent a surgical procedure during study
`treatment. The most commonly performed procedures were incision and
`drainage, and wound debridement. Two patients were designated clinical
`failure on the basis of surgical removal ofthe primary site ofinfection;
`one patient in the daptomycin group had an above knee amputation on
`Day 4 and one patient in the comparator group had a below knee
`amputation on Day 4.
`
`MO Comments:
`
`In study 9801 , ~ 40% ofpatients had concomitant surgical procedures and
`~30% received concomitant antibiotics for Gram negative and or
`anaerobic coverage which again points to the diflerences in the patient
`population enrolled in the two studies. It may also represent di erences in
`treatment practices between US and non- US sites.
`
`Analysis of Efficacy
`Primary Efficacv Analysis
`
`The sponsor has presented clinical outcomes in the MlTT and CE
`populations in the main body of the final study report. Results for the UT
`and ME populations were provided in the additional tables included in the
`study report. Sponsor's analyses of the 1TT, MlTl", CE, and ME
`populations using the SDCO are included in this review.
`
`Page 98
`
`

`

`CLINICAL REVIEW '
`
`Clinical Review Section
`
`As discussed for study 9801 , the ITT and CE populations are considered
`the primary efficacy populations. The sponsor’s results for the ITT and CE
`populations, and the results for the FDA-defined ITI‘ and CE populations
`for sponsor-defined clinical outcomes are presented in the following
`tables:
`
`Sponsor’s Results
`Clinical success rates in the ITT population were 80.7% in the daptomycin
`arm and 81.2% in the comparator arm (95% CI: -6.1, 6.9). In the CE
`population, clinical success rates were 88.6% (217/245) and 89.7%
`(235/262) in the daptomycin and comparator arms, respectively (95% C1: ~
`4.3, 6.5).
`
`Table 51: Sponsor-defined clinical outcome (Population: ITT)
`
`
`
`N = 270
`
`
`
`N= 292
`
`linical Success
`
`linical Failure
`
`
`
`
`Unable to Evaluate
`
`Source: Table 14.2.1.1, Section 14.2
`
`
`
`Table 52 (Sponsor table 11-7): Sponsor-defined clinical outcome
`(Population: CE)
`
`Clinical Response
`
`
`
`linical Success
`Cure
`
`
`Clinical lmrovemenl
`
`
`linical Failure
`
`I ailure
`
`
`
`Daptomycin
`N = 245
`217 (88.6%
`103 (42.0%
`
`
`
`Comparator
`N = 262
`235 (89.7%
`122 (46.6%
`
`95% C1
`
`-4.3, 6.5
`
`-
`
`28 (11.4%
`28 11.4%
`
`27 (10.3%
`27 10.3%
`
`
`
`2.133%
`
`
`
`
`
`
`
`Table 53: Sponsor-defined clinical outcome (Population: ITT)
`
`
`
`Clinical Response
`
`
`
`_
`'=292
`‘=270
`--—-.
`Clinical Success
`' Clinical Failure —---g
`; Difference in Success Rate
`-0.1%, 95% CL: -7.0%, 6.8%
`
`
`
`
`I1
`
`
`
`Page 99
`
`
`
`

`

`I
`
`.
`
`CLINICAL REVIEW
`
`Clinical Review Section
`
`l
`
`Table 54: Sponsor-defined clinical outcome (Population: CE)
`
`: Clinical Response
`l
`
`'=238
`
`Comparator
`'‘=250
`
`:
`
`
`
`
`3 Clinical Failure
`
`1 Difference in Success Rate
`-0.5%. 95% C.l.: -6.2%. 5.2% 3
`
`
`
`
`
`
`24 (9.6%
`
`-
`
`
`
`
`MO Comments:
`
`Point estimatesfor cure rates in the FDA definedpopulations were similar
`to those of the sponsor. Cure rates were comparable in the two treatment
`groups using a non-inferiority margin of 10 %. The lower bound ofthe
`95% C] around the diflerence in success rates was less than 10 % in the
`FDA analysis and the upper bound of the 95% C] was less than 10 % in
`the sponsor '5 analysis. Also, the 95% CI include the value ofzero
`consistent with non-inferiority.
`
`The sponsor’s results in the MlTT and ME populations, and the results in
`the FDA defined MlTT and ME populations for sponsor-defined clinical
`outcomes are presented in the following tables:
`
`S onsor’s Results
`
`Table 55 (Sponsor table 11-6): Sponsor-defined clinical outcome
`(Population: MITT)
`
`Clinical Response
`
`
`
` linical Success
`
`
`
`
`
`Iinical Imrovemem
`linical Failure
`
`
`
`
`
`nable to Evaluate
`
`
`
`
`Daptomycin
`N = 213
`
`180 (84.5%
`82 (38.5%
`
`Comparator
`N = 255
`
`2H (83.9%)
`110 (43.l%
`
`_ 95% C]
`
`
`
`
`
`As per the statistical analysis plan, patients who were judged cured or
`improved by the investigator at the TOC evaluation and were assigned a
`SDCO of non-evaluable only because of compliance <80% were
`considered as success in the HT and MlTT populations. Three patients
`(one in the daptomycin arm, two in the comparator arm) met these criteria.
`Thus, the number of successes in the HT and MlTT populations is higher
`than in the CE and ME populations respectively.
`
`.-.‘_. .,.
`_-..._..
`
`Page 100
`
`

`

`l
`
`CLINICAL REVIEW
`
`Clinical Review Section
`
`Table 56: Sponsor-defined clinical outcome (Population: ME)
`
`Daptom\cin
`= 196
`
`
`
`Clinical Response
`linicalSucc_ss
`
`linical lm-rovemenl
`
`
`linical Failure
`
`Source: Table 14.2.1.4, Section 14.2 '
`
`Comparator
`N= 23]
`
`
`
`
`
`95% CI
`-4.9, 5.7
`
`
`
`
`FDA Results
`
`Table 57: Sponsor-defined clinical outcome (Population: MITT)
`
`Clinical Response
`
`-
`
`Clinical Success
`Clinical Failure
`2 Difference in Success Rate
`1 Da-Iomvcin vs. Com-armor:
`
`_
`
`0.9%. 95% C.l.: ~6.3°/o. 8.1%
`
`‘
`
`(N=213
`179 (84.0%
`34 16.0%)
`
`Comparator
`(N=255
`212 (83.1%)
`43 (16.9%
`
`1
`1
`
`Table 58: Sponsor-defined clinical outcome (ME population)
`
`Clinical Response
`
`
`
`DaptomycinComparator
`
`
`=19]
`'=220
`I
`
`
`
`
`i Clinical Success
`203 (92. 3%)
`176 (92.1%
`
`[ Clinical Failure
`17 (7.7%)
`15 (7.9%
`Difference in Success Rate
`
`
` -O.l%, 95% C.l.: -5.8%. 5.6%
`Datomvcin vs. Comarator:
`
`
`
`
`MO comments:
`
`Point estimates for cure rates in the FDA defined populations were similar
`to those ofthe sponsor. Cure rates were comparable in the two treatment
`groups using a non-inferiority margin of l 0 %. The lower bound of the
`95 % Cl around the diflerence in success rates was less than 10 % in the
`FDA analysis and the upper bound of the 95 % Cl was less than 10 % in
`the sponsor '5 analysis. Also, the 95 % Cl include the value ofzero
`consistent with non—inferiority.
`
`Secondary efficacy analyses
`
`Sponsor’s Results
`
`Sponsor-Defined Clinical Outcome by lnfecting Pathogen
`1n the MITT population, clinical success rates using the SDCO were
`comparable for both treatment groups for patients infected with S. aureus
`h“-
`and S pyogezzes, the pathogens isolated most frequently at baseline.
`
`Page 101
`
`

`

`CLINICAL REVIEW
`
`Clinical Review Section
`
`Clinical success rates for patients infected with less commonly represented
`pathogens, (e.g.., S. agalactiae and Efaecalis) were also clinically
`comparable, but the number of isolates were smaller. Similar results were
`observed in the ME population. Sponsor's results in the MITT population
`. are summarized in table 59.
`'
`
`Table 59 (Sponsor table 11-9): SDCO by infecting pathogen
`(Population: MITT)
`
`lnfecting Pathogen
`
`Daptomycin
`N = 213
`
`Comparator
`N = 255
`
`95% C]
`
`
`la : hvlococcus aureus
`
`
`
`tre tococcus a alactiae
`
`
`Other stretococcus 5-.
`nterococcus faecalis
`
`
`
`
`
`
`
`
`_--—
`_-I—
`
`-l-_—
`
`For patients infected with S. aureus, the clinical success rates were also
`evaluated by the oxacillin susceptibility of the baseline isolate for patients
`in the MlTT and the ME populations. These analyses were restricted to
`isolates that were tested by the central laboratory. Only 16 isolates were
`reported as oxacillin-resistant. Clinical success rates for patients with
`oxacillin-resistant S. aureus in the Ml'I'I‘ population were 80.0% (4/5) in
`the daptomycin and 81.8% (9/11) in the comparator arm respectively.
`
`Table 60: Sponsor defined clinical success rates by oxacillin
`susceptibility”
`
`- xaciIIin susce - n‘bilirv
`err
`
`is - 129
`
`
`
`
`mm— 104/124 83.9%
`1' esistam
`
`
`
`ME
`
`usce-tible
`I' esistant
`
`N = 151
`
`119/140 (85.0%
`
`
`
`
`
`
`
`
`
`Source: Appendix 2 and Appendix 3, 1513
`' Only isolates tested at central laboratory
`
`- MO Comments:
`
`The number of MRSA isolates was far less than that seen in study 9901,
`reflecting the epidemiologic factors associated with antimicrobial
`resistance. A greater proportion ofpatients in study 9801 had other co-
`morbidities, hence they were more likely to have been exposed to MRSA in
`healthcare settings. They were also more likely to have other riskfactors
`for MRSA acquisition such as prolonged hospitalization, prior antibiotic
`exposure, and admission to intensive care units.
`.. “v
`_ M..-
`
`Page 102
`
`

`

`I.
`
`CLINICAL REVIEW
`
`Clinical Review Section
`
`|
`
`Three patients in the comparator arm were treated with semi-synthetic
`penicillin and not vancomycin. Two of these patients were classified as
`clinical success, again raising the question ofwhether these MRSA
`isolates represent colonization or true infection.
`
`Microbiologic response by pathogen
`
`Pathogen specific microbiologic response rates for those Gram positive
`pathogens most commonly isolated at baseline are summarized in Table
`61 for the ME population.
`
`Table 6]: Microbiologic response rates by pathogen
`(Population: ME)
`
`101/133 75.9
`84/114 (73.7)
`3 /4 (75.0
`
`Comparator
`n/N %
`
`127/155 (81.9
`103/128 (80.5
`8/9 88.9
`
`Pathogen Daptomycin
`
`
`an %
`
`IOIhI'IOCOCCUS aureus (all)
`
`
`Sta hvlococcus aureus (MSSA
`
`Slahi'lococcus aureus MRSA
`trean-Iococms'voenes
`
`
`
`
`nterococcus aecalis (all)
`
`
`Source: Appendix 5, lSE
`
`trelococcus a_alactiae
`Iretococcus drs-alactiae e uisimilis
`iridans Sue-lococci Grou-
`
`Microbiologic response by patient
`Microbiologic success rates in the MITT population were 73.2% for the
`daptomycin and 74.9% for the comparator arm, and'in the ME population,
`79.6% and 82.3%, respectively.
`
`Table 62: Microbiologic response by patient (ME population)
`
`
`
`Response
`
`
`Daptomycin
`N =l96
`
`
`
`Comparator
`N =23]
`
`156 79.6%
`40 20.4%
`iicrobiologic Failure ‘
`
`Modified from sponsor table 1 1-8
`
`190 (82.3%
`41 (17.7%
`
`
`
`95% CI
`
`4.8.10.2
`
`-
`
`
`
`
`M R
`
`esults of FDA analyses are presented in the following tables. Viridans
`group streptococci were not considered significant pathogens and hence
`are not included in the following tables.
`
`1l
`
`Page 103
`
`

`

`I
`
`CLINICAL REVIEW
`
`Clinical Review Section
`
`I
`
`Table 63:Clinical success by pathogen (Population: MlTT)
`
`I §
`
`Baseline Patho-en
`_--—
`
`
`
`
`
`
`
`}-'-__-
`l__—
`I——_
`
`Stretococcus dvs alactiae
`
`
`
`
`
`
`Table 64: Microbiologic success by pathogen (Population: ME)
`
`.
`
`a
`
`
`
`v
`
`
`
`
`
`
`
`
`
`
`
`
`
`—--—-
`— 13/1 6 (81 3%
`17/24 70.8%
`f Stretococcus di'salactiae
`2/2 (100%)
`7/9 (77.8%)
`
`Table 65: Microbiologic success by subject (Population: ME)
`
`1 Microbiologic Response
`‘
`
`Microbioloeic Success
`Microbioloeic Failure
`
`1 Difference in Success Rate
`Dastomvcin vs. Comoarator:
`
`-2.6%. 95% C.I.: 40.7%, 5.4%
`
`Daptomycin
`(N=I9]
`153 (80 1%)
`38 19.9%
`
`Comparator
`‘=
`182 (82.7%)
`38 (17.3%)
`
`MO Comments:
`
`Microbiologic eradication rates by pathogen and by subject and clinical
`success rate by pathogen were essentially similar in the two treatment
`arms in both the FDA and sponsor '5 analyses.
`
`Analyses by diabetic ulcer stratification
`
`At the time of randomization, patients were stratified based on the
`presence or absence of diabetic ulcer. Sponsor‘s results for the SDCO
`based on stratification by diabetic ulcer are summarized in table 66,
`followed by the FDA resul