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`|
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`comparator subjects in these studies. In Phase III cSSSl and CAP
`studies 7/989 (0.7%) daptomycin—treated patients and 7/1018
`(0.7%) comparator-treated patients experienced paresthesias. New
`or worsening peripheral neuropathy was not diagnosed in any of
`these patients. In animals, effects of daptomycin on peripheral
`nerve were observed (see ANIMAL PHARMACOLOGY).
`Therefore, physicians should be alert to the possibility of signs and
`symptoms of neuropathy in patients receiving Cubicin." Since
`peripheral neuropathy characterized by axonal degeneration were
`observed in adult dogs and monkeys; this paragraph was added to
`provide the practitioner with all available clinical experience with
`neuropathy in human studies.
`GERIATRIC USE
`
`o The following sentence was added to the demographic information
`and efficacy data to complete the characterization of daptomycin in
`the geriatric population. "In addition, treatment-emergent adverse
`events were more common in patients 265 years old than in
`patients <65 years of age in both cSSSI studies."
`ADVERSE EVENTS
`
`0 The second paragraph was modified to read "Clinical studies
`sponsored by Cubist enrolled 1,409 patients treated with
`daptomycin and 1,185 treated with comparator. Most adverse
`events reported in these clinical studies were described as mild or
`moderate in intensity. In Phase III cSSSI trials, daptomycin was
`discontinued in 15/534 (2.8%) patients due to an adverse event
`while comparator was discontinued in 17/558 (30%) patients."
`These changes were made to modify language to include AEs of
`severe intensity as well as to more accurately reflect the
`discontinuation rate due to AEs.
`
`0 The following paragraph was added in order to provide
`'
`practitioners information regarding the adverse event profile of
`daptomycin in the treatment of CAP, as well as the cause:
`" In
`Phase III studies of community-acquired pneumonia (CAP), the
`death rate and rates of serious cardiorespiratory adverse events
`were higher in daptomycin—treated patients than in comparator-
`treated patients. These differences were due to lack of therapeutic
`effectiveness of daptomycin in the treatment of CAP in patients
`experiencing these adverse events (see INDICATIONS AND
`USAGE)
`0 The sentence
`
`\
`
`\
`
`\
`"was deleted from this section. A more complete
`summary of the Lilly and Cubist experience with neuropathy15
`now includedin PRECAUTIONS.
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`0 Under Laboratory Changes: The FDA proposed changes in the
`ADVERSE EVENTS section include the addition ofa table
`
`(Table 6) showing rates of various degrees of CPK elevation in
`daptomycin and comparator-treated patients in cSSSI studies.
`
`This table provides information to prescribers on the relative rates
`of CPK elevation in the population of patients for whom
`daptomycin is indicated, and illustrates that extreme elevations of
`CPK consistent with myopathy occur in daptomycin-treated
`patients, although at a low rate In this context, it is important to
`note that the reported incidence of statin-associated myopathy (2.3
`per 10,000 person-years [Epidemiology 2001 ;12:565-9] is lower
`than the corresponding incidence reported in Phase III trials for
`daptomycin (0.2%).
`
`DOSAGE AND ADMINISTRATION
`
`o The following was added to the first paragraph under
`"Complicated Skin and Skin Structure Infections": "Doses of
`daptomycin higher than 4 mg/kg/day have not been studied in
`Phase III controlled clinical trials. In Phase I and 2 clinical
`
`studies, CPK elevations appeared to be more frequent when
`daptomycin was dosed more frequently than once daily.
`Therefore, daptomycin should not be dosed more frequently
`than once a day." The sentence regarding dosing was added to
`provide practitioners who may be considering off~label use at a
`higher dose than 4 mg/kg q 24h that safety data to support such
`use has not yet been collected. The sentence regarding
`frequency of dosing was added to reflect that in a Phase 1 dose-
`escalation study (Study B8B-MC-AVAP) conducted by Lilly
`daptomycin at 4 mg/kg quh for 14 days was administered to
`five normal subjects. At about Day 8 of treatment, two of the
`five subjects experienced muscle pain and weakness as well as
`rapid elevations in CPK. Study medication was discontinued
`and the effects resolved within a few days without sequelae.
`Subsequent animal studies indicated that for a given level of
`drug exposure the frequency and severity of skeletal muscle
`toxicity were decreased with once daily dosing compared with
`divided doses.
`
`D.
`
`Dosing
`
`Daptomycin exhibits concentration-dependent bactericidal activity
`in vitro against the claimed Gram-positive organisms. No formal
`dose response or concentration response study was performed by
`Cubist. The recommended daptomycin dosage regimen is based on
`clinicalfiexperience in the primary comparative studies, and on
`
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`microbiological and pharmacokinetic considerations. The primary
`comparative studies in complicated skin and skin structure
`infections were each performed using a daptomycin regimen of 4
`mg/kg intravenously q24h for 7 to 14 days. The two studies of
`daptomycin in community acquired pneumonia also used a dose of
`4 mg/kg q 24h for 5-14 days; this data was submitted to the NDA
`in support of safety.
`
`In a multicenter Phase II trial, daptomycin (2 mg/kg q24h) was as
`effective as conventional therapy (oxacillin, vancomycin,
`penicillin, or ampicillin plus an aminoglycoside) in the treatment
`of Gram-positive skin and soft tissue infections. Thirty (96.8%) of
`31 evaluable subjects treated with daptomycin had a favorable
`response, compared to 41/43 (95.3%) of the evaluable subjects
`who received conventional therapy..Bacteriological eradication
`was observed in 30/31 (96.8%) daptomycin-treated subjects,
`compared with 34/43 (79.1%) of subjects treated with conventional
`therapy. Daptomycin was effective against a variety of infecting
`pathogens, including Staphylococcus aureus, Streptococcus
`pneumoniae, other species of streptococci, and enterococci. In this
`study, daptomycin at 2 mg/kg q24h was less effective than
`conventional therapy in the treatment of bacteremia. In a
`subsequent Phase II trial in which daptomycin dose was increased
`to 3 mg/kg q12h, a successful clinical and bacteriologic outcome
`was seen in 21/24 (87.5%) subjects with bacteremia treated with
`daptomycin. This result was similar to the percentage of favorable
`outcomes for conventional therapy in both Phase II studies (8/9
`[88.9%] in the first study and 3/4 [75.0%] in the second study).
`
`'
`
`In studies conducted to date by Lilly and Cubist, the incidence of
`CPK elevations does not appear to be dose-related. In Phase I and
`2 clinical studies, CPK elevations did appear to be more frequent
`when daptomycin was dosed more frequently than once daily. In a
`Phase 1 dose~escalation study (Study B8B-MC-AVAP) conducted
`by Lilly, daptomycin at 4 mg/kg q12h for 14 days was
`administered to five normal subjects. At about Day 8 of treatment,
`two of the five subjects experienced muscle pain and weakness as
`well as rapid elevations in CPK. Study medication was
`discontinued and the effects resolved within a few days without
`sequelae. Subsequent animal studies indicated that for a given
`level of drug exposure the frequency and severity of skeletal
`muscle toxicity were decreased with once daily dosing compared
`with divided doses. Therefore, when Cubist acquired the drug for
`development, the choice was made to use only single daily dosing.
`.. “u
`_. -“ .-
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`Conclusions
`
`In Phase II clinical trials conducted by Eli Lilly and company and
`by Cubist, daptomycin was administered at 2, 4, and 6 mg/kg q24h
`and at 3 mg/kg quh to 349 patients with a variety of serious
`infections due to Gram-positive organisms, including bacteremia,
`endocarditis, skin and soft tissue infectidn, and pneumonia. In
`these studies, the incidence and nature of adverse events associated
`with daptomycin were comparable to that seen with conventional
`therapy. In Cubist sponsored Phase ll/Ill studies, 70 patients
`received the proposed dose of 4 mg/kg q 24h.
`
`There is adequate efficacy and safety data to recommend approval of
`daptomycin 4 mg/kg/day intravenously for 7-14 days, in patients 18
`years of age or older, with complicated skin and skin structure
`infections due to Gram-positive bacteria including Staphylococcus
`aureus (methicillin~resistant and susceptible strains), Streptococcus
`pyogenes, Enterococcusfaecalis (vancomycin—susceptible strains),
`Streptococws agalactiae, and Streptococcus dysgalactiae.
`
`Sufficient numbers of patients with complicated skin and skin
`structure infections such as major abscesses, infected ulcers, wound
`infections, and cellulitis were included in the studies to justify
`inclusion in the label.
`
`Data were inadequate to include patients with infected diabetic ulcers.
`
`Gastrointestinal disorders such as nausea, constipation, diarrhea, and
`vomiting were the most common adverse events reported in Phase III
`cSSSI studies. The rates of overall adverse events, deaths, serious
`
`adverse events other than death, and adverse events leading to
`discontinuation were similar in both treatment groups.
`
`One daptomycin treated patient had biochemical and clinical evidence
`of myopathy while on therapy.-
`
`There was no clinical or laboratory evidence for daptomycin
`cardiotoxicity in pre-clinical studies or in Phase I, II, and Ill data.
`
`There was no clinical or laboratory evidence for daptomycin
`hepatotoxicity in pre-clinical studies or in Phase I, ll, and Ill data.
`
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`This is a representation of an electronic record that was signed electronically am!
`this page IS the manifestation of the electronic signature.
`
`Sumathi Nambiar
`9/12/03 02:23:52-PM
`MEDICAL OFFICER
`
`Susan Thompson
`9/12/03 02:29:55 PM
`MEDICAL OFFICER
`
`David Ross
`
`9/12/03 02:33:34 PM
`MEDICAL OFFICER
`
`Janice Soreth
`9/12/03 02:36:29 PM
`MEDICAL OFFICER
`
`

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`CLINICAL REVIEW
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`I
`
`Appendix A to Integrated Review of
`Safety and Efficacy
`
`NDA 21-572
`
`. Cubicin (daptomycin for injection)
`
`Original New Drug Application for marketing approval for treatment of
`complicated skin and skin structure infections (cSSSI) due to Gram—positive
`bacteria including Staphylococcus aureus (methicillin-resistant and susceptible
`strains), Streptococcus pyogenes, Enterococcusfaecalis (vancomycin-susceptible
`strains), Streptococcus agalactiae, Streptococcus afitsgalactiae subsp. equisimilis
`W
`
`- Sponsor: Cubist Pharmaceuticals, Inc.
`Lexington, MA 0242]
`
`Clinical Reviewer:
`
`Sumathi Nambiar, MD. MPH
`
`Date of Submission: December 19, 2002
`
`Date Assigned:
`
`December 19, 2002
`
`Date Review Begun: December 19, 2002
`
`Date Review to Supervisor: August 31, 2002
`
`PDUFA Deadline:
`
`September 19, 2002
`
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`

` CLINICAL REVIEW
`
`Table 01 Contents
`
`Table of Contents .........
`
`............
`
`..... . ........ . ...... . ........ . ............................2
`
`Executive Summary........ .......................................... . .............NJ
`
`1.
`
`Recommendations ...........................................3...................................................5
`
`A.
`
`B.
`
`Recommendation on Approvability ...........................................................5
`
`Recommendation on Phase 4 Studies and/or Risk Management Steps...._6
`
`II.
`
`Summary of Clinical Findings ......................................................................... ”.6
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`Brief Overview of Clinical Program ......................................................... .6
`
`Efficacy ..................................................................................................... -9
`
`Safety ......................................................................................................... 12
`
`Dosing ....................................................................................................... 29
`
`Special Populations ....................................................................................31
`
`Clinical Review.. ............... . .......... . ................................................................. . ........35
`
`I.
`
`Introduction and Background ........................................................................... 35
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`Drug Established and Proposed Trade Name, Drug Class, Sponsor’s
`Proposed Indication(s), Dose, Regimens, Age Groups .............................. 35
`
`State of Annamentan'um for Indication(s) .................................................35
`
`Important Milestones in Product Development ......................................... 35
`
`Other Relevant Information ....................................................................... 37
`
`Important Issues with Pharmacologically Related Agents ........................38
`
`ll.
`
`Clinically Relevant Findings From Chemistry, Animal Pharmacology and
`Toxicology, Microbiology, Biopharmaceutics, Statistics and/or Other
`Consultant Reviews ............................................................................................. 38
`
`- H...
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`.
`
`I
`
`111.
`
`Human Pharmacokinetics and Pharmacodynamics ........................................ 39'
`
`A.
`
`B.
`
`Pharrnacokinetics ..................................................................................... 39
`
`Pharmacodynamics ....................................................................................40
`
`IV.
`
`Description of Clinical Data and Sources ......................................................... 40
`
`A.
`
`B.
`C.
`D.
`
`Overall Data ...............................................................................................40
`
`Tables Listing the Clinical Trials ...............................................................40
`Postmarketing Experience .........................................................................41
`Literature Review...... ................................................................................41
`
`V.
`
`Clinical Review Methods .................................................................................... 41
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`How the Review was Conducted ...............................................................41
`
`Overview of Materials Consulted in Review .............................................42
`
`Overview of Methods Used to Evaluate Data Quality and Integrity ......... 42
`
`Were Trials Conducted in Accordance with Accepted Ethical Standards.42
`
`Evaluation of Financial Disclosure ............................................................43
`
`VI.
`
`Integrated Review of Efficacy ............................................................................ 43
`A.
`L Brief Statement of Conclusions .................................................................43
`
`B.
`
`C.
`
`D.
`
`General Approach to Review of the Efficacy of the Drug .........................44
`
`Detailed Review of Trials by Indication............... .....................................44
`
`Efficacy Conclusions .................................................................................45
`
`VII.
`
`Integrated Review of Safety .......................................................................I...... I 12
`
`VIII. Dosing, Regimen, and Administration Issues ................................................. 112
`
`1X.
`
`Use in Special Populations ................................................................................ 112
`
`A.
`
`B.
`
`Evaluation of Sponsor’s Gender Effects Analyses and Adequacy of
`Investigation ................................._............................................................ 1 12
`
`Evaluation of Evidence for Age, Race, or Ethnicity Effects on Safety or
`Efficacy “._.................................................'.............................................. 1 12
`h”
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`3.x"
`
`C.
`‘ D.
`
`Evaluation ofPediatric Program..................................................,............. 1 13
`Comments on Data Available or Needed in Other Populations .............. 113
`
`X.
`
`Conclusions and Recommendations ................................................................ 113
`
`A.
`
`B.
`
`Conclusions .............................................................................................. l 13
`
`Recommendations .................................................................................... l 14
`
`XI.
`
`Appendix ............................................................................................................ 119
`
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`Executive Summary Section
`
`% 2]
`
`Clinical Review for NBA 21-572
`
`Executive Summam
`
`1.
`
`Recommendations
`
`A.
`
`Recommendation on Approvability
`
`the lead
`is
`injection; Cubist Pharmaceuticals)
`CubicinTM (daptomycin for
`investigational antibiotic in a new class of drugs known as cyclic lipopeptides.
`Based on evidence from two randomized, active-controlled clinical
`trials
`submitted by the sponsor, there is adequate efficacy and safety data to recommend
`approval of daptomycin 4 mg/kg/day intravenously for 7‘14 days, in patients 18—
`85 years of age, with complicated skin and skin structure infections (cSSSl) due
`to Gram-positive bacteria including Staphylococcus aureus (methicillin-resistant
`and
`susceptible
`strains), Streptococcus pyogenes, Enterococcus
`faecalis
`(vancomycin-susceptible strains), Streptococcus agalactiae, and Streptococcus
`drsgalactiae. 1n combined cSSSl studies, a total of 534 patients were treated with
`daptomycin. The safety database comprised data on 602 daptomycin-treated
`patients in Phase 1 studies, 349 daptomycin—treated patients in Phase II studies,
`and 989 patients in Phase Ill studies.
`
`The-two clinical studies conducted by Cubist in cSSSl were similar in trial design,
`but differed in certain baseline patient characteristics, such as underlying diabetes
`and peripheral vascular disease. Such differences in baseline characteristics may
`have had a significant effect on wound healing. Observed success rates were in
`fact quite different in the two studies. In both trials, daptomycin was demonstrated
`to be non-inferior to the comparator (vancomycin/semi-synthetic penicillins),
`using a non-inferiority margin of 10%.
`
`Sufficient numbers of patients with complicated skin and skin structure infections
`such as major abscesses, infected ulcers, wound infections, and cellulitis were
`included in the studies to justify inclusion in the label. Data were inadequate to
`include patients with infected diabetic ulcers. The number of patients enrolled
`with infected diabetic ulcers was small, errors in classification of diabetic ulcers
`occurred, and the clinical success rates observed in these limited data were low.
`
`The safety profile of daptomycin is derived from 1755 subjects exposed to
`daptomycin in clinical studies conducted by Cubist and Lilly; limited 120- day
`safety data are available for an additional 52 patients enrolled in ongoing studies,
`most of whom received a higher dose of daptomycin at 6 mg/kg IV given once
`daily. Overall, the MedDRA system organ class (SOC) with the greatest
`percentages of reported adverse events was gastrointestinal disorders, most
`.- “-1-
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`
`frequently nausea, constipation, diarrhea, and vomiting. The rates of overall
`adverse events, deaths, serious adverse events (SAEs) other than death, and
`adverse events (AEs) leading to discontinuation were similar in both treatment
`groups. Preclinical studies had predicted that the primary target of daptomycin
`toxicity was skeletal muscle. This prediction was confirmed in Phase 1 studies by
`the observed elevation of CPK with muscle-related symptoms in 2/5 subjects
`given 4 mg/kg IV q12h and 2/4 subjects administered daptomycin at 4 mg/kg IV
`q24h. In Phase 3 (ZSSSI tn'als, elevations in serum CPK were reported as clinical
`adverse events in 15/534 (2.8%) daptomycin-heated patients, compared to 10/58
`(1.8%) comparator-treated patients. Symptoms consistent with muscle injury
`were observed in 1/534 (0.2%) of daptomycin- treated patients.
`
`B.
`
`Recommendation on Phase 4 Studies and/or Risk Management Steps
`
`The Agency and Cubist have agreed that Cubist will conduct two Phase 4 studies.
`
`' The first study will consist of a safety and efficacy study in patients with
`cSSSl. This study is scheduled to start in the first quarter of 2004 and has an
`estimated 18-month study duration. The study will be open-label, randomized,
`multicenter, non-comparative study. The patient population for this study will
`consist of 72 patients with renal insufficiency in the following categories: Clcr
`30-50 mL/min an Clcr <30 mL/rnin. Patients in the latter category may be on
`hemodialysis, continuous ambulatory peritoneal dialysis, or may not be
`maintained on dialysis. Phannacokinetic data will also be collected in this
`study.
`' L
`
`11.
`
`Summary of Clinical Findings
`
`A.
`
`Brief Overview of Clinical Program
`Daptomycin [Cubicin®] is a cyclic lipopep‘tide antibiotic that is administered
`intravenously.
`Phase 1, and 2 studies
`The Cubist Phase 1 studies enrolled 240 subjects who received daptomycin. The
`Cubist human pharmacology studies included single-‘ and repeat-dose
`phannacokinetic studies in normal healthy subjects and in special populations.
`Repeat—dose studies were conducted in healthy subjects and in subjects with
`various degrees of renal impairment, including end-stage renal disease (ESRD).
`Single-dose studies were conducted in subjects with moderate hepatic impairment
`(Child-Pugh Classification B), in geriatric subjects, and in obese subjects, and in
`M
`healthy subjects. Drug interaction studies with aztreonam, probenecid, warfan'n,
`-~ 5‘”
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`.
`
`I
`
`and simvastatin were conducted in healthy subjects. Studies on daptomycin
`protein binding were conducted in healthy subjects and in subjects with various
`degrees of renal impairment, including ESRD. A placebo-controlled study was
`conducted to examine the effect of daptomycin given to healthy subjects at 6
`mg/kg q24h for 14 days on cardiac repolarization (QT interval) and peripheral
`nerve conduction. Cubist also studied the penetration of daptomycin into
`inflammatory exudate from cantharides-induced skin blisters. In vitro studies were
`conducted to assess the influence of daptomycin on induction or inhibition of
`cytochrome P450 enzymes in human hepatocytes.
`
`' The Lilly Phase 1 studies enrolled 362 subjects who received daptomycin. These
`human pharmacology studies included single- and multiple-dose safety and
`pharmacokinetic studies in healthy subjects. Multiple-dose studies examined
`various doses and regimens up to 4 mg/kg q 12h x 14 days. Also included are in
`vivo protein binding studies; a metabolism and excretion study using radiolabeled
`daptomycin, a study in subjects with various degrees of renal impairment and drug
`interaction studies with tobramycin and amikacin.
`Cubist conducted two Phase 11 studies; a third study was discontinued due to slow
`enrollment. DAP—BAC-9803, is an open-label, Phase 11, dose-ranging trial in
`subjects with culture-confirmed Gram-positive bacteremia or presumed
`bacteremia. The study compared three doses of daptomycin (4 mg/k g q24h, 6
`mg/kg q24h, or 3 mg/kg q12h with a 6 mg/kg loading dose) with standard therapy
`(vancomycin 1 g every 12 hours or nafcillin or oxacillin 4—12 g daily in equally
`divided doses) and enrollment was threezone daptomycin:comparator._ The second
`Phase 11 study, DAP-RRC-9804, is an open-label, non-comparative, multicenter
`study utilizing three dose regimens of daptomycin in hospitalized subjects with
`bacteremia (4 mg/kg q24h, 6 mg/kg q24h, 3 mg/kg quh following a 6 mg/kg
`loading dose), complicated skin and skin structure infections (c8881) (4 mg/kg
`q24h), lower respiratory tract infections (LRTI) (6 mg/kg q24h), intra-abdominal
`infections (1A1) (6 mg/kg q24h), or complicated urinary tract infections (UTl) (4
`mg’kg q24h potentially adjusted according to MlC level) caused by Gram-positive
`pathogens that were resistant to vancomycin or whose infection was otherwise
`refractory to currently available therapy or for whom currently available therapy
`was contraindicated. Study DAP-RRC~9804 was terminated due to slow
`enrollment. Study DAP—OO-03 was an open-label, microbiologist-blinded, Phase
`11] study comparing daptomycin at a dosage of 4 mg/kg q24h with ciprofloxacin
`400 mg in subjects with complicated urinary tract infections caused primarily by
`Gram-positive pathogens. Due to slow enrollment, this trial was terminated.
`
`Three Phase II studies were conducted by Lilly during the years 1987 - 1990.
`Study B8B-MC—AVAE/B8B-EW-AVAG is described below, as it was submitted
`with the NDA as supportive of the cSSSl indication. The second Phase 11 study,
`BSB-MC-AVAM, was a randomized, open-label study in which subjects with
`endocarditis and bacteremia were given daptomycin (loading dose of 6 mg/kg
`followed by 3 mg/kg q 12h) for up to 42 days; pharmacodynamic data was
`collected in “115}:qu The third Phase 11 study, B8B-EW-AVAH, was an open
`
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`
`label, uncontrolled study to evaluate the efficacy of daptomycin in subjects with
`Gram-positive skin and skin structure infections. This study was terminated after
`only 4 of the planned 50 subjects were enrolled due to adverse events..
`
`One controlled study, B8B-MC-AVAE/AVAG conducted by Lilly, was submitted
`as a supportive study. The dose of daptomycin used in this study was 2 mg/kg q
`24 hours for a total duration of five days. As the dosing regimen of daptomycin
`used in this study is different from that used in the two phase 3 cSSSI clinical
`trials, results of this study are not included in the overall efficacy analyses and
`will not be discussed in this review.
`
`Phase 3 studies
`
`Complicated skin and skin structure infections
`Results of two phase 3 studies, DAP-SST-9801 and DAP-SST-9901, were
`included in this NDA to support the indication of complicated skin and skin
`structure infections. The safety and efficacy of daptomycin was compared to that
`of vancomycin or a semi-synthetic penicillin (cloxacillin, flucloxacillin, oxacillin,
`nafcillin etc) for the treatment of hospitalized patients with complicated skin and
`skin structure infections due to Gram-positive bacteria. The two studies were
`similar in design and conduct to a great extent. Both studies were randomized,
`active-controlled, and investigator-blinded. Study 9801 was conducted at 68 study
`sites, 63 in the United States and 5 in South Africa. Study 9901 was conducted at
`67 study sites including Europe, South Africa, Australia, and Israel.
`
`In the two pivotal studies, patients with complicated skin and skin structure
`infections including ulcers (diabetic and non-diabetic), wound infections, and
`major abscesses were randomized on a 1:1 basis to receive 7-14 days treatment
`with daptomycin 4 mg/kg intravenously as a single daily dose or a comparator
`agent. The comparator drug could be either vancomycin or a semi-synthetic
`penicillin. Investigators could select the semi-synthetic penicillin based on local
`availability and treatment practice. Randomization was stratified based on the
`presence or absence of an infected diabetic ulcer as the primary site of infection.
`Adjunctive treatment with aztreonam or metronidazole could be given for Gram-
`negative or anaerobic organisms, respectively. Ancillary surgical treatment (e. g.,
`debridement) was permitted.
`
`In study 9801, a total of 547 patients were randomized and 530 received at least
`one dose of study medication. In study 9901, a total of 571 patients were
`randomized and 562 received at least one dose of study medication.
`
`Community-acquired pneumonia
`Cubist conducted two controlled clinical trials, DAP-CAP-OO-OS and DAP-CAP-
`
`00-08, of essentially identical design to evaluate daptomycin in the treatment of
`moderate to severe community-acquired pneumonia (CAP) due to S. pneumoniae,
`including penicillin-resistant strains. Each study was a randomized, multicenter,
`
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`CLINICAL REVIEW
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`Executive Summary Section
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`i}
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`multinational, double-blinded, parallel group, active-treatment controlled trial
`using a dosage of 4 mg/kg q24h. The comparator in each trial was cefiriaxone lg
`q24h. At the discretion of the investigator, adjunctive treatment with aztreonam
`could be given for suspected Gram—negative organisms. Therapy was to be
`administered 5 to 14 days, followed by Test—of-Cure_and Post-Study visits
`conducted 7 to 14 and 21 to 28 days, respectively, after the last dose of study
`drug. Men and women who were 18 years of age or older and had pneumonia
`which required hospitalization and intravenous therapy for at least 5 days were
`eligible for the study. The infection must have been known or suspected to be
`due, at least in part, to Gram-positive bacteria. Subjects previously treated with
`potentially effective anti-infective agents for >24 hours (or one dosing day) with
`72 hours of enrollment were excluded. Protocol DAP-CAP-OO-OS enrolled
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`patients in the U.S., Europe, Canada, Australia, South America, and New
`Zealand. Study DAP-CAP-OO-OS enrolled 355 patients in the daptomycin arm all
`359 in the comparator arm and was completed in October 2000.
`
`B.
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`~
`'
`Efficacy
`DAP-SST-980] and DAP-SST-9901: Complicated skin and skin structure
`infections
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`Cubist has provided sufficient data to support granting the indication of
`complicated skin and skin structure infections. Intravenous daptomycin 4
`mg/kg/day as a single dose was demonstrated to be non-inferior to comparator
`(semi-synthetic penicillins or vancomycin). The 95% confidence intervals around
`the difference in clinical cure rates demonstrated that the two treatment regimens
`were equivalent using a non-inferiority margin of 10%.
`
`Patients 18 .years of age and older with complicated skin and skin structure
`infections including wound infections, major abscess, cellulitis, or infected ulcer
`(diabetic and non—diabetic) were enrolled in the studies. Patients with bacterernia,
`osteomyelitis, patients on hemodialysis or peritoneal dialysis, those receiving
`HMG-CoA reductase inhibitors, and those with creatinine clearance < 30 ml/min
`were excluded.
`'
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`The primary efficacy endpoint was sponsor-defined clinical outcome at the test of
`cure (TOC) visit, 6-20 days after the end of therapy. The sponsor defined clinical
`outcome took into account the length of therapy in addition to the investigator’s
`clinical response. The patient must have received 2 4 calendar days of study'
`medication to be classified as a cure or > 2 days to be classified as a failure.
`Investigator response of either improved/cure at the TOC visit was considered a
`clinical success.
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`Study 9801 was conducted at sites in the United States and South Africa, while
`study 9901 was conducted entirely outside the Unites States, mainly in South
`Africa and Europe. Both studies were similar in design, but differed significantly
`in patient baseline characteristics that potentially impact the overall cure rates.
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`CLINICAL REVIEW
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`Executive Summary Section
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`Patients in study 9801 tended to be sicker, with more co-morbid conditions,
`required concomitant antibiotics for Gram-negative/anaerobic coverage more
`commonly, and needed concomitant surgical procedures more often. Patients in
`study 9901 were less sick, had fewer complicating medical illnesses, and the need
`for concomitant antibiotics for Gram-negative/anaerobic coverage or concomital
`surgical procedures was also less frequent. Efficacy estimates differed
`significantly in the two studies in both the daptomycin and comparator arms.
`Results of the two studies will thus be presented separately rather than in an
`integrated manner.
`
`In both cSSSl studies, daptomycin was non-inferior to the comparator drugs using
`a non-inferiority margin of 10 %. Results of sponsor’s and FDA analyses were
`comparable. In the FDA analyses, 95% confidence intervals (Cl) around the
`difference in success rates (daptomycin~comparator) were calculated, while the
`sponsor calculated the 95% CI for difference in success rates between comparator
`and daptomycin. Hence, Using a non-inferiority margin of 10 %, non-inferiority '5
`established ifthe value ofthe lower bound ofthe 95% Cl is less than 10 % in the
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`FDA analyses and a value ofthe upper bound of the 95% Cl is less than 10 % in
`the sponsor's analyses.
`
`The primary efficacy populations were the Intent To Treat (HT) and Clinically
`Evaluable (CE) populations. Clinical success rates using the sponsor defined
`' clinical outcome for the ITT and CE populations for both studies are presented
`below. Sponsor’s results are presen