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`CLINICAL REVIEW
`
`Clinical Review Section
`
`|
`
`B.
`
`Overview of Materials Consulted in Review
`
`The following materials were consulted during the review process
`0
`Final study reports, submitted electronically
`0 Case report forms
`0 Data sets submitted by sponsor and some additional data sets requested by
`FDA
`
`Proposed package insert
`0
`0 Literature review
`
`C.
`
`Overview of Methods Used to Evaluate Data Quality and Integrity
`
`DSI audits were performed at two clinical trial sites for study 9801. No audits
`were performed for sites that enrolled patients in study 9901.There were many
`protocol deficiencies at both sites related mainly to eligibility determinations
`and laboratory assessments. Most of these deviations were considered not to
`impact the study significantly, hence data from these two sites were not
`excluded from the analyses.
`'
`
`A summary of audited sites is displayed in the following table.
`
`
`
`Investigator Name
`(Number)
`
`
`
` Tidman (168)
`
`
`Location
`
`Study
`number
`
`Blue Ridge, GA
`
`9801
`
`Honolulu, Hawaii
`
`9801
`
`
`
`Number of
`patients
`randomized
`
`
`
`
`
`A random sample of 10% of the case report forms for both studies were
`reviewed by the medical officer for concurrence with the sponsor's
`evaluability and outcome assessments. Overall, no major inconsistencies
`were seen in the evaluability or outcome assessments. Hence, this sample
`was considered to be adequately representative of the quality of data and
`the sponsor's data were used for FDA analyses.
`
`D.
`
`Were Trials Conducted in Accordance m’th Accepted Ethical
`Standards
`
`According to the sponsor, the protocol, informed consent form (ICF), and
`all other written documents provided to the investigator or subject were
`reviewed andgpproved by an Institutional Review Board (IRB) or
`
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`l
`
`Independent Ethics Committee (lEC) at each site before the study was
`initiated. Copies ofthe approval letter and all other correspondence with
`
`the lRB/lEC were sent to
`-
`, a Contract
`~—
`Research Organization (CRO) located
`these documents are retained in the Trial Master Files.
`
`All of
`
`The sponsor and the investigators agreed to submit to the lRB/IEC any
`subsequent protocol amendments, reports of all serious adverse events,
`and any other information relevant to the safety of the subjects or the
`conduct ofthe dial.
`
`The sponsor also stated that the study was conducted in accordance with
`the ethical principles articulated in the Declaration of Helsinki (Republic
`of South Africa, amendment October 1996), with the Harmonized
`Tripartite Guidelines for Good Clinical Practice (GCP) issued by the
`lntemational Conference on Harmonization (lCH), and with the local laws
`and regulations for the use of investigational therapeutic agents. All
`subjects provided voluntary written informed consent. The lCF was signed
`and dated by both the subject and the investigator or designee. A copy of
`the signed lCF was provided to the study subject, and the original was
`retained in the source documents. Any modifications to the ICF requested
`by the IRB or IEC were reviewed and approved by Cubist prior to
`implementation.
`
`Evaluation of Financial Disclosure
`
`The sponsor (Michael Bonney, President and Chief Operating Officer,
`Cubist Pharmaceuticals Inc.) has submitted form FDA 3454, Certification:
`Financial interests and arrangements of clinical investigators. The sponsor
`certifies that he has not entered into any financial arrangement with the
`listed clinical investigators whereby the value of the compensation will be
`affected by the outcome ofthe studies as defined in CFR 54.2(a). He also
`certified that each listed clinical investigator was required to disclose to
`the sponsor whether the investigator had a proprietary interest in this
`product or a significant equity in the sponsor as defined in 2] CFR
`54.2(b), and that no listed investigator was the recipient of significant
`payments of other sorts as defined in 21 CFR 54.2(1).
`
`VI.
`
`Integrated Review of Efficacy
`
`A.
`
`Brief Statement of Conclusions
`
`Both study 9801 and 9901, comparing the use of daptomycin with
`comparator drugs (vancomycin/semi-synthetic penicillins), showed that
`daptomycin was non-inferior to the comparator drugs in the treatment of
`__ ~_.'_';
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`
`i‘ ‘
`
`complicated skin and skin structure infections due to Gram positive
`bacteria using a non-inferiority margin of 10 %. Gram positive bacteria
`studied include Staphylococcus aureus (methicillin-resistant and
`susceptible strains), Streptococcus pyogenes, Enterococcusfaecalis
`(vancomycin-susceptible strains), Streptococcus agalactiae, and
`Streptococcus dysgalactt'ae.
`
`Data submitted were not adequate to include infected diabetic ulcers in the
`indications and usage section. Viridans group streptococci should not be
`included in the list of pathogens as their role a§pathogens in skin and skin
`structure infections is unclear, except for members of the S. intermedius
`(milleri) group. The number of patients with S. intermedius isolates was
`very few in both studies. As patient characteristics and clinical success
`rates differed significantly between the two studies, the results of the two
`studies should be considered separately and not included in the product
`label in an integrated manner as proposed by the sponsor.
`
`B.
`
`General Approach to Review of the Efficacy of the Drug
`All data in this NDA were submitted electronically and are available in the
`electronic document room.
`
`.
`DAP-SST-9801
`\‘tCDSESUBt\N21572\N 000‘2002—12-l9\clinstat\dapsst980l .pdf
`
`DAP-SST-9901
`
`mosrzsuei \N2 1 572m 00000024 2-1 9\clinstal\dapsst9901 .pdf
`
`BSB-NIC—AVAE/AVAG
`\\CDSESUB1'\N21572\N OOO'QOOZ-l2-19‘thinstat\b8bmca\'aeewavag.pdf
`
`C.
`
`Detailed Review of Trials by Indication
`
`In this application, the sponsor is only seeking approval for the indication
`of complicated skin and skin structure infections. Results from two
`primary comparative studies, DAP-SST-980] and DAP-SST-9901 were
`submitted in the NDA to support this indication of. Both studies had
`similar study design and primary endpoints. in this review, study 980] is
`described in detail and the differences between the two studies are
`summarized in table number 3.
`
`An additional study (BSB-MC-VAE/AVAG) was submitted as a
`supportive study. This study was conducted by Lilly and was a multi~
`indication supportive protocol that included patients with skin and skin
`structure infections due to susceptible Gram positive bacteria. The dose of
`daptomycin used in this study was 2 mg/kg q 24h for a total duration of 5 .
`2' Q2: :,_~
`
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`' g
`
`I
`
`*7 which is different from that used in the other two phase 3 clinical
`studies. Hence, results of this study are not included in the overall efficacy
`analyses and will not be discussed further in this review.
`Parts of this review are excerpted from the final study reports provided by
`the sponsor. Comments by the medical officer are provided in Italics.
`
`DAP-SST-9801
`
`Objectives
`The primary objective of this study was to campare the safety and efficacy
`of daptomycin to that of vancomycin or selected semi-synthetic penicillins
`in the treatment of complicated skin and skin structure infections due to
`Gram positive bacteria.
`
`Design
`This was a multicenter, international, investigator-blinded, randomized,
`Phase 3 tn‘al.
`
`Population and procedures
`Inclusion criteria
`
`Patients were eligible for inclusion in the study if they met all of the
`following criteria:
`-
`General inclusion criteria
`
`0 Age 18-85 years
`
`0
`
`1f female, the patient must have been post-menopausal for at least one
`year, or have had a hysterectomy or a tubal ligation or, if of child-
`bearing potential
`
`0
`
`0
`
`0
`
`have maintained her normal menstrual pattern for the 3 months
`prior to study entry and
`
`have taken hormonal contraceptives for at least one month prior to
`study entry, or agree to use spermicide and barrier methods or be
`using another acceptable method of contraception and agree to
`continue with the same method during the study, and
`
`have a negative serum pregnancy test (serum B-hCG) immediately
`prior to enrollment. lf obtaining the serum pregnancy test result
`would have caused a delay in treatment, a subject could be entered
`on the basis of a urine pregnancy test sensitive to at least
`50 mU/mL of B hCG, pending results of the serum test.
`
`0
`
`Signed, written, informed consent must have been obtained after the
`nature of the study had been fully explained and before any protocol-
`specific procedure was performed. In the event that the subject was
`unable to give consent, the subject's legal representative could do so
`‘-'_-
`
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`
`by means approved by the investigator's Independent Ethics
`Committee (IEC).
`'
`
`Specific inclusion criteria
`
`I A diagnosis of skin and soft tissue infection known or suspected to be
`due to Gram positive bacteria. Staphylococcus epidermis and
`corynebacteria were not to be considered pathogenic unless also
`identified in blood and deep tissue sites.
`
`I Diagnosis of bacterial skin and soft tissue infection in the presence of
`some complicating factor, including infections involving deeper soft
`tissue or requiring significant surgical intervention. Complicating
`factors include a pre—existing skin lesion or some underlying condition
`that adversely effects either the delivery of drug to the affected area,
`the immunologic response, or the tissue healing response.
`
`I At least 3 ofthe following clinical signs and symptoms of skin
`infection must have been present:
`
`I Temperature >38°C rectal or >37.5°C oral
`
`- WBC count >12 x10 3 /L or with 210% bands
`
`I
`
`Pain
`
`I Tenderness to palpation
`
`I Erythema (extending at least 1 cm beyond wound edge)
`
`I
`
`I
`
`I
`
`Swelling
`
`lnduration
`
`Pus formation
`
`I
`
`Skin and soft tissue infections appropriate for this study included:
`
`I Wound infections, including wounds due to:
`
`I Traumatic injury
`
`I
`
`Surgical incision
`
`I Animal or human bites provided tissue damage existed
`
`I
`
`Foreign body (e. g., septic phlebitis associated with intravenous
`catheter sites)
`
`I Major abscesses, with or without recognized preceding trauma that
`required antibiotic therapy in addition to surgical incision and
`drainage.
`
`I
`
`Infected ulcers (except multiple infected ulcers) associated with
`diabetes, vascular insufficiency or pressure.
`._-~.__.,,
`
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`I
`
`0
`
`Infections in immunosuppressed patients:
`
`. 1 Patients known to be HIV-infected (provided CD4 counts 2200
`cells/mm 3)
`
`I
`
`-
`
`Patients on chronic systemic steroids (>20 mg prednisone daily
`or the equivalent)
`
`Patients with diabetes mellitus necessitating treatment with oral
`hypoglycemic agents and/or insulin.
`
`-
`
`Patients with multiple sites of infection could be entered into the study
`(except multiple infected ulcers). The most severely affected site or the
`one most likely to yield a positive culture was chosen to follow
`throughout the course of evaluations.
`
`0 An appropriate specimen of the infected site was to be obtained for
`Gram stain and culture within 48 hours prior to initiation of study
`treatment. Cultures of infected ulcers should be obtained by needle
`aspiration of obviously purulent material or biopsy to avoid
`contamination with superficial, colonizing bacterial flora that may not
`represent the causative pathogen.
`
`Medical Officer (MO) Comments:
`According to the FDA draft guidancefor industry (Uncomplicated and
`Complicated Skin and Skin Structure Infections, Developing Antimicrobial
`Drugs for Treatment, July 1998), studies in support of this indication
`'
`should include infections of the deeper soft tissue, or those requiring
`significant surgical intervention such as infected ulcers, burns, and major
`abscesses or a significant underlying disease state that complicates the
`response to treatment.
`The enrollment criteria specified by the sponsor conform to a great extent
`to the guidance, since the study included patients with infected ulcers,
`burns and major abscesses; only patients with third degree burns were
`excluded. Conditions such as infected ulcers, especially when associated
`with vascular insufficiency or diabetes mellitus, difler substantially from
`acute abscesses and wound infections, in their chronicity, microbiology,
`response to therapy and needfor adjunct surgical therapy. 50, the
`dijferent diagnoses should befairly well represented to support this
`indication.
`
`Exclusion criteria
`
`General exclusion criteria
`
`Patients were not eligible for enrollment if they met any of the following
`criteria at baseline:
`
`0 Patients known to have bacteremia. Patients whose baseline blood
`M .
`cultures were positive could be continued in the trial.
`'
`
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`
`I
`
`0
`
`Patients with one of the following infections:
`
`I minor or superficial skin infections (e.g., furuncles, simple
`abscesses, acne, impetigo)
`
`I
`
`I
`
`I
`
`cellulitis not associated with complicating factors. Patients with
`cellulitis associated with more serious infection (e.g., surgical
`wound, diabetic ulcer, deep tissue) could be enrolled
`
`petirectal abscess
`
`hidradenitis suppurativa
`
`I myositis (with or without skin and soft tissue infection)
`
`I multiple infected ulcers at distant sites
`
`I
`
`infected third-degree burn wounds
`
`0 Conditions requiring surgery that in and of itself would cure the
`.
`infection or remove the infected sit'e (e. g., amputation)
`
`0 Conditions requiring emergent surgical intervention at the site of
`infection (e.g., progressive necrotizing infections)
`
`0 Diagnosis of osteomyelitis
`
`0
`
`Infection due to an organism known to be resistant to study drug prior
`to study entry
`
`0 Any disorder or disease that could interfere with the evaluation in this
`protocol including primary muscle disorders or deep site infection,
`including known or suspected endocarditis and pneumonia at study
`entry
`
`I
`
`Shock or hypotension (supine systolic blood pressure <80 mm Hg)
`' unresponsive to fluids or pressors within 4 hours or oliguria (urine
`output <20 mL/hr)
`
`0 Any type of hemodialysis or peritoneal dialysis
`
`-
`
`Pregnancy or nursing mothers
`
`0 Grossly underweight (S 40 kg) .
`
`0 Previous allergic or serious reaction to daptomycin or vancomycin.
`
`MO Comments:
`
`Exclusion ofpatients with necrotizingfasciitis is consistent with the FDA
`draft guidance. Patients with infected atopic dermatitis are usually
`excluded as it is dtfiicult to assess efficacy ofantimicrobials due to co-
`existing inflammation. As patients with bacteremia were excludedfrom the
`study, this should be reflected in the product label. Exclusion ofpatients
`with osteomyelitis was based an x-ray findings alone. As x-rays have low
`4"— “7.
`
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`
`I
`
`sensitivity in the early detection of osteomyelitis, it is possible that some
`patients .with osteomyelitis were actually enrolled in these studies. Patients
`receiving concomitant HMG Coenzyme A reductase inhibitors were
`excluded, as skeletal muscle toxicity can be seen with daptomycin use.
`However, in clinical practice it is very likely that patients receiving
`daptomycin could also receive HMG CoA reductase inhibitor drugs. Post-
`marketing surveillance can provide important information about the
`potentialfor increased muscle toxicity in patients receiving both drugs.
`
`Exclusion criteria related to medications
`
`0 Requirement for a non-study systemic antibacterial to which the target
`pathogen was susceptible or use of a topical antibacterial at the site of
`infection.
`-
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`Previous systemic antibacterial therapy for the treatment of Gram-
`positive skin and soft tissue infections for more than 24 hours within
`48 hours prior to the day of first infusion of study drug unless:
`
`I
`
`I
`
`the infecting Gram positive pathogen was resistant to the previous
`antibacterial therapy or
`-
`
`the previous antibacterial therapy was administered for 3 or more
`calendar days and was found to be ineffective.
`
`Patients admitted to the hospital for drug overdose or other conditions
`associated with rhabdomyolysis.
`
`Patients requiring intramuscular injections.
`
`Patients receiving HMG Coenzyrne A reductase inhibitors.
`
`Patients who were known or suspected drug abusers.
`
`Previous treatment under this protocol or protocol DAP—SST-990l.
`
`0 Exposure to any investigational agent within 30 days of entry into
`study.
`
`Comments:
`
`_
`
`The FDA draft guidance indicates that prior anti-infective use, even up to
`the day ofpatient enrollment would exclude a patient unless a culture is
`obtained showing the persistence ofa pathogen. Even 24 hours of
`treatment with non-study antimicrobials couldpotentially aflect outcome.
`In certain clinical situations, like infected ulcers or complicated cellulitis
`persistence ofsome signs ofinflammation does not necessarily imply
`clinicalfailure. The use of clinical criteria alone to assess failure to prior
`therapy in the absence ofa documentedpathogen could be erroneous,
`leading tofalsely elevated cure rates in study drugs.
`
`'
`
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`
`‘ fl
`
`Exclusion criteria related to laboratory values
`
`0
`
`Patients were to be excluded if at the time of randomization one or
`
`more laboratory results were known to be abnormal as defined below:
`
`I Absolute neutrophjl count $0.5 x10 3 /L
`
`- HIV-infection with CD4 lymphocytes 50.2 x103 IL
`
`' CPK >50% above upper limit of normal
`
`I Calculated creatinine clearance <30 mL/min
`
`MO Comments:
`
`As patients with creatinine clearance less than 30 ml/min were excluded,
`safety and efficacy information in this group ofpatients will be gained in
`post—marketing experience and in the phase 4 commitment study as
`described in the executive summary section I B.
`
`Removal of patients from therapy or assessment
`
`Patients participation could be temu'nated prior to completing the study for
`any of the following reasons:
`
`0 Adverse event
`
`0 Clinical failure
`
`0
`Subject chose to withdraw from the study
`0 Baseline bacteriological cultures yielded a resistant pathogen
`
`Study visits
`
`Baseline visit: Evaluations were to be performed within 48 hours prior to
`the first dose of study medication. At this visit, medical history was
`obtained and physical examination performed. Gram stain and culture of
`the infection site, blood culture, X~ray (to rule out osteomyelitis), and
`clinical laboratory tests were also performed.
`
`On therapy visit: Was conducted on day 3 or 4 of treatment.
`
`End-ot-Therapy (BOT) visit: Was conducted up to 3 days after the last
`dose of study drug or at early termination.
`
`Post-Therapy (Test-of-Cure) visit: Was conducted 7 to 12 days post-
`treatment.
`
`The EDT and TOC visits were to be performed for all patients and
`included the following procedures:
`
`0 Monitoring for treatment emergent adverse events, significant
`procedures, use of any antibacterials or concurrent medications.
`
`0 Assessment by the blinded investigator of pertinent clinical signs and
`symptomsofinfection.
`
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`
`0 Gram stain and culture ofthe infection site ifa clinically significant
`lesion and/or drainage persisted, repeat blood cultures for patients with
`positive cultures at baseline or in the case of clinical deterioration, and
`a blood sample for clinical laboratory tests, including CPK.
`
`Post-Study visit: Was conducted 21 to 28 days post-treatment and was to
`be performed only for those patients who were considered cured or
`improved by the blinded investigator at the TOC visit. Procedures
`included evaluation of pertinent clinical signs and symptoms of infection
`and Gram stain and culture of the infection site if a clinically significant
`lesion and/or drainage persisted.
`
`MO Comments.-
`
`The FDA guidance recommends a test ofcure visit at least seven days
`after the tissue levels of the sluafi' drug have gone lower than the minimum
`inhibitory concentration (MIC) of the expectedpathogens, hence a test of
`cure visit at 7-14 days after completion of therapy is appropriate. Though
`these visit windows were specified in the protocol, the T0C visit for
`analytical purposes was 6-20 days after end of therapy.
`
`Blinding
`
`The protocol was conducted using an investigator-blinded design. To
`facilitate the investigator~blind and eliminate other sources of potential
`bias, the subject was also blinded to study medication. A double-blind
`design was deemed impractical for the following reasons:
`
`0 The dosing schedule of the investigational agent was substantially
`different from that of the comparator agents.
`
`0 The infusion times of the study agents were different.
`
`0
`
`0
`
`-The,investigational drug is active against both methicillin-susceptible
`S. aureus (MSSA) and methicillin~resistant S. aureus (MRSA);
`however, among the comparators, the agent of choice fcir MSSA is a
`semi-synthetic penicillin and for MRSA, vancomycin.
`
`In patients with moderately decreased renal function, vancomycin
`requires monitoring of drug levels and adjustment of dosing intervals.
`
`Prior to randomization the blinded investigator was expected to:
`
`-
`
`0
`
`0
`
`obtain signed informed consent from the subject,
`
`determine that a subject met the inclusion/exclusion criteria
`
`and evaluate the subject, choose the appropriate comparator agent,
`dose, and regimen to be used if the subject was randomized to
`comparator.
`
`Following randomization, the blinded investigator was expected to:
`
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`|
`
`0
`
`0
`
`0
`
`0
`
`determine that the subject was making appropriate clinical progress,
`
`perform the scheduled evaluations, including assessing the subject's
`clinical signs and symptoms and assigning clinical outcomes,
`
`determine the appropriate duration of therapy,
`
`and assess relationship of adverse events to study therapy. '
`
`Unblinded persdnnel at each site were expected to do the following:
`
`0
`
`o
`
`0
`
`access the centralized randomization system to enroll each subject and
`receive the treatment assignment,
`'
`
`prepare the study medication, including cover the infusion bags with
`an opaque plastic cover prior to leaving the pharmacy or drug
`preparation station,
`
`and administer the study medication, review the safety variables,
`monitor the subject daily for adverse events, ensure that all treatment-
`specific procedures were performed according to the protocol and as
`much as possible manage the subject’s routine daily care.
`
`MO Comment.-
`
`A double-blinded study would have been ideal, but differences in dosing
`regimens and needfor therapeutic drug monitoring and dosage
`modifications with vancomycin made this impractical. As responsibilities
`were shared between the blinded and unblinded investigator there is a
`potential that the blind could have been broken.
`
`Randomization
`
`Patients were randomized on a 121 basis to receive either daptomycin or
`the comparator. Patients were assigned to treatment groups by a computer-
`generated randomization schedule that was prepared prior to initiation of
`the study, balanced by using permuted blocks of four, and stratified by
`study center and by presence or absence of a diagnosis of infected diabetic
`ulcer. Numbers assigned to patients who withdrew before receiving study
`drug were not to be reused.
`
`After a subject was determined to be eligible for the study and had given
`signed informed consent, the investigator was to choose, based on the
`subject's clinical history and condition, the comparator agent, dose, and
`regimen to be used in the event the subject was randomized to comparator.
`The agent chosen was to be recorded on the randomization form. '
`
`Treatments administered
`
`The comparator agents selected (vancomycin, oxacillin, cloxacillin, and
`nafcillin) are currently approved for the treatment of complicated skin and
`' soft tissue infections caused by susceptible pathogens in the countries in
`.-. a?
`
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`
`which they were used. Vancomycin was included as treatment for patients
`known or suspected to be penicillin-allergic or to be infected with MRSA.
`Investigators could select an agent based on local availability and normal
`treatment practice.
`
`Eligible patients received either daptomycin 4 mg/kg intravenously (i.v.)
`q24h or one of the following comparator agents:
`
`Vancomycin l gi.v.q12h, or
`
`Selected semi-synthetic penicillins:
`Nafcillin 4-12 g per day i.v. in equally divided.doses
`
`Oxacillin 4-12 g per day i.v. in equally divided doses
`
`Cloxacillin 4-12 g per day i.v'. in equally divided doses
`
`Patients assessed to have creatinine clearance of 30 to 70 ml/min were to
`
`receive daptomycin 4 mg/kg loading dose, followed by 3 mg/kg q36 hr;
`Patients with creatinine clearance <30 ml/rnin were excluded from the
`
`trial. Vancomycin dosing was to be adjusted according to a published
`nomogram or results of therapeutic drug monitoring:
`
`Patients with polyrnicrobial infections proven or suspected to involve
`Gram negative or anaerobic bacteria in addition to Gram positive
`organisms, could receive aztreonam or metronidazole or both in addition
`to study therapy. Duration of therapy was to be 7 to 14 days. If a subject
`required more than 14 days of therapy, the duration could be extended
`following discussion with the medical monitor.
`
`Patients could be switched to oral therapy if all of the following conditions
`were met:
`
`-— There was a compelling reason for such a switch
`
`— There was an oral therapy to which the pathogen was susceptible
`
`— The subject had received at least 4 days of intravenous study therapy;
`the signs and symptoms at the site of infection had shown clear clinical
`improvement as documented by an evaluation by the blinded
`investigator prior to the switch
`
`— The medical monitor had given permission
`
`MO Comments:
`
`Semi-synthetic penicillins are approvedfor the treatment of infections due
`to penicillinase-producing strains ofstaphylococci. Vancomycin is
`approvedfor infections due to methicillin-resistant Saureus. Vancomycin
`is an appropriate choice for the treatment ofWSA infections. However,
`for the treatment of infections due to MSSA, semi-synthetic penicillins are
`superior compared to vancomycin. Cloxacillin is not approvedfor use in
`-~ '“V. ”\w
`
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`
`the United States, but is very similar to oxacillin and nafcillin in its
`spectrum ofactivity andpharmacokinetics and hence is an acceptable
`comparator.
`
`Prior and concomitant therapy
`
`The use of HMG Coenzyme A reductase inhibitors was to be avoided
`throughout the study period. The use of topical antiseptics (e.g., Betadine,
`iodine, povidone, peroxide, alcohol) and topical antimicrobial agents were
`prohibited. Wound care including the use of wet to dry dressings and
`adjunctive surgical treatment (e.g., debridement, incision and drainage)
`was allowed. Amputation or en bloc excision of the primary infection was
`a criterion for clinical failure.
`
`Administration of non-study systemic antibacterial agents active against
`Gram positive pathogens for treatment of the primary infection was
`considered evidence of lack ofefficacy of the study drug and was a
`criterion for clinical failure. Administration of such agents for other
`reasons for more than two days was a criterion for a non~evaluable
`outcome.
`
`MO Comments:
`
`Adjunctive surgical treatment in itselfcan be curative in certain patients
`with complicated skin infections especially those with abscesses and hence
`could confound assessment ofthe role ofantimicrobials in clinical cure.
`Surgical procedures alone may be curative in some patients with diabetic
`ulcers.
`
`Treatment compliance
`
`Measures taken to assure compliance included recording date and time of
`each dose, recording of receipt and diSpensing of study drug and, at the
`completion of the study, verifying the accuracy of the accounting of study
`drug.
`‘
`
`Evaluation of clinical response
`
`At each visit following the end of study therapy, the blinded investigator
`was to determine the subject's clinical response to treatment by comparing
`the subject's signs and symptoms at the visit to those observed and
`recorded at baseline.
`
`The following definitions for clinical response applied to the EDT and
`TOC evaluations:
`
`Cure: Resolution of clinically significant signs and symptoms associated
`with the skin infection present at baseline.
`
`
`
`' Chantelau E, Tanudjaja T, Altenhofer, et al. Antibiotic treatment for uncomplicated neuropathic foot
`ulcers in diabetes: Acontrolled trials Diabetic Medicine 1996', 13: 156-159.
`
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`

`CLINICAL REVIEW
`
`. Clinical Review Section
`
`Improved: Partial resolution of clinical signs and symptoms of the skin
`infection so that no further antibiotic therapy was required.
`
`Failure: Inadequate response to therapy.
`
`Unable to Evaluate: Unable to determine response because subject was
`lost to follow-up.
`
`The following definitions for clinical response applied to the Post-Study
`visit:
`
`Cure: Continued absence of clinically significant signs and symptoms
`associated with the skin infection present at baseline.
`
`Clinical Relapse/New Infection: Recurrence of clinically significant
`signs and symptoms associated with the skin infection that was present at
`baseline so that antibiotic therapy was warranted.
`
`Unable to Evaluate: Unable to determine response because the subject
`was lost to follow-up.
`
`Microbiologic methods
`
`A specimen for Gram stain and aerobic culture was to be obtained from
`the infected area at the baseline visit. Culture specimens of debrided tissue
`or pure pus were preferred to swabs or aspirates of non-purulent material.
`Cultures ofinfected ulcers were to be obtained by needle aspiration of
`obviously purulent material or biopsy to avoid contamination with
`superficial, colonizing bacterial flora that might not represent the causative
`pathogen. Gram stain results were to include a description ofthe bacteria
`seen and the. number of polymorphonuclear leukocytes per low power
`field. All Gram positive pathogens were to be identified to the level of
`genus and species and susceptibility testing was to be performed. Patients
`from whom a specimen could not be obtained were not to be enrolled.
`
`Patients were to be discontinued prematurely if baseline cultures yielded
`only Gram negative organisms and/or yeasts. However, patients who were
`improving clinically at the time such results became available could at the
`discretion of the investigator continue in the study.
`
`Blood cultures
`
`At least two sets of blood cultures from separate venipuncture sites were
`to be obtained using aseptic technique within 48 hours prior to the first
`infusion of study drug. If necessary, one of the two specimens could be
`drawn from an indwelling intravascular catheter. If baseline blood cultures
`were positive, blood cultures were to be repeated at the on~therapy, EDT
`and TOC visits, or whenever the subject‘s condition deteriorated raising
`suspicion of bacteremia.
`
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`CLINICAL REVIEW
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`Clinical Review Section
`
`Susceptibility testing of Gram positive pathogens
`
`The local microbiology laboratory was to perform susceptibility testing of
`all Gram positive pathogens to daptomycin, vancomycin, and a semi-
`synthetic penicillin using Kirby-Bauer (K~B) disk diffusion methods
`performed according to the guidelines of the National Committee for
`Clinical Laboratory Standards (NCCLS).
`
`At the central microbiology reference laboratory, all Gram positive
`pathogens were also to be identified to the level of genus and species.
`Discordant identifications were to be resolved by the local laboratory
`sending the frozen duplicate aliquot of the isolate. The central
`microbiology laboratory was to perform susceptibility testing for each
`isolate by both K-B and microdilution MIC methods.
`
`Radiological assessments
`
`Patients with a diagnosis of infected ulcer were to have an X-ray of bone
`adjacent to the site of infection. If the X-ray results were consistent with
`osteomyelitis, the subject was not to be enrolled. Patients in whom
`osteomyelitis was diagnosed during study treatment were to be
`prematurely terminated.
`
`MO Comments:
`
`Radiologic changes of osteomyelitis like osteopenia, osteolytic lesions or
`periosteal reaction may not be detected by a plain x-rayfor 10-14 days
`after the onset ofsymptoms. It is thus possible that some patients with
`osteomyelitis will be enrolled in the study based on a negative x-ray.
`Other imaging modalities like radionuclide scanning or magnetic
`resonance imaging can identify bony involvement earlier than
`conventional x-ray.
`
`Clinical laboratory assessments
`
`Laboratory tests, including hematology, clinical chemistry and urinalysis,
`were to be obtained at the baseline and EOT visits. Hematology was to be
`repeated at the TOC visit; clinical chemistries and urinalysis were als