Daptomycin (Page 8 of 9)

14 CLINICAL STUDIES

14.1 Complicated Skin and Skin Structure Infections

Adults with cSSSI

Adult patients with clinically documented complicated skin and skin structure infections (cSSSI) (Table 15) were enrolled in two randomized, multinational, multicenter, investigator-blinded trials comparing daptomycin for injection (4 mg/kg IV q24h) with either vancomycin (1 g IV every 24h) or an anti- staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, or flucloxacillin; 4 to 12 g IV per day). Patients could switch to oral therapy after a minimum of 4 days of IV treatment if clinical improvement was demonstrated. Patients known to have bacteremia at baseline were excluded. Patients with creatinine clearance (CLCR ) between 30 and 70 mL/min were to receive a lower dose of daptomycin for injection as specified in the protocol; however, the majority of patients in this subpopulation did not have the dose of daptomycin for injection adjusted.

Table 15. Investigator’s Primary Diagnosis in the cSSSI Trials in Adult Patients (Population: ITT)

Primary Diagnosis Adult Patients (Daptomycin For Injection/Comparator*)
Study 9801 N=264 / N=266 Study 9901 N=270 / N=292 Pooled N=534 / N=558
Wound Infection 99 (38%) / 116 (44%) 102 (38%) / 108 (37%) 201 (38%) / 224 (40%)
Major Abscess 55 (21%) / 43 (16%) 59 (22%) / 65 (22%) 114 (21%) / 108 (19%)
Ulcer Infection 71 (27%) / 75 (28%) 53 (20%) / 68 (23%) 124 (23%) / 143 (26%)
Other Infection 39 (15%) / 32 (12%) 56 (21%) / 51 (18%) 95 (18%) / 83 (15%)

* Comparator: vancomycin (1 g IV q12h) or an anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, or flucloxacillin; 4 to 12 g/day IV in divided doses).

† The majority of cases were subsequently categorized as complicated cellulitis, major abscesses, or traumatic wound infections.

One trial was conducted primarily in the United States and South Africa (study 9,801), and the second was conducted at non-US sites only (study 9,901). The two trials were similar in design but differed in patient characteristics, including history of diabetes and peripheral vascular disease. There were a total of 534 adult patients treated with daptomycin for injection and 558 treated with comparator in the two trials. The majority (89.7%) of patients received IV medication exclusively.

The efficacy endpoints in both trials were the clinical success rates in the intent-to-treat (ITT) population and in the clinically evaluable (CE) population. In study 9801, clinical success rates in the ITT population were 62.5% (165/264) in patients treated with daptomycin for injection and 60.9% (162/266) in patients treated with comparator drugs. Clinical success rates in the CE population were 76% (158/208) in patients treated with daptomycin for injection and 76.7% (158/206) in patients treated with comparator drugs. In study 9901, clinical success rates in the ITT population were 80.4% (217/270) in patients treated with daptomycin for injection and 80.5% (235/292) in patients treated with comparator drugs. Clinical success rates in the CE population were 89.9% (214/238) in patients treated with daptomycin for injection and 90.4% (226/250) in patients treated with comparator drugs.

The success rates by pathogen for microbiologically evaluable patients are presented in Table 16.

Table 16. Clinical Success Rates by Infecting Pathogen in the cSSSI Trials in Adult Patients (Population: Microbiologically Evaluable)

Pathogen Success Rate n/N (%)
Daptomycin For Injection Comparator*
Methicillin-susceptible Staphylococcus aureus (MSSA) 170/198(86%) 180/207 (87%)
Methicillin-resistant Staphylococcus aureus (MRSA) 21/28 (75%) 25/36 (69%)
Streptococcus pyogenes 79/84 (94%) 80/88 (91%)
Streptococcus agalactiae 23/27 (85%) 22/29 (76%)
Streptococcus dysgalactiae subsp. equisimilis 8/8 (100%) 9/11 (82%)
Enterococcus faecalis (vancomycin-susceptible only) 27/37 (73%) 40/53 (76%)

* Comparator: vancomycin (1 g IV q12h) or an anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, or flucloxacillin; 4 to 12 g/day IV in divided doses).

As determined by the central laboratory.

Pediatric Patients (1 to 17 Years of Age) with cSSSI

The cSSSI pediatric trial was a single prospective multi-center, randomized, comparative trial. A total of 396 pediatric patients aged 1 to 17 years with cSSSI caused by Gram positive pathogens were enrolled into the study. Patients known to have bacteremia, osteomyelitis, endocarditis, and pneumonia at baseline were excluded. Patients were enrolled in a stepwise approach into four age groups and given age-dependent doses of daptomycin once daily for up to 14 days. The different age groups and doses evaluated were as follows: Adolescents (12 to 17 years) treated with 5 mg/kg of daptomycin (n=113), Children (7 to 11 years) treated with 7 mg/kg of daptomycin (n=113), Children (2 to 6 years) treated with 9 mg/kg of daptomycin (n=125) and Infants (1 to <2 years) treated with 10 mg/kg (n= 45).

Patients were randomized 2:1 to receive daptomycin or a standard of care (SOC) comparator, which included intravenous therapy with either vancomycin, clindamycin, or an anti-staphylococcal semi-synthetic penicillin (nafcillin, oxacillin, or cloxacillin). Patients could switch to oral therapy after clinical improvement was demonstrated (no minimum IV dosing was required).

The primary objective of this study was to evaluate the safety of daptomycin. The clinical outcome was determined by resolution or improvement of symptoms at the End-of-Treatment (EOT), 3 days after the last dose, and Test-of-Cure (TOC), 7 to 14 days after the last dose. Investigator observed outcomes were verified in a blinded fashion. Of the 396 subjects randomized in the study, 389 subjects were treated with daptomycin or comparator and included in the ITT population. Of these, 257 subjects were randomized to the daptomycin group and 132 subjects were randomized to the comparator group. Approximately 95% of subjects switched to oral therapy. The mean day of switch was day 4, and ranged from day 1 to day 14. The clinical success rates determined at 7 to 14 days after last dose of therapy (IV and oral) (TOC visit) were 88% (227/257) for daptomycin and 86% (114/132) for comparator.

14.2 S. aureus Bacteremia/Endocarditis

Adults with S.aureus Bacteremia/Endocarditis

The efficacy of daptomycin for injection in the treatment of adult patients with S. aureus bacteremia was demonstrated in a randomized, controlled, multinational, multicenter, open-label trial. In this trial, adult patients with at least one positive blood culture for S. aureus obtained within 2 calendar days prior to the first dose of study drug and irrespective of source were enrolled and randomized to either daptomycin for injection (6 mg/kg IV every 24h) or standard of care [an anti-staphylococcal semi-synthetic penicillin 2 g IV q4h (nafcillin, oxacillin, cloxacillin, or flucloxacillin) or vancomycin 1 g IV q12h, each with initial gentamicin 1 mg/kg IV every 8 hours for first 4 days]. Of the patients in the comparator group, 93% received initial gentamicin for a median of 4 days, compared with 1 patient (<1%) in the daptomycin for injection group. Patients with prosthetic heart valves, intravascular foreign material that was not planned for removal within 4 days after the first dose of study medication, severe neutropenia, known osteomyelitis, polymicrobial bloodstream infections, creatinine clearance <30 mL/min, and pneumonia were excluded.

Upon entry, patients were classified for likelihood of endocarditis using the modified Duke criteria (Possible, Definite, or Not Endocarditis). Echocardiography, including a transesophageal echocardiogram (TEE), was performed within 5 days following study enrollment. The choice of comparator agent was based on the oxacillin susceptibility of the S. aureus isolate. The duration of study treatment was based on the investigator’s clinical diagnosis. Final diagnoses and outcome assessments at Test of Cure (6 weeks after the last treatment dose) were made by a treatment-blinded Adjudication Committee, using protocol-specified clinical definitions and a composite primary efficacy endpoint (clinical and microbiological success) at the Test of Cure visit.

A total of 246 patients ≥18 years of age (124 daptomycin for injection, 122 comparator) with S. aureus bacteremia were randomized from 48 centers in the US and Europe. In the ITT population, 120 patients received daptomycin for injection and 115 received comparator (62 received an anti-staphylococcal semi-synthetic penicillin and 53 received vancomycin). Thirty-five patients treated with an anti-­staphylococcal semi-synthetic penicillin received vancomycin initially for 1 to 3 days, pending final susceptibility results for the S. aureus isolates. The median age among the 235 patients in the ITT population was 53 years (range: 21 to 91 years); 30/120 (25%) in the daptomycin for injection group and 37/115 (32%) in the comparator group were ≥65 years of age. Of the 235 ITT patients, there were 141 (60%) males and 156 (66%) Caucasians across the two treatment groups. In addition, 176 (75%) of the ITT population had systemic inflammatory response syndrome (SIRS) at baseline and 85 (36%) had surgical procedures within 30 days prior to onset of the S. aureus bacteremia. Eighty-nine patients (38%) had bacteremia caused by methicillin-resistant S. aureus (MRSA). Entry diagnosis was based on the modified Duke criteria and comprised 37 (16%) Definite, 144 (61%) Possible, and 54 (23%) Not Endocarditis. Of the 37 patients with an entry diagnosis of Definite Endocarditis, all (100%) had a final diagnosis of infective endocarditis, and of the 144 patients with an entry diagnosis of Possible Endocarditis, 15 (10%) had a final diagnosis of infective endocarditis as assessed by the Adjudication Committee. Of the 54 patients with an entry diagnosis of Not Endocarditis, 1 (2%) had a final diagnosis of infective endocarditis as assessed by the Adjudication Committee.

In the ITT population, there were 182 patients with bacteremia and 53 patients with infective endocarditis as assessed by the Adjudication Committee, including 35 with right-sided endocarditis and 18 with left-sided endocarditis. The 182 patients with bacteremia comprised 121 with complicated S. aureus bacteremia and 61 with uncomplicated S. aureus bacteremia.

Complicated bacteremia was defined as S. aureus isolated from blood cultures obtained on at least 2 different calendar days, and/or metastatic foci of infection (deep tissue involvement), and classification of the patient as not having endocarditis according to the modified Duke criteria. Uncomplicated bacteremia was defined as S. aureus isolated from blood culture(s) obtained on a single calendar day, no metastatic foci of infection, no infection of prosthetic material, and classification of the patient as not having endocarditis according to the modified Duke criteria. The definition of right-sided infective endocarditis (RIE) used in the clinical trial was Definite or Possible Endocarditis according to the modified Duke criteria and no echocardiographic evidence of predisposing pathology or active involvement of either the mitral or aortic valve. Complicated RIE comprised patients who were not intravenous drug users, had a positive blood culture for MRSA, serum creatinine ≥2.5 mg/dL, or evidence of extrapulmonary sites of infection. Patients who were intravenous drug users, had a positive blood culture for methicillin­-susceptible S. aureus (MSSA), had serum creatinine <2.5 mg/dL, and were without evidence of extrapulmonary sites of infection were considered to have uncomplicated RIE.

The coprimary efficacy endpoints in the trial were the Adjudication Committee success rates at the Test of Cure visit (6 weeks after the last treatment dose) in the ITT and Per Protocol (PP) populations. The overall Adjudication Committee success rates in the ITT population were 44.2% (53/120) in patients treated with daptomycin for injection and 41.7% (48/115) in patients treated with comparator (difference = 2.4% [95% CI −10.2, 15.1]). The success rates in the PP population were 54.4% (43/79) in patients treated with daptomycin for injection and 53.3% (32/60) in patients treated with comparator (difference = 1.1% [95% CI −15.6, 17.8]).

Adjudication Committee success rates are shown in Table 17.

Table 17. Adjudication Committee Success Rates at Test of Cure in the S. aureus Bacteremia/Endocarditis Trial in Adult Patients (Population: ITT)

Population Success Rate n/N (%) Difference: Daptomycin for Injection -Comparator (Confidence Interval)
Daptomycin for Injection 6 mg/kg Comparator*
Overall 53/120 (44%) 48/115 (42%) 2.4% (−10.2, 15.1)
Baseline Pathogen
Methicillin-susceptible S. aureus 33/74 (45%) 34/70 (49%) −4.0% (−22.6, 14.6)
Methicillin-resistant S. aureus 20/45 (44%) 14/44 (32%) 12.6% (−10.2, 35.5)
Entry Diagnosis§
Definite or Possible Infective Endocarditis 41/90 (46%) 37/91 (41%) 4.9% (−11.6, 21.4)
Not Infective Endocarditis 12/30 (40%) 11/24 (46%) −5.8% (−36.2, 24.5)
Final Diagnosis
Uncomplicated Bacteremia 18/32 (56%) 16/29 (55%) 1.1% (−31.7, 33.9)
Complicated Bacteremia 26/60 (43%) 23/61 (38%) 5.6% (−17.3, 28.6)
Right-Sided Infective Endocarditis 8/19 (42%) 7/16 (44%) −1.6% (−44.9, 41.6)
Uncomplicated Right-Sided Infective Endocarditis 3/6 (50%) 1/4 (25%) 25.0% (−51.6, 100.0)
Complicated Right-Sided Infective Endocarditis 5/13 (39%) 6/12 (50%) −11.5% (−62.4, 39.4)
Left-Sided Infective Endocarditis 1/9 (11%) 2/9 (22%) −11.1% (−55.9, 33.6)

* Comparator: vancomycin (1 g IV q12h) or an anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, or flucloxacillin; 2 g IV q4h), each with initial low-dose gentamicin.

† 95% Confidence Interval

‡ 97.5% Confidence Interval (adjusted for multiplicity)

§ According to the modified Duke criteria5

¶ 99% Confidence Interval (adjusted for multiplicity)

Eighteen (18/120) patients in the daptomycin for injection arm and 19/116 patients in the comparator arm died during the trial. These comprise 3/28 daptomycin for injection-treated patients and 8/26 comparator-treated patients with endocarditis, as well as 15/92 daptomycin for injection-treated patients and 11/90 comparator-treated patients with bacteremia. Among patients with persisting or relapsing S. aureus infections, 8/19 daptomycin for injection-treated patients and 7/11 comparator-treated patients died.

Overall, there was no difference in time to clearance of S. aureus bacteremia between daptomycin for injection and comparator. The median time to clearance in patients with MSSA was 4 days and in patients with MRSA was 8 days.

Failure of treatment due to persisting or relapsing S. aureus infections was assessed by the Adjudication Committee in 19/120 (16%) daptomycin for injection-treated patients (12 with MRSA and 7 with MSSA) and 11/115 (10%) comparator-treated patients (9 with MRSA treated with vancomycin and 2 with MSSA treated with an anti-staphylococcal semi-synthetic penicillin). Among all failures, isolates from 6 daptomycin for injection-treated patients and 1 vancomycin-treated patient developed increasing MICs (reduced susceptibility) by central laboratory testing during or following therapy. Most patients who failed due to persisting or relapsing S. aureus infection had deep-seated infection and did not receive necessary surgical intervention [see Warnings and Precautions (5.9)].

Pediatric Patients (1 to 17 Years of Age) with S. aureus Bacteremia

The pediatric S. aureus bacteremia study was designed as a prospective multi-center, randomized, comparative trial to treat pediatric patients aged 1 to 17 years with bacteremia. Patients known to have endocarditis or pneumonia at baseline were excluded. Patients were enrolled in a stepwise approach into three age groups and given age-dependent doses of daptomycin once daily for up to 42 days. The different age groups and doses evaluated were as follows: Adolescents (12 to 17 years, n=14 patients) treated with daptomycin dosed at 7 mg/kg once daily, Children (7 to 11 years, n=19 patients) treated with daptomycin dosed at 9 mg/kg once daily and Children (2 to 6 years, n=22 patients) treated with daptomycin dosed at 12 mg/kg once daily. No patients 1 to <2 years of age were enrolled.

Patients were randomized 2:1 to receive daptomycin or a standard of care comparator, which included intravenous therapy with vancomycin, semi-synthetic penicillin, first generation cephalosporin or clindamycin. Patients could switch to oral therapy after clinical improvement was demonstrated (no minimum IV dosing was required).

The primary objective of this study was to assess the safety of daptomycin. The clinical outcome was determined by resolution or improvement of symptoms at test-of-cure (TOC) visit, 7 to 14 days after the last dose, which was assessed by the site level Blinded Evaluator.

Of the 82 subjects randomized in the study, 81 subjects were treated with daptomycin or comparator and included in the safety population, and 73 had a proven S. aureus bacteremia at Baseline. Of these, 51 subjects were randomized to the daptomycin group and 22 subjects were randomized to the comparator group. The mean duration of IV therapy was 12 days, with a range of 1 to 44 days. Forty-eight subjects switched to oral therapy, and the mean duration of oral therapy was 21 days. The clinical success rates determined at 7 to 14 days after last dose of therapy (IV and oral) (TOC visit) were 88% (45/51) for daptomycin and 77% (17/22) for comparator.

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