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  5. More Information for Sivextro (tedizolid)
  1. Development & Approval Process | Drugs

More Information for Sivextro (tedizolid)

Who participated in the study?

The approval of tedizolid came predominantly from 2 randomized, double-blind, active (linezolid)-controlled Phase 3 clinical trials, Studies 112 and 113. Study 112 (n= 667) was conducted in North America, Latin America, and Europe; Study 113 (n=666) was conducted in North America, Latin America, Europe, South Africa and Australia/New Zealand. These 2 trials included 1,333 subjects: 664 randomized to tedizolid and 669 randomized to the active-comparator linezolid.

Table 2: Baseline Demographics
  Study TR 701-112 Study TR 701-113
  SIVEXTRO
(N = 332)
Linezolid
(N = 335)
SIVEXTRO
(N = 332)  
Linezolid
(N = 334)
Sex        
Female, n(%) 128 (38.6) 137 (40.9) 107 (32.2) 120 (35.9)
Male, n(%) 204 (61.4) 198 (59.1) 225 (67.8) 214 (64.1)
Age (years)        
Mean (SD) 43.6 (14.96) 43.1 (15.06) 45.6 (15.79) 45.6 (15.57)
Min, Max 18, 86 18, 100 17, 86 15, 89
Age group        
< 65 years, n(%) 303 (91.3) 309 (92.2) 289 (87.0) 301 (90.1)
≥ 65 to ≤ 75 years, n(%) 19 (5.7) 19 (5.7) 32 (9.6) 19 (5.7)
> 75 years, n (%) 7 (3.0) 7 (2.1) 11 (3.3) 14 (4.2)
Ethnicity        
Hispanic or Latino, n(%) 115 (34.6) 108 (32.2) 67 (20.2) 63 (18.9)
Not Hispanic or Latino, n(%) 217 (65.4) 227 (67.8) 265 (79.8) 271 (81.1)
Race        
White, n(%) 280 (84.3) 275 (82.1) 285 (85.8) 282 (8.4)
Asian, n(%) 2 (0.6) 7 (2.1) 4 (1.2) 7 (2.1)
Black or African American, n(%) 39 (11.7) 38 (11.3) 38 (11.4) 37 (11.1)
Native Hawaiian or Pacific Islander, n(%) 0 2 (0.6) 2 (0.6) 1 (0.3)
American Indian or Alaskan Native, n(%) 4 (1.2) 5 (1.5) 3 (0.9) 4 (1.2)
Other 7 (2.1) 8 (2.4) 0 3 (0.9)

Source: Adapted from FDA Statistical Review, Table 3-3

How was the study designed? 

Efficacy of SIVEXTRO was evaluated with a total of 1315 adults with acute bacterial skin and skin structure infections (ABSSSI), randomized in two multicenter, multinational, double-blind, non-inferiority trials. Both trials compared SIVEXTRO 200 mg once daily for 6 days versus linezolid 600 mg every 12 hours for 10 days. In Trial 1, patients were treated with oral therapy, while in Trial 2, patients could receive oral therapy after a minimum of one day of intravenous therapy. Patients with cellulitis/erysipelas, major cutaneous abscess, or wound infection were enrolled in the trials. Patients with wound infections could have received aztreonam and/or metronidazole as adjunctive therapy for gram-negative bacterial coverage, if needed. The intent-to-treat (ITT) patient population included all randomized patients.

Safety of SIVEXTRO was evaluated with 1050 patients treated with SIVEXTRO and 662 patients treated with the comparator antibacterial drug in two Phase 2 and two Phase 3 clinical trials. The median age of patients treated with SIVEXTRO in the Phase 2 and Phase 3 trials was 42 years, ranging between 17 and 86 years old. Patients treated with SIVEXTRO were predominantly male (65%) and White (82%).

What are the results of the efficacy study? 

The primary endpoint in Trial 1 was early clinical response defined as no increase from baseline lesion area at 48-72 hours after the first dose and oral temperature of ≤37.6°C, confirmed by a second temperature measurement within 24 hours in the ITT population. The primary endpoint in Trial 2 was early clinical response defined as at least a 20% decrease from baseline lesion area at 48-72 hours after the first dose in the ITT population.

Table 3. Early Clinical Response in the ITT Patient Population 
    SIVEXTRO (200 mg) Linezolid (1200 mg) Treatment Difference (2-sided 95% CI)
No increase in lesion surface area from baseline and oral temperature of ≤37.6 °C, confirmed by a second temperature measurement within 24 hours at 48-72 hours*
Trial 1, N 323 326  
Responder, n (%) 256 (79.3) 258 (79.1) 0.1 (-6.2, 6.3)
Trial 2, N 332 334 334
Responder, n (%) 286 (86.1) 281 (84.1) 2.0 (-3.5, 7.3)
At least a 20% decrease from baseline in lesion area at 48-72 hours**
Trial 1, N 323 326  
Responder, n (%) 252 (78.0) 246 (75.5) 2.6 (-4.0, 9.1)
Trial 2, N 332 334  
Responder, n (%) 283 (85.2) 276 (82.6) 2.6 (-3.0, 8.2)

CI=confidence interval
* Primary endpoint for Trial 1; sensitivity analysis for Trial 2
** Primary endpoint for Trial 2; sensitivity analysis for Trial 1
Source: Drug Label, Section 14 Table 7

Were there any differences in how well the drug worked in clinical trials among sex, race and age?

Subgroup analyses were conducted for sex, race and age.

  • Sex: SIVEXTRO is similarly effective in men and women.
  • Race: Subgroup analyses were conducted for non-whites and whites, but the number of patients in the non-white subgroup was limited. It is not possible to determine whether there were any clinically meaningful differences.
  • Age: Subgroup analyses were conducted for those above and below 65 years of age, but the number of patients above 65 years of age was limited. It is not possible to determine whether there were any clinically meaningful differences.

Table 4 Early clinical   response   rates   at   the  48-72   Hour  Visit   by  demographic characteristics in for the ITT population

  Study TR 701-112 (MITT) Study TR 701-113 (MITT)
  Sivextro Linezolid Sivextro Linezolid
  N = 323
n(%)
N = 326
n(%)
N = 332
n(%)
N = 334
n(%)
 
Age        
< 65years 294 302 289 301
Responder 232 (78.9) 236 (78.1) 250 (86.5) 250 (83.1)
≥ 65 years 29 24 43 33
Responder 24 (82.8) 22 (91.7) 36 (83.7) 31 (93.9)
Sex        
Male 198 195 225 214
Responder 155 (78.3) 155 (79.5) 196 (87.1) 180 (84.1)
Female 125 131 107 120
Responder 101 (80.8) 103 (78.6) 90 (84.1) 101 (84.2)
Race        
White 274 268 285 282
Responder 223 (81.4) 211 (78.7) 244 (85.6) 240 (85.1)
Black or African American 36 36 38 37
Responder 25 (69.4) 29 (80.6) 35 (92.1) 28 (75.7)
Asian 2 7 4 7
Responder 2 (100.0) 6 (85.7) 4 (100.0) 6 (85.7)
Other 11 15 5 8
Responder 6 (54.5) 12 (80.0) 3 (60.0) 7 (87.5)
Region        
North America 261 259 156 158
Responder 205 (78.5) 208 (80.3) 128 (82.1) 131 (82.9)
Europe 53 55 112 111
Responder 45(84.9) 41 (74.5) 104 (92.9) 99 (89.2)
Rest of the World 9 12 64 65
Responder 6 (66.7) 9 (75.0) 51 (79.7) 46 (70.8)

Source: Adapted from FDA Statistical Review, Table 4.1 

What are the results of the trials used to assess safety? 

The most common adverse reactions in patients treated with SIVEXTRO were nausea (8%), headache (6%), diarrhea (4%), vomiting (3%), and dizziness (2%). The median time of onset of adverse reactions was 5 days for both SIVEXTRO and linezolid with 12% occurring on the second day of treatment in both treatment groups. The table below lists selected adverse reactions occurring in at least 2% of patients treated with SIVEXTRO in clinical trials.

Table 5. Selected Adverse Reactions Occurring in ≥2% of Patients Receiving SIVEXTRO in the Pooled Phase 3 ABSSSI Clinical Trials

 

Adverse
Reactions

Pooled Phase 3 ABSSSI Clinical Trials

SIVEXTRO
(200 mg oral/intravenous once daily for
6 days) (N=662)
Linezolid
(600 mg oral/intravenous twice daily for
10 days) (N=662)

Gastrointestinal Disorders

Nausea

8% 12%

Diarrhea

4% 5%

Vomiting

3% 6%

Nervous System Disorder

Headache

6% 6%

Dizziness

2% 2%

Source: Drug Label Section 6.1, Table 2 

Were there any differences in side effects among sex, race and age? 

Subgroup analyses were conducted for sex, race and age.

  • Sex:  The frequency of side effects was similar among men and women.
  • Race:  As the number of patients in the non-white subgroup was limited, it is not possible to determine if there were any clinically meaningful differences.
  • Age:  As the number of patients above 65 years of age was limited, it is not possible to determine if there were any clinically meaningful differences.

Table 6: Treatment Emergent Adverse Events by Age Group in Phase 2 and Phase 3 Studies

Category Age Group Phase 2 Studies Phase 3 Studies
Tedizolid phosphate (≥200 mg) N=388 Tedizolid phosphate (200mg) N=662 Linezoli d (1200 mg) N=662
n (%) n (%) n (%)
N1 < 65 years 379 590 603
≥ 65 years 9 72 59
≥ 75 years 0 24 25
All 388 662 662
TEAE < 65 years 217 (57.3%) 260 (44.1%) 267 (44.3%)
≥ 65 years 4 (44.4%) 23 (31.9%) 19 (32.2%)
≥ 75 years 0 9 (37.5%) 8 (32.0%)
All 221 (57.0%) 283 (42.7%) 286 (43.2%)
Severe TEAE < 65 years 9 (2.4%) 9 (1.5%) 13 (2.2%)
≥ 65 years 0 4 (5.6%) 0
≥ 75 years 0 3 (12.5%) 0
All 9 (2.3%) 13 (2.0%) 13 (2.0%)
Serious TEAE < 65 years 7 (1.8%) 6 (1.0%) 12 (2.0%)
≥ 65 years 0 6 (8.3%) 1 (1.7%)
≥ 75 years 0 4 (16.7%) 0
All 7 (1.8%) 12 (1.8%) 13 (2.0%)
TEAE Leading to Study Drug Discontinuation < 65 years 2 (0.5%) 3 (0.5%) 5 (0.8%)
≥ 65 years 0 0 1 (1.7%)
≥ 75 years 0 0 1 (4.0%)
All 2 (0.5%) 3 (0.5%) 6 (0.9%)
TEAE with Outcome of Death < 65 years 0 0 1 (0.2%)
≥ 65 years 0 2 (2.8%) 0
≥ 75 years 0 2 (8.3%) 0
All 0 2 (0.3%) 1 (0.2%)

Source: FDA Medical Review, Table 5.7.3-1  

Table 7: Treatment Emergent Adverse Events by Sex in Phase 2 and Phase 3 Studies
Category Sex Phase 2 Studies Phase 3 Studies
Tedizolid phosphate (≥;200 mg) N=388
n (%)
Tedizolid phosphate (200 mg) N=662
n (%)
Linezolid (1200 mg) N=662
n (%)
N1

Male

251 429 408

Female

137 233 254
TEAE

Male

137 (54.6%) 179 (41.7%) 164 (40.2%)

Female

84 (61.3%) 104 (44.6%) 122 (48.0%)
Severe TEAE

Male

5 (2.0%) 7 (1.6%) 8 (2.0%)

Female

4 (2.9%) 6 (2.6%) 5 (2.0%)
Serious TEAE

Male

4 (1.6%) 5 (1.2%) 7 (1.7%)

Female

3 (2.2%) 7 (3.0%) 6 (2.4%)
TEAE Leading to Study Drug Discontinuation

Male

2 (0.8%) 1 (0.2%) 3 (0.7%)

Female

0 2 (0.9%) 3 (1.2%)
TEAE with Outcome of Death

Male

0 2 (0.5%) 0

Female

0 0 1 (0.4%)

Source: FDA Medical Review, Table 5.7.3-2

Table 8: Treatment Emergent Adverse Events by Race in Phase 2 and Phase 3 Studies
Category Race Phase 2 Phase 3 Studies
Tedizolid phosphate(≥200 mg)
N=388
n (%)
Tedizolid phosphate (200 mg)
N=662
n (%)
Linezolid (1200 mg)
N=662
n (%)
Number of patients in subgroup (N1) White 294 563 555
Black or African American 79 77 71
Asian 4 6 14
Other 11 16 22
Number (%) of patients with at least one TEAE White 167 (56.8%) 256 (45.5%) 250 (45.0%)
Black or African American 46 (58.2%) 23 (29.9%) 21 (29.6%)
Asian 2 (50.0%) 1 (16.7%) 7 (50.0%)
Other 6 (54.5) 3 (18.8) 8 (36.4%)

Source: FDA Medical Review, Table 5.7.3-3