Original Research ajog.

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1 GYNECOLOGY 56
2 57
3 A phase-3, double-blind, placebo-controlled study of the 58
4
5
effectiveness and safety of single oral doses of secnidazole 59
60
6 2 g for the treatment of women with bacterial vaginosis 61
7 62
Q10 Jane R. Schwebke, MD; Franklin G. Morgan Jr, MD, FACOG; William Koltun, MD; Paul Nyirjesy, MD
8 63
9 64
10 65
11 BACKGROUND: A novel single oral dose granule formulation of withdrawal of randomized, treated patients with a Nugent score <4 or with 66
secnidazole 2 g, a 5-nitroimidazole with a longer half-life (w17 hours) a separate sexually transmitted infection, this modified intent-to-treat 67
12
than metronidazole (w8 hours), is being developed to treat bacterial population was the primary analysis population. Statistical comparisons
13 68
vaginosis. used a stratified Cochran-Mantel-Haenszel test with a .05 level of sig-
14 69
OBJECTIVE: We sought to evaluate the effectiveness and safety of nificance (2-sided).
15 70
single-dose secnidazole 2 g compared to placebo for the treatment of RESULTS: Single-dose secnidazole 2 g was superior to placebo for the
16 women with bacterial vaginosis. primary and all secondary efficacy measures in the modified intent-to-treat
71
17 STUDY DESIGN: In all, 189 women with bacterial vaginosis were population, with clinical outcome responder rates of 53.3% (57/107) vs 72
18 randomized 2:1 to receive a single oral dose of secnidazole 2 g (N ¼ 125) 19.3% (11/57; P < .001). Clinical cure rates, based on an alternate 73
19 or matched placebo (N ¼ 64) at 21 centers in the United States. The definition of responder, which accounted for resolution of abnormal 74
20 primary endpoint was the proportion of clinical outcome responders, discharge consistent with bacterial vaginosis, were consistent with the 75
21 defined as those with: (1) normal vaginal discharge; (2) negative 10% clinical outcome responder rate analysis (58.9% vs 24.6%; P < .001) for 76
22 potassium hydroxide whiff test; and (3) <20% clue cells of total epithelial single-dose secnidazole 2 g vs placebo. Clinical cure rates based on the 77
23 cell count on microscopic examination of the vaginal wet mount, using 2016 US Food and Drug Administration guidance were 64.0% vs 26.4% 78
24 saline at the test of cure/end of study visit (study days 21-30). Secondary for single-dose secnidazole 2 g vs placebo. Based on the investigator’s 79
25 efficacy analyses included clinical cure rates, defined as: (1) responders clinical assessment at the test of cure/end of study visit, significantly more 80
26 with normal discharge or abnormal discharge not consistent with bacterial patients receiving single-dose secnidazole 2 g vs placebo required 81
27 vaginosis after treatment; (2) negative potassium hydroxide whiff tests; no additional bacterial vaginosis treatment (68.0% [68/100] vs 29.6% 82
28 and (3) clue cells <20% assessed at the interim visit (study days 7-14), [16/54]; P < .001). Adverse events considered by the investigator to be 83
29 and test of cure/end of study (study days 21-30). In addition, based on the related to study drug occurred in only 20.0% of single-dose secnidazole 2 84
30 2016 US Food and Drug Administration draft guidance, patients with getreated patients vs 10.9% of placebo patients, and they included 85
31 baseline Nugent scores 7-10 were evaluated for clinical cure using the diarrhea (4.0% vs 1.6%), headache (4.0% vs 3.1%), nausea (4.8% vs 86
32 following clinical assessments on study days 7-14: (1) resolution of the 1.6%), and vulvovaginal candidiasis (4.0% vs 3.1%). 87
33 abnormal vaginal discharge; (2) a negative potassium hydroxide whiff test; CONCLUSION: Single-dose secnidazole 2 g was superior to placebo 88
34 and (3) clue cells <20%. The study was designed and powered on all primary and secondary outcomes and was well tolerated; these 89
to demonstrate the efficacy of single-dose secnidazole 2 g compared results support its role for the treatment of women with bacterial vaginosis. 90
35
to placebo; safety and tolerability were also assessed. Due to a
36 91
prespecified institutional review boardeapproved protocol calling for Key words: bacterial vaginosis, secnidazole, single-dose treatment
37 92
38 93
39 Introduction common vaginal infection among girls adherence to antiinfective therapy in- 94
40 Bacterial vaginosis (BV) affects >21 and women aged 15-44 years.1,2 BV is creases with the length (w7 days for 95
41 Q3 million girls and women (29.2%) be- associated with a 2-fold increased risk of current standard of care) and complexity 96
42 tween the ages of 14-49 years in the serious health complications, including of the drug regimen, and it contributes to 97
43 United States annually, and it is the most susceptibility to and transmission of HIV treatment failure, recurrent disease, and 98
44 and herpes simplex type 2 virus; acqui- possibly more rapid development of 99
45 sition of other sexually transmitted in- resistant microorganisms.6 For example, 100
46 fections, including Neisseria gonorrhoeae studies have shown that w50% of pa- 101
Cite this article as: Schwebke JR, Morgan FG Jr, Koltun W,
47 and Chlamydia trachomatis; and, in tients do not comply with a 5- to 7-day 102
et al. A phase-3, double-blind, placebo-controlled study of
48 the effectiveness and safety of single oral doses of secni- pregnant women, preterm delivery and treatment regimen.7,8 These outcomes 103
49 dazole 2 g for the treatment of women with bacterial vagi- premature rupture of membranes.3,4 may lead to higher health care costs, 104
50 nosis. Am J Obstet Gynecol 2017;volume;x.ex-x.ex.
Currently recommended treatments including increased out-of-pocket ex- 105
51 0002-9378/$36.00 include a 7-day regimen of twice-daily penses, increased office visits and tests, 106
52 ª 2017 Elsevier Inc. All rights reserved. oral metronidazole 500 mg, a 5-day additional treatment costs, and lost pro- 107
53 http://dx.doi.org/10.1016/j.ajog.2017.08.017 108
regimen of intravaginal metronidazole ductivity.9 Poor adherence to the 7-day
54 0.75% gel, and a 7-day regimen of intra- regimens may also be contributing to 109
55 vaginal clindamycin 2% cream.5 Poor the emergence of an increasing number of 110

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111 167
112 cases of chronic BV, which require mul- placebo-controlled study that assessed biomedical research involving human 168
113 tiple antibiotic treatments.5,9 the effectiveness, safety, and tolerability subjects adopted by the 18th World 169
114 Single-dose secnidazole 2 g (Solosec of single-dose secnidazole 2 g in women Medical Assembly, Helsinki, Finland, 170
115 [secnidazole], Symbiomix Therapeutics and postmenarchal adolescent girls with 1964, and later revisions (insofar as such 171
116 LLC, Newark, NJ) is a novel oral granule BV. The study is registered with revisions are consistent with US treaty 172
117 formulation being developed to treat BV. ClinicalTrials.gov, NCT02418845. obligations and in accordance with US 173
118 Secnidazole is a 5-nitroimidazole with All patients provided written law). The study was performed in keep- 174
119 demonstrated in vitro antimicrobial ac- informed consent or, when applicable, ing with local legal requirements. Before 175
120 tivity against many anaerobic Gram- assent with parental/legal guardian con- the start of the study, the study protocol 176
121 negative and Gram-positive bacterial sent before the performance of any and other appropriate documents were 177
122 species, while sparing Lactobacillus spe- study-related procedures. Patients were submitted to the institutional review 178
123 cies.10,11 Several published clinical studies screened for study eligibility at the board (IRB) (Schulman Associates IRB, 179
124 demonstrated clinical and/or microbio- baseline visit (day 1). Patients deter- Cincinnati, OH; Western IRB, Puyallup, 180
125 logic evidence of activity of secnidazole in mined to be eligible were centrally ran- WA). The IRB confirmed the ethics of 181
126 the treatment of BV.10 Single-dose secni- domized at a 2:1 ratio to receive either conducting a placebo-controlled study 182
127 dazole 2 g has a favorable safety profile, single-dose secnidazole 2 g or matched that ensured placebo-randomized sub- 183
128 has not been shown to have any clinically placebo. Randomization was stratified by jects received effective treatment delayed 184
129 meaningful drug-drug interactions, has a the number of reported episodes of BV by 1 week for the patient population and 185
130 longer half-life than metronidazole (w17 in the past 12 months (3 vs 4 epi- their demographics. Letters document- 186
131 vs w8 hours), and can be administered sodes), including the current episode, ing the IRB approvals were provided to 187
132 with or without a meal. These character- and race (black vs all others). Study drug the sponsor or its representative prior to 188
133 istics and the single-dose regimen have was self-administered on day 1 without initiation of the study. 189
134 the potential to improve treatment regard to meals. For administration, 190
135 adherence, which could lead to improved study drug granules were mixed in 4 oz Study population 191
136 clinical outcomes for women with BV. of unsweetened applesauce. The match- The mITT was specified as the primary 192
137 The efficacy and tolerability of single- ing placebo contained the same in- analysis population in the protocol 193
138 dose secnidazole 2 g for the treatment of gredients as the active formulation, because these patients were confirmed to 194
139 BV was demonstrated in a randomized, except for the absence of secnidazole and have BV. The protocol states patient 195
140 placebo-controlled, phase-2 hypothesis- the addition of sucrose octaacetate as a disposition based on the intent-to-treat 196
141 generating study in which single-dose bittering agent. After receiving study (ITT) population. It was prespecified in 197
142 secnidazole 1 g and 2 g were investigated drug or placebo, patients were instructed the IRB-approved protocol that patients 198
143 vs placebo.12 The primary efficacy to immediately drink 8 oz of water. were to be randomized and treated if 199
144 endpoint analysis (clinical cure rate) in the Patients returned to the study center they met the clinical criteria for enroll- 200
145 modified intent-to-treat (mITT) popula- for an interim visit between study days ment, but they were then to be with- 201
146 tion demonstrated significantly greater 7-14 for response assessments and drawn if centrally analyzed Nugent 202
147 response rates for both single-dose secni- evaluation for adverse events (AEs). A scoring resulted in a Nugent score <4 or 203
148 dazole 1 g and 2 g vs placebo (P < .001). test of cure (TOC) visit was conducted if baseline laboratory tests revealed a 204
149 Secondary efficacy endpoint analyses between study days 21-30, at least 10 positive result for a separate sexually 205
150 (microbiologic cure and therapeutic cure days after the interim visit. Patients transmitted infection. Adult females or 206
151 rates) were consistent with the primary were allowed to withdraw their postmenarchal adolescent girls 12 207
152 results.12 Overall, both levels of single-dose participation from the study at any years of age were planned to be enrolled 208
153 secnidazole were well tolerated compared time, for any reason. If they chose to at 21 study centers in the United States. 209
154 to placebo. Additionally, it was the first withdraw, an end of study (EOS) visit All patients had a clinical diagnosis of 210
155 secnidazole efficacy study and evaluated 2 was conducted comprising the same BV, defined as meeting 4 Amsel criteria 211
156 dose levels to answer questions about dose assessments as the TOC visit. If pa- for BV (discharge; pH 4.7; 20% clue 212
157 and the degree of cure compared to pla- tients withdrew because they were cells; and positive 10% potassium hy- 213
158 cebo. Predicated on the enhanced efficacy dissatisfied with treatment, they were droxide [KOH] whiff test) and Nugent 214
159 and tolerability of single-dose secnidazole offered the option to receive any US scores 4. Baseline laboratory tests and 215
160 2 g over 1 g in the phase-2 study,12 the 2-g Food and Drug Administration (FDA)- vaginal sample slides for Gram staining 216
161 dose was selected for further investigation approved treatment for BV. and Nugent scoring were analyzed cen- 217
162 in this phase-3 confirmatory study. The study was conducted in accor- trally; thus, results were unavailable at 218
163 dance with the International Conference the time of randomization. Accordingly, 219
164 Materials and Methods on Harmonization Good Clinical Prac- patients remained in the study until 220
165 Study design tice Guidelines. The study was also per- laboratory tests and Nugent scores Q4 221
166 This was a phase-3, multicenter, pro- formed in accordance with the became available. Baseline scores ulti- 222
spective, randomized, double-blind, recommendations guiding physicians in mately were used as criteria for inclusion

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223 279
new 2016 FDA draft guidance for the
224 FIGURE 280
225Q8 study of treatment for BV issued in 2016, 281
---
226 patients with baseline Nugent scores 7- 282
227 10 were evaluated for clinical cure using 283
228 the following clinical assessments on 284
229 days 7-14: (1) resolution of the abnormal 285
230 vaginal discharge; (2) negative KOH 286
231 whiff test; and (3) clue cells <20%. The 287
232 investigator’s clinical opinion regarding 288
233 whether the patient required additional 289
234 BV treatment was documented at the 290
235 TOC/EOS visit. 291
236 Safety outcomes included rates of 292
237 treatment-emergent AE (TEAEs), 293
238 including those that were severe or 294
239 serious AEs. As per the study protocol, 295
240 the definition of TEAEs was, where 296
241 treatment-emergent was defined as any 297
242 AE that occurred after administration 298
243 of the first dose of study drug and 299
244 through the TOC/EOS visit, any event 300
245 that was considered treatment related, 301
246 Consort diagram. regardless of the start date of the event, 302
247 mITT, modified intent to treat; STI, sexually transmitted infection. or any event that was present at baseline 303
248 Schwebke et al. Single-dose secnidazole for BV treatment. Am J Obstet Gynecol 2017. but worsened in intensity or was sub- 304
249 sequently considered treatment related 305
250 by the investigator. Treatment-related 306
251 TEAEs were the subset of TEAEs 307
252 in the mITT, the primary population for administration through 3 days considered related to study drug by the 308
253 the efficacy analyses. following treatment. Patients were investigator. For clarity throughout this 309
254 Patients who were pregnant, asked to refrain from vaginal inter- report, TEAEs will be referred to as AEs 310
255 lactating, menstruating, menopausal, or course or use of any vaginal products and treatment-related TEAEs will be 311
256 who were suspected or confirmed for at least 7 days following treatment. referred to as AEs considered by the 312
257 clinically of having alternative causes of All subjects with BV at EOS were investigator to be related to study drug. 313
258 vaginal symptoms (eg, candidiasis, C offered FDA-approved treatment at no Changes from baseline in vital signs, 314
259 trachomatis, Trichomonas vaginalis, N cost. physical and pelvic examination find- 315
260 gonorrhoeae, or herpes simplex infec- ings, and clinical laboratory test results 316
261 tion) were excluded. C trachomatis, N Outcomes also were assessed. 317
262 gonorrhoeae, and T vaginalis results The primary endpoint was the propor- Subset analyses based on race, 318
263 were unavailable at the time of tion of clinical outcome responders ethnicity, and socioeconomic status 319
264 randomization. Patients with a history (CORs), defined as those with: (1) could not be made due to the small 320
265 of secnidazole use were also excluded normal vaginal discharge; (2) negative number of patients recruited at each of 321
266 from the study, as were those who had 10% KOH whiff test; and (3) clue cells the 21 study centers in the United States. 322
267 received antifungal or antimicrobial <20% of total epithelial cells on micro- The study was centrally randomized and 323
268 therapy (systemic or intravaginal) scopic examination of the vaginal wet was not stratified by site. The overall 324
269 within 14 days prior to baseline. mount using saline at the TOC/EOS visit demographic profile was similar for the 325
270 Concomitant systemic and topical (study days 21-30). Secondary efficacy treatment and placebo arms. 326
271 antimicrobial therapies were not analyses included clinical cure rates 327
272 permitted during the course of the defined as: (1) responders with normal Statistical analyses 328
273 study. Topical antifungal and immu- discharge after treatment or abnormal Primary and secondary efficacy analyses 329
274 nomodulatory therapies, warfarin, and discharge that is inconsistent with BV, were performed on the mITT popula- 330
275 systemic corticosteroids were also pro- likely due to Candida infection; (2) tion, defined as all randomized patients 331
276 hibited. Systemic antifungal therapy to negative KOH whiff test; (3) clue cells who met all entry criteria. 332
277 treat intercurrent conditions was <20% assessed at the interim visit (study The primary endpoint was compared 333
278 permitted. Alcohol was not permitted days 7-14) and TOC/EOS (study days between the single-dose secnidazole 334
for 12 hours prior to study drug 21-30).13,14 In addition, based on the 2 g and placebo groups using a

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335 391
336 TABLE 1 392
337 Demographics and baseline characteristics (modified intent-to-treat population), overall and by treatment group 393
338 394
339 Parameter Single-dose secnidazole 2 g, N ¼ 107 Placebo, N ¼ 57 Overall, N ¼ 164 395
340 Age, y 396
341 n 107 57 164 397
342 398
Mean (SD) 32 (8.7) 30 (7.6) 31 (8.4)
343 399
344 Median 31 28 30 400
345 Minimum, maximum 18, 54 18, 46 18, 54 401
346 P valuea .064 402
347 403
Race, n (%)
348 404
349 White 46 (43.0) 26 (45.6) 72 (43.9) 405
350 Black or African American 59 (55.1) 29 (50.9) 88 (53.7) 406
351 Asian 0 1 (1.8) 1 (0.6) 407
352 408
American Indian or Alaska native 0 0 0
353 409
354 Native Hawaiian or other Pacific Islander 0 0 0 410
355 Other 2 (1.9) 1 (1.8) 3 (1.8) 411
356 Race strata, n (%) 412
357 413
Black 59 (55.1) 29 (50.9) 88 (53.7)
358 414
359 All others 48 (44.9) 28 (49.1) 76 (46.3) 415
360 P value b
.625 416
361 No. of BV episodes in past 12 mo 417
362 418
n 107 57 164
363 419
364 Mean (SD) 3 (2.4) 3 (2.6) 3 (2.5) 420
365 Median 2 2 2 421
366 Minimum, maximum 1, 12 1, 12 1, 12 422
367 423
P value a
.926
368 424
369 BV strata, n (%) 425
370 3 episodes in past 12 mo 83 (77.6) 43 (75.4) 126 (76.8) 426
371 4 episodes in past 12 mo 24 (22.4) 14 (24.6) 38 (23.2) 427
372 428
P value b
.846
373 429
374 Nugent score category, n (%) 430
375 Nugent score 4e6 18 (16.8) 4 (7.0) 22 (13.4) 431
376 Nugent score 7e10 89 (83.2) 53 (93.0) 142 (86.6) 432
377 433
P value b
.095
378 434
379 BV, bacterial vaginosis. 435
a
380 From t test for treatment difference; b From Fisher exact test for treatment difference. 436
Schwebke et al. Single-dose secnidazole for BV treatment. Am J Obstet Gynecol 2017.
381 437
382 438
383 439
384 Cochran-Mantel-Haenszel test adjusted 7-14) and TOC/EOS (days 21-30) visits for all patients in the safety population, 440
385 for BV and race strata. For each treat- by BV and race strata and baseline defined as all randomized patients who 441
386 ment group, an exact 95% binomial Nugent score (4-6 vs 7-10) in the mITT received study drug. 442
387 confidence interval was calculated for population. For simplicity in assessing 443
388 the COR rate. Secondary efficacy end- baseline comparability, a t test was used Sample size calculation 444
389 points were analyzed similarly. The pri- for all continuous variables. Medians Assuming a COR rate of 50% in the 445
390 mary and secondary endpoints were also and ranges are also provided. Safety single-dose secnidazole 2 g group and 446
separately analyzed at the interim (days variables were tabulated and presented 25% in the placebo group, a sample size

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447 503
448 score was 8 (range: 0-10), with most 504
TABLE 2
449 patients (81.0%; 153/189) having a 505
Summary of clinical outcome responder rates in modified intent-to-treat
450 baseline score of 7-10. In the mITT 506
population, by treatment group
451 population, the treatment groups were 507
452 Single-dose secnidazole well balanced regarding demographics 508
Time point 2 g, N ¼ 107 Placebo, N ¼ 57 and baseline characteristics.
453 509
454 TOC/EOS visit 510
455 COR,a n (%) 57 (53.3) 11 (19.3)
Efficacy 511
456 b
Single-dose secnidazole 2 g was superior 512
Nonresponder, n (%) 50 (46.7) 46 (80.7) to placebo for the primary (TOC/EOS;
457 513
P value c
<.001 days 21-30) and all secondary efficacy
458 514
459 95% Exact binomial CI for responder rate 43.4e63.0 10.0e31.9 outcome measures. In the mITT popu- 515
460 lation, the COR rate for single-dose 516
Interim visit
461 secnidazole 2 g and placebo was 53.3% 517
COR,a n (%) 62 (57.9) 14 (24.6) (57/107) vs 19.3% (11/57), respectively
462 518
(P < .001) (Table 2). Although it was ½T2 519
b
Nonresponder, n (%) 45 (42.1) 43 (75.4)
463
464 P value c
<.001 prespecified that mITTwas designated as 520
465 95% Exact binomial CI for responder rate 48.0e67.4 14.1e37.8
the primary analysis population, the ITT 521
466 population showed similar COR rates: 522
Clinical cure rate, using alternative criteria 53.6% (67/125) in the single-dose sec-
467 for vaginal discharged 523
468 nidazole 2 g group and 21.9% (14/64) in 524
469
Responder, n (%) 63 (58.9) 14 (24.6) the placebo group (P < .001). With 525
470 Nonresponder, n (%) 44 (41.1) 43 (75.4) respect to secondary COR rate assess- 526
471 P value <.001 ments, single-dose secnidazole 2 g was 527
472 superior to placebo, including in the 528
95% Exact binomial CI for responder rate 49.0e68.3 14.1e37.8
473 mITT population at the interim visit 529
n ¼ 89 f,g
n ¼ 53f,g (days 7-14; P < .001). Using the alter-
474 530
475 FDA-defined clinical cure rates, n (%) e
57 (64.0) 14 (26.4) native criteria for clinical cure rates, 531
476 CI, confidence interval; COR, clinical outcome responder; EOS, end of study; FDA, US Food and Drug Administration; TOC, test of
single-dose secnidazole 2 g was superior 532
477
cure. to placebo at the TOC/EOS visits. Single- Q5 533
478
a
Patient who had all 3 of following clinical assessments: normal vaginal discharge, negative potassium hydroxide whiff test, dose secnidazole 2 g was also superior to 534
and clue cells <20%; b 8 Single-dose secnidazole patients and 3 placebo patients were missing 1 clinical assessments and
479 classified as nonresponders at EOS visit/10 single-dose secnidazole patients and 12 placebo patients were missing 1 placebo using the 2016 FDA definition of 535
480
clinical assessments and classified as nonresponders at interim visit; c P value vs placebo from Cochran-Mantel-Haenszel test clinical cure, which recommends 536
adjusted for bacterial vaginosis (3 or >3 episodes in past 12 mo) and race (black or all others) strata; d Alternative definition
481 of clinical cure rate is patient with: (1) normal discharge after treatment or abnormal discharge that is inconsistent with
assessment between days 7-14 and uti- 537
bacterial vaginosis likely due to Candida infection, (2) negative potassium hydroxide whiff test, and (3) clue cells <20%; lized data from patients with a baseline
482 e
Clinical cure, resolution of abnormal discharge due to bacterial vaginosis, normal potassium hydroxide whiff test, and clue 538
483 cells <20% by day 7e14 visit; f Modified intent-to-treat population with Nugent score of 7e10 at baseline; g Patients
Nugent score of 7-10, single-dose sec- 539
missing 1 of clinical assessments were considered “no cure.” nidazole 2 g was also superior to placebo
484 540
485
Schwebke et al. Single-dose secnidazole for BV treatment. Am J Obstet Gynecol 2017. (64.0% [n ¼ 57] vs 26.4% [n ¼ 14], 541
486 respectively) (Table 2). 542
487 In the mITT population, the per- 543
488 of 132 patients randomized at a 2:1 ratio assigned (2:1) to single-dose secnidazole centage of patients in the single-dose 544
489 provided 80% power to detect a statis- 2 g and placebo, respectively. The secnidazole 2 g and placebo groups 545
490 tically significant difference between numbers of patients included in the with normal Nugent scores was 43.9% 546
491 single-dose secnidazole 2 g and placebo single-dose secnidazole 2 g and placebo (47/107) vs 5.3% (3/57), respectively, at 547
492 at a .05 level of significance (2-sided). groups in the mITT population, as well the TOC/EOS visit (P <.001), and 45.8% 548
493 Assuming 75% of patients would have as reasons for exclusion, are listed in (49/107) vs 3.5% (2/57), respectively, at 549
494 met the mITT criteria, the plan was for Figure. the interim visit (P <.001). Based on the ½F1 550
495 120 patients to be randomized to the Among all 189 patients randomized, investigator’s clinical assessment at the 551
496 single-dose secnidazole 2 g group and 60 the mean age was 32 years (range: 18-54 TOC/EOS visit, significantly more pa- 552
497 patients to the placebo group. years). Most patients were black (52.9%; tients in the single-dose secnidazole 2 g 553
498 100/189) or white (44.4%; 84/189) group compared with placebo required 554
499 Results (Table 1). The mean number of BV epi- no additional BV treatment (68.0% [68/ ½T1 555
500 Disposition and demographics sodes in the previous 12 months was 3 107] vs 29.6% [16/57]; P < .001). 556
501 A total of 189 patients were enrolled at 21 (range: 1-12); most patients (77.2%; When analyzed by BV strata, results in 557
502 study centers from May 4, 2015, through 146/189) had 3 BV episodes in the the 3 baseline BV strata were consistent 558
Aug. 26, 2015; 125 and 64 patients were previous 12 months. The mean Nugent with the efficacy results for the mITT

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559 615
560 TABLE 3 616
561 Summary of primary and secondary efficacy results (modified intent-to-treat population), bacterial vaginosis 617
562 stratification factor, and treatment group 618
563 619
564 Treatment group/BV strata 620
565 Single-dose secnidazole 2 g, N ¼ 107 Placebo, N ¼ 57 621
566 3 BV episodes, 4 BV episodes, 3 BV episodes, 4 BV episodes, 622
567 Endpoint/statistic n ¼ 83 n ¼ 24 n ¼ 43 n ¼ 14 623
568 COR (primary endpoint),a n (%) 50 (60.2) 7 (29.2) 8 (18.6) 3 (21.4) 624
569 625
P value vs placebob <.001 .614 e e
570 626
571 95% Exact binomial CI for 48.9e70.8 12.6e51.1 8.4e33.4 4.7e50.8 627
572 responder rate 628
573 Nugent score 629
574 N 76 23 40 14 630
575 631
Mean (SD) 3.6 (3.17) 5.7 (2.90) 7.8 (2.39) 8.4 (1.65)
576 632
577 P value vs placebob <.001 .028 e e 633
578 BV, bacterial vaginosis; CI, confidence interval; COR, clinical outcome responder. 634
579 a
Patient who had all 3 of these clinical assessments: normal vaginal discharge, negative potassium hydroxide whiff test, and clue cells <20%; b P value vs placebo from Cochran-Mantel-Haenszel 635
test adjusted for race strata (black or all others).
580 Schwebke et al. Single-dose secnidazole for BV treatment. Am J Obstet Gynecol 2017.
636
581 637
582 638
583 639
584 population (60.2% for single-dose sec- 5-nitroimidazole family. Previous studies thus its efficacy had not been demon- 640
585 nidazole 2 g vs 18.6% for placebo; P < demonstrated favorable pharmacoki- strated. Although several studies evalu- 641
586½T3 .001) (Table 3). In the 4 strata, results netics: the 2-g single dose has a longer ating secnidazole have been reported in 642
587 were not different from placebo. The half-life (w17 hours) than metronida- the literature, most are small, non- 643
588 efficacy results of the baseline race strata zole (w8 hours), high bioavailability, and rigorous designed studies. Only 1 was a 644
589 were consistent with the efficacy analyses rapid absorption.15,16 While secnidazole randomized, well-controlled study 645
590 for the mITT population, with statistical has been used worldwide primarily for designed to show noninferiority to 646
591 superiority demonstrated (P < .05) for the treatment of trichomoniasis and its metronidazole.19 It is unclear from the 647
592 the single-dose secnidazole 2 g group in efficacy/tolerability confirmed in publication if and how the assumptions 648
593 both race strata for all efficacy outcome numerous BV studies,10,17-20 secnidazole used to select the noninferiority margin 649
594 measures at both the interim and TOC/ is currently unavailable as a treatment for would meet current standards as 650
595½T4 EOS visits (Table 4). women with BV in the United States. This described in the FDA 2016 guidance 651
596 is the first phase-3 secnidazole single- since there were no placebo-controlled 652
597 Safety/tolerability dose 2 g clinical trial in the United study results in women with BV at the 653
598 All 189 randomized patients received a States, with a representative, diverse time the aforementioned study19 was 654
599 single dose of study treatment and were population. Although there were no de- conducted. For a disease as common as 655
600 included in the safety population. The mographic differences between study BV, clinicians would expect assurance 656
601 overall AE rate was 34.4% (43/125) for groups, the overall patient population from >1 adequate and well-controlled 657
602 single-dose secnidazole 2 g vs 21.9% was racially diverse (>50% African study to support claims of clinical 658
603½T5 (14/64) for placebo (Table 5). Most American) and included patients with benefit. Therefore, this phase-3 study Q6 659
604 AEs were mild or moderate in intensity recurrent BV, who were stratified by was conducted to demonstrate the effi- 660
605 and nonserious, and none led to study number of prior BV episodes. cacy of secnidazole. Lastly, placebo was 661
606 discontinuation. No notable differences The current phase-3 study was con- chosen as a control to facilitate mainte- 662
607 between treatment groups were seen ducted to: (1) confirm the efficacy and nance of the blind (due to differences in 663
608 regarding change from baseline in safety of single-dose secnidazole 2 g seen treatment regimens between single-dose 664
609 clinical laboratory or vital sign pa- in the phase-2 dose-ranging study12 in secnidazole 2 g and metronidazole) and 665
610 rameters or physical examination US patients with BV; and (2) support compliance with study medications. 666
611 findings. licensure of single-dose secnidazole 2 g Results from this phase-3 confirma- 667
612 for the treatment of this patient popu- tory study of the hypothesis that the 2-g 668
613 Comment lation. In addition, SYM-1219 2 g is a dose has a given treatment effect based 669
614 Single-dose secnidazole 2 g is a novel granule formulation of secnidazole on that seen in the phase-2 study12 670
novel drug candidate from the and has a unique manufacturing process, support the single-dose regimen of

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671 727
672 These results are largely consistent 728
TABLE 4
673Q9 with recent phase-2 and -3 secnidazole 729
Summary of clinical outcome responder rates by time point, race strata, and
674 published data.12,14,19 In the phase-2 730
treatment of modified intent-to-treat population
675 randomized, double-blind, placebo- 731
676 Single-dose secnidazole Placebo, controlled study that assessed the effec- 732
Time point 2 g, N ¼ 107 N ¼ 57 tiveness of single-dose secnidazole 1 g
677 Race strata n (%) n (%) 733
678 and 2 g, the clinical cure (defined as 734
679
TOC/EOS visit normal discharge, negative KOH whiff 735
680
Black race test, and clue cells <20%) rate in the 2 g 736
681 CORa 27 (45.8) 6 (20.7) group was 67.7%.12 In a double-blind, 737
682 Nonresponder b
32 (54.2) 23 (79.3) double-dummy, randomized phase-3 738
683 noninferiority trial comparing secnida- 739
P value c
.025
684 zole and metronidazole performed in 740
95% Exact binomial CI for responder rate 32.7e59.2 8.0e39.7 France, the primary endpoint was FDA
685 741
686 All others defined (2010) and included a composite 742
687 CORa 30 (62.5) 5 (17.9) of clinical (normalization of 3 Amsel 743
688 b criteria) and bacterial (Nugent score 3) 744
Nonresponder 18 (37.5) 23 (82.1)
689 cure at day 28. Single-dose secnidazole 745
P valuec <.001 2 g was shown to be at least as effective
690 746
691 95% Exact binomial CI for responder rate 47.4e76.0 6.1e36.9 as the multiple-dose metronidazole 747
692 Interim visit regimen (500 mg for 7 days; 60.1% vs 748
693 Black race 59.5%, respectively); rates of AEs were 749
694 CORa 29 (49.2) 5 (17.2)
similar between treatment groups.19 The 750
695 b
most striking difference between the 751
Nonresponder 30 (50.8) 24 (82.8) results of the present study and a previ-
696 752
P value c
.004 ous phase-2 trial12 were noted when the
697 753
698 95% Exact binomial CI for responder rate 35.9e62.5 5.8e35.8 data were analyzed by BV strata. Our 754
699 All others finding that response rates for single- 755
700 dose secnidazole 2 g were not different 756
CORa 33 (68.8) 9 (32.1)
701 from placebo in the 4 strata is incon- 757
b
Nonresponder 15 (31.3) 19 (67.9) sistent with data from a previously re-
702 758
703 P valued .002 ported phase-2 study of secnidazole in 759
704 95% Exact binomial CI for responder rate 53.7e81.3 15.9e52.4 which response rates were statistically 760
705 significant compared to placebo (57.1% 761
CI, confidence interval; COR, clinical outcome responder; EOS, end of study; TOC, test of cure.
706 a
vs 5.3%, P < .001).12 The reason for this 762
Patient who had all 3 of these clinical assessments: normal vaginal discharge, negative potassium hydroxide whiff test, and
707 clue cells <20%; b 6 Single-dose secnidazole 2 g patients and 2 placebo patients were missing 1 clinical assessments and inconsistency is unclear; however, it is 763
classified as nonresponders; c P value vs placebo from Cochran-Mantel-Haenszel test adjusted for bacterial vaginosis strata generally agreed that there are com-
708 (3 or >3 episodes in past 12 mo). 764
709 Schwebke et al. Single-dose secnidazole for BV treatment. Am J Obstet Gynecol 2017.
plexities associated with treating recur- 765
710 rent BV. Furthermore, the disparate 766
711 results may be attributable to multiple 767
712 secnidazole 2 g for the treatment of BV. results. In the subgroup of patients factors associated with the design of the 768
713 The primary endpoint analysis, the COR with 4 prior BV episodes, COR rates current study, including the fact that the 769
714 rate in the mITT population at the TOC/ at TOC/EOS were lower (29.2% vs phase-3 study was not designed to show 770
715 EOS visit, demonstrated significant 21.4%) compared with interim rates a statistical difference on subgroup 771
716 response rates with single-dose secnida- (58.3% vs 35.7%). There was also a (strata) analyses, the 2:1 randomization 772
717 zole 2 g compared to placebo. Similar considerable difference in COR rates (secnidazole 2 g:placebo), the marked 773
718 results were obtained for the primary when compared to patients with 3 BV imbalance between the <3 (n ¼ 131) 774
719 efficacy endpoint when analyzed in the episodes (60.2%), as well as the rates for and >4 (n ¼ 28) episodes of BV per 775
720 3 baseline BV strata and in each race primary and secondary outcomes at 12 months subgroups, and the small 776
721 strata. These results were supported by TOC/EOS mentioned earlier. Single- number of subjects in the >4-episode 777
722 the statistical superiority of single-dose dose secnidazole 2 g was well tolerated. group. The 2:1 imbalance between the 778
723 secnidazole 2 g over placebo in all Consistent with published data of sec- secnidazole 2 g and placebo groups 779
724 secondary assessments of the CORs, nidazole monotherapy in BV,18,19,21,22 skews the results and limits interpreta- 780
725 including at the interim visit. Secondary there were very few AEs, none of which tion of statistical testing. However, 781
726 efficacy endpoint analyses in the mITT were regarded as serious by the despite these differences, a greater 782
population supported the primary investigators. treatment effect was observed for

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783 839
784 results of 51.3% and 35.6% for 1 g, once- 840
TABLE 5
785 daily, 5-day vs 2 g, once-daily, 2-day 841
Tolerability by treatment group (safety population)
786 regimens, respectively.23 In trials for 842
787 Incidence/prevalence of AEs metronidazole, clinical cure rates, defined 843
788 as return to normal vaginal pH (4.5), 844
Single-dose secnidazole Placebo,
789 2 g, N ¼ 125 N ¼ 64 absence of a “fishy” amine odor, and 845
790 Parameter n (%) n (%) absence of clue cells, were 61% vs 59% 846
791 Patients with 1 AE 43 (34.4) 14 (21.9) and 62% vs 43% for clindamycin cream 847
792 across 2 randomized, well-controlled, 848
Patients with 1 AE considered by investigator 25 (20.0) 7 (10.9)
793 investigator-blind trials.24 In this study, 849
to be related to study drug
794 alternate criteria were used to determine 850
Patients with 1 severe AEa 5 (4.0) 0 clinical cure: discharge criteria were
795 851
Patients with 1 serious AE 2 (1.6) 0 defined as resolution of abnormal
796 852
797 Patients who stopped treatment due to TEAE 0 0 discharge consistent with BV after treat- 853
798 ment. As a result, the responder rates 854
Total no. of Aes 84 18
799 (58.9% vs 24.6%; P < .001) were higher 855
Total no. of AEs considered by investigator 52 8 than for the primary endpoint analysis
800 to be related to study drug 856
801 (53.3% vs 19.3%; P <.001). Furthermore, 857
Total no. of severe Aes 7 0 in 2016, the FDA provided draft guidance
802 858
803 Total no. of serious Aes 2 0 for BV treatment trial design, which 859
covered numerous trial considerations,
804 AEs (incidence 3%) 860
805 including efficacy endpoints. The rec- 861
Abdominal pain 4 (3.2) 2 (3.1) ommended primary efficacy endpoint
806 862
807
Diarrhea 5 (4.0) 1 (1.6) was defined as follows: “Clinical cure: 863
808 Headache 6 (4.8) 2 (3.1) resolution of the abnormal vaginal 864
809 discharge, negative whiff test, and the 865
Nausea 6 (4.8) 1 (1.6)
810 presence of clue cells <20% of the total 866
Vulvovaginal candidiasis/mycotic infectionb 17 (13.6) 3 (4.7) epithelial cells on microscopic examina-
811 867
812 Vulvovaginal pruritus 3 (2.4) 2 (3.1) tion of the saline wet mount.”13 Notably, 868
813 AEs considered by investigator to be related using these criteria, patients can be clini- 869
814 to study drug (incidence 3%) cally cleared of BV, but abnormal 870
815 discharge can persist due to treatment- 871
Diarrhea 5 (4.0) 1 (1.6)
816 induced Candida infection. Thus, one 872
Headache 5 (4.0) 2 (3.1) can expect that future studies of BV
817 873
818
Nausea 6 (4.8) 1 (1.6) treatments will use the new FDA criteria 874
819 Vulvovaginal candidiasis/mycotic infection b
5 (4.8) 2 (3.1) for cure, which differ from those used in 875
820 AE, adverse event; TEAE, treatment-emergent adverse event.
previous studies. 876
821 a
Severe AEs among single-dose secnidazole 2 getreated patients included diarrhea and syncope (2 patients each) and
To our knowledge, the previously 877
822 dehydration, ectopic pregnancy, and vulvovaginal mycotic infection (1 patient each)eof these events, both cases of diarrhea mentioned phase-2 study12 and the cur- 878
823
and vulvovaginal mycotic infection were assessed as treatment-relatede2 severe events, ectopic pregnancy and 1 case of
syncope, also were seriouseboth events were assessed as unrelated to study drug; b Vulvovaginal mycotic infection and
rent study are the first adequately 879
824 vulvovaginal candidiasis were both listed as preferred terms for recording AEsedesignation of term for AE was at discretion of designed, placebo-controlled studies 880
investigatoreterms are listed together in table as it is likely that all mycotic infections could be attributed to Candida spp. assessing the efficacy of secnidazole in
825 Schwebke et al. Single-dose secnidazole for BV treatment. Am J Obstet Gynecol 2017. 881
826 women with BV that utilized the newly 882
827 recommended FDA criteria in a post hoc 883
828 analysis. To be compliant and ensure ac- 884
829 single-dose secnidazole 2 g in both the visit, and the secondary efficacy endpoint curate and transparent assessment in the 885
830 phase-2 and -3 studies. was the interim visit (days 7-14). Because present study, a new analysis using the 886
831 The current study also evaluated an guidance from the FDA has changed over mITT population was conducted when 887
832 interim time point, which is a relevant time, past studies evaluating other medi- the FDA guidance for clinical cure was 888
833 topic in the BV space based on the un- cations to treat BV have yielded results issued. This analysis of the mITT popu- 889
834 known appropriate TOC time point. that used different criteria for cure and lation per the FDA guidance issued after 890
835 Current medical texts refer to “early” and thus cure rates have varied widely. For study completion yielded even higher 891
836 “delayed” responses, which happen to be instance, in registration studies for tini- responder rates (64.0% vs 36.4%) than 892
837 nonspecific time points. In the current dazole, clinical cure was defined as return those observed in preguidance studies. 893
838 study, the primary efficacy endpoint was to normal vaginal discharge and resolu- Furthermore, our results were similar to 894
assessed at the TOC/EOS (days 21-30) tion of all Amsel criteria and yielded cure rates in a real-world clinical setting as

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895 951
896 assessed by investigators (68% vs 29.6%), 2. Centers for Disease Control and Prevention. healthy female volunteers. Adv Ther 2017;33:
952
and higher than the primary COR Bacterial vaginosis statistics. Available at: http:// 2229-41.
897 www.cdc.gov/std/bv/stats.htm. Accessed Dec. 16. Benazet F, Guillaume L. Amoebecide and 953
898 outcome (53.3% vs 19.3%) and clinical 6, 2016. trichomonacide activities of secnidazole in the 954
899 cure defined using alternative criteria 3. Centers for Disease Control and Prevention. laboratory [in French]. Bull Soc Pathol Exot Fili- 955
900 (58.9% vs 24.6%) for single-dose secni- STD treatment guidelines. Bacterial vaginosis. ales 1976;69:309-19.
956
dazole vs placebo, respectively. Based on Available at: http://www.cdc.gov/std/tg2015/ 17. Saraçog  lu F, Göl K, Sahin Ï, Türkkani B,
901 bv.htm. Accessed Dec. 6, 2016. Atalay C, Öztopcu C. Treatment of bacterial 957
902 our results, demonstration of superiority 958
4. Bradshaw CS, Sobel JD. Current treatment of vaginosis with oral or vaginal ornidazole, secni-
903 over placebo in a clinical study was bacterial vaginosiselimitations and need for dazole and metronidazole. Int J Gynaecol 959
904 feasible in women with BV and is the best innovation. J Infect Dis 2016;214(Suppl): Obstet 1998;62:59-61. 960
905 method to prove benefit, free of as- S14-20. 18. Núñez JT, Gómez G. Low-dose secnidazole
961
906 sumptions without a need to rely on other 5. Workowski KA, Bolan GA. Centers for Dis- in the treatment of bacterial vaginosis. Int J
962
information. Such external information ease Control and Prevention. Sexually trans- Gynaecol Obstet 2005;88:281-5.
907 mitted diseases treatment guidelines, 2015. 19. Bohbot JM, Vicaut E, Fagnen D, 963
908 can be limited by methodology, change in MMWR Recomm Rep 2015;64:1-137. Brauman M. Treatment of bacterial vaginosis: a 964
909 medical practice, population differences, 6. Kardas P. Patient compliance with antibiotic multicenter, double-blind, double-dummy, ran- 965
910 etc. Because this study was statistically treatment for respiratory tract infections. domized phase III study comparing secnidazole
966
911 powered to detect differences in efficacy, J Antimicrob Chemother 2002;49:897-903. and metronidazole. Infect Dis Obstet Gynecol
967
but not incidence of AEs between treat- 7. Bartley JB, Ferris DG, Allmond LM, 2010;2010.
912 Dickman ED, Dias JK, Lambert J. Personal 20. Thulkar J, Kriplani A, Agarwal N. 968
913 ment groups, safety data should be digital assistants used to document compliance A comparative study of oral single dose of 969
914 considered exploratory. Additional safety of bacterial vaginosis treatment. Sex Transm Dis metronidazole, tinidazole, secnidazole and 970
915 data will likely be derived from post- 2004;31:488-91. ornidazole in bacterial vaginosis. Indian J Phar-
971
916 marketing surveillance. 8. Cockburn J, Gibberd RW, Reid AL, Sanson- macol 2012;44:243-5.
972
Fisher RW. Determinants of non-compliance 21. Videau D, Niel G, Siboulet A, Catalan F.
917 with short term antibiotic regimens. Br Med J Secnidazole. A 5-nitroimidazole derivative 973
918 Conclusions (Clin Res Ed) 1987;295:814-8. with a long half-life. Br J Vener Dis 1978;54: 974
919 This study was designed and powered to 9. Kardas P, Bishai WR. Compliance in anti- 77-80. 975
920 demonstrate the efficacy of single-dose infective medicine. Adv Stud Med 2006;6: 22. Moraes ME, Cunha GH, Bezerra MM, et al.
976
921 secnidazole 2 g compared to placebo; S652-8. Efficacy of the Mentha crispa in the treatment of
977
safety and tolerability were also assessed. 10. Gillis JC, Wiseman LR. Secnidazole. A re- women with Trichomonas vaginalis infection.
922 view of its antimicrobial activity, pharmacokinetic Arch Gynecol Obstet 2012;286:125-30. 978
923 The results reported both here and pre- properties and therapeutic use in the manage- 23. Tindamax [package insert]. San Antonio, TX: 979
924 viously demonstrate that the efficacy for ment of protozoal infections and bacterial vagi- Mission Pharmacal Company; 2014. 980
925 single-dose secnidazole 2 g, coupled with nosis. Drugs 1996;51:621-38. 24. Flagyl ER. (metronidazole) [prescribing in-
981
926 a tolerability profile similar to that of 11. Petrina M, Cosentino L, Rabe L, Hillier SL. formation]. New York, NY: GD Searle, a Division
982
placebo, support an effective and well- Susceptibility of bacterial vaginosis (BV)-asso- of Pfizer; 2016.
927 ciated bacteria to secnidazole, metronidazole, 983
928 tolerated treatment for BV. Manage- tinidazole and clindamycin. Presented at: 43rd 984
ment of BV can be complex because it annual meeting of the Infectious Diseases Soci-
Author and article information
929 From the Division of Infectious Diseases, University of Q1
985
930 can recur frequently, leading to repeat ety for Obstetrics and Gynecology; August 11-
986
Alabama at Birmingham School of Medicine, Birming-
931 office visits and discomfort for patients. 13, 2016; Annapolis, MD.
987
12. Hillier SL, Nyirjesy P, Waldbaum AS, et al. ham, AL (Dr Schwebke); Tidewater Physicians for
932 A single-dose treatment option may Women, Virginia Beach, VA (Dr Morgan); Medical Center 988
Secnidazole treatment of bacterial vaginosis: a
933 improve treatment adherence, which randomized controlled trial. Obstet Gynecol for Clinical Research, San Diego, CA (Dr Koltun); and 989
934 may be beneficial for both patients and 2017;130:379-86. Obstetrics and Gynecology, Drexel University College of
990
935 health care practitioners. n 13. US Department of Health and Human Ser- Medicine, Philadelphia, PA (Dr Nyirjesy).
991
vices. US Food and Drug Administration, Center Received April 26, 2017; revised July 20, 2017;
936 for Drug Evaluation and Research. Bacterial accepted Aug. 16, 2017. 992
Acknowledgment The study was funded by Symbiomix Therapeutics. Q2
937 vaginosis: developing drugs for treatment. 993
Editorial and medical writing assistance was Dr Schwebke received grant funding from Symbiomix
938 provided by Maryn Padula, PhD, of Virtuoso
Guidance for industry. Rockville (MD): US Food 994
and Drug Administration; 2016. Therapeutics, BD Diagnostics, Hologic, Curatek Phar-
939 Healthcare Communications, supported by maceuticals, Toltec Pharmaceuticals, Alfa Wasserman,
995
14. Schwebke JR, et al. Results from a phase 3,
940 Symbiomix Therapeutics, the manufacturer of StarPharma, and LabCorp of America. She is also a paid 996
randomized, double-blind, placebo-controlled
941 Solosec (secnidazole) oral granules. The authors
study confirming efficacy/safety of a single, oral consultant for Symbiomix Therapeutics. Dr Nyirjesy 997
942 were fully responsible for the content, editorial received grant funding from Symbiomix Therapeutics, BD 998
dose study of SYM-1219 for the treatment of
decisions, and opinions expressed in the current Diagnostics, Curatek Pharmaceuticals, and Alfa Was-
943 article. The authors did not receive an honorarium
bacterial vaginosis. Presented at: 43rd annual 999
meeting of the Infectious Diseases Society for serman SpA. He is also a paid consultant for Hologic,
944 related to the development of this manuscript. Perrigo Company, and Symbiomix Therapeutics. Drs
1000
Obstetrics and Gynecology; Aug. 11-13, 2016;
945 Morgan and Koltun report no conflicts of interest. Q7
1001
Annapolis, MD.
946 References 15. Pentikis HS, Adetoro N, Braun CJ. Lack of a Presented in oral format at the 43rd annual meeting of 1002
947 1. Allsworth JE, Peipert JF. Prevalence of bac- pharmacokinetic interaction between SYM- the Infectious Diseases Society for Obstetrics and Gy- 1003
948 terial vaginosis: 2001-2004 National Health and 1219 granules containing 2 grams of secnida- necology; Annapolis, MD; Aug. 11-13, 2016. 1004
949 Nutrition Examination Survey data. Obstet zole and a combined oral contraceptive in a Corresponding author: Jane R. Schwebke, MD. 1005
Gynecol 2007;109:114-20. phase 1, randomized, open-label study in schwebke@uab.edu
950 1006

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