塞克硝唑栓治疗细菌性阴道病的有效性和安全性临床研究
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摘要
研究背景与目的：
细菌性阴道病(Bacterial Vaginosis, BV)主要由加德纳菌及一系列厌氧微生物引起的一种无阴道粘膜炎症的临床综合症,是以阴道分泌物紊乱为特征的临床感染性疾病。塞克硝唑(Secnidazole)由法国罗纳普朗克制药公司于1980年研发上市,属于5-硝基咪唑类药物,与甲硝唑、替硝唑化学结构相似,生理活性也相似,对多种革兰氏阳性厌氧菌和革兰氏阴性厌氧菌及原虫有很强的杀伤力,临床上主要用来治疗由上述致病微生物引起的感染。国内现有塞克硝唑的口服剂型主要缺点为口服用药剂量大,导致的毒副作用大,而且发病部位血药浓度低。塞克硝唑栓(Secnidazole Suppository)为塞克硝唑的栓剂,于患者阴道内放药,直接接触病原菌,可改善塞克硝唑口服剂型的缺点。
目前国内尚无对塞克硝做栓临床研究的报道,本试验采用随机、平行对照方法进行临床研究,评价塞克硝唑栓对细菌性阴道病患者的治疗作用、安全性和量效关系,为Ⅲ期临床试验研究设计和给药剂量方案的确定提供依据。
研究方法：
1、本研究入组细菌性阴道病患者144例,根据患者就诊顺序编号,采用随机数表法随机分为两组(塞可硝唑栓组和甲硝唑栓组),每组各72例,对每例患者进行三次随访。
2、用药前(访视1),填写患者一般资料,进行病史采集及妇科症状和妇科体征的评估。
3、发给患者研究药品,告知患者用药方法,并嘱患者在治疗结束后第3-7天(访视2)、月经结束后第3-7天(访视3)来院进行妇科检查及实验室检查。
4、研究开始后的的三次随访都需询问并记录入组患者不良事件的情况,如实填写不良事件记录表。若存在不良事件,则根据不良事件的严重程度进行相应的处理,并详细记录处理方式。
5、研究结束后,根据随访记录,比较两组患者临床疗效和病原学疗效,同时比较两组患者用药后实验室检查异常和不良事件的发生情况。
研究结果：
1、临床疗效评价比较：以全分析集(Full Analysis Set, FAS)为分析集的比较结果显示,在治疗结束后第3-7天及月经干净后第3-7天时,两组患者的有效率、痊愈率比较差异无统计学意义(P>0.05)。以符合方案集(Per Protocol Set, PPS)为分析集的比较中,两组的有效率、痊愈率比较差异无统计学意义(P>0.05)。
2、病原学疗效评价比较：两组病人治疗前后阴道分泌物涂片(包括清洁度、清洁度变化、pH值、pH值变化、胺试验、阴道排液及其他异常)比较、两组病人治疗前后细菌病原学(包括病原学、病原学变化、病原学总分及病原学总分变化)比较,差异均无统计学意义(P>0.05)。
3、妇科症状、体征比较：两组病人妇科症状、体征比较(FAS),除“外阴充血”指标外,其他比较均无显著的统计学差异(P>0.05)。“外阴充学”指标治疗全两组间相比差异没有统计学意义(P>0.05),具有可比性。治疗结束后第3-7天时,塞克硝唑栓组阳性率为0.00%,甲硝唑栓组阳性率为8.70%,两组间相比有明显的统计学差异(P=0.0133)。治疗结束后第3-7天时,塞克硝唑栓组外阴充血消失率为100.00%,甲硝唑栓消失率为62.50%,两组间相比差异存在统计学意义(P=0.0205)。
4、实验室检查指标比较：经研究者判断,本次临床研究实验室检查出现的异常数据均与试验用药无关。
5、不良事件比较：对进入FAS集的两组病人不良事件发生情况进行比较,塞克硝唑栓组不良事件发生率为14.29%,甲硝唑栓不良事件发生率为4.35%,两组不良事件发生率相比无明显的统计学差异(p>0.05)。
研究结论：
塞克硝唑栓和甲硝唑栓对于治疗细菌性阴道病均取得了显著的效果,两组临床疗效及临床安全性相比均无显著的统计学差异。
Background and Objective
Bacterial vaginosis (BV) is a clinical infectious disease characterized by polymicrobial anaerobic overgrowth of the vaginal epithelium without vaginal mucosal inflammation. Secnidazole is a5-nitroimidazole product with a broad spectrum of activity against gram-positive anaerobic bacterium, Gram-negative anaerobic bacteria and protozoan, which was researched and developed, and then marked by Rhone Poulenc Rorer in1980. Its chemical structure and physiological activity are similar to metronidazole and tinidazole. In clinic, it is applied to treat infections caused by above-mentioned pathogenic microorganisms. The disadvantages of secnidazole in peroral dosage form marked in our country are its too large dosage resulting in high toxic side effect and low blood concentration reached in pathogenic location. Secnidazole suppository is a new dosage form, and can be placed in vagina directly to contact pathogenic bacteria. As a result, the new dosage form can improve the disadvantages of secnidazole in peroral dosage form. By now, there have been no clinical reports on secnidazole suppository. It is necessary to conduct a research to evaluate clinical efficacy and safety and dose-effect relationship of secnidazole suppository on treatment of bacterial vaginosis, so as to provide a scientific basis for phase Ⅲ clinical trial.
Methods
1. This research intended to include144patients diagnosed as bacterial vaginosis. According to the order of visit, they were randomly divided into two groups (secnidazole suppository group and metronidazole suppository group). And each group had72cases. The included patients had to complete three follow-up.
2. Before treatment (visit1), it was necessary to fill in the general data, to collect anamnesis and to evaluate gynecological gynecological symptoms and signs of patients.
3. The patients were told to come back to do gynecological examination and laboratory examination separately when the3-7days after finishing treatment (visit2) and the first3-7days after the end of menstruation (visit3).
4. During the three follow-up, it was necessary to inquire and record adverse events (AE), and truthfully complete the adverse event record. If there were adverse events, we should make a corresponding treatment according to the severity of adverse events, and then, we should record the treatment in detail.
5. After completing the study, we compared their clinical and pathogenic efficacy, and observed the occurrence of adverse drug events and laboratory abnormalities.
Results
1. Comparison of clinical efficacy:In the3-7days after finishing treatment and the first3-7days after the end of menstruation, given in the full analysis set (FAS), the comparison result of effective rate and cure rate was that the two groups had no significant difference (P>0.05). And given in the per protocol set (PPS), the comparison result also showed no significant difference (P>0.05).
2. Comparison of pathogenic efficacy:Before and after treatment, there were no significant differences (P>0.05) when compared vaginal smears (including cleanliness, cleanliness change, pH, pH change, KOH whiff test, vaginal discharge and other abnormalities) and bacterial pathogens (including etiology, pathogenic changes, total score of etiology and total score change of etiology).
3. Comparison of gynecologic symptoms and physical signs:There were no significant differences (P>0.05) between two groups when comparing gynecological symptoms and signs except for vulva congestion. Before treatment, when compared vulva congestion, it was no significant difference (P=0.5371). which indicated that two groups could be compared. After3-7days when finishing treatment, the positive rate of secnidazole suppository group was0%, however, it was8.70%in metronidazole suppository group. When compared, it came up a significant difference between the two groups (P=0.0133). After3-7days when finishing treatment, the disappearance rate of vulva congestion was separately100.00%and62.50%in secnidazole suppository group and in metronidazole suppository group, there was a significant difference (P=0.0205).
4. Comparison of laboratory examination:It was not related to the study medication that the abnormal data appeared in laboratory examination after the judgement of the researchers.
5. Comparison of adverse events:In terms of the patients who were included into full analysis set, when compared the incidence rate of adverse events, two groups had no significant difference (P>0.05), coupled with that it was14.29%and4.35%separately in secnidazole suppository group and in metronidazole suppository group.
Conclusions
Secnidazole suppository and metronidazole suppository on treatment of bacterial vaginosis both have achieved significant clinical efficacy and safety, with no significant differences between the two groups.
细菌性阴道病(Bacterial Vaginosis, BV)主要由加德纳菌及一系列厌氧微生物引起的一种无阴道粘膜炎症的临床综合症,是以阴道分泌物紊乱为特征的临床感染性疾病。塞克硝唑(Secnidazole)由法国罗纳普朗克制药公司于1980年研发上市,属于5-硝基咪唑类药物,与甲硝唑、替硝唑化学结构相似,生理活性也相似,对多种革兰氏阳性厌氧菌和革兰氏阴性厌氧菌及原虫有很强的杀伤力,临床上主要用来治疗由上述致病微生物引起的感染。国内现有塞克硝唑的口服剂型主要缺点为口服用药剂量大,导致的毒副作用大,而且发病部位血药浓度低。塞克硝唑栓(Secnidazole Suppository)为塞克硝唑的栓剂,于患者阴道内放药,直接接触病原菌,可改善塞克硝唑口服剂型的缺点。
目前国内尚无对塞克硝做栓临床研究的报道,本试验采用随机、平行对照方法进行临床研究,评价塞克硝唑栓对细菌性阴道病患者的治疗作用、安全性和量效关系,为Ⅲ期临床试验研究设计和给药剂量方案的确定提供依据。
研究方法：
1、本研究入组细菌性阴道病患者144例,根据患者就诊顺序编号,采用随机数表法随机分为两组(塞可硝唑栓组和甲硝唑栓组),每组各72例,对每例患者进行三次随访。
2、用药前(访视1),填写患者一般资料,进行病史采集及妇科症状和妇科体征的评估。
3、发给患者研究药品,告知患者用药方法,并嘱患者在治疗结束后第3-7天(访视2)、月经结束后第3-7天(访视3)来院进行妇科检查及实验室检查。
4、研究开始后的的三次随访都需询问并记录入组患者不良事件的情况,如实填写不良事件记录表。若存在不良事件,则根据不良事件的严重程度进行相应的处理,并详细记录处理方式。
5、研究结束后,根据随访记录,比较两组患者临床疗效和病原学疗效,同时比较两组患者用药后实验室检查异常和不良事件的发生情况。
研究结果：
1、临床疗效评价比较：以全分析集(Full Analysis Set, FAS)为分析集的比较结果显示,在治疗结束后第3-7天及月经干净后第3-7天时,两组患者的有效率、痊愈率比较差异无统计学意义(P>0.05)。以符合方案集(Per Protocol Set, PPS)为分析集的比较中,两组的有效率、痊愈率比较差异无统计学意义(P>0.05)。
2、病原学疗效评价比较：两组病人治疗前后阴道分泌物涂片(包括清洁度、清洁度变化、pH值、pH值变化、胺试验、阴道排液及其他异常)比较、两组病人治疗前后细菌病原学(包括病原学、病原学变化、病原学总分及病原学总分变化)比较,差异均无统计学意义(P>0.05)。
3、妇科症状、体征比较：两组病人妇科症状、体征比较(FAS),除“外阴充血”指标外,其他比较均无显著的统计学差异(P>0.05)。“外阴充学”指标治疗全两组间相比差异没有统计学意义(P>0.05),具有可比性。治疗结束后第3-7天时,塞克硝唑栓组阳性率为0.00%,甲硝唑栓组阳性率为8.70%,两组间相比有明显的统计学差异(P=0.0133)。治疗结束后第3-7天时,塞克硝唑栓组外阴充血消失率为100.00%,甲硝唑栓消失率为62.50%,两组间相比差异存在统计学意义(P=0.0205)。
4、实验室检查指标比较：经研究者判断,本次临床研究实验室检查出现的异常数据均与试验用药无关。
5、不良事件比较：对进入FAS集的两组病人不良事件发生情况进行比较,塞克硝唑栓组不良事件发生率为14.29%,甲硝唑栓不良事件发生率为4.35%,两组不良事件发生率相比无明显的统计学差异(p>0.05)。
研究结论：
塞克硝唑栓和甲硝唑栓对于治疗细菌性阴道病均取得了显著的效果,两组临床疗效及临床安全性相比均无显著的统计学差异。
Background and Objective
Bacterial vaginosis (BV) is a clinical infectious disease characterized by polymicrobial anaerobic overgrowth of the vaginal epithelium without vaginal mucosal inflammation. Secnidazole is a5-nitroimidazole product with a broad spectrum of activity against gram-positive anaerobic bacterium, Gram-negative anaerobic bacteria and protozoan, which was researched and developed, and then marked by Rhone Poulenc Rorer in1980. Its chemical structure and physiological activity are similar to metronidazole and tinidazole. In clinic, it is applied to treat infections caused by above-mentioned pathogenic microorganisms. The disadvantages of secnidazole in peroral dosage form marked in our country are its too large dosage resulting in high toxic side effect and low blood concentration reached in pathogenic location. Secnidazole suppository is a new dosage form, and can be placed in vagina directly to contact pathogenic bacteria. As a result, the new dosage form can improve the disadvantages of secnidazole in peroral dosage form. By now, there have been no clinical reports on secnidazole suppository. It is necessary to conduct a research to evaluate clinical efficacy and safety and dose-effect relationship of secnidazole suppository on treatment of bacterial vaginosis, so as to provide a scientific basis for phase Ⅲ clinical trial.
Methods
1. This research intended to include144patients diagnosed as bacterial vaginosis. According to the order of visit, they were randomly divided into two groups (secnidazole suppository group and metronidazole suppository group). And each group had72cases. The included patients had to complete three follow-up.
2. Before treatment (visit1), it was necessary to fill in the general data, to collect anamnesis and to evaluate gynecological gynecological symptoms and signs of patients.
3. The patients were told to come back to do gynecological examination and laboratory examination separately when the3-7days after finishing treatment (visit2) and the first3-7days after the end of menstruation (visit3).
4. During the three follow-up, it was necessary to inquire and record adverse events (AE), and truthfully complete the adverse event record. If there were adverse events, we should make a corresponding treatment according to the severity of adverse events, and then, we should record the treatment in detail.
5. After completing the study, we compared their clinical and pathogenic efficacy, and observed the occurrence of adverse drug events and laboratory abnormalities.
Results
1. Comparison of clinical efficacy:In the3-7days after finishing treatment and the first3-7days after the end of menstruation, given in the full analysis set (FAS), the comparison result of effective rate and cure rate was that the two groups had no significant difference (P>0.05). And given in the per protocol set (PPS), the comparison result also showed no significant difference (P>0.05).
2. Comparison of pathogenic efficacy:Before and after treatment, there were no significant differences (P>0.05) when compared vaginal smears (including cleanliness, cleanliness change, pH, pH change, KOH whiff test, vaginal discharge and other abnormalities) and bacterial pathogens (including etiology, pathogenic changes, total score of etiology and total score change of etiology).
3. Comparison of gynecologic symptoms and physical signs:There were no significant differences (P>0.05) between two groups when comparing gynecological symptoms and signs except for vulva congestion. Before treatment, when compared vulva congestion, it was no significant difference (P=0.5371). which indicated that two groups could be compared. After3-7days when finishing treatment, the positive rate of secnidazole suppository group was0%, however, it was8.70%in metronidazole suppository group. When compared, it came up a significant difference between the two groups (P=0.0133). After3-7days when finishing treatment, the disappearance rate of vulva congestion was separately100.00%and62.50%in secnidazole suppository group and in metronidazole suppository group, there was a significant difference (P=0.0205).
4. Comparison of laboratory examination:It was not related to the study medication that the abnormal data appeared in laboratory examination after the judgement of the researchers.
5. Comparison of adverse events:In terms of the patients who were included into full analysis set, when compared the incidence rate of adverse events, two groups had no significant difference (P>0.05), coupled with that it was14.29%and4.35%separately in secnidazole suppository group and in metronidazole suppository group.
Conclusions
Secnidazole suppository and metronidazole suppository on treatment of bacterial vaginosis both have achieved significant clinical efficacy and safety, with no significant differences between the two groups.
引文
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