Efficacy and safety of a novel pain management device, AT-04, for endometriosis-related pain: study protocol for a phase III randomized controlled trial.

BACKGROUND: Endometriosis-related pain encompassing dysmenorrhea, dyspareunia, and chronic pelvic pain, reduces the quality of life in premenopausal women. Although treatment options for endometriosis alleviate this pain, approximately one-third of women still experience pain even after receiving treatment, indicating the need for novel approaches to pain relief in those women. The Angel Touch device (AT-04) is a portable magnetic fields irradiation device that incorporates a combination of mixed alternative magnetic fields at 2 kHz and 83.3 MHz. A phase III trial confirmed the efficacy and safety of AT-02, a prototype of AT-04, for pain relief in patients with fibromyalgia. METHODS: This is a phase III, multicenter, prospective, randomized, sham device-controlled, double-blind, parallel study. The participants will be premenopausal women aged > 18 years who have endometriosis-related pain with at least moderate severity. Considering dropouts, 50 participants have been deemed appropriate. Eligible women will be centrally registered, and the data center will randomly allocate them in a 1:1 ratio to the intervention and control groups. Women in the intervention group will receive electromagnetic wave irradiation generated by AT-04 and those who in the control group will wear a sham device for 16 weeks, and both groups will wear AT-04 for another 4 weeks. The primary outcome measure is the change in the Numeric Rating Scale score at 16 weeks compared with the baseline. Secondary outcome measures are efficacy for pelvic pain including dysmenorrhea and non-menstrual pain, and chronic pelvic pain not related to menstruation, dysmenorrhea, and dyspareunia, and improvement of quality of life during the study period. Safety will be evaluated by device defects and the frequency of adverse events. The study protocol has been approved by the Clinical Study Review Board of Chiba University Hospital, Chiba, Japan, and will be conducted in accordance with the principles of the Declaration of Helsinki and the Japanese Clinical Trials Act and relevant notifications. DISCUSSION: This study aims to develop a novel method of managing endometriosis-related pain. The AT-04 is an ultralow-invasive device that can be used without inhibiting ovulation, suggesting potential benefits to women of reproductive-age. Trial registration number Japan Registry of Clinical Trials (jRCTs032230278).

Endometriosis is a chronic inflammatory disorder that negatively impacts reproductive health via endometriosis-related pain, infertility, and endometriosis-associated ovarian cancer. Although current therapeutic options for endometriosis are effective for the endometriosis-related pain, approximately one-third of women still experience pain even after receiving treatment, indicating the need for novel approaches to pain relief in those women. This is the first randomized controlled trial to investigate the efficacy and safety of a novel portable pain management device, AT-04, that incorporates a combination of mixed alternating magnetic fields, for endometriosis-related pain. This is a multicenter, prospective, sham device-controlled, double-blind, parallel study. Enrolled women will have undergone standard hormonal treatment for endometriosis at baseline, and this allows for assessing whether the device remains effective when used in conjunction with existing treatment methods. The study also will explore the impact of AT-04 on reducing the size of ovarian endometriotic cysts that reflect the activity of endometriosis. The study reflects the strong desire by physicians to liberate women from the unbearable pain associated with endometriosis. The sole efficacy of AT-04 in treating endometriosis-related pain is difficult to evaluate as there is a possibility that menstrual cycles may influence the assessment of pain and quality of life. However, the study findings regarding the effectiveness of AT-04 for the treatment of endometriosis-related pain may benefit women with endometriosis who have pain that is not effectively relieved by other treatments. Consequently, it may contribute to the improvement of reproductive health within society.

Impact of nausea/vomiting on EQ-5D-5L utility scores in patients taking iron preparations for heavy menstrual bleeding or anemia.

BACKGROUND: The purpose of this study was to establish an estimating equation to predict the 5-level EQ-5D version (EQ-5D-5L) utility score in patients taking iron preparations for heavy menstrual bleeding (HMB) or anemia and to evaluate whether the presence of nausea or vomiting was a significant predictor of EQ-5D-5L-based quality of life. METHODS: A cross-sectional survey was conducted to collect EQ-5D-5L utility scores and other patient reported outcomes from 385 patients taking iron preparations for HMB or anemia who were selected from the disease patient panel. Using the utility scores as objective variables, explanatory variable candidates were selected considering correlations, multicollinearity, and clinical validity. Predicting models were constructed using regression-based models (linear model, generalized linear model (GLM), Tobit model). Stepwise regression method was applied for selecting statistically significant (p < 0.05) predictors. Goodness-of-fit of models were assessed by mean absolute error and mean squared error (MSE). RESULTS: The EQ-5D-5L utility scores (mean ± standard deviation) of 96 patients with nausea/vomiting and 289 patients without nausea/vomiting were 0.67 ± 0.16 and 0.84 ± 0.14, respectively (p < 0.001). The presence of nausea/vomiting was shown to be the most significant factor reducing the utility score in the statistical models using the explanatory variable candidates selected in the study. As the results of the goodness-of-fit test, GLM with the smallest MSE was selected to establish the estimating equation. CONCLUSION: The estimating equation to predict the EQ-5D-5L utility scores in patients taking iron preparations for HMB or anemia was established. The presence of nausea/vomiting was found to be a factor significantly reducing utility scores, with a decrement of the value estimated to be -0.117. TRIAL REGISTRATION: UMIN000045700 ( http://www.umin.ac.jp/ctr/ ). Registered on October 11, 2021.

Clinical feasibility of absorbable gelatin film adhesion barrier (GM142 "TENALEAF®") in gynecological laparoscopic surgery: Safety assessment for first-in-human use and surgical video.

AIM: To evaluate the safety and operability of the GM142 (TENALEAF®, Medical Division, Gunze Limited, Tokyo, Japan) adhesion barrier applied in patients undergoing surgery for benign gynecologic disease. METHODS: This multicenter open study enrolled 34 patients from November 2018 to October 2019. RESULTS: The primary outcome was the incidence of adverse events (AE) within 12 weeks postoperatively. None of the 30 patients completing the study experienced a life-threatening AE. Thirteen patients (43.3%) suffered 30 mild or moderate AE in total. No intestinal obstruction (0/30) was observed, with the sample size justified by the AdSpray® trial (8/61 patients with AE). No gelatin-specific Immunoglobulin E (IgE) antibodies were induced in the patients. The adhesion barrier could be easily inserted (even via trocar) and positioned. After malfunctions were reported in six patients, the instructions for use were updated for trocar use. CONCLUSION: This study showed the safety and clinical feasibility GM142 as an adhesion barrier.

Hysteroscopy-guided laparoscopic resection of a cesarean scar defect in 5 steps: the usefulness of nonperfusion hysteroscopy.

OBJECTIVE: To demonstrate a 5-step approach to accurately identify the extent of resection of a cesarean scar defect (CSD) and perform excision and repair of the lesion. DESIGN: Technical video introducing laparoscopic scar repair using nonperfusion hysteroscopy for patients with a CSD. SETTING: Tertiary referral facility for gynecology. PATIENT(S): A 33-year-old woman who underwent intrauterine insemination for secondary infertility 3 times but did not conceive complained of repeated irregular bleeding caused by a CSD during infertility treatment. INTERVENTION(S): This video presents a systematic 5-step approach to laparoscopic repair of a CSD. Step 1: the lesion was coagulated and marked using a hysteroscope. Step 2: the lesion was thinned by cutting it using the hysteroscope. Step 3: after laparoscopic dissection of the bladder from the lower uterine segment and turning off the laparoscope's light source, the thinned lesion could be identified using light from the hysteroscope. Step 4: an incision was made at the lit-up point from the abdominal cavity side using an ultrasonic coagulation incision device to access the uterus. Step 5: once the uterine lumen was reached, reflux from the hysteroscope was stopped. Intraperitoneal insufflation gas then flowed into the uterus through the uterine wall perforation, and the lesion could be observed without the use of a reflux fluid. This technique is called nonperfusion hysteroscopy. By observing the marked lesion using nonperfusion hysteroscopy, it could be resected laparoscopically along the appropriate incision line. MAIN OUTCOME MEASURE(S): Advantage of performing 5 successive surgical steps to completely resect a CSD using laparoscopic repair and resolve the patient's symptoms. RESULT(S): Laparoscopic repair using nonperfusion hysteroscopy allowed recognition of the upper and lower edges of the lesion from the abdominal cavity side. CONCLUSION(S): The combined use of nonperfusion hysteroscopy allows observation of the uterine lumen without the use of a reflux fluid because pneumoperitoneum gas fills the uterine lumen. Intraoperative monitoring using a hysteroscope and laparoscope allows visualization of the lesion site from both sides while resection is being performed. This 5-step procedure permits precise identification of the lesion area, complete removal of lesions, and prevention of excessive resection that may reduce uterine function and increase perinatal risk.

Real-world outcomes of the levonorgestrel-releasing intrauterine system for heavy menstrual bleeding or dysmenorrhea in Japanese patients: A prospective observational study (J-MIRAI).

OBJECTIVES: We collected real-world data on the safety and clinical outcomes of the levonorgestrel-releasing intrauterine system (LNG-IUS) for heavy menstrual bleeding and dysmenorrhea. STUDY DESIGN: This was a prospective, multicenter, single-cohort, open-label, post-authorization 12-month follow-up study of Japanese patients initiating the LNG-IUS for heavy menstrual bleeding and/or dysmenorrhea. The primary endpoint was the safety profile based on adverse events and adverse drug reactions (ADRs), including expulsions and abnormal bleeding, within 12 months of LNG-IUS insertion. Secondary endpoints included changes from baseline in menstrual blood loss based on bleeding days and dysmenorrhea graded on a visual analog scale (VAS). RESULTS: Of the 595 patients included, many had underlying conditions such as adenomyosis (39.5%), uterine leiomyoma (30.8%), or endometriosis (12.9%). The incidences of ADRs and serious ADRs were 59.7% and 0.3%, respectively. Frequently reported ADRs were metrorrhagia (48.9%), procedural pain (14.1%), and ovarian cyst (6.2%). The cumulative incidence of expulsions at 12 months was 8.7%. Risk factors for expulsion were obesity (body mass index ≥25 kg/m2), adenomyosis, and uterine cavity length ≥8 cm. The median [interquartile range] VAS score for dysmenorrhea improved from 46.5 [13.0-68.0] at insertion to 1.0 [0.0-13.0] at 12 months, and improvements were also observed in chronic pelvic pain and painful defecation. CONCLUSIONS: The LNG-IUS safely and effectively reduced dysmenorrhea, chronic pelvic pain, and painful defecation. Risk factors for expulsion suggest that patients with underlying organic disease should be monitored carefully when using the LNG-IUS. IMPLICATIONS: The LNG-IUS is an effective treatment for secondary dysmenorrhea with organic disease, and for the reduction of chronic pelvic pain; however, physicians should be aware of the increased risk of expulsion in patients with organic conditions.

Quality of Life of Japanese Dysmenorrhea/Heavy Menstrual Bleeding Patients Treated with Levonorgestrel Intrauterine Delivery System in a Real-World Setting.

INTRODUCTION: The present study collected 1-year follow-up patient-reported outcome data from Japanese women with dysmenorrhea and/or heavy menstrual bleeding (HMB) who underwent insertion of the levonorgestrel-releasing intrauterine system (LNG-IUS) 52 mg. We aimed to evaluate the quality of life (QOL) of Japanese women over the course of the investigational period. METHODS: This was a multicenter, non-interventional, prospective, single-cohort, post-marketing surveillance study (J-MIRAI). The primary outcome was the median change in the Menstrual Distress Questionnaire (MDQ) and Menorrhagia Multi-Attribute Scale (MMAS) scores from baseline to 3 and 12 months after LNG-IUS insertion, with decreasing and increasing scores, respectively, indicating improvement. The secondary outcomes were the statistical relationships between the MDQ and menstrual pain (measured by a visual analog scale, VAS), and between the MMAS and pictorial blood loss assessment chart (PBAC) scores by regression analysis. RESULTS: In total, 593 patients were evaluated; 376, 467, and 250 patients were diagnosed with dysmenorrhea, HMB, or both, respectively. The median MDQ score decreased significantly at 3 and 12 months after LNG-IUS insertion in both the premenstrual and menstrual periods (both p < 0.001 vs baseline), and the median MMAS score showed a similar improvement during the menstrual period. Changes in median MDQ and MMAS scores were observed regardless of patient background. Correlations between MDQ and menstrual pain (VAS) and between MMAS and PBAC scores were found (estimated regression coefficients 0.29 and - 0.15, respectively). CONCLUSION: The LNG-IUS contributed to improvements in the QOL of patients with dysmenorrhea, HMB, and both, regardless of patient background characteristics. TRIAL REGISTRATION: Registered at ClinicalTrials.gov (NCT02475356) on 18 June 2015.

Bleeding patterns of women with heavy menstrual bleeding or dysmenorrhoea using the levonorgestrel-releasing intrauterine system: results from a real-world observational study in Japan (J-MIRAI).

PURPOSE: To collect real-world safety and clinical outcome data on the levonorgestrel-releasing intrauterine system (LNG-IUS) for functional/organic heavy menstrual bleeding (HMB) and dysmenorrhoea in Japanese women (J-MIRAI). MATERIALS AND METHODS: In this prospective, multicentre, single-cohort, open-label, post-authorisation study, we assessed menstrual blood loss after LNG-IUS insertion by changes from baseline in pictorial blood loss assessment chart (PBAC) scores. Scores for the menorrhagia multi-attribute scale (MMAS) were collected for 12 months to assess quality of life. RESULTS: We included 47 patients with complete PBAC score and patient diary data. The median PBAC score before LNG-IUS insertion was 159.0, which decreased significantly to 6.0 at 12 months post-insertion; for patients with adenomyosis (n = 20), PBAC score decreased from 174.5 pre-insertion to 19.5 at 12 months. The number of patient-reported bleeding days was correlated with PBAC score ≥5. The proportion of women with prolonged bleeding decreased from 85.7% to 34.6% by the study's end. Some women reported no bleeding after the first 90-day reference period. The mean MMAS overall score significantly increased from 50.50 before insertion to 88.67 at 12 months. CONCLUSIONS: Japanese women with functional/organic HMB experienced substantial reductions in bleeding symptoms and improvements in quality of life after 12-month use of the LNG-IUS.

A case of two ovarian tissue transplantations that led to a biochemical pregnancy in Japan.

Ovarian tissue cryopreservation (OTC) and ovarian tissue transplantation (OTT) are fertility preservation options for prepubertal girls or those in whom cancer treatment cannot be delayed. They are important to increasing number of cancer survivors, but there are very few reports on this topic in Japan. This is the first report of a biochemical pregnancy after OTT in Japan. An 18-year-old woman, diagnosed with Ewing sarcoma of the seventh thoracic vertebra, underwent tumor resection. OTC was performed before postoperative chemotherapy. After 7 years, she decided to undergo OTT following the diagnosis of chemotherapy-induced premature ovarian insufficiency. On postoperative day 104, ovarian stimulation was started, yielding one embryo after 3 days. Embryo transfer was performed during a hormone replacement cycle. At 6 weeks and 1 day, the human chorionic gonadotropin level was 81.5 mIU/mL; however, no gestational sac was observed on ultrasonography, indicating a biochemical pregnancy. Our data will be useful for the further development of fertility preservation options in Japan in the future.

Influence of a patient education and care program on women undergoing non-assisted reproductive technology fertility treatment.

PURPOSE: To determine the influence of a patient education and care program on the quality of life (QOL) of female patients undergoing non-assisted reproductive technology (ART) fertility treatment. METHODS: Participants completed the MOS 36-Item Short-Form Health Survey and fertility QOL (FertiQoL) questionnaires at baseline and at 3, 6, and 12 months of treatment. The responses of patients who underwent three sessions of the program (at baseline, 3 months, and 6 months of treatment) were compared with those of patients who did not receive the program. RESULTS: This study compared 69 patients who received an additional care program with 104 patients in the control group, all from 13 facilities. Treatment FertiQoL responses (p = 0.004) and treatment tolerability (p = 0.043) differed between the program and control groups at 3 months using the repeated measures mixed model. The cost of treatment per pregnancy was lower in the program group than in the control group. CONCLUSION: The patient education and care program provided by reproductive fertility specialists or fertility nurses during non-ART fertility programs improves patient satisfaction.

An assessment of the efficacy and safety of dydrogesterone in women with ovarian endometrioma: An open-label multicenter clinical study.

PURPOSE: To assess the efficacy and safety of dydrogesterone in Japanese women with ovarian endometrioma in a real-world setting. METHODS: The post-marketing study involved 15 sites in Japan. Dydrogesterone 10 mg twice daily orally was administered for 21 days (day 5-25 of each menstrual cycle) for 4 cycles. The primary outcome measure was the change in ovarian endometrioma volume from baseline. Secondary outcome measures included total dysmenorrhea score (0 = absent to 3 = severe), severity of dysmenorrhea pain [0-10cm visual analog scale (VAS)], serum carbohydrate antigen 125 (CA-125) levels, and safety. RESULTS: The study group comprised women with an endometrioma aged 20 to 49 (47.4% cases aged ≥40 years). Endometrioma volume was reduced in 50% (26/52), unchanged in 25% (13/52), and increased in 25% (13/52) of women from baseline to the end of cycle 5; three-quarters of patients thus had either reduced or unchanged ovarian endometrioma volume. Dydrogesterone significantly reduced total dysmenorrhea scores and severity of dysmenorrhea pain VAS during treatment compared with baseline. CA-125 levels were not significantly changed during the study. The incidence of adverse events and adverse drug reactions in 59 subjects was 13.6% and 11.9%. CONCLUSIONS: Dydrogesterone prevented an increase in endometrioma size in many women, and it also significantly improved total dysmenorrhea scores and severity of dysmenorrhea pain, and was well tolerated. The ClinicalTrials.gov identifier of the study was NCT02921763.

Efficacy of cyclic and extended regimens of ethinylestradiol 0.02 mg -levonorgestrel 0.09 mg for dysmenorrhea: A placebo-controlled, double-blind, randomized trial.

PURPOSE: We aimed to evaluate the efficacy and safety of 28-day Cyclic and 84-day Extended regimens of NPC-16 (ethinylestradiol 0.02 mg plus levonorgestrel 0.09 mg) in patients with dysmenorrhea. METHODS: This was a placebo-controlled, double-blind, randomized trial conducted in Japan. A total of 251 primary and secondary dysmenorrhea patients were randomly assigned to the NPC-16-Cyclic group, NPC-16-Extended group, or the Placebo group. The primary end point was a comparison of the efficacy and safety of the Cyclic and Extended NPC-16 regimen for the treatment of dysmenorrhea relative to the Placebo. MAIN FINDINGS: Significantly greater reductions in total dysmenorrhea score and visual analog scale score were observed in the Cyclic and Extended groups compared with the Placebo group. Compared with the Cyclic regimen as a secondary end point, the Extended regimen exhibited greater efficacy in the treatment of dysmenorrhea over the course of the study period, particularly in patients with severe dysmenorrhea. The incidence of adverse drug reactions (ADRs) was significantly higher in the Cyclic and Extended groups than in the Placebo group. CONCLUSION: The Cyclic and Extended regimens of NPC-16 significantly reduced dysmenorrhea severity compared to placebo. The Extended regimen was superior to cyclic regimen in reducing the dysmenorrhea.

Quality of Life in Japanese Patients with Dysmenorrhea Treated with Ethinylestradiol 20 µg/Drospirenone 3 mg in a Real-World Setting: An Observational Study.

BACKGROUND: Dysmenorrhea affects approximately 80% of women in Japan and has a negative impact on health-related quality of life (HRQoL). Low-dose estrogen/progestin combined oral contraceptives have been shown to reduce the severity of dysmenorrhea symptoms. This study characterized HRQoL in Japanese women with dysmenorrhea before and after ethinylestradiol/drospirenone (EE/DRSP) treatment. METHODS: This prospective, observational study recruited 531 patients, of which 186 were evaluated after treatment with EE 20 µg/DRSP 3 mg for dysmenorrhea in a 24/4 cyclic regimen. The primary endpoints were mean baseline and post-treatment 36-Item Short-Form Health Survey version 2.0 (SF-36v2) scores for study patients compared with the general female population of Japan (calculated using norm-based scoring), and mean changes in study patient SF-36v2 scores between baseline and 6 to 8 treatment cycles. RESULTS: Compared with Japanese norms, women with dysmenorrhea had lower pre-treatment SF-36v2 scores, except for the physical functioning domain. After 6-8 cycles of EE/DRSP treatment, all 8 SF-36v2 domain scores were significantly higher than baseline. The greatest improvements were observed in bodily pain and social functioning (mean change [standard deviation (SD)]: physical functioning: 1.4 [5.7], role physical: 3.2 [8.1], bodily pain: 7.8 [10.0], general health: 3.0 [7.0], vitality: 2.7 [8.1], social functioning: 3.5 [9.8], role emotional: 3.3 [9.2], and mental health: 3.0 [7.3]; p< 0.001 for all). Compared with the Japanese general population, study patients' post-treatment scores were significantly higher for the general health domain (p= 0.008) and physical summary scores (p= 0.033). CONCLUSION: Dysmenorrhea has a profound impact on all aspects of functioning and well-being. This study, conducted in a real-world setting, found that physical, social, and mental HRQoL improved significantly after a cyclic regimen of EE/DRSP in Japanese patients with dysmenorrhea. This regimen may have the potential to provide an effective option to improve patient HRQoL. TRIAL REGISTRATION: Study sample was drawn from patients enrolled in a post-marketing surveillance study, registered June 20, 2011 (NCT01375998).

Burden of Menstrual Pain Measured by Heatmap Visualization of Daily Patient-Reported Data in Japanese Patients Treated with Ethinylestradiol/Drospirenone: A Randomized Controlled Study.

PURPOSE: Dysmenorrhea negatively affects women's quality of life and poses a considerable economic burden. A recent study in Japanese patients with dysmenorrhea (NCT01892904) reported a significant reduction in the number of days with menstrual pain after treatment with a flexible extended regimen of ethinylestradiol (EE)/drospirenone (DRSP) compared with a cyclic regimen. However, individual patients' menstrual pain patterns and intensities were not indicated. Heatmapping was used to visualize menstrual pain patterns and intensities by re-evaluating the previously published data from NCT01892904. PATIENTS AND METHODS: NCT01892904 was a Phase III, multicenter, randomized, open-label, active-control study of 212 women aged ≥20 years randomized 1:1 to receive flexible extended or 28-day cyclic EE/DRSP treatment. Daily pain levels were recorded in patient diaries, and menstrual pain patterns and intensities were visualized using heatmapping. Patients were stratified by baseline dysmenorrhea scores and primary or secondary dysmenorrhea. RESULTS: The heatmap data demonstrated that EE/DRSP reduced the degree of menstrual pain. Regular peaks of menstrual pain were alleviated in the extended regimen group but were still observed in the cyclic regimen group. While a decrease in the days with menstrual pain was observed in patients with higher baseline dysmenorrhea scores (5-6), those with lower baseline scores (3-4) were more likely to experience lower intensities of menstrual pain. Although pain relief was less likely in patients with secondary dysmenorrhea, those who had lower baseline dysmenorrhea scores (3-4) and received the flexible extended regimen experienced a greater reduction in the number of days with menstrual pain than those who received the cyclic regimen. CONCLUSION: Heatmapping effectively visualized the daily burden of menstrual pain in Japanese patients with dysmenorrhea. The analysis using heatmaps suggested that the flexible extended EE/DRSP treatment regimen was more likely to alleviate the regular occurrence of menstrual pain peaks compared with the cyclic regimen.

Comparison of efficacy and safety between intravenous ferric carboxymaltose and saccharated ferric oxide in Japanese patients with iron-deficiency anemia due to hypermenorrhea: a multi-center, randomized, open-label noninferiority study.

The intravenous formulation for supplementing iron currently available in Japan requires frequent administration. In contrast, ferric carboxymaltose (FCM) can improve iron-deficiency anemia (IDA) with only a small number of administrations; however, its efficacy and safety have not been established in Japanese patients. In this randomized, open-label study, we verified the noninferiority of FCM to saccharated ferric oxide (SFO) in Japanese patients with IDA due to hypermenorrhea, with the mean change from baseline to the highest observed hemoglobin level as the primary endpoint. Two hundred and thirty-eight eligible subjects (119 in FCM group, 119 in SFO group) were administered the investigational medicinal product and included in the analysis. The adjusted mean change from baseline to the highest observed hemoglobin level (95% CI) was 3.90 g/dL (3.77, 4.04) in the FCM group and 4.05 g/dL (3.92, 4.19) in the SFO group, and the difference between the groups (95% CI) was - 0.15 g/dL (- 0.35, 0.04). The noninferiority of FCM was verified. Incidence of adverse events was < 60% in both groups, and no significant difference was observed between the treatment groups. These results indicate that FCM can be a new, well-tolerated, and rapid treatment option for Japanese patients with IDA.

Cost-effectiveness of the recommended medical intervention for the treatment of dysmenorrhea and endometriosis in Japan.

BACKGROUND AND OBJECTIVE: This study aims to assess the cost-effectiveness of early physician consultation and guideline-based intervention to prevent endometriosis and/or disease progression using oral contraceptive (OC) and progestin compared to follow-up of self-care for dysmenorrhea in Japan. METHODS: A yearly-transmitted Markov model of five major health states with four sub-medical states was constructed. Transition probabilities among health and medical states were derived from Japanese epidemiological patient surveys and converted to appropriate parameters for inputting into the model. The dysmenorrhea and endometriosis-associated direct costs included inpatient, outpatient visit, surgery, and medication (OC agents, over-the-counter drugs), etc. The utility measure for patients with phase I-IV endometriosis comprised a visual analogue scale. We estimated the cost per quality-adjusted life year (QALY) at a time horizon of 23 years. An annual discount rate at 3% for both cost and outcome was considered. RESULTS: The base case outcomes indicated that the intervention would be more cost-effective than self-care, as the incremental cost-effectiveness ratio (ICER) yielded 115,000 JPY per QALY gained from the healthcare payers' perspective and the societal monetary value (SMV) was approximately positive 3,130,000 JPY, favoring the intervention in the cost-benefit estimate. A tornado diagram depicting the stochastic sensitivity analysis of the ICER and SMV from both the healthcare payers' and societal perspectives confirmed the robustness of the base case. A probabilistic analysis resulting from 10,000-time Monte Carlo simulations demonstrated efficiency at willingness-to-pay thresholds in more than 90% of the iterations. CONCLUSIONS: The present analysis demonstrated that early physician consultation and guideline-based intervention would be more cost-effective than self-care in preventing endometriosis and/or disease progression for patients with dysmenorrhea in Japan.

Ethinylestradiol 20 µg/drospirenone 3 mg in a flexible extended regimen for the management of endometriosis-associated pelvic pain: a randomized controlled trial.

OBJECTIVE: To investigate the efficacy and safety of ethinylestradiol 20 µg/drospirenone 3 mg in a flexible extended regimen (FlexibleMIB) compared with placebo to treat endometriosis-associated pelvic pain (EAPP). DESIGN: A phase 3, randomized, double-blind, placebo-controlled, parallel-group study, consisting of a 24-week double-blind treatment phase followed by a 28-week open-label extension phase with an unblinded reference arm. SETTING: Thirty-two centers. PATIENT(S): A total of 312 patients with endometriosis. INTERVENTION(S): Patients were randomized to FlexibleMIB, placebo, or dienogest. The FlexibleMIB and placebo arms received 1 tablet per day continuously for 120 days, with a 4-day tablet-free interval either after 120 days or after ≥3 consecutive days of spotting and/or bleeding on days 25-120. After 24 weeks, placebo recipients were changed to FlexibleMIB. Patients randomized to dienogest received 2 mg/d for 52 weeks in an unblinded reference arm. MAIN OUTCOME MEASURE(S): Absolute change in the most severe EAPP based on visual analog scale scores from the baseline observation phase to the end of the double-blind treatment phase. RESULT(S): Compared with placebo, FlexibleMIB significantly reduced the most severe EAPP (mean difference in visual analog scale score: -26.3 mm). FlexibleMIB also improved other endometriosis-associated pain and gynecologic findings and reduced the size of endometriomas. CONCLUSION(S): FlexibleMIB improved EAPP and was well tolerated, suggesting it may be a new alternative for managing endometriosis. CLINICAL TRIALS REGISTRATION NUMBER: NCT01697111.

Efficacy and safety of a flexible extended regimen of ethinylestradiol/drospirenone for the treatment of dysmenorrhea: a multicenter, randomized, open-label, active-controlled study.

BACKGROUND: Dysmenorrhea is a common condition in women, which is characterized by menstrual pain. Low-dose estrogen/progestin combined oral contraceptives have been shown to reduce the severity of dysmenorrhea symptoms, and a 28-day cyclic regimen of ethinylestradiol/drospirenone (28d regimen) is approved for this indication in Japan. AIM: The aim of this study was to assess the safety and efficacy of a flexible extended regimen of ethinylestradiol/drospirenone (flexible regimen) in Japanese women with dysmenorrhea. METHODS: This multicenter, open-label study was performed in Japanese women with dysmenorrhea who, after a baseline observational phase, were randomized to receive ethinylestradiol 20 µg/drospirenone 3 mg in a flexible regimen (one tablet each day for 24-120 days followed by a 4-day tablet-free interval) or in the standard 28d regimen (one tablet each day for 24 days, followed by 4 days of placebo tablets for six cycles). The primary endpoint was the number of days with dysmenorrhea of at least mild intensity over a 140-day evaluation period. Dysmenorrhea scores, bleeding patterns, and other pain-related parameters were also assessed. RESULTS: A total of 216 women (mean age 29.7 years) were randomized to the flexible regimen (n=108) or 28d regimen (n=108) and 212 were included in the full analysis sets (flexible regimen, n=105; 28d regimen, n=107). Women in the flexible-regimen group reported a mean of 3.4 fewer days with dysmenorrheic pain than women in the 28d-regimen group, with similar decreases in disease severity reported in both treatment groups. According to the investigators, 64.8% and 59.4% of women in the flexible-regimen and 28d-regimen treatment groups had "very much improved" or "much improved" disease, while 54.3% and 50.9% of patients reported being "very much satisfied" or "much satisfied" with their treatment, respectively. CONCLUSION: In Japanese women with dysmenorrhea, a flexible extended regimen of ethinylestradiol/drospirenone decreased the number of days with dysmenorrheic pain versus the traditional 28d regimen.

Evaluation of an ultra-low-dose oral contraceptive for dysmenorrhea: a placebo-controlled, double-blind, randomized trial.

OBJECTIVE: To evaluate the efficacy and safety of an ultra-low-dose oral contraceptive (NPC-01; 0.02 mg ethinyl estradiol and 1 mg norethisterone) in subjects with dysmenorrhea. DESIGN: Placebo-controlled, double-blind, randomized trial. SETTING: Clinical trial sites. PATIENT(S): Two hundred fifteen subjects with dysmenorrhea. INTERVENTION(S): Subjects were randomly assigned to receive NPC-01, placebo, or IKH-01 (0.035 mg ethinyl estradiol and 1 mg norethisterone) for four cycles. MAIN OUTCOME MEASURE(S): Total dysmenorrhea score (verbal rating scale) assessing pain on the basis of limited ability to work and need for analgesics. RESULT(S): The reductions of total dysmenorrhea score and visual analog scale score after the treatment were significantly higher in the NPC-01 group than in the placebo group. Furthermore, the efficacy of NPC-01 was comparable to that of IKH-01. The overall incidence of side effects was significantly higher in the NPC-01 group than in the placebo group. All side effects that occurred in the NPC-01 group were previously reported in patients receiving IKH-01. No serious side effects occurred. CONCLUSION(S): The ultra-low-dose contraceptive NPC-01 relieved dysmenorrhea as effectively as IKH-01. Thus, NPC-01 could represent a new option for long-term treatment of dysmenorrhea. CLINICAL TRIAL IDENTIFICATION NUMBER: NCT01129102.