A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Nalbuphine ER Tablets for Uremic Pruritus.

BACKGROUND: Pruritus is a distressing hallmark of the uremic condition, affecting approximately 60% of hemodialysis patients. Abnormal endogenous opioid ligand activity at µ and κ-opioid receptors has been postulated as a mechanism in uremic pruritus. Nalbuphine is a µ-opioid antagonist and κ-opioid agonist. METHODS: In this multicenter, randomized, double-blind, placebo-controlled trial, 373 hemodialysis patients with moderate or severe uremic pruritus were randomized in a 1: 1:1 ratio to nalbuphine extended-release tablets 120 mg (NAL 120), 60 mg (NAL 60), or placebo and treated for 8 weeks. Three hundred seventy-one were analyzed for efficacy. The primary endpoint was the change from baseline to treatment weeks 7 and 8 in itching intensity on a Numerical Rating Scale (NRS, 0 [no itching]; 10 [worst possible itching]) using an intent-to-treat approach. The aim was to evaluate the safety and antipruritic efficacy of NAL. RESULTS: The mean duration of itching was 3.2 years. From a baseline NRS of 6.9 (1.5), the mean NRS declined by 3.5 (2.4) and by 2.8 (2.2) in NAL 120 mg and the placebo groups, respectively (p = 0.017). There was no evidence of tolerance. A trend for less sleep disruption due to itching (p = 0.062, NAL 120 vs. placebo) was also observed. There were no significant differences between NAL 60 vs. placebo. Serious adverse events occurred in 6.7, 12.7, and 15.4% in the NAL 120, NAL 60, and placebo groups respectively. CONCLUSIONS: In this largest-to-date randomized controlled trial in uremic pruritus, NAL 120 durably and significantly reduced the itching intensity among hemodialysis patients.

Pharmacokinetics of nalbuphine hydrochloride extended release tablets in hemodialysis patients with exploratory effect on pruritus.

BACKGROUND: Uremic pruritus is a common and deleterious condition among hemodialysis (HD) patients. Central gating of µ/κ opiate circuitry plays an important role in mediating and countering pruritogenic sensation. The objective of this study was to assess the safety and pharmacokinetics (PK) of the mixed µ-antagonist/κ-agonist nalbuphine, administered orally as nalbuphine HCl extended release (ER) tablets in HD patients, and explore its effect on pruritus. METHODS: In this open-label multiple escalating dose study, 15 HD patients with pruritus and 9 matched healthy subjects were enrolled. Nalbuphine HCl ER dose was escalated from 30 mg QD to 240 mg BID over 15 days. A full PK profile was obtained under dialysis and non-dialysis conditions as a function of dose. Clearance during dialysis was determined by sampling dialysate and arterial/venous blood during dialysis. Pruritus severity was assessed twice daily using a Visual Analog Scale (VAS). Safety monitoring included extensive monitoring of EKG, blood pressure, and pulse oximetry. RESULTS: In HD patients, nalbuphine concentration peaked within 4-9 hours and attained steady state within 2-3 days, with no significant accumulation. Mean half-life was 14.2 hours, mean Cmax and AUCtau ranged between 13 and 83 ng/mL and 118 and 761 ng∙h/mL, respectively, with exposure increasing in a nearly dose-proportional fashion. Exposure in HD patients was about 2-fold higher than in healthy subjects. There was no meaningful difference between exposure on dialysis and non-dialysis days with 1% or less of the dose removed by dialysis. Nalbuphine suppressed itch in a dose-dependent manner, reducing mean VAS score from 4.0 to 1.2 at 180 mg and 0.4 at 240 mg. CONCLUSIONS: Nalbuphine HCl ER tablets can be safely administered to HD patients without dose adjustment up to 240 mg BID and may hold promise in treating uremic pruritus.

Progesterone replacement with vaginal gel versus i.m. injection: cycle and pregnancy outcomes in IVF patients receiving vitrified blastocysts.

STUDY QUESTION: Does the type of luteal support affect pregnancy outcomes in recipients of vitrified blastocysts? SUMMARY ANSWER: Luteal support with vaginal progesterone gel or i.m. progesterone (IMP) results in comparable implantation and pregnancy rates in IVF patients receiving vitrified blastocysts. WHAT IS KNOWN ALREADY: In fresh IVF cycles, both IMP and vaginal progesterone have become the standard of care for luteal phase support. Due to conflicting data in replacement cycles, IMP is often considered to be the standard of care. STUDY DESIGN, SIZE, DURATION: Retrospective analysis of 920 frozen embryo transfer (FET) cycles between 1 January 2010 and 1 September 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients from a large, private practice undergoing autologous and donor FET using IMP or vaginal progesterone gel for luteal support were included in the analysis. IMP was used for luteal support in 682 FET cycles and vaginal progesterone gel was used in 238 FET cycles. Standard clinical outcomes of positive serum hCG levels, implantation, clinical pregnancy, spontaneous abortion and live birth were reported. MAIN RESULTS AND THE ROLE OF CHANCE: The IMP and vaginal progesterone gel groups had similar patient demographics for all characteristics assessed. Implantation rates (46.4 versus 45.6%, P = 0.81), clinical pregnancy rates (61.7 versus 60.5%, P = 0.80) and live birth rates (49.1 versus 48.9%, P > 0.99) were not significantly different between IMP and vaginal progesterone gel, respectively. LIMITATIONS, REASONS FOR CAUTION: This study is limited by its retrospective design and by its lack of randomization to the type of luteal support. In addition, because no a priori expected rates of success could be provided for this retrospective investigation, it was not possible to estimate statistical power associated with the various outcomes presented. WIDER IMPLICATIONS OF THE FINDINGS: With the recent trends toward single embryo transfer (SET) and use of vitrified blastocysts in FET cycles, our data with ∼40% of cycles being SET and use of exclusively vitrified blastocysts are more relevant to current practices than previous studies. STUDY FUNDING/COMPETING INTERESTS: Support for data collection and analysis was provided by Actavis, Inc. D.S. has received honoraria for lectures and participation in Scientific Advisory Boards for Actavis, Inc. J.P. is an employee of Actavis, Inc. N.E. has received payment from Actavis, Inc., for her time for data collection. H.H. has received payment from Actavis, Inc., for statistical analyses. Z.P.N. has nothing to disclose.

A phase 3, randomized, double-blind, placebo-controlled study of the safety and efficacy of the live, oral adenovirus type 4 and type 7 vaccine, in U.S. military recruits.

Adenovirus (ADV) types 4 (ADV-4) and 7 (ADV-7) are presently the major cause of febrile acute respiratory disease (ARD) in U.S. military recruits. We conducted a multi-center, randomized, double-blind, placebo-controlled phase 3 study of the new vaccine to assess its safety and efficacy. Healthy adults at two basic training sites were randomly assigned to receive either vaccine (two enteric-coated tablets consisting of no less than 4.5 log10 TCID50 of live ADV-4 or ADV-7) or placebo in a 3:1 ratio. Volunteers were observed throughout the approximate eight weeks of their basic training and also returned for four scheduled visits. The primary endpoints were prevention of febrile ARD due to ADV-4 and seroconversion of neutralizing serum antibodies to ADV-7, which was not expected to circulate in the study population during the course of the trial. A total of 4151 volunteers were enrolled and 4040 (97%) were randomized and included in the primary analysis (110 were removed prior to randomization and one was removed after randomization due to inability to swallow tablets). A total of 49 ADV-4 febrile ARD cases were identified with 48 in the placebo group and 1 in the vaccine group (attack rates of 4.76% and 0.03%, respectively). Vaccine efficacy was 99.3% (95% CI, 96.0-99.9; P<0.001). Seroconversion rates for vaccine recipients for ADV-4 and ADV-7 were 94.5% (95% CI, 93.4-95.5%) and 93.8% (95% CI: 93.4-95.2%), respectively. The vaccine was well tolerated as compared to placebo. We conclude that the new live, oral ADV-4 and ADV-7 vaccine is safe and effective for use in groups represented by the study population.

A randomized, evaluator-blind, phase 2 study comparing the safety and efficacy of omadacycline to those of linezolid for treatment of complicated skin and skin structure infections.

A randomized, investigator-blind, multicenter phase 2 trial involving patients with complicated skin and skin structure infections (cSSSI) compared the safety and efficacy of omadacycline, a broad-spectrum agent with activity against methicillin-resistant Staphylococcus aureus (MRSA), to those of linezolid (with or without aztreonam). Patients were randomized 1:1 to omadacycline (100 mg intravenously [i.v.] once a day [QD] with an option to transition to 200 mg orally QD) or linezolid (600 mg i.v. twice daily [BID] with an option to transition to 600 mg orally BID) at 11 U.S. sites. Patients suspected or documented to have infections caused by Gram-negative bacteria were given aztreonam (2 g i.v. every 12 h [q12h]) if randomized to linezolid or matching placebo infusions if randomized to omadacycline. Adverse events were reported in 46 (41.4%) omadacycline-treated and 55 (50.9%) linezolid-treated patients. Adverse events related to treatment were assessed by investigators in 24 (21.6%) omadacycline-treated and 33 (30.6%) linezolid-treated patients. The gastrointestinal tract was most commonly involved, with adverse events reported in 21 (18.9%) patients exposed to omadacycline and 20 (18.5%) exposed to linezolid. Rates of successful clinical response in the intent-to-treat (ITT) and clinical evaluable (CE) populations favored omadacycline (ITT, 88.3% versus 75.9%; 95% confidence interval [CI], 1.9 to 22.9; CE, 98.0% versus 93.2%; 95% CI, -1.7 to 11.3). For microbiologically evaluable (ME) patients with S. aureus infections, the clinical success rates were 97.2% (70/72) in omadacycline-treated and 92.7% (51/55) in linezolid-treated patients. This phase 2 experience supports conclusions that omadacycline is well tolerated in cSSSI patients and that this aminomethylcycline has potential to be an effective treatment for serious skin infections.

Body weight does not impact pregnancy rates during use of a low-dose extended-regimen 91-day oral contraceptive.

BACKGROUND: This study evaluated the impact of weight on efficacy during use of an extended oral contraceptive (OC). STUDY DESIGN: Data were from a Phase 3 clinical trial evaluating the efficacy of a low-dose 91-day extended regimen of 100 mcg levonorgestrel/20 mcg ethinyl estradiol (LNG/EE; 84 days)+10 mcg EE (7 days) for the prevention of pregnancy. Crude pregnancy rates were calculated for weight and body mass index (BMI) deciles. RESULTS: Of the 1736 women in this analysis, 878 (50.6%) had a BMI greater than 25 kg/m2, and 770 (44.4%) were heavier than 70 kg. Pregnancies occurred in 36 women. Crude pregnancy rates were similar across weight and BMI deciles, with no discernable differences observed between deciles using either classification criterion. CONCLUSIONS: No evidence of any reduction in the level of contraceptive efficacy was observed with this low-dose extended OC regimen in overweight and obese women.

Synthetic conjugated estrogens-B and postmenopausal nocturnal vasomotor symptoms: a randomized controlled trial.

OBJECTIVE: To evaluate two doses of oral synthetic conjugated estrogens-B tablets compared with placebo on the frequency of awakenings resulting from nocturnal vasomotor symptoms in postmenopausal women over a 12-week treatment period. METHODS: A double-blind, randomized, placebo-controlled multicenter study enrolled a total of 157 women who were experiencing daytime vasomotor symptoms and a minimum of at least three nocturnal awakenings per night as a result of hot flushes. Participants were evenly randomized to one of three treatment groups (0.3 mg, 0.625 mg, or matching placebo) and treated for up to 12 weeks. Subjective sleep quality also was assessed. RESULTS: Significantly greater reductions from baseline in the weekly mean frequency of awakenings resulting from hot flushes occurred for participants randomized to either synthetic conjugated estrogens-B dose relative to placebo (mean reductions, 3.55, P=.004, and 4.65, P<.001 for 0.3 mg and 0.625 mg, respectively). In addition, a significantly greater proportion of participants at either estrogen dose had complete elimination of nocturnal awakenings (36.5% for 0.3 mg, 34% for 0.625 mg compared with 9.8% for placebo; P ≤.002) with a general finding of improved sleep based on actigraphy data. No differences were observed in measures of sleep quality or daytime sleepiness. CONCLUSION: In this symptomatic postmenopausal population of women experiencing sleep disruption resulting from nocturnal vasomotor symptoms, a daily dose of synthetic conjugated estrogens-B as low as 0.3 mg appears to be effective in treating nocturnal hot flushes that lead to unwanted awakenings. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00592839.

A look at the long-term safety of an extended-regimen OC.

BACKGROUND: Oral contraceptives (OCs) are the most widely used method of reversible contraception. Recent alterations of the standard 28-day regimen have included shortening the traditional hormone-free interval (HFI), supplementing the HFI with low-dose estrogen, or increasing the number of active pills administered, thus extending the time between withdrawal bleeding episodes by a variable number of months. In light of these changes in regimens, clinicians may be seeking evidence that the new regimens are safe and will not result in unexpected adverse events. METHODS: We initiated a long-term extension trial to evaluate the safety of a 91-day extended-regimen OC containing 150 mcg levonorgestrel/30 mcg ethinyl estradiol (EE) for 84 days, followed by 7 days of 10 mcg EE. After participation in a 1-year, open-label, phase 3 contraceptive program, 320 women qualified for enrollment in a multicenter, nonrandomized study of 91-day extended-regimen OCs for up to 3 additional consecutive years; 116 completed the study. We evaluated incidence of reported adverse events (AEs), rates of study discontinuation, and reported bleeding patterns. RESULTS: Total exposure was equivalent to 8292 28-day cycles. Participants reported no thromboembolic events. Thirty-one (9.7%) women discontinued treatment due to AEs. Unscheduled bleeding and spotting diminished during the course of the trial. Overall rates of study discontinuation and incidence of AEs were consistent with those observed in the phase 3 clinical program. CONCLUSION: This study demonstrated that the AE profile of the 91-day extended-regimen OC over 4 years was similar to that seen in the 1-year clinical trials, with no unexpected adverse events.

Adding low-dose estrogen to the hormone-free interval: impact on bleeding patterns in users of a 91-day extended regimen oral contraceptive.

BACKGROUND: A cross-study analysis of contraceptive clinical trials for two different 91-day oral contraceptive (OC) regimens was performed to examine the impact on bleeding patterns when supplementing the 7-day hormone-free interval with 10 mcg ethinyl estradiol (EE) daily. STUDY DESIGN: Two separate 1-year Phase 3 clinical programs were conducted using similar study designs. The percentages of subjects reporting bleeding and spotting using electronic diaries for each 91-day cycle were compared. RESULTS: Scheduled bleeding with the EE regimen was less than that reported with the regimen utilizing placebo during Days 85-91, with significant differences noted for all four 91-day cycles. Unscheduled bleeding decreased more quickly with the 91-day regimen containing low-dose EE in place of placebo, with significant differences noted during the third cycle. CONCLUSIONS: This cross-study comparison suggests that the administration of low-dose estrogen in place of placebo in a 91-day extended regimen OC improves the bleeding profile.

Twice-weekly synthetic conjugated estrogens vaginal cream for the treatment of vaginal atrophy.

OBJECTIVE: The aim of this study was to evaluate low-dose synthetic conjugated estrogens A (SCE-A) cream administered twice weekly for the treatment of moderate to severe vulvovaginal atrophy (VVA) in a symptomatic postmenopausal population. METHODS: In a multicenter, double-blind, randomized, placebo-controlled study, 305 women with symptoms of VVA were treated with either 1 g SCE-A cream (n = 150) or matching placebo (n = 155) for a period of up to 12 weeks. Participants had to have a vaginal pH of greater than 5, less than or equal to 5% superficial cells on a vaginal smear, and at least one of five symptoms of VVA (dryness, soreness, irritation, pain with intercourse, and bleeding after intercourse) that was moderate or severe in intensity. Women had to select one moderate or severe symptom as the most bothersome. RESULTS: Efficacy was assessed at 2, 3, 4, 8, and 12 weeks and included the change from baseline in the severity of the most bothersome symptom (MBS), maturation index, and pH. Most women identified vaginal dryness as the MBS (48%) followed by pain with intercourse (31.3%). A statistically significant increase in the maturation index and significant decreases in pH and severity of the MBS were observed for those treated with SCE-A vaginal cream compared with placebo. CONCLUSIONS: A low dose (1 g = 0.625 mg) of SCE-A vaginal cream administered twice weekly was shown to be effective compared with placebo in treating VVA in postmenopausal women for the three coprimary efficacy measures of maturation index, pH, and severity of the MBS.

Measuring symptom relief in studies of vaginal and vulvar atrophy: the most bothersome symptom approach.

OBJECTIVE: To assess the importance and usefulness of self-reported symptom data, especially the most bothersome symptom, in the evaluation of treatment for vulvovaginal atrophy. DESIGN: This was a double-blind, placebo-controlled multicenter study. Women rated symptoms associated with vaginal atrophy (vaginal dryness, vaginal/vulvar irritation/itching, vaginal/vulvar soreness, and dyspareunia) before and during treatment and selected one moderate to severe symptom as the most bothersome. RESULTS: Among 310 women (n = 156 placebo), vaginal dryness and dyspareunia were most commonly classified as moderate to severe and as most bothersome (44.4% and 30.2%, respectively). For both symptoms, the effect size favoring active treatment consistently increased as the cohort was more narrowly defined (all treated women, women who classified the symptom as moderate or severe, and those who classified the symptom as most bothersome). Compared with the standardized effect sizes for all women, those calculated from the most bothersome symptom were 49% and 62% greater for dyspareunia and dryness, respectively. CONCLUSION: : The most bothersome symptom approach represents a meaningful new standard for measurement of self-assessed vulvovaginal atrophy symptom change, but evaluation of change in individual symptoms remains an important, unbiased primary analysis of efficacy in vulvovaginal atrophy studies.

Efficacy and safety of a 28-day oral contraceptive with 7 days of low-dose estrogen in place of placebo.

BACKGROUND: The study was conducted to evaluate the efficacy and safety for the prevention of pregnancy of a 28-day oral contraceptive (OC) containing 150 mcg desogestrel (DSG)/20 mcg ethinyl estradiol (EE) for 21 days followed by 7 days of 10 mcg EE (Cette-28). STUDY DESIGN: A 6-month, prospective, multicenter, single-arm study was conducted in 1302 women aged 18-45 years. RESULTS: Over six cycles of treatment, the cumulative risk of pregnancy among all treated subjects (n=1262) was 0.9%. The Pearl Index for women 18-35 years of age (n=1042) was 2.20, including 9 pregnancies with estimated conception dates during active drug ingestion or up to 7 days after the last combination tablet. The rate of unscheduled bleeding was low and the duration of scheduled bleeding was approximately 2 days during each of the six treatment cycles. The safety profile was similar to what has been reported for other OCs. CONCLUSION: This low-dose, 28-day OC incorporating 7 days of 10 mcg EE during the hormone free interval is effective and safe for the prevention of pregnancy and is well-tolerated by women.

Randomized, multicenter, double-blind, placebo-controlled trial to evaluate the efficacy and safety of synthetic conjugated estrogens B for the treatment of vulvovaginal atrophy in healthy postmenopausal women.

OBJECTIVE: To evaluate the safety and efficacy of synthetic conjugated estrogens B (SCE-B; 0.3 mg/d) for 12 weeks in the treatment of vulvovaginal atrophy in symptomatic, postmenopausal women. DESIGN: Prospective, randomized, multicenter, double-blind, placebo-controlled trial. SETTING: Forty-two participating sites in the United States. PATIENT(S): Postmenopausal women with at least one moderate to severe symptom of vaginal atrophy. INTERVENTION(S): Daily oral administration, in a randomized, placebo-controlled setting, of SCE-B (0.3 mg) or of placebo for 12 weeks. MAIN OUTCOME MEASURE(S): Mean changes in vaginal maturation index, percentage of parabasal and superficial cells, vaginal pH, and severity of the most bothersome symptom (MBS) between baseline and predetermined time points were assessed. Safety and tolerability were evaluated. RESULT(S): A total of 310 women (mean age, 58.6 y) were enrolled. Synthetic conjugated estrogens B yielded statistically significantly greater differences in vaginal maturation index and vaginal pH from baseline to the end of treatment. Vaginal dryness (44.4%) and pain during intercourse (30.2%) were the symptoms most commonly identified as the MBS. A statistically significant mean reduction in the severity of the MBS was noted for SCE-B. There were no clinically significant differences observed between the two groups for findings related to safety. CONCLUSION(S): Synthetic conjugated estrogens B (0.3 mg/d) was effective in treating vulvovaginal atrophy in symptomatic postmenopausal women. Significant improvement was seen in vaginal maturation index, vaginal pH, and severity of MBS from baseline to the end of treatment.

Endometrial microstructure after long-term use of a 91-day extended-cycle oral contraceptive regimen.

OBJECTIVE: To assess the effect on the endometrial microstructure of an extended-cycle oral contraceptive (OC) regimen containing ethinyl estradiol (EE) and levonorgestrel (LNG). METHODOLOGY: Subjects received up to four cycles of a 91-day extended-cycle OC regimen (84 consecutive days of monophasic 30 microg EE/150 microg LNG followed by 7 days of placebo). Endometrial biopsies were performed prior to the initiation and at the completion of therapy. All endometrial samples were processed centrally and reviewed by three independent pathologists blinded to treatment groups. RESULTS: Endometrial biopsies were performed in 50 women. In general, samples taken after completion of therapy with no further hormonal exposure demonstrated rapid return to normal endometrial cycling. In contrast, the majority of subjects still on active extended hormonal OC therapy at the time of biopsy had inactive or atrophic endometrium. No intravascular blood clots were observed in any of the specimens. CONCLUSION: The endometrial findings observed in this cohort of women treated with a 91-day extended-cycle OC regimen for up to 1 year showed no significant pathology. Additionally, the endometrium reverted quickly to normal cyclic changes in those subjects who, after completing therapy, elected not to continue with hormonal contraception.

A phase I/IIA trial of continuous five-day infusion of squalamine lactate (MSI-1256F) plus carboplatin and paclitaxel in patients with advanced non-small cell lung cancer.

PURPOSE: Squalamine is an antitumor agent that has been shown to have antiangiogenic activity in animal models. This Phase I/IIA study was designed to assess the safety, clinical response, and pharmacokinetics of squalamine when administered as a 5-day continuous infusion in conjunction with standard chemotherapy every 3 weeks in patients with stage IIIB (pleural effusion) or stage IV non-small cell lung cancer. EXPERIMENTAL DESIGN: Patients with chemotherapy-naive non-small cell lung cancer were treated with escalating doses of squalamine in combination with standard doses of paclitaxel and carboplatin. Paclitaxel and carboplatin were administered on day 1, followed by squalamine as a continuous infusion on days 1-5, every 21 days. RESULTS: A total of 45 patients were enrolled (18 patients in the Phase I dose escalation arm and 27 in the Phase IIA arm). The starting dose of squalamine was 100 mg/m(2)/day and escalated to 400 mg/m(2)/day; two of three patients at 400 mg/m(2)/day had dose-limiting toxicity that included grade 3/4 arthralgia, myalgia, and neutropenia. On the basis of safety and toxicity, 300 mg/m(2)/day was selected as the Phase II dose of squalamine in this combination regimen. An additional 27 patients (a total of 33) were enrolled according to the protocol treatment schema at 300 mg/m(2)/day. There was no pharmacokinetic evidence of drug interactions for the combination of squalamine, carboplatin, and paclitaxel. Forty-three patients were evaluable for response. Partial tumor responses were observed in 12 (28%) of these patients; an additional 8 evaluable patients (19%) were reported to have stable disease. For all of the patients treated, the median survival was 10.0 months; and 1-year survival was 40%. CONCLUSIONS: The combination of squalamine given continuously daily for 5 days, with paclitaxel and carboplatin given on day 1, is well tolerated. Patient survival data and the safety profile of this drug combination suggests that the use of squalamine given at its maximum tolerated dose with cytotoxic chemotherapy should be explored further as a potentially effective therapeutic strategy for patients with stage IIIB or IV non-small cell lung cancer.

A multicenter, randomized study of an extended cycle oral contraceptive.

OBJECTIVE: To assess the efficacy and safety of Seasonale, 91-day extended cycle oral contraceptive (OC). METHODS: A parallel, randomized, multicenter open-label, 1-year study of the OC Seasonale [30 microg ethinyl estradiol (EE)/150 microg levonorgestrel (LNG), and Nordette-28 (30 microg EE/150 microg LNG)] in sexually active, adult women (18-40 years) of childbearing potential. Patients received either four 91-day cycles of extended cycle regimen OC, or 13 cycles of the conventional 28-day OC with daily monitoring of compliance and bleeding via electronic diaries. RESULTS: When taken daily for 84 days followed by 7 days of placebo, the extended cycle regimen was effective in preventing pregnancy and had a safety profile that was comparable to that observed with the 28-day OC regimen that served as the control. While unscheduled (breakthrough) bleeding was reported among patients treated with the extended cycle regimen, it decreased with each successive cycle of therapy and was comparable to that reported by patients who received the conventional OC regimen by the fourth extended cycle. CONCLUSION: This study demonstrated that Seasonale, 91-day extended cycle OC containing 84 days of 30 microg EE/150 microg LNG followed by 7 days of placebo, was effective, safe and well tolerated.