EVAPIL-R Scale: Continuous development and validation of a tool to assess patient-reported tolerability of different contraceptive methods in longitudinal studies.

OBJECTIVE: The objective of this study was to modify the EVAPIL, a questionnaire designed to assess user-reported tolerability of combined oral contraceptives (COCs) in cross-sectional studies, to make it appropriate for assessing the tolerability of intrauterine systems (IUSs), subdermal implants, and COCs in longitudinal studies. METHODS: Development of the EVAPIL-Revised (EVAPIL-R) was informed by a targeted literature review, qualitative interviews with IUS-prescribing gynecologists (n = 5), and IUS and implant users in the United States, Germany, and France (n = 36). RESULTS: Evidence generated supports the content validity of the EVAPIL-R for assessing user-reported tolerability of COCs, IUSs, and implants. Modifications to improve the relevance and usability of the questionnaire in longitudinal studies included specification of a defined recall period, addition of separate assessments of frequency and intensity (where relevant), and inclusion of additional items measuring concepts of importance to IUS and implant users (eg, vaginal discharge). CONCLUSIONS: The EVAPIL-R is a valuable tool for use in research and clinical practice to identify tolerability concerns in hormonal contraceptive users. Future research will evaluate the psychometric validity and responsiveness of the EVAPIL-R. Understanding of user-reported tolerability of contraceptive methods is critical for facilitating patient adherence and potentially reducing the number of unintended pregnancies. The EVAPIL-R may be used to facilitate "women-centered" research and contraceptive counseling and provision.

Different Pearl Indices in studies of hormonal contraceptives in the United States: impact of study population.

OBJECTIVE: To examine the impact of subject characteristics on efficacy as measured by the Pearl Index (PI) in clinical trials and to make study populations similar by matching. METHODS: Our analysis used US data from four large Phase III studies. We compared results from one fertility control patch study with pooled data from three studies with virtually identical design on oral hormonal contraceptives. First, we identified three characteristics that had the most impact on the PI. Second, we used these three variables and matched subjects from the patch study with those from the oral contraceptive (OC) studies. Finally, we calculated the PIs for matched and unmatched subjects from both the patch study and the OC studies. RESULTS: A total of 3706 subjects were included in our analysis. The variables 'Hispanic ethnicity', 'previous pregnancy' and 'previous use of hormonal contraceptives' had the most impact on the PI. The PIs for the matched patch cohort and the matched OC cohort were 2.97 and 2.48, respectively. Those for the unmatched patch cohort and the unmatched OC cohort were 10.17 and 0.90, respectively. CONCLUSION: Subject characteristics strongly influence the PI in clinical studies of hormonal contraceptives. In particular, Hispanic ethnicity, previous pregnancies and no previous use of hormonal contraceptives result in a higher PI. IMPLICATIONS: PIs from different clinical trials cannot be meaningfully compared unless subject characteristics that have most impact on the PI are similar or are made to be similar statistically as we did here by matching.

Suppression of ovarian activity with a low-dose 21/7-day regimen oral contraceptive containing ethinylestradiol 20 mcg/drospirenone 3 mg in Japanese and Caucasian women.

BACKGROUND: Two studies assessed the effect of a low-estrogen-dose 21/7-day oral contraceptive containing ethinylestradiol and drospirenone (EE 20 mcg/drsp 3 mg) on ovarian activity in Japanese and Caucasian women. STUDY DESIGN: Study 1 was conducted in Japanese women (20-35 years), and Study 2 was conducted in Caucasian women (18-35 years). All women received EE 20 mcg/drsp 3 mg in a 21-day active pill regimen. The primary endpoint was the proportion of women with ovulation inhibition (Hoogland score <6; as assessed by transvaginal ultrasonography) during treatment cycle 2. RESULTS: Japanese (n=23) and Caucasian (n=30) women received two cycles of study treatment. During treatment cycle 2, ovulation was inhibited in 100% and 92.9% of Japanese and Caucasian women, respectively. CONCLUSIONS: EE 20 mcg/drsp 3 mg in a 21/7-day regimen provides comparable ovarian suppression in Japanese and Caucasian women, with normal ovarian function resuming shortly after treatment end in both populations.

A randomized, phase II study describing the efficacy, bleeding profile, and safety of two low-dose levonorgestrel-releasing intrauterine contraceptive systems and Mirena.

OBJECTIVE: To identify an appropriate dose for a new contraceptive levonorgestrel intrauterine system (LNG-IUS). DESIGN: Randomized, open-label, three-arm, phase II study. SETTING: Thirty-seven centers in five European countries. PATIENT(S): Parous or nulliparous women aged 21-40 years. INTERVENTION(S): Treatment with LNG-IUSs with initial in vitro release rates of 12 or 16 µg/d (LNG-IUS12/16) or 20 µg/d (Mirena). MAIN OUTCOME MEASURE(S): Pearl index, bleeding profile, ease/pain of placement/removal, adverse events. RESULT(S): A total of 738 subjects had an LNG-IUS placed (LNG-IUS12, n = 239; LNG-IUS16, n = 245; Mirena, n = 254). One, 5, and 0 pregnancies occurred in the LNG-IUS12, LNG-IUS16, and Mirena groups, respectively (3-year unadjusted Pearl indices: 0.17, 0.82, and 0). The bleeding profiles were similar in all groups, although total bleeding and spotting days decreased with increasing LNG dose. During 3 years, 10 subjects in the LNG-IUS12 (2 women), LNG-IUS16 (3 women), and Mirena (5 women) groups reported serious adverse events, possibly related to study treatment. Placement of LNG-IUS12 and LNG-IUS16 was considered easy in 94% versus 86.2% in the Mirena group and 72.3% in the LNG-IUS12/LNG-IUS16 group reported either "no pain" or only "mild pain" during placement versus 57.9% in the Mirena group. CONCLUSION(S): LNG-IUS12 and LNG-IUS16 provided effective contraception, acceptable bleeding patterns, and were well tolerated compared with Mirena.

Rate of pregnancy after using drospirenone and other progestin-containing oral contraceptives.

OBJECTIVES: To determine whether prior oral-contraceptive use has a negative effect on the ability of women to conceive in both the short-term and long-term. METHODS: The European Active Surveillance Study on Oral Contraceptives (EURAS-OC) was a controlled, prospective, noninterventional cohort study of 59,510 users of oral contraceptives containing drospirenone or other progestins in clinical practice in seven European countries. In a planned secondary analysis, pregnancy outcomes were investigated in 2,064 participants in EURAS-OC who stopped oral-contraceptive use after study entry because of planned pregnancy. The influence of age, parity, progestin type, ethinylestradiol dose, duration of oral-contraceptive use, and smoking status on the rate of pregnancy was assessed. RESULTS: Overall, 21.1% (95% confidence interval [CI] 19.4-23.0%) of the past oral-contraceptive users were pregnant one cycle after oral-contraceptive cessation. This rate increased to 79.4% (95% CI 77.6-81.1%) at 1 year (13 cycles). Progestin type, ethinylestradiol dose, duration of oral-contraceptive use, and parity had no major influence on the rate of pregnancy after oral-contraceptive cessation. Up to age 35 years, age had only a minor influence on the rate of pregnancy. Rates of pregnancy were reduced in women older than 35 years and in current smokers. CONCLUSION: Previous oral-contraceptive use does not negatively affect initial and 1-year rates of pregnancy after oral-contraceptive cessation. A comparison of these data with data external to this study indicates that the negative effect of aging on fecundity is not amplified by oral-contraceptive use. LEVEL OF EVIDENCE: II.

Oral contraceptive effectiveness according to body mass index, weight, age, and other factors.

OBJECTIVE: The purpose of this study was to assess the use-effectiveness of oral contraceptives (OCs) in Europe according to body mass index (BMI), weight, age, and other factors. STUDY DESIGN: In a planned secondary analysis, we used data from the European Active Surveillance Study on Oral Contraceptives, which was a prospective active cohort surveillance study of 59,510 OC users, to assess the effectiveness of OCs overall and by BMI, weight, age, duration of use, ethinylestradiol dose, regimen type, starting/switching status, and parity. Self-reported unplanned pregnancies during OC use were confirmed by interview. RESULTS: An analysis of OC effectiveness (112,659 women-years of exposure and 545 unplanned pregnancies) found little variation in effectiveness by BMI/weight. Failure rates decreased after 30 years of age and with an increasing duration of use. CONCLUSION: OC users in Europe reported high contraceptive effectiveness with "typical use." Failure rates decreased with age and duration of use. BMI and weight had little, if any, influence on effectiveness.

Efficacy of a combined oral contraceptive containing 0.030 mg ethinylestradiol/2 mg dienogest for the treatment of papulopustular acne in comparison with placebo and 0.035 mg ethinylestradiol/2 mg cyproterone acetate.

BACKGROUND: Acne is a multifactorial disease characterized by androgenic stimulation of sebaceous glands. Therefore, combined oral contraceptives (COCs) containing anti-androgenic progestogens are suitable candidates for acne treatment. This study aimed to show that a COC containing the anti-androgen dienogest (DNG) is superior to placebo and not inferior to a COC containing the potent anti-androgen cyproterone acetate (CPA) in improving mild to moderate acne. STUDY DESIGN: Healthy women between 16 and 45 years old with mild to moderate facial acne were randomly assigned to receive ethinylestradiol (EE)/DNG (n=525), EE/CPA (n=537) or placebo (n=264) for six cycles in a multinational, multicenter, three-arm, double-blind and randomized trial. The primary efficacy variables were the percentages of change (from baseline to cycle 6) in inflammatory and total lesion count and the percentage of patients with acne improvement according to the Investigator Global Assessment. RESULTS: All primary analyses proved that EE/DNG was superior to placebo and non-inferior to EE/CPA (p<.05). For inflammatory lesions, the reduction (+/-SD) rates were -65.6+/-29.9% for EE/DNG, -64.6+/-31.2% for EE/CPA and -49.4+/-41.0% for placebo. For total lesions, the reduction rates were -54.7+/-26.3% for EE/DNG, -53.6+/-27.5% for EE/CPA and -39.4+/-33.6% for placebo. The percentages of patients with improvement of facial acne were 91.9% for EE/DNG, 90.2% for EE/CPA and 76.2% for placebo. CONCLUSION: EE/DNG was superior to placebo, in spite of the prominent placebo effects, and as effective as EE/CPA in the treatment of mild to moderate acne, thus proving a valid option for the treatment of acne in women seeking oral contraception.

The use of an oral contraceptive containing ethinylestradiol and drospirenone in an extended regimen over 126 days.

OBJECTIVE: To assess the bleeding profile, acceptance and safety of an extended 126-day regimen of the oral contraceptive Yasmin [30 microg ethinylestradiol (EE) and 3 mg drospirenone (DRSP)]. METHODS: Using daily diaries, 177 women recorded bleeding events throughout the 126-day cycle. At end of treatment, the women completed questionnaires reflecting their satisfaction with the extended regimen. A subset of 30 women underwent endometrial histology sampling after completion of the extended regimen. RESULTS: Of 177 women assigned to the extended regimen, 80.8% completed the extended 126-day regimen. Approximately 40% of the women reported complete absence of bleeding, while in 60% a shift towards less intense bleeding was observed. The first onset of bleeding occurred after a median of 99.0 days into the extended cycle. The acceptance of the extended regimen was high, with 68.4% of the women expressing satisfaction. The general safety profile with the extended use was comparable to that seen with the conventional 21+7-day regimen. All endometrial biopsies with sufficient material for analysis were normal and supported the endometrial safety of the extended regimen. CONCLUSION: This study showed that the continuous use of a 30-microg EE and 3-mg DRSP formulation over 126 days was safe, efficacious, well accepted by the users and resulted in a considerable reduction of bleeding.

Superiority of a combined contraceptive containing drospirenone to a triphasic preparation containing norgestimate in acne treatment.

This double-blind study compared the efficacy and tolerability of a combined oral contraceptive containing 30 microg ethinyl estradiol and 3 mg drospirenone (EE/DRSP; Yasmin) with a triphasic preparation containing 35 microg EE and 0.180, 0.215, 0.250 mg norgestimate (EE/NGM; Pramino, also known as Ortho Tri-Cyclen) in the treatment of acne vulgaris. The combined presence of antiandrogenic and antimineralocorticoid activities of drospirenone is unique to this novel progestin in that these characteristics most closely resemble those of progesterone. The study was designed to show that EE/DRSP was noninferior or superior to EE/NGM as to the relative decrease from baseline to cycle 6 in percentage of inflammatory and total lesion counts and the investigators' assessment of acne improvement. Other outcomes included subjects' assessment of therapeutic effect, sebum production, and hormone levels. Female subjects were randomized to EE/DRSP (n = 568) or EE/NGM (n = 586) for 6 treatment cycles, consisting of 21 consecutive days of hormone intake, followed by 7 hormone-free days. The preparation containing EE/DRSP was superior to EE/NGM for reduction in total lesion count (-3.3% in favor of EE/DRSP [95% CI, -6.5 to -0.1; P = .020]) and for investigators' assessment of therapeutic effect on facial acne (+3.6% in favor of EE/DRSP [95% CI, 0.8 to 6.3; P = .006]). The 2 preparations were comparable as to their decreases in inflammatory lesion count. Evaluation of the effect of treatment by subjects was consistent with that of the investigators. Furthermore, both preparations increased the level of sex hormone-binding globulin (SHBG) and decreased the levels of androgens, changes typically associated with acne improvement. Both preparations were well tolerated. In conclusion, owing to the unique pharmacologic activities of drospirenone, the combined oral contraceptive EE/DRSP provides an effective treatment option in female patients with mild to moderate acne.

An effective hormonal male contraceptive using testosterone undecanoate with oral or injectable norethisterone preparations.

Suppression of spermatogenesis to azoospermia is the goal of hormonal male contraception based on T combined with gestagens. The combination of the long-acting T, ester testosterone undecanoate (TU), with norethisterone (NET) enanthate (E) showed high efficacy. In the present study, we tested the validity of this approach by varying the NET dose and mode of application. The aim of the study was to achieve high rates of suppression of spermatogenesis as reflected by sperm counts, monitor gonadotropins as well as other hormones, and evaluate any possible side effects. In a phase II clinical trial, groups of normal volunteers received: 1000 mg TU im at wk 2, 6, 12, and 18 combined with 200 mg NETE im at wk 0, 6, 12, and 18 (group I); 1000 mg TU im and 400 mg NETE im at wk 0, 6, 12, and 18 (group II); and 1000 mg TU im at wk 0, 6, 12, and 18 with daily oral NET acetate (NETA) from wk 0 to 24 (group III). In all groups marked suppression of gonadotropins resulted in a significant decrease of spermatogenesis and azoospermia in 13/14, 11/12, and 12/14 men in groups I to III, respectively. The remaining men all had less than 1 million sperm/ml. Reversible side effects included increase in body weight, erythrocytes, hemoglobin, and hematocrit and decrease in high-density lipoprotein cholesterol and alkaline phosphatase in all groups and increase in liver enzymes in the oral NETA group. This study documents the high efficacy of TU in combination with NET and confirms that this dose and mode of application (1000 mg TU im every 6 wk plus 400 mg NETE im every 6 wk or plus 10 mg daily oral NETA) is as effective as the previously reported regimen containing 1000 mg TU + 200 mg NETE im every 6 wk. The contraceptive efficacy of this combination of TU and NETE should be evaluated in further clinical trials.