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Efficacy, safety, and tolerability of a levonorgestrel/ethinyl estradiol transdermal delivery system: Phase 3 clinical trial results

Open AccessPublished:November 28, 2020DOI:https://doi.org/10.1016/j.contraception.2020.11.011

      Abstract

      Objective

      To assess the contraceptive efficacy, safety, and tolerability of a contraceptive transdermal delivery system, (TDS; TWIRLA) containing levonorgestrel (LNG) and ethinyl estradiol (EE).

      Study design

      This single-arm, open-label, multicenter, 1-year (13 cycle), phase 3 study enrolled sexually active women ≥18 years old at risk for pregnancy irrespective of body mass index (BMI). Women used patches in 28-day cycles (3 consecutive administrations of 7-day patches followed by 7 days off-treatment/patch-free week). We assessed contraceptive efficacy by the Pearl Index (PI) in women 18 to 35 years, excluding cycles without intercourse or when other contraceptive methods were used.

      Results

      The study enrolled 2032 demographically diverse women in the US, of which 35.3% had a BMI ≥30 kg/m2. In the primary efficacy analysis, the PI (95% confidence interval) was 5.8 (4.5–7.2) pregnancies per 100 woman-years. PIs trended higher as BMI increased; the PI was 4.3 (2.9–5.8) in women with BMI <30 kg/m2 and 8.6 (5.8–11.5) in women with BMI ≥30 kg/m2. Hormone-related treatment-emergent adverse events included nausea (4.1%) and headache (3.6%); 11% of women discontinued due to adverse events. Four women (all with BMIs ≥30 kg/m2) reported thromboembolic events considered related to treatment.

      Conclusions

      The low-dose LNG/EE TDS was effective in preventing pregnancy in a population of women representative of US demographics. Efficacy was reduced in women with BMI ≥30 kg/m2. The TDS safety and tolerability profile was consistent with other similar dose combined hormonal contraceptives. Results of this phase 3 study supported the US Food and Drug Administration approval of TWIRLA for prevention of pregnancy in women with BMI <30 kg/m2.

      Implications

      TDS (120 µg/day levonorgestrel and 30 µg/day ethinyl estradiol) is an effective, low-dose transdermal contraceptive patch with favorable tolerability profile approved for prevention of pregnancy in women with BMI <30 kg/m2. TDS has reduced effectiveness in women with BMI ≥30 kg/m2.

      Keywords

      1. Introduction

      The contraceptive transdermal delivery system (TDS; TWIRLA, Agile Therapeutics, Inc., Princeton, NJ) was designed to address the need for a low-dose, noninvasive transdermal contraceptive patch that avoids daily dosing. TDS was designed as a once-weekly patch delivering exposure similar to daily oral doses of 120 µg levonorgestrel (LNG)/30 µg ethinyl estradiol (EE). The first marketed contraceptive patch was associated with high levels of EE exposure (comparable to a 50 µg pill) and norelgestromin, which has been thought to have higher prothrombotic impacts than LNG. Use of this patch declined following concerns of higher rates of thromboembolism [
      • Nelson AL
      Transdermal contraception methods: today's patches and new options on the horizon.
      ,
      • Stegeman BH
      • de Bastos M
      • Rosendaal FR
      • van Hylckama Vlieg A
      • Helmerhorst FM
      • Stijnen T
      • et al.
      Different combined oral contraceptives and the risk of venous thrombosis: systematic review and network meta-analysis.
      . In collaboration with the US Food and Drug Administration (FDA), the phase 3 Study to Evaluate Contraceptive Use, Reliability, and Effectiveness (SECURE) evaluated the contraceptive efficacy, safety, and tolerability of TDS in a representative population of potential users in the United States.

      2. Methods

      SECURE (ClinicalTrials.gov NCT02158572) was an open-label, single-arm, multicenter, 13 cycle, phase 3 study of TDS in women ≥18 years old, and included rigorous design features consistent with the latest FDA recommendations for hormonal contraceptive trials, including no BMI restrictions [
      US Food and Drug Administration.
      ,
      US Food and Drug Administration.
      ].

      2.1 Study treatment

      Each TDS contains 2.6 mg levonorgestrel (LNG) and 2.3 mg ethinyl estradiol (EE) and delivers daily hormone exposure similar to oral doses of 120 µg LNG/30 µg EE pills [
      • Archer DF
      • Stanczyk FZ
      • Rubin A
      • Foegh M
      Ethinyl estradiol and levonorgestrel pharmacokinetics with a low-dose transdermal contraceptive delivery system, AG200-15: a randomized controlled trial.
      ]. Each <1 mm thick TDS is round, with a soft, flexible fabric outer surface covering an active drug core of 15 cm2 in area; this core is surrounded by an outer perimeter adhesive system designed to ensure drug delivery in the event of partial patch lifting, for a total area of 28 cm2 [
      TWIRLA (levonorgestrel and ethinyl estradiol) transdermal system [prescribing information].
      ]. A cycle of TDS consists of 3 consecutive weekly patches (21 days of active treatment) followed by a patch-free week (7 days).

      2.2 Participants, inclusion and exclusion criteria

      The study was conducted at 102 US-based sites (see Supplemental Materials). The protocol was approved by the Advarra Institutional Review Board and local IRBs. All women provided written informed consent.
      The target enrollment for the study included approximately 2100 women, ≥18 years old (200 women were aged >35 years) with regular 21 to 38 day cycles, at risk for pregnancy, desiring hormonal contraception for ≥1 year, and meeting the 2016 US Medical Eligibility Criteria for Contraceptive Use for combined hormonal methods [
      • Curtis KM
      • Tepper NK
      • Jatlaoui TC
      • Berry-Bibee E
      • Horton LG
      • Zapata LB
      • et al.
      U.S. medical eligibility criteria for contraceptive use, 2016.
      ]. Women confirmed anticipated sexual intercourse ≥1 per cycle for the duration of their participation and agreed to rely exclusively on the TDS for contraception. Exclusion criteria included known or suspected pregnancy, desire for pregnancy within the study period, anticipated need for other contraception, and dermal hypersensitivity to patches, adhesives, or any other components of the patch. Complete inclusion and exclusion criteria are described in Appendices A.1 and A.2, respectively.

      2.3 Contraceptive history

      Women who had never used any hormonal contraceptives were categorized as “naïve users”; “former users” had used hormonal contraceptives previously but not within 6 months of enrollment; “recent users” were not currently using hormonal contraception but had used one within 6 months before enrollment; and “current users” were using hormonal contraception at the time of enrollment.

      2.4 Study visits

      Following the initial screening visit, women were assessed on their ability to enter study-related data into electronic diaries (eDiaries; LogPad 5.9.1 or LogPad LW 5.9.1 devices) over a 2-week period. eDiary data were transmitted as an XML document for analysis. Women were eligible for TDS initiation if they had 90% compliance with daily data entry and responded to 2 phone calls from the study site during that 2-week period.
      At the patch initiation visit on the first day of the next menses, enrolled women were given instructions on patch application and subsequently applied the first patch onto the abdomen, buttock, or upper torso (excluding the breast) under direct supervision of an investigator. Women applied subsequent patches at home; sites reviewed instructions for at-home patch applications at each study visit. Women returned at cycles 2, 3, 5, 7, 9, and 13, when lab urine pregnancy tests were performed, concomitant medications, compliance, patch application site (skin), patch adhesion, and treatment-emergent adverse events (TEAEs) were recorded. Six telephone contacts were conducted between study visits to assess study medication and eDiary compliance and to record TEAEs. A Data Safety Monitoring Board regularly monitored the progress of the trial and made recommendations on whether the trial should be stopped, undergo modifications, or continue, based on periodic review of safety.

      2.5 Populations and analysis datasets

      The study defined 5 populations for analysis: Safety, Contraceptive Efficacy, intention-to-treat (ITT), Cycle Control, and Completer Population. The Safety Population included all women who wore ≥1 patch for any period; safety outcomes included incidence of TEAEs and study discontinuation information. The Contraceptive Efficacy population included women who wore ≥1 patch for any period and had a negative enrollment serum beta human chorionic gonadotropin (β-hCG). The ITT population was a subset of the Contraceptive Efficacy population that included all complete or incomplete cycles in which intercourse occurred and no backup contraception was used. The Cycle Control population included women in the Contraceptive Efficacy population who provided information on bleeding and patch application to assess scheduled and unscheduled bleeding/spotting days. Women who completed the study were included in the Completer Population.
      Women received home pregnancy tests and were advised to test for pregnancy in the event of delayed patch application and/or symptoms concerning for pregnancy. Positive urine pregnancy test was confirmed using serum β-hCG testing, pelvic examination, and transvaginal ultrasound. An independent adjudication committee classified each pregnancy as pretreatment, on-treatment, or post-treatment; the sponsor and the FDA determined final pregnancy classification. The primary efficacy analysis (ITT) evaluated the Pearl Index (PI) in all women 18 to 35 years old. The PI was defined as the number of pregnancies times 1300, divided by the number of eligible 28-day on-therapy cycles; this yielded the number of pregnancies per 100 woman-years of product use. We counted all pregnancies where conception occurred after placement of the first patch or within 7 days of removal of the last patch. We included all complete or incomplete on-study cycles (excluding cycles where no intercourse occurred or when other contraceptives were used) in the denominator. We analyzed the primary endpoint by BMI subgroups using protocol-specified analyses and performed secondary efficacy analysis according to BMI above and below 30 kg/m2. To estimate cumulative probabilities of pregnancy, we computed supportive life table analyses by Kaplan-Meier method within SAS PROC LIFETEST (SAS Institute, Cary, NC).

      2.6 Cycle control evaluation

      Women reported daily bleeding (use of ≥1 tampon or sanitary pad) and/or spotting (use of pantyliners or less) occurrence and intensity in their eDiaries. We defined a bleeding/spotting episode as ≥1 consecutive days of bleeding/spotting bounded on either side by ≥2 days of no bleeding/spotting. “Scheduled” bleeding/spotting occurred when the patch was not worn; “unscheduled” bleeding/spotting occurred while women wore a patch, except for when bleeding/spotting had begun in the previous hormone-free period and continued through no more than day 4 of the new treatment cycle.

      2.7 Patch wearability

      Women recorded patch application timing, anatomic placement, patch adhesion, patch site skin irritation/itching information, and reasons for unscheduled patch changes in daily eDiaries. Women graded patch adhesion as 0 = no lifting/small amount of lifting at patch edges, 1 = some edges showing lifting, 2 = at least half of system lifting, 3 = more than half of patch is lifted, but remains attached, or 4 = patch completely off. Skin irritation/itching were graded daily as 0 = none, 1 = mild, 2 = moderate, or 3 = severe. At each scheduled visit, investigators rated patch adhesion and irritation using the same scales.

      3. Results

      3.1 Enrollment, disposition, and participant characteristics

      SECURE enrolled 2032 women, of whom 2031 were included in the Safety population and 1736 women in the ITT population, which included women ≤35 years who contributed 15,165 cycles in the primary efficacy PI analysis (Fig. 1). Overall, 48.7% women (989/2031) completed the study; of the 1042 women who discontinued the study prematurely, the most common reasons cited were woman's decision (15%, n = 310), lost to follow-up (LTFU; 11%, n = 229), and TEAE (11%, n = 224).
      Fig 1
      Fig. 1Study population disposition of the SECURE study.
      The Safety population included women who wore at least one patch for any period of time. The Contraceptive Efficacy population included women who wore at least one patch and had a negative enrollment serum β-hCG. The ITT population was a subset of the Contraceptive Efficacy population and included all complete or incomplete cycles in which intercourse occurred and no backup contraception was used.
      aReasons for screen failure included: medical reason, eDiary compliance, unwillingness to participate, abnormal pap test, limited ability to comply with protocol as deemed by the investigator, irregular menses, unwilling to use TDS.
      ITT = intention-to-treat; TDS = transdermal delivery system.
      The mean ± SD age of participants was 27.5 ± 6.2 years (Table 1). Mean ± SD BMI was 28.3 ± 7.1 kg/m2 (median: 26.8, range 15.1–63.0). One woman's weight was not recorded. Of 2030 women, 35.3% had BMI of ≥30 kg/m2 including 7.5% who had BMI of ≥40 kg/m2. The majority of the women in the Safety population were white (66.9%) and were of non-Hispanic/Latina origin (80.3%). Race and ethnicity were separately assessed. Most women (82.7%) had never used transdermal contraception, and 9.4% (n = 190) had never used systemic hormonal contraception.
      Table 1Demographics, baseline characteristics, and previous contraceptive use in the phase 3 trial for TDS.
      CharacteristicOverall
      (N = 2031)
      Age in years, mean ± SD27.5 ± 6.2
       ≤351830 (90.1)
       >35201 (9.9)
      Race, n (%)
       White1358 (66.9)
       Black or African American493 (24.3)
       Asian65 (3.2)
       American Indian or Alaska Native11 (0.5)
       Native Hawaiian or Other Pacific Islander8 (0.4)
       Other96 (4.7)
      Ethnicity, n (%)
       Hispanic or Latina400 (19.7)
       Not Hispanic or Latina1631 (80.3)
      BMI (kg/m2), n (%)
      One woman's weight/BMI was not recorded (n = 2030).
       Normal (<25)800 (39.4)
       Overweight (≥25 to <30)513 (25.3)
       Obese (≥30)717 (35.3)
      Previous contraceptive use
      Naïve = women who have never used any hormonal contraceptive; Former = women with use of hormonal contraceptives >6 months before enrollment; Recent = women not currently using a hormonal contraceptive but who have used a hormonal contraceptive within 6 months of enrollment; Current = women who are currently using a hormonal contraceptive.
       Naive190 (9.4)
       Former875 (43.1)
       Recent262 (12.9)
       Current704 (34.7)
      Naïve to transdermal contraceptive, n (%)
       Yes1680 (82.7)
       No351 (17.3)
      BMI, body mass index; SD, standard deviation; TDS, transdermal delivery system.
      Safety population = women who wore at least one patch for any length of time.
      a One woman's weight/BMI was not recorded (n = 2030).
      b Naïve = women who have never used any hormonal contraceptive; Former = women with use of hormonal contraceptives >6 months before enrollment; Recent = women not currently using a hormonal contraceptive but who have used a hormonal contraceptive within 6 months of enrollment; Current = women who are currently using a hormonal contraceptive.

      3.2 Efficacy

      The primary efficacy analysis for women ≤35 years old (ITT; n = 1736) yielded a PI (95% CI) of 5.8 (4.5–7.2) pregnancies per 100 woman-years (Table 2). Women with BMI <30 kg/m2 had a lower PI (95% CI) (4.3, 2.9–5.8) than women with BMI ≥30 kg/m2 (8.6, 5.8–11.5). BMI subgroup analysis showed a trend toward higher PIs as BMI increased (Fig. 2). PIs were lower for current (3.2, 1.5–4.8) and naïve (4.6, 0.6–8.6) contraceptive users than for former (7.5, 5.0–9.9) and recent (9.6, 4.6–14.7) users. The estimated life table cumulative pregnancy rate through Cycle 13 in all women ≤35 years in the Contraceptive Efficacy population (n = 1823) was 5.3% (Fig 3). Consistent with the differences in PI analysis by BMI, life table analysis followed similar outcomes with respect to BMI.
      Table 2Efficacy analysis of TDS in women ≤35 years old (ITT population), >35 years old, and overall.
      Age group
      Statistic≤35 years (primary analysis)>35 yearsOverall
      Number of women17361961932
      Number of pregnancies68674
      Number of cycles15,165196117,126
      Pearl Index, 95% CI5.8 (4.5–7.2)4.0 (0.8–7.2)5.6 (4.3–6.9)
      ITT, intention-to-treat; TDS, transdermal delivery system.
      ITT population = a subset of the Contraceptive Efficacy population that includes all complete or incomplete on-therapy cycles in which intercourse occurred and no back-up contraception was used (unless a woman became pregnant during the cycle).
      Fig 2
      Fig. 2Forest plot of the efficacy analyses in women ≤35 years by median BMI and BMI subgroups in the ITT dataset. aMedian BMI was 26.8.
      BMI = body mass index; ITT = intention-to-treat.
      Fig 3
      Fig. 3Cumulative probability of pregnancy in women ≤35 years over 13 cycles of use with the TDS (Contraceptive Efficacy population).
      Contraceptive Efficacy population = women who wore ≥1 patch and had a negative enrollment serum β-hCG.
      TDS = transdermal delivery system.

      3.3 Cycle control

      In the Cycle Control population (n = 2017), the mean ± SD number of total bleeding/spotting days in a cycle decreased from 6.2 ± 4.5 in Cycle 1 to 4.9 ± 3.5 in Cycle 13 (Fig. 4). The percentage of women with no bleeding/spotting days (amenorrhea) in 13 cycles ranged from 6.3% to 11.9% (excluding days 1–7 in cycle 1). The mean ± SD number of scheduled bleeding/spotting days was 3.7 ± 2.5 in Cycle 2 and 3.3 ± 2.5 in Cycle 13. The proportion of women reporting ≥1 day of unscheduled bleeding/spotting decreased from 60.4% (Cycle 1) to 42.3% (Cycle 13). The mean ± SD number of unscheduled bleeding/spotting days ranged from 3.1 ± 3.4 in Cycle 1 to 1.6 ± 2.5 in Cycle 13. A total of 45 women (2.2%) discontinued the study due to bleeding/spotting-related TEAEs.
      Fig 4
      Fig. 4Mean number (SD) of (A) total bleeding and/or spotting days and (B) spotting-only days by cycle in the Cycle Control population. Number within bars is the mean number of days.
      Cycle Control population = women who contributed cycle data and reported bleeding and/or spotting data via eDiaries (n = 2017). Bleeding = evidence of blood loss on any cycle day that required the use of sanitary protection with at least one tampon or sanitary pad. Spotting = evidence of minimal blood loss on any cycle day that required the use of pantyliners only or no sanitary protection.
      SD = standard deviation.

      3.4 Safety

      In the Safety population (n = 2031), 53.4% of women (n = 1085) reported experiencing a TEAE and 27.2% of women (n = 552) reported experiencing a study-drug related TEAE (Table 3). The incidence of TEAEs was similar between the 2 BMIs (<30 kg/m2 and ≥30 kg/m2) groups. The most frequently reported hormone-related TEAEs were nausea (4.1%, n = 84) and headache (3.6%, n = 72). Most women rated their highest severity TEAEs as mild (23.0%, n = 467) or moderate (25.9%, n = 526) in severity; 130 (6.4%) women reported experiencing at least one TEAE that was “definitely” related to treatment.
      Table 3Summary of women experiencing treatment-emergent adverse events with the TDS over 13 cycles of use by BMI category (Safety population).
      BMI category
      <30 kg/m2 (n = 1313)≥30 kg/m2 (n = 717)Overall (N = 2031)
      Women with any TEAE
      Adverse events are coded using MedDRA version 18.1. TEAEs were defined as adverse events with an onset date on or after the first patch application through Day 28 of the woman's final treatment cycle.
      ,n (%)
      700 (53.3)381 (53.1)1085 (53.4)
      Women with study-drug related TEAE361 (27.5)188 (26.2)552 (27.2)
      TEAEs leading to early discontinuation, n (%)153 (11.7)69 (10.0)224 (11.0)
      Relationship of TEAEs, n (%)
      Assessed by the investigator.
       Unrelated533 (26.2)
       Possibly related286 (14.1)
       Probably related136 (6.7)
       Definitely related130 (6.4)
      Intensity of TEAEs
       Mild467 (23.0)
       Moderate526 (25.9)
       Severe92 (4.5)
      BMI, body mass index; TDS, transdermal delivery system; TEAE, treatment-emergent adverse event.
      Safety population = women who wore at least one patch for any length of time.
      a Adverse events are coded using MedDRA version 18.1. TEAEs were defined as adverse events with an onset date on or after the first patch application through Day 28 of the woman's final treatment cycle.
      b Assessed by the investigator.
      Of 2031 women, 40 women (2.0%) reported having experienced ≥1 serious TEAE (SAE) during the study (Table 4); 3.1% (22/717) were in the BMI ≥30 kg/m2 group and 1.4% (18/1313) were in the BMI <30 kg/m2 group. Between Cycles 5 and 13, 5 women, all with BMIs >30 kg/m2, experienced 6 venous thromboembolism events (VTE; deep vein thrombosis [DVT], n = 3; pulmonary embolism [PE], n = 3). Of the 6 embolic events, investigators considered 5 events from 4 women related to treatment (DVT, n = 2; PE, n = 3). Three women with treatment-related VTE had at least one other potential risk factor, including family history of clots and recent air travel, and the fourth woman was diagnosed with new onset hyperthyroidism during her admission for PE. The fifth woman, who used the patch for 2 days, experienced a DVT postoperatively more than 2 months later; the FDA deemed it unrelated to treatment. No application site or bleeding SAEs were reported; no deaths were reported.
      Table 4Summary of women experiencing serious treatment-emergent adverse events with use of the TDS over 13 cycles of use (Safety population).
      BMI category
      <30 kg/m2 (n = 1313)≥30 kg/m2 (n = 717)Overall (N = 2031)
      Women with SAEs, n (%)
      Adverse events are coded using MedDRA version 18.1. A SAE is treatment-emergent if it has an onset date on or after the first patch application.
      18 (1.4)22 (3.1)40 (2.0)
       Cholelithiasis04 (0.6%)4 (0.2%)
       Deep vein thrombosis03 (0.4%)3 (0.2%)
       Pulmonary embolism03 (0.4%)3 (0.2%)
       Major depression1 (0.1%)2 (0.3%)3 (0.2%)
       Cholecystitis02 (0.3%)2 (0.1%)
       Ectopic pregnancy02 (0.3%)2 (0.1%)
       Gastroenteritis2 (0.2%)02 (0.1%)
      Relationship of SAEs, n (%)
      Assessed by the investigator.
       Unrelated25 (1.2)
       Possibly related12 (<1)
       Probably related3 (<1)
       Definitely related0
      Intensity of SAEs
       Mild1 (<1)
       Moderate13 (<1)
       Severe26 (1.2)
      BMI, body mass index; SAE, serious treatment-emergent adverse event; TDS, transdermal delivery system.
      Safety population = women who wore at least one patch for any length of time.
      a Adverse events are coded using MedDRA version 18.1. A SAE is treatment-emergent if it has an onset date on or after the first patch application.
      b Assessed by the investigator.
      The most common hormone-related TEAE resulting in discontinuation was nausea (0.9%, n = 18), application site irritation (1.1%, n = 23), pruritus (0.8%, n = 16), rash (0.7%, n = 14), dermatitis (0.5%, n = 10), and erythema (0.4%, n = 9).

      3.5 Compliance/Wearability

      The most common site for patch placement was the buttock area (44.8%). Throughout the study, 78% of women applied all 3 patches per cycle; 7.1% of patches were changed at an unscheduled time with complete detachment cited as the most common reason (2.4%). During Cycles 1 to 13, <1% of women did not wear the patch on ≥2 consecutive days during cycle days 1–21 per cycle. During Cycles 2 to 13, the percentage of women with >7 days between last patch removal and first patch application in the subsequent cycle ranged from 3.9% to 7.1%.
      Most investigators (99.4%) and women (88.7%) reported adhesion scores of 0 = no detachment or 1 = some edge lifting. Women reported improvement in adhesion scores over time (0/1 score: Cycle 2, 84.1%; Cycle 13, 92.5%). In total, 5.0% of the cumulative number of patches applied completely detached (Score = 4); complete detachment rates decreased over time (Cycle 1, 9.9%; Cycle 13, 2.4%). Low rates of moderate/severe irritation were reported by investigators (2/3 score: Cycle 2, 0.2%; Cycle 13, 0.3%; overall, 0.5%) and by women (Cycle 2, 6.9%; Cycle 13, 4.7%; overall, 6.3%); itching was reported by 13.1% and 9.6% of women in Cycle 2 and Cycle 13, respectively.

      4. Discussion

      The phase 3 SECURE trial demonstrated the safety and efficacy of the LNG/EE TDS in a demographically representative US population of women, using stringent design and analysis methods reflected in the 2019 FDA Draft Guidance “Establishing Effectiveness and Safety for Hormonal Drug Products Intended to Prevent Pregnancy” [
      US Food and Drug Administration.
      ,
      US Food and Drug Administration.
      ]. The SECURE trial did not restrict eligibility based on weight or BMI. The rigorous study design, distinguishing study features, and regular and frequent pregnancy testing ensured accurate determination of pregnancy.
      The primary efficacy analysis yielded a PI of 5.8 (ITT). Women with BMI <30 kg/m2 had a PI of 4.3 but effectiveness was reduced in women with BMI ≥30 kg/m2. These results are consistent with results from the FDA meta-analysis demonstrating a tendency of higher pregnancy rate with combined hormonal contraceptive (CHC) by obese women (BMI ≥30 kg/m2) than nonobese women [
      • Yamazaki M
      • Dwyer K
      • Sobhan M
      • Davis D
      • Kim MJ
      • Soule L
      • et al.
      Effect of obesity on the effectiveness of hormonal contraceptives: an individual participant data meta-analysis.
      ]. The higher proportion of women with elevated BMIs enabled evaluation of these groups independently and distinguishes the study from other phase 3 CHC trials. The use of eDiaries with associated prompts and reminders might result in greater compliance than in the general population outside of a clinical trial. A woman was considered “noncompliant” if she entered a “no” response to patch wear in her eDiary for ≥2 consecutive days during days 1 to 21 of each cycle. Self-reported noncompliance rates were low (0%–0.8% in Cycles 1–13), so it is difficult to evaluate between pregnancy rates due to noncompliance. Additional analyses could evaluate whether compliance was impacted by other parameters, such as BMI [
      • Westhoff CL
      • Torgal AT
      • Mayeda ER
      • Shimoni N
      • Stanczyk FZ
      • Pike MC
      Predictors of noncompliance in an oral contraceptive clinical trial.
      ,
      • Nguyen BT
      • Elia JL
      • Ha CY
      • Kaneshiro BE
      Pregnancy intention and contraceptive use among women by class of obesity: results from the 2006-2010 and 2011-2013 National Survey of Family Growth.
      ]. The overall discontinuation rate in SECURE was 51.3%, similar to rates seen in other phase 3 CHC trials. The segesterone acetate vaginal ring study [
      • Archer DF
      • Merkatz RB
      • Bahamondes L
      • Westhoff CL
      • Darney P
      • Apter D
      • et al.
      Efficacy of the 1-year (13-cycle) segesterone acetate and ethinylestradiol contraceptive vaginal system: results of two multicentre, open-label, single-arm, phase 3 trials.
      ] and various oral LNG/EE studies [
      • Portman DJ
      • Kaunitz AM
      • Howard B
      • Weiss H
      • Hsieh J
      • Ricciotti N
      Efficacy and safety of an ascending-dose, extended-regimen levonorgestrel/ethinyl estradiol combined oral contraceptive.
      ,
      • Archer DF
      • Jensen JT
      • Johnson JV
      • Borisute H
      • Grubb GS
      • Constantine GD
      Evaluation of a continuous regimen of levonorgestrel/ethinyl estradiol: phase 3 study results.
      ] report discontinuation rates between 42% and 57%. Additionally, the LTFU rate in SECURE (11%) fell within the range of the LTFU rates reported in these studies (10%–16%). Overall, the efficacy results suggest that the aggregate effect of all these design elements, in particular the enrollment of women without BMI exclusions, had substantial impacts on contraceptive effectiveness.
      The TDS was well tolerated, with low rates of patch detachment and site irritation. Most TEAEs were mild or moderate; SAE rates were low. Five women all with BMI ≥30 kg/m2 experienced 6 embolic events, of which 4 women were considered to have study-drug related events consistent with the increased baseline risk of embolic events in obese women [
      • Pomp ER
      • le Cessie S
      • Rosendaal FR
      • Doggen CJM
      Risk of venous thrombosis: obesity and its joint effect with oral contraceptive use and prothrombotic mutations.
      ]. Due to increased risk of VTE and reduced efficacy in women with BMI ≥30 kg/m2 from SECURE, TDS is contraindicated in these women. As patient populations in contraceptive trials such as SECURE become more representative of the real-world population, rates of embolic events may be higher than seen in past studies, with absolute risk remaining relatively low in women with BMI <30 kg/m2.
      The results of the primary efficacy analysis, in conjunction with key secondary and subgroup efficacy analyses, demonstrate that TDS was effective in preventing pregnancy in a diverse population of sexually active, reproductive-aged US women. The SECURE trial results led to the FDA approval of TWIRLA in February 2020 as a contraceptive method for women with BMI <30 kg/m2. TDS addresses a gap in the contraceptive landscape by offering nonobese women a nondaily transdermal contraceptive option that reduces estrogen exposure with favorable efficacy, safety, and tolerability [
      • Nelson AL
      Transdermal contraception methods: today's patches and new options on the horizon.
      ,
      • Crosignani PG
      • Nappi C
      • Ronsini S
      • Bruni V
      • Marelli S
      • Sonnino D
      • et al.
      Satisfaction and compliance in hormonal contraception: the result of a multicentre clinical study on women's experience with the ethinylestradiol/norelgestromin contraceptive patch in Italy.
      ].

      Acknowledgments

      The authors would like to acknowledge the contributions of investigators and staff at the 102 sites in the United States. Medical writing assistance was provided by Ying Hou, PhD, and Rebecca Miles, PhD, of PharmaWrite, LLC (Princeton, NJ), and was funded by Agile Therapeutics, Inc. (Princeton, NJ). This manuscript was prepared according to the International Society for Medical Publication Professionals’ “Good Publication Practice for Communicating Company-Sponsored Medical Research: GPP3.”
      Clinical trial registration: This clinical trial was registered at www.ClinicalTrials.gov as: NCT02158572; Efficacy, Safety and Tolerability Study of Agile AG200-15 Transdermal Contraceptive Delivery System. The URL can be found at: https://clinicaltrials.gov/ct2/show/NCT02158572.
      Funding: This study was funded by Agile Therapeutics, Inc., Princeton, NJ. Medical writing was provided by PharmaWrite, LLC, and was funded by Agile Therapeutics, Inc. Agile Therapeutics, Inc. provided a full review of the article and had a role in the design, execution, data collection and analysis, reporting, and funding of the study.
      Declaration of competing interest:
      The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
      ALN: Consultant/Advisor: Agile Therapeutics, Inc., AMAG, American Regent, Bayer HealthCare, Merck, Sebela Pharmaceuticals, TherapeuticsMD; Honoraria/Speaker: American Regent, Bayer HealthCare, Merck, TherapeuticsMD; Grants/Research Support: Agile Therapeutics, Inc., Mayne Pharma, Merck, Myovant Sciences, Sebela Pharmaceuticals.
      AMK: Consultant/Advisor: Merck, Mithra, Pfizer; Research Support (institution): AbbVie, Agile Therapeutics, Inc., Mithra.
      RK: Research Support: Astellas, Myovant Sciences, Sebela, TherapeuticsMD.
      JAS: Consultant/Advisor: AbbVie, Allergan, AMAG, Amgen, Ascend, Azure, Millendo, Nuelle, Radius, Regeneron, Roivant, Sanofi, Sebela Pharmaceuticals, Sermonix, Shionogi, Symbiotec, TherapeuticsMD, Valeant; Speaker: Novo Nordisk, Shionogi, Valeant; Research Support: AbbVie, Agile, Allergan, Bayer HealthCare, New England Research Institute, Palatin, Symbio, TherapeuticsMD; Stock Ownership: Sermonix.
      ANP: Consultant/Advisor: Agile Therapeutics, Inc., Allergan, Bayer HealthCare, Pfizer; Research Support: Agile Therapeutics, Inc.
      PMC: Consultant/Advisor: Bayer HealthCare, Merck; Research Support: Agile Therapeutics, Inc., Bayer HealthCare.
      RTA: Research Support: Abbott, AbbVie, Agile Therapeutics, Inc., Allergan, Acoustic Wave, Sebela Pharmaceuticals, Starpharma, VivEve.
      JAC: Employee: Agile Therapeutics, Inc., Princeton, NJ.
      LF: Employee/Consultant: Agile Therapeutics, Inc., Princeton, NJ.
      EIOG: Employee (CMO 2014-2019)/Consultant: Agile Therapeutics, Inc., Princeton, NJ.

      Appendix. Supplementary materials

      References

        • Nelson AL
        Transdermal contraception methods: today's patches and new options on the horizon.
        Expert Opin Pharmacother. 2015; 16: 863-873
        • Stegeman BH
        • de Bastos M
        • Rosendaal FR
        • van Hylckama Vlieg A
        • Helmerhorst FM
        • Stijnen T
        • et al.
        Different combined oral contraceptives and the risk of venous thrombosis: systematic review and network meta-analysis.
        BMJ. 2013; 347: f5298
        • US Food and Drug Administration.
        Final summary minutes: Advisory Committee for Reproductive Health Drugs meeting. 2007 (Available at:) (. Accessed February 25, 2020)
        • US Food and Drug Administration.
        Establishing effectiveness and safety for hormonal drug products intended to prevent pregnancy: guidance for industry. 2019 (Available at: https://www.fda.gov/media/128792/download. Accessed November 18, 2019)
        • Archer DF
        • Stanczyk FZ
        • Rubin A
        • Foegh M
        Ethinyl estradiol and levonorgestrel pharmacokinetics with a low-dose transdermal contraceptive delivery system, AG200-15: a randomized controlled trial.
        Contraception. 2012; 85: 595-601
      1. TWIRLA (levonorgestrel and ethinyl estradiol) transdermal system [prescribing information].
        Corium International, Inc., Grand Rapids, MIFebruary 2020
        • Curtis KM
        • Tepper NK
        • Jatlaoui TC
        • Berry-Bibee E
        • Horton LG
        • Zapata LB
        • et al.
        U.S. medical eligibility criteria for contraceptive use, 2016.
        MMWR Recomm Rep. 2016; 65: 1-103
        • Yamazaki M
        • Dwyer K
        • Sobhan M
        • Davis D
        • Kim MJ
        • Soule L
        • et al.
        Effect of obesity on the effectiveness of hormonal contraceptives: an individual participant data meta-analysis.
        Contraception. 2015; 92: 445-452
        • Westhoff CL
        • Torgal AT
        • Mayeda ER
        • Shimoni N
        • Stanczyk FZ
        • Pike MC
        Predictors of noncompliance in an oral contraceptive clinical trial.
        Contraception. 2012; 85: 465-469
        • Nguyen BT
        • Elia JL
        • Ha CY
        • Kaneshiro BE
        Pregnancy intention and contraceptive use among women by class of obesity: results from the 2006-2010 and 2011-2013 National Survey of Family Growth.
        Womens Health Issues. 2017; 28: 51-58
        • Archer DF
        • Merkatz RB
        • Bahamondes L
        • Westhoff CL
        • Darney P
        • Apter D
        • et al.
        Efficacy of the 1-year (13-cycle) segesterone acetate and ethinylestradiol contraceptive vaginal system: results of two multicentre, open-label, single-arm, phase 3 trials.
        Lancet Glob Health. 2019; 7: e1054-e1e64
        • Portman DJ
        • Kaunitz AM
        • Howard B
        • Weiss H
        • Hsieh J
        • Ricciotti N
        Efficacy and safety of an ascending-dose, extended-regimen levonorgestrel/ethinyl estradiol combined oral contraceptive.
        Contraception. 2014; 89: 299-306
        • Archer DF
        • Jensen JT
        • Johnson JV
        • Borisute H
        • Grubb GS
        • Constantine GD
        Evaluation of a continuous regimen of levonorgestrel/ethinyl estradiol: phase 3 study results.
        Contraception. 2006; 74: 439-445
        • Pomp ER
        • le Cessie S
        • Rosendaal FR
        • Doggen CJM
        Risk of venous thrombosis: obesity and its joint effect with oral contraceptive use and prothrombotic mutations.
        Br J Haematol. 2007; 139: 289-296
        • Crosignani PG
        • Nappi C
        • Ronsini S
        • Bruni V
        • Marelli S
        • Sonnino D
        • et al.
        Satisfaction and compliance in hormonal contraception: the result of a multicentre clinical study on women's experience with the ethinylestradiol/norelgestromin contraceptive patch in Italy.
        BMC Womens Health. 2009; 9: 18