Once-weekly Transdermal patch TWIRLA effectively prevents pregnancy: Clinical trial results

In collaboration with the US Food and Drug Administration (FDA), Anita L. Nelson and team conducted the phase 3 Study to Evaluate Contraceptive Use, Reliability, and Effectiveness (SECURE) in a representative population of potential users in the United States.

SECURE 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.

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. 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. A cycle of TDS consists of three consecutive weekly patches (21 days of active treatment) followed by a patch free week (7 days).

The target enrollment for the study included approximately 2,100 women, ≥18 years old with regular 21–38 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.

Women used patches in 28-day cycles (three consecutive administrations of 7-day patches followed by 7 days off-treatment/patch-free week). Authors assessed contraceptive efficacy by the Pearl Index (PI) in women 18–35 years, excluding cycles without intercourse or when other contraceptive methods were used.

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.

• SECURE enrolled 2,032 women, of whom 2,031 were included in the Safety population and 1,736 women in the ITT population, which included women ≤35 years who contributed 15,165 cycles in the primary efficacy PI analysis.

• The mean ± SD age of participants was 27.5 ± 6.2 years. Mean ± SD BMI was 28.3 ± 7.1 kg/m2.

• The primary efficacy analysis for women ≤35 years old yielded a PI of 5.8 pregnancies per 100 woman-years

• Women with BMI <30 kg/m2 had a lower PI (4.3) than women with BMI ≥30 kg/m2 (8.6). BMI subgroup analysis showed a trend toward higher PIs as BMI increased

• In the Cycle Control population, 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

• 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 proportion of women reporting ≥1 day of unscheduled bleeding/spotting decreased from 60.4% (Cycle 1) to 42.3% (Cycle 13).

• In the Safety population, 53.4% of women reported experiencing a treatment-emergent adverse events (TEAE) and 27.2% of women reported experiencing a study-drug related TEAE. The incidence of TEAEs was similar between the two 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)><30 kg/m2 and ≥30 kg/m2) groups. The most frequently reported hormone-related TEAEs were nausea (4.1%) and headache (3.6%).

• Between Cycles 5–13, five women, all with BMIs >30 kg/m2, experienced six venous thromboembolism events (VTE; deep vein thrombosis [DVT], n=3; pulmonary embolism [PE], n=3). Of the six embolic events, investigators considered five events from four women related to treatment

• The most common hormone-related TEAE resulting in discontinuation was nausea (0.9%), application site irritation (1.1%), pruritus (0.8%), rash (0.7%), dermatitis (0.5%), and erythema (0.4%).

• The most common site for patch placement was the buttock area (44.8%).

• Most investigators (99.4%) and women (88.7%) reported adhesion scores of 0=no detachment or 1=some edge lifting. 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.

The results of the primary efficacy analysis, in conjunction with key secondary and subgroup efficacy analyses, demonstrated 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 non-obese women a non-daily transdermal contraceptive option that reduces estrogen exposure with favorable efficacy, safety, and tolerability. Efficacy was reduced in women with BMI ≥30 kg/m2 . Results of this phase 3 study supported the FDA approval of TWIRLA® for prevention of pregnancy in women with BMI.

Source: Anita L. Nelson MD , Andrew M. Kaunitz MD , Robin Kroll MD et al, for the SECURE Investigators, Efficacy, Safety, and Tolerability of a Levonorgestrel/Ethinyl Estradiol Transdermal Delivery System: Phase 3 Clinical Trial Results, Contraception (2020)

doi: https://doi.org/10.1016/j.contraception.2020.11.011