Objective
The safety and tolerability of a new low-dose levonorgestrel/ethinyl estradiol (LNG/EE) contraceptive patch was compared with 2 combination oral contraceptives in 2 clinical studies in which approximately 30% of enrolled participants were obese.
Study Design
Two phase 3, open-label, randomized, parallel-group, multicenter trials compared the LNG/EE contraceptive patch (n = 1579) with combination oral contraceptives (n = 581) in healthy women 17–40 years of age. Combination oral contraceptives were LNG 100 μg per EE 20 μg (combination oral contraceptive 20; n = 375) or LNG 150 μg per EE 30 μg (combination oral contraceptive 30; n = 206). Safety and tolerability data from the 2 trials were evaluated in integrated safety analyses.
Results
Treatment-emergent adverse events of 2% or greater in the LNG/EE contraceptive patch were nasopharyngitis (5.2%), nausea (4.1%), upper respiratory infection (3.5%), headache (3.4%), sinusitis (2.9%), cervical dysplasia (2.3%), and urinary tract infection (2.1%). Including skin reaction–related treatment-emergent adverse events, the proportion of women who experienced any treatment-emergent adverse event was similar among women randomized to the contraceptive patch (47.5%), the combination oral contraceptive 20 (47.4%), or the combination oral contraceptive 30 (46.8%). The incidence of treatment-emergent adverse events was similar in obese vs nonobese participants in all groups. Serious adverse events occurred in less than 1% of participants in any of the treatment groups.
Conclusion
The LNG/EE contraceptive patch and combination oral contraceptives were well tolerated and associated with similar treatment-emergent adverse event incidences in obese and nonobese women.
Combination oral contraceptives (COCs) represent an effective and safe means of contraception. Nevertheless, inadequate compliance with daily COCs among some women can reduce their ability to effectively prevent pregnancy. The transdermal contraceptive patch (CP), applied weekly in clinical trials, has been associated with improved compliance compared with COCs.
The only transdermal contraceptive approved by the US Food and Drug Administration is the norelgestromin (NGMN)/ethinyl estradiol (EE) patch, Ortho Evra. Although the initial package label claimed this patch delivered a low dose of EE (the equivalent of a 20 μg COC), the NGMN patch actually produces EE levels (area under the curve) that are approximately 60% higher than those of a COC containing EE 35 μg. Increased estrogen exposure may increase the risk of serious adverse events (SAEs; eg, venous thromboembolism [VTE]) as well as other hormone-related treatment-emergent adverse events (TEAEs; eg, breast symptoms). Three phase 3 clinical trials found that approximately 1 in 5 women treated with Ortho Evra (Janssen Pharmaceuticals, Inc, Titusville, NJ) experienced hormone-related TEAEs such as breast symptoms and/or headache and/or nausea.
The risk of VTE among women without risk factors using COCs is 3-9 per 10,000 woman-years. The risk of VTE associated with contraceptive estrogen exposure may be increased in women with higher body mass index (BMI). For example, in a study of 3834 patients with VTE, obese women (BMI of ≥30 kg/m 2 ) not using COCs had a 2.4-fold higher risk of VTE compared with normal-weight women (BMI <25 kg/m 2 ) not using COCs. However, among obese women using COCs, the risk of VTE was 24-fold higher than that for normal-weight women who did not use COCs. Whether obese women may be at increased risk of other TEAEs related to hormonal contraception is largely unknown because obese women have previously been excluded from clinical studies of contraceptives.
Twirla (Agile Therapeutics, Inc, Princeton, NJ) is an investigational CP developed with the goal of delivering a dose of levonorgestrel (LNG) and EE that is effective and maintains serum EE exposure similar to that attained with low-dose COCs (ie, EE dose of 35 μg/d or less). This 7 day LNG/EE CP consistently produced LNG and EE levels under the curve equivalent to those associated with the use of an LNG 120 μg/EE 30 μg COC in phase 1 and 2 trials.
A report summarizing the findings of the phase 3 trial comparing the LNG/EE CP with a COC containing 100 μg of LNG and 20 μg of EE (COC20) and focusing on compliance and contraceptive efficacy has been published. Here we present integrated safety and tolerability data from the previously reported trial and a second phase 3 clinical trial that compared the efficacy and safety of the LNG/EE CP with a COC containing LNG 150 μg and EE 30 μg (COC30). Safety and tolerability were assessed based on the incidence of TEAEs, SAEs, discontinuation rates, and changes in physical examinations, vital signs, and clinical laboratory tests.
Because the 2 studies were conducted using similar protocols and during the same time period, data from the 2 studies were pooled to add increased numbers of participants to the safety analyses. These phase 3 studies were designed to enroll a population of women with BMIs representative of the US population; approximately 33% of the participants were to be obese (BMI of ≥30 kg/m 2 ) and approximately 50% of obese women were to have a BMI of 35 kg/m 2 or greater, permitting a comparison of the safety profiles of patch and COC in obese vs nonobese women.
Materials and Methods
Study design
Two phase 3, open-label, randomized, multicenter, parallel-group clinical studies were conducted to evaluate the safety and efficacy of the LNG/EE CP. Eligible participants in study CL12 were randomized in a 3:1 ratio to treatment with LNG/EE CP for 13 cycles or to treatment with COC20 for 6 cycles followed by LNG/EE CP for 7 cycles ( Figure 1 , A).
Participants in study CL13 were randomized in a 1:1 ratio to LNG/EE CP for 6 cycles or to COC30 for 6 cycles ( Figure 1 , B). A cycle was defined as a 28 day period with 21 days on treatment (consecutive administration of three 7 day patches or 21 days of active pill taking) followed by 7 days off treatment (ie, no patch applied or no active pills taken) in both studies. All patches were applied to the abdomen, buttock, or upper torso (excluding the breasts) according to participant preference.
Participants
Both studies enrolled sexually active women aged 17-40 years of any body weight with regular menses (every 24-35 days) who were requesting contraception. All participants were in good general health, as confirmed by medical history, physical and gynecologic examinations, and screening laboratory values and were appropriate candidates for combination estrogen/progestin contraception.
Any healthy woman with any BMI was included. Smokers were permitted if they were younger than 35 years of age. Women with well-controlled hypertension or diabetes mellitus without vascular disease were enrolled if their BMI was less than 32 kg/m 2 and they were 17-40 years of age. The BMI cutoff of 32 for women with hypertension or diabetes mellitus was selected to avoid compounding VTE risk among these at-risk populations.
Centralized stratified randomization was used to achieve high BMI enrollment targets (approximately 33% with BMI of ≥30 kg/m 2 ; approximately 50% of obese participants with BMI of ≥35 kg/m 2 ). The study protocols were approved by applicable institutional review boards (New England Institutional Review Board, Newton, MA; Schulman Associates, Cincinnati, OH; Crescent City Institutional Review Board, New Orleans, LA; Western Institutional Review Board, Olympia, WA), received ethics committee approval, and all participants provided written informed consent before screening.
New users of hormonal contraceptives were defined as women with no exposure to hormonal contraceptives within 6 months prior to the start of the study medication; current users were those who stopped a hormonal contraceptive within 7 days of starting study treatment; recent users were those who had used a hormonal contraceptive within the previous 6 months (but not within 7 days of study start).
Study drugs
Patch
Adhesive patches contained LNG and EE in a 15.0 cm 2 active matrix core surrounded by a perimeter adhesive system (26.0 cm 2 total area). The LNG/EE CP is manufactured by Corium International (Grand Rapids, MI).
COCs
Each COC20 pill contained LNG 100 μg and EE 20 μg (Lessina 0.1/20–28; Watson Pharma, Inc, Parsippany, NJ [manufactured by Patheon, Inc, Mississauga, Ontario, Canada]). COC30 pills contained LNG 150 μg and EE 30 μg (Levora 0.15/30–28; Watson Pharma, Inc).
Safety assessments
Clinic visits were made by all active participants during cycles 2, 4, 6, 9 (CL12 only), and 13 (CL12 only). At each of these visits, adverse events (AEs), vital signs (body weight, temperature, respiratory rate, pulse rate, systolic and diastolic blood pressure) were assessed by the investigator. Clinical laboratory tests (hematology, clinical chemistry, lipid panel, and urinalysis) were conducted at screening, during cycle 6 (COC only), and 14 days after the last dose of study drug. The severity of an AE as categorized as mild (discomfort noted but no disruption of normal daily activity), moderate (discomfort noted of sufficient severity to reduce or adversely affect normal activity), or severe (incapacitating, with an inability to work or perform normal daily activity) by the investigator. TEAEs were defined as those AEs occurring after a study participant had received at least 1 dose of study drug. Safety evaluations were based on the incidence of TEAEs, SAEs, application site reactions, study discontinuation information, changes from screening to last assessment in physical and gynecological examinations, vital signs, and clinical laboratory tests, including hematology, blood chemistry, blood lipids, and urinalysis.
Statistical analysis
The safety population included all participants who received any amount of study drug in either study. Discontinuation information, TEAEs, and SAEs were tallied for all participants in the following treatment groups: CP cycles 1-13 (all participants randomized to CP in study CL12 or CL13), CP cycles 1-6 (safety and discontinuation data from cycles 1-6 for all participants randomized to CP in CL12 and CL13), COC20 cycles 1-6 (study CL12 only), and COC30 cycles 1-6 (study CL13 only). Data were also summarized by BMI category (<30 kg/m 2 ; ≥30 kg/m 2 ). All statistical analyses were conducted using SAS (version 9.2; SAS Institute, Cary, NC).
Results
Disposition and demographics
A total of 1579 women were randomized to CP (6 cycles, 13 cycles, or 7 cycles following COC20), 375 women to COC20, and 206 participants to COC30. The disposition of participants following treatment randomization is summarized by treatment in Figure 2 . The most common reasons for early withdrawal from CP treatment over all treatment cycles (1-13) were lost to follow-up (19.6%), participant’s decision (14.7%), and AEs (19.7%).
The proportion of participants lost to follow-up was similar in each COC treatment group (15.5–16.3%), but rates of discontinuation because of participant’s decision (6.3–8.0%) and AEs (1.9–4.0%) were lower in the COC groups than in the LNG/EE CP group. Of all participants discontinuing in either of the 2 studies, 21% in the patch group and 18% in the COC groups dropped out before cycle 2. Current and recent users of hormonal contraceptives were more likely to complete the study (CP cycles 1-13, 57.1%; COC cycles 1-6, 80.7–86.4%) compared with new users (CP cycles 1-13, 41.8%; COC cycles 1-6, 57.6–59.8%).
Demographic characteristics are summarized by treatment group in Table 1 . Participants in each treatment group were comparable with respect to age, weight, height, BMI, and race/ethnicity. The groups were also comparable with respect to the highest level of education achieved, smoking status, current alcohol use, and previous contraceptive use status (data not shown). In all treatment groups, approximately 30% of women were obese (BMI of ≥30 kg/m 2 ) and approximately 50% of obese women had BMIs of 35 kg/m 2 or greater. More than half (CP, 58%; COC, 56%) of the women enrolled in the 2 trials were new users of hormonal contraceptives.
| Mean (SD), unless otherwise noted | LNG/EE patch | COC | ||
|---|---|---|---|---|
| Cycles 1-6 (n = 1220) | Cycles 1-13 (n = 1450) | COC20 Cycles 1-6 (n = 344) | COC30 Cycles 1-6 (n = 188) | |
| Age, y | 26.3 (5.6) | 26.4 (5.6) | 26.4 (5.7) | 26.7 (5.7) |
| Weight, kg | 72.9 (19.3) | 72.9 (19.2) | 73.7 (19.6) | 66.2 (10.9) |
| Height, cm | 163.8 (6.9) | 163.7 (7.0) | 163.5 (7.2) | 163.0 (6.2) |
| BMI (kg/m²), n (%) | 27.2 (6.9) | 27.2 (6.8) | 27.5 (6.8) | 24.9 (3.6) |
| BMI subgroup (kg/m²), n (%) | ||||
| <25 | 558 (45.7) | 661 (45.5) | 146 (42.4) | 103 (54.8) |
| 25 to <30 | 343 (28.1) | 408 (28.1) | 99 (28.8) | 64 (34.0) |
| 30 to <35 | 156 (12.8) | 185 (12.8) | 45 (13.1) | 21 (11.2) |
| ≥35 | 163 (13.4) | 196 (13.6) | 54 (15.7) | 0 (0.0) |
| Race/ethnicity, n (%) | ||||
| White (not Hispanic) | 699 (57.3) | 839 (57.9) | 191 (55.5) | 111 (59.0) |
| Hispanic (white) | 182 (14.9) | 219 (15.1) | 61 (17.7) | 37 (19.7) |
| Black | 273 (22.4) | 309 (21.3) | 71 (20.6) | 30 (16.0) |
| Asian | 41 (3.4) | 50 (3.4) | 12 (3.5) | 2 (1.1) |
| Other | 25 (2.0) | 33 (2.3) | 9 (2.6) | 8 (4.3) |
Safety and tolerability
Nasopharyngitis was the only TEAE that occurred in more than 5% of participants in the patch group (5.2%) and more frequently than in the COC20 (3.5%) or COC30 (4.3%) groups. TEAEs reported for 2% or more of participants receiving the patch, COC20, or COC30 are listed in Table 2 . Application site reactions observed in women receiving the LNG/EE CP are summarized in Table 3 . Including application site–related TEAEs, the proportion of women who experienced any TEAE was similar among the women randomized to the patch or COC ( Table 2 ).
| Percentage of participants | LNG/EE Patch (n = 1220) | COC20 (n = 344) | COC30 (n = 188) |
|---|---|---|---|
| Any TEAE excluding patch site reactions | 41.9 | 47.4 | 46.8 |
| Any TEAE including patch reactions | 47.5 | 47.4 | 46.8 |
| Nasopharyngitis | 5.2 | 3.5 | 4.3 |
| Nausea | 4.1 | 4.1 | 5.9 |
| Upper respiratory infection | 3.5 | 2.0 | 4.3 |
| Headache | 3.4 | 4.7 | 1.1 |
| Sinusitis | 2.9 | 2.6 | 2.7 |
| Cervical dysplasia | 2.3 | 4.9 | 5.9 |
| Urinary tract infection | 2.1 | 3.2 | 2.1 |
| Breast tenderness | 2.0 | 1.5 | 0.0 |
| Weight increased | 1.9 | 0.6 | 2.1 |
| Dysmenorrhea | 1.8 | 2.6 | 0.5 |
| Vomiting | 1.4 | 2.9 | 3.2 |
| Acne | 1.4 | 2.3 | 1.1 |
| Asthma | 1.2 | 2.0 | 1.1 |
| Fungal infection | 1.0 | 2.0 | 1.6 |
| HPV positive | 1.0 | 2.0 | 2.7 |
| Application site irritation | 2.0 | 0.0 | 0.0 |
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