Clinical data for NEXTSTELLIS®
NEXTSTELLIS was studied in a population that included a range of ages and BMIs. See how NEXTSTELLIS delivered across key endpoints in a large, multiphase clinical trial program.1
Overview of the NEXTSTELLIS clinical trial program
NEXTSTELLIS demonstrated efficacy and safety in a robust clinical trial program. In Phase 2 studies, NEXTSTELLIS was compared head-to-head against 2 standard-of-care birth control pills—EE/DRSP (Yaz®) and EE/LNG (e.g. Nordette® or Microgynon®). The Phase 3 pooled population included women 16 to 50 years of age with a BMI up to 35 kg/m2.1
Click below to learn more about the trial design and endpoints in the:
Phase 2 trial program
Dose-finding studies
In 2 Phase 2 dose-finding studies, 2 progestins (DRSP and LNG) were evaluated in combination with estetrol to determine21,27:
- Minimum effective dose of estetrol
- Most complementary progestin
Endpoints included21,27:
- Ovulation inhibition
- Bleeding patterns
- Effect on liver parameters
- Effect on sex hormone-binding globulin (SHBG)
Safety studies
In the Phase 2 safety studies, NEXTSTELLIS was studied head-to-head against 2 standard-of-care COCs8,26,30
- Yaz® (20 mcg EE/3 mg DRSP)
- Nordette® or Microgynon® (30 mcg EE/150 mcg LNG)
Endpoints included8,26,30:
- Haemostasis parameters
- Endocrine parameters, as well as SHBG
- Lipid and carbohydrate metabolism parameters
- Ovulation inhibition
Phase 3 trial program
Patient demographics reflect a real-world range in age, weight and contraceptive history1,7,25
Study Details
The two Phase 3 trials of NEXTSTELLIS studied 3632 women (ages 16-50 years). The efficacy population in the North American trial was 1524 (ages 16-35 years), and in the EU/Russian study, it was 1313 (ages 18-35 years). Women were studied over 12 months for 13 menstrual cycles, totaling 26,455 at-risk cycles.1,7,29
Patient demographics (pooled population n=3417)23,24
CONTRACEPTIVE HISTORY
- Switching: 50.7%
- Starting: 49.3%
- Naive users: 19.7%
SMOKERS
- 13.7%
(current smokers aged >35 years excluded)
WEIGHT
- BMI (kg/m2) mean 24.6 ± 4.4
<30.0 84.8%
≥30.0* 15.2% *23% in North American study
RACE
- White: 82.9%
- Black: 11%
- Asian: 2.8%
- Other: 3.3%
Switchers: previous hormonal contraceptive use within 3 months before screening.
Starters: previous hormonal contraceptive use >3 months before screening (starters) and none (true new users)
Phase 3 data: Results from a large and inclusive trial program
Key clinical endpoints from the Phase 3 trials
Up to 99.6%
Contraceptive efficacy
NEXTSTELLIS was 99.6% effective in preventing pregnancy in the Phase 3 European study (18-35 years - Pearl index: 0.47).1,25
BMI ≥30
Effective across body sizes
In the North American Study the high BMI subgroup (BMI 30-35 kg/m2) had a Pearl index of 2.94 and no VTEs.1,7*
* One VTE in EU study
In the Phase 3 studies, most women had bleeding patterns similar to a natural, predictable menstrual cycle1,24
NEXTSTELLIS, with its 24/4 monophasic regimen, delivers a predictable bleeding pattern1
Scheduled
Bleeding
90%
90% of women experienced regular withdrawal bleeding. Average duration was 4-5 days.1
Unscheduled
Bleeding
<2%
<2% of patients experienced unscheduled bleeding-only episodes after cycle 2.23,24
Average
Duration
<1 day
<1 day of any unscheduled spotting or bleeding on average per cycle after cycle 1.1
Minimal unscheduled spotting or bleeding in the Phase 3 studies1
99% of patients who reported unscheduled spotting and/or bleeding experienced spotting only 1,23,24
- Spotting was defined as minimal bleeding that did not require the use of any sanitary protection (including pantyliners)
- 27.1% of patients had unscheduled spotting or bleeding at cycle 1, decreased to 20.6% at cycle 2, remained <20% after cycle 4 and continued to decrease to 15% (cycle 12)
- The average duration of unscheduled bleeding or spotting per cycle was <1 day after cycle 1 with most being spotting only (62.7%)
Per cycle, percentage of women reporting unscheduled spotting, mixed bleeding/spotting, or bleeding in the pooled bleeding analysis23,24
- Bleeding-only episodes occurred in <2% of women23,24
- The bleeding profile was similar across patient subgroups (BMI ≥30 kg/m2, starters, and switchers)23,24
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PBS Information: THIS PRODUCT IS NOT LISTED ON THE PBS. |
IMPORTANT SAFETY INFORMATION FOR NEXTSTELLIS® (estetrol/drospirenone tablets)
As NEXTSTELLIS contains estetrol, a new molecular entity, it qualifies for the TGA’s Black Triangle Scheme. ▼ This medicinal product is subject to additional monitoring in Australia. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse events at www.tga.gov.au/reporting-problems
BMI=body mass index; COC=combined oral contraceptive; EU=European Union; HDL=high-density lipoprotein; LDL=low-density lipoprotein; LNG=levonorgestrel. EE=ethinylestradiol; DRSP=drospirenone
References
1. NEXTSTELLIS Product Information. 2. Gérard C, et al. Profile of estetrol, a promising native estrogen for oral contraception and the relief of climacteric symptoms of menopause. Expert Review of Clinical Pharmacology 2022; 15:2, 121-137. 3. Drovelis EMEA authorisation. European Medicines Agency (EMA). https://www.ema.europa.eu/en/medicines/human/EPAR/drovelis#authorisation-details-section [accessed on 18 Jul 2022]. 4. Coelingh Bennink HJT, et al. Estetrol review: profile and potential clinical applications. Climacteric. 2008;11(suppl 1):47-58. 5. Lydisilka EMEA authorisation. European Medicines Agency (EMA). https://www.ema.europa.eu/en/medicines/human/EPAR/lydisilka#authorisation-details-section [accessed on 18 Jul 2022]. 6. Foidart JM, et al. Unique vascular benefits of estetrol, a natural fetal estrogen with specific actions in tissues (NEST). In: Brinton RD, Genazzani AR, Simoncini T, Stevenson JC, eds. Sex Steroids’ Effects on Brain, Heart and Vessels. Volume 6: Frontiers in Gynecological Endocrinology. New York, NY: Springer International Publishing; 2019:169‐195. 7. Creinin M, et al. Estetrol-drospirenone combination oral contraceptive: North American phase 3 efficacy and safety results. Contraception. 2021; 104: 222–228 8. Douxfils J, et al. Evaluation of the effect of a new oral contraceptive containing estetrol and drospirenone on hemostasis parameters. Contraception. 2020;102(6): 396–402. 9. Arnal JF, et al. Membrane and nuclear estrogen receptor alpha actions: from tissue specificity to medical implications. Physiol Rev. 2017;97(3):1045-1087. 10. Nextstellis Approval FDA. U.S. Food & Drug Administration (FDA). https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=214154 [accessed on 18 Jul 2022]. 11. Stanczyk FZ, et al. Ethinyl estradiol and 17β-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment. Contraception. 2013;87(6):706-727. 12. Jensen JT, et al. Pooled efficacy results of estetrol/drospirenone combined oral contraception phase 3 trials. Contraception. 2022; DOI: https://doi.org/10.1016/j.contraception.2022.07.009. Epub ahead of print. PMID: 35921870. 13. Abot A, et al. The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor α modulation, uncoupling nuclear and membrane activation. EMBO Mol Med. 2014;6(10):1328-1346. 14. Ascenzi P, et al. Structure-function relationship of estrogen receptor alpha and beta: impact on human health. Mol Aspects Med. 2006;27(4):299-402. 15. Coelingh Bennink HJT, et al. Oral bioavailability and bone-sparing effects of estetrol in an osteoporosis model. Climacteric. 2008;11(suppl 1):2-14. 16. Benoit T, et al. Estetrol, a fetal selective estrogen receptor modulator, acts on the vagina of mice through nuclear estrogen receptor α activation. Am J Pathol. 2017;187(11):2499-2507. 17. Fruzzetti F, et al. Estetrol: A New Choice for Contraception. J. Clin. Med. 2021, 10, 5625. https://doi.org/10.3390/jcm10235625. 18. Visser M, et al. In vitro effects of estetrol on receptor binding, drug targets, and human liver cell metabolism. Climacteric. 2008;11(suppl 1):64-68. 19. Nextstellis Approval Health Canada. Health Canada, Government of Canada. 25 April 2012. https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=100241 [accessed on 18 Jul 2022]. 20. Kestemont P, et al. 2020. Poster 0175 presented at the Society of Family Planning Virtual Annual Meeting October 9 10, 2020. 21. Apter D, et al. Bleeding pattern and cycle control with estetrol-containing combined oral contraceptives: results from a phase II, randomised, dose-finding study (FIESTA). Contraception. 2016;94(4):366-373. 22. Regidor PA, et al. Antiandrogenic and antimineralocorticoid health benefits of COC containing newer progestogens: dienogest and drospirenone. Oncotarget. 2017;8(47):83334-83342. 23. Data on file – Mithra Pharmaceuticals from MIT-ES0001-C301; MIT-ES0001-C302. 24. Kaunitz AM, et al. Pooled analysis of two phase 3 trials evaluating the effects of a novel combined oral contraceptive containing estetrol/drospirenone on bleeding patterns in healthy women. Contraception. 2022 Jul 31:S0010-7824(22)00218-9. doi: 10.1016/j.contraception.2022.07.010. Epub ahead of print. PMID: 35921872. 25. Gemzell-Danielsson K, et al. Estetrol-Drospirenone combination oral contraceptive: a clinical study of contraceptive efficacy, bleeding pattern and safety in Europe and Russia. BJOG. 2022; 129: 63-71. 26. Klipping C, et al. Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone. Contraception. 2021;103(4): 213–221. 27. Mawet M, et al. Unique effects on hepatic function, lipid metabolism, bone and growth endocrine parameters of estetrol in combined oral contraceptives. Eur. J. Contracept. Reprod. Health Care 2015, 20, 463–475. 28. NEXTSTELLIS ARTG ID 341876 available at http://www.ebs.tga.gov.au [accessed on 21 June 2021]. 29. Chen M, et al. Submitted Manuscript 2022. 30. Duijkers I, et al. Effects of an oral contraceptive containing estetrol and drospirenone on ovarian function. Contraception 103 (2021) 386–393. 31. Holinka CF & Gurpide E. In vivo effects of estetrol on the immature rat uterus. Biology of Reproduction. 1979;20:242-246. 32. Gérard C, et al. Estetrol is a weak estrogen antagonizing estradiol-dependent mammary gland proliferation. Journal of Endocrinology 2015; 224, 85–95. 33. Lee A & Syed YY. Estetrol/Drospirenone: A Review in Oral Contraception. Drugs. 2022 Jul 4. doi: 10.1007/s40265-022-01738-8. Epub ahead of print. PMID: 35781795. 34. Holinka CF, et al. Estetrol: A unique steroid in human pregnancy. J Steroid Biochem Mol Biol. 2008; 110(1–2): 138–143. 35. Warmerdam EG, et al. A new route of synthesis of estetrol. Climacteric. 2008; 11(suppl 1): 59–63. 36. YAZ Product Information. 37. 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