LF111 or Drospirenone Chew vs Non-hormonal Contraceptive Methods on Bone Mineral Density in Adolescent and Adult Women

Inclusion Criteria:

• Female subjects with regular menstrual cycles (postmenarcheal for at least two yearsand premenopausal) aged 14 to 45 years.

• Female subjects aged between 14 to 17 years (inclusive) will only be includedprovided that:

• Applicable national, state, and local laws allow subjects in this age group toconsent/assent to receive contraceptive services, and

• All applicable laws and regulations regarding the informed consent/assent ofthe subjects to participate in clinical trials are observed.

• Systolic blood pressure < 140 mmHg, diastolic blood pressure < 90 mmHg at Visit 1,in sitting position after 5 minutes of rest.

• Menstruation restarted for at least 6 months since last pregnancy (only applicablefor women that were pregnant).

• Be able and willing to provide written informed consent, or assent if the subject isan adolescent, prior to undergoing any trial-related procedures.

• Willing to use trial contraception for thirteen 28-day cycles (hormonal treatmentarm) or to use non-hormonal contraceptive methods for the duration of the trial (non-hormonal contraceptive arm), respectively.

Exclusion Criteria:

• Contraindications to the use of LF111 or DRSP 3.5 mg chewable tablets (such asactive arterial or venous thromboembolic disorders, liver tumors benign ormalignant, hepatic impairment, renal impairment, adrenal insufficiency, presence orhistory of cervical cancer or progestin-sensitive cancers, known or suspectedsex-steroid sensitive malignancies, undiagnosed abnormal uterine bleeding,undiagnosed vaginal bleeding, hypersensitivity to active substance or excipient) oradverse effects due to previous contraceptive use (for the hormonal treatment armonly).

• BMD Z-score below -1.50. The TBLH Z-score applies only to Cohort 1 (adolescents) andthe total body Z-score applies only to Cohort 2 (adults) when assessing studyeligibility.

• Low trauma fracture(s) defined as a fracture that results from a fall from astanding height or less, excluding fingers, toes, face, and skull.

• Medical conditions associated with low bone mass:

• Metabolic bone disease such as osteogenesis imperfecta, Paget's disease of thebone, osteomalacia/rickets.

• Collagen vascular diseases such as Marfan syndrome and Ehlers-Danlos syndrome.

• Chronic kidney disease stage 3 with estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 using the Bedside Schwartz equation for adolescents and theModification of Diet in Renal Disease (MDRD) method for adult subjects.

• Gastrointestinal (malabsorptive) disease including inflammatory bowel disease,gastric bypass surgery and current post-gastrectomy syndrome.

• Liver disease.

• Abnormal bone mineral metabolism (hypocalcemia/hypercalcemia,hypophosphatemia/hyperphosphatemia, hypomagnesemia).

• In adolescents only: Short stature defined as height-for-age percentile less thanthe fifth percentile.

• Use of progestin-only contraceptive pills in the previous month or use ofimplantable hormonal contraceptives in the previous 6 months.

• Laboratory values at screening which are considered clinically significant and whichin the opinion of the investigator would be detrimental for participation in thestudy.

• Ongoing pregnancy or wish for pregnancy.

• Currently lactating or stopped lactating within the last 12 months.

• Eating disorders (e.g., anorexia nervosa, bulimia).

• Celiac disease.

• Endocrine disorders (e.g., diabetes, hypothyroidism or hyperthyroidism,hyperparathyroidism, Cushing's disease) not adequately controlled with a stabletreatment regiment for > 2 months.

• Rheumatoid arthritis.

• Current or ever use of medications or supplements known to increase BMD includingbisphosphonates, denosumab, teriparatide, abaloparatide, romosozumab, calcitonin,fluoride and strontium.

• Treatment with medications that are known to decrease bone mass:

• Glucocorticoids (oral, intravenous, chronic inhaled, chronic extensive topical [> 3 months]) within the previous 3 months. Note: Subjects taking chronicoral/intravenous glucocorticoids (prednisone ≥ 2.5 mg daily for ≥ 3 months, orthe equivalent) will have a washout period of 12 months.

• Depo-medroxyprogesterone acetate within the previous 24 months (if duration ofuse was less than 2 consecutive years). Note: Subjects usingdepo-medroxyprogesterone acetate for a duration of use greater than 2 yearswill be excluded.

• Aromatase inhibitors and/or raloxifene within the previous 24 months.

• Anticonvulsants (phenytoin, phenobarbital, carbamazepine and valproate),anti-retroviral protease inhibitors, cyclosporine, heparin, warfarin,thiazolidinedione, SGLT-2 inhibitors, tricyclic antidepressants, chronic protonpump inhibitor (PPI) use (> 3 months), or selective serotonin reuptakeinhibitors (SSRIs) within the previous 3 months.

• Conditions that preclude BMD measurement i.e. lumbar spine/bilateral hip surgerywith hardware in place, abdominal clips, umbilical ring (not willing to remove) orweight that exceeds the DXA machine limitation.

• Any condition that, in the opinion of the investigator, may jeopardize the trialconduct according to the protocol.

• Persons committed to an institution by virtue of an order issued either by thejudicial or other authorities.