A Multicenter, Open-label, Controlled Study to Investigate the Effect of Either LF111 or Drospirenone Chewable Tablets on Bone Mineral Density in Adolescent and Adult Women in Comparison With Non-users of Hormonal Contraceptive Methods
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 发起方
- 入组人数
- 1,710
- 试验地点
- 20
- 主要终点
- Cohort 1: Mean absolute change in lumbar spine (L1-L4) Z-score in adolescents
研究概览
简要总结
The primary objective of this study is to evaluate the impact of LF111 and drospirenone (DRSP) 3.5 mg chewable tablets on bone mineral density (BMD) at the lumbar spine after 12 months (13 medication cycles) of investigation in comparison to non-hormonal contraceptive methods. Secondary objectives include further evaluating the impact of LF111 and DRSP 3.5 mg chewable tablets on BMD and bone turnover after 12 months (13 medication cycles) in comparison to non-hormonal contraceptive methods and assessing the general safety and tolerability of LF111 and DRSP 3.5 mg chewable tablets in comparison to non-hormonal contraceptive methods. Exploratory objectives include evaluating the impact of LF111 and DRSP 3.5 mg chewable tablets on body fat and lean mass after 12 months (13 medication cycles) of investigation.
详细描述
This is a Phase IV, prospective, multicenter, open-label, controlled, non-randomized trial in female subjects between 14 to 45 years of age who are postmenarcheal for at least two years and premenopausal. Subjects who choose to take the trial medication (LF111 tablet or drospirenone [DRSP] 3.5 mg chewable tablet [USA only]) will be compared to subjects who choose to use non-hormonal contraceptive methods, enrolled in a 1:1 ratio. Subjects will also be separated into two cohorts: cohort 1 as adolescents aged 14-17, and cohort 2 as adults aged 18-45.
At Visit 1 (screening), informed consent/assent will be obtained, and the screening procedures will be performed. At Visit 2 (allocation to treatment), after confirming the subject's eligibility, subjects who choose to use LF111 or DRSP 3.5 mg chewable tablets (USA only) for pregnancy prevention will be provided with LF111 or DRSP 3.5 mg chewable tablets. The subjects will attend additional on-site visits 6 months and 12 months after Visit 2 (end of investigational phase) or within one week after premature trial discontinuation for routine safety assessments.
The primary objective of this study is to evaluate the impact of LF111 and DRSP 3.5 mg chewable tablets on bone mineral density (BMD) at the lumbar spine after 12 months (13 medication cycles) of investigation in comparison to non-hormonal contraceptive methods. Secondary objectives include further evaluating the impact of LF111 and DRSP 3.5 mg chewable tablets on BMD and bone turnover after 12 months (13 medication cycles) in comparison to non-hormonal contraceptive methods and assessing the general safety and tolerability of LF111 and DRSP 3.5 mg chewable tablets in comparison to non-hormonal contraceptive methods. Exploratory objectives include evaluating the impact of LF111 and DRSP 3.5 mg chewable tablets on body fat and lean mass after 12 months (13 medication cycles) of investigation.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Factorial
- 主要目的
- Screening
- 盲法
- None
入排标准
- 年龄范围
- 14 Years 至 45 Years（Child, Adult）
- 性别
- Female
- 接受健康志愿者
- 是
入选标准
- •Female subjects with regular menstrual cycles (postmenarcheal for at least two years and premenopausal) aged 14 to 45 years.
- •Female subjects aged between 14 to 17 years (inclusive) will only be included provided that:
- •Applicable national, state, and local laws allow subjects in this age group to consent/assent to receive contraceptive services, and
- •All applicable laws and regulations regarding the informed consent/assent of the 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 applicable for women that were pregnant).
- •Be able and willing to provide written informed consent, or assent if the subject is an adolescent, prior to undergoing any trial-related procedures.
- •Willing to use trial contraception for thirteen 28-day cycles (hormonal treatment arm) or to use non-hormonal contraceptive methods for the duration of the trial (non-hormonal contraceptive arm), respectively.
排除标准
- •Contraindications to the use of LF111 or DRSP 3.5 mg chewable tablets (such as active arterial or venous thromboembolic disorders, liver tumors benign or malignant, hepatic impairment, renal impairment, adrenal insufficiency, presence or history of cervical cancer or progestin-sensitive cancers, known or suspected sex-steroid sensitive malignancies, undiagnosed abnormal uterine bleeding, undiagnosed vaginal bleeding, hypersensitivity to active substance or excipient) or adverse effects due to previous contraceptive use (for the hormonal treatment arm only).
- •BMD Z-score below -1.
- •The TBLH Z-score applies only to Cohort 1 (adolescents) and the total body Z-score applies only to Cohort 2 (adults) when assessing study eligibility.
- •Low trauma fracture(s) defined as a fracture that results from a fall from a standing 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 the bone, 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 the Modification 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 than the fifth percentile.
- •Use of progestin-only contraceptive pills in the previous month or use of implantable hormonal contraceptives in the previous 6 months.
- •Laboratory values at screening which are considered clinically significant and which in the opinion of the investigator would be detrimental for participation in the study.
- •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 stable treatment regiment for > 2 months.
- •Rheumatoid arthritis.
- •Current or ever use of medications or supplements known to increase BMD including bisphosphonates, 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 chronic oral/intravenous glucocorticoids (prednisone ≥ 2.5 mg daily for ≥ 3 months, or the equivalent) will have a washout period of 12 months.
- •Depo-medroxyprogesterone acetate within the previous 24 months (if duration of use was less than 2 consecutive years). Note: Subjects using depo-medroxyprogesterone acetate for a duration of use greater than 2 years will 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 proton pump inhibitor (PPI) use (> 3 months), or selective serotonin reuptake inhibitors (SSRIs) within the previous 3 months.
- •Conditions that preclude BMD measurement i.e. lumbar spine/bilateral hip surgery with hardware in place, abdominal clips, umbilical ring (not willing to remove) or weight that exceeds the DXA machine limitation.
- •Any condition that, in the opinion of the investigator, may jeopardize the trial conduct according to the protocol.
- •Persons committed to an institution by virtue of an order issued either by the judicial or other authorities.
研究组 & 干预措施
Cohort 1 (adolescents aged 14-17) Hormonal Treatment Arm
Subjects in the USA will choose to use the LF111 tablets or drospirenone (DRSP) 3.5 mg chewable tablets; 1/3 of subjects in the USA should receive DRSP 3.5 mg chewable tablets. Only LF111 will be available to subjects in Europe.
干预措施: LF111 (drospirenone 4 mg oral tablet) or drospirenone (DRSP) 3.5 mg chewable tablet (Drug)
Cohort 2 (adults aged 18-45) Hormonal Treatment Arm
Subjects in the USA will choose to use the LF111 tablets or drospirenone (DRSP) 3.5 mg chewable tablets; 1/3 of subjects in the USA should receive DRSP 3.5 mg chewable tablets. Only LF111 will be available to subjects in Europe.
干预措施: LF111 (drospirenone 4 mg oral tablet) or drospirenone (DRSP) 3.5 mg chewable tablet (Drug)
结局指标
主要结局
Cohort 1: Mean absolute change in lumbar spine (L1-L4) Z-score in adolescents
时间窗: Baseline to 12 months
Measured by dual-energy X-ray absorptiometry (DXA)
Cohort 2: Mean percentage change in lumbar spine (L1-L4) BMD in adults
时间窗: Baseline to 12 months
Measured by DXA
次要结局
- Cohort 2: Mean absolute changes in Z-scores (lumbar spine, femoral neck, total hip, and total body) in adults(Baseline to 6 months (hormonal treatment arm only) and to 12 months)
- Cohort 1: Mean absolute and percentage changes in lumbar spine, femoral neck, total hip, and TBLH BMD in adolescents(Baseline to 6 months (hormonal treatment arm only) and to 12 months)
- Cohort 1: Mean absolute and percentage changes in TBLH bone mineral content (BMC) in adolescents(Baseline to 6 months (hormonal treatment arm only) and to 12 months)
- Cohort 1: Proportion of adolescent subjects with percentage changes in lumbar spine, femoral neck, total hip, and TBLH BMD by categories(Baseline to 12 months)
- Cohort 1: Proportion of adolescent subjects with absolute changes in Z-scores (lumbar spine, femoral neck, total hip, and TBLH) by categories(Baseline to 6 months (hormonal treatment arm only) and to 12 months)
- Cohort 2: Mean absolute changes in lumbar spine (L1-L4) BMD in adults(Baseline to 12 months)
- Cohort 2: Mean absolute and percentage changes in femoral neck, total hip, and total body BMD in adults(Baseline to 12 months)
- Cohort 1: Mean absolute changes in lumbar spine (L1-L4) Z-score in adolescents (hormonal treatment arm only)(Baseline to 6 months)
- Cohort 1: Mean absolute changes in Z-scores (femoral neck, total hip, and total body less head [TBLH]) in adolescents(Baseline to 6 months (hormonal treatment arm only) and to 12 months)
- Cohort 2: Mean absolute and percentage changes in BMD (lumbar spine, femoral neck, total hip, and total body) in adults (hormonal treatment arm only)(Baseline to 6 months)
- Cohort 2: Proportion of adult subjects with percentage changes in lumbar spine, femoral neck, total hip, and total body BMD by categories(Baseline to 12 months)
- Cohort 2: Proportion of adult subjects with absolute changes in Z-scores (lumbar spine, femoral neck, total hip, and total body) by categories(Baseline to 6 months (hormonal treatment arm only) and to 12 months)
- Changes in body weight and body mass index (BMI)(Baseline to 12 months)
- Routine laboratory values(Baseline to 6 months and to 12 months)
- Serum estradiol (E2) levels (hormonal treatment arm only)(Baseline to 6 months and to 12 months)
- Number of subjects with adverse events as a measure of safety(Up to 12 months following treatment)