Clinical trial NCT05303636: LF111 or Drospirenone Chew vs Non-hormonal Contraceptive Methods on Bone Mineral Density in Adolescent and Adult Women
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Change in Bone Mineral Density
Bone Loss
Keywords: Osteoporosis
Lead sponsor: Insud Pharma
Sponsor class: INDUSTRY
Collaborators: name: Chemo Research
First posted: 2022-03-31
Enrollment: 1710
Sex: FEMALE
Minimum age (years): 14
Maximum age (years): 45
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: FACTORIAL
Intervention model description: Two cohorts: Cohort 1 (adolescents); Cohort 2 (adults)
Primary purpose: SCREENING

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* 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.

Exclusion Criteria:

* 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 -1.50. 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.

Primary outcomes:
measure: Cohort 1: Mean absolute change in lumbar spine (L1-L4) Z-score in adolescents
timeFrame: Baseline to 12 months
measure: Cohort 2: Mean percentage change in lumbar spine (L1-L4) BMD in adults
timeFrame: Baseline to 12 months
Secondary outcomes:
measure: Cohort 1: Mean absolute changes in lumbar spine (L1-L4) Z-score in adolescents (hormonal treatment arm only)
timeFrame: Baseline to 6 months
measure: Cohort 1: Mean absolute changes in Z-scores (femoral neck, total hip, and total body less head [TBLH]) in adolescents
timeFrame: Baseline to 6 months (hormonal treatment arm only) and to 12 months
measure: Cohort 1: Mean absolute and percentage changes in lumbar spine, femoral neck, total hip, and TBLH BMD in adolescents
timeFrame: Baseline to 6 months (hormonal treatment arm only) and to 12 months
measure: Cohort 1: Mean absolute and percentage changes in TBLH bone mineral content (BMC) in adolescents
timeFrame: Baseline to 6 months (hormonal treatment arm only) and to 12 months
measure: Cohort 1: Proportion of adolescent subjects with percentage changes in lumbar spine, femoral neck, total hip, and TBLH BMD by categories
timeFrame: Baseline to 12 months
measure: Cohort 1: Proportion of adolescent subjects with absolute changes in Z-scores (lumbar spine, femoral neck, total hip, and TBLH) by categories
timeFrame: Baseline to 6 months (hormonal treatment arm only) and to 12 months
measure: Cohort 2: Mean absolute changes in lumbar spine (L1-L4) BMD in adults
timeFrame: Baseline to 12 months
measure: Cohort 2: Mean absolute and percentage changes in femoral neck, total hip, and total body BMD in adults
timeFrame: Baseline to 12 months
measure: Cohort 2: Mean absolute and percentage changes in BMD (lumbar spine, femoral neck, total hip, and total body) in adults (hormonal treatment arm only)
timeFrame: Baseline to 6 months
measure: Cohort 2: Proportion of adult subjects with percentage changes in lumbar spine, femoral neck, total hip, and total body BMD by categories
timeFrame: Baseline to 12 months
measure: Cohort 2: Mean absolute changes in Z-scores (lumbar spine, femoral neck, total hip, and total body) in adults
timeFrame: Baseline to 6 months (hormonal treatment arm only) and to 12 months
measure: Cohort 2: Proportion of adult subjects with absolute changes in Z-scores (lumbar spine, femoral neck, total hip, and total body) by categories
timeFrame: Baseline to 6 months (hormonal treatment arm only) and to 12 months
measure: Changes in body weight and body mass index (BMI)
timeFrame: Baseline to 12 months
measure: Routine laboratory values
timeFrame: Baseline to 6 months and to 12 months
measure: Serum estradiol (E2) levels (hormonal treatment arm only)
timeFrame: Baseline to 6 months and to 12 months
measure: Number of subjects with adverse events as a measure of safety
timeFrame: Up to 12 months following treatment
Other outcomes:
measure: Changes in body fat and lean mass
timeFrame: Baseline to 12 months
Locations:
city: Phoenix
country: United States
facility: Cactus Clinical Research, Inc.
state: Arizona
city: Denver
country: United States
facility: Velocity Clinical Research
state: Colorado
city: Coral Gables
country: United States
facility: Advanced Clinical Research Network
state: Florida
city: Hialeah
country: United States
facility: Health Care Family Rehab & Research Center
state: Florida
city: Hialeah
country: United States
facility: Vital Pharma Research
state: Florida
city: Longwood
country: United States
facility: Cornerstone Research Institute
state: Florida
city: Miami
country: United States
facility: New Age Medical Research Corporation
state: Florida
city: South Miami
country: United States
facility: Florida Pharmaceutical Research and Associates, Inc.
state: Florida
city: West Palm Beach
country: United States
facility: Comprehensive Clinical Research, LLC
state: Florida
city: Sandy Springs
country: United States
facility: M3 Wake Research, Inc.
state: Georgia
city: Boise
country: United States
facility: Family Care Research
state: Idaho
city: Marrero
country: United States
facility: Tandem Clinical Research
state: Louisiana
city: Metairie
country: United States
facility: Clinical Trials Management, LLC - Southshore
state: Louisiana
city: Norfolk
country: United States
facility: Meridian Clinical Research
state: Nebraska
city: Raleigh
country: United States
facility: M3 Wake Research
state: North Carolina
city: Fargo
country: United States
facility: Lillestol Research LLC
state: North Dakota
city: Corpus Christi
country: United States
facility: Corpus Christi Women's Clinic
state: Texas
city: Fort Worth
country: United States
facility: Signature Gyn Services
state: Texas
city: Houston
country: United States
facility: TMC Life Research, Inc.
state: Texas
city: Seattle
country: United States
facility: Seattle Clinical Research Center
state: Washington
Study officials:
affiliation: Chemo Research SL
name: Enrico Colli, MD
role: STUDY_DIRECTOR
References:
citation: Rosenbaum P, Schmidt W, Helmerhorst FM, Wuttke W, Rossmanith W, Freundl F, Thomas K, Grillo M, Wolf A, Heithecker R. Inhibition of ovulation by a novel progestogen (drospirenone) alone or in combination with ethinylestradiol. Eur J Contracept Reprod Health Care. 2000 Mar;5(1):16-24. doi: 10.1080/13625180008500376.
citation: Cibula D, Skrenkova J, Hill M, Stepan JJ. Low-dose estrogen combined oral contraceptives may negatively influence physiological bone mineral density acquisition during adolescence. Eur J Endocrinol. 2012 Jun;166(6):1003-11. doi: 10.1530/EJE-11-1047. Epub 2012 Mar 21.
citation: Beksinska ME, Smit JA. Hormonal contraception and bone mineral density. Expert Rev of Obstet Gynecol. 2011;6(3);305-319.
citation: Weaver CM, Gordon CM, Janz KF, Kalkwarf HJ, Lappe JM, Lewis R, O'Karma M, Wallace TC, Zemel BS. The National Osteoporosis Foundation's position statement on peak bone mass development and lifestyle factors: a systematic review and implementation recommendations. Osteoporos Int. 2016 Apr;27(4):1281-1386. doi: 10.1007/s00198-015-3440-3. Epub 2016 Feb 8.
citation: Rizzo ADCB, Goldberg TBL, Biason TP, Kurokawa CS, Silva CCD, Corrente JE, Nunes HRC. One-year adolescent bone mineral density and bone formation marker changes through the use or lack of use of combined hormonal contraceptives. J Pediatr (Rio J). 2019 Sep-Oct;95(5):567-574. doi: 10.1016/j.jped.2018.05.011. Epub 2018 Jun 28.
citation: Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL. New equations to estimate GFR in children with CKD. J Am Soc Nephrol. 2009 Mar;20(3):629-37. doi: 10.1681/ASN.2008030287. Epub 2009 Jan 21.
citation: Pierce CB, Munoz A, Ng DK, Warady BA, Furth SL, Schwartz GJ. Age- and sex-dependent clinical equations to estimate glomerular filtration rates in children and young adults with chronic kidney disease. Kidney Int. 2021 Apr;99(4):948-956. doi: 10.1016/j.kint.2020.10.047. Epub 2020 Dec 8.
citation: Carr B, Dmowski WP, O'Brien C, Jiang P, Burke J, Jimenez R, Garner E, Chwalisz K. Elagolix, an oral GnRH antagonist, versus subcutaneous depot medroxyprogesterone acetate for the treatment of endometriosis: effects on bone mineral density. Reprod Sci. 2014 Nov;21(11):1341-51. doi: 10.1177/1933719114549848. Epub 2014 Sep 23.