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

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ClinicalTrials.gov Identifier: NCT05303636
Recruitment Status : Recruiting
First Posted : March 31, 2022
Last Update Posted : June 18, 2023
Sponsor:
Collaborator:
Chemo Research
Information provided by (Responsible Party):
Insud Pharma

Tracking Information
First Submitted Date  ICMJE March 22, 2022
First Posted Date  ICMJE March 31, 2022
Last Update Posted Date June 18, 2023
Actual Study Start Date  ICMJE March 28, 2022
Estimated Primary Completion Date July 2026   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 15, 2023)
  • Cohort 1: Mean absolute change in lumbar spine (L1-L4) Z-score in adolescents [ Time Frame: 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 [ Time Frame: Baseline to 12 months ]
    Measured by DXA
Original Primary Outcome Measures  ICMJE
 (submitted: March 22, 2022)
  • Cohort 1: Mean absolute change in lumbar spine (L1-L4) Z-score (adolescents) [ Time Frame: Baseline to 12 months ]
    Measured by dual-energy X-ray absorptiometry (DXA)
  • Cohort 2: Mean percentage change in lumbar spine BMD in adults (aged 18-45) [ Time Frame: Baseline to 12 months ]
    Measured by dual-energy X-ray absorptiometry (DXA)
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 15, 2023)
  • Cohort 1: Mean absolute changes in lumbar spine (L1-L4) Z-score in adolescents (hormonal treatment arm only) [ Time Frame: Baseline to 6 months ]
    Measured by DXA
  • Cohort 1: Mean absolute changes in Z-scores (femoral neck, total hip, and total body less head [TBLH]) in adolescents [ Time Frame: Baseline to 6 months (hormonal treatment arm only) and to 12 months ]
    Measured by DXA
  • Cohort 1: Mean absolute and percentage changes in lumbar spine, femoral neck, total hip, and TBLH BMD in adolescents [ Time Frame: Baseline to 6 months (hormonal treatment arm only) and to 12 months ]
    Measured by DXA
  • Cohort 1: Mean absolute and percentage changes in TBLH bone mineral content (BMC) in adolescents [ Time Frame: Baseline to 6 months (hormonal treatment arm only) and to 12 months ]
    Measured by DXA
  • Cohort 1: Proportion of adolescent subjects with percentage changes in lumbar spine, femoral neck, total hip, and TBLH BMD by categories [ Time Frame: Baseline to 12 months ]
    Categories are ≥ 0%, < 0% to -1.5%, < -1.5% to -3%, < -3% to -5%, < -5% to -8% and < -8%
  • Cohort 1: Proportion of adolescent subjects with absolute changes in Z-scores (lumbar spine, femoral neck, total hip, and TBLH) by categories [ Time Frame: Baseline to 6 months (hormonal treatment arm only) and to 12 months ]
    Categories are ≥ 0.50, < 0.50 to 0.30, < 0.30 to 0, < 0 to -0.30, < -0.30 to -0.50 and < -0.50
  • Cohort 2: Mean absolute changes in lumbar spine (L1-L4) BMD in adults [ Time Frame: Baseline to 12 months ]
    Measured by DXA
  • Cohort 2: Mean absolute and percentage changes in femoral neck, total hip, and total body BMD in adults [ Time Frame: Baseline to 12 months ]
    Measured by DXA
  • Cohort 2: Mean absolute and percentage changes in BMD (lumbar spine, femoral neck, total hip, and total body) in adults (hormonal treatment arm only) [ Time Frame: Baseline to 6 months ]
    Measured by DXA
  • Cohort 2: Proportion of adult subjects with percentage changes in lumbar spine, femoral neck, total hip, and total body BMD by categories [ Time Frame: Baseline to 12 months ]
    Categories are ≥ 0%, < 0% to -1.5%, < -1.5% to -3%, < -3% to -5%, < -5% to -8% and < -8%
  • Cohort 2: Mean absolute changes in Z-scores (lumbar spine, femoral neck, total hip, and total body) in adults [ Time Frame: Baseline to 6 months (hormonal treatment arm only) and to 12 months ]
    Measured by DXA
  • Cohort 2: Proportion of adult subjects with absolute changes in Z-scores (lumbar spine, femoral neck, total hip, and total body) by categories [ Time Frame: Baseline to 6 months (hormonal treatment arm only) and to 12 months ]
    Categories are ≥ 0.5, < 0.5 to 0.3, < 0.3 to 0, < 0 to -0.3, < -0.3 to -0.5 and < -0.5
  • Changes in body weight and body mass index (BMI) [ Time Frame: Baseline to 12 months ]
    Changes in body weight and body mass index (BMI)
  • Routine laboratory values [ Time Frame: Baseline to 6 months and to 12 months ]
    Mean absolute and relative changes in routine laboratory values
  • Serum estradiol (E2) levels (hormonal treatment arm only) [ Time Frame: Baseline to 6 months and to 12 months ]
    Mean absolute and relative changes in serum estradiol (E2) levels
  • Number of subjects with adverse events as a measure of safety [ Time Frame: Up to 12 months following treatment ]
    Adverse events include laboratory and vital sign abnormalities that are considered clinically significant, require treatment, fulfill any serious adverse event criterion, or cause the subject to change the trial schedule and are judged by either the reporting investigator or the sponsor as having a reasonable causal relationship to the trial medication (drospirenone) or placebo comparator (non-hormonal contraceptive methods).
Original Secondary Outcome Measures  ICMJE
 (submitted: March 22, 2022)
  • Cohort 1: Mean absolute changes in lumbar spine Z-score in adolescents (LF111 arm only) [ Time Frame: Baseline to 6 months ]
    Measured by DXA
  • Cohort 1: Mean absolute changes in Z-scores (femoral neck, total hip, and total body less head [TBLH]) in adolescents [ Time Frame: Baseline to 6 months (LF111 arm only) and to 12 months ]
    Measured by DXA
  • Cohort 1: Mean absolute and percentage changes in BMD (lumbar spine, femoral neck, total hip, and TBLH) in adolescents [ Time Frame: Baseline to 6 months (LF111 arm only) and to 12 months ]
    Measured by DXA
  • Cohort 1: Mean absolute and percentage changes in TBLH bone mineral content (BMC) in adolescents [ Time Frame: Baseline to 6 months (LF111 arm only) and to 12 months ]
    Measured by DXA
  • Cohort 1: Proportion of adolescent subjects with percentage changes in lumbar spine, femoral neck, total hip, and TBLH BMD by categories [ Time Frame: Baseline to 12 months ]
    Categories are ≥ 0%, < 0% to -1.5%, < -1.5% to -3%, < -3% to -5%, < -5% to -8% and < -8%
  • Cohort 1: Proportion of adolescent subjects with absolute changes in Z-scores (lumbar spine, femoral neck, total hip, and TBLH) by categories [ Time Frame: Baseline to 6 months (LF111 arm only) and to 12 months ]
    Categories are ≥ 0.5, < 0.5 to 0.3, < 0.3 to 0, < 0 to -0.3, < -0.3 to -0.5 and < -0.5
  • Cohort 2: Mean absolute changes in lumbar spine BMD in adults [ Time Frame: Baseline to 12 months ]
    Measured by DXA
  • Cohort 2: Mean absolute and percentage changes in BMD (femoral neck, total hip, and total body) in adults [ Time Frame: Baseline to 12 months ]
    Measured by DXA
  • Cohort 2: Mean absolute and percentage changes in BMD (lumbar spine, femoral neck, total hip, and total body) in adults (LF111 arm only) [ Time Frame: Baseline to 6 months ]
    Measured by DXA
  • Cohort 2: Proportion of adult subjects with percentage changes in lumbar spine, femoral neck, total hip, and total body BMD by categories [ Time Frame: Baseline to 12 months ]
    Categories are ≥ 0%, < 0% to -1.5%, < -1.5% to -3%, < -3% to -5%, < -5% to -8% and < -8%
  • Cohort 2: Mean absolute changes in Z-scores (lumbar spine, femoral neck, total hip, and total body) in adults [ Time Frame: Baseline to 6 months (LF111 arm only) and to 12 months ]
    Measured by DXA
  • Cohort 2: Proportion of adult subjects with absolute changes in Z-scores (lumbar spine, femoral neck, total hip, and total body) by categories [ Time Frame: Baseline to 6 months (LF111 arm only) and to 12 months ]
    Categories are ≥ 0.5, < 0.5 to 0.3, < 0.3 to 0, < 0 to -0.3, < -0.3 to -0.5 and < -0.5
  • Changes in body weight and body mass index (BMI) [ Time Frame: Baseline to 12 months ]
    Changes in body weight and body mass index (BMI)
  • Routine laboratory values [ Time Frame: Baseline to 6 months and to 12 months ]
    Mean absolute and relative changes in routine laboratory values
  • Serum estradiol (E2) levels in the LF111 arm [ Time Frame: Baseline to 6 months and to 12 months ]
    Mean absolute and relative changes in serum estradiol (E2) levels in the LF111 arm
  • Adverse events [ Time Frame: Up to 12 months following treatment ]
    Adverse events
Current Other Pre-specified Outcome Measures
 (submitted: June 15, 2023)
Changes in body fat and lean mass [ Time Frame: Baseline to 12 months ]
Fat mass and lean mass will be expressed in grams (g). Changes will be summarized using descriptive statistics for baseline and percentage change from baseline by cohort and treatment group.
Original Other Pre-specified Outcome Measures
 (submitted: March 22, 2022)
Body lean and fat mass distribution [ Time Frame: Baseline to 12 months ]
Changes in body lean and fat mass distribution
 
Descriptive Information
Brief Title  ICMJE LF111 or Drospirenone Chew vs Non-hormonal Contraceptive Methods on Bone Mineral Density in Adolescent and Adult Women
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Factorial Assignment
Intervention Model Description:
Two cohorts: Cohort 1 (adolescents); Cohort 2 (adults)
Masking: None (Open Label)
Primary Purpose: Screening
Condition  ICMJE
  • Change in Bone Mineral Density
  • Bone Loss
Intervention  ICMJE Drug: LF111 (drospirenone 4 mg oral tablet) or drospirenone (DRSP) 3.5 mg chewable tablet
LF111 (drospirenone 4 mg tablet orally daily on days 1-24, followed by placebo tablet orally daily on days 25-28) or drospirenone (DRSP) 3.5 mg chewable tablet chewed daily on days 1-24, followed by placebo tablet chewed daily on days 25-28) (USA only). Subjects in the USA who choose to use the hormonal contraceptive method may choose between LF111 and DRSP 3.5 mg chewable tablets. The DRSP 3.5 mg chewable tablets are not available to subjects in Europe. Subjects in Europe who choose to use the hormonal contraceptive method will only receive LF111.
Study Arms  ICMJE
  • Experimental: 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.
    Intervention: Drug: LF111 (drospirenone 4 mg oral tablet) or drospirenone (DRSP) 3.5 mg chewable tablet
  • No Intervention: Cohort 1 (adolescents aged 14-17) Non-Hormonal Contraceptive Arm
    Subjects in this group will not receive any investigational product. They will be free to use a non-hormonal contraceptive method of their choice. Non-hormonal contraceptive methods include barrier contraceptive methods (condoms, female condoms, cervical caps, diaphragms, and contraceptive sponges), double barrier methods, non-hormonal IUD (e.g., copper IUD), surgical female sterilization, vasectomized partner, spermicides, and sexual abstinence.
  • Experimental: 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.
    Intervention: Drug: LF111 (drospirenone 4 mg oral tablet) or drospirenone (DRSP) 3.5 mg chewable tablet
  • No Intervention: Cohort 2 (adults aged 18-45) Non-Hormonal Contraceptive Method Arm
    Subjects in this group will not receive any investigational product. They will be free to use a non-hormonal contraceptive method of their choice. Non-hormonal contraceptive methods include barrier contraceptive methods (condoms, female condoms, cervical caps, diaphragms, and contraceptive sponges), double barrier methods, non-hormonal IUD (e.g., copper IUD), surgical female sterilization, vasectomized partner, spermicides, and sexual abstinence.
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 22, 2022)
1710
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 2027
Estimated Primary Completion Date July 2026   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 14 Years to 45 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: Study Director +34 - 91 771 15 00 comunicacion@insudpharma.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT05303636
Other Study ID Numbers  ICMJE LF111/401
2020-000412-30 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Current Responsible Party Insud Pharma
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Insud Pharma
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Chemo Research
Investigators  ICMJE
Study Director: Enrico Colli, MD Chemo Research SL
PRS Account Insud Pharma
Verification Date February 2023

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP