To evaluate the safety, compliance, and pharmacokinetics profile of estetrol monohydrate (E4) 15 mg combined with drospirenone (DRSP) 3 mg in post-menarchal participants between the age of 12 and 17 years + 2 months.
This is a Phase 3, open-label, non-controlled study in healthy post-menarchal female participants who will be enrolled to receive once daily E4/DRSP 15/3 mg for six (6) 28-day cycles in a 24/4-day regimen (i.e. 24 days of active tablets followed by 4 days of placebo tablets \[4-day hormone-free interval\]). The study will include 6 visits: At screening visit (Visit 1), informed consent will be signed by the participants and their parent(s) or legal representative(s) and the screening procedures will be performed. The site will also complete an Eligibility confirmation phone call to the participant after Visit 1. During the enrollment visit (Visit 2, between Days 12 and 19 of the pre-treatment cycle), eligibility criteria will be reviewed and the participant participation will be confirmed. Participants will be trained in the use of an electronic diary and will receive the study drug. A follow-up call will be performed after Visit 2, within 7 days following the first investigational product intake. Afterwards, the participants will attend 3 on-treatment visits at the clinical site \[between Days 14 and 21 of the Cycle 1(Visit 3), Cycle 3 (Visit 4), and Cycle 6 (Visit 5)\] and one visit after end of Cycle 6 (Visit 6). For participants who consent to participate in a pharmacokinetics sub-study, blood samples for this sub-study will be taken at Visit 3 and Visit 5. Adverse events will be followed throughout the study.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
PREVENTION
Masking
NONE
Enrollment
145
One E4/DRSP 15/3 mg combined tablet once per day for 24 days followed by 4 days of placebo tablets; this 28-day cyclic regimen should be taken for 6 consecutive cycles.
KVL Medical Office/KVL Arstikabinet
Pärnu, Estonia
East-Tallinn Central Hospital
Tallinn, Estonia
Number of participants with treatment-emergent adverse events
Treatment emergent adverse events (TEAEs) are those adverse events occurring from time point of first ingestion of the investigational product until last visit or any event already present that worsens in either intensity or frequency following exposure to the treatment.
Time frame: From Cycle 1 to end of study (between Days 16 and 23 of Cycle 7) (each cycle is 28 days)
Number of participants with treatment-emergent adverse events related to the investigational product
Treatment emergent adverse events (TEAEs) are those adverse events occurring from time point of first ingestion of the investigational product until last visit or any event already present that worsens in either intensity or frequency following exposure to the treatment. The causality of TEAEs (related or not related) is based on the following considerations: associative connections (time and/or place), pharmacological explanations, previous knowledge of the drug, presence of characteristic clinical or pathological phenomena, exclusion of other causes, and/or absence of alternative explanations.
Time frame: From Cycle 1 to end of study (between Days 16 and 23 of Cycle 7) (each cycle is 28 days)
Number of participants with abnormal physical examination results
The physical examination will include an evaluation of the following: body as a whole, skin, head, eyes, ears, nose, and throat, neck, cardiovascular, respiratory, musculoskeletal, neurologic, lymphatic/thyroid, abdomen.
Time frame: At Baseline and at the end of treatment (Cycle 6) (each cycle is 28 days)
Number of participants with abnormal vital sign results
Vital signs will include sitting systolic and diastolic blood pressures and heart rate.
Time frame: From Baseline to end of treatment (Cycle 6) (each cycle is 28 days)
Number of participants with abnormal electrocardiogram (ECG) results
The ECG interpretation scheme will include the analysis of the morphology, rhythm, conduction, ST segment, PR, QRS, QT and QTc (according to QTcFrid) intervals, T waves, U waves and the presence or absence of any pathological changes.
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Sexual Health Clinic, Tallinn
Tallinn, Estonia
Sexual Health Clinic, Tartu
Tartu, Estonia
VL-Medi Oy
Helsinki, Finland
Lääkärikeskus Mehiläinen
Kuopio, Finland
Lääkärikeskus Gyneko
Oulu, Finland
Estetra Study Site
Batumi, Georgia
Estetra Study Site
Tbilisi, Georgia
Estetra Study Site
Tbilisi, Georgia
...and 13 more locations
Time frame: At Baseline and at the end of treatment (Cycle 6) (each cycle is 28 days)
Number of participants with abnormal clinical laboratory assessment results
Laboratory assessment will include blood hematology and biochemistry.
Time frame: At Baseline and at the end of treatment (Cycle 6) (each cycle is 28 days)
Percentage of compliance by cycle [Estonia-specific: and overall compliance]
The percentage of compliance per cycle is calculated as the ratio of the total number pills taken during the cycle based on the daily response values entered by the participant in the e-diary and the number of pills expected to be taken during the cycle based on the total number of treatment days. \[Estonia-specific: the percentage of overall compliance is calculated as the ratio of the total number of pills taken across all cycles based on the daily response values entered by the participant in the e-diary and the number of pills expected to be taken from the start date of cycle 1 until the day of the last dose.\]
Time frame: At Cycles 1, 2, 3, 4, 5 ,6 (each cycle is 28 days)
Mean plasma estetrol (E4) concentration
Time frame: At Cycle 1 and at the end of treatment (Cycle 6) (each cycle is 28 days)
Mean plasma drospirenone (DRSP) concentration
Time frame: At Cycle 1 and at the end of treatment (Cycle 6) (each cycle is 28 days)
Number of participants with unscheduled bleeding and/or spotting episodes
Time frame: At Cycles 1,2, 3, 4, 5, 6 (each cycle is 28 days)
Number of participants with absence of bleeding/spotting episodes
Time frame: At Cycles 1,2, 3, 4, 5, 6 (each cycle is 28 days)
Mean number of unscheduled bleeding and spotting days per cycle
Time frame: At Cycles 1,2, 3, 4, 5, 6 (each cycle is 28 days)
Mean number of scheduled bleeding and spotting days per cycle
Time frame: At Cycles 1,2, 3, 4, 5, 6 (each cycle is 28 days)
Change in the Score of the Menstrual Distress Questionnaire (MDQ) from baseline to Cycles 1, 3 and 6
The MDQ is a standard method for measuring cyclical perimenstrual symptoms. The participants will rate common symptoms and feelings associated with menstruation using the following scale: 0 (no experience of symptom), 1 (present, mild), 2 (present, moderate), 3 (present, strong),and 4 (present, severe) observed during pre-menstrual (4 days before menstruation), menstrual (most recent flow) and intermenstrual (remainder of the cycle) phases.
Time frame: At Baseline and at Cycles 1, 3 and 6 (each cycle is 28 days)
Change in the Visual Analogue Scale (VAS) score of dysmenorrhea from baseline to Cycles 1, 3 and 6
Each day participants will be asked to score their menstruation pain of the previous 24 hours using a scale from 0 to 10, with 0 = no hurt and 10 = hurts worst.
Time frame: At Baseline, Cycles 1, 3, and at the end of treatment (Cycle 6) (each cycle is 28 days)
Change in the number of days with dysmenorrhea from baseline to Cycles 1, 3 and 6
Time frame: At Baseline, Cycles 1, 3, and at the end of treatment (Cycle 6) (each cycle is 28 days)
Number of participants who will use rescue medication for dysmenorrheal pain from baseline to Cycles 1, 3 and 6
Time frame: At Baseline, Cycles 1, 3, and at the end of treatment (Cycle 6) (each cycle is 28 days)
Change in Health Questionnaire for children and Young People (KIDSCREEN-27 questionnaire) from baseline to Cycles 1, 3 and 6
KIDSCREEN-27 is a validated health-related quality of life questionnaire developed for children and adolescents. This questionnaire measures five Rasch scaled dimensions of well-being including: (1) Physical Well-being (5 items), (2) Psychological Well-being (7 items), (3) Autonomy and Parents (7 items), (4) Peers and Social Support (4 items), and (5) School Environment (4 items). Responses are indicated using a 5-point ordinal scale with responses ranging from 'never' to 'always', 'not at all' to 'extremely', or 'poor' to 'excellent'.
Time frame: At Baseline, Cycles 1, 3, and at the end of treatment (Cycle 6) (each cycle is 28 days)
Change in sex-hormone binding globulin (SHBG) level from baseline to Cycle 6
Time frame: At Baseline and at the end of treatment (Cycle 6) (each cycle is 28 days)
Change in Activated protein C resistance endogenous thrombin potential based (APCr [ETP based]) level from baseline to Cycle 6
Time frame: At Baseline and at the end of treatment (Cycle 6) (each cycle is 28 days)