Clinical Trial Results:
Multicentre, Open-Label Trial to Assess the Safety and Tolerability of LF111 (Drospirenone 4.0 mg) Over 6 Cycles in Female Adolescents, With a 7-Cycle Extension Phase
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Summary
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EudraCT number |
2013-005234-37 |
Trial protocol |
DE NL FI SE |
Global end of trial date |
19 Sep 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
04 Oct 2019
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First version publication date |
04 Oct 2019
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
CF111/304
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Additional study identifiers
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ISRCTN number |
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US NCT number |
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WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
Chemo France
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Sponsor organisation address |
7 rue Victor Hugo, Sevres, France, 92310
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Public contact |
Project Leader, CHEMO France, 0034 917711500, laura.ullate@exeltis.com
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Scientific contact |
Project Leader, CHEMO France, 0034 917711500, laura.ullate@exeltis.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-001495-PIP01-13 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
19 Sep 2016
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
19 Sep 2016
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To demonstrate safety and tolerability including bleeding pattern.
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Protection of trial subjects |
Due to the vulnerability of adolescents and absence of marketing authorization for LF111, an Independent Data Monitoring Committee (IDMC) was constituted.
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Background therapy |
N/A | ||
Evidence for comparator |
N/A | ||
Actual start date of recruitment |
01 Mar 2014
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Sweden: 2
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Country: Number of subjects enrolled |
Finland: 19
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Country: Number of subjects enrolled |
Germany: 42
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Country: Number of subjects enrolled |
Ukraine: 40
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Worldwide total number of subjects |
103
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EEA total number of subjects |
63
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
103
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Following the national legislations, the lower age limit in Germany was 14 years, in Sweden 15 years and in Ukraine 16 years. In Finland, based on the trial centre’s decision, it was 15 years, because parental consent was not needed at this age. It was planned to screen about 130 subjects to have approximately 100 subjects evaluable for safety. | ||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Inclusion criteria: female adolescents aged 12-17 years, with or without intact hymen; postmenarcheal for at least six months; starters of oral contraceptives with at least four regular menstrual cycles during the last six months before screening. Eight subjects were screening failures. | ||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||||||
Blinding implementation details |
N/A
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Arms
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Arm title
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experimental | ||||||||||||||||||||||||||
Arm description |
out of the 103 subjects who started the trial, 85 subjects entered the extension phase and 74 subjects completed the extension phase and overall trial (11 subjects prematurely terminated the extension phase) | ||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||
Investigational medicinal product name |
Drospirenone 4 mg film-coated tablets
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Investigational medicinal product code |
LF111
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Other name |
Slinda
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Pharmaceutical forms |
Coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Blister package with 28 LF111 coated tablets (24 white tablets containing 4.0 mg drospirenone, 4 green placebo tablets), oral administration once daily. Duration of the treatment.: 7 cycles x 28 days = 196 days (extension phase)
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Baseline characteristics reporting groups
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Reporting group title |
Overall trial
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Safety Set
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
A total of 103 subjects were allocated to treatment with DRSP 4.0 mg, of these 102 subjects received at least one dose of IMP and were included in the Safety Set.
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Subject analysis set title |
Core Per Protocol Set
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The Core Per Protocol Set (CPPS), defined in the core phase DRM consisted of all subjects who were included in the SS and did not present any major protocol deviation during the core phase of the trial.
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Subject analysis set title |
Per Protocol Set
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The Per Protocol Set consisted of all subjects who were included in the SS and did not present any major protocol deviation
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End points reporting groups
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Reporting group title |
experimental
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Reporting group description |
out of the 103 subjects who started the trial, 85 subjects entered the extension phase and 74 subjects completed the extension phase and overall trial (11 subjects prematurely terminated the extension phase) | ||
Subject analysis set title |
Safety Set
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
A total of 103 subjects were allocated to treatment with DRSP 4.0 mg, of these 102 subjects received at least one dose of IMP and were included in the Safety Set.
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Subject analysis set title |
Core Per Protocol Set
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
The Core Per Protocol Set (CPPS), defined in the core phase DRM consisted of all subjects who were included in the SS and did not present any major protocol deviation during the core phase of the trial.
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Subject analysis set title |
Per Protocol Set
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
The Per Protocol Set consisted of all subjects who were included in the SS and did not present any major protocol deviation
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End point title |
Assessment of bleeding pattern over the 6 months of the core study [1] | ||||||||||||
End point description |
Analysis of the vaginal bleeding pattern included:
- Number and rate of subjects with different bleeding patterns, with bleeding and /or spotting, separately for bleeding and spotting, including bleeding by intensity were to be presented for each day of treatment in the corresponding cycle, for each treatment cycle and cumulatively by reference period (Cycles 2 to 4 and Cycles 2 to 6).
- Number of bleeding and/or spotting days, separately for bleeding and spotting, and numbers of days with bleeding by intensity were to be summarised by means of the default summary statistics for each treatment cycle and by reference period. Scheduled and unscheduled bleeding presented separately.
-Correlation between incidence of unscheduled bleeding and/or spotting and number of missing tablets or entries. Default summary statistics for missed tablets or diary entries by treatment cycle and reference period. p-values from the Wilcoxon-rank-sum-test are presented
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End point type |
Primary
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End point timeframe |
6 cycles
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This is a single arm, open label study. Thus, a comparison to a reference product is not planned |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Withdrawal due to TEAEs based on abnormal bleeding in the core phase [2] | |||||||||
End point description |
The number of subjects with at least one TEAE leading to premature discontinuation based on abnormal bleeding in the core phase will be analysed descriptively for the safety set.
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End point type |
Primary
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End point timeframe |
during the 6 cycles core phase
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This is a single arm, open label study. Thus, a comparison to a reference product is not planned |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Adverse events | |||||||||
End point description |
A detailed description of each adverse event (AE) includes:
- Adverse Event
- The start and stop date of the adverse event or “ongoing”
- Severity (mild, moderate, severe)
- Relationship to the IMP (not related, unlikely related, possibly related, related)
- Frequency (single, intermittent, continuous)
- Action taken on trial treatment (dose not changed, drug interrupted, drug withdrawn, unknown, not
applicable)
- Other actions (none, medication required, tests required, hospitalisation required or prolonged, other)
- Outcome (recovered/resolved, recovering/resolving, not recovered/not resolved, recovered/resolved
with sequelae, fatal, unknown)
- Serious (yes, no)
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End point type |
Secondary
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End point timeframe |
anytime during the 13 months trial, including extension phase
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| No statistical analyses for this end point | ||||||||||
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End point title |
Clinical Laboratory Evaluation | |||||||||
End point description |
Haematology: Haemoglobin, red blood cell count, mean corpuscular volume (MCV) and associated parameters, haematocrit, MCH, white blood cell count, differential white blood cell count including neutrophils, lymphocytes, eosinophils, basophils and monocytes, platelet count.
Biochemistry: Sodium, potassium, chloride, creatinine, blood urea nitrogen (BUN), calcium, glucose, total proteins, albumin, total cholesterol (HDL, LDL cholesterol), triglycerides, gamma glutamyl transferase, total and direct bilirubin, alkaline phosphatase (ALP), alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), creatine phosphokinase (CPK), lactate dehydrogenase (LDH), Thyroid function (TSH)
Urinalysis: Leukocytes, nitrite, protein, glucose, ketones, blood, pH, urobilinogen, bilirubin,
haemoglobin (dipstick test).
Pregnancy test: Urine human chorionic gonadotropin (HCG) test
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End point type |
Secondary
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End point timeframe |
Blood samples and urine samples taken at Visit 1a,Visit 6/EDV and at Visit 8/EDV.
Clinical laboratory variables summarised at Visit 1a,Visit 6/EDV and at Visit 8/EDV.
Urine pregnancy test at V1a, V1b, V2, V3, V4, V5, V6/EDV, V7, V8/EDV and at V FU
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| No statistical analyses for this end point | ||||||||||
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End point title |
vital sign | |||||||||
End point description |
- Systolic blood pressure 1st, 2nd and 3rd measurements (mmHg)
- Diastolic blood pressure 1st, 2nd and 3rd measurements (mmHg)
- Pulse rate 1st, 2nd and 3rd measurements (bpm)
- Weight (kg)
- Height (cm)
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End point type |
Secondary
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End point timeframe |
Collected at V1a, V2, V3, V4, V5, V6/EDV, V7 and at V8/EDV
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| No statistical analyses for this end point | ||||||||||
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End point title |
Gynaecological Examination and Intravaginal Ultrasound | |||||||||
End point description |
The gynaecological examination comprises inspection of:
- Internal genitals
- External genitals
- Breasts.
Intravaginal ultrasound comprises inspection of:
- Uterus
- Endometrium
- Ovaries.
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End point type |
Secondary
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End point timeframe |
Gynaecological examination, including intravaginal ultrasound assessments at Visit 1a, Visit 6/EDV and at Visit 8/EDV and will be summarised at Visit 1a,Visit 6/EDV, Visit 8/EDV and at endpoint
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| No statistical analyses for this end point | ||||||||||
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End point title |
physical examination findings | |||||||||
End point description |
Comprises inspection of:
- General appearance
- Eyes, ears, nose and throat
- Lung/chest
- Heart
- Abdomen
- Pelvic
- Back
- Thyroid
- Lymph nodes
- Skin
- Extremities (incl. lower legs)
- Other
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End point type |
Secondary
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End point timeframe |
Visit 1a, Visit 6/EDV and at Visit 8/EDV
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| No statistical analyses for this end point | ||||||||||
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End point title |
Vaginal bleeding pattern over 13 cycles (subject diaries) | ||||||||||||
End point description |
Analysis of the vaginal bleeding pattern over 13 cycles will be performed in the same manner as for the vaginal bleeding pattern over 6 cycles in the core phase
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End point type |
Secondary
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End point timeframe |
over 13 cycles
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| No statistical analyses for this end point | |||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
From the first administration of the IMP to 14 days after the last administration of the IMP (FPFV: 22-May-2014; LPLV: 19-Sep-2016)
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Adverse event reporting additional description |
TEAEs leading to trial termination were obtained from the AE form where the field "Action taken on trial treatment” was indicated as “drug withdrawn”
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
17.0
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Reporting groups
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Reporting group title |
Safety Set
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Reporting group description |
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| Frequency threshold for reporting non-serious adverse events: 2% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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06 Jun 2014 |
Global Protocol Amendment No.1, Final Version 1.0, 06-JUN-2014 was prepared based on the Opinion of the Paediatric Committee on the agreement of a Paediatric Investigation Plan for LF111 (drospirenone). The following changes were implemented:
The coordinating investigator from the Netherlands was replaced by one from Finland.
Final Version no. 1.0, 10-MAR-2017 CONFIDENTIAL Page 53 of 125
The Dutch CCMO did not approve the trial, thus Sweden was added.
Inclusion criterion no 8 “Subjects willing to use an oral contraceptive for at least six cycles” was discarded, to emphasize the voluntary nature of trial participation.
At V6, an eligibility check for the extension phase was added.
V7 (at the start of cycle 10) was changed from a telephone visit to an on-site visit.
Two additional telephone visits V6a (mid of cycle 8) and V7a (end of cycle 11) were added.
Handling of the home pregnancy tests at V6a and V7a was added.
Documentation of the IMP intake and vaginal bleeding pattern in the diary during the extension phase (cycles 7-13) was added.
The possibility to also send a text message to the site on the day of the first IMP intake was added.
Eight questions regarding IMP acceptability at V6/EDV and V8/EDV were added. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| N/A | |||
