Relapsing Multiple Sclerosis (RMS)
Conditions
Keywords
Multiple Sclerosis, Cladribine, Microgynon®
Brief summary
The purpose of this study was to investigate the potential effects of cladribine on the pharmacokinetics (PK) of monophasic oral contraceptive microgynon® by assessment of its constituents, ethinyl estradiol (EE) and levonorgestrel (LNG).
Interventions
DRUGCladribine
Participants received cladribine once-daily for 5 consecutive days in treatment period 1 and 2.
DRUGPlacebo
Participants received placebo matched to cladribine once-daily for 5 consecutive days in treatment period 1 and 2.
DRUGMicrogynon®
Participants received Microgynon® tablet once daily for 21 days in treatment period 1 and 2. Participants received Microgynon® for 21 days, starting on the first day of the menstrual cycle in Run-in period.
Sponsors
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 45 Years
Healthy volunteers
No
Inclusion criteria
* Are pre-menopausal women with or without child-bearing potential with a negative serum pregnancy test, and women with child-bearing potential receiving adequate birth control * Participants with diagnosis of clinically stable and definite relapsing multiple sclerosis (RMS) * Adequate hematological, hepatic and renal function as defined in the protocol * Are able and willing to accept dietary restrictions and restrictions regarding the use of concomitant medications (including over-the-counter products, herbal medicines and dietary supplements) over the course of the study * Had a body weight and body mass index (BMI) within the range at screening * Other protocol defined inclusion criteria could apply
Exclusion criteria
* History of clinically relevant allergy or known hypersensitivity to the active substance or to any of the excipients of cladribine tablets or hypersensitivity to drugs with a similar chemical structure to cladribine - History of clinically relevant allergy or known hypersensitivity to 1 of the active substances levonorgestrel (LNG) or ethinylestradiol (EE) or to any excipients of Microgynon® tablets * Positive results from serology examination for Hepatitis B surface antigen (HbsAg) not due to vaccination, hepatitis B core antibody (HbcAb), Hepatitis C virus antibody (anti- HCV) or Human Immunodeficiency antibody (anti-HIV) * Presence or risk of venous thromboembolism (VTE) arterial thromboembolism (ATE) * Diabetes mellitus (Type 1 or Type 2) with vascular manifestations * Signs or symptoms of neurological disease other than multiple sclerosis (MS) that could explain the symptoms of the participant * Presence of gastrointestinal (GI) disease or history of gastrointestinal -tract surgery * Exposure to another investigational drug within the last 2 months or within last 6 month if agent is known to be immunosuppressive * Other protocol defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Concentration at End of Dosing Interval at Steady State (Ctrough) of Ethinyl Estradiol and Levonorgestrel | Pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 14 | Plasma concentration at end of dosing interval at steady state (Ctrough) of ethinyl estradiol and levonorgestrel were reported. Calculated from descriptive statistics. |
| Time to Reach the Maximum Observed Plasma Concentration At Steady State (Tmax,ss) of Ethinyl Estradiol and Levonorgestrel | Pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 14 | Time to reach the maximum observed plasma concentration at steady state (Tmax,ss) of Ethinyl Estradiol and Levonorgestrel were reported. Calculated using descriptive statistics. |
| Average Plasma Concentration at Steady State (Cav,ss) of Ethinyl Estradiol and Levonorgestrel | Pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 14 | Average plasma concentration at steady state (Cav,ss) ) of Ethinyl Estradiol and Levonorgestrel were reported. Cav,ss =AUCt,ss/ tau, where, AUCt,ss was defined as the area under the plasma concentration-time curve in steady state during a complete dosing interval (tau) and Tau is the Complete dosing interval. Calculated using descriptive statistics. |
| Peak-to-Trough Fluctuation Over One Complete Dosing Interval At Steady State (PTF%) | Pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 14 | The PTF within complete dosing interval at steady state, calculated as PTF (%) = (\[Cmax - Cmin\]/Cav) multiplied by 100. Here, Cmin means the minimum plasma concentration, Cmax means the maximum plasma concentration and Cav means the average plasma concentration of drug and metabolite. |
| Area Under the Plasma Concentration-Time Curve From Zero to Tau at Steady State (AUCt,ss) of Ethinyl Estradiol and Levonorgestrel | Pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 14 | Area under the plasma concentration-time curve from zero to tau at steady state (AUCt,ss) of ethinyl estradiol and levonorgestrel were reported. Calculated using descriptive statistics. |
| Maximum Observed Plasma Concentration in Steady State (Cmax,ss) of Ethinyl Estradiol And Levonorgestrel | Pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 14 | Maximum observed plasma concentration in steady state (Cmax,ss) of ethinyl estradiol and levonorgestrel were reported. Calculated using descriptive statistics. |
| Minimum Observed Plasma Concentration in Steady State (Cmin,ss) of Ethinyl Estradiol and Levonorgestrel | Pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 14 | Minimum observed plasma concentration in steady state (Cmin,ss) of ethinyl estradiol and levonorgestrel were reported. Calculated from descriptive statistics. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinically Relevant Change From Baseline in Vital Signs | Up to Day 84 | Vital signs included oral body temperature, systolic blood pressure, diastolic blood pressure, and pulse rate. Clinical Relevance was decided by the investigator. Number of participants with clinically relevant change from baseline in vital signs were reported. |
| Maximum Plasma Concentration (Cmax) of Cladribine | Pre-dose, 0.25, 0.5, 1, 1.5 and 2 hours post-dose on Day 10, 11, 12 and 13 | Cmax was obtained from plasma concentration time curve. |
| Time to Reach the Maximum Observed Plasma Concentration (Tmax) of Cladribine | Pre-dose, 0.25, 0.5, 1, 1.5 and 2 hours post-dose on Day 10, 11, 12 and 13 | Tmax was obtained from plasma concentration time curve. |
| Number of Participants With Treatment -Emergent Adverse Events (TEAEs) | Up to Day 84 | Adverse event (AE): any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. Serious AE: an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAE: AE with onset after start of treatment or with onset date before the treatment start date but worsening after the treatment start date. TEAEs included both serious and non-serious TEAEs. |
| Number of Participants With Clinically Relevant Change From Baseline in Laboratory Values | Up to Day 84 | Laboratory investigation included hematology, biochemistry and urinalysis. Clinical relevance was decided by the investigator. Number of participants with clinically relevant change from baseline in laboratory values were reported. |
| Number of Participants With Clinically Relevant Change From Baseline in Electrocardiogram (ECG) | Up to Day 84 | The 12-lead ECGs were recorded after the participants have rested for at least 5 minutes in supine position. The parameters included heart rate (HR), Respiratory Rate, Pulse Rate, QRS, QT and QTcB calculated by the Bazett formula. Clinical Relevance was decided by the investigator. Number of participants with clinical relevant change from baseline in ECG parameters were reported. |
Countries
Germany, Poland
Participant flow
Pre-assignment details
A total of 37 participants were screened, out of which 28 participants enrolled in the study.
Participants by arm
| Arm | Count |
|---|---|
| All Participants All participants who received Microgynon® for 21 days and received cladribine treatment of 10 to 20 mg depending on body weight or matching placebo treatment in either of Treatment groups. | 28 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Period 1 | Other | 0 | 0 | 1 |
| Run-in-Period (Day 0 to Day 28) | Other | 4 | 0 | 0 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 34 Years STANDARD_DEVIATION 6.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 28 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 28 Participants |
| Sex: Female, Male Female | 28 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 28 | 0 / 13 | 0 / 13 | 0 / 13 | 0 / 13 | 0 / 13 | 0 / 11 | 0 / 10 | 0 / 10 | 0 / 10 |
| other Total, other adverse events | 7 / 28 | 3 / 13 | 9 / 13 | 5 / 13 | 5 / 13 | 4 / 13 | 1 / 11 | 5 / 10 | 1 / 10 | 7 / 10 |
| serious Total, serious adverse events | 0 / 28 | 0 / 13 | 0 / 13 | 0 / 13 | 0 / 13 | 0 / 13 | 0 / 11 | 0 / 10 | 0 / 10 | 0 / 10 |
Outcome results
Primary
Area Under the Plasma Concentration-Time Curve From Zero to Tau at Steady State (AUCt,ss) of Ethinyl Estradiol and Levonorgestrel
Area under the plasma concentration-time curve from zero to tau at steady state (AUCt,ss) of ethinyl estradiol and levonorgestrel were reported. Calculated using descriptive statistics.
Time frame: Pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 14
Population: Pharmacokinetic Analysis Set included all participants in the Safety Set without clinically important protocol deviations/violations and absence of factors/events likely to affect Pharmacokinetics (PK).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Microgynon + Cladribine | Area Under the Plasma Concentration-Time Curve From Zero to Tau at Steady State (AUCt,ss) of Ethinyl Estradiol and Levonorgestrel | Ethinyl Estradiol | 789 hour*picograms per millilitre(h*pg/ml) | Geometric Coefficient of Variation 56.9 |
| Microgynon + Cladribine | Area Under the Plasma Concentration-Time Curve From Zero to Tau at Steady State (AUCt,ss) of Ethinyl Estradiol and Levonorgestrel | Levonorgestrel | 91400 hour*picograms per millilitre(h*pg/ml) | Geometric Coefficient of Variation 45.2 |
| Microgynon + Placebo | Area Under the Plasma Concentration-Time Curve From Zero to Tau at Steady State (AUCt,ss) of Ethinyl Estradiol and Levonorgestrel | Ethinyl Estradiol | 817 hour*picograms per millilitre(h*pg/ml) | Geometric Coefficient of Variation 52.6 |
| Microgynon + Placebo | Area Under the Plasma Concentration-Time Curve From Zero to Tau at Steady State (AUCt,ss) of Ethinyl Estradiol and Levonorgestrel | Levonorgestrel | 92000 hour*picograms per millilitre(h*pg/ml) | Geometric Coefficient of Variation 46.8 |
Primary
Average Plasma Concentration at Steady State (Cav,ss) of Ethinyl Estradiol and Levonorgestrel
Average plasma concentration at steady state (Cav,ss) ) of Ethinyl Estradiol and Levonorgestrel were reported. Cav,ss =AUCt,ss/ tau, where, AUCt,ss was defined as the area under the plasma concentration-time curve in steady state during a complete dosing interval (tau) and Tau is the Complete dosing interval. Calculated using descriptive statistics.
Time frame: Pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 14
Population: Pharmacokinetic Analysis Set included all participants in the Safety Set without clinically important protocol deviations/violations and absence of factors/events likely to affect Pharmacokinetics (PK).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Microgynon + Cladribine | Average Plasma Concentration at Steady State (Cav,ss) of Ethinyl Estradiol and Levonorgestrel | Ethinyl Estradiol | 32.9 pg/ml | Geometric Coefficient of Variation 56.9 |
| Microgynon + Cladribine | Average Plasma Concentration at Steady State (Cav,ss) of Ethinyl Estradiol and Levonorgestrel | Levonorgestrel | 3810 pg/ml | Geometric Coefficient of Variation 45.2 |
| Microgynon + Placebo | Average Plasma Concentration at Steady State (Cav,ss) of Ethinyl Estradiol and Levonorgestrel | Ethinyl Estradiol | 34.1 pg/ml | Geometric Coefficient of Variation 52.6 |
| Microgynon + Placebo | Average Plasma Concentration at Steady State (Cav,ss) of Ethinyl Estradiol and Levonorgestrel | Levonorgestrel | 3830 pg/ml | Geometric Coefficient of Variation 46.8 |
Primary
Maximum Observed Plasma Concentration in Steady State (Cmax,ss) of Ethinyl Estradiol And Levonorgestrel
Maximum observed plasma concentration in steady state (Cmax,ss) of ethinyl estradiol and levonorgestrel were reported. Calculated using descriptive statistics.
Time frame: Pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 14
Population: Pharmacokinetic Analysis Set included all participants in the Safety Set without clinically important protocol deviations/violations and absence of factors/events likely to affect Pharmacokinetics (PK).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Microgynon + Cladribine | Maximum Observed Plasma Concentration in Steady State (Cmax,ss) of Ethinyl Estradiol And Levonorgestrel | Ethinyl Estradiol | 88.3 pg/ml | Geometric Coefficient of Variation 46.5 |
| Microgynon + Cladribine | Maximum Observed Plasma Concentration in Steady State (Cmax,ss) of Ethinyl Estradiol And Levonorgestrel | Levonorgestrel | 7950 pg/ml | Geometric Coefficient of Variation 33.9 |
| Microgynon + Placebo | Maximum Observed Plasma Concentration in Steady State (Cmax,ss) of Ethinyl Estradiol And Levonorgestrel | Ethinyl Estradiol | 88.1 pg/ml | Geometric Coefficient of Variation 45.7 |
| Microgynon + Placebo | Maximum Observed Plasma Concentration in Steady State (Cmax,ss) of Ethinyl Estradiol And Levonorgestrel | Levonorgestrel | 8150 pg/ml | Geometric Coefficient of Variation 34.6 |
Primary
Minimum Observed Plasma Concentration in Steady State (Cmin,ss) of Ethinyl Estradiol and Levonorgestrel
Minimum observed plasma concentration in steady state (Cmin,ss) of ethinyl estradiol and levonorgestrel were reported. Calculated from descriptive statistics.
Time frame: Pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 14
Population: Pharmacokinetic Analysis Set included all participants in the Safety Set without clinically important protocol deviations/violations and absence of factors/events likely to affect Pharmacokinetics (PK).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Microgynon + Cladribine | Minimum Observed Plasma Concentration in Steady State (Cmin,ss) of Ethinyl Estradiol and Levonorgestrel | Ethinyl Estradiol | 14.8 pg/ml | Geometric Coefficient of Variation 66.3 |
| Microgynon + Cladribine | Minimum Observed Plasma Concentration in Steady State (Cmin,ss) of Ethinyl Estradiol and Levonorgestrel | Levonorgestrel | 2520 pg/ml | Geometric Coefficient of Variation 49.5 |
| Microgynon + Placebo | Minimum Observed Plasma Concentration in Steady State (Cmin,ss) of Ethinyl Estradiol and Levonorgestrel | Ethinyl Estradiol | 14.7 pg/ml | Geometric Coefficient of Variation 65.6 |
| Microgynon + Placebo | Minimum Observed Plasma Concentration in Steady State (Cmin,ss) of Ethinyl Estradiol and Levonorgestrel | Levonorgestrel | 2430 pg/ml | Geometric Coefficient of Variation 56.3 |
Primary
Peak-to-Trough Fluctuation Over One Complete Dosing Interval At Steady State (PTF%)
The PTF within complete dosing interval at steady state, calculated as PTF (%) = (\[Cmax - Cmin\]/Cav) multiplied by 100. Here, Cmin means the minimum plasma concentration, Cmax means the maximum plasma concentration and Cav means the average plasma concentration of drug and metabolite.
Time frame: Pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 14
Population: Pharmacokinetic Analysis Set included all participants in the Safety Set without clinically important protocol deviations/violations and absence of factors/events likely to affect Pharmacokinetics (PK).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Microgynon + Cladribine | Peak-to-Trough Fluctuation Over One Complete Dosing Interval At Steady State (PTF%) | Ethinyl Estradiol | 220 percentage fluctuation | Geometric Coefficient of Variation 28 |
| Microgynon + Cladribine | Peak-to-Trough Fluctuation Over One Complete Dosing Interval At Steady State (PTF%) | Levonorgestrel | 140 percentage fluctuation | Geometric Coefficient of Variation 29.7 |
| Microgynon + Placebo | Peak-to-Trough Fluctuation Over One Complete Dosing Interval At Steady State (PTF%) | Ethinyl Estradiol | 213 percentage fluctuation | Geometric Coefficient of Variation 23.2 |
| Microgynon + Placebo | Peak-to-Trough Fluctuation Over One Complete Dosing Interval At Steady State (PTF%) | Levonorgestrel | 145 percentage fluctuation | Geometric Coefficient of Variation 29 |
Primary
Plasma Concentration at End of Dosing Interval at Steady State (Ctrough) of Ethinyl Estradiol and Levonorgestrel
Plasma concentration at end of dosing interval at steady state (Ctrough) of ethinyl estradiol and levonorgestrel were reported. Calculated from descriptive statistics.
Time frame: Pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 14
Population: Pharmacokinetic Analysis Set included all participants in the Safety Set without clinically important protocol deviations/violations and absence of factors/events likely to affect Pharmacokinetics (PK).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Microgynon + Cladribine | Plasma Concentration at End of Dosing Interval at Steady State (Ctrough) of Ethinyl Estradiol and Levonorgestrel | Ethinyl Estradiol | 15.5 pg/ml | Geometric Coefficient of Variation 66.8 |
| Microgynon + Cladribine | Plasma Concentration at End of Dosing Interval at Steady State (Ctrough) of Ethinyl Estradiol and Levonorgestrel | Levonorgestrel | 2580 pg/ml | Geometric Coefficient of Variation 48.5 |
| Microgynon + Placebo | Plasma Concentration at End of Dosing Interval at Steady State (Ctrough) of Ethinyl Estradiol and Levonorgestrel | Ethinyl Estradiol | 15.4 pg/ml | Geometric Coefficient of Variation 66.9 |
| Microgynon + Placebo | Plasma Concentration at End of Dosing Interval at Steady State (Ctrough) of Ethinyl Estradiol and Levonorgestrel | Levonorgestrel | 2580 pg/ml | Geometric Coefficient of Variation 56 |
Primary
Time to Reach the Maximum Observed Plasma Concentration At Steady State (Tmax,ss) of Ethinyl Estradiol and Levonorgestrel
Time to reach the maximum observed plasma concentration at steady state (Tmax,ss) of Ethinyl Estradiol and Levonorgestrel were reported. Calculated using descriptive statistics.
Time frame: Pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 14
Population: Pharmacokinetic Analysis Set included all participants in the Safety Set without clinically important protocol deviations/violations and absence of factors/events likely to affect Pharmacokinetics (PK).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Microgynon + Cladribine | Time to Reach the Maximum Observed Plasma Concentration At Steady State (Tmax,ss) of Ethinyl Estradiol and Levonorgestrel | Ethinyl Estradiol | 1.00 hours |
| Microgynon + Cladribine | Time to Reach the Maximum Observed Plasma Concentration At Steady State (Tmax,ss) of Ethinyl Estradiol and Levonorgestrel | Levonorgestrel | 1.00 hours |
| Microgynon + Placebo | Time to Reach the Maximum Observed Plasma Concentration At Steady State (Tmax,ss) of Ethinyl Estradiol and Levonorgestrel | Ethinyl Estradiol | 1.00 hours |
| Microgynon + Placebo | Time to Reach the Maximum Observed Plasma Concentration At Steady State (Tmax,ss) of Ethinyl Estradiol and Levonorgestrel | Levonorgestrel | 1.00 hours |
Secondary
Maximum Plasma Concentration (Cmax) of Cladribine
Cmax was obtained from plasma concentration time curve.
Time frame: Pre-dose, 0.25, 0.5, 1, 1.5 and 2 hours post-dose on Day 10, 11, 12 and 13
Population: Pharmacokinetic Analysis Set included all participants in the Safety Set without clinically important protocol deviations/violations and absence of factors/events likely to affect Pharmacokinetics (PK).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Microgynon + Cladribine | Maximum Plasma Concentration (Cmax) of Cladribine | Day 10 | 29.3 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 39.4 |
| Microgynon + Cladribine | Maximum Plasma Concentration (Cmax) of Cladribine | Day 11 | 28.2 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 45.5 |
| Microgynon + Cladribine | Maximum Plasma Concentration (Cmax) of Cladribine | Day 12 | 23.6 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 37.5 |
| Microgynon + Cladribine | Maximum Plasma Concentration (Cmax) of Cladribine | Day 13 | 22.7 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 40.7 |
Secondary
Number of Participants With Clinically Relevant Change From Baseline in Electrocardiogram (ECG)
The 12-lead ECGs were recorded after the participants have rested for at least 5 minutes in supine position. The parameters included heart rate (HR), Respiratory Rate, Pulse Rate, QRS, QT and QTcB calculated by the Bazett formula. Clinical Relevance was decided by the investigator. Number of participants with clinical relevant change from baseline in ECG parameters were reported.
Time frame: Up to Day 84
Population: Safety Analysis Set included all participant who were administered any dose of the trial medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Microgynon + Cladribine | Number of Participants With Clinically Relevant Change From Baseline in Electrocardiogram (ECG) | 0 Participants |
| Microgynon + Placebo | Number of Participants With Clinically Relevant Change From Baseline in Electrocardiogram (ECG) | 0 Participants |
| Sequence 1 Period 1: Microgynon + Cladribine (Day 9-28) | Number of Participants With Clinically Relevant Change From Baseline in Electrocardiogram (ECG) | 0 Participants |
| Sequence 1 Period 2: Microgynon Alone (Day 1-8) | Number of Participants With Clinically Relevant Change From Baseline in Electrocardiogram (ECG) | 0 Participants |
| Sequence 1 Period 2: Microgynon + Placebo (Day 9-14) | Number of Participants With Clinically Relevant Change From Baseline in Electrocardiogram (ECG) | 0 Participants |
| Sequence 1 Period 2: Microgynon + Cladribine (Day 15-28) | Number of Participants With Clinically Relevant Change From Baseline in Electrocardiogram (ECG) | 0 Participants |
| Sequence 2 Period 1: Microgynon Alone (Day 1-8) | Number of Participants With Clinically Relevant Change From Baseline in Electrocardiogram (ECG) | 0 Participants |
| Sequence 2 Period 1: Microgynon + Placebo (Day 9-28) | Number of Participants With Clinically Relevant Change From Baseline in Electrocardiogram (ECG) | 0 Participants |
| Sequence 2 Period 2: Microgynon Alone (Day 1-8) | Number of Participants With Clinically Relevant Change From Baseline in Electrocardiogram (ECG) | 0 Participants |
| Sequence 2 Period 2: Microgynon + Cladribine (Day 9-28) | Number of Participants With Clinically Relevant Change From Baseline in Electrocardiogram (ECG) | 0 Participants |
Secondary
Number of Participants With Clinically Relevant Change From Baseline in Laboratory Values
Laboratory investigation included hematology, biochemistry and urinalysis. Clinical relevance was decided by the investigator. Number of participants with clinically relevant change from baseline in laboratory values were reported.
Time frame: Up to Day 84
Population: Safety Analysis Set included all participant who were administered any dose of the trial medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Microgynon + Cladribine | Number of Participants With Clinically Relevant Change From Baseline in Laboratory Values | 0 Participants |
| Microgynon + Placebo | Number of Participants With Clinically Relevant Change From Baseline in Laboratory Values | 0 Participants |
| Sequence 1 Period 1: Microgynon + Cladribine (Day 9-28) | Number of Participants With Clinically Relevant Change From Baseline in Laboratory Values | 0 Participants |
| Sequence 1 Period 2: Microgynon Alone (Day 1-8) | Number of Participants With Clinically Relevant Change From Baseline in Laboratory Values | 0 Participants |
| Sequence 1 Period 2: Microgynon + Placebo (Day 9-14) | Number of Participants With Clinically Relevant Change From Baseline in Laboratory Values | 0 Participants |
| Sequence 1 Period 2: Microgynon + Cladribine (Day 15-28) | Number of Participants With Clinically Relevant Change From Baseline in Laboratory Values | 0 Participants |
| Sequence 2 Period 1: Microgynon Alone (Day 1-8) | Number of Participants With Clinically Relevant Change From Baseline in Laboratory Values | 0 Participants |
| Sequence 2 Period 1: Microgynon + Placebo (Day 9-28) | Number of Participants With Clinically Relevant Change From Baseline in Laboratory Values | 0 Participants |
| Sequence 2 Period 2: Microgynon Alone (Day 1-8) | Number of Participants With Clinically Relevant Change From Baseline in Laboratory Values | 0 Participants |
| Sequence 2 Period 2: Microgynon + Cladribine (Day 9-28) | Number of Participants With Clinically Relevant Change From Baseline in Laboratory Values | 0 Participants |
Secondary
Number of Participants With Clinically Relevant Change From Baseline in Vital Signs
Vital signs included oral body temperature, systolic blood pressure, diastolic blood pressure, and pulse rate. Clinical Relevance was decided by the investigator. Number of participants with clinically relevant change from baseline in vital signs were reported.
Time frame: Up to Day 84
Population: Safety Analysis Set included all participant who were administered any dose of the trial medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Microgynon + Cladribine | Number of Participants With Clinically Relevant Change From Baseline in Vital Signs | 0 Participants |
| Microgynon + Placebo | Number of Participants With Clinically Relevant Change From Baseline in Vital Signs | 0 Participants |
| Sequence 1 Period 1: Microgynon + Cladribine (Day 9-28) | Number of Participants With Clinically Relevant Change From Baseline in Vital Signs | 0 Participants |
| Sequence 1 Period 2: Microgynon Alone (Day 1-8) | Number of Participants With Clinically Relevant Change From Baseline in Vital Signs | 0 Participants |
| Sequence 1 Period 2: Microgynon + Placebo (Day 9-14) | Number of Participants With Clinically Relevant Change From Baseline in Vital Signs | 0 Participants |
| Sequence 1 Period 2: Microgynon + Cladribine (Day 15-28) | Number of Participants With Clinically Relevant Change From Baseline in Vital Signs | 0 Participants |
| Sequence 2 Period 1: Microgynon Alone (Day 1-8) | Number of Participants With Clinically Relevant Change From Baseline in Vital Signs | 0 Participants |
| Sequence 2 Period 1: Microgynon + Placebo (Day 9-28) | Number of Participants With Clinically Relevant Change From Baseline in Vital Signs | 0 Participants |
| Sequence 2 Period 2: Microgynon Alone (Day 1-8) | Number of Participants With Clinically Relevant Change From Baseline in Vital Signs | 0 Participants |
| Sequence 2 Period 2: Microgynon + Cladribine (Day 9-28) | Number of Participants With Clinically Relevant Change From Baseline in Vital Signs | 0 Participants |
Secondary
Number of Participants With Treatment -Emergent Adverse Events (TEAEs)
Adverse event (AE): any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. Serious AE: an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAE: AE with onset after start of treatment or with onset date before the treatment start date but worsening after the treatment start date. TEAEs included both serious and non-serious TEAEs.
Time frame: Up to Day 84
Population: Safety Analysis Set included all participant who were administered any dose of the trial medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Microgynon + Cladribine | Number of Participants With Treatment -Emergent Adverse Events (TEAEs) | 7 Participants |
| Microgynon + Placebo | Number of Participants With Treatment -Emergent Adverse Events (TEAEs) | 3 Participants |
| Sequence 1 Period 1: Microgynon + Cladribine (Day 9-28) | Number of Participants With Treatment -Emergent Adverse Events (TEAEs) | 9 Participants |
| Sequence 1 Period 2: Microgynon Alone (Day 1-8) | Number of Participants With Treatment -Emergent Adverse Events (TEAEs) | 5 Participants |
| Sequence 1 Period 2: Microgynon + Placebo (Day 9-14) | Number of Participants With Treatment -Emergent Adverse Events (TEAEs) | 5 Participants |
| Sequence 1 Period 2: Microgynon + Cladribine (Day 15-28) | Number of Participants With Treatment -Emergent Adverse Events (TEAEs) | 4 Participants |
| Sequence 2 Period 1: Microgynon Alone (Day 1-8) | Number of Participants With Treatment -Emergent Adverse Events (TEAEs) | 1 Participants |
| Sequence 2 Period 1: Microgynon + Placebo (Day 9-28) | Number of Participants With Treatment -Emergent Adverse Events (TEAEs) | 5 Participants |
| Sequence 2 Period 2: Microgynon Alone (Day 1-8) | Number of Participants With Treatment -Emergent Adverse Events (TEAEs) | 1 Participants |
| Sequence 2 Period 2: Microgynon + Cladribine (Day 9-28) | Number of Participants With Treatment -Emergent Adverse Events (TEAEs) | 7 Participants |
Secondary
Time to Reach the Maximum Observed Plasma Concentration (Tmax) of Cladribine
Tmax was obtained from plasma concentration time curve.
Time frame: Pre-dose, 0.25, 0.5, 1, 1.5 and 2 hours post-dose on Day 10, 11, 12 and 13
Population: Pharmacokinetic Analysis Set included all participants in the Safety Set without clinically important protocol deviations/violations and absence of factors/events likely to affect Pharmacokinetics (PK).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Microgynon + Cladribine | Time to Reach the Maximum Observed Plasma Concentration (Tmax) of Cladribine | Day 10 | 0.500 hours |
| Microgynon + Cladribine | Time to Reach the Maximum Observed Plasma Concentration (Tmax) of Cladribine | Day 11 | 0.500 hours |
| Microgynon + Cladribine | Time to Reach the Maximum Observed Plasma Concentration (Tmax) of Cladribine | Day 12 | 0.500 hours |
| Microgynon + Cladribine | Time to Reach the Maximum Observed Plasma Concentration (Tmax) of Cladribine | Day 13 | 0.500 hours |