Effects of Cladribine Tablets on the PK of Microgynon®
- Conditions
- Relapsing Multiple Sclerosis (RMS)
- Interventions
- Registration Number
- NCT03745144
- Lead Sponsor
- Merck KGaA, Darmstadt, Germany
- 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).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Female
- Target Recruitment
- 28
- 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
- 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 exclusion criteria could apply
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Sequence 1: First Cladribine, Then Placebo Placebo Period 1: Participants received a single once daily dose of Microgynon® tablet from Day 1-8 followed by 5-day once-daily Cladribine 10 to 20 milligram(mg) depending on body weight along with Microgynon® tablet once daily from Day 9-28. Period 2: Participants received a single once daily dose of Microgynon® tablet from Day 1-8 followed by 5-day once-daily Cladribine matched Placebo along with Microgynon® from Day 9-14. From Day 15-28 participants received once daily Microgynon® along with 5-day once-daily Cladribine 10 to 20 mg depending on body weight. Microgynon® Microgynon® Participants received Microgynon® for 21 days, starting on the first day of the menstrual cycle. Sequence 1: First Cladribine, Then Placebo Microgynon® Period 1: Participants received a single once daily dose of Microgynon® tablet from Day 1-8 followed by 5-day once-daily Cladribine 10 to 20 milligram(mg) depending on body weight along with Microgynon® tablet once daily from Day 9-28. Period 2: Participants received a single once daily dose of Microgynon® tablet from Day 1-8 followed by 5-day once-daily Cladribine matched Placebo along with Microgynon® from Day 9-14. From Day 15-28 participants received once daily Microgynon® along with 5-day once-daily Cladribine 10 to 20 mg depending on body weight. Sequence 2: First Placebo, Then Cladribine Placebo Participants 5-day once daily Period 1: Participants received a single once daily dose of Microgynon® tablet from Day 1-8 followed by 5-day once-daily Cladribine matched Placebo along with Microgynon® tablet once daily from Day 9-28. Period 2: Participants received a single once daily dose of Microgynon® tablet from Day 1-8 followed by 5-day once-daily Cladribine 10 to 20 mg depending on body weight along with Microgynon® tablet once daily from Day 9-28. Sequence 2: First Placebo, Then Cladribine Microgynon® Participants 5-day once daily Period 1: Participants received a single once daily dose of Microgynon® tablet from Day 1-8 followed by 5-day once-daily Cladribine matched Placebo along with Microgynon® tablet once daily from Day 9-28. Period 2: Participants received a single once daily dose of Microgynon® tablet from Day 1-8 followed by 5-day once-daily Cladribine 10 to 20 mg depending on body weight along with Microgynon® tablet once daily from Day 9-28. Sequence 1: First Cladribine, Then Placebo Cladribine Period 1: Participants received a single once daily dose of Microgynon® tablet from Day 1-8 followed by 5-day once-daily Cladribine 10 to 20 milligram(mg) depending on body weight along with Microgynon® tablet once daily from Day 9-28. Period 2: Participants received a single once daily dose of Microgynon® tablet from Day 1-8 followed by 5-day once-daily Cladribine matched Placebo along with Microgynon® from Day 9-14. From Day 15-28 participants received once daily Microgynon® along with 5-day once-daily Cladribine 10 to 20 mg depending on body weight. Sequence 2: First Placebo, Then Cladribine Cladribine Participants 5-day once daily Period 1: Participants received a single once daily dose of Microgynon® tablet from Day 1-8 followed by 5-day once-daily Cladribine matched Placebo along with Microgynon® tablet once daily from Day 9-28. Period 2: Participants received a single once daily dose of Microgynon® tablet from Day 1-8 followed by 5-day once-daily Cladribine 10 to 20 mg depending on body weight along with Microgynon® tablet once daily from Day 9-28.
- Primary Outcome Measures
Name Time Method 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.
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.
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.
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.
- Secondary Outcome Measures
Name Time Method 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.
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.
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 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.
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.
Trial Locations
- Locations (7)
BioVirtus Research Site Sp
🇵🇱Otwock, Poland
St. Josef und St. Elisabeth Hospital gGmbH
🇩🇪Bochum, Germany
M.A. - LEK A.M.Maciejowscy SC.
🇵🇱Katowice, Poland
Nuvisan GmbH
🇩🇪Neu-Ulm, Germany
BioResearch Group Sp. z o. o
🇵🇱Nadarzyn, Poland
IKARDIA Hospital Cardiology
🇵🇱Nałęczów, Poland
MTZ Clinical Research Sp. z o.o.
🇵🇱Warszawa, Poland