Effects of Cladribine Tablets on the PK of Microgynon®

Relapsing Multiple Sclerosis (RMS) Clinical Trial

Official title:

A Randomized, Double-blind, 2-Period, 2-Sequence Crossover Phase I Study With a 1 Month run-in Period to Examine the Effect of Cladribine Tablets on the PK of a Monophasic Oral Contraceptive Containing Ethinyl Estradiol and Levonorgestrel (Microgynon®) in Pre-Menopausal Women With RMS

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03745144
• Other study ID #: MS700568_0031
• Secondary ID: 2018-001015-70
• Status: Completed
• Phase: Phase 1
• Start date: January 17, 2019
• Est. completion date: September 16, 2022

Study information

• Verified date: August 2023
• Source: Merck KGaA, Darmstadt, Germany
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Other known NCT identifiers

• NCT04086225

Recruitment information / eligibility

• Status: Completed
• Enrollment: 28
• Est. completion date: September 16, 2022
• Est. primary completion date: September 2, 2022
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 45 Years

Eligibility

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 exclusion criteria could apply

Related Conditions & MeSH terms

• Multiple Sclerosis
• Relapsing Multiple Sclerosis (RMS)
• Sclerosis

Intervention

Drug:
• Cladribine
Participants received cladribine once-daily for 5 consecutive days in treatment period 1 and 2.
• Placebo
Participants received placebo matched to cladribine once-daily for 5 consecutive days in treatment period 1 and 2.
• Microgynon®
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.

Locations

Country	Name	City	State
Germany	St. Josef und St. Elisabeth Hospital gGmbH	Bochum
Germany	Nuvisan GmbH	Neu-Ulm
Poland	M.A. - LEK A.M.Maciejowscy SC.	Katowice
Poland	BioResearch Group Sp. z o. o	Nadarzyn
Poland	IKARDIA Hospital Cardiology	Naleczów
Poland	BioVirtus Research Site Sp	Otwock
Poland	MTZ Clinical Research Sp. z o.o.	Warszawa

Sponsors (1)

Lead Sponsor	Collaborator
Merck KGaA, Darmstadt, Germany

Countries where clinical trial is conducted

Germany,  Poland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	Pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 14
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.	Pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 14
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.	Pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 14
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.	Pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 14
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.	Pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 14
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.	Pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 14
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.	Pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 14
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.	Up to Day 84
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.	Up to Day 84
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.	Up to Day 84
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.	Up to Day 84
Secondary	Maximum Plasma Concentration (Cmax) of Cladribine	Cmax was obtained from plasma concentration time curve.	Pre-dose, 0.25, 0.5, 1, 1.5 and 2 hours post-dose on Day 10, 11, 12 and 13
Secondary	Time to Reach the Maximum Observed Plasma Concentration (Tmax) of Cladribine	Tmax was obtained from plasma concentration time curve.	Pre-dose, 0.25, 0.5, 1, 1.5 and 2 hours post-dose on Day 10, 11, 12 and 13

External Links

•   Trial Awareness and Transparency website