Multiple Sclerosis
Conditions
Brief summary
The purpose of the study is to assess the influence of pantoprazole on the pharmacokinetic profile of cladribine, especially in terms of extent of absorption of cladribine since pH-modifying drug may potentially affect the stability of cladribine and thereby its bioavailability
Interventions
DRUGCladribine
Subjects will receive two single doses of 10 mg cladribine orally in either first or second intervention period followed by a washout period of 10-25 days.
DRUGPantoprazole
Subjects will receive a pantoprazole 40 mg orally for 2 consecutive days either in first or second intervention period.
Sponsors
Merck Serono S.A., Geneva
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Subjects with a body mass index less than or equal to (\<=) 28 and have a body weight greater than (\>) 60 kilogram (kg) and less than (\<) 120 kg, at screening * Able to understand informed consent and had given written, informed consent * Had a diagnosis of clinically stable and definite multiple sclerosis (MS) by either McDonald or Poser criteria * Expanded disability status scale (EDSS) score not to exceed 5.0 * Male or non-pregnant, non-breast feeding women aged 18 to 65 years, inclusive at the time that informed consent was obtained * Female subjects lacking childbearing potential defined as post-menopausal for at least two years, surgically or medically sterile or sexually inactive; or willing to avoid pregnancy by using an adequate method of birth control for 28 days prior to, during and up to 90 days after the last administration of trial medication Other protocol defined inclusion criteria could apply.
Exclusion criteria
* Subjects presenting a severe or unstable disorder: poorly controlled diabetes or arterial hypertension, severe cardiac insufficiency, unstable ischemic heart disease, a significant pre-existing hematological disease, or any medical condition, which in the opinion of the investigator, would constitute a risk or a contraindication for the participation of the subject to the study or that could interfere with the study objectives, conduct or evaluation * Subjects who were on MS treatment; and subjects who were on a non-stable symptomatic MS treatment (stable dose was defined as 3 weeks or longer prior to first study dose) * Clinically significant abnormal laboratory test results or electrocardiogram findings that in the opinion of the investigator could increase the safety risk to the subject * 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) * Signs and symptoms of Transmissible Spongiform Encephalopathy at screening, or family members who suffered from such * Presence of chronic or recurrent infection or any acute infection within the last 2 weeks before first dosing in each study period * Presence of gastrointestinal disease that, in the opinion of the investigator, could affect the pharmacokinetic outcome of the study * Consumption of any concomitant medication that could directly influence gastric acidity (example: use of antacids, histamine receptor (H2) antagonists or other proton pump inhibitor) taken within 7 days of study day 1 and throughout the study period * Intake of alcoholic beverages, caffeine and caffeine containing beverages, grapefruit, oranges, cranberries and juices of these three fruits or smoking in the 48 hours prior to first dose and 48 hours post dose (cladribine) * Exposure to any investigational drug or the use of any investigational device in the 12 weeks prior to first dose * Intake of any medications that could directly influence gastrointestinal motility and absorption of cladribine (example, use of H2-antagonists, proton pump inhibitors) 7 days prior to cladribine administration * Any immunomodulatory therapy (including but not limited to glatiramer acetate, interferons, or natalizumab) and treatment with oral or systemic corticosteroids or adrenocorticotropic hormone within 28 days of first dosing * Any cytokine or anti-cytokine therapy, IV immunoglobulin administration or plasmapheresis was prohibited in the 3 months prior to first dosing * Current history or presence of drug or alcohol abuse, confirmed by positive test results for drugs of abuse and/or alcohol or had a history of drug or alcohol abuse. Alcohol abuse was defined as: an average daily intake of more than 3 units or a weekly intake of more than 21 for males and 14 units for females where 1 unit equals 8-10 gram alcohol (1 unit equals 340 milliliter \[mL\] of beer, 115 mL of wine or 43 mL of spirits) * History or presence of hypertension or other significant cardiovascular abnormality, history of heart or kidney disease * Current diagnosis or personal history of cancer * Smoke 10 cigarettes or more per day or equivalent * Loss or donation of more than 400 mL of blood in the 12 weeks prior to first dose. * Definite or suspected personal history or family history of adverse drug reaction or hypersensitivity to drugs with a similar chemical structure to cladribine or pantoprazole or with known hypersensitivity to cladribine or pantoprazole excipients * Presence or history of any serious allergy (requiring hospitalization or prolonged systemic treatment) * Pregnant or nursing women. Treatment of pregnant and nursing women with cladribine in this study was prohibited * Signs or symptoms of neurological disease other than MS that could explain the symptoms of the subject
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Cladribine | Pre-dose (within 30 minutes prior to dosing) and at 0.5,1, 3, 6, 8, 12,16, 24, 36, 48 Hour post-dose | The AUC(0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. |
| Maximum Plasma Concentration (Cmax) of Cladribine | Pre-dose (within 30 minutes prior to dosing) and at 0.5,1, 3, 6, 8, 12,16, 24, 36, 48 Hour post-dose | The maximum or peak plasma concentration observed after the administration of cladribine. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Reach the Maximum Plasma Concentration (Tmax) of Cladribine | Pre-dose (within 30 minutes prior to dosing) and at 0.5,1, 3, 6, 8, 12,16, 24, 36, 48 Hour post-dose | The tmax was defined as time taken by the drug cladribine to reach Cmax. |
| Apparent Terminal Half-life (t1/2) of Cladribine | Pre-dose (within 30 minutes prior to dosing) and at 0.5,1, 3, 6, 8, 12,16, 24, 36, 48 Hour post-dose | The apparent terminal half-life was defined as the time required for the plasma concentration of drug cladribine to decrease 50 percent (%) in the final stage of its elimination. |
| Percentage of Subjects With Any Treatment Emergent Adverse Events (TEAEs), Serious AEs, AEs Leading to Death, and AEs Leading to Discontinuation | Up to 1 year | An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 1 year, that were absent before treatment or that worsened relative to pre treatment state. AEs Leading to Death and AEs Leading to Discontinuation were also presented in the outcome measure. |
| Total Body Clearance From Plasma Following Extravascular Administration (CL/f) of Cladribine | Pre-dose (within 30 minutes prior to dosing) and at 0.5,1, 3, 6, 8, 12,16, 24, 36, 48 Hour post-dose | Clearance of a drug was a measure of the rate at which cladribine is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose was influenced by the fraction of the dose absorbed. |
| Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of Cladribine | Pre-dose (within 30 minutes prior to dosing) and at 0.5,1, 3, 6, 8, 12,16, 24, 36, 48 Hour post-dose | The AUC (0-t) was defined as the area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-t). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/f) of Cladribine | Pre-dose (within 30 minutes prior to dosing) and at 0.5,1, 3, 6, 8, 12,16, 24, 36, 48 Hour post-dose | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed. |
Participant flow
Pre-assignment details
This was a crossover study.18 subjects were included and washout of 10 to 25 days separated each treatment period. Overall 17 subjects completed the trial.1 subject withdrew consent after completion of the first period (cladribine alone) and was excluded from Pharmacokinetic population.18 subjects were included in safety population.
Participants by arm
| Arm | Count |
|---|---|
| Cladribine Followed by Cladribine + Pantoprazole Subjects received a single 10 milligram (mg) cladribine dose orally on Day 1 followed by a wash out period of 10-25 days. Subjects then received pantoprazole 40 mg orally for 2 consecutive days. A single 10 mg cladribine dose was administered orally after 3 hours of fasting post the pantoprazole dose on second day. After administration of cladribine, subjects were required to fast for an additional 2 hours. | 9 |
| Cladribine + Pantoprazole Followed by Cladribine Subjects received pantoprazole 40 mg orally for 2 consecutive days. A single 10 mg cladribine dose was administered orally after 3 hours of fasting post the pantoprazole dose on second day. After a wash out period of 10-25 days, subjects received a single 10 mg cladribine dose orally. | 9 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Cladribine Followed by Cladribine + Pantoprazole | Cladribine + Pantoprazole Followed by Cladribine | Total |
|---|---|---|---|
| Age, Continuous | 44.56 years STANDARD_DEVIATION 11.75 | 46.89 years STANDARD_DEVIATION 8.31 | 45.72 years STANDARD_DEVIATION 9.95 |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 8 Participants |
| Sex: Female, Male Male | 5 Participants | 5 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 18 | 0 / 17 |
| serious Total, serious adverse events | 0 / 18 | 0 / 17 |
Outcome results
Primary
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Cladribine
The AUC(0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity.
Time frame: Pre-dose (within 30 minutes prior to dosing) and at 0.5,1, 3, 6, 8, 12,16, 24, 36, 48 Hour post-dose
Population: The PK analysis set included all the subjects who received cladribine alone and cladribine + pantoprazole according to the randomization and completed the full PK sampling.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cladribine | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Cladribine | 74.6 hour*nanogram/milliliter | Geometric Coefficient of Variation 27.7 |
| Cladribine + Pantoprazole | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Cladribine | 75.0 hour*nanogram/milliliter | Geometric Coefficient of Variation 34.8 |
Primary
Maximum Plasma Concentration (Cmax) of Cladribine
The maximum or peak plasma concentration observed after the administration of cladribine.
Time frame: Pre-dose (within 30 minutes prior to dosing) and at 0.5,1, 3, 6, 8, 12,16, 24, 36, 48 Hour post-dose
Population: Pharmacokinetic (PK) analysis set included all the subjects who received cladribine alone and cladribine + pantoprazole according to the randomization and completed the full PK sampling.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cladribine | Maximum Plasma Concentration (Cmax) of Cladribine | 20.7 nanogram/milliliter | Geometric Coefficient of Variation 28.2 |
| Cladribine + Pantoprazole | Maximum Plasma Concentration (Cmax) of Cladribine | 20.3 nanogram/milliliter | Geometric Coefficient of Variation 46 |
Secondary
Apparent Terminal Half-life (t1/2) of Cladribine
The apparent terminal half-life was defined as the time required for the plasma concentration of drug cladribine to decrease 50 percent (%) in the final stage of its elimination.
Time frame: Pre-dose (within 30 minutes prior to dosing) and at 0.5,1, 3, 6, 8, 12,16, 24, 36, 48 Hour post-dose
Population: The PK analysis set included all the subjects who received cladribine alone and cladribine + pantoprazole according to the randomization and completed the full PK sampling.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cladribine | Apparent Terminal Half-life (t1/2) of Cladribine | 14.0 hour | Geometric Coefficient of Variation 18.2 |
| Cladribine + Pantoprazole | Apparent Terminal Half-life (t1/2) of Cladribine | 14.9 hour | Geometric Coefficient of Variation 23.8 |
Secondary
Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of Cladribine
The AUC (0-t) was defined as the area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-t).
Time frame: Pre-dose (within 30 minutes prior to dosing) and at 0.5,1, 3, 6, 8, 12,16, 24, 36, 48 Hour post-dose
Population: The PK analysis set included all the subjects who received cladribine alone and cladribine + pantoprazole according to the randomization and completed the full PK sampling.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cladribine | Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of Cladribine | 71.5 hour*nanogram/milliliter | Geometric Coefficient of Variation 28 |
| Cladribine + Pantoprazole | Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of Cladribine | 71.3 hour*nanogram/milliliter | Geometric Coefficient of Variation 36.6 |
Secondary
Percentage of Subjects With Any Treatment Emergent Adverse Events (TEAEs), Serious AEs, AEs Leading to Death, and AEs Leading to Discontinuation
An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 1 year, that were absent before treatment or that worsened relative to pre treatment state. AEs Leading to Death and AEs Leading to Discontinuation were also presented in the outcome measure.
Time frame: Up to 1 year
Population: Safety analysis set included all the randomized subjects who received treatment with at least one dose of either cladribine or pantoprazole during the study period.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cladribine | Percentage of Subjects With Any Treatment Emergent Adverse Events (TEAEs), Serious AEs, AEs Leading to Death, and AEs Leading to Discontinuation | TEAEs | 11.1 percentage of subjects |
| Cladribine | Percentage of Subjects With Any Treatment Emergent Adverse Events (TEAEs), Serious AEs, AEs Leading to Death, and AEs Leading to Discontinuation | SAEs | 0.0 percentage of subjects |
| Cladribine | Percentage of Subjects With Any Treatment Emergent Adverse Events (TEAEs), Serious AEs, AEs Leading to Death, and AEs Leading to Discontinuation | AEs Leading to Death | 0.0 percentage of subjects |
| Cladribine | Percentage of Subjects With Any Treatment Emergent Adverse Events (TEAEs), Serious AEs, AEs Leading to Death, and AEs Leading to Discontinuation | AEs Leading to Discontinuation | 0.0 percentage of subjects |
| Cladribine + Pantoprazole | Percentage of Subjects With Any Treatment Emergent Adverse Events (TEAEs), Serious AEs, AEs Leading to Death, and AEs Leading to Discontinuation | AEs Leading to Discontinuation | 0.0 percentage of subjects |
| Cladribine + Pantoprazole | Percentage of Subjects With Any Treatment Emergent Adverse Events (TEAEs), Serious AEs, AEs Leading to Death, and AEs Leading to Discontinuation | TEAEs | 0.0 percentage of subjects |
| Cladribine + Pantoprazole | Percentage of Subjects With Any Treatment Emergent Adverse Events (TEAEs), Serious AEs, AEs Leading to Death, and AEs Leading to Discontinuation | AEs Leading to Death | 0.0 percentage of subjects |
| Cladribine + Pantoprazole | Percentage of Subjects With Any Treatment Emergent Adverse Events (TEAEs), Serious AEs, AEs Leading to Death, and AEs Leading to Discontinuation | SAEs | 0.0 percentage of subjects |
Secondary
Time to Reach the Maximum Plasma Concentration (Tmax) of Cladribine
The tmax was defined as time taken by the drug cladribine to reach Cmax.
Time frame: Pre-dose (within 30 minutes prior to dosing) and at 0.5,1, 3, 6, 8, 12,16, 24, 36, 48 Hour post-dose
Population: The PK analysis set included all the subjects who received cladribine alone and cladribine + pantoprazole according to the randomization and completed the full PK sampling.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cladribine | Time to Reach the Maximum Plasma Concentration (Tmax) of Cladribine | 0.5 hour |
| Cladribine + Pantoprazole | Time to Reach the Maximum Plasma Concentration (Tmax) of Cladribine | 0.6 hour |
Secondary
Total Body Clearance From Plasma Following Extravascular Administration (CL/f) of Cladribine
Clearance of a drug was a measure of the rate at which cladribine is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose was influenced by the fraction of the dose absorbed.
Time frame: Pre-dose (within 30 minutes prior to dosing) and at 0.5,1, 3, 6, 8, 12,16, 24, 36, 48 Hour post-dose
Population: The PK analysis set included all the subjects who received cladribine alone and cladribine + pantoprazole according to the randomization and completed the full PK sampling.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cladribine | Total Body Clearance From Plasma Following Extravascular Administration (CL/f) of Cladribine | 134.0 liter/hour | Geometric Coefficient of Variation 27.7 |
| Cladribine + Pantoprazole | Total Body Clearance From Plasma Following Extravascular Administration (CL/f) of Cladribine | 133.3 liter/hour | Geometric Coefficient of Variation 34.8 |
Other Pre-specified
Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/f) of Cladribine
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.
Time frame: Pre-dose (within 30 minutes prior to dosing) and at 0.5,1, 3, 6, 8, 12,16, 24, 36, 48 Hour post-dose
Population: The PK analysis set included all the subjects who received cladribine alone and cladribine + pantoprazole according to the randomization and completed the full PK sampling.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cladribine | Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/f) of Cladribine | 2709 liter | Geometric Coefficient of Variation 32 |
| Cladribine + Pantoprazole | Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/f) of Cladribine | 2875 liter | Geometric Coefficient of Variation 46 |