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| Name | Class |
|---|---|
| Merck Serono S.A., Geneva | INDUSTRY |
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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
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cladribine followed by Cladribine + Pantoprazole | Experimental | Subjects will receive a single dose of cladribine10 milligram (mg) orally on Day 1. After a wash out period of 10-25 days, subjects will receive pantoprazole 40 mg orally for 2 consecutive days. On Day 2 of the pantoprazole administration, a single dose of cladribine 10 mg will be administered orally 3 hours after the second pantoprazole dose. |
|
| Cladribine + pantoprazole followed by Cladribine | Experimental | Subjects will receive pantoprazole 40 mg orally for 2 consecutive days. On Day 2 of the pantoprazole administration, a single dose of cladribine 10 mg will be administered orally 3 hours after the second pantoprazole dose. After a wash out period of 10-25 days, subjects will receive a single dose of cladribine 10 mg orally. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Cladribine | Drug | 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. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Maximum Plasma Concentration (Cmax) of Cladribine | The maximum or peak plasma concentration observed after the administration 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 |
| 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. | Pre-dose (within 30 minutes prior to dosing) and at 0.5,1, 3, 6, 8, 12,16, 24, 36, 48 Hour post-dose |
| Measure | Description | Time Frame |
|---|---|---|
| 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). | Pre-dose (within 30 minutes prior to dosing) and at 0.5,1, 3, 6, 8, 12,16, 24, 36, 48 Hour post-dose |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Pre-dose (within 30 minutes prior to dosing) and at 0.5,1, 3, 6, 8, 12,16, 24, 36, 48 Hour post-dose |
Inclusion Criteria:
Other protocol defined inclusion criteria could apply.
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Medical Responsible, PhD | Merck Serono S.A. - Geneva, an affiliate of MerckKGaA, Darmstadt, Germany | Study Director |
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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 pantoprazole dose on second day. After administration of cladribine, subjects were required to fast for an additional 2 hours. |
| FG001 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Baseline analysis population included all randomized subjects.
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Maximum Plasma Concentration (Cmax) of Cladribine | The maximum or peak plasma concentration observed after the administration of cladribine. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | nanogram/milliliter | Pre-dose (within 30 minutes prior to dosing) and at 0.5,1, 3, 6, 8, 12,16, 24, 36, 48 Hour post-dose |
|
Up to 1 year
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Cladribine | Subjects received two single doses of cladribine 10 mg orally in either first or second intervention period followed by a washout period of 10-25 days. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal distension | Gastrointestinal disorders | MedDRA Version 10.1 | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Merck KGaA Communication Center | Merck Serono, a division of Merck KGaA | +49-6151-72-5200 | service@merckgroup.com |
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| ID | Term |
|---|---|
| D009103 | Multiple Sclerosis |
| ID | Term |
|---|---|
| D020278 | Demyelinating Autoimmune Diseases, CNS |
| D020274 | Autoimmune Diseases of the Nervous System |
| D009422 | Nervous System Diseases |
| D003711 | Demyelinating Diseases |
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| ID | Term |
|---|---|
| D017338 | Cladribine |
| D000077402 | Pantoprazole |
| ID | Term |
|---|---|
| D015762 | 2-Chloroadenosine |
| D000241 | Adenosine |
| D011684 | Purine Nucleosides |
| D011687 | Purines |
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| Pantoprazole | Drug | Subjects will receive a pantoprazole 40 mg orally for 2 consecutive days either in first or second intervention period. |
|
| Time to Reach the Maximum Plasma Concentration (Tmax) of Cladribine | The tmax was defined as time taken by the drug cladribine to reach Cmax. | Pre-dose (within 30 minutes prior to dosing) and at 0.5,1, 3, 6, 8, 12,16, 24, 36, 48 Hour post-dose |
| 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. | Pre-dose (within 30 minutes prior to dosing) and at 0.5,1, 3, 6, 8, 12,16, 24, 36, 48 Hour post-dose |
| 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. | Pre-dose (within 30 minutes prior to dosing) and at 0.5,1, 3, 6, 8, 12,16, 24, 36, 48 Hour post-dose |
| 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. | Up to 1 year |
| BG001 | 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. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
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 in either first or second intervention period. |
|
|
| 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). | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | hour*nanogram/milliliter | Pre-dose (within 30 minutes prior to dosing) and at 0.5,1, 3, 6, 8, 12,16, 24, 36, 48 Hour post-dose |
|
|
|
| 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | hour*nanogram/milliliter | Pre-dose (within 30 minutes prior to dosing) and at 0.5,1, 3, 6, 8, 12,16, 24, 36, 48 Hour post-dose |
|
|
|
| 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. | 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. | Posted | Median | Full Range | hour | Pre-dose (within 30 minutes prior to dosing) and at 0.5,1, 3, 6, 8, 12,16, 24, 36, 48 Hour post-dose |
|
|
|
| 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | hour | Pre-dose (within 30 minutes prior to dosing) and at 0.5,1, 3, 6, 8, 12,16, 24, 36, 48 Hour post-dose |
|
|
|
| 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | liter/hour | Pre-dose (within 30 minutes prior to dosing) and at 0.5,1, 3, 6, 8, 12,16, 24, 36, 48 Hour post-dose |
|
|
|
| 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | liter | Pre-dose (within 30 minutes prior to dosing) and at 0.5,1, 3, 6, 8, 12,16, 24, 36, 48 Hour post-dose |
|
|
|
| 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. | 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. | Posted | Number | percentage of subjects | Up to 1 year |
|
|
|
| 0 |
| 18 |
| 2 |
| 18 |
| EG001 | Cladribine + Pantoprazole | 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 in either first or second intervention period. | 0 | 17 | 0 | 17 |
| Nasal congestion | Respiratory, thoracic and mediastinal disorders | MedDRA Version 10.1 | Non-systematic Assessment |
|
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| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D006574 |
| Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D003839 | Deoxyadenosines |
| D003853 | Deoxyribonucleosides |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
| D012263 | Ribonucleosides |
| D053799 | 2-Pyridinylmethylsulfinylbenzimidazoles |
| D013454 | Sulfoxides |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
| D011725 | Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D001562 | Benzimidazoles |
| AEs Leading to Death |
|
| AEs Leading to Discontinuation |
|