Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Also known as Evobrutinib, M2951, M2951 Low Dose, M2951 High Dose
MSC2364447C · 11 trials · 5 indications
ACR 20 response: greater than or equal to (\>=) 20 percent (%) improvement in both tender joint counts (based on a total of 68 joints) and swollen joint counts (based on a total of 66 joints) together with \>=20% improvement in at least 3 of the following: 1) participant's assessment of pain; 2) participant's global assessment of disease activity; 3) physician's global assessment of disease activity; 4) participant's assessment of physical function measured by Health Assessment Questionnaire-Disability Index (HAQ-DI); and 5) acute phase reactant as measured by high-sensitivity C-reactive protein (hsCRP). Proportion of ACR20 responders = Number of participants with ACR20 response divided by total participants.
TEAEs will be defined as the adverse events (AEs) that occur between first dose of study drug administration up to 4 weeks after the last dose of study drug administration that were absent before treatment or that worsened relative to pretreatment state.
The severity of TEAEs will be graded using National cancer institute-Common Terminology Criteria for Adverse Events version 4.03 (NCI-CTCAE v 4.03) definitions of Grade 1 through Grade 5 following his/her best medical judgment. The severity of the AEs will be classified as follows: Grade 1 or mild, Grade 2 or moderate, Grade 3 or severe, Grade 4 or life-threatening and Grade 5 or death.
Clinical laboratory parameters being monitored for safety will be summarized using descriptive statistics, by postdose shifts relative to Baseline for relevant parameters using relevant cut-offs. Clinical significance will be determined by investigator.
Observed values and changes from Baseline in vital signs will be summarized for each treatment group using descriptive statistics. Clinically noteworthy changes in vital signs will be listed and summarized as appropriate. A semi-automated blood pressure and pulse rate recording device with an appropriate cuff size will be utilized. Blood pressure and pulse rate will be measured after 10 minutes' rest in the semi-supine position with the subject's arm unconstrained by clothing or other material. The blood pressure should be assessed on the same arm for each subject throughout the trial. Clinical significance will be determined by investigator.
Observed values and changes from Baseline in ECG will be summarized for each treatment group using descriptive statistics. Clinically noteworthy changes in ECG will be listed and summarized as appropriate. Clinical significance will be determined by investigator.
A linear mixed-effects model was used to analyze the relationship between evobrutinib and MSC2729909A concentrations and ΔQTc. Based on this model, drug-induced ΔΔQTc and its two-sided 90% CI was predicted over the clinical concentration range and at concentrations corresponding to the observed geometric mean Cmax following administration of 45 mg and 225 mg evobrutinib. The higher geometric mean Cmax calculated based on the PK and ECG Analysis Sets was considered.
AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.
Cmax was obtained from plasma concentration time curve.
The AUC from time zero (= dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from lambda z determination: AUC0-inf= AUC0-tlast + Clast pred/lambda z, where AUC0-tlast was the AUC from time zero (= dosing time) to the last sampling time (tlast) at which the concentration is at or above the lower limit of quantification. Calculated using the mixed log-linear trapezoidal rule (linear up, log down); Clast pred was defined as the predicted concentration at the last sampling time, calculated from the log-linear regression line for lambda z determination and Lambda z was the apparent terminal rate constant. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on digoxin in this outcome measure.
The AUC from time zero (= dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from lambda z determination: AUC0-inf= AUC0-tlast + Clast pred/lambda z, where AUC0-tlast was the AUC from time zero (= dosing time) to the last sampling time (tlast) at which the concentration is at or above the lower limit of quantification. Calculated using the mixed log-linear trapezoidal rule (linear up, log down); Clast pred was defined as the predicted concentration at the last sampling time, calculated from the log-linear regression line for lambda z determination and Lambda z was the apparent terminal rate constant. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on metformin in this outcome measure.
The AUC from time zero (= dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from lambda z determination: AUC0-inf= AUC0-tlast + Clast pred/lambda z, where AUC0-tlast was the AUC from time zero (= dosing time) to the last sampling time (tlast) at which the concentration is at or above the lower limit of quantification. Calculated using the mixed log-linear trapezoidal rule (linear up, log down); Clast pred was defined as the predicted concentration at the last sampling time, calculated from the log-linear regression line for lambda z determination and Lambda z was the apparent terminal rate constant. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on rosuvastatin in this outcome measure.
The AUC from time zero (= dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from lambda z determination: AUC0-inf= AUC0-tlast + Clast pred/lambda z, where AUC0-tlast was the AUC from time zero (= dosing time) to the last sampling time (tlast) at which the concentration is at or above the lower limit of quantification. Calculated using the mixed log-linear trapezoidal rule (linear up, log down); Clast pred was defined as the predicted concentration at the last sampling time, calculated from the log-linear regression line for lambda z determination and Lambda z was the apparent terminal rate constant. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on sumatriptan in this outcome measure.
Cmax was obtained directly from the concentration versus time curve. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on digoxin in this outcome measure.
Cmax was obtained directly from the concentration versus time curve. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on metformin in this outcome measure.
Cmax was obtained directly from the concentration versus time curve. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on rosuvastatin in this outcome measure.
Cmax was obtained directly from the concentration versus time curve. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on sumatriptan in this outcome measure.
AUC0-inf was calculated by combining AUC0-tlast and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.
Cmax was obtained directly from the plasma concentration versus time curve.
| Arm | Type | Description |
|---|---|---|
| Placebo: Double-Blind Treatment Period | PLACEBO_COMPARATOR | - |
| M2951: Double-Blind Treatment Period | EXPERIMENTAL | - |
| Placebo/M2951: Open Label Extension Period | EXPERIMENTAL | - |
| M2951/M2951: Open Label Extension Period | EXPERIMENTAL | - |
| MSC2364447C 25 mg | EXPERIMENTAL | - |
| MSC2364447C 75 mg | EXPERIMENTAL | - |
| Placebo | PLACEBO_COMPARATOR | - |
| Treatment Sequence 1 | EXPERIMENTAL | Participants will receive one of the four interventions in a sequence decided at randomization. |
| Treatment Sequence 2 | EXPERIMENTAL | Participants will receive one of the four interventions in a sequence decided at randomization. |
| Treatment Sequence 3 | EXPERIMENTAL | Participants will receive one of the four interventions in a sequence decided at randomization. |
| Treatment Sequence 4 | EXPERIMENTAL | Participants will receive one of the four interventions in a sequence decided at randomization. |
| Evobrutinib plus Carbamazepine | EXPERIMENTAL | Participants received a single oral dose of Evobrutinib 45 mg on Day 1 and Day 19 under fed condition followed by Cabamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily. |
| Part 1: Cocktail (Day 1) | EXPERIMENTAL | Participants received single oral dose of Cocktail (digoxin 0.25 mg tablet, metformin 10 mg solution, rosuvastatin 10 mg tablet) on Day 1 in Part 1 under fed conditions. |
| Part 1: Evobrutinib (Days 4 to 12) | EXPERIMENTAL | Participants received Evobrutinib film-coated tablets, at a dose of 45 mg, orally, twice a day on Days 4 to 12 in Part 1 under fed conditions. |
| Part 1: Evobrutinib + Cocktail (Day 10) | EXPERIMENTAL | Participants received Evobrutinib film-coated tablets, at a dose of 45 mg, orally, twice a day and cocktail (digoxin 0.25 mg tablet, metformin 10 mg solution, rosuvastatin 10 mg tablet) on Day 10 in Part 1 under fed conditions. |
| Part 2: Sumatriptan (Day 1) | EXPERIMENTAL | Participants received single oral dose of Sumatriptan 25 mg tablet on Day 1 in Part 2 under fed conditions. |
| Part 2: Evobrutinib (Days 2 to 8) | EXPERIMENTAL | Participants received Evobrutinib film-coated tablets, at a dose of 45 mg, orally, twice a day on Days 2 to 8 in Part 2 under fed conditions. |
| Part 2: Evobrutinib + Sumatriptan (Day 8) | EXPERIMENTAL | Participants received Evobrutinib film-coated tablets, at a dose of 45 mg, orally, twice a day and single oral dose of Sumatriptan 25 mg tablet on Day 8 in Part 2 under fed conditions. |
| Midazolam and/or M2951 | EXPERIMENTAL | - |
| Group 1: Normal Hepatic Function (Reference) | EXPERIMENTAL | Participants with normal hepatic function received single oral dose of 30 milligrams (mg) M2951 (3 film-coated tablets of 10 mg) on Day 1 after a standard breakfast. |
| Group 2: Mild Hepatic Impairment | EXPERIMENTAL | Participants with mild hepatic impairment (Child-Pugh Class A, score 5 to 6) received single oral dose of 30 mg M2951 (3 film-coated tablets of 10 mg) on Day 1 after a standard breakfast. The Child-Pugh Score was a scoring system used to determine the prognosis with cirrhosis and need for liver transplantation. Scoring is based upon serum albumin, ascites, serum bilirubin, prothrombin time, and encephalopathy. Each category is based on a scoring system of 1-3 with 3 being the worst and a total score range of 5-15. It is broken into categories A (score of 5-6), B (score of 7-9), and C (score of 10-15) with worsening from A to C for prognosis. |
| Group 3: Moderate Hepatic Impairment | EXPERIMENTAL | Participants with moderate hepatic impairment (Child-Pugh Class B, score 7 to 9) received single oral dose of 30 mg M2951 (3 film-coated tablets of 10 mg) on Day 1 after a standard breakfast. The Child-Pugh Score was a scoring system used to determine the prognosis with cirrhosis and need for liver transplantation. Scoring is based upon serum albumin, ascites, serum bilirubin, prothrombin time, and encephalopathy. Each category is based on a scoring system of 1-3 with 3 being the worst and a total score range of 5-15. It is broken into categories A (score of 5-6), B (score of 7-9), and C (score of 10-15) with worsening from A to C for prognosis. |
| Evobrutinib: Treatment Sequence 1: A-B-C | EXPERIMENTAL | Participants will receive single oral dose of TF1 (Treatment A) evobrutinib on Day 1 under fasted condition in period 1, followed by single oral dose of TF2 (Treatment B) on Day 3 under fasted condition in period 2, followed by TF2 (Treatment C) on Day 5 under fed condition in period 3. There will be 48 hours washout period between each treatment period. |
| Evobrutinib: Treatment Sequence 2: A-C-B | EXPERIMENTAL | Participants will receive single oral dose of TF1 (Treatment A) evobrutinib on Day 1 under fasted condition in period 1, followed by TF2 (Treatment C) on Day 3 under fed condition in period 2, followed by single oral dose of TF2 (Treatment B) on Day 5 under fasted condition in period 3. There will be 48 hours washout period between each treatment period. |
| Evobrutinib: Treatment Sequence 3: B-A-C | EXPERIMENTAL | Participants will receive single oral dose of TF2 (Treatment B) on Day 1 under fasted condition in period 1, followed by single oral dose of TF1 (Treatment A) evobrutinib on Day 3 under fasted condition in period 2, followed by TF2 (Treatment C) on Day 5 under fed condition in period 3. There will be 48 hours washout period between each treatment period. |
| Evobrutinib: Treatment Sequence 4: B-C-A | EXPERIMENTAL | Participants will receive single oral dose of TF2 (Treatment B) on Day 1 under fasted condition in period 1, followed by TF2 (Treatment C) on Day 3 under fed condition in period 2, followed by single oral dose of TF1 (Treatment A) evobrutinib on Day 5 under fasted condition in period 3. There will be 48 hours washout period between each treatment period. |
| Evobrutinib: Treatment Sequence 5: C-A-B | EXPERIMENTAL | Participants will receive single oral dose of TF2 (Treatment C) on Day 1 under fed condition in period 1, followed by single oral dose of TF1 (Treatment A) evobrutinib on Day 3 under fasted condition in period 2, followed by single oral dose of TF2 (Treatment B) on Day 5 under fasted condition in period 3. There will be 48 hours washout period between each treatment period. |
| Evobrutinib: Treatment Sequence 6: C-B-A | EXPERIMENTAL | Participants will receive single oral dose of TF2 (Treatment C) on Day 1 under fed condition in period 1, followed by single oral dose of TF2 (Treatment B) on Day 3 under fasted condition in period 2, followed by single oral dose of TF1 (Treatment A) evobrutinib on Day 5 under fasted condition in period 3. There will be 48 hours washout period between each treatment period. |
| Evobrutinib: Treatment Sequence A, B, C, D | EXPERIMENTAL | Participant will receive single oral dose of evobrutinib after an overnight fast of at least 10 hours (Treatment A) for 3 days, followed by within 30 minutes after start of a light meal (Treatment B) for 2 days, followed by 1 hour prior to a low-fat meal (Treatment C) for 2 days, followed by 2 hours after start of low-fat meal (Treatment D) for 2 days. There will be 48 hours washout period between each treatment period. |
| Evobrutinib: Treatment Sequence B, D, A, C | EXPERIMENTAL | Participant will receive single oral dose of evobrutinib within 30 minutes after start of a light meal (Treatment B) for 3 days, followed by 2 hours after start of a low-fat meal (Treatment D) for 2 days, followed by after an oversight fast of at least 10 hours (Treatment A) for 2 days, followed by 1 hour prior to a low-fat meal (Treatment C) for 2 days. There will be 48 hours washout period between each treatment period. |
| Evobrutinib: Treatment Sequence C, A, D, B | EXPERIMENTAL | Participant will receive single oral dose of evobrutinib 1 hour prior to a low-fat meal (Treatment C) for 3 days, followed by after an oversight fast of at least 10 hours (Treatment A) for 2 days, followed by 2 hours after start of a low-fat meal (Treatment D) for 2 days followed by within 30 minutes after start of a light meal (Treatment B) for 2 days. There will be 48 hours washout period between each treatment period. |
| Evobrutinib: Treatment Sequence D, C, B, A | EXPERIMENTAL | Participant will receive single oral dose of evobrutinib 2 hours after start of a low-fat meal (Treatment D) for 3 days, followed by 1 hour prior to a low-fat meal (Treatment C) for 2 days, followed by within 30 minutes after start of a light meal (Treatment B) for 2 days, followed by after an overnight fast of at least 10 hours (Treatment A) for 2 days. There will be 48 hours washout period between each treatment period. |
| Evobrutinib | EXPERIMENTAL | - |
| Evobrutinib: Normal Renal Function | EXPERIMENTAL | Subjects with estimated glomerular filtration rate (eGFR) greater than or equal to (\>=) 90 milliliter per minute per 1.73 meter square (mL/min/1.73 m\^2) will receive a single oral dose of evobrutinib under fasting conditions. |
| Evobrutinib: Severe Renal Impairment | EXPERIMENTAL | Subjects with eGFR less than (\<) 30 mL/min/1.73 m\^2 will receive a single oral dose of evobrutinib under fasting conditions. |
| Evobrutinib: Moderate Renal Impairment | EXPERIMENTAL | Subjects with eGFR \>= to 30 mL/min/1.73 m\^2 and \< 60 mL/min/1.73 m\^2 will receive a single oral dose of evobrutinib under fasting conditions. |
| Evobrutinib: Mild Renal Impairment | EXPERIMENTAL | Subjects with eGFR \>= to 60 mL/min/1.73 m\^2 and \< 90 mL/min/1.73 m\^2 will receive a single oral dose of evobrutinib under fasting conditions. |
| Name | Type | Description |
|---|---|---|
| Placebo | DRUG | Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period. |
| M2951 | DRUG | Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period. |
| MSC2364447C | DRUG | Subjects will be administered with MSC2364447C 25 milligrams orally once daily for 4 weeks. |
| Placebo matched to M2951 | DRUG | Participants will receive single oral dose of placebo matched to M2951 in either of study periods (period 1 or period 2 or period 3 or period 4) under fasted conditions. |
| Moxifloxacin | DRUG | Participants will receive single oral dose of moxifloxacin in either of study periods (period 1 or period 2 or period 3 or period 4) under fasted conditions. |
| M2951 Low Dose | DRUG | Participants will receive single oral low dose of M2951 in either of study periods (period 1 or period 2 or period 3 or period 4) under fasted conditions. |
| M2951 High Dose | DRUG | Participants will receive single oral high dose of M2951 in either of study periods (period 1 or period 2 or period 3 or period 4) under fasted conditions. |
| Evobrutinib | DRUG | Participants received a single oral dose of Evobrutinib 45 mg on Day 1 and Day 19 |
| Carbamazepine | DRUG | Participants received Carbamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily. |
| Evobrutinib (45mg) | DRUG | Participants received film-coated Evobrutinib tablet at a dose of 45 milligrams (mg), orally twice daily on Days 4 to 12 in Part 1 and Days 2 to 8 in Part 2 under fed conditions. |
| Digoxin (0.25mg) | DRUG | Participants received single oral dose of digoxin tablet (0.25 mg) on Day 1 and Day 10 in Part 1 under fed conditions. |
| Metformin (10mg) | DRUG | Participants received single oral dose of metformin 10 mg solution on Day 1 and Day 10 in Part 1 under fed conditions. |
| Rosuvastatin (10mg) | DRUG | Participants received single oral dose of rosuvastatin tablet (10 mg) on Day 1 and Day 10 in Part 1 under fed conditions. |
| Sumatriptan (25mg) | DRUG | Participants received single dose of sumatriptan tablet (25 mg) on Day 1 and Day 8 in Part 2 under fed conditions. |
| Midazolam | DRUG | Participants will receive single oral dose of midazolam on Days 1, 3 and 13 under fed conditions. |
| M2951 (BTK inhibitor) | DRUG | Participants received a single oral dose of M2951 (BTK inhibitor) on Day 1. |
Inclusion Criteria: * Men or women 18 to 75 years of age at the time of informed consent signature * Confirmed diagnosis of RA according to 2010 American College of Rheumatology (ACR)/The European League Against Rheumatism (EULAR) RA classification criteria of at least 6 months duration * Positive ...