Rheumatoid Arthritis
Conditions
Keywords
Rheumatoid arthritis, RA, Rituximab, Rituxan, MabThera, Methotrexate, Rheumatrex, Trexall, MK-8808
Brief summary
This is a study of the overall safety, tolerability, and pharmacokinetics (PK) of MK-8808 versus rituximab (MabThera® and Rituxan®) in participants with moderate to severe RA with an inadequate response or intolerance to methotrexate.
Detailed description
In Part A of the base study, participants are randomized to either MK-8808 or MabThera®. In Part B of the base study, participants are randomized to either MK-8808, MabThera®, or Rituxan®. Participants enrolled in Part A are not eligible to participate in Part B. In both Parts A and B, participants will receive one or two courses of therapy, with each course including two infusions of the study drugs. The extension portion of the study (Part C) will sequentially follow the base study beginning at Week 52 and continue for an additional 54 weeks. All participants who meet eligibility criteria and continue into the study extension will be treated with open-label MK-8808. Participants randomized to MK-8808 in the base study will remain on the same therapy. Participants randomized to rituximab (MabThera® or Rituxan®) in the base study will be switched to MK-8808 for the extension study.
Interventions
BIOLOGICALMK-8808
MK-8808 500 mg/m\^2 administered by IV on Day 1 and Day 15 or MK-8808 1000 mg administered by IV at Week 54 and Week 56
BIOLOGICALMabThera® (rituximab)
MabThera® 500 mg/m\^2 or 1000 mg administered by IV on Day 1 and Day 15
DRUGMethotrexate
Methotrexate 10-25 mg administered orally, SC, or IM as a weekly stable dose
BIOLOGICALRituxan® (rituximab)
Rituxan® 1000 mg administered by IV on Day 1 and Day 15
DRUGMethylprednisolone
Methylprednisolone 100 mg administered IV before initiation of each infusion as pre-medication to reduce the incidence and severity of infusion reactions
DRUGAcetaminophen
Acetaminophen 1000 to 1350 mg administered orally before initiation of each infusion as pre-medication to reduce the incidence and severity of infusion reactions
DRUGLoratadine
Loratidine 10 mg administered orally before initiation of each infusion as pre-medication to reduce the incidence and severity of infusion reactions
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Female participants of reproductive potential must demonstrate a serum β-human chorionic gonadotropin (hCG) level consistent with the nongravid state at the pre-study (screening) visit, and a negative urine pregnancy test within 24 hours prior to all doses and agree to use (and/or have their partner use) two acceptable methods of birth control beginning at least 2 weeks prior to administration of the first dose of study drug, throughout the study (including washout intervals between treatment periods/panels) and until at least 12 months after administration of the last dose of study drug in the last treatment period * The participant has a Body Mass Index (BMI) ≤35 kg/m\^2 at the prestudy (screening) visit * For Part A Only: The participant has a body surface are (BSA) ≤2.0 m\^2 at the prestudy (screening) visit. * Has satisfied at least 4 of 7 American Rheumatology Association (ARA) 1987 revised criteria for the diagnosis of RA * Is American College of Rheumatology (ACR) Functional Class I, II, or III * Had a diagnosis of RA made at least 6 months prior to the prestudy (screening) visit, was ≥ 16 years of age when diagnosed, and has active disease * Is on a stable oral, IM, or SC dose of methotrexate and is continuing to take methotrexate * Has an inadequate response or intolerance to at least one disease-modifying antirheumatic drug (DMARD) * For Part A: Participant is either naïve to biological therapy for RA or has had an inadequate response to previous or current treatment with an anti-tumor necrosis factor (TNF) treatment (patient could have failed up to three anti-TNF agents treatments) or participant has had intolerance up to three anti-TNF treatments. * For Part B: Participant has had an inadequate response to previous or current treatment with an anti-TNF treatment (patient could have failed up to three anti-TNF agents treatments) or participant has had intolerance up to three anti-TNF treatments * Participant has no clinically significant abnormality on electrocardiogram performed at the prestudy (screening) visit and/or prior to administration of the initial dose of study drug * For Part B Only: Participant is positive for rheumatoid factor (RF) or, if negative for RF, is positive for anti-CCP at screening visit * For Part C Only: Participant must have completed the first 52 weeks of treatment in the base study * For Part C Only: Participant achieved a minimum 20% response from baseline on the American College of Rheumatology (ACR) Responder Index (ACR20) at Visit 19 (last visit for the base study)
Exclusion criteria
* Mentally or legally incapacitated, has significant emotional problems at the time of the prestudy (screening) visit or during the conduct of the study or has a history of a clinically significant psychiatric disorder over the last 5 years * Creatinine clearance of ≤ 80 mL/min * History of stroke, chronic seizures or major neurological disorder * History of neoplastic disease, except treated basal cell carcinoma or carcinoma in situ of the cervix or other malignancies which have been successfully treated ≥ 5 years * History of leukemia, lymphoma, malignant melanoma, or myeloproliferative disease regardless of the time since treatment * History of coronary artery disease, congestive heart failure (New York Heart Association Class I-IV), or a history of clinically significant arrhythmia (including any history of atrial fibrillation, atrial flutter, or any sustained ventricular arrhythmia) * Hypersensitivity or allergy to rituximab or any of the excipients of MK-8808 or rituximab (MabThera® or Rituxan® ) * History of a rheumatic autoimmune disease other than RA (e.g. systemic lupus erythematosus (SLE), polymyositis, etc.) * Severe active infection of any type or history of a medically serious infection as defined by a history of treatment requiring hospitalization, long term IV outpatient treatment for systemic bacterial, viral or fungal infection, use of IV antibiotics within 30-days of screening, or use of antibiotic therapy three or more times in the last six months prior to screening * History of opportunistic infection * Active-virus vaccination within 4 weeks * Active tuberculosis with or without adequate treatment, history of latent tuberculosis without written confirmation from health care provider of adequate prophylaxis or any evidence of tuberculosis on a chest X-ray performed within 3 months of dosing * Chronic hepatitis B or hepatitis C infection or has human immunodeficiency virus (HIV) infection * Previously treated with rituximab (MabThera® or Rituxan®) or any investigational anti-CD20 antibody * Active use or planned use of a prohibited DMARD during the course of study participation, and/or insufficient washout from a prohibited DMARD at the time of the planned first dose of MK-8808/rituximab (MabThera® or Rituxan®) * Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks * Participated in another investigational study with length of time within at least 5 half-lives of the previous investigational study drug * Pregnant or breastfeeding or expecting to conceive * Allergy to murine proteins * Allergy or sensitivity to components of the drug vial or any of the materials used for infusion
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Area Under the Concentration-time Curve From Day 0 to Day 84 (AUC0-84day) After a Single Course of Treatment | Day 1 (pre- and post-dose), Day 3, Day 5, Day 8, Day 15, Day 17, Day 19, Day 22, Day 29, Day 43, Day 57, Day 85 | AUC is a measure of the amount of drug in the plasma over time; samples are collected at intervals from pre-dose up to 84 days after the dose. Descriptive data values and associated dispersion measures (confidence intervals) are expressed in terms of the factor 10E6. |
| Part B: Area Under the Concentration-time Curve From Day 0 to Day 84 (AUC0-84day) After a Single Course of Treatment | Day 1 (pre- and post-dose), Day 3, Day 5, Day 8, Day 15, Day 17, Day 19, Day 22, Day 29, Day 43, Day 57, Day 85 | AUC is a measure of the amount of drug in the plasma over time; samples are collected at intervals from pre-dose up to 84 days after the dose. |
| Number of Participants Who Experienced at Least One Adverse Event | Parts A and B: Up to 52 weeks; Extension A and B: Up to 106 weeks | An adverse event is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure. |
| Number of Participants Who Discontinued Study Drug Due to Adverse Events | Parts A and B: Up to Week 28; Extension A and B: Up to 82 weeks | Discontinuation/withdrawal of study treatment due to an adverse event was performed at the discretion of the investigator or the Sponsor for safety concerns. An adverse event is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure. |
| Number of Participants With Immunoglobulin G (IgG) Response in the Extension Study | Week 54, Week 68, Week 80, Week 94, Week 106 | Serum IgG levels are determined over course of therapy with MK-8808 in the Extension Study. |
| Number of Participants Positive for Anti-Drug Antibody (ADA) Formation in the Extension Study | Week 54, Week 56, Week 68, Week 80, Week 82, Week 94, Week 106 | Serum ADA positivity is determined over course of therapy with MK-8808 in the Extension Study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Maximum Concentration (Cmax) After the Second Infusion of a Single Course of Treatment | Day 15 | Cmax is a measure of the maximum plasma concentration of drug; samples are collected on Day 15 after the second infusion of the first course of treatment. Descriptive data values and associated dispersion measures (confidence intervals) are expressed in terms of the factor 10E3. |
| Part B: Cmax After the Second Infusion of a Single Course of Treatment | Day 15 | Cmax is a measure of the maximum plasma concentration of drug; samples are collected on Day 15 after the second infusion of the first course of treatment. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Part A: Number of ACR20, ACR50, and ACR70 Responders at Week 24 | Week 24 | American College of Rheumatology (ACR) Responder Index is based on a set of evaluations: the Investigator Tender Joint Count/Number of Tender Joints (out of 68 Joints); Investigator Swollen Joint Count/Number of Swollen Joints (out of 66 Joints); Patient Global Assessment of Disease Activity (PGAD); Investigator Global Assessment of Disease Activity (IGAD); Patient Global Assessment of Pain (PGAP); Health Assessment Questionnaire Disability Index (HAQ-DI); and ESR. ACR response indicates percent change (ie, improvement) from baseline (20%, 50%, 70%) PGAD & IGAD: assessment of function on a 4-point Likert scale: 0=very well to 3=unable to do PGAP: pain due to arthritis measured on a 0-100 mm visual analog scale: Left hand marker-no pain; right hand marker-extreme pain HAQ-DI: assessment of 8 daily living activities (dress/groom; arise; eat; walk; reach; grip; hygiene; common daily activities) on 4-point Likert scale: 0=no difficulty to 3=unable to do |
| Part B: Number of ACR20, ACR50, and ACR70 Responders at Week 24 | Week 24 | American College of Rheumatology (ACR) Responder Index is based on a set of evaluations: the Investigator Tender Joint Count/Number of Tender Joints (out of 68 Joints); Investigator Swollen Joint Count/Number of Swollen Joints (out of 66 Joints); Patient Global Assessment of Disease Activity (PGAD); Investigator Global Assessment of Disease Activity (IGAD); Patient Global Assessment of Pain (PGAP); Health Assessment Questionnaire Disability Index (HAQ-DI); and ESR. ACR response indicates percent change (ie, improvement) from baseline (20%, 50%, 70%) PGAD & IGAD: assessment of function on a 4-point Likert scale: 0=very well to 3=unable to do PGAP: pain due to arthritis measured on a 0-100 mm visual analog scale: Left hand marker-no pain; right hand marker-extreme pain HAQ-DI: assessment of 8 daily living activities (dress/groom; arise; eat; walk; reach; grip; hygiene; common daily activities) on 4-point Likert scale: 0=no difficulty to 3=unable to do |
| Change From Baseline in Disease Activity in 28 Joints C-Reactive Protein Score (DAS28-CRP) by Time-point | Baseline, Week 6, Week 12 | The DAS28-CRP is a combination scoring method for function using the European League against Rheumatism (EULAR) 28 joint count and the CRP value. The DAS28-CRP scores range from 2.0 to 10.0 with higher values indicating a higher disease activity. A DAS28-CRP below the score of 2.6 is interpreted as Remission. CRP values below lower limit of quantification (LLQ) (\<0.4 mg/dL) were set to 0.2 mg/dL in the calculation of DAS28-CRP. |
Participant flow
Recruitment details
The study enrolled participants 18 to 65 years of age with a diagnosis of moderate/severe rheumatoid arthritis (RA), naive to treatment or having failed \>=1 anti-TNF agent, and on a stable dose of methotrexate. Not all participants completing the Treatment Period entered the Extension Period due to study early termination.
Pre-assignment details
For Part B only, positive for rheumatoid factor (RF) or, if negative for RF, positive for anti-cyclic citrullinated protein antibodies at the screening visit.
Participants by arm
| Arm | Count |
|---|---|
| Part A: MK-8808 500 mg/m^2 Participants receive one course of MK-8808 (500 mg/m\^2) administered intravenously (IV) on Day 1 and Day 15; (2nd optional course of treatment at Weeks 26 and 28) + methotrexate 12.5 to 25 mg/week (or 10 mg if greater dose not tolerated) either orally, SC, or IM for the duration of the trial. | 23 |
| Part A: MabThera® 500 mg/m^2 Participants receive one course of MabThera® (500 mg/m\^2) administered IV on Day 1 and Day 15 (2nd optional course of treatment at Weeks 26 and 28) + methotrexate 12.5 to 25 mg/week (or 10 mg if greater dose not tolerated) either orally, SC, or IM for the duration of the trial. | 22 |
| Part B: MK-8808 1000 mg Participants receive one course of MK-8808 (1000 mg) IV on Day 1 and Day 15 (2nd optional course of treatment at Weeks 26 and 28) + methotrexate 12.5 to 25 mg/week (or 10 mg if greater dose not tolerated) either orally, SC, or IM for the duration of the trial. | 18 |
| Part B: MabThera® 1000 mg Participants receive one course of MabThera® (1000 mg) IV on Day 1 and Day 15 (2nd optional course of treatment at Weeks 26 and 28) + methotrexate 12.5 to 25 mg/week (or 10 mg if greater dose not tolerated) either orally, SC, or IM for the duration of the trial. | 19 |
| Part B: Rituxan® 1000 mg Participants receive one course of Rituxan® (1000 mg) administered IV on Day 1 and Day 15 (2nd optional course of treatment at Weeks 26 and 28) + methotrexate 12.5 to 25 mg/week (or 10 mg if greater dose not tolerated) either orally, SC, or IM for the duration of the trial. | 18 |
| Total | 100 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Extension Period | Protocol Violation | 3 | 1 | 0 | 1 | 0 |
| Treatment Period | Adverse Event | 0 | 0 | 1 | 1 | 2 |
| Treatment Period | Lack of Efficacy | 0 | 0 | 0 | 0 | 1 |
| Treatment Period | Lost to Follow-up | 1 | 0 | 0 | 0 | 0 |
| Treatment Period | Physician Decision | 0 | 0 | 0 | 1 | 0 |
| Treatment Period | Protocol Violation | 0 | 1 | 0 | 0 | 0 |
| Treatment Period | Unknown due to early stopping of study | 0 | 0 | 8 | 11 | 7 |
| Treatment Period | Withdrawal by Subject | 0 | 0 | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Part A: MK-8808 500 mg/m^2 | Part A: MabThera® 500 mg/m^2 | Part B: MK-8808 1000 mg | Part B: MabThera® 1000 mg | Part B: Rituxan® 1000 mg | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 51.7 years STANDARD_DEVIATION 6.7 | 51.5 years STANDARD_DEVIATION 8.4 | 46.4 years STANDARD_DEVIATION 10.9 | 48.7 years STANDARD_DEVIATION 12.4 | 46.2 years STANDARD_DEVIATION 10.5 | 49.1 years STANDARD_DEVIATION 9.9 |
| Sex: Female, Male Female | 20 Participants | 19 Participants | 14 Participants | 16 Participants | 15 Participants | 84 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 4 Participants | 3 Participants | 3 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 15 / 23 | 17 / 22 | 11 / 18 | 16 / 19 | 13 / 18 | 2 / 15 | 2 / 13 | 0 / 1 | 0 / 1 | 0 / 3 |
| serious Total, serious adverse events | 1 / 23 | 1 / 22 | 2 / 18 | 0 / 19 | 0 / 18 | 0 / 15 | 0 / 13 | 0 / 1 | 0 / 1 | 0 / 3 |
Outcome results
Primary
Number of Participants Positive for Anti-Drug Antibody (ADA) Formation in the Extension Study
Serum ADA positivity is determined over course of therapy with MK-8808 in the Extension Study.
Time frame: Week 54, Week 56, Week 68, Week 80, Week 82, Week 94, Week 106
Population: The analysis was not performed due to early termination of the study after Part A. Blood sampling in the Extension Study was performed without further laboratory quantification for this outcome measure.
Primary
Number of Participants Who Discontinued Study Drug Due to Adverse Events
Discontinuation/withdrawal of study treatment due to an adverse event was performed at the discretion of the investigator or the Sponsor for safety concerns. An adverse event is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure.
Time frame: Parts A and B: Up to Week 28; Extension A and B: Up to 82 weeks
Population: APaT population defined as all participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: MK-8808 500 mg/m^2 | Number of Participants Who Discontinued Study Drug Due to Adverse Events | 2 Participants |
| Part A: MabThera® 500 mg/m^2 | Number of Participants Who Discontinued Study Drug Due to Adverse Events | 2 Participants |
| Part B: Rituxan® 1000 mg | Number of Participants Who Discontinued Study Drug Due to Adverse Events | 1 Participants |
| Part B: MabThera 1000 mg | Number of Participants Who Discontinued Study Drug Due to Adverse Events | 1 Participants |
| Part B: Rituxan 1000 mg | Number of Participants Who Discontinued Study Drug Due to Adverse Events | 2 Participants |
| Extension A: MK-8808 500 mg/m^2 /MK-8808 1000 mg | Number of Participants Who Discontinued Study Drug Due to Adverse Events | 0 Participants |
| Extension A: MabThera 500 mg/m^2 /MK-8808 1000 mg | Number of Participants Who Discontinued Study Drug Due to Adverse Events | 0 Participants |
| Extension B: MK-8808 1000 mg /MK-8808 1000 mg | Number of Participants Who Discontinued Study Drug Due to Adverse Events | 0 Participants |
| Extension B: MabThera 1000 mg /MK-8808 1000 mg | Number of Participants Who Discontinued Study Drug Due to Adverse Events | 0 Participants |
| Extension B: Rituxan1000 mg/MK-8808 1000 mg | Number of Participants Who Discontinued Study Drug Due to Adverse Events | 0 Participants |
Primary
Number of Participants Who Experienced at Least One Adverse Event
An adverse event is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure.
Time frame: Parts A and B: Up to 52 weeks; Extension A and B: Up to 106 weeks
Population: All Participants as Treated (APaT) population defined as all participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: MK-8808 500 mg/m^2 | Number of Participants Who Experienced at Least One Adverse Event | 18 Participants |
| Part A: MabThera® 500 mg/m^2 | Number of Participants Who Experienced at Least One Adverse Event | 21 Participants |
| Part B: Rituxan® 1000 mg | Number of Participants Who Experienced at Least One Adverse Event | 12 Participants |
| Part B: MabThera 1000 mg | Number of Participants Who Experienced at Least One Adverse Event | 16 Participants |
| Part B: Rituxan 1000 mg | Number of Participants Who Experienced at Least One Adverse Event | 13 Participants |
| Extension A: MK-8808 500 mg/m^2 /MK-8808 1000 mg | Number of Participants Who Experienced at Least One Adverse Event | 2 Participants |
| Extension A: MabThera 500 mg/m^2 /MK-8808 1000 mg | Number of Participants Who Experienced at Least One Adverse Event | 2 Participants |
| Extension B: MK-8808 1000 mg /MK-8808 1000 mg | Number of Participants Who Experienced at Least One Adverse Event | 0 Participants |
| Extension B: MabThera 1000 mg /MK-8808 1000 mg | Number of Participants Who Experienced at Least One Adverse Event | 0 Participants |
| Extension B: Rituxan1000 mg/MK-8808 1000 mg | Number of Participants Who Experienced at Least One Adverse Event | 0 Participants |
Comparison: The difference in percent AE incidence was determined for the treatment comparison (Part A: MK-8808 500 mg/m\^2 - Part A: MabThera 500 mg/m\^2) when \>=4 participants in an arm experienced an event.95% CI: [-38.6, 3.6]Miettinen-Nurminen
Comparison: The difference in percent AE incidence was determined for the treatment comparison (Part B: MK-8808 1000 mg - Part B: MabThera 1000 mg) when \>=4 participants in an arm experienced an event.95% CI: [-44.4, 10.9]Miettinen-Nurminen
Comparison: The difference in percent AE incidence was determined for the treatment comparison (Part B: MK-8808 1000 mg - Part B: Rituxan® 1000 mg) when \>=4 participants in an arm experienced an event.95% CI: [-34.9, 24.6]Miettinen-Nurminen
Comparison: The difference in percent AE incidence was determined for the treatment comparison (Part B: MabThera® 1000 mg - Part B: Rituxan® 1000 mg) when \>=4 participants in an arm experienced an event.95% CI: [-15.6, 38.9]Miettinen-Nurminen
Primary
Number of Participants With Immunoglobulin G (IgG) Response in the Extension Study
Serum IgG levels are determined over course of therapy with MK-8808 in the Extension Study.
Time frame: Week 54, Week 68, Week 80, Week 94, Week 106
Population: The analysis was not performed due to early termination of the study after Part A. Blood sampling in the Extension Study was performed without further laboratory quantification for this outcome measure.
Primary
Part A: Area Under the Concentration-time Curve From Day 0 to Day 84 (AUC0-84day) After a Single Course of Treatment
AUC is a measure of the amount of drug in the plasma over time; samples are collected at intervals from pre-dose up to 84 days after the dose. Descriptive data values and associated dispersion measures (confidence intervals) are expressed in terms of the factor 10E6.
Time frame: Day 1 (pre- and post-dose), Day 3, Day 5, Day 8, Day 15, Day 17, Day 19, Day 22, Day 29, Day 43, Day 57, Day 85
Population: Participants who completed a full course of MK-8808 or MabThera® (two full doses of 500 mg/m\^2 on Days 1 and 15), had no major protocol violations, had a complete pharmacokinetic (PK) profile, had serum MK-8808 or MabThera® concentrations prior to the first dose of the first course not exceeding 5% of Cmax after the first dose of the first course
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Part A: MK-8808 500 mg/m^2 | Part A: Area Under the Concentration-time Curve From Day 0 to Day 84 (AUC0-84day) After a Single Course of Treatment | 110.56 hr*mg/mL |
| Part A: MabThera® 500 mg/m^2 | Part A: Area Under the Concentration-time Curve From Day 0 to Day 84 (AUC0-84day) After a Single Course of Treatment | 110.12 hr*mg/mL |
Comparison: Back-transformed least squares mean and confidence interval from fixed effects model performed on natural log-transformed values containing treatment as a fixed effect and gender as a covariate.90% CI: [0.87, 1.16]ANOVA
Primary
Part B: Area Under the Concentration-time Curve From Day 0 to Day 84 (AUC0-84day) After a Single Course of Treatment
AUC is a measure of the amount of drug in the plasma over time; samples are collected at intervals from pre-dose up to 84 days after the dose.
Time frame: Day 1 (pre- and post-dose), Day 3, Day 5, Day 8, Day 15, Day 17, Day 19, Day 22, Day 29, Day 43, Day 57, Day 85
Population: PK analysis for Part B was not performed due to early termination of the study after Part A. Blood sampling in Part B was performed without further laboratory quantification for this outcome measure.
Secondary
Part A: Maximum Concentration (Cmax) After the Second Infusion of a Single Course of Treatment
Cmax is a measure of the maximum plasma concentration of drug; samples are collected on Day 15 after the second infusion of the first course of treatment. Descriptive data values and associated dispersion measures (confidence intervals) are expressed in terms of the factor 10E3.
Time frame: Day 15
Population: Participants who completed a full course of MK-8808 or MabThera® (two full doses of 500 mg/m\^2 on Days 1 and 15); had no major protocol violations; had a complete PK profile; had serum MK-8808 or MabThera® concentrations prior to the first dose of the first course not exceeding 5% of Cmax after the first dose of the first course.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Part A: MK-8808 500 mg/m^2 | Part A: Maximum Concentration (Cmax) After the Second Infusion of a Single Course of Treatment | 326.49 ng/mL |
| Part A: MabThera® 500 mg/m^2 | Part A: Maximum Concentration (Cmax) After the Second Infusion of a Single Course of Treatment | 332.39 ng/mL |
Comparison: Back-transformed least squares mean and confidence interval from fixed effects model performed on natural log-transformed values containing treatment as a fixed effect and gender as a covariate.90% CI: [0.87, 1.1]ANOVA
Secondary
Part B: Cmax After the Second Infusion of a Single Course of Treatment
Cmax is a measure of the maximum plasma concentration of drug; samples are collected on Day 15 after the second infusion of the first course of treatment.
Time frame: Day 15
Population: PK analysis for Part B was not performed due to early termination of the study after Part A. Blood sampling in Part B was performed without further laboratory quantification for this outcome measure.
Other Pre-specified
Change From Baseline in Disease Activity in 28 Joints C-Reactive Protein Score (DAS28-CRP) by Time-point
The DAS28-CRP is a combination scoring method for function using the European League against Rheumatism (EULAR) 28 joint count and the CRP value. The DAS28-CRP scores range from 2.0 to 10.0 with higher values indicating a higher disease activity. A DAS28-CRP below the score of 2.6 is interpreted as Remission. CRP values below lower limit of quantification (LLQ) (\<0.4 mg/dL) were set to 0.2 mg/dL in the calculation of DAS28-CRP.
Time frame: Baseline, Week 6, Week 12
Population: FAS defined as all randomized participants who received at least one complete treatment course (2 doses) and had at least one post-treatment measurement. Patients were included in the treatment group to which they were randomized. A patient might have been be excluded from the FAS population for a given endpoint for multiple reasons.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: MK-8808 500 mg/m^2 | Change From Baseline in Disease Activity in 28 Joints C-Reactive Protein Score (DAS28-CRP) by Time-point | Week 6 (n=22, n=20) | -1.39 Score | Standard Deviation 1.02 |
| Part A: MK-8808 500 mg/m^2 | Change From Baseline in Disease Activity in 28 Joints C-Reactive Protein Score (DAS28-CRP) by Time-point | Week 12 (n=21, n=21) | -1.68 Score | Standard Deviation 1.12 |
| Part A: MabThera® 500 mg/m^2 | Change From Baseline in Disease Activity in 28 Joints C-Reactive Protein Score (DAS28-CRP) by Time-point | Week 12 (n=21, n=21) | -2.04 Score | Standard Deviation 1.39 |
| Part A: MabThera® 500 mg/m^2 | Change From Baseline in Disease Activity in 28 Joints C-Reactive Protein Score (DAS28-CRP) by Time-point | Week 6 (n=22, n=20) | -1.16 Score | Standard Deviation 1.26 |
Comparison: Estimated difference vs MabThera® at 6 weeks.95% CI: [-0.9, 0.5]ANCOVA
Comparison: Estimated difference vs MabThera® at 12 weeks.95% CI: [-0.4, 1.2]ANCOVA
Other Pre-specified
Part A: Number of ACR20, ACR50, and ACR70 Responders at Week 24
American College of Rheumatology (ACR) Responder Index is based on a set of evaluations: the Investigator Tender Joint Count/Number of Tender Joints (out of 68 Joints); Investigator Swollen Joint Count/Number of Swollen Joints (out of 66 Joints); Patient Global Assessment of Disease Activity (PGAD); Investigator Global Assessment of Disease Activity (IGAD); Patient Global Assessment of Pain (PGAP); Health Assessment Questionnaire Disability Index (HAQ-DI); and ESR. ACR response indicates percent change (ie, improvement) from baseline (20%, 50%, 70%) PGAD & IGAD: assessment of function on a 4-point Likert scale: 0=very well to 3=unable to do PGAP: pain due to arthritis measured on a 0-100 mm visual analog scale: Left hand marker-no pain; right hand marker-extreme pain HAQ-DI: assessment of 8 daily living activities (dress/groom; arise; eat; walk; reach; grip; hygiene; common daily activities) on 4-point Likert scale: 0=no difficulty to 3=unable to do
Time frame: Week 24
Population: Full Analysis Set defined as all randomized participants who received at least one complete treatment course (2 doses) and had at least one post-treatment measurement. Patients were included in the treatment group to which they were randomized. A patient might have been be excluded from the FAS population for a given endpoint for multiple reasons.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: MK-8808 500 mg/m^2 | Part A: Number of ACR20, ACR50, and ACR70 Responders at Week 24 | ACR20 | 23 Participants |
| Part A: MK-8808 500 mg/m^2 | Part A: Number of ACR20, ACR50, and ACR70 Responders at Week 24 | ACR50 | 16 Participants |
| Part A: MK-8808 500 mg/m^2 | Part A: Number of ACR20, ACR50, and ACR70 Responders at Week 24 | ACR70 | 4 Participants |
| Part A: MabThera® 500 mg/m^2 | Part A: Number of ACR20, ACR50, and ACR70 Responders at Week 24 | ACR20 | 20 Participants |
| Part A: MabThera® 500 mg/m^2 | Part A: Number of ACR20, ACR50, and ACR70 Responders at Week 24 | ACR50 | 15 Participants |
| Part A: MabThera® 500 mg/m^2 | Part A: Number of ACR20, ACR50, and ACR70 Responders at Week 24 | ACR70 | 4 Participants |
Other Pre-specified
Part B: Number of ACR20, ACR50, and ACR70 Responders at Week 24
American College of Rheumatology (ACR) Responder Index is based on a set of evaluations: the Investigator Tender Joint Count/Number of Tender Joints (out of 68 Joints); Investigator Swollen Joint Count/Number of Swollen Joints (out of 66 Joints); Patient Global Assessment of Disease Activity (PGAD); Investigator Global Assessment of Disease Activity (IGAD); Patient Global Assessment of Pain (PGAP); Health Assessment Questionnaire Disability Index (HAQ-DI); and ESR. ACR response indicates percent change (ie, improvement) from baseline (20%, 50%, 70%) PGAD & IGAD: assessment of function on a 4-point Likert scale: 0=very well to 3=unable to do PGAP: pain due to arthritis measured on a 0-100 mm visual analog scale: Left hand marker-no pain; right hand marker-extreme pain HAQ-DI: assessment of 8 daily living activities (dress/groom; arise; eat; walk; reach; grip; hygiene; common daily activities) on 4-point Likert scale: 0=no difficulty to 3=unable to do
Time frame: Week 24
Population: FAS defined as all randomized participants who received at least one complete treatment course (2 doses) and had at least one post-treatment measurement. Patients were included in the treatment group to which they were randomized. A patient might have been be excluded from the FAS population for a given endpoint for multiple reasons.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: MK-8808 500 mg/m^2 | Part B: Number of ACR20, ACR50, and ACR70 Responders at Week 24 | ACR50 | 12 Participants |
| Part A: MK-8808 500 mg/m^2 | Part B: Number of ACR20, ACR50, and ACR70 Responders at Week 24 | ACR20 | 16 Participants |
| Part A: MK-8808 500 mg/m^2 | Part B: Number of ACR20, ACR50, and ACR70 Responders at Week 24 | ACR70 | 2 Participants |
| Part A: MabThera® 500 mg/m^2 | Part B: Number of ACR20, ACR50, and ACR70 Responders at Week 24 | ACR50 | 12 Participants |
| Part A: MabThera® 500 mg/m^2 | Part B: Number of ACR20, ACR50, and ACR70 Responders at Week 24 | ACR20 | 17 Participants |
| Part A: MabThera® 500 mg/m^2 | Part B: Number of ACR20, ACR50, and ACR70 Responders at Week 24 | ACR70 | 1 Participants |
| Part B: Rituxan® 1000 mg | Part B: Number of ACR20, ACR50, and ACR70 Responders at Week 24 | ACR20 | 15 Participants |
| Part B: Rituxan® 1000 mg | Part B: Number of ACR20, ACR50, and ACR70 Responders at Week 24 | ACR70 | 1 Participants |
| Part B: Rituxan® 1000 mg | Part B: Number of ACR20, ACR50, and ACR70 Responders at Week 24 | ACR50 | 13 Participants |