A Study of the Pharmacokinetics and Safety of MK-8808 (MK-8808-002)

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Two-Part, Phase I Randomized, Double-Blind, Active-Comparator Controlled, Parallel Group Study to Assess the Pharmacokinetics, Safety, and Tolerability of MK-8808 and to Compare the Pharmacokinetics of MK-8808 With EU-approved MabThera® and US-licensed Rituxan® in Patients With Rheumatoid Arthritis (RA)

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Biological: MK-8808
* Biological: MabThera® (rituximab)
* Drug: Methotrexate
* Biological: Rituxan® (rituximab)
* Drug: Methylprednisolone
* Drug: Acetaminophen
* Drug: Loratadine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: MK-8808 500 mg/m^2 / Extension A: MK-8808 1000 mg<br>During the Treatment Period, participants receive one course of MK-8808 (500 mg/m^2) administered intravenously (IV) on Day 1 and Day 15 (with a second optional course of treatment at Weeks 26 and 28). Participants are followed up to Week 52 in the Treatment Period. During the Extension Period, participants receive open-label MK-8808 (1000 mg) administered IV at Week 54 and Week 56 (with a second optional course at Weeks 80 and 82). Participants are followed up to Week 106 in the Extension Period. Methotrexate 12.5 to 25 mg/week is administered either orally, subcutaneously (SC), or intramuscularly (IM) for the duration of the trial. A 10 mg dose may be administered if a greater dose is not tolerated. | Biological: MK-8808<br>* 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<br>Drug: Methotrexate<br>* Methotrexate 10-25 mg administered orally, SC, or IM as a weekly stable dose<br>* Other names: Rheumatrex®;Drug: Methylprednisolone<br>* Methylprednisolone 100 mg administered IV before initiation of each infusion as pre-medication to reduce the incidence and severity of infusion reactions<br>Drug: Acetaminophen<br>* Acetaminophen 1000 to 1350 mg administered orally before initiation of each infusion as pre-medication to reduce the incidence and severity of infusion reactions<br>* Other names: Paracetamol;Drug: Loratadine<br>* Loratidine 10 mg administered orally before initiation of each infusion as pre-medication to reduce the incidence and severity of infusion reactions<br>* Other names: Claritin®;|
| Active Comparator: Part A: MabThera® 500 mg/m^2 / Extension A: MK-8808 1000 mg<br>During the Treatment Period, participants receive one course of MabThera® (500 mg/m^2) administered IV on Day 1 and Day 15 (with a second optional course of treatment at Weeks 26 and 28). Participants are followed up to Week 52 in the Treatment Period. During the Extension Period, participants receive open label MK-8808 (1000 mg) administered IV at Week 54 and Week 56 (with a second optional course at Weeks 80 and 82). Participants are followed up to Week 106 in the Extension Period. Methotrexate 12.5 to 25 mg/week is administered either orally, SC, or IM for the duration of the trial. A 10 mg dose may be administered if a greater dose is not tolerated. | Biological: MK-8808<br>* 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<br>Biological: MabThera® (rituximab)<br>* MabThera® 500 mg/m^2 or 1000 mg administered by IV on Day 1 and Day 15<br>* Other names: Rituximab;Drug: Methotrexate<br>* Methotrexate 10-25 mg administered orally, SC, or IM as a weekly stable dose<br>* Other names: Rheumatrex®;Drug: Methylprednisolone<br>* Methylprednisolone 100 mg administered IV before initiation of each infusion as pre-medication to reduce the incidence and severity of infusion reactions<br>Drug: Acetaminophen<br>* Acetaminophen 1000 to 1350 mg administered orally before initiation of each infusion as pre-medication to reduce the incidence and severity of infusion reactions<br>* Other names: Paracetamol;Drug: Loratadine<br>* Loratidine 10 mg administered orally before initiation of each infusion as pre-medication to reduce the incidence and severity of infusion reactions<br>* Other names: Claritin®;|
| Experimental: Part B: MK-8808 1000 mg / Extension B: MK-8808 1000 mg<br>In the Treatment Period, participants receive one course of MK-8808 (1000 mg) administered IV on Day 1 and Day 15 (with a second optional course of treatment at Weeks 26 and 28). Participants are followed up to Week 52 in the Treatment Period. In the Extension Period, participants receive open label MK-8808 (1000 mg) adminstered IV at Week 54 and Week 56 (with a second optional course at Weeks 80 and 82). Participants are followed up to Week 106 in the Extension Period. Methotrexate 12.5 to 25 mg/week is administered either orally, SC, or IM for the duration of the trial. A 10 mg dose may be administered if a greater dose is not tolerated. | Biological: MK-8808<br>* 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<br>Drug: Methotrexate<br>* Methotrexate 10-25 mg administered orally, SC, or IM as a weekly stable dose<br>* Other names: Rheumatrex®;Drug: Methylprednisolone<br>* Methylprednisolone 100 mg administered IV before initiation of each infusion as pre-medication to reduce the incidence and severity of infusion reactions<br>Drug: Acetaminophen<br>* Acetaminophen 1000 to 1350 mg administered orally before initiation of each infusion as pre-medication to reduce the incidence and severity of infusion reactions<br>* Other names: Paracetamol;Drug: Loratadine<br>* Loratidine 10 mg administered orally before initiation of each infusion as pre-medication to reduce the incidence and severity of infusion reactions<br>* Other names: Claritin®;|
| Active Comparator: Part B: MabThera® 1000 mg / Extension B: MK-8808 1000 mg<br>In the Treatment Period, participants receive one course of MabThera® (1000 mg) administered IV on Day 1 and Day 15 (with a second optional course of treatment at Weeks 26 and 28). Participants are followed up to Week 52 in the Treatment Period. In the Extension Period, participants receive open label MK-8808 (1000 mg) administered IV at Week 54 and Week 56 (with a second optional course at Weeks 80 and 82). Participants are followed up to Week 106 in the Extension Period. Methotrexate 12.5 to 25 mg/week is administered either orally, SC, or IM for the duration of the trial. A 10 mg dose may be administered if a greater dose is not tolerated. | Biological: MK-8808<br>* 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<br>Biological: MabThera® (rituximab)<br>* MabThera® 500 mg/m^2 or 1000 mg administered by IV on Day 1 and Day 15<br>* Other names: Rituximab;Drug: Methotrexate<br>* Methotrexate 10-25 mg administered orally, SC, or IM as a weekly stable dose<br>* Other names: Rheumatrex®;Drug: Methylprednisolone<br>* Methylprednisolone 100 mg administered IV before initiation of each infusion as pre-medication to reduce the incidence and severity of infusion reactions<br>Drug: Acetaminophen<br>* Acetaminophen 1000 to 1350 mg administered orally before initiation of each infusion as pre-medication to reduce the incidence and severity of infusion reactions<br>* Other names: Paracetamol;Drug: Loratadine<br>* Loratidine 10 mg administered orally before initiation of each infusion as pre-medication to reduce the incidence and severity of infusion reactions<br>* Other names: Claritin®;|
| Experimental: Part B: Rituxan® 1000 mg / Extension B: MK-8808 1000 mg<br>In the Treatment Period, participants receive one course of Rituxan® (1000 mg) administered IV on Day 1 and Day 15 (with a second optional course of treatment at Weeks 26 and 28). Participants are followed up to Week 52 in the Treatment Period. In the Extension Period, participants receive open label MK-8808 (1000 mg) administered IV at Week 54 and Week 56 (with a second optional course at Weeks 80 and 82). Participants are followed up to Week 106 in the Extension Period. Methotrexate 12.5 to 25 mg/week is administered either orally, SC, or IM for the duration of the trial. A 10 mg dose may be administered if a greater dose is not tolerated. | Biological: MK-8808<br>* 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<br>Drug: Methotrexate<br>* Methotrexate 10-25 mg administered orally, SC, or IM as a weekly stable dose<br>* Other names: Rheumatrex®;Biological: Rituxan® (rituximab)<br>* Rituxan® 1000 mg administered by IV on Day 1 and Day 15<br>* Other names: Rituximab;Drug: Methylprednisolone<br>* Methylprednisolone 100 mg administered IV before initiation of each infusion as pre-medication to reduce the incidence and severity of infusion reactions<br>Drug: Acetaminophen<br>* Acetaminophen 1000 to 1350 mg administered orally before initiation of each infusion as pre-medication to reduce the incidence and severity of infusion reactions<br>* Other names: Paracetamol;Drug: Loratadine<br>* Loratidine 10 mg administered orally before initiation of each infusion as pre-medication to reduce the incidence and severity of infusion reactions<br>* Other names: Claritin®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 | 
| 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. | 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 | 
| 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. | Parts A and B: Up to 52 weeks; Extension A and B: Up to 106 weeks | 
| 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. | Parts A and B: Up to Week 28; Extension A and B: Up to 82 weeks | 
| 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. | Week 54, Week 68, Week 80, Week 94, Week 106 | 
| 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. | Week 54, Week 56, Week 68, Week 80, Week 82, Week 94, Week 106 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Day 15 | 
| 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. | Day 15 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rheumatoid arthritis, RA, Rituximab, Rituxan, MabThera, Methotrexate, Rheumatrex, Trexall, MK-8808