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

NCT01390441 | Terminated Phase 1 Results

• 1 other identifier: 8808-002
• Study Type: interventional
• Target: 100
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Rheumatoid Arthritis

Keywords

Rheumatoid arthritis; RA; Rituximab; Rituxan; MabThera; Methotrexate; Rheumatrex; Trexall; MK-8808

Outcome Measures

Primary Outcomes (6)

• 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 Outcomes (2)

• Part A: Maximum Concentration (Cmax) After the Second Infusion of a Single Course of Treatment

  Day 15

• Part B: Cmax After the Second Infusion of a Single Course of Treatment

  Day 15

Other Outcomes (3)

• Part A: Number of ACR20, ACR50, and ACR70 Responders at Week 24

  Week 24

• Part B: Number of ACR20, ACR50, and ACR70 Responders at Week 24

  Week 24

• Change From Baseline in Disease Activity in 28 Joints C-Reactive Protein Score (DAS28-CRP) by Time-point

  Baseline, Week 6, Week 12

Study Arms (5)

Part A: MK-8808 500 mg/m^2 / Extension A: MK-8808 1000 mg

EXPERIMENTAL

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; Drug: Methotrexate; Drug: Methylprednisolone; Drug: Acetaminophen; Drug: Loratadine

Part A: MabThera® 500 mg/m^2 / Extension A: MK-8808 1000 mg

ACTIVE COMPARATOR

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; Biological: MabThera® (rituximab); Drug: Methotrexate; Drug: Methylprednisolone; Drug: Acetaminophen; Drug: Loratadine

Part B: MK-8808 1000 mg / Extension B: MK-8808 1000 mg

EXPERIMENTAL

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; Drug: Methotrexate; Drug: Methylprednisolone; Drug: Acetaminophen; Drug: Loratadine

Part B: MabThera® 1000 mg / Extension B: MK-8808 1000 mg

ACTIVE COMPARATOR

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; Biological: MabThera® (rituximab); Drug: Methotrexate; Drug: Methylprednisolone; Drug: Acetaminophen; Drug: Loratadine

Part B: Rituxan® 1000 mg / Extension B: MK-8808 1000 mg

EXPERIMENTAL

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; Drug: Methotrexate; Biological: Rituxan® (rituximab); Drug: Methylprednisolone; Drug: Acetaminophen; Drug: Loratadine

Interventions

MK-8808 BIOLOGICAL

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

Part A: MK-8808 500 mg/m^2 / Extension A: MK-8808 1000 mg; Part A: MabThera® 500 mg/m^2 / Extension A: MK-8808 1000 mg; Part B: MK-8808 1000 mg / Extension B: MK-8808 1000 mg; Part B: MabThera® 1000 mg / Extension B: MK-8808 1000 mg; Part B: Rituxan® 1000 mg / Extension B: MK-8808 1000 mg

MabThera® (rituximab) BIOLOGICAL

MabThera® 500 mg/m\^2 or 1000 mg administered by IV on Day 1 and Day 15

Also known as: Rituxan®, Rituximab

Part A: MabThera® 500 mg/m^2 / Extension A: MK-8808 1000 mg; Part B: MabThera® 1000 mg / Extension B: MK-8808 1000 mg

Methotrexate DRUG

Methotrexate 10-25 mg administered orally, SC, or IM as a weekly stable dose

Also known as: Trexall®, Rheumatrex®

Part A: MK-8808 500 mg/m^2 / Extension A: MK-8808 1000 mg; Part A: MabThera® 500 mg/m^2 / Extension A: MK-8808 1000 mg; Part B: MK-8808 1000 mg / Extension B: MK-8808 1000 mg; Part B: MabThera® 1000 mg / Extension B: MK-8808 1000 mg; Part B: Rituxan® 1000 mg / Extension B: MK-8808 1000 mg

Rituxan® (rituximab) BIOLOGICAL

Rituxan® 1000 mg administered by IV on Day 1 and Day 15

Also known as: Rituximab

Part B: Rituxan® 1000 mg / Extension B: MK-8808 1000 mg

Methylprednisolone DRUG

Methylprednisolone 100 mg administered IV before initiation of each infusion as pre-medication to reduce the incidence and severity of infusion reactions

Part A: MK-8808 500 mg/m^2 / Extension A: MK-8808 1000 mg; Part A: MabThera® 500 mg/m^2 / Extension A: MK-8808 1000 mg; Part B: MK-8808 1000 mg / Extension B: MK-8808 1000 mg; Part B: MabThera® 1000 mg / Extension B: MK-8808 1000 mg; Part B: Rituxan® 1000 mg / Extension B: MK-8808 1000 mg

Acetaminophen DRUG

Acetaminophen 1000 to 1350 mg administered orally before initiation of each infusion as pre-medication to reduce the incidence and severity of infusion reactions

Also known as: Paracetamol

Part A: MK-8808 500 mg/m^2 / Extension A: MK-8808 1000 mg; Part A: MabThera® 500 mg/m^2 / Extension A: MK-8808 1000 mg; Part B: MK-8808 1000 mg / Extension B: MK-8808 1000 mg; Part B: MabThera® 1000 mg / Extension B: MK-8808 1000 mg; Part B: Rituxan® 1000 mg / Extension B: MK-8808 1000 mg

Loratadine DRUG

Loratidine 10 mg administered orally before initiation of each infusion as pre-medication to reduce the incidence and severity of infusion reactions

Also known as: Claritin®

Part A: MK-8808 500 mg/m^2 / Extension A: MK-8808 1000 mg; Part A: MabThera® 500 mg/m^2 / Extension A: MK-8808 1000 mg; Part B: MK-8808 1000 mg / Extension B: MK-8808 1000 mg; Part B: MabThera® 1000 mg / Extension B: MK-8808 1000 mg; Part B: Rituxan® 1000 mg / Extension B: MK-8808 1000 mg

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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®)

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

MeSH Terms

Conditions

Arthritis, Rheumatoid

Interventions

Rituximab; Methotrexate; Methylprednisolone; Acetaminophen; Loratadine

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Acetanilides; Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines; Cyproheptadine; Dibenzocycloheptenes; Benzocycloheptenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Piperidines; Heterocyclic Compounds, 1-Ring

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 7, 2011
• First Posted: July 11, 2011
• Study Start: July 1, 2011
• Primary Completion: April 1, 2014
• Study Completion: April 1, 2014
• Last Updated: July 20, 2016
• Results First Posted: July 20, 2016

Record last verified: 2016-05