Outcome
| Type |
Measure |
Description |
Time frame |
Safety issue |
| Primary |
Maximum Observed Serum Concentration (Cmax) of Adalimumab |
Cmax refers to maximum observed serum concentration of drug. The geometric coefficient of variation is expressed in percentage. |
Pre-dose, 48, 72, 96, 144, 240 and 336 hours post dose on Day 211 (Week 30) |
|
| Primary |
Area Under the Serum Concentration-Time Curve Over the Dosing Interval (AUCtau) of Adalimumab |
Area under the serum concentration curve from time 0 to end of dosing interval (tau), where dosing interval was once every two weeks. The geometric coefficient of variation is expressed in percentage. |
Pre-dose, 48, 72, 96, 144, 240 and 336 hours post dose on Day 211 (Week 30) |
|
| Secondary |
Time to Reach Cmax (Tmax) of Adalimumab |
Tmax is the time taken (in hours) to reach the maximum serum drug concentration. |
Pre-dose, 48, 72, 96, 144, 240 and 336 hours post dose on Day 211 (Week 30) |
|
| Secondary |
Average Serum Concentration (Cav) of Adalimumab |
Cav was defined as average serum concentration over the dosing interval. The geometric coefficient of variation is expressed in percentage. |
Pre-dose, 48, 72, 96, 144, 240 and 336 hours post dose on Day 211 (Week 30) |
|
| Secondary |
Apparent Clearance (CL/F) of Serum Adalimumab |
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/F was calculated as dose administered divided by area under the concentration curve from time 0 extrapolated to infinite time (AUCinf). The geometric coefficient of variation is expressed in percentage. |
Pre-dose, 48, 72, 96, 144, 240 and 336 hours post dose on Day 211 (Week 30) |
|
| Secondary |
Pre-dose Serum Concentration During Multiple Dosing (Ctrough) of Adalimumab |
Ctrough was defined as pre-dose serum concentration during multiple dosing and observed directly from data. |
Pre-dose on Day 1, 71,113, 155, 169, 183, 197 and 211 |
|
| Secondary |
Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs and Treatment Related TEAEs: TP1 |
An adverse event (AE) was any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An SAE was any untoward medical occurrence that, at any dose: resulted in death; required inpatient hospitalization or prolongation of existing hospitalization; was life-threatening; resulted in persistent or significant disability/ incapacity; congenital anomaly/birth defect and other important medical events. Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. TEAE for TP1 was defined as any AE that occurred after the beginning of study treatment in TP1 and before the first dose of study treatment administration after randomization in TP2. AEs included both serious and all non-serious AEs. |
Day 1 up to maximum of 10 Weeks |
|
| Secondary |
Number of Participants With TEAEs, Serious TEAEs and Treatment Related TEAEs: TP2 and Beyond |
An AE was any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An SAE was any untoward medical occurrence that, at any dose: resulted in death; required inpatient hospitalization or prolongation of existing hospitalization; was life-threatening; resulted in persistent or significant disability/ incapacity; congenital anomaly/birth defect and other important medical events. Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. TEAE for TP2 and beyond was defined as any AE that occurred after administering the first dose of study treatment after randomization in TP2 and up to 4 weeks after last dose. AEs included both serious and all non-serious AEs. |
Post randomization up to maximum of 4 weeks after last dose (maximum of 26 weeks) |
|
| Secondary |
Number of Participants With Grade 3 or Higher TEAEs: TP1 |
An AE was any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. TEAE for TP1 was defined as any AE that occurred after the beginning of study treatment in TP1 and before the first dose of study treatment administration after randomization in TP2. AEs were graded using the Common Terminology Criteria for Adverse Events where, grade 1=mild AE; grade 2=moderate AE; grade 3=severe AE; grade 4= life-threatening consequences; urgent intervention indicated; and grade 5= death related to AE. Number of participants with grade 3 or higher TEAEs were presented. |
Day 1 up to maximum of 10 Weeks |
|
| Secondary |
Number of Participants With Grade 3 or Higher TEAEs: TP2 and Beyond |
An AE was any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. TEAE for TP2 and beyond was defined as any AE that occurred after the first dose of study treatment administration after randomization in TP2 and up to 4 weeks after last dose. AEs were graded using the Common Terminology Criteria for Adverse Events where, grade 1=mild AE; grade 2=moderate AE; grade 3=severe AE; grade 4= life-threatening consequences; urgent intervention indicated; and grade 5= death related to AE. Number of participants with grade 3 or higher TEAEs were presented. |
Post randomization up to maximum of 4 weeks after last dose (maximum of 26 weeks) |
|
| Secondary |
Number of Participants Who Discontinued Treatment and Study Due to TEAEs: TP1 |
An AE was any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. TEAE for TP1 was defined as any AE that occurred after the beginning of study treatment in TP1 and before the first dose of study treatment administration after randomization in TP2. Participants who discontinued treatment due to TEAEs were those who had an AE record indicating that action taken with study treatment was drug withdrawn but AE did not cause the participant to be discontinued from study. Participants who discontinued from study due to TEAE were those who had an TEAE in TP1 indicating that the AE caused the participant to be discontinued from the study. |
Day 1 up to maximum of 10 Weeks |
|
| Secondary |
Number of Participants Who Discontinued Treatment and Study Due to TEAEs: TP2 and Beyond |
An AE was any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. TEAE for TP2 and beyond was defined as any AE that occurred after the first dose of study treatment administration after randomization in TP2 and up to 4 weeks after last dose. AEs included both serious and all non-serious AEs. Participants who discontinued treatment due to TEAEs were those who had an AE record indicating that action taken with study treatment was drug withdrawn but AE did not cause the participant to be discontinued from study. Participants who discontinued from study due to TEAE were those who had an AE record indicating that the AE caused the participant to be discontinued from the study. |
Post randomization up to maximum of 4 weeks after last dose (maximum of 26 weeks) |
|
| Secondary |
Number of Participants With TEAEs of Special Interest: TP2 and Beyond |
AEs of special interest (AESI) included: hypersensitivity events (anaphylactic reaction, hypersensitivity, angioedema, delayed immune responses and injection site reactions [ISRs]); blood and lymphatic system events (white blood cell disorders and anemias nonhemolytic and marrow depression); cardiovascular events (cardiac failure, hypertension and myocardial infarction); demyelinating conditions, gastric/hepatic events (gastrointestinal perforation, ulceration, hemorrhage or obstruction and hepatic disorders); infections and infestations (including TB and other opportunistic infections); malignancies (neoplasms benign, malignant and unspecified [including cysts and polyps]) and lupus like syndrome. TEAE was defined as any AE that occurred after the first dose of study treatment administered after randomization in TP2. Number of participants with any AESI were presented in this outcome measure. |
Post randomization up to maximum of 4 weeks after last dose (maximum of 26 weeks) |
|
| Secondary |
Number of Participants With Potential Immunogenic AEs to Study Treatment: TP2 and Beyond Among Anti-drug Antibody (ADA) Positive Participants During TP1 |
In this outcome, participants who were antidrug antibody (ADA) positive during TP1 were assessed in TP2 and beyond per visit for their ADA status at the time of start of their potential immunogenic AEs including ISRs, medically evaluated board standard MedDRA query (SMQ) of potential hypersensitivity (anaphylactic reactions, hypersensitivity and angioedema), medically evaluated AEs meeting Sampson criteria, cytokine storm and delayed immune responses (DIR). ADA positive was defined as ADA titer >=1.88. |
TP2 and Beyond: Week 16, 22, 24, 26, 28, 30, 32 |
|
| Secondary |
Number of Participants With Potential Immunogenic AEs to Study Treatment: TP2 and Beyond Among ADA Negative Participants During TP1 |
In this outcome, participants who were ADA negative during TP1 were assessed in TP2 and beyond per visit for their ADA status at the time of start of their potential immunogenic AEs including ISRs, medically evaluated board SMQ of potential hypersensitivity (anaphylactic reactions, hypersensitivity and angioedema), medically evaluated AEs meeting Sampson criteria, cytokine storm and DIR. ADA negative was defined as ADA titer <1.88. |
TP2 and Beyond: Week 16, 22, 24, 26, 28, 30, 32 |
|
| Secondary |
Number of Participants With TEAEs and Serious TEAEs Related to COVID-19: TP1 |
An AE was any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An SAE was any untoward medical occurrence that, at any dose: resulted in death; required inpatient hospitalization or prolongation of existing hospitalization; was life-threatening; resulted in persistent or significant disability/ incapacity; congenital anomaly/birth defect and other important medical events. TEAE for TP1 was defined as any AE that occurred after the beginning of study treatment in TP1 and before the first dose of study treatment administration after randomization in TP2. AEs included both serious and all non-serious AEs. TEAEs and serious TEAEs related to Covid-19 as per investigator's assessment were presented. |
Day 1 up to maximum of 10 Weeks |
|
| Secondary |
Number of Participants With TEAEs and Serious TEAEs Related to COVID-19: TP2 and Beyond |
An AE was any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An SAE was any untoward medical occurrence that, at any dose: resulted in death; required inpatient hospitalization or prolongation of existing hospitalization; was life-threatening; resulted in persistent or significant disability/ incapacity; congenital anomaly/birth defect and other important medical events. TEAE for TP2 and beyond was defined as any AE that occurred after the first dose of study treatment administration after randomization in TP2 and up to 4 weeks after last dose. AEs included both serious and all non-serious AEs. TEAEs and serious TEAEs related to Covid-19 as per investigator's assessment were presented. |
Post randomization up to maximum of 4 weeks after last dose (maximum of 26 weeks) |
|
| Secondary |
Number of Participants Who Discontinued Treatment and Study Due to TEAEs Related to COVID-19: TP1 |
An AE was any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. TEAE for TP1 was defined as any AE that occurred after the beginning of study treatment in TP1 and before the first dose of study treatment administration after randomization in TP2. Participants who discontinued treatment due to TEAEs were those who had an AE record indicating that action taken with study treatment was drug withdrawn but AE did not cause the participant to be discontinued from study. Participants who discontinued from study due to TEAE were those who had an AE record indicating that the AE caused the participant to be discontinued from the study. TEAEs were related to Covid-19. |
Day 1 up to maximum of 10 Weeks |
|
| Secondary |
Number of Participants Who Discontinued Treatment and Study Due to TEAEs Related to COVID-19: TP2 and Beyond |
An AE was any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. TEAE for TP2 and beyond was defined as any AE that occurred after the first dose of study treatment administration after randomization in TP2 and up to 4 weeks after last dose. AEs included both serious and all non-serious AEs. Participants who discontinued treatment due to TEAEs were those who had an AE record indicating that action taken with study treatment was drug withdrawn but AE did not cause the participant to be discontinued from study. Participants who discontinued from study due to TEAE were those who had an AE record indicating that the AE caused the participant to be discontinued from the study. TEAEs were related to Covid-19. |
Post randomization up to maximum of 4 weeks after last dose (maximum of 26 weeks) |
|
| Secondary |
Number of Participants With Laboratory Abnormalities: TP1 |
Blood samples were collected for the analysis of following laboratory parameters: hematology parameters (hemoglobin, erythrocyte mean corpuscular volume, erythrocyte mean corpuscular hemoglobin, erythrocyte mean corpuscular hemoglobin concentration platelet count, leukocytes, lymphocytes, neutrophils, eosinophils, monocytes); clinical chemistry parameters (bilirubin, alanine aminotransferase [ALT], blood urea nitrogen [BUN], creatinine, potassium, bicarbonate); urine parameters: urine protein, urine hemoglobin, nitrite, leukocyte esterase and bacteria. Number of participants with any laboratory abnormalities is presented. |
Day 1 up to maximum of 10 Weeks |
|
| Secondary |
Number of Participants With Laboratory Abnormalities: TP2 and Beyond |
Blood samples were collected for the analysis of following laboratory parameters: hematology parameters (hemoglobin, erythrocyte mean corpuscular volume, erythrocyte mean corpuscular hemoglobin, erythrocyte mean corpuscular hemoglobin concentration platelet count, leukocytes, lymphocytes, neutrophils, eosinophils, monocytes); clinical chemistry parameters (bilirubin, ALT, BUN, creatinine, potassium, bicarbonate); urine parameters: urine protein, urine hemoglobin, nitrite, leukocyte esterase and bacteria. Number of participants with any laboratory abnormalities is presented. |
Post randomization up to end of study treatment (maximum of 22 weeks) |
|
| Secondary |
Number of Participants With Hematology Results by Maximum Common Toxicity Criteria (CTC) Grade: TP2 and Beyond |
Blood samples were collected for the analysis of following hematology parameters: anemia, hemoglobin increased, leukocytosis, lymphocyte count decreased, lymphocyte count increased, neutrophil count decreased, platelet count decreased, white blood cell decreased. Laboratory parameters were graded according to National Cancer Institute-CTC version 4.03 where, Grade 0= within normal limits; Grade1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences and Grade 5: death. Categories with at least 1 non-zero value were reported in this outcome measure. |
Post randomization up to end of study treatment (maximum of 22 weeks) |
|
| Secondary |
Number of Participants With Chemistry Results by Maximum CTC Grade: TP2 and Beyond |
Blood samples were collected for analysis of clinical chemistry parameters: ALT increased, alkaline phosphatase increased (ALP), aspartate aminotransferase increased (AST), blood bilirubin increased, creatinine increased, hypercalcemia, hyperkalemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypokalemia, hyponatremia. Laboratory parameters were graded according to NCI-CTC version 4.03 where, grade 0= within normal limits; Grade1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences and Grade 5: death. Categories with at least 1 non-zero value were reported. |
Post randomization up to end of study treatment (maximum of 22 weeks) |
|
| Secondary |
Number of Participants With Laboratory Results Based on Evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) Analysis: TP2 and Beyond |
In this outcome measure, liver function laboratory parameters, which included: normal bilirubin and AST/ALT, Temple's Corollary (AST/ALT [more than or equal to] >=3*upper limit normal [ULN] and normal bilirubin), Gilbert's Syndrome or cholestasis (normal AST/ALT and bilirubin >=2*ULN) and Potential Hy's Law Cases (AST/ALT >=3*ULN and Bilirubin>=2*ULN) according to eDISH criteria, were reported. |
Post randomization up to end of study treatment (maximum of 22 weeks) |
|
| Secondary |
Baseline, Absolute Week 32 Values for Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Change From Baseline in SBP, DBP at Week 32 (EOT/ ET) |
SBP and DBP were measured in a supine position using an automated device preceded by at least 5 minutes of rest for the participant in a quiet setting without any distractions. Baseline value was defined as the most recent measurement prior to the first dose of study treatment after randomization in TP2. |
Baseline and Week 32 (end of treatment [EOT]/early termination [ET]) |
|
| Secondary |
Baseline, Absolute Week 32 Values for Pulse Rate and Change From Baseline in Pulse Rate at Week 32 (EOT/ET) |
Pulse rate was measured in a supine position using an automated device preceded by at least 5 minutes of rest for the participant in a quiet setting without any distractions. Baseline value was defined as the most recent measurement prior to the first dose of study treatment after randomization in TP2. |
Baseline and Week 32 (EOT/ET) |
|
| Secondary |
Baseline, Absolute Week 32 Values for Temperature and Change From Baseline in Temperature at Week 32 (EOT/ET) |
Baseline value was defined as the most recent measurement prior to the first dose of study treatment after randomization in TP2. |
Baseline and Week 32 (EOT/ET) |
|
| Secondary |
Baseline, Absolute Week 32 Values for Respiratory Rate and Change From Baseline in Respiratory Rate at Week 32 (EOT/ET) |
Baseline value was defined as the most recent measurement prior to the first dose of study treatment after randomization in TP2. |
Baseline and Week 32 (EOT/ET) |
|
| Secondary |
Number of Participants Who Were Anti-Drug Antibodies (ADA) Positive and Neutralizing Antibodies (NAb) Positive |
Serum samples were analyzed using a validated electrochemoluminescent (ECL) immunoassay for ADA assessment. Samples positive for ADA were further tested for neutralizing activity using a validated cell based NAb assay. ADA positive was defined as ADA titer >=1.88 while NAb positive was defined as NAb titer >=0.70. |
Week 10, 16, 22, 24, 26, 28, 32 |
|
| Secondary |
Mean ADA Titers |
Serum samples were analyzed using a validated ECL immunoassay for ADA assessment. Endpoint titer was defined as log10 of the reciprocal of the ADA serum dilution at which the sample response was equal to the cut-point of the assay. |
Week 10, 16, 22, 24, 26, 28, 30, 32 |
|
| Secondary |
Mean NAb Titers |
Serum samples were analyzed using a validated ECL immunoassay for ADA assessment. Endpoint titer was defined as log10 of the reciprocal of the NAb serum dilution at which the sample response was equal to the cut-point of the assay. |
Week 10, 16, 22, 24, 26, 28, 30, 32 |
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