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PK, PD, Safety, and Efficacy of SAIT101 Versus MabThera® Versus Rituxan® in Patients With Rheumatoid Arthritis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02819726
Recruitment Status : Completed
First Posted : June 30, 2016
Results First Posted : February 17, 2020
Last Update Posted : February 17, 2020
Sponsor:
Information provided by (Responsible Party):
Archigen Biotech Limited

Brief Summary:
A randomised, double blind, parallel group, multicentre study yo compare the pharmacokinetics, pharmacokinetics, safety and efficacy of SAIT101 versus MabThera® versus Rituxan® in patients with rheumatoid arthritis.

Condition or disease Intervention/treatment Phase
Rheumatoid Arthritis Biological: SAIT101 Biological: MabThera Biological: Rituxan Phase 1

Detailed Description:
This is a randomized, double-blind, parallel group, multicenter study to compare the pharmacokinetics (PK), pharmacodynamics (PD), safety, efficacy, tolerability, and immunogenicity of SAIT101 (biosimilar rituximab) versus MabThera® versus Rituxan® in patients with rheumatoid arthritis (RA). This study will take place globally across approximately 75 study centers in order to randomize approximately 282 patients. The study consists of Part A from baseline for PK and efficacy analysis, followed by Part B from Week 24 to 52 for safety follow-up in which collects transition data.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 294 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

In Part A, patients are randomized in a 1:1:1 ratio to receive one course (baseline and Week 2) of SAIT101 (n=94) versus Rituxan® (n=94) versus MabThera® (n=94).

At Week 24, patients are evaluated for the second course (Week 24 and 26) of the infusion.

In Part B, eligible patients in the SAIT101 arm receive the second course of SAIT101 treatment. Eligible patients in the MabThera® arm receive the second course of MabThera® treatment. Eligible patients in the Rituxan® arm are randomized in a 1:1 ratio to receive SAIT101 or Rituxan® treatment. Patients are followed up for safety until Week 52.

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Double-blind, Parallel Group, Multicenter Study to Compare the Pharmacokinetics, Pharmacodynamics, Safety, and Efficacy of SAIT101 Versus MabThera® Versus Rituxan® in Patients With Rheumatoid Arthritis (RA)
Actual Study Start Date : October 11, 2016
Actual Primary Completion Date : April 30, 2018
Actual Study Completion Date : November 7, 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Rituximab

Arm Intervention/treatment
Experimental: SAIT101
In Part A, each patient will receive one course of two 1000 mg SAIT101 infusions: one on Day 1 and the second on Day 15. In Part B, patients with an inadequate response (<50% improvement from Baseline in swollen and tender joint count at Week 24) will be eligible for a further course of two 1000 mg infusions of SAIT101 on Week 24 and Week 26.
Biological: SAIT101
1,000 mg i.v. of SAIT101 on Day 1 and 15. 1,000 mg i.v. of SAIT101 on week 24 and 26 for eligible patients.

Active Comparator: Rituxan
In Part A, each patient will receive one course of two 1000 mg Rituxan infusions: one on Day 1 and the second on Day 15. In Part B, patients with an inadequate response (<50% improvement from Baseline in swollen and tender joint count at Week 24) will be randomised in a 1:1 ratio to receive Rituxan or SAIT101 10000 mg infusions on Week 24 and Week 26.
Biological: Rituxan
1,000 mg i.v. of Rituxan® on Day 1 and 15. 1,000 mg i.v. of Rituxan® on week 24 and 26 for eligible patients.
Other Name: Rituximab

Active Comparator: MabThera
In Part A, each patient will receive one course of two 1000 mg MabThera infusions: one on Day 1 and the second on Day 15. In Part B, patients with an inadequate response (<50% improvement from Baseline in swollen and tender joint count at Week 24) will be eligible for a further course of two 1000 mg infusions of MabThera on Week 24 and Week 26.
Biological: MabThera
1,000 mg i.v. of MabThera® on Day 1 and 15. 1,000 mg i.v. of MabThera® on week 24 and 26 for eligible patients.
Other Name: Rituximab




Primary Outcome Measures :
  1. Area Under the Concentration Time Cure From Time 0 to Last Quantifiable Concentration (AUC0-t) [ Time Frame: Samples for pharmacokinetic evaluation were taken at Baseline and Weeks 0, 1, 2, 3, 4, 8, 12, 16, 20 and 24. Unscheduled visit samples were taken at the discretion of the investigator. ]
    Pharmacokinetic endpoint: Area under the concentration-time curve from time 0 (immediately predose on Day 1) to last quantifiable concentration (AUC0-t). Geometric means by treatment (Pharmacokinetic Analysis Set).

  2. Area Under the Plasma Concentration Versus Time Curve (AUC0-∞) [ Time Frame: Samples for pharmacokinetic evaluation were taken at Baseline and Weeks 0, 1, 2, 3, 4, 8, 12, 16, 20 and 24. Unscheduled visit samples were taken at the discretion of the investigator. ]
    Pharmacokinetic endpoint: Area Under the Plasma Concentration from time 0 to infinity (AUC0-∞ (infinity). Calculated by linear up/log down trapezoidal summation and extrapolated to infinity by addition of the last quantifiable concentration divided by the elimination rate constant: AUC(0-last) + C(last)/λz.

  3. Area Under the Plasma Concentration Versus Time Curve (AUC0-D15) [ Time Frame: Samples for pharmacokinetic evaluation were taken at Baseline and Weeks 0, 1, 2, 3, 4, 8, 12, 16, 20 and 24. Unscheduled visit samples were taken at the discretion of the investigator. ]
    Pharmacokinetic endpoint: Area Under the Concentration verses time from time 0 to Day 15 prior to infusion (AUC0-D15) calculated by linear up/log down trapezoidal summation. Actual time/concentration on Day 15 was used for the calculation of this parameter unless the parameter was derived by interpolation.

  4. Peak Plasma Concentration (Cmax) After Day 15 Infusion [ Time Frame: Samples for pharmacokinetic evaluation were taken at Baseline and Weeks 0, 1 and 2 (Pre-dose 2). Unscheduled visit samples were taken at the discretion of the investigator. ]
    Pharmacokinetic endpoint: Maximum Plasma Concentration (Cmax) after Day 15 infusion (Dose 2)

  5. Trough Concentration (Ctrough) Before the Second Infusion on Day 15 [ Time Frame: Samples for pharmacokinetic evaluation were taken at Baseline and Weeks 0, 1 and 2 (Pre-dose 2). Unscheduled visit samples were taken at the discretion of the investigator. ]
    Pharmacokinetic endpoint: Trough concentration (Ctrough) before the second infusion on Day 15 (Dose 2). Trough (pre-dose) concentration prior to second infusion on Day 15 obtained directly from the observed concentration versus time data.

  6. Change From Baseline in DAS28-CRP at Week 24 [ Time Frame: Baseline and Week 24 ]

    Disease Activity Score 28 C-reactive protein score (DAS28-CRP) at Week 24 (Full Analysis Set). CRP samples were collected at Baseline and Weeks 8, 16 and 24. DAS28-CRP was calculated using the following equation: [0.56*Square Root (SQRT) (tender 28 joint count)+0.28*SQRT(swollen 28 joint count)+0.36*ln(CRP+1)]*1.10+1.15.

    Total DAS28-CRP scores were calculates and range from 2.0 (minimum) to 10 (maximum). Lower scores represent a better patient outcome. Disease remission is considered achieved if the score is between 0 and <2.6. Low disease activity corresponds to 2.6 to <3.2. Moderate activity is between 3.2 & ≤5.1, while high activity is above 5.1.



Secondary Outcome Measures :
  1. Area Under the Concentration Time Curve Week 2 to Week 24 (AUC(w2-24) [ Time Frame: Samples for pharmacokinetic evaluation were taken at Baseline and Weeks 0, 1, 2, 3, 4, 8, 12, 16, 20 and 24. Unscheduled visit samples were taken at the discretion of the investigator. ]
    Pharmacokinetic endpoint: Area under the concentration time curve week 2 to week 24 (AUC(w2-24) calculated by linear up/log down trapezoidal summation.

  2. Area Under the Concentration Time Curve Day 0 to Week 12 (AUC(0-w12)) [ Time Frame: Samples for pharmacokinetic evaluation were taken at Baseline and Weeks 0, 1, 2, 3, 4, 8 and 12. Unscheduled visit samples were taken at the discretion of the investigator. ]
    Pharmacokinetic endpoint: Area under the concentration time curve Day 0 to Week 12 calculated by linear up/log down trapezoidal summation.

  3. Time to Maximum Plasma Concentration (Tmax) (Dose 1) [ Time Frame: Samples for pharmacokinetic evaluation were taken at Baseline and Weeks 0, 1, 2, 3, 4, 8, 12, 16, 20 and 24. Unscheduled visit samples were taken at the discretion of the investigator. ]
    Pharmacokinetic endpoint: Maximum plasma concentration over the first dosing interval obtained directly from the observed concentration versus time data.

  4. Time to Maximum Plasma Concentration (Tmax) (Dose 2) [ Time Frame: Samples for pharmacokinetic evaluation were taken at Baseline and Weeks 0, 1, 2, 3, 4, 8, 12, 16, 20 and 24. Unscheduled visit samples were taken at the discretion of the investigator. ]
    Time of maximum concentration postinfusion over the second dosing interval, obtained directly from the observed concentration versus time data.

  5. Apparent Terminal Rate Constant (λz) [ Time Frame: Samples for pharmacokinetic evaluation were taken at Baseline and Weeks 0, 1, 2, 3, 4, 8, 12, 16, 20 and 24. Unscheduled visit samples were taken at the discretion of the investigator. ]
    Pharmacokinetic endpoint: Apparent terminal rate constant (λz) determined by linear regression of the terminal points of the log-linear concentration-time curve. Best fit method followed by visual assessment was used to identify the terminal linear phase of the concentration-time profile. A minimum of 3 data points was used for determination.

  6. Systemic Clearance (CL) [ Time Frame: Samples for pharmacokinetic evaluation were taken at Baseline and Weeks 0, 1, 2, 3, 4, 8, 12, 16, 20 and 24. Unscheduled visit samples were taken at the discretion of the investigator. ]
    Pharmacokinetic endpoint: Systemic clearance (CL) over the first dosing period calculated as dose (first + second dose) divided by AUC(0-∞).

  7. Volume of Distribution (VD) [ Time Frame: Samples for pharmacokinetic evaluation were taken at Baseline and Weeks 0, 1, 2, 3, 4, 8, 12, 16, 20 and 24. Unscheduled visit samples were taken at the discretion of the investigator. ]
    Pharmacokinetic endpoint: Volume of distribution (VD) over the first dosing period calculated as dose (first + second dose) divided by [λz AUC(0-∞)]

  8. Terminal Half-life (T1/2) [ Time Frame: Samples for pharmacokinetic evaluation were taken at Baseline and Weeks 0, 1, 2, 3, 4, 8, 12, 16, 20 and 24. Unscheduled visit samples were taken at the discretion of the investigator. ]
    Pharmacokinetic endpoint: Terminal half-life determined as ln2/λz.

  9. Change From Baseline in DAS28-CRP at Weeks 8, 16, 36 and 52 [ Time Frame: Baseline and Weeks 8, 16, 24, 36 and 52 (EOS) ]

    Disease Activity Score 28-C-Reactive Protein (DAS28-CRP) samples taken at Baseline and Weeks 8, 16, 24, 36 and 52. DAS28-CRP was calculated using the following equation: [0.56*Square Root (SQRT) (tender 28 joint count)+0.28*SQRT(swollen 28 joint count)+0.36*ln(CRP+1)]*1.10+1.15.

    Total DAS28-CRP scores are presented and range from 2.0 (minimum) to 10 (maximum). Lower scores represent a better patient outcome. Disease remission is considered achieved if the score is between 0 and <2.6. Low disease activity corresponds to 2.6 to <3.2. Moderate activity is between 3.2 & ≤5.1, while high activity is above 5.1.


  10. American Collage of Rheumatology 20% Response Criteria (ACR20) Response Rates at Weeks 8, 16, 24, 36 and 52 [ Time Frame: Baseline and Weeks 8, 16, 24, 36 and 52 (EOS) ]

    American Collage of Rheumatology (ACR) 20% response criteria (ACR20) response rates were assessed at Baseline and Weeks 8, 16, 24, 36 and 52.

    An ACR20 response is defined as both improvement of 20% in the number of tender and number of swollen joints, and a 20% improvement in three of the following five criteria: patient global assessment, physician global assessment, functional ability measure [Health Assessment Questionnaire (HAQ)], visual analogue pain scale, and erythrocyte sedimentation rate or C-reactive protein (CRP).


  11. American Collage of Rheumatology 50% Response Criteria (ACR50) Response Rates and American Collage of Rheumatology 70% Response Criteria (ACR70) at Weeks 8, 16, 24, 36 and 52 [ Time Frame: Baseline and Weeks 8, 16, 24, 36 and 52 (EOS) ]

    Efficacy endpoint: American Collage of Rheumatology 50% response criteria (ACR50) response rates and American Collage of Rheumatology 70% response criteria (ACR70) at weeks 8, 16, 24, 36 and 52.

    An ACR50 response is defined as both improvement of 50% in the number of tender and number of swollen joints, and a 50% improvement in three of the following five criteria: patient global assessment, physician global assessment, functional ability measure [Health Assessment Questionnaire (HAQ)], visual analogue pain scale, and erythrocyte sedimentation rate or C-reactive protein (CRP).

    An ACR70 response is defined as both improvement of 70% in the number of tender and number of swollen joints, and a 70% improvement in three of the following five criteria: patient global assessment, physician global assessment, functional ability measure [Health Assessment Questionnaire (HAQ)], visual analogue pain scale, and erythrocyte sedimentation rate or C-reactive protein (CRP).


  12. Individual Components of the ACR Improvement Criteria on Day 1 and at Weeks 8, 16, 24, 36 and 52: Swollen Joint Count (SJC) and Tender Joint Count (TJC) (the 66/68 Joint Count System) [ Time Frame: Baseline and Weeks 8, 16, 24, 36 and 52 (EOS) ]
    Efficacy endpoint: Individual components of the ACR improvement criteria on Day 1 and at weeks 8, 16, 24, 36 and 52: Swollen Joint Count (SJC) and tender joint count (TJC) (the 66/68 joint count system). SJC and TJC assess the level of skeletal disease involvement. The 66/68 Joint Count evaluates 66 joints for swelling and 68 joints for tenderness.

  13. Individual Components of the ACR Improvement Criteria on Day 1 and at Weeks 8, 16, 24, 36 and 52: Physicians Global Assessment of Disease Activity (Assessed on 1 to 100 mm Visual Analog Scale [VAS]) [ Time Frame: Baseline and Weeks 8, 16, 24, 36 and 52 (EOS) ]
    Efficacy endpoint: Individual Components of the ACR Improvement Criteria on Day 1 and at Weeks 8, 16, 24, 36 and 52: Physicians global assessment of disease activity (assessed on 1 to 100 mm Visual Analog Scale [VAS]). Where 0 = no disease activity and 100 = maximum disease activity.

  14. Individual Components of the ACR Improvement Criteria on Day 1 and at Weeks 8, 16, 24, 36 and 52: Participants Assessment of Pain (Assessed on 1 to 100 mm Visual Analog Scale [VAS]) [ Time Frame: Baseline and Weeks 8, 16, 24, 36 and 52 (EOS) ]
    Participants assessment of pain (assessed on 1 to 100 mm Visual Analog Scale [VAS]). Participants assessment of pain (assessed on 1 to 100 mm Visual Analog Scale [VAS]) where 0 = no pain and 100 = severe pain.

  15. Individual Components of the ACR Improvement Criteria on Day 1 and at Weeks 8, 16, 24, 36 and 52: Participants Global Assessment of Disease Activity (Assessed on 1 to 100 mm VAS) [ Time Frame: Baseline and Weeks 8, 16, 24, 36 and 52 (EOS) ]
    Efficacy endpoint: Individual Components of the ACR Improvement Criteria on Day 1 and at Weeks 8, 16, 24, 36 and 52: Participants global assessment of disease activity (assessed on 1 to 100 mm visual analogue scale [VAS]). Patients rate how their Rheumatoid Arthritis has affected them, where 0 = very well and 100 = very poor.

  16. Individual Components of the ACR Improvement Criteria on Day 1 and at Weeks 8, 16, 24, 36 and 52: Participants Assessment of Disability (Health Assessment Questionnaire-Disability Index [HAQ-DI]) [ Time Frame: Baseline and Weeks 8, 16, 24, 36 and 52 (EOS) ]

    the Health Assessment Questionnaire-Disability Index (HAQ-DI) contains 20 questions split into 8 categories (dressing & grooming, arising, eating, walking, hygiene, reach, grip & activities). Scores were: 0 = Without ANY Difficulty; 1 = With SOME Difficulty; 2 = With MUCH Difficulty; 3 = UNABLE to Do. Total scores were calculated as the summed category scores divided by the number of categories.

    Total HAQ-DI scores are presented which range from 0 to 3. Higher scores represent a worse outcome. Scores of 0 to 1 represent mild to moderate difficulty, 1 to 2 moderate disability, and 2 to 3 severe to very severe disability.


  17. Individual Components of the ACR Improvement Criteria on Day 1 and at Weeks 8, 16, 24, 36 and 52: C-reactive Protein (CRP) Level [ Time Frame: Baseline and Weeks 8, 16, 24, 36 and 52 (EOS) ]

    C-reactive protein (CRP) level (Mg/L). CRP is a marker for inflammation. a normal reading is <3 Mg/L. Higher values indicate disease related inflammation and increased cardiovascular risk.

    CRP levels between 3 Mg/L and 10 Mg/L are mildly elevated. Levels between 10 Mg/L and 100 Mg/L are moderately elevated and CRP levels above 100 Mg/L are severely elevated.


  18. Change From Baseline DAS28-erythrocyte Sedimentation Rate (ESR) at Weeks 8, 16, 24, 36 and 52 [ Time Frame: Baseline and Weeks 8, 16, 24, 36 and 52 (EOS) ]

    Disease Activity Score 28- Erythrocyte Sedimentation Rate (DAS28-ESR) consisted of tender joint counts (TJC), swollen joint counts (SJC) & erythrocyte sedimentation rate (ESR). The formula is: [0.56*SQRT(tender 28 joint count)+0.28*SQRT(swollen 28 joint count)+0.7*ln(ESR)]+0.014*patient global health assessment.

    Total DAS28-ESR scores are presented. Total scores range from 2 (minimum) to 10 (maximum). A lower score represents a better patient outcome. A DAS28-ESR of greater than 5.1 implies active disease, less than 3.2 low disease activity, and less than 2.6 remission.


  19. Number of Participants With a Major Clinical Response (Continuous ACR70) for at Least 24 Weeks [ Time Frame: Baseline and Weeks 8, 16, 24, 36 and 52 (EOS) ]

    Efficacy endpoint: number of participants with a major clinical response defined as a continuous ACR70 from Baseline (Day 1) for at least 24 weeks.

    ACR70 is a measure based on American College of Rheumatology criteria of at least a 70% improvement in the number of tender and swollen joints, and a 70% improvement in at least 3 of the following: the patient's global assessment of disease status; the patient's assessment of pain; the patient's assessment of function measured using the Stanford Health Assessment Questionnaire the physician's global assessment of disease status; serum C-reactive protein levels.


  20. Number of Participants With a Clinical Remission Response (CRR) at Weeks 8, 16, 24, 36 and 52 [ Time Frame: Baseline and Weeks 8, 16, 24, 36 and 52 (EOS) ]
    Number if Participants with a Clinical Remission Response (CRR) defined by the Simplified Disease Activity Index (SDAI) <3.3 at weeks 8, 16, 24, 36 and 52 (EOS).

  21. Proportion of Participants With European League Against Rheumatism (EULAR) Response at Weeks 8, 16, 24 36 and 52 [ Time Frame: Baseline and Weeks 8, 16, 24, 36 and 52 (EOS) ]
    Efficacy endpoint: Proportion of participants with European League Against Rheumatism (EULAR) response (defined as good response, moderate response or no response) at weeks 8, 16, 24 36 and 52 (EOS). EULAR (European League Against Rheumatism) response was classified using the individual amount of change in the DAS28-CRP score. The DAS28-CRP was classified into 3 categories: low disease activity (<= 3.2), moderate disease activity (> 3.2 and <= 5.1) and high disease activity (> 5.1). Good response was defined as >1.2 improvement in the DAS28-CRP from baseline with low disease activity.

  22. Pharmacodynamic Endpoint: Change From Baseline in Immunoglobulin (IgG, IgM and IgA Levels) [ Time Frame: Baseline (Day 1) and Weeks 8, 16, 24, 36 and 52 (EOS) ]
    Change from baseline (Day 1) in immunoglobulin G (IgG), Immunoglobulin M (IgM) and Immunoglobulin A (IgA) levels (mg/dL) at Week 8, 16, 24 36 and 52 (End of study)


Other Outcome Measures:
  1. Pharmacodynamic Endpoint: Depletion of B-lymphocyte Antigen CD19 (CD19+) B-cell Count up to Week 24 [ Time Frame: Samples for pharmacodynamic evaluation (CD19+ B-cell) were taken at Baseline and Weeks 0, 1, 2, 3, 4, 8, 12, 16, 20 and 24. Unscheduled visit samples were taken at the discretion of the investigator. ]
    Pharmacodynamic endpoint: proportion of participants (n) with depletion of CD19+ B-cell count up to week 24 (Pharmacodynamic analysis set).

  2. Pharmacodynamic Endpoint: Time Needed to CD19+ B-cell Depletion [ Time Frame: Samples for pharmacodynamic evaluation (CD19+ B-cell) were taken at Baseline and Weeks 0, 1, 2, 3, 4, 8, 12, 16, 20, 24, 36 and 52. Unscheduled visit samples were taken at the discretion of the investigator. ]
    Time needed to CD19+ B-cell depletion in Part A (calculated as the first time CD19+ B-cell count below 20/µL minus time of first dosing in days).

  3. Pharmacodynamic Endpoint: Duration of CD19+ B-cell Depletion [ Time Frame: Samples for pharmacodynamic evaluation (CD19+ B-cell) were taken at Baseline and Weeks 0, 1, 2, 3, 4, 8, 12, 16, 20, 24, 36 and 52. Unscheduled visit samples were taken at the discretion of the investigator. ]
    Duration of CD19+ B-cell depletion (only participants that returned to non-depletion at or before week 24 were included)

  4. Pharmacodynamic Endpoint: Number of Participants With CD19+ B-cell Count Recover Versus Baseline [ Time Frame: Samples for pharmacodynamic evaluation (CD19+ B-cell) were taken at Baseline and Weeks 0, 1, 2, 3, 4, 8, 12, 16, 20, 24, 36 and 52. Unscheduled visit samples were taken at the discretion of the investigator. ]
    Number of participants with CD19+ B-cell count recover versus baseline. Incidence of B-Cell recovery was defined as either CD19+ B-cell counts retuned to baseline or the lower limit or normal of 110 cells/µL at week 24).

  5. Pharmaco Endpoint: Area Under the Concentration Time Curve of CD19 B-cell Count Change at Day 15 and Week 24 [ Time Frame: Samples for pharmacodynamic evaluation (CD19+ B-cell) were taken at Baseline and Weeks 0, 1, 2, 3, 4, 8, 12, 16, 20, 24, 36 and 52. Unscheduled visit samples were taken at the discretion of the investigator. ]
    Area under the concentration time curve of CD19 B-cell count change at Day 15 (AUEC0-d15) and week 24 (AUEC0-w24) based on change from baseline and percent of baseline values

  6. Pharmacodynamic Endpoint: Change From Baseline in CD19+ B-cell Count During the Study Period [ Time Frame: Samples for pharmacodynamic evaluation (CD19+ B-cell) were taken at Baseline and Weeks 0, 1, 2, 3, 4, 8, 12, 16, 20 and 24. Unscheduled visit samples were taken at the discretion of the investigator. ]
    Pharmacodynamic endpoint: Descriptive statistics (mean [SD]) of the change from baseline in CD19+ B-cell count during the study period (Day 15 [AUEC(0-d15] and Week 24 [AUEC(0-w24])

  7. Pharmacodynamic Endpoint: Change From Baseline in C-reactive Protein (CRP) Levels at Weeks 8, 16, 24, 36 and 52 [ Time Frame: Baseline (Day 1) and Weeks 8, 16, 24, 26 & 52 (EOS) ]
    Pharmacodynamic endpoint: Change from baseline (Day 1) in C-reactive protein (CRP) levels (mg/dL) at weeks 8, 16, 24, 36 and 52 (EOS)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

1. Severe RA defined as:

  • Diagnosis of RA according to the revised (1987) American College of Rheumatology (ACR) criteria for the classification of RA for at least 3 months prior to screening visit (see Appendix 3).
  • And ≥6 swollen joints and ≥6 tender/painful joints (from the 66/68 joint count system).
  • And C-reactive protein (CRP) ≥1.0 mg/dL or an erythrocyte sedimentation rate (ESR) ≥28 mm/hour at Screening.
  • And positive rheumatoid factor (RF) (≥20 units/mL) or anti cyclic citrullinase peptide (CCP) antibodies (≥10 units/mL) at Screening.

    2. Patients with severe RA who have had an inadequate response to at least 3 months' treatment (according to the approved treatment and dosage) or intolerance (at Investigator's discretion and/or experience of intolerable AE or toxicity such as infusion related reaction, hypersensitivity, anaphylaxis or severe toxicity) to anti-tumour necrosis factor (TNF) therapy (experience of severe adverse event (AE) or toxicity).

    3. Current treatment for RA on an outpatient basis:

  • Receiving methotrexate (MTX) 7.5 - 25mg/week (oral or parenteral) for at least 12 weeks, including the last 4 weeks prior to Day 1 at a stable dose, via the same route of administration, dose, and formulation. Patients receiving a lower dose of MTX (<10 mg/week), stable for 4 weeks prior to Day 1, should be doing so as a result of a documented evidence of intolerance to higher doses of MTX.

Exclusion Criteria:

  1. Females who are pregnant, breastfeeding, or planning a pregnancy during the Treatment Period of and 12 months after the last infusion of study drug.
  2. Class IV as per the Classification of Global Functional Status in Rheumatoid Arthritis (as per ACR 1991 Revised Criteria) (see Appendix 4) or wheelchair/bed bound.
  3. History of or current inflammatory joint disease other than RA (including but not limited to gout, reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy or Lyme disease).
  4. History of or current systemic autoimmune disorder (including but not limited to systemic lupus erythematosus, inflammatory bowel disease, pulmonary fibrosis, Felty syndrome, scleroderma, inflammatory myopathy, fibromyalgia, juvenile idiopathic arthritis, mixed connective tissue disease, vasculitis or other overlap syndrome), with the exception of the secondary Sjögren's syndrome.
  5. Primary or secondary immunodeficiency (history of, or currently active), including known history of human immunodeficiency virus (HIV) infection or positive test at screening.
  6. History of opportunistic infection.
  7. History of deep space/tissue infection (e.g., fasciitis, abscess, osteomyelitis) and infected prosthetic joint.
  8. Active infection of any kind (excluding fungal infection of nail beds) or any major episode of infection requiring hospitalization or treatment with i.v. anti infective agents within 4 weeks prior to Screening or oral anti-infective agents within 2 weeks prior to Screening or use of antibiotic therapy three or more times in the last six months prior to Screening
  9. Positive serological test for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb) or hepatitis C serology.

    • Patients with a negative HBsAg and positive HBcAb must have a hepatitis B virus (HBV) deoxyribonucleic acid (DNA) level <20 IU/mL (or 112 copies/mL) by polymerase chain reaction (PCR). These HBV patients must be willing to undergo monthly PCR HBV DNA testing during treatment and may participate following consultation with a hepatitis expert regarding monitoring and use of HBV antiviral therapy, and provided they agree to receive treatment as indicated. An HBV re-test will be performed monthly including Day 1, Weeks 4, 8, 12, 16, 20, 24, 36, 52, and unscheduled visit if required.
    • Patients with a positive test because of HBV vaccine may be included (i.e., anti-HBs+ and anti HBc-).
    • Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCR is negative for HCV ribonucleic acid (RNA).
  10. Confirmed current active tuberculosis (TB). • Patients with latent TB as determined by positive QuantiFERON-TB test may be enrolled if such patients have written confirmation from health care provider (e.g., Pulmonologist or Infection Specialist) of adequate prophylaxis before or within the screening period and no evidence of tuberculosis on a chest X-ray performed within 3 months from Day 1.

    • Screening period can be extended to 60 days for prophylaxis of latent TB.

    • QuantiFERON-TB test can be re-tested, if inconclusive.

  11. Any significant cardiac disease (e.g., coronary artery disease with unstable angina, coronary heart failure New York Heart Association Class III and IV, familial long QT syndrome, uncontrolled cardiac disease).
  12. History of moderate to severe chronic obstructive pulmonary disease (COPD) and/or history of severe COPD exacerbation(s) within the last 12 months of Screening.
  13. Vaccination with live or attenuated vaccines within 6 weeks prior to first dose of study drug or planned administration during study participation or within 4 weeks following last dose of study drug. Treatment with IV Gamma Globulin or the Prosorba® Column within 6 months prior to Day 1.
  14. History of a severe allergic reaction or anaphylactic reaction to a biological agent or history of hypersensitivity to any component of the study drug including known hypersensitivity or allergy to a murine product.
  15. Hypogammaglobulinemia at screening (Immunoglobulin G (IgG) <600 mg/dL).
  16. Patients with hemoglobin <8.5 g/dL, absolute neutrophil count (ANC) <1,500 cells/µL or platelet count <75,000 cells/µL at Screening. If a patient has findings marginally below this limit, re testing is allowed, at the Investigator's discretion, within the 30 day period between Visit 1 and Visit 2.

• Creatinine clearance < 50 mL/min (Cockcroft-Gault formula)

• Liver function: Total bilirubin >2.0 mg/dL (>34 µmol/L) except for patients with Gilbert's Syndrome or hemolysis. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) >3 × upper limit of normal (ULN). Patients with total bilirubin >2.0 mg/dL possibly due to Gilbert's Syndrome should have a direct bilirubin checked. If the direct bilirubin is normal and medical history is suggestive/positive for Gilbert's Syndrome, the patient successfully meets the criteria.

The AST and ALT may be repeated once within the Screening period if the initial result exceeds this limit, and the lesser value accepted if it meets this criterion.

18. History of cancer within the last 5 years prior to Screening, treated with anti-cancer chemotherapy, including solid tumors and hematologic malignancies and carcinoma in situ (except basal cell and squamous cell carcinomas of the skin or carcinoma in situ of the cervix uteri that have been excised and cured).

19. Major surgical procedure within 4 weeks prior to or planned within 24 weeks of Day 1, with the exception of surgical procedures for dental prosthesis.

20. Previous treatment with a B cell modulating or B cell depletion therapy, such as, but not limited to rituximab, belimumab, atacicept, tabalumab, ocrelizumab, ofatumumab, obinutuzumab, epratuzumab and other experimental treatments.

21. Injectable corticosteroids within 6 weeks prior to Day 1.

22. Participation in a previous clinical study within 4 weeks of Screening or having received treatment with a drug that has not received regulatory approval for any indication within a minimum of 5 half-lives prior to Day 1.

23. Patients who, based on the Investigator's judgment, have a clinically significant or unstable medical or surgical condition that may preclude safe and complete study participation. Conditions may also include cardiovascular, vascular, pulmonary, hepatic, renal, endocrine or neurological conditions as determined by medical history, physical examination, laboratory tests or electrocardiogram (ECG).

24. Patients who, in the judgment of the Investigator, are likely to be non-compliant or uncooperative during the study.

25. History of substance abuse (alcohol or drug).

26. History of demyelinating disorders (such as multiple sclerosis or Guillain-Barré syndrome).

27. Patients at risk of progressive multifocal leukoencephalopathy (PML):

  • Patients with immune deficiency such as transplant patients on immunosuppressive medications
  • Patients receiving certain kinds of chemotherapy
  • Patients receiving natalizumab (Tysabri®) for multiple sclerosis
  • Patients with psoriasis on longer term efalizumab (Raptiva®) or patients with acquired immunodeficiency syndrome (AIDS)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02819726


Locations
Show Show 75 study locations
Sponsors and Collaborators
Archigen Biotech Limited
  Study Documents (Full-Text)

Documents provided by Archigen Biotech Limited:
Study Protocol  [PDF] April 27, 2017
Statistical Analysis Plan  [PDF] February 13, 2019

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Responsible Party: Archigen Biotech Limited
ClinicalTrials.gov Identifier: NCT02819726    
Other Study ID Numbers: AGB001
First Posted: June 30, 2016    Key Record Dates
Results First Posted: February 17, 2020
Last Update Posted: February 17, 2020
Last Verified: February 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Archigen Biotech Limited:
an inadequate response to anti -TNF therapy
Additional relevant MeSH terms:
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Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Rituximab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents