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

NCT02819726 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: AGB001
• Study Type: interventional
• Target: 294
• Locations: 11 countries
• Sites: 75

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.

Conditions

Rheumatoid Arthritis

Keywords

an inadequate response to anti -TNF therapy

Outcome Measures

Primary Outcomes (6)

• Area Under the Concentration Time Cure From Time 0 to Last Quantifiable Concentration (AUC0-t)

  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).

  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.

• Area Under the Plasma Concentration Versus Time Curve (AUC0-∞)

  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.

  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.

• Area Under the Plasma Concentration Versus Time Curve (AUC0-D15)

  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.

  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.

• Peak Plasma Concentration (Cmax) After Day 15 Infusion

  Pharmacokinetic endpoint: Maximum Plasma Concentration (Cmax) after Day 15 infusion (Dose 2)

  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.

• Trough Concentration (Ctrough) Before the Second Infusion on Day 15

  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.

  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.

• Change From Baseline in DAS28-CRP at 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.

  Baseline and Week 24

Secondary Outcomes (22)

• Area Under the Concentration Time Curve Week 2 to Week 24 (AUC(w2-24)

  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.

• Area Under the Concentration Time Curve Day 0 to Week 12 (AUC(0-w12))

  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.

• Time to Maximum Plasma Concentration (Tmax) (Dose 1)

  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 to Maximum Plasma Concentration (Tmax) (Dose 2)

  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.

• Apparent Terminal Rate Constant (λz)

  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.

Other Outcomes (7)

• Pharmacodynamic Endpoint: Depletion of B-lymphocyte Antigen CD19 (CD19+) B-cell Count up to Week 24

  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: Time Needed to CD19+ B-cell Depletion

  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.

• Pharmacodynamic Endpoint: Duration of CD19+ B-cell Depletion

  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.

Study Arms (3)

SAIT101

EXPERIMENTAL

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

Rituxan

ACTIVE COMPARATOR

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

MabThera

ACTIVE COMPARATOR

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

Interventions

SAIT101 BIOLOGICAL

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.

SAIT101

MabThera BIOLOGICAL

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.

Also known as: Rituximab

MabThera

Rituxan BIOLOGICAL

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.

Also known as: Rituximab

Rituxan

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \. 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.
• \. 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).
• \. 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.

You may not qualify if:

• Females who are pregnant, breastfeeding, or planning a pregnancy during the Treatment Period of and 12 months after the last infusion of study drug.
• 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.
• 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).
• 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.
• Primary or secondary immunodeficiency (history of, or currently active), including known history of human immunodeficiency virus (HIV) infection or positive test at screening.
• History of opportunistic infection.
• History of deep space/tissue infection (e.g., fasciitis, abscess, osteomyelitis) and infected prosthetic joint.
• 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
• 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).
• 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.

Sponsors & Collaborators

• Archigen Biotech Limited: lead

Study Sites (75)

Research Site

Anniston, Alabama, 36207, United States

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El Cajon, California, 92020, United States

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La Mesa, California, 91942, United States

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Lakewood, California, 90712, United States

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Los Angeles, California, 90017, United States

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Los Angeles, California, 90017, United States

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San Leandro, California, 94578, United States

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Orlando, Florida, 32804, United States

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Tampa, Florida, 33612, United States

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Tampa, Florida, 33613, United States

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Boise, Idaho, 83642, United States

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Kansas City, Kansas, 66160, United States

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Lansing, Michigan, 48917, United States

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Waco, Texas, 76710, United States

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Tacoma, Washington, 98405, United States

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Mostar, 88000, Bosnia and Herzegovina

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Sarajevo, 71000, Bosnia and Herzegovina

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Plovdiv, 4002, Bulgaria

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Plovdiv, 4002, Bulgaria

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Sofia, 1336, Bulgaria

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Sofia, 1612, Bulgaria

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Brno, 656 91, Czechia

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Ostrava, 702 00, Czechia

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Prague, 128 50, Czechia

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Uherské Hradiště, 686 01, Czechia

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Bad Doberan, Mecklegurg-Vorpommern, 18209, Germany

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Ratingen, North Rhine-Westphalia, 40882, Germany

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Dresden, Saxony, 01067, Germany

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Vogelsang, Saxony-Anhalt, 39245, Germany

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Hamburg, 22143, Germany

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Rendsburg, 24768, Germany

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Budapest, 1027, Hungary

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Budapest, 1083, Hungary

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Bangalore, Karnataka, 560054, India

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Hubli, Karnataka, 580021, India

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Pune, Maharashtra, 411001, India

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Pune, Maharashtra, 411005, India

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Pune, Maharashtra, 411007, India

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Bikaner, Rajasthan, 334003, India

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Jaipur, Rajasthan, 302001, India

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Kolkata, West Bengal, 700107, India

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Durango, 34000, Mexico

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Mexico City, 06700, Mexico

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Mexico City, 07020, Mexico

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Gdansk, 80-952, Poland

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Krakow, 30-033, Poland

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Krakow, 30-363, Poland

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Kłodzko, 57-300, Poland

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Nowa Sól, 67-100, Poland

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Oświęcim, 32-600, Poland

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Poznan, 60-773, Poland

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Poznan, 61-113, Poland

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Tychy, 43-100, Poland

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Warsaw, 00-660, Poland

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Warsaw, 03-291, Poland

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Wroclaw, 51-128, Poland

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Zamość, 22-400, Poland

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Anyang, 14068, South Korea

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Busan, 49201, South Korea

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Busan, 49241, South Korea

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Daegu, 41944, South Korea

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Daegu, 42472, South Korea

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Daejeon, 35015, South Korea

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Gwangju, 61469, South Korea

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Jeju City, 63241, South Korea

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Seoul, 03080, South Korea

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Seoul, 04763, South Korea

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Seoul, 07061, South Korea

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Suwon, 16247, South Korea

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A Coruña, 15006, Spain

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A Coruña, 15702, Spain

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A Coruña, 15706, Spain

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Fuenlabrada, 28942, Spain

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Seville, 41010, Spain

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Seville, 41014, Spain

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MeSH Terms

Conditions

Arthritis, Rheumatoid

Interventions

Rituximab

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

Results Point of Contact

• Title: Medical Director
• Organization: Archigen Biotech Ltd

info@archigenbio.com

+44(0)20 3749 5000

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

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

Model Details: 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.

Study Record Dates

• First Submitted: June 20, 2016
• First Posted: June 30, 2016
• Study Start: October 11, 2016
• Primary Completion: April 30, 2018
• Study Completion: November 7, 2018
• Last Updated: February 17, 2020
• Results First Posted: February 17, 2020

Record last verified: 2020-02

Locations

BU (4); ME (3); KR (12); HU (2); CZ (4); IN (8); US (15); BO (2); ES (6); PL (13); DE (6)