A Study to Evaluate the Safety and Efficacy of VIB4920 in Participants With Rheumatoid Arthritis (MIDORA)

• ClinicalTrials.gov Identifier: NCT04163991
• Recruitment Status: Completed
• First Posted: November 15, 2019
• Results First Posted: February 14, 2023
• Last Update Posted: February 14, 2023
• Sponsor: Viela Bio (acquired by Horizon Therapeutics)
• Information provided by (Responsible Party): Viela Bio (acquired by Horizon Therapeutics)

Study Description

Brief Summary:

The purpose of the study is to evaluate the efficacy, safety, and pharmacokinetics (PK) of VIB4920 (formerly MEDI4920) in adult participants with rheumatoid arthritis (RA).

Condition or disease	Intervention/treatment	Phase
Rheumatoid Arthritis	Drug: VIB4920; Drug: Placebo	Phase 2

Detailed Description:

The overall study period will be approximately 337 days. After a screening period of up to 28 days, the participants will be randomized in a 1:1:1:1:1 ratio to receive intravenous dose of VIB4920 and/or placebo in 5 cohorts. Participants are to be followed on their stable background anti-RA therapy at least through 12 weeks (Day 85), at which time rescue therapy may be instituted. All participants will be followed at least through the primary (interim) analysis (Day 113), and those who have not instituted rescue therapy will be followed through Day 309 to determine the duration of clinical response. The primary analysis will be after all participants have completed Day 113, and the final analysis will be after all participants have completed follow-up.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 78 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Mechanistic Insight and Dosage Optimization Study of the Efficacy and Safety of VIB4920 in Patients With Rheumatoid Arthritis (RA)
• Actual Study Start Date: December 9, 2019
• Actual Primary Completion Date: December 28, 2021
• Actual Study Completion Date: December 28, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: VIB4920 1500 mg 4 Times; Participants receive intravenous (IV) infusion of VIB4920 1500 mg on Days 1, 15, 29, and 57	Drug: VIB4920; liquid for IV infusion following dilution in normal saline; Other Names: MEDI4920; dazodalibep
Experimental: VIB4920 1500 mg Twice; Participants receive IV infusion of VIB4920 1500 mg on Days 1 and 57, placebo on Days 15 and 29.	Drug: VIB4920; liquid for IV infusion following dilution in normal saline; Other Names: MEDI4920; dazodalibep; Drug: Placebo; 0.9% saline for IV infusion
Experimental: VIB4920 3000 mg Twice; Participants receive IV infusion of VIB4920 3000 mg on Days 1 and 57, placebo on Days 15 and 29.	Drug: VIB4920; liquid for IV infusion following dilution in normal saline; Other Names: MEDI4920; dazodalibep; Drug: Placebo; 0.9% saline for IV infusion
Experimental: VIB4920 3000 mg Once; Participants receive IV infusion of VIB4920 3000 mg on Day 1 and placebo on Days 15, 29, and 57.	Drug: VIB4920; liquid for IV infusion following dilution in normal saline; Other Names: MEDI4920; dazodalibep; Drug: Placebo; 0.9% saline for IV infusion
Placebo Comparator: Placebo; Participants receive IV infusion of placebo matched to VIB4920 on Days 1, 15, 29, and 57.	Drug: Placebo; 0.9% saline for IV infusion

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline to Day 113 in DAS28-CRP [ Time Frame: Day 1 (Baseline), Day 113 ]
   The DAS28-CRP is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100 mm), and high-sensitivity C-reactive protein (hsCRP; in mg/L). Scores on the DAS28-CRP range from 0 to approximately 10, where higher scores indicate more disease activity. A negative change from baseline indicates improvement in disease activity. Results are from a mixed-effect model for repeated measures (MMRM) analysis with treatment, visit, visit by treatment interaction, and baseline DAS28-CRP score included in the model.
2. Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs), and Treatment-emergent Adverse Events of Special Interest (TEAESIs) [ Time Frame: From first dose of study drug through Day 309 ± 7 days ]
   Adverse event (AE): any untoward medical occurrence associated with the use of an intervention in humans, whether or not it is considered intervention-related. Serious adverse event (SAE): an AE that results in any of the following outcomes: death; life-threatening AE; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant incapacity; congenital anomaly/birth defect; other important medical event jeopardizing the participant's well-being. AEs of special interest (AESIs) include: thrombotic and embolic events; anaphylaxis and clinically significant (Common Terminology Criteria for Adverse Events [CTCAE] Grade 3 or higher) hypersensitivity reactions; severe infusion-related reactions (CTCAE Grade 3 or higher); immune complex disease; severe (CTCAE Grade 3 or higher) and/or opportunistic infections; hepatic function abnormality meeting the definition of Hy's Law; malignant neoplasm. (CTCAE Grade 3=Severe; Grade 4=Life-threatening; Grade 5=Fatal.)

Secondary Outcome Measures :

1. Pharmacokinetics (PK) of VIB4920: Maximum Observed Concentration (Cmax) [ Time Frame: Predose (within 30 minutes prior to start of infusion), and within 10 minutes of the end of infusion on Days 1 (Dose 1), 15 ± 1 day (d; Dose 2), 29 ± 3d (Dose 3), 57 ± 3d (Dose 4), and Days 85 ± 3d, 113 ± 5d, 141 ± 5d, 169 ± 5d, 197 ± 7d, 225 ± 7d ]
2. PK of VIB4920: Time to Cmax (Tmax) [ Time Frame: Predose (within 30 minutes prior to start of infusion), and within 10 minutes of the end of infusion on Days 1 (Dose 1), 15 ± 1 day (d; Dose 2), 29 ± 3d (Dose 3), 57 ± 3d (Dose 4), and Days 85 ± 3d, 113 ± 5d, 141 ± 5d, 169 ± 5d, 197 ± 7d, 225 ± 7d ]
3. PK of VIB4920: Area Under the Concentration-Time Curve From Time 0 to the Last Quantifiable Concentration (AUClast) [ Time Frame: Predose (within 30 minutes prior to start of infusion), and within 10 minutes of the end of infusion on Days 1 (Dose 1), 15 ± 1 day (d; Dose 2), 29 ± 3d (Dose 3), 57 ± 3d (Dose 4), and Days 85 ± 3d, 113 ± 5d, 141 ± 5d, 169 ± 5d, 197 ± 7d, 225 ± 7d ]
4. PK of VIB4920: Area Under the Concentration-Time Curve From Time 0 to Day 56 (AUC0-56D) [ Time Frame: Predose (within 30 minutes prior to start of infusion), and within 10 minutes of the end of infusion on Days 1 (Dose 1), 15 ± 1 day (d; Dose 2), 29 ± 3d (Dose 3), Day 56 ]
5. PK of VIB4920: Total Body Clearance (CL) for Dose 1 and Total Body Clearance at Steady State (CLss) for Doses 2 to 4 [ Time Frame: Predose (within 30 minutes prior to start of infusion), and within 10 minutes of the end of infusion on Days 1 (Dose 1), 15 ± 1 day (d; Dose 2), 29 ± 3d (Dose 3), 57 ± 3d (Dose 4), and Days 85 ± 3d, 113 ± 5d, 141 ± 5d, 169 ± 5d, 197 ± 7d, 225 ± 7d ]
6. PK of VIB4920: Terminal Elimination Half-Life (t1/2) [ Time Frame: Predose (within 30 minutes prior to start of infusion), and within 10 minutes of the end of infusion on Days 1 (Dose 1), 15 ± 1 day (d; Dose 2), 29 ± 3d (Dose 3), 57 ± 3d (Dose 4), and Days 85 ± 3d, 113 ± 5d, 141 ± 5d, 169 ± 5d, 197 ± 7d, 225 ± 7d ]
7. PK of VIB4920: Volume of Distribution at Steady State (Vss) [ Time Frame: Predose (within 30 minutes prior to start of infusion), and within 10 minutes of the end of infusion on Days 1 (Dose 1), 15 ± 1 day (d; Dose 2), 29 ± 3d (Dose 3), 57 ± 3d (Dose 4), and Days 85 ± 3d, 113 ± 5d, 141 ± 5d, 169 ± 5d, 197 ± 7d, 225 ± 7d ]
8. Total Soluble Cluster of Differentiation 40 Ligand (sCD40L) Plasma Concentration Over Time [ Time Frame: Day 1 (Baseline), Days 15, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309 ]
   Total sCD40L (free sCD40L and sCD40L bound to VIB4920) was measured in plasma samples using a modified commercially available kit.
9. Percentage of Participants With Positive Anti-Drug Antibodies (ADA) to VIB4920 [ Time Frame: Day 1 (Baseline) to Day 309 Day 1 (Baseline) up to Day 309 (± 7 days) ]

   ADA positive at any time: observed at least once during the study (baseline included).

   Treatment-emergent ADA: ADA positive post-baseline only or boosted pre-existing ADA during the study period.

   Persistent positive: treatment-induced ADA positive at ≥ 2 post-baseline assessments (with ≥ 16 weeks between first and last positive) or positive at last post-baseline assessment.

   Transient positive: treatment-induced ADA post-baseline positive but does not fulfill the criteria of persistent positive.

10. Change From Baseline to Day 113 in Anti-Citrullinated Protein Antibodies (ACPAs) [ Time Frame: Day 1 (Baseline), Day 113 ]
    Excluding data after rescue. Adjusted geometric mean ratio to baseline (90% CI) results are from MMRM analysis on log(ratio to baseline) with treatment, visit, visit by treatment interaction, and log(baseline) included in the model. Ratios less than 1 indicate a decrease.
11. Change From Baseline to Day 113 in Rheumatoid Factor (RF) [ Time Frame: Day 1 (Baseline), Day 113 ]
    Excluding data after rescue. Adjusted geometric mean ratio to baseline (90% CI) results are from MMRM analysis on log(ratio to baseline) with treatment, visit, visit by treatment interaction, and log(baseline) included in the model. Ratios less than 1 indicate a decrease.
12. Percentage of Participants With Clinical Remission at Day 113 [ Time Frame: Day 113 ]
    Clinical remission is defined as DAS28-CRP < 2.6. The DAS28-CRP is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100 mm), and high-sensitivity C-reactive protein (hsCRP; in mg/L). Scores on the DAS28-CRP range from 0 to approximately 10, where higher scores indicate more disease activity.
13. Time to Start of New Treatment for Rheumatoid Arthritis (Rescue Medication) [ Time Frame: Day 1 (Baseline) up to Day 309 (± 7 days) ]
    Based on Kaplan-Meier method.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 99 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Principal Inclusion Criteria:

1. Male or female adults, >= 18 years of age at time of informed consent.
2. Diagnosed with RA according to the European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) 2010 criteria >= 6 months prior to screening.
3. Disease Activity Score in 28 Joints (DAS 28) using C-reactive Protein (DAS28-CRP) > 3.2 at screening with >= 4 tender joint count (TJC) and >= 4 swollen joint count (SJC) out of the 28 joints assessed for DAS28 present at screening and confirmed present at visit 2 prior to randomization.
4. Positive for rheumatoid factor (RF) and/or anti-citrullinated protein antibodies (ACPA) at screening, in accordance with criteria at the central laboratory.
5. Treated with methotrexate (MTX), with or without a concomitant conventional disease-modifying anti-rheumatic drug (cDMARD).
6. Agreeing to use of protocol defined contraception methods.

Principal Exclusion Criteria:

1. Prior or current inflammatory joint disease other than RA.
2. Severe interstitial lung disease.
3. Prior receipt of any biologic B-cell-depleting therapy.
4. Receipt of any anti - tumor necrosis factor alpha (TNF-α) biologic agent < 8 weeks prior to screening.
5. Receipt of any biologic disease-modifying anti-rheumatic drug (bDMARD) with a mechanism of action other than direct TNF-α blockade, < 12 weeks or < 5 half-lives of the drug prior to screening.
6. Injectable corticosteroids or treatment with > 10 mg/day dose of oral prednisolone or equivalent within 4 weeks prior to screening.
7. Previous treatment with anti-cluster of differentiation 40 ligand (CD40L) compounds at any time before randomization.
8. Hepatitis B, hepatitis C, or human immunodeficiency virus infection.
9. Pregnant or lactating or planning to get pregnant during the duration of the study.
10. Evidence of active tuberculosis (TB) or being at high risk for TB.
11. History of more than one episode of herpes zoster in the 12 months prior to screening or any opportunistic infection in the 12 months prior to screening, excluding localized mucocutaneous candidiasis.
12. Receipt of live vaccine or live therapeutic infectious agent within the 4 weeks prior to screening.

Contacts and Locations

Locations

United States, Alabama

Research Site

Anniston, Alabama, United States, 36207

United States, Arizona

Research Site

Sun City, Arizona, United States, 85704

United States, California

Research Site

Upland, California, United States, 91786

United States, Florida

Research Site

Clearwater, Florida, United States, 33765

Research Site

Margate, Florida, United States, 33063

Research Site

Miami Lakes, Florida, United States, 33014

Research Site

Zephyrhills, Florida, United States, 33542

United States, Georgia

Research Site

Atlanta, Georgia, United States, 30342

United States, Kentucky

Research Site

Lexington, Kentucky, United States, 40504

United States, Maryland

Research Site

Wheaton, Maryland, United States, 20902

United States, North Carolina

Research Site

Charlotte, North Carolina, United States, 28210

Research Site

Rocky Mount, North Carolina, United States, 27804

Research Site

Salisbury, North Carolina, United States, 28144

United States, Ohio

Research Site

Vandalia, Ohio, United States, 45377

United States, Oklahoma

Research Site

Norman, Oklahoma, United States, 73069

United States, Pennsylvania

Research Site

Duncansville, Pennsylvania, United States, 16635

United States, Texas

Research Site

Baytown, Texas, United States, 77477

Research Site

Dallas, Texas, United States, 75231

Poland

Research Site

Nadarzyn, Mazowieckie, Poland

Research Site

Siedlce, Mazowieckie, Poland

Research Site

Krakow, Małopolskie, Poland

Research Site

Bialystok, Podlaskie, Poland

Research Site

Elblag, Warmińsko-mazurskie, Poland

Research Site

Poznan, Wielkopolskie, Poland

Research Site

Warszawa, Poland

Sponsors and Collaborators

Viela Bio (acquired by Horizon Therapeutics)

Investigators

• Study Director: Ilias Alevizos, PhD, DMD; Horizon Therapeutics

  Study Documents (Full-Text)

Documents provided by Viela Bio (acquired by Horizon Therapeutics):

Study Protocol  [PDF] October 2, 2020

Statistical Analysis Plan  [PDF] June 7, 2021

More Information

• Responsible Party: Viela Bio (acquired by Horizon Therapeutics)
• ClinicalTrials.gov Identifier: NCT04163991
• Other Study ID Numbers: VIB4920.P2.S3; 2019-003697-70 ( EudraCT Number )
• First Posted: November 15, 2019
• Results First Posted: February 14, 2023
• Last Update Posted: February 14, 2023
• Last Verified: January 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Viela Bio (acquired by Horizon Therapeutics):

Rheumatoid Arthritis; RA; VIB4920; MEDI4920

Additional relevant MeSH terms:

Arthritis; Arthritis, Rheumatoid; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases