Safety and Efficacy of Daratumumab in Patients With Anti-Aquaporin 4 Antibody Positive Neuromyelitis Optica Spectrum Disorders (DAWN)

A Multi-center, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Safety and Efficacy of Daratumumab in Patients With Anti-Aquaporin 4 Antibody Positive Neuromyelitis Optica Spectrum Disorders (NMOSD)

The objectives of this time-to-event study were to assess the efficacy and safety of Daratumumab as compared with placebo in participants with neuromyelitis optica spectrum disorder (NMOSD) who were anti-aquaporin-4 (AQP4) antibody-positive. NMOSD is an autoimmune disease of the central nervous system that predominantly affects the spinal cord, optic nerves, and area postrema. It is usually mediated by the pathogenic AQP4-IgG. Antibody-secreting cells (ASCs) have been recognized as essential sources of AQP4-IgG. CD38 is a glycoprotein that is highly expressed on ASCs. Daratumumab, a CD38-directed monoclonal antibody, has been shown to decrease the levels of autoantibodies in lupus, myasthenia gravis, or autoimmune encephalitis. This randomized controlled study aims to evaluate the therapeutic potential of daratumumab in NMOSD.

Study Overview

• Status: Recruiting
• Conditions: Neuromyelitis Optica; Neuromyelitis Optica Spectrum Disorder; NMO Spectrum Disorder
• Intervention / Treatment: Drug: Daratumumab; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 72
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Fu-Dong Shi, M.D., Ph.D.; Phone Number: +8602260814587; Email: fshi@tmu.edu.cn
• Study Contact Backup: Name: Chao Zhang, M.D., Ph.D.; Email: chaozhang@tmu.edu.cn

Study Locations

• China
  • Tianjin
    • Tianjin, Tianjin, China, 300052
      • Recruiting
      • Tianjin Medical University General Hospital
      • Contact: Chao Zhang, M.D., Ph.D.
      • Contact: Fu-Dong Shi, M.D., Ph.D.
      • Principal Investigator: Fu-Dong Shi, M.D., Ph.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male or female participants ≥ 18 years old.
2. Diagnosis of NMO or NMOSD.
3. Anti-AQP4 antibody seropositive.
4. Historical relapse of at least 1 relapses in the last 12 months or 2 relapses in the last 24 months with at least 1 relapse in the 12 months prior to the screening.
5. Expanded Disability Status Scale score ≤ 7.5.
6. Patients must give written informed consent.

Exclusion Criteria:

1. Use of intravenous steroid pulse therapy or intravenous immunoglobulin or plasma exchange/adsorption within 3 weeks prior to Screening.
2. Use of tocilizumab, satralizumab, belimumab, ofatumumab within 1 months prior to Screening.
3. Patients treated with oral immunosuppressive agents other than steroids (e.g. azathioprine, mycophenolate mofetil, methotrexate, tacrolimus, cyclosporine in the 3 months prior to allocation.
4. Use of rituximab or inebilizumab within 6 months prior to Screening.
5. Patients infected with hepatitis B or C virus, or human immunodeficiency virus, or those having active infectious diseases.
6. Patients with a severe chronic infection or a history of recurrent infections.
7. Patients with a history of radiation treatment (whole body irradiation or lymphoid irradiation) or stem cell transplantation.
8. Patients who are pregnant or breast-feeding.
9. Patients who are participating in other clinical trials for NMOSD.
10. Patients diagnosed with cancer.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Daratumumab; Induction Period: Participants received daratumumab (8mg/kg) via intravenous (IV) every 2 weeks for two cycles. This was followed by the Maintenance Period: Participants received daratumumab (4mg/kg) via IV infusion every 4 weeks from the third dose (Week 4) onwards.	Drug: Daratumumab; Induction Phase: (8mg/kg) via intravenous (IV) evey 2 weeks for two cycles. Maintenance Phase: (4mg/kg) IV every 4 weeks.; Other Names: Darzalex
Placebo Comparator: Placebo; Placebo contains the same buffer components without the active ingredient. Induction Period: Participants received matching placebo (8mg/kg) via intravenous (IV) every 2 weeks for two cycles. This was followed by the Maintenance Period: Participants received matching placebo (4mg/kg) via IV infusion every 4 weeks from the third dose (Week 4) onwards.	Drug: Placebo; Induction Phase: matching placebo (8mg/kg) via intravenous (IV) every 2 weeks for two cycles; Maintenance Phase: matching placebo (4mg/kg) IV every 4 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Participants With An Adjudicated On-trial Relapse	An On-trial Relapse was defined as a new onset of neurologic symptoms or worsening of existing neurologic symptoms with an objective change (clinical sign) on neurologic examination that persisted for more than 24 hours as confirmed by the treating physician. An adjudicated On-trial Relapse was defined by the protocol and positively adjudicated by the relapse adjudication committee.	Baseline, Up To 52 Weeks (End of Study)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adjudicated On-trial Annualized Relapse Rate (ARR)	The adjudicated On-trial ARR was computed as the total number of relapses divided by the total number of patient years in the study period. A central independent committee was used to adjudicate all On-trial Relapses as determined by the treating physician. Results reported as adjusted adjudicated On-trial ARR based on a Poisson regression adjusted for randomization strata and historical ARR in 24 months prior to Screening.	Baseline, Up To 52 Weeks (End of Study)
Percentage of Participants With Worsening in Expanded Disability Severity Scale (EDSS) Score From Baseline to the end of study	Disease-related disability was measured by the EDSS. The EDSS was an ordinal clinical rating scale that ranges from 0 (normal neurologic examination) to 10 (death) in half-point increments. A decrease in score indicates improvement.	Baseline, Up To 52 Weeks (End of Study)
Change From Baseline in Best Corrected Binocular Visual Acuity to the end of study	Best corrected binocular visual acuity was measure with Early Treatment Diabetic Retinopathy Study (ETDRS) chart held at a distance of 2.52 meters.	Baseline, Up To 52 Weeks (End of Study)
Change From Baseline in Low-Contrast Visual Acuity Binocular Score to the end of study	Low-contrast visual acuity test was used to determine the number of letters that can be read on a standardized low-contrast retro-illuminated 2.5% Sloan letter chart held at a distance of 2.52 meters. Binocular score was the number of letters read correctly on the chart using both eyes simultaneously. The total score ranges from 0-70. Higher score indicates better vision.	Baseline, Up To 52 Weeks (End of Study)
Blood AQP4-IgG Concentration Over Time	Blood AQP4-IgG Concentration was measured by Cell-Based Assay (CBA).	Baseline, Weeks 2, 4, 8, 12, 24, 48
Percentage of Blood Antibody-Secreting Cells (ASCs) Over Time	Percentage of Blood ASCs was measured by flow cytometry.	Baseline, Weeks 2, 4, 8, 12, 24, 48
Percentage of Blood Neurofilament Light Chain (NFL) Over Time	Percentage of Blood NFL was measured with Simoa (Single-molecule array).	Baseline, Weeks 2, 4, 8, 12, 24, 48
Percentage of Blood Glial Fibrillary Acidic Protein (GFAP) Over Time	Percentage of Blood GFAP was measured with Simoa (Single-molecule array).	Baseline, Weeks 2, 4, 8, 12, 24, 48
Change From Baseline In Modified Rankin Scale (mRS) Score At End Of Study	Disease-related disability was measured by the mRS score. The mRS is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered from a neurological disability. The scale ranges from 0 (no disability) to 6 (death) in whole-point increments. A decrease in score indicates improvement.	Baseline, Up To 52 Weeks (End of Study)
Change From Baseline In Hauser Ambulation Index (HAI) Score At End of Study	The HAI was used to evaluate gait and assess the time and effort used by the participant to walk 25 feet (8 meters). The scale ranges from 0 to 9, with 0 being the best score (asymptomatic; fully ambulatory with no assistance) and 9 being the worst (restricted to wheel chair; unable to transfer self independently). A decrease in score indicates improvement.	Baseline, Up To 52 Weeks (End of Study)
Change From Baseline In European Quality Of Life (EuroQoL) Health 5-Dimension Questionnaire (EQ-5D) Visual Analogue Scale At End Of Study	The EuroQoL EQ-5D was a generic, standardized, self-administered instrument that provides a simple, descriptive profile and a single index value for health status. Assessments were made using the EQ-5D Visual Analogue Scale, which captures the self-rating of current health status using a visual "thermometer" with the endpoints of 100 (best imaginable health state) at the top and zero (worst imaginable health state) at the bottom. An increase in score indicates improvement.	Baseline, Up To 52 Weeks (End of Study)
Change From Baseline In EuroQoL EQ-5D Index Score At End Of Study	The EuroQoL EQ-5D was a generic, standardized, self-administered instrument that provides a simple, descriptive profile and a single index value for health status. Index scores range from less than 0 to 1, with higher scores representing a better health status.	Baseline, Up To 52 Weeks (End of Study)
Change From Baseline in Speed of Timed 25-Foot Walk (T25W) at 24 Week Intervals During the DB Period	The T25W was an assessment of walking ability. The time (in seconds) that the participant took to walk 25 feet was measured. Speed is calculated as 1/Timed 25-Foot Walk where time is measured in seconds. A positive change from baseline indicates an improvement.	Baseline, Up To 52 Weeks (End of Study)
Number of Participants With Adverse Events (AEs)	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship.	Baseline, Up To 52 Weeks (End of Study)
Number of Participants With Adverse Events Serious Adverse Events (SAEs)	A SAE was any AE that resulted in death, life threatening, inpatient hospitalization or prolongation of existing hospitalization	Baseline, Up To 52 Weeks (End of Study)

Collaborators and Investigators

• Sponsor: Tianjin Medical University General Hospital

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2022
• Primary Completion (Estimated): August 1, 2024
• Study Completion (Estimated): October 1, 2024

Study Registration Dates

• First Submitted: May 30, 2022
• First Submitted That Met QC Criteria: May 30, 2022
• First Posted (Actual): June 3, 2022

Study Record Updates

• Last Update Posted (Actual): June 27, 2023
• Last Update Submitted That Met QC Criteria: June 24, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Eye Diseases; Optic Nerve Diseases; Cranial Nerve Diseases; Myelitis, Transverse; Optic Neuritis; Neuromyelitis Optica; Antineoplastic Agents; Daratumumab
• Other Study ID Numbers: 2022023

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No