Back to resultsSafety and Efficacy of Daratumumab in Patients With Anti-Aquaporin 4 Antibody Positive Neuromyelitis Optica Spectrum Disorders (DAWN)
Primary Purpose
Neuromyelitis Optica, Neuromyelitis Optica Spectrum Disorder, NMO Spectrum Disorder
Status
Recruiting
Phase
Phase 2
Locations
China
Study Type
Interventional
Intervention
Daratumumab
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Neuromyelitis Optica
Eligibility Criteria
Inclusion Criteria:
- Male or female participants ≥ 18 years old.
- Diagnosis of NMO or NMOSD.
- Anti-AQP4 antibody seropositive.
- 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.
- Expanded Disability Status Scale score ≤ 7.5.
- Patients must give written informed consent.
Exclusion Criteria:
- Use of intravenous steroid pulse therapy or intravenous immunoglobulin or plasma exchange/adsorption within 3 weeks prior to Screening.
- Use of tocilizumab, satralizumab, belimumab, ofatumumab within 1 months prior to Screening.
- Patients treated with oral immunosuppressive agents other than steroids (e.g. azathioprine, mycophenolate mofetil, methotrexate, tacrolimus, cyclosporine in the 3 months prior to allocation.
- Use of rituximab or inebilizumab within 6 months prior to Screening.
- Patients infected with hepatitis B or C virus, or human immunodeficiency virus, or those having active infectious diseases.
- Patients with a severe chronic infection or a history of recurrent infections.
- Patients with a history of radiation treatment (whole body irradiation or lymphoid irradiation) or stem cell transplantation.
- Patients who are pregnant or breast-feeding.
- Patients who are participating in other clinical trials for NMOSD.
- Patients diagnosed with cancer.
Sites / Locations
- Tianjin Medical University General HospitalRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Daratumumab
Placebo
Arm Description
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.
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.
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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.
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.
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.
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.
Blood AQP4-IgG Concentration Over Time
Blood AQP4-IgG Concentration was measured by Cell-Based Assay (CBA).
Percentage of Blood Antibody-Secreting Cells (ASCs) Over Time
Percentage of Blood ASCs was measured by flow cytometry.
Percentage of Blood Neurofilament Light Chain (NFL) Over Time
Percentage of Blood NFL was measured with Simoa (Single-molecule array).
Percentage of Blood Glial Fibrillary Acidic Protein (GFAP) Over Time
Percentage of Blood GFAP was measured with Simoa (Single-molecule array).
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.
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.
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.
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.
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.
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.
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
Full Information
NCT ID
NCT05403138
First Posted
May 30, 2022
Last Updated
June 24, 2023
Sponsor
Tianjin Medical University General Hospital
1. Study Identification
Unique Protocol Identification Number
NCT05403138
Brief Title
Safety and Efficacy of Daratumumab in Patients With Anti-Aquaporin 4 Antibody Positive Neuromyelitis Optica Spectrum Disorders
Acronym
DAWN
Official Title
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)
Study Type
Interventional
2. Study Status
Record Verification Date
June 2023
Overall Recruitment Status
Recruiting
Study Start Date
November 1, 2022 (Actual)
Primary Completion Date
August 1, 2024 (Anticipated)
Study Completion Date
October 1, 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Tianjin Medical University General Hospital
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
5. Study Description
Brief Summary
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Neuromyelitis Optica, Neuromyelitis Optica Spectrum Disorder, NMO Spectrum Disorder
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
72 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Daratumumab
Arm Type
Experimental
Arm Description
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.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Daratumumab
Other Intervention Name(s)
Darzalex
Intervention Description
Induction Phase: (8mg/kg) via intravenous (IV) evey 2 weeks for two cycles. Maintenance Phase: (4mg/kg) IV every 4 weeks.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
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.
Primary Outcome Measure Information:
Title
Participants With An Adjudicated On-trial Relapse
Description
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.
Time Frame
Baseline, Up To 52 Weeks (End of Study)
Secondary Outcome Measure Information:
Title
Adjudicated On-trial Annualized Relapse Rate (ARR)
Description
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.
Time Frame
Baseline, Up To 52 Weeks (End of Study)
Title
Percentage of Participants With Worsening in Expanded Disability Severity Scale (EDSS) Score From Baseline to the end of study
Description
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.
Time Frame
Baseline, Up To 52 Weeks (End of Study)
Title
Change From Baseline in Best Corrected Binocular Visual Acuity to the end of study
Description
Best corrected binocular visual acuity was measure with Early Treatment Diabetic Retinopathy Study (ETDRS) chart held at a distance of 2.52 meters.
Time Frame
Baseline, Up To 52 Weeks (End of Study)
Title
Change From Baseline in Low-Contrast Visual Acuity Binocular Score to the end of study
Description
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.
Time Frame
Baseline, Up To 52 Weeks (End of Study)
Title
Blood AQP4-IgG Concentration Over Time
Description
Blood AQP4-IgG Concentration was measured by Cell-Based Assay (CBA).
Time Frame
Baseline, Weeks 2, 4, 8, 12, 24, 48
Title
Percentage of Blood Antibody-Secreting Cells (ASCs) Over Time
Description
Percentage of Blood ASCs was measured by flow cytometry.
Time Frame
Baseline, Weeks 2, 4, 8, 12, 24, 48
Title
Percentage of Blood Neurofilament Light Chain (NFL) Over Time
Description
Percentage of Blood NFL was measured with Simoa (Single-molecule array).
Time Frame
Baseline, Weeks 2, 4, 8, 12, 24, 48
Title
Percentage of Blood Glial Fibrillary Acidic Protein (GFAP) Over Time
Description
Percentage of Blood GFAP was measured with Simoa (Single-molecule array).
Time Frame
Baseline, Weeks 2, 4, 8, 12, 24, 48
Title
Change From Baseline In Modified Rankin Scale (mRS) Score At End Of Study
Description
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.
Time Frame
Baseline, Up To 52 Weeks (End of Study)
Title
Change From Baseline In Hauser Ambulation Index (HAI) Score At End of Study
Description
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.
Time Frame
Baseline, Up To 52 Weeks (End of Study)
Title
Change From Baseline In European Quality Of Life (EuroQoL) Health 5-Dimension Questionnaire (EQ-5D) Visual Analogue Scale At End Of Study
Description
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.
Time Frame
Baseline, Up To 52 Weeks (End of Study)
Title
Change From Baseline In EuroQoL EQ-5D Index Score At End Of Study
Description
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.
Time Frame
Baseline, Up To 52 Weeks (End of Study)
Title
Change From Baseline in Speed of Timed 25-Foot Walk (T25W) at 24 Week Intervals During the DB Period
Description
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.
Time Frame
Baseline, Up To 52 Weeks (End of Study)
Title
Number of Participants With Adverse Events (AEs)
Description
An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship.
Time Frame
Baseline, Up To 52 Weeks (End of Study)
Title
Number of Participants With Adverse Events Serious Adverse Events (SAEs)
Description
A SAE was any AE that resulted in death, life threatening, inpatient hospitalization or prolongation of existing hospitalization
Time Frame
Baseline, Up To 52 Weeks (End of Study)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Male or female participants ≥ 18 years old.
Diagnosis of NMO or NMOSD.
Anti-AQP4 antibody seropositive.
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.
Expanded Disability Status Scale score ≤ 7.5.
Patients must give written informed consent.
Exclusion Criteria:
Use of intravenous steroid pulse therapy or intravenous immunoglobulin or plasma exchange/adsorption within 3 weeks prior to Screening.
Use of tocilizumab, satralizumab, belimumab, ofatumumab within 1 months prior to Screening.
Patients treated with oral immunosuppressive agents other than steroids (e.g. azathioprine, mycophenolate mofetil, methotrexate, tacrolimus, cyclosporine in the 3 months prior to allocation.
Use of rituximab or inebilizumab within 6 months prior to Screening.
Patients infected with hepatitis B or C virus, or human immunodeficiency virus, or those having active infectious diseases.
Patients with a severe chronic infection or a history of recurrent infections.
Patients with a history of radiation treatment (whole body irradiation or lymphoid irradiation) or stem cell transplantation.
Patients who are pregnant or breast-feeding.
Patients who are participating in other clinical trials for NMOSD.
Patients diagnosed with cancer.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Fu-Dong Shi, M.D., Ph.D.
Phone
+8602260814587
Email
fshi@tmu.edu.cn
First Name & Middle Initial & Last Name or Official Title & Degree
Chao Zhang, M.D., Ph.D.
Email
chaozhang@tmu.edu.cn
Facility Information:
Facility Name
Tianjin Medical University General Hospital
City
Tianjin
State/Province
Tianjin
ZIP/Postal Code
300052
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Fu-Dong Shi, M.D., Ph.D.
First Name & Middle Initial & Last Name & Degree
Chao Zhang, M.D., Ph.D.
First Name & Middle Initial & Last Name & Degree
Fu-Dong Shi, M.D., Ph.D.
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Safety and Efficacy of Daratumumab in Patients With Anti-Aquaporin 4 Antibody Positive Neuromyelitis Optica Spectrum Disorders
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