A Phase 2 Efficacy and Safety Study of Dapirolizumab Pegol (DZP) in Systemic Lupus Erythematosus

Study Overview
=================
Brief Summary
-----------------
The purpose is to evaluate the efficacy and safety of three different doses of Dapirolizumab Pegol (DZP) versus placebo in adult subjects with moderately to severely active systemic Lupus Erythematosus.

Official Title
-----------------
A Multi-center, Randomized, Double-blind, Placebo-controlled, Parallel-group, Dose-ranging Study Followed by an Observational Period to Evaluate the Efficacy and Safety of Dapirolizumab Pegol in Subjects With Moderately to Severely Active Systemic Lupus Erythematosus

Conditions
-----------------
Systemic Lupus Erythematosus (SLE)

Intervention / Treatment
-----------------
* Drug: Placebo
* Drug: Dapirolizumab pegol (DZP)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Clinical diagnosis of Systemic Lupus Erythematosus (SLE) confirmed by Systemic Lupus International Collaborating Clinics (SLICC) classification criteria Moderate to severe SLE disease activity Evidence for at least 1 of the following SLE markers: Anti-dsDNA antibodies confirmed by central laboratory or Low complement confirmed by central laboratory or Antinuclear antibody (ANA) titer of >= 1:80 in combination with at least 1 of the following: Historical positivity for anti-dsDNA or Positivity for extractable nuclear antigen (anti-ENA) confirmed by central laboratory The subject is receiving stable SLE standard-of-care medication Exclusion Criteria: Mixed connective tissue disease, scleroderma, and/or overlap syndromes of SLE Subjects with severe neuropsychiatric SLE or other neurological symptoms that in the opinion of the Investigator, would prevent the subject from completing protocol required procedures and assessments. New or worsening Class III or IV lupus nephritis Chronic kidney failure stage 3b Evidence of human immunodeficiency virus (HIV) infection, agammaglobulinemias, T-cell deficiencies, or human T-cell lymphotropic virus-1 infection at any time prior to or during the study Clinically significant active or latent infection (eg. chronic viral hepatitis B or C) Known tuberculosis (TB) infection, at high risk of acquiring TB infection, or latent TB (LTB) infection Live/live attenuated vaccines within 6 weeks prior to the first study drug infusion (Visit 2) or who plan to receive these vaccines during the study or 12 weeks after the final dose of study drug History of thromboembolic events within 12 months of screening Subject has used protocol defined prohibited medications

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo in a specified sequence for a total of 24 weeks | Drug: Placebo<br>* Solution for infusion, 0,9% saline<br>|
| Experimental: DZP dose 1<br>Dapirolizumab pegol (DZP) dose 1 in a specified sequence for a total of 24 weeks | Drug: Dapirolizumab pegol (DZP)<br>* Solution for infusion<br>|
| Experimental: DZP dose 2<br>Dapirolizumab pegol (DZP) dose 2 in a specified sequence for a total of 24 weeks | Drug: Dapirolizumab pegol (DZP)<br>* Solution for infusion<br>|
| Experimental: DZP dose 3<br>Dapirolizumab pegol (DZP) dose 3 in a specified sequence for a total of 24 weeks | Drug: Dapirolizumab pegol (DZP)<br>* Solution for infusion<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With British Isles Lupus Assessment Group Disease Activity Index 2004 (BILAG 2004)-Based Composite Lupus Assessment (BICLA) (mNRI) Response Across 3 Doses of Dapirolizumab Pegol (DZP) and Placebo (PBO) at Week 24 | The primary efficacy variable was assessed by establishing if there was a dose response relationship between BICLA response at Week 24 and dose, using Multiple Comparison Procedure - Modelling (MCP-Mod). Four candidate dose-response models were evaluated: a linear model, a logistic model, and 2 Emax models, and the MCP-Mod methodology controlled for multiplicity. BICLA response was defined as meeting all of the following criteria: BILAG 2004 improvement: A scores at Baseline improved to B, C or D; B scores improved to C or D; no new A scores and ≤ 1 new B. No worsening in Systemic Lupus Erythematosus Activity Index 2000 (SLEDAI-2K), defined as no increase in SLEDAI-2K total score. No worsening in Physician's Global Assessment of Disease Activity (PGA), defined as < 10 millimeter (mm) increase on a 100 mm visual analog scale (VAS). No disallowed changes in concomitant medications, mainly including increases in corticosteroids, immunosuppressants, and antimalarials. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Percentage of Participants With BICLA (mNRI) Response in the Individual Dose Groups at Week 24 | BICLA response was defined as meeting all of the following criteria: BILAG 2004 improvement: A scores at Baseline improved to B, C or D; B scores improved to C or D; no new A scores and ≤ 1 new B. No worsening in Systemic Lupus Erythematosus Activity Index 2000 (SLEDAI-2K), defined as no increase in SLEDAI-2K total score. No worsening in Physician's Global Assessment of Disease Activity (PGA), defined as < 10 millimeter (mm) increase on a 100 mm visual analog scale (VAS). No disallowed changes in concomitant medications, mainly including increases in corticosteroids, immunosuppressants, and antimalarials. | Week 24 | 
| Percentage of Participants With at Least One Adverse Events (AEs) | An AE was any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product that did not necessarily have a causal relationship with this treatment. An adverse event (AE) was therefore any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. All AEs that occurred during the study were considered related unless clearly unrelated. | From Baseline (Week 1) until end of the study (Week 48) | 
| Percentage of Participants With a Serious Adverse Event (SAE) | A Serious Adverse Event (SAE) must have met 1 or more of the following criteria: Death Life threatening Significant or persistent disability/incapacity Congenital anomaly/birth defect (including that occurring in a fetus) Important medical event that, based upon appropriate medical judgment, may have jeopardized the study participant, and may have required medical or surgical intervention to prevent 1 of the other outcomes listed in the definition of serious Initial inpatient hospitalization or prolongation of hospitalization. | From Baseline (Week 1) until end of the study (Week 48) | 
| Percentage of Participants With at Least One Adverse Events (AEs) of Interest | Adverse events of interest (AEOI) were identified by the Investigator based on definitions per protocol, documented on the electronic Case Report Form (eCRF), adequately monitored, and source controlled. AEOI (regardless of seriousness): Moderate to severe infections, including opportunistic infections and tuberculosis (TB) Infusion reactions (including hypersensitivity and anaphylaxis) Thromboembolic events (including but not limited to cardiovascular events, stroke, myocardial infarction, pulmonary embolism, and deep vein thrombosis) Prespecified neurological events: severe and/or serious headache, positional headache, cranial nerve dysfunction, or signs and symptoms of meningitis (photophobia, neck stiffness) Malignancies. | From Baseline (Week 1) until end of the study (Week 48) | 
| Percentage of Participants Who Permanently Withdrew of Study Drug Due to an Adverse Event (AE) | An AE was any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product that did not necessarily have a causal relationship with this treatment. An adverse event (AE) was therefore any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. All AEs that occurred during the study were considered related unless clearly unrelated. | From Baseline (Week 1) until end of the study (Week 48) | 
| Mean Change From Baseline in Systolic Blood Pressure | Blood pressure was measured in millimetre of mercury (mmHg). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Diastolic Blood Pressure | Blood pressure was measured in millimetre of mercury (mmHg). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Pulse Rate | Pulse Rate was measured in beats per minute (beats/min). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Temperature | Temperature was measured in Grad Celsius (°C). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Weight | Weight was measured in kilograms (kg). | Baseline (Week 1), Week 4, Week 8, Week 12, Week 16, and Week 20 | 
| Mean Change From Baseline in Height | Height was measured in centimeters (cm). | From Baseline (Week 1) to Week 48 | 
| Number of Participants With 12-Lead Electrocardiogram (ECG) Abnormal Findings | Twelve-lead ECG assessments should have been performed prior to dosing (if applicable) and prior to obtaining pharmacokinetic (PK) or other laboratory samples. Electrocardiograms were recorded digitally and read by the Investigator for recording in the electronic Case Report Form (eCRF). | Screening, Week 4, Week 24, Week 28 and Week 48 | 
| Mean Change From Baseline in Hemoglobin | Hemoglobin was measured in grams per liter (g/L). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Hematocrit | Hematocrit was measured in volume percentage (%) of red blood cells in blood. | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Erythrocytes | Erythrocytes was measured in number of erythrocytes per liter (10^12/L). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Erythrocytes Mean Corpuscular Volume | Erythrocytes Mean Corpuscular Volume was measured in femtolitres (fL). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Erythrocytes Mean Corpuscular Hemoglobin (HGB) Concentration | Erythrocytes Mean Corpuscular Hemoglobin (HGB) Concentration was measured in grams per liter (g/L). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Erythrocytes Mean Corpuscular Hemoglobin | Erythrocytes Mean Corpuscular Hemoglobin was measured in picograms (pg). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Leukocytes | Leukocytes was measured in number of leukocytes per liter (10^9/L). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Basophils | Basophils was measured in number of basophils per liter (10^9/L). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Basophils/Leukocytes | Basophils/Leukocytes was measured in percentages (%). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Eosinophils | Eosinophils was measured in number of eosinophils per liter (10^9/L). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Eosinophils/Leukocytes | Eosinophils/Leukocytes was measured in percentages (%). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Lymphocytes | Lymphocytes was measured in number of lymphocytes per liter (10^9/L). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Lymphocytes/Leukocytes | Lymphocytes/Leukocytes was measured in percentages (%). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Monocytes | Monocytes was measured in number of monocytes per liter (10^9/L). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Monocytes/Leukocytes | Monocytes/Leukocytes was measured in percentages (%). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Neutrophils | Neutrophils was measured in number of neutrophils per liter (10^9/L). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Neutrophils/Leukocytes | Neutrophils/Leukocytes was measured in percentages (%). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Platelets | Platelets was measured in number of platelets per liter (10^9/L). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Cluster of Differentiation 3 (CD3) | Cluster of differentiation 3 (CD3) was measured in cells per microliter (cells/µL). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in CD3/Lymphocytes | CD3/Lymphocytes was measured in percentages (%). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Cluster of Differentiation 19 (CD19) | Cluster of differentiation 19 (CD19) was measured in cells per microliter (cells/µL). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in CD19/Lymphocytes | CD19/Lymphocytes was measured in percentages (%). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Aspartate Aminotransferase | Aspartate Aminotransferase was measured in units per liter (U/L). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Alanine Aminotransferase | Alanine Aminotransferase was measured in units per liter (U/L). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Alkaline Phosphatase | Alkaline Phosphatase was measured in units per liter (U/L). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Gamma Glutamyl Transferase | Gamma Glutamyl Transferase was measured in units per liter (U/L). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Bilirubin | Bilirubin was measured in micromols per liter (µmol/L). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Direct Bilirubin | Direct Bilirubin was measured in micromols per liter (µmol/L). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Lactate Dehydrogenase | Lactate Dehydrogenase was measured in units per liter (U/L). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Creatinine | Creatinine was measured in micromols per liter (µmol/L). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Urea Nitrogen | Urea Nitrogen was measured in millimoles per liter (mmol/L). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Sodium | Sodium was measured in millimoles per liter (mmol/L). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Potassium | Potassium was measured in millimoles per liter (mmol/L). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Calcium | Calcium was measured in millimoles per liter (mmol/L). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Phosphate | Phosphate was measured in millimoles per liter (mmol/L). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Cholesterol | Cholesterol was measured in millimoles per liter (mmol/L). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Triglycerides | Triglycerides was measured in millimoles per liter (mmol/L). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Protein | Protein was measured in grams per liter (g/L). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Albumin | Albumin was measured in grams per liter (g/L). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Glucose | Glucose was measured in millimoles per liter (mmol/L). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Lipase, Pancreatic | Lipase, Pancreatic was measured in units per liter (U/L). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Creatine Kinase | Creatine Kinase was measured in units per liter (U/L). | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in pH |  | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Erythrocytes (/HPF) |  | From Baseline (Week 1) to Week 48 | 
| Mean Change From Baseline in Leukocytes (/HPF) |  | From Baseline (Week 1) to Week 48 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Systemic Lupus Erythematosus (SLE), Dapirolizumab Pegol (DZP)