A Phase II Study to Evaluate Safety and Efficacy of ALX-0061 in Subjects With Systemic Lupus Erythematosus

Study Overview
=================
Brief Summary
-----------------
Primary objective: To assess the efficacy and safety of different dose regimens of ALX-0061 administered subcutaneously (s.c.) to subjects with moderate to severe active, seropositive systemic lupus erythematosus (SLE) compared to placebo. Secondary objectives: To assess the pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, flare rate, steroid reduction and health-related quality of life, with different dose regimens of ALX-0061.

Official Title
-----------------
A Phase II Multicenter, Randomized, Double-blind, Placebo Controlled, Dose-range Finding Study to Evaluate the Safety and Efficacy of ALX-0061 Administered Subcutaneously in Subjects With Moderate to Severe Active Systemic Lupus Erythematosus

Conditions
-----------------
Lupus Erythematosus, Systemic

Intervention / Treatment
-----------------
* Biological: ALX-0061
* Biological: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Man or woman ≥ 18 years and < 65 years of age Have a diagnosis of SLE for at least 6 months prior to screening and fulfill the 1997 American College of Rheumatology (ACR) or 2012 Systemic Lupus International Collaborating Clinics (SLICC) classification criteria Have moderate to severe active SLE Have seropositive disease at screening Subject must be at least on one or more of the treatments for SLE as listed in the protocol Others as defined in the protocol Exclusion Criteria: Have an A score on the revised BILAG-2004 other than in the mucocutaneous and/or musculoskeletal system at screening and at baseline for the organ systems that can be clinically assessed Have a systemic inflammatory disease other than SLE Clinically significant infection treated or needing treatment Any active or recurrent viral infection that based on the Investigator´s clinical assessment makes the subject unsuitable for the study Have received prior therapy blocking the interleukin-6 (IL-6) pathway Others as defined in the protocol

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 64 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>Two s.c. injections with placebo every 2 weeks (q2w). *** Placebo was supplied as a sterile liquid for s.c. injection at a volume of 0.5 mL and 1.0 mL in pre-filled single-use syringes. To maintain the blind, subjects randomly assigned to the placebo group received 2 s.c. injections q2w: Syringe A with placebo (1 mL) q2w starting at Day 1, up to and including Week 46. Syringe B with placebo (0.5 mL) q2w starting at Day 1, up to and including Week 46. | Biological: Placebo<br> <br> |
| Experimental: ALX-0061 75 mg q4w<br>ALX-0061 75 mg every 4 weeks (q4w). *** Vobarilizumab (ALX-0061) and placebo were supplied as a sterile liquid for s.c. injection at a volume of 0.5 mL and 1.0 mL in pre-filled single-use syringes. To maintain the blind, subjects randomly assigned to ALX-0061 75 mg q4w received 2 s.c. injections q2w: Syringe A with placebo (1 mL) q2w starting at Day 1, up to and including Week 46. Syringe B with ALX-0061 (0.5 mL) q4w at Day 1, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44, and syringe B with placebo (0.5 mL) q4w at Weeks 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, and 46. | Biological: ALX-0061<br> <br> Biological: Placebo<br> <br> |
| Experimental: ALX-0061 150 mg q4w<br>ALX-0061 150 mg every 4 weeks (q4w). *** Vobarilizumab (ALX-0061) and placebo were supplied as a sterile liquid for s.c. injection at a volume of 0.5 mL and 1.0 mL in pre-filled single-use syringes. To maintain the blind, subjects randomly assigned to ALX-0061 150 mg q4w received 2 s.c. injections q2w: Syringe A with ALX-0061 (1 mL) q4w at Day 1, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44, and syringe A with placebo (1 mL) q4w at Weeks 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, and 46. Syringe B with placebo (0.5 mL) q2w starting at Day 1, up to and including Week 46. | Biological: ALX-0061<br> <br> Biological: Placebo<br> <br> |
| Experimental: ALX-0061 150 mg q2w<br>ALX-0061 150 mg every 2 weeks (q2w). *** Vobarilizumab (ALX-0061) and placebo were supplied as a sterile liquid for s.c. injection at a volume of 0.5 mL and 1.0 mL in pre-filled single-use syringes. To maintain the blind, subjects randomly assigned to ALX-0061 150 mg q2w received 2 s.c. injections q2w: Syringe A with ALX-0061 (1 mL) q2w starting at Day 1, up to and including Week 46. Syringe B with placebo (0.5 mL) q2w starting at Day 1, up to and including Week 46. | Biological: ALX-0061<br> <br> Biological: Placebo<br> <br> |
| Experimental: ALX-0061 225 mg q2w<br>ALX-0061 225 mg every 2 weeks (q2w). *** Vobarilizumab (ALX-0061) was supplied as a sterile liquid for s.c. injection at a volume of 0.5 mL and 1.0 mL in pre-filled single-use syringes. To maintain the blind, subjects randomly assigned to ALX-0061 225 mg q2w received 2 s.c. injections q2w: Syringe A with ALX-0061 (1 mL) q2w starting at Day 1, up to and including Week 46. Syringe B with ALX-0061 (0.5 mL) q2w starting at Day 1, up to and including Week 46. | Biological: ALX-0061<br> <br> |

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and Percentage of Subjects Who Achieved a Response at Week 24 According to the Modified British Isles Lupus Assessment Group (BILAG)-Based Composite Lupus Assessment (mBICLA) Score | The primary endpoint was evaluated by determining if there was a dose-response relationship between the mBICLA response rate at Week 24 and the dose administered, using the Multiple Comparison Procedure - Modelling (MCP-Mod) methodology. The existence of several candidate parametric models was assumed and multiple comparison techniques were used to choose the model(s) most likely to represent the true underlying dose-response curve. The selected model could further be used to guide the choice of adequate doses. mBICLA responders were defined as subjects who met all of the following criteria: BILAG-2004 normal improvement: all A scores at Baseline improved to B, C or D, and all B scores improved to C or D. No worsening in disease activity: no new BILAG-2004 A scores and ≤ 1 new increase to B. No worsening of total mSLEDAI-2K score from Baseline. No significant deterioration (< 10% worsening from Baseline) in PGA. No treatment failure (including the premature | At Week 24 visit | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and Percentage of Subjects With mBICLA Response at Week 24 and Week 48 | Number and percentage of mBICLA responders at Week 24 and Week 48 | At Week 24 and Week 48 | 
| Number and Percentage of Subjects With Modified Systemic Lupus Erythematosus Responder Index (mSRI-4) Response at Week 24 and Week 48 | The composite index mSRI-4 enables quantification of decrease and increase in disease activity in a broad spectrum of manifestations thereby offering a comprehensive assessment of SLE disease status. mSRI combines advantages from 3 validated measurement tools. The mSRI-4 criteria for response are: modified SLE disease activity index 2000 (mSLEDAI-2K): ≥ 4 point reduction (covers global disease improvement), British Isles Lupus Assessment Group 2004 (BILAG-2004): no new A domain score and no more than 1 new increase to B (covers organ-specific disease improvement), Physician's Global Assessment (PGA) (is used as validity and safety net for items that were not addressed by the other two indices): < 10% increase from Baseline (no worsening) When all 3 criteria are met, the subject is a mSRI-4 responder at that time point. Subjects who were treatment failures or discontinued from treatment were considered non-responder after treatment failure/discontinuation. | At Week 24 and Week 48 | 
| Number and Percentage of Subjects With mSRI-5 Response at Week 24 and Week 48 | The mSRI-5 criteria for response are: mSLEDAI-2K: ≥ 5 point reduction BILAG-2004: no new A domain score and no more than 1 new increase to B domain score PGA: no worsening (< 10% increase from Baseline) Only subjects with Baseline mSLEDAI-2K ≥ 5 were considered for the derivation of that endpoint. Subjects who were treatment failures or discontinued from treatment were considered non-responder after treatment failure/discontinuation. | At Week 24 and Week 48 | 
| Number and Percentage of Subjects With mSRI-6 Response at Week 24 and Week 48 | The mSRI-6 criteria for response are: mSLEDAI-2K: ≥ 6 point reduction BILAG-2004: no new A domain score and no more than 1 new increase to B domain score PGA: no worsening (< 10% increase from Baseline) Only subjects with Baseline mSLEDAI-2K ≥ 6 were considered for the derivation of that endpoint. Subjects who were treatment failures or discontinued from treatment were considered non-responder after treatment failure/discontinuation | At Week 24 and Week 48 | 
| Number and Percentage of Subjects With mSRI-7 Response at Week 24 and Week 48 | The mSRI-7 criteria for response are: mSLEDAI-2K: ≥ 7 point reduction BILAG-2004: no new A domain score and no more than 1 new increase to B domain score PGA: no worsening (< 10% increase from Baseline) Only subjects with Baseline mSLEDAI-2K ≥ 7 were considered for the derivation of that endpoint. Subjects who were treatment failures or discontinued from treatment were considered non-responder after treatment failure/discontinuation. | At Week 24 and Week 48 | 
| Number and Percentage of Subjects With mSRI-8 Response at Week 24 and Week 48. | The mSRI-8 criteria for response are: mSLEDAI-2K: ≥ 8 point reduction BILAG-2004: no new A domain score and no more than 1 new increase to B domain score PGA: no worsening (< 10% increase from Baseline) Only subjects with Baseline mSLEDAI-2K ≥ 8 were considered for the derivation of that endpoint. Subjects who were treatment failures or discontinued from treatment were considered non-responder after treatment failure/discontinuation. | At Week 24 and Week 48 | 
| Change From Baseline in Modified Systemic Lupus Erythematosus Disease Activity Index 2000 (mSLEDAI-2K) Score at Week 24 and Week 48 | The Systemic Lupus Erythematosus Disease Activity Index 2000 is a 1-page weighted score for 24 items (seizure, psychosis, organic brain syndrome, visual disturbance, cranial nerve disorder, lupus headache, cerebrovascular accident, vasculitis, arthritis, myositis, urinary casts, hematuria, proteinuria, pyuria, rash, alopecia, mucosal ulcers, pleurisy, pericarditis, low complement, etc). The manifestations felt to be most commonly contributing to disease activity are included and scored based on the presence (= 1 multiplied by weight) or absence (= 0) within 30 days prior to the evaluation. The total score ranges from 0-105 (= sum of individual scores), with 105 being higher disease activity. mSLEDAI-2K derives from the standard index by omitting low complement. Mean changes from baseline were derived from an ANCOVA model with treatment as factor and baseline mSLEDAI-2K Score and geographic region as covariates. A negative change from baseline reflects an improvement. | At Week 24 and Week 48 | 
| Number and Percentage of Subjects With BILAG-2004 Normal Improvement at Week 24 and Week 48 | Normal Improvement: all A scores at baseline improved to B/C/D, and all B scores improved to C or D. Only subjects with non-missing BILAG-2004 who had at least one A or B score at Baseline were assessed for this endpoint | At Week 24 and Week 48 | 
| Number and Percentage of Subjects With BILAG-2004 Enhanced Improvement at Week 24 and Week 48 | Enhanced improvement: all A scores at baseline improved to B/C/D, and all B scores improved to C or D and no worsening between consecutive visits from baseline up to the considered visit Only subjects with non-missing BILAG-2004 who had at least one A or B score at Baseline were assessed for this endpoint | At Week 24 and Week 48 | 
| BILAG-2004 Total Score at Baseline, Week 24 and Week 48 | The British Isles Lupus Assessment Group 2004 (BILAG-2004) is a comprehensive composite clinical index that has been developed based on the principle of a physician's intention to treat using a nominal consensus approach. In the index, the nine systems (not organs) considered are: constitutional, mucocutaneous, neuropsychiatric, musculoskeletal, cardiorespiratory, gastrointestinal, renal, ophthalmic and hematological. Disease activity in each of the nine systems is categorized into five levels: grades A (= severe disease activity requiring systemic high dose oral corticosteroids, i.v. pulse corticosteroids, etc.) to E (= system never involved). BILAG total score is derived by assigning the following value to each grade and summing the sores over all organ systems: A = 12, B = 8, C = 1, D/E = 0. The total score ranges from 0-108, with 108 representing high disease activity in all 9 systems requiring high doses of corticosteroids, starting/increasing immunosuppressive drugs, etc. | At Baseline, Week 24 and Week 48 | 
| Number and Percentage of Subjects With BILAG-2004 Normal Improvement in Mucocutaneous System at Week 24 and Week 48 | An improvement is defined as an A score at Baseline improved to B/C/D, or a B score improved to C or D. Only subjects with non-missing BILAG-2004 who had at least one A or B score at Baseline were assessed for this endpoint | At Week 24 and Week 48 | 
| Number and Percentage of Subjects With BILAG-2004 Normal Improvement in Musculoskeletal System at Week 24 and Week 48 | An improvement is defined as an A score at Baseline improved to B/C/D, or a B score improved to C or D. Only subjects with non-missing BILAG-2004 who had at least one A or B score at Baseline were assessed for this endpoint | At Week 24 and Week 48 | 
| Number and Percentage of Subjects With Persistent Minimal or no Activity in 9 Organ Systems According to BILAG-2004 Systems Tally at Week 24 and Week 48 |  | At Week 24 and Week 48 | 
| Change From Baseline in Physician's Global Assessment (PGA) at Week 24 and Week 48 | The physician makes a mark between 0 (no disease) and 100 mm (severe disease) on the visual analogue scale (VAS) to indicate disease activity (independent of the subject's self-assessment). Mean changes from baseline were derived from an analysis of covariance (ANCOVA) model with treatment as factor and baseline PGA score and geographic region as covariates. A negative change from baseline reflects an improvement. | At Week 24 and Week 48 | 
| Change From Baseline in Patient's Global Assessment at Week 24 and Week 48 | The subject makes a mark between 0 (very good) and 100 mm (very bad) on the VAS to indicate how the subject is doing, while considering all the ways SLE affects him/her. Mean changes from baseline were derived from an analysis of covariance (ANCOVA) model with treatment as factor and baseline Patient's Global Assessment and geographic region as covariates. A negative change from baseline reflects an improvement. | At Week 24 and Week 48 | 
| Change From Baseline in Proteinuria at Week 24 and Week 48 | Mean changes from baseline were derived from an analysis of covariance (ANCOVA) model with treatment as factor and baseline proteinuria and geographic region as covariates | At Week 24 and Week 48 | 
| Number of Subjects Who Were Treatment-emergent Urine Sediment Positive at Week 24 and Week 48 | Efficacy Laboratory Parameters (Urinalysis) - Active Urine Sediment Number of subjects who were urine sediment negative at Baseline, but positive at Week 24 and Week 48, respectively. | At Week 24 and Week 48 | 
| Change From Baseline in Serum Creatinine at Week 24 and Week 48 | Mean changes from baseline were derived from an analysis of covariance (ANCOVA) model with treatment as factor and baseline serum creatinine and geographic region as covariates | At Week 24 and Week 48 | 
| Change From Baseline in Creatinine Clearance Estimation (eGFR) at Week 24 and Week 48 | Mean changes from baseline were derived from an analysis of covariance (ANCOVA) model with treatment as factor and baseline eGFR and geographic region as covariates | At Week 24 and Week 48 | 
| Number of and Percentage Treatment Failures From Baseline to Week 24 and Week 48 | Defined as non-protocol allowed increase in steroid dose, start i.v. or i.m. steroids, or start or increase of immunosuppressant | From Baseline to Week 24 and Week 48 | 
| Number and Percentage of Subjects Experiencing Severe Flares According to BILAG-2004 Flare Index From Baseline to Week 24 and Week 48 |  | From Baseline to Week 24 and Week 48 | 
| Number and Percentage of Subjects Experiencing Severe Flares According to mSLEDAI-2K Flare Index (mSFI) From Baseline to Week 24 and Week 48 |  | From Baseline to Week 24 and Week 48 | 
| Percent Change From Baseline in Daily Dose of Steroids at Week 24 and Week 48 | Mean changes from baseline were derived from an analysis of covariance (ANCOVA) model with treatment as factor and baseline prednisone equivalent total daily dose and geographic region as covariates | At Week 24 and Week 48 | 
| Number and Percentage of Subjects Whose Daily Dose of Steroids Was Reduced Without Severe Flares During Weeks 40-48 | Number and percentage of subjects whose prednisone equivalent dose was >7.5 mg/day at baseline and reduced to ≤7.5 mg/day during Weeks 40-48 without experiencing a BILAG-2004-defined or mSFI-defined severe flare after the first prednisone equivalent dose decrease. | Between Week 40 and Week 48 | 
| Number and Percentage of Subjects Who Discontinued Prednisone (or Equivalent) by Week 48 Without Experiencing a Severe Flare | Number and percentage of subjects who discontinued Prednisone (or equivalent) by Week 48 without experiencing a BILAG-2004-defined or mSFI-defined severe flare | Up to and including Week 48 | 
| Change From Baseline in Physical Component Scores of Short Form (36) Health Survey (SF-36) at Week 24 and Week 48 | The Short Form (36) Health Survey (SF-36) consists of 36 items that can be summarized into 8 domains: physical functioning, role limitations due to physical health problems (role-physical), bodily pain, general health, vitality, social functioning, role limitations due to emotional problems (role-emotional), and mental health. Two summary measures, the physical component summary and the mental component summary, can be derived based on these domain scores. Each score is directly transformed into a 0-100 score on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability. Mean changes from baseline were derived from an analysis of covariance (ANCOVA) model with treatment as factor and baseline SF-36 Score and geographic region as covariates. A positive change denotes an improvement. | At Week 24 and Week 48 | 
| Change From Baseline in Mental Component Scores of SF-36 at Week 24 and Week 48 | The Short Form (36) Health Survey (SF-36) consists of 36 items that can be summarized into 8 domains: physical functioning, role limitations due to physical health problems (role-physical), bodily pain, general health, vitality, social functioning, role limitations due to emotional problems (role-emotional), and mental health. Two summary measures, the physical component summary and the mental component summary, can be derived based on these domain scores. Each score is directly transformed into a 0-100 score on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability. Mean changes from baseline were derived from an analysis of covariance (ANCOVA) model with treatment as factor and baseline SF-36 Score and geographic region as covariates. A positive change denotes an improvement. | At Week 24 and Week 48 | 
| Change From Baseline in 28 Joint Count Swollenness (SJC28) Score at Week 24 and Week 48 | Twenty-eight joints are assessed for swollenness (a score of 1 for a joint denotes a presence of swollenness). The sum is derived to create a total score (ranging from 0 to 28; where the highest score indicate all 28 joints are swollen). Mean changes from baseline were derived from an analysis of covariance (ANCOVA) model with treatment as factor and baseline SJC28 Score and geographic region as covariates. A negative change denotes an improvement. | At Week 24 and Week 48 | 
| Change From Baseline in 28 Joint Count Tenderness (TJC28) Score at Week 24 and Week 48 | Twenty-eight joints are assessed for tenderness (a score of 1 for a joint denotes a presence of tenderness). The sum is derived to create a total score (ranging from 0 to 28; where the highest score indicate all 28 joints are tender). Mean changes from baseline were derived from an analysis of covariance (ANCOVA) model with treatment as factor and baseline TJC28 Score and geographic region as covariates. A negative change denotes and improvement. | At Week 24 and Week 48 | 
| Change From Baseline in Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) Activity Score at Week 12, Week 24 and Week 48 | CLASI Activity is scored based on erythema, scale/hyperkeratosis, mucous membrane involvement, acute hair loss and nonscarring alopecia. Evaluation of erythema and scale/hyperkeratosis is based on a table: rows represent anatomical areas and columns represent major clinical symptoms. The extent of involvement for each of the skin symptoms is documented for each anatomic area (erythema: 0=absent, 1=pink, 2=red, 3=dark red; scale: 0=absent, 1=scale, 2=verrucous/hypertrophic). Mucous membrane involvement and acute hair loss are scored based on the presence (=1) or absence (=0). Nonscarring alopecia is scored as 0=absent, 1=diffuse/non-inflammatory, 2=focal or patchy in 1 quadrant, 3=focal or patchy in >1 quadrant. The total score ranges from 0-70, with higher scores indicating more severe skin disease. Mean changes from baseline were derived from an ANCOVA model with treatment as factor and baseline CLASI Activity Score and geographic region as covariates. Negative change = improvement | At Week 12, Week 24 and Week 48 | 
| Change From Baseline in CLASI Damage Score at Week 12, Week 24 and Week 48 | CLASI Damage is scored based on dyspigmentation and scarring. Evaluation of dyspigmentation and scarring is based on a table: rows represent anatomical areas and columns represent major clinical symptoms. The extent of involvement for each of the skin symptoms is documented for each anatomic area (dyspigmentation: 0=absent, 1=present; scarring: 0=absent, 1=scarring, 2=severely atrophic scarring or panniculitis). Subjects are also asked whether dyspigmentation due to SLE lesions usually remains visible for >12 months, which is considered permanent and results in doubling of the dyspigmentation score. Scarring alopecia is scored as follows: 0=absent, 3=1 quadrant, 4=2 quadrants, 5=3 quadrants, 6=affects the whole skull. Total score ranges from 0-56, with higher scores indicating more damaged skin. Mean changes from baseline were derived from an ANCOVA model with treatment as factor and baseline CLASI Damage Score and geographic region as covariates. Negative change = improvement. | At Week 12, Week 24 and Week 48 | 
| ALX-0061 Serum Concentrations at Week 24 and Week 48 |  | At Week 24 and Week 48 | 
| Actual Values of Soluble Interleukin 6 Receptor (sIL-6R) Concentrations at Baseline, Week 24, and Week 48 |  | At Baseline, Week 24, and Week 48 | 
| Actual Values of C-reactive Protein (CRP) Concentrations at Baseline, Week 24, and Week 48 |  | At Baseline, Week 24, and Week 48 | 
| Actual Values of Fibrinogen Concentrations at Baseline, Week 24, and Week 48 |  | At Baseline, Week 24, and Week 48 | 
| Actual Values of Anti-double-stranded (ds) DNA Concentrations at Baseline, Week 24, and Week 48 |  | at Baseline, Week 24, and Week 48 | 
| Actual Values of Complement C3 Concentrations at Baseline, Week 24, and Week 48 |  | At Baseline, Week 24, and Week 48 | 
| Actual Values of Complement C4 Concentrations at Baseline, Week 24, and Week 48 |  | At Baseline, Week 24, and Week 48 | 
| Actual Values for Hemolytic Complement Component 50 (CH50) at Baseline, Week 24, and Week 48 |  | At Baseline, Week 24, and Week 48 | 
| Number and Percentage of Subjects Who Were Treatment-emergent (TE) Anti-drug Antibody (ADA) Positive |  | From first administration of ALX-0061 up to and including follow-up |