Clinical trial NCT03371251: Study of BOS161721 in Systemic Lupus Erythematosus (SLE) Patients on a Background of Limited Standard of Care
Official title: A Randomized Double-Blind Phase 1b/2 Combined Staggered Multiple Dose Escalation Study of BOS161721 in Systemic Lupus Erythematosus (SLE) Patients on a Background of Limited Standard of Care
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Systemic Lupus Erythematosus
Keywords: Adults
BOS161721
standard of care
moderately to severely active Systemic Lupus Erythematosus
Lead sponsor: Boston Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2017-12-13
Enrollment: 143
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will be conducted to assess the safety, tolerability, and immunogenicity of repeat doses of BOS161721 (20 milligrams \[mg\], 60 mg, and 120 mg) administered subcutaneously in adult participants with moderately to severely active Systemic Lupus Erythematosus (SLE) on limited background standard of care treatment, in order to estimate the optimal dose.

BOS161721 at the chosen dose will be compared to placebo for response on the SLE Responder Index 4, with sustained reduction of oral corticosteroids, in the same participant population.


Eligibility criteria: Inclusion Criteria:

* Men and women, ages 18 to 70 years, inclusive
* Participants must be mentally capable of giving consent and there must be evidence of a personally signed and dated informed consent document indicating that the participant has been informed of all pertinent aspects of the study
* Participants must have Systemic Lupus Erythematosus (SLE) as defined by meeting 4 of the Systemic Lupus International Collaborating Clinics classification criteria for SLE (with at least 1 clinical and 1 immunologic criterion OR Lupus nephritis as the sole clinical criterion in the presence of anti-nuclear antibodies (ANA) or anti-double stranded deoxyribonucleic acid (dsDNA) antibodies), either sequentially or simultaneously
* At screening, participants must have at least 1 of the following:

  1. Elevated ANA ≥ 1:80 via immunofluorescent assay at the central laboratory
  2. Positive anti-dsDNA or anti-Smith (anti-Sm) above the normal level as determined by the central laboratory
* At screening, the total Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score must be ≥ 8, including points from at least 1 of the following clinical components:

  a. Arthritis, rash, myositis, mucosal ulcers, pleurisy, pericarditis, and vasculitis Note: Points from lupus headache and organic brain syndrome will also be excluded from qualifying total and clinical SLEDAI-2K scores at screening and Day 0.
* A clinical SLEDAI-2K score of ≥ 6 at screening at Day 0. Clinical SLEDAI-2K score is defined as follows:

  1. Contains points from arthritis, rash, myositis, mucosal ulcers, pleurisy, pericarditis, or vasculitis
  2. Excludes parameters which require central laboratory results: hematuria, pyuria, urinary casts, proteinuria, positive anti-dsDNA, decreased complement, thrombocytopenia, and leukopenia Note: Points from lupus headache and organic brain syndrome will also be excluded from qualifying total and clinical SLEDAI-2K scores at screening and Day 0.
* Participants must have at least 1 qualifying A or 2Bs from the following manifestations of SLE, as defined by the British Isles Lupus Assessment Group (BILAG) criteria as modified for use in this study, which must be confirmed by the central data reviewer:

  1. BILAG A or B score in the mucocutaneous body system. If a BILAG B score is due to BILAG number 6, mild skin eruption, the CLASI activity score including erythema and scale/hypertrophy must be ≥ 3 excluding points from mucosal ulcers and alopecia.
  2. BILAG A or B score in the musculoskeletal body system due to active polyarthritis Note: Hips, shoulders, back, neck, and temporomandibular joints do not count towards the total number of joints with active synovitis.

If only one "B" and no "A" score is present in the mucocutaneous body system or in the musculoskeletal body system due to arthritis, then at least 1 "B" must be present in at least 1 other body system for a total of 2 "B" BILAG body system scores.

- Participants must be currently receiving at least 1 of the following:

1. Administration for a minimum of 12 weeks, and a stable dose for at least 56 days (8 weeks prior to Day 0) of the following permitted steroid sparing agents: azathioprine (AZA), mycophenolate mofetil or mycophenolic acid, chloroquine, hydroxychloroquine, or methotrexate
2. If AZA, myocophenolate mofetil, mycophenolic acid, hydroxychloroquine, or MTX were discontinued prior to screening, the washout period must be ≥ 12 weeks.
3. Corticosteroids (CSs) (prednisone or prednisone-equivalent) at a stable dose of up to 30 mg/day for at least 6 weeks prior to Day 0

i. For participants whose only SLE treatment is CSs, the stable CS dose must be ≥ 10 mg/day for at least 6 weeks prior to Day 0 and no more than 30 mg/day at the time of randomization.

ii. Topical steroids may be used, but the dose must be stable for at least 6 weeks prior to Day 0. PRN topical steroids are not permitted.

* Women of childbearing potential (WOCBP):

  1. Must have a negative serum pregnancy test at screening. Urine pregnancy test must be negative prior to first dose
  2. Must not be breastfeeding
  3. Must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug plus 52 weeks
* Men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug plus 52 weeks
* Participants must demonstrate willingness and ability to comply with the scheduled study visits, treatment plans, laboratory tests, and other procedures

Exclusion Criteria:

Participants presenting with any of the following will not be included in this study:

* Drug-induced SLE, rather than "idiopathic" SLE
* Other systemic autoimmune disease (eg, erosive arthritis, rheumatoid arthritis \[RA\], multiple sclerosis \[MS\], systemic sclerosis, or vasculitis not related to SLE). RA-Lupus overlap (Rupus), and secondary Sjogren syndrome are allowed.
* Any major surgery within 6 weeks of study drug administration (Day 0) or any elective surgery planned during the course of the study
* Any history or risk for tuberculosis (TB), specifically those with:

  1. Current clinical, radiographic, or laboratory evidence of active TB
  2. History of active TB
  3. Latent TB defined as positive QuantiFERON-TB Gold In Tube or other diagnostic test in the absence of clinical manifestations. Latent TB is not excluded if the participant has documented completion of adequate course of prophylactic treatment with regimen recommended by local health authority guideline, or the participant has started treatment with isoniazid, or other regimen recommended by local health authority guidelines for at least 1 month before Day 0 and continues to receive the prophylactic treatment during study until the treatment course is completed
* Active or unstable lupus neuropsychiatric manifestations, including but not limited to any condition defined by BILAG A criteria, with the exception of mononeuritis multiplex and polyneuropathy, which are allowed
* Severe proliferative lupus nephritis (World Health Organization Class III, IV), which requires or may require induction treatment with cytotoxic agents or high dose CSs
* Concomitant illness that, in the opinion of the investigator or the Sponsor or their designee, is likely to require additional systemic glucocorticosteroid therapy during the study, (eg, asthma), is exclusionary. However, treatment for asthma with inhalational CSs therapy is allowed.
* Use or planned use of concomitant medication outside of standard of baseline treatment for SLE from Day -1 or for any time during the study
* Active and clinically significant infection (bacterial, fungal, viral, or other) within 60 days prior to first dose of study drug. Clinically significant is defined as requiring systemic parenteral antibiotics or hospitalization
* A history of opportunistic infection, or a history of recurrent or severe disseminated herpes zoster or disseminated herpes simplex within the last 3 years
* Chronic viral hepatitis B (HBV) and hepatitis C (HCV), unless participant received curative treatment for HCV and has a documented negative viral load, known human immunodeficiency virus (HIV), or acquired immunodeficiency syndrome (AIDS)-related illness
* Cryptosporidium in the stool sample at screening
* White blood cells \< 1,200/millimeters cubed (mm\^3) (1.2 × 10\^9/Liter \[L\]) at screening
* Absolute neutrophil count \< 500/mm\^3 at screening
* CD4+ count \< 150/microliter (µL) at screening
* Platelets \< 50,000/mm\^3 (50 × 10\^9/L) or \< 35,000/mm\^3 (35 × 10\^9/L) if related to SLE, at screening
* Hemoglobin \< 8 grams per deciliter (g/dL) or \< 7 g/dL at screening if related to SLE
* Proteinuria \> 3.0 g/day (3000 milligrams per day \[mg/day\]) at screening or equivalent level of proteinuria as assessed by protein/creatinine ratio (3 mg/mg or 339 milligrams per millimole \[mg/mmol\])
* Serum creatinine \> 2.0 mg/dL at screening or creatinine clearance \< 40 milliliters per minute (mL/minute) based on Cockcroft-Gault calculation
* Serum alanine aminotransferase and/or serum aspartate aminotransferase \> 2 × the upper limit of normal (ULN) at screening, unless explicitly related to lupus based on the investigator's judgment
* Creatinine kinase \> 3.0 × ULN at screening unless related to lupus myositis
* Total bilirubin \> 1.5 × ULN at screening (unless related to Gilbert's syndrome)
* Any other laboratory test results that, in the opinion of the Investigator or the Sponsor or Sponsor's designee, might place a participant at unacceptable risk for participating in this study
* History of allergic or anaphylactic reaction to any therapeutic or diagnostic monoclonal antibodies (mAb) (eg, IgG protein) or molecules made of components of mAbs
* History substance and/or alcohol abuse, or dependence within the past 1 year, at the investigator's judgment
* History of cancer within the last 5 years (except for cutaneous basal cell or squamous cell cancer, or cervical cancer in situ resolved by excision)
* Any other severe acute or chronic medical or psychiatric condition, including recent (within the past year) medical conditions (eg, cardiovascular conditions, respiratory illnesses) that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, Sponsor, or Sponsor's designee, would make the participant inappropriate for entry into this study
* Investigational site staff members directly involved in the conduct of the trial and their family members, site staff members otherwise supervised by the investigator, or participants who are employees of the sponsor or directly involved in the conduct of the trial
* Currently participating in, or who have participated in other interventional (drug or device) clinical study within 30 days or 5 half-lives of baseline, whichever is longer
* Recent (within the past 12 months) or active suicidal ideation or behavior based on participant responding "yes" to question 3, 4, or 5 on the Columbia Suicide severity Rating Scale
* Current or pending incarceration
* Current or pending compulsory detainment for treatment of either a psychiatric or physical (eg, infectious disease) illness
* Currently taking a total daily dose of \> 30 mg morphine or morphine equivalent
* Body mass index (BMI) ≥ 40.0

Primary outcomes:
measure: Phase 1b: Number of Participants With Adverse Events (AEs)
timeFrame: Up to Day 270
measure: Phase 2: Number of Participants With an SLE Responder Index 4 (SRI-4) Response at Day 210
timeFrame: Day 210
Secondary outcomes:
measure: Phase 1b: Maximum Observed Concentration (Cmax)
timeFrame: Pre-dose: Days 0, 30, 60, 90, 120, 150, and 180. Post-dose: Days 0, 7, 15, 30, 180, 187, 195, 210, 240, and 270. Post-dose samples were collected at 4, 8, and 24 hours after study drug administration on Days 0, 30, and 180
measure: Phase 1b: First Time to Maximum Concentration (Tmax)
timeFrame: Pre-dose: Days 0, 30, 60, 90, 120, 150, and 180. Post-dose: Days 0, 7, 15, 30, 180, 187, 195, 210, 240, and 270. Post-dose samples were collected at 4, 8, and 24 hours after study drug administration on Days 0, 30, and 180
measure: Phase 1b: The Area Under the Plasma Concentration Versus Time Curve, From Time 0 to the Last Quantifiable Concentration (AUClast)
timeFrame: Pre-dose: Days 0, 30, 60, 90, 120, 150, and 180. Post-dose: Days 0, 7, 15, 30, 180, 187, 195, 210, 240, and 270. Post-dose samples were collected at 4, 8, and 24 hours after study drug administration on Days 0, 30, and 180
measure: Phase 1b: Terminal Elimination Half-life (t1/2)
timeFrame: Pre-dose: Days 0, 30, 60, 90, 120, 150, and 180. Post-dose: Days 0, 7, 15, 30, 180, 187, 195, 210, 240, and 270. Post-dose samples were collected at 4, 8, and 24 hours after study drug administration on Days 0, 30, and 180
measure: Phase 1b: Apparent Plasma Clearance After Extravascular Administration (CL/F)
timeFrame: Pre-dose: Days 0, 30, 60, 90, 120, 150, and 180. Post-dose: Days 0, 7, 15, 30, 180, 187, 195, 210, 240, and 270. Post-dose samples were collected at 4, 8, and 24 hours after study drug administration on Days 0, 30, and 180
measure: Phase 1b: Apparent Volume of Distribution After Extravascular Administration (Vz/F)
timeFrame: Pre-dose: Days 0, 30, 60, 90, 120, 150, and 180. Post-dose: Days 0, 7, 15, 30, 180, 187, 195, 210, 240, and 270. Post-dose samples were collected at 4, 8, and 24 hours after study drug administration on Days 0, 30, and 180
measure: Phase 1b: Mean Change From Baseline in Phosphorylated Signal Transducer and Activator of Transcription 3 (pSTAT3)
timeFrame: Baseline (Day 0); Days 30, 44, 60, and 90 (pre-dose [trough] samples only)
measure: Phase 1b: Mean Change From Baseline in Complement 3 (C3) and Complement (C4) Levels
timeFrame: Baseline (Day 0); Day 210
measure: Phase 1b: Mean Change From Baseline in Leukocyte Immunophenotype
timeFrame: Baseline (Day 0); Day 180
measure: Phase 1b: Mean Change From Baseline in Anti-double-stranded DNA (dsDNA) Autoantibodies at Each Visit
timeFrame: Baseline (Day 0); Days 30, 60, 90, 120, 150, 180, 210, 240, and 270
measure: Phase 1b: Mean Change From Baseline in Anti-Sjögren's Syndrome A and B (SSA, SSB)
timeFrame: Baseline (Day 0); Day 180
measure: Phase 1b: Mean Change From Baseline in Anti-Smith Antibody (Sm)
timeFrame: Baseline (Day 0); Day 180
measure: Phase 1b: Mean Change From Baseline in Antiphospholipid (APL) Autoantibodies (Beta 2 Glycoprotein, Cardiolipin IgG)
timeFrame: Baseline (Day 0); Day 180
measure: Phase 1b: Mean Change From Baseline in Abrogation of IL-21 Gene Signature
timeFrame: Baseline (Day 0); Days 15, 90, 180, and 270
measure: Phase 2: Number of Participants With an SRI-4, SRI-5, and SRI-6 Response at Each Visit
timeFrame: Days 30, 60, 90, 120, 150, 180, 210, 240, and 270
measure: Phase 2: Number of Participants With a Sustained Reduction From Baseline of Oral Corticosteroid (CS) (≤ 7.5 mg/Day and < Day 0 Dose) Between Day 150 and Day 210
timeFrame: Day 150 to Day 210
measure: Phase 2: Number of Participants With New or Recurrent BILAG Flares (≥ 1 Qualifying BILAG A or > 1 Qualifying BILAG B) Through Day 210
timeFrame: Days 30, 60, 90, 120, 150, 180, 210
measure: Phase 2: Number of Participants With Physician's Global Assessment (PGA) Worsening
timeFrame: Days 30, 60, 90, 120, 150, 180, and 210
measure: Phase 2: Number of Participants With a BILAG-based Composite Lupus Assessment (BICLA) Response at Day 210
timeFrame: Day 210
measure: Phase 2: Number of Participants With a Cutaneous Lupus Erythematosus Area and Severity Index (CLASI) Response at Day 210
timeFrame: Day 210
measure: Phase 2: Number of Participants With Medication Failures
timeFrame: Days 30, 60, 90, 120, 150, 180, and 210
measure: Phase 2: Mean Change From Baseline in CLASI at Day 210
timeFrame: Baseline, Day 210
measure: Phase 2: Mean Change From Baseline in PGA
timeFrame: Baseline, Day 210
measure: Phase 2: Mean Change From Baseline in the Total Number of Swollen Joints, Tender Joints, and Active Joints (Swelling and Tenderness in the Same Joint) in the American College of Rheumatology-28 (ACR-28) Joint Count
timeFrame: Baseline, Day 210
measure: Phase 2: Mean Change From Baseline in SLEDAI-2K at Day 210
timeFrame: Baseline, Day 210
measure: Phase 2: Mean Change From Baseline in Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index
timeFrame: Baseline; Day 180
measure: Phase 2: Time to Medication Failure
timeFrame: Up to Day 270
measure: Mean Percent Change in CS Administration From the Baseline Day 0 Dose Through Day 210 in Participants Receiving ≥ 7.5 mg/Day Prednisone Equivalent at Day 0
timeFrame: Baseline; Day 210
measure: Phase 2: Duration of Longest SRI-4 Response
timeFrame: Up to Day 270
measure: Phase 2: Time to First BILAG Flare (≥ 1 New or Recurrent BILAG A or > 1 New or Recurrent BILAG B) Relative to Baseline Through Day 210
timeFrame: Baseline; Day 210
measure: Phase 2: Number of Participants With AEs
timeFrame: Up to Day 270
Other outcomes:
Locations:
city: Anniston
country: United States
facility: Pinnacle Research Group
state: Alabama
city: El Cajon
country: United States
facility: TriWest Research Associates
state: California
city: Los Alamitos
country: United States
facility: Valerius Medical Group and Research Center
state: California
city: Thousand Oaks
country: United States
facility: Westlake Medical Research
state: California
city: Clearwater
country: United States
facility: Clinical Research of West Florida
state: Florida
city: DeBary
country: United States
facility: Omega Research Consultants
state: Florida
city: Fort Lauderdale
country: United States
facility: Centre for Rheumatology Immunology and Arthritis
state: Florida
city: Ormond Beach
country: United States
facility: Millennium Research
state: Florida
city: Palm Harbor
country: United States
facility: The Arthritis Center
state: Florida
city: Tampa
country: United States
facility: Clinical Research of West Florida
state: Florida
city: Skokie
country: United States
facility: Clinic of Robert Hozman/Clinical Investigation Specialists, Inc.
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University School of Medicine
state: Indiana
city: Grand Blanc
country: United States
facility: Aa Mrc Llc
state: Michigan
city: Lansing
country: United States
facility: June DO PC
state: Michigan
city: Charlotte
country: United States
facility: Joint and Muscle Research Institute
state: North Carolina
city: Memphis
country: United States
facility: Ramesh C. Gupta M.D.
state: Tennessee
city: Houston
country: United States
facility: Accurate Clinical Research Inc
state: Texas
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: Hospital Militar Central - Servicio de Reumatología
city: La Plata
country: Argentina
facility: Framingham Centro Medico
city: San Miguel De Tucumán
country: Argentina
facility: Centro Medico Privado de Reumatologia
city: San Miguel De Tucumán
country: Argentina
facility: Centro de Investigaciones Reumatologicas
city: Plovdiv
country: Bulgaria
facility: Diagnostic Consultative Center Sveti Georgi EOOD
city: Plovdiv
country: Bulgaria
facility: University Multiprofile Hospital for Active Treatment Plovdiv
city: Sevlievo
country: Bulgaria
facility: Medical Center - 1 - Sevlievo EOOD
city: Barranquilla
country: Colombia
facility: Centro Integral de Reumatologia del Caribe CIRCARIBE S.A.S
city: Bogota
country: Colombia
facility: Preventive Care S.A.S.
city: Bucaramanga
country: Colombia
facility: Medicity S.A.S.
city: Bucaramanga
country: Colombia
facility: Servimed S.A.S.
city: Cali
country: Colombia
facility: Clinica de Artritis Temprana
city: Medellín
country: Colombia
facility: Hospital Pablo Tobon Uribe
city: Tbilisi
country: Georgia
facility: V. Tsitlanadze Scientifically-Practical Rheumatology Center Ltd
city: Tbilisi
country: Georgia
facility: Research Institute of Clinical Medicine Ltd
city: Tbilisi
country: Georgia
facility: LTD New Hospitals
city: Tbilisi
country: Georgia
facility: Mtskheta Street Clinic Ltd
city: Tbilisi
country: Georgia
facility: First Medical Center
city: Tbilisi
country: Georgia
facility: Multiprofile Clinic Consilium Medulla Ltd
city: Budapest
country: Hungary
facility: Qualiclinic Kft.
city: Debrecen
country: Hungary
facility: DE Klinikai Központ
city: Gyula
country: Hungary
facility: Békés Megyei Központi Kórház Pándy Kálmán Tagkórház
city: Guadalajara
country: Mexico
facility: Centro Integral en Reumatología S.A. de C.V. (CIRSA)
city: Guadalajara
country: Mexico
facility: Hospital Civil de Guadalajara Fray Antonio Alcalde
city: Mexico City
country: Mexico
facility: CLIDITER S.A. de C.V. (Centro de Investigación y Tratamiento de las Enfermedades Reumaticas)
city: Cayma
country: Peru
facility: Hogar Clinica San Juan De Dios
city: La Libertad
country: Peru
facility: Centro de Investigación Clínica Trujillo E.I.R.L.
city: Lima
country: Peru
facility: Hospital Nacional Cayetano Heredia
city: Lima
country: Peru
facility: Clinica San Juan Bautista
city: Santiago De Surco
country: Peru
facility: Instituto de Ginecología y Reproducción
city: Angeles City
country: Philippines
facility: Angeles University Foundation Medical Center
city: Davao City
country: Philippines
facility: Southern Philippines Medical Center
city: Lipa City
country: Philippines
facility: Mary Mediatrix Medical Center
city: Manila
country: Philippines
facility: Philippine General Hospital
city: Manila
country: Philippines
facility: University of Santo Tomas Hospital
city: Elbląg
country: Poland
facility: Centrum Kliniczno - Badawcze J. Brzezicki, B. Gronkiewicz Brzezicka Spółka Lekarska
city: Kraków
country: Poland
facility: Centrum Medyczne Plejady
city: Kraków
country: Poland
facility: Centrum Nowoczesnych Terapii Dobry Lekarz sp. z o.o
city: Nadarzyn
country: Poland
facility: NZOZ Lecznica MAK-MED
city: Poznań
country: Poland
facility: Prywatna Praktyka Lekarska Prof. UM dr hab. med Pawel Hrycaj
city: Stalowa Wola
country: Poland
facility: SANUS Szpital Specjalistyczny sp. z o.o
city: Warszawa
country: Poland
facility: Reumatika-Centrum Reumatologii
city: Łódź
country: Poland
facility: Centrum Medyczne AMED oddział w Łodzi
city: Braşov
country: Romania
facility: Centrul Medical de Diagnostic si Tratament Ambulatoriu Neomed SRL
city: Cluj-Napoca
country: Romania
facility: Spitalul Clinic Judetean De Urgenta Cluj Napoca
city: Iaşi
country: Romania
facility: Spitalul Clinic de Recuperare Iasi #2
city: Kyiv
country: Ukraine
facility: National Scientific Center at Institute of Cardiology named after acad. M.D. Strazhesko
city: Kyiv
country: Ukraine
facility: Kyiv Regional Clinical Hospital
city: Odesa
country: Ukraine
facility: Odesa Regional Clinical Hospital
city: Ternopil
country: Ukraine
facility: Communal Non-Profit Enterprise "Ternopil University Clinic" of Ternopil Regional Council
city: Vinnytsia
country: Ukraine
facility: Vinnytsia Regional Clinical Hospital
Study officials:
References: