| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Systemic lupus erythematosus |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10042945 |
| E.1.2 | Term | Systemic lupus erythematosus |
| E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Proof of Concept (POC) Phase 2 Primary Objective:
To demonstrate a superior effect of BOS161721 at the chosen dose compared with placebo for response on the SRI-4. |
|
| E.2.2 | Secondary objectives of the trial |
POC Phase 2 Secondary Objectives:
To demonstrate a superior effect of BOS161721 at the chosen dose compared with placebo for response on clinical indicators of SLE activity, in adult patients with moderately to severely active SLE on limited background standard of care treatment. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Men and women, ages 18 to 70 years, inclusive
2. Patients must be mentally capable of giving consent and there must
be evidence of a personally signed and dated informed consent
document indicating that the patient has been informed of all pertinent
aspects of the study
3. Patients must have SLE as defined by meeting 4 of the Systemic Lupus
International Collaborating Clinics (SLICC) 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 antinuclear antibodies
[ANA] or anti- double-stranded deoxyribonucleic acid [dsDNA]
antibodies), either sequentially or simultaneously
4. At screening, patients must have at least 1 of the following:
a. Elevated ANA ≥ 1:80 via immunofluorescent assay at the central
laboratory
b. Positive anti-dsDNA or anti-Smith (Sm) above the normal level asdetermined by the central laboratory
5. At screening, the total 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.
6. A clinical SLEDAI-2K score of ≥ 6 at screening at Day 0. Clinical
SLEDAI-2K score is defined as follows:
a. Contains points from arthritis, rash, myositis, mucosal ulcers, pleurisy,
pericarditis, or vasculitis
b. 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.
7. Patients must have at least 1 qualifying A or 2Bs from the following
manifestations of SLE, as defined by the BILAG criteria as modified for
use in this study, which must be confirmed by the central data reviewer:
a. 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.
b. BILAG A or B score in the musculoskeletal body system due to active
polyarthritis as defined in the protocol Section 4.4
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.
8. Patients must be currently receiving at least 1 of the following:
a. 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:
i. Azathioprine (AZA), mycophenolate mofetil or mycophenolic acid,
chloroquine, hydroxychloroquine, or methotrexate (MTX)
b. If AZA, myocophenolate mofetil, mycophenolic acid,
hydroxychloroquine, or MTX were discontinued prior to screening, the
washout period must be ≥ 12 weeks.
c. Corticosteroids (prednisone or prednisone-equivalent) at a stable dose
of up to 30 mg/day for at least 6 weeks prior to Day 0 (see APPENDIX 3)
i. For patients 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.
9. Women of childbearing potential (WOCBP; see Section 4.7 for full
information regarding WOCBP, definition of menopause, and
contraception):
a. Must have a negative serum pregnancy test at screening. Urine
pregnancy test must be negative prior to first dose
b. Must not be breastfeeding
c. Must agree to follow instructions for method(s) of contraception for
the duration of treatment with study drug plus 52 weeks
10. 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
11. Patients must demonstrate willingness and ability to comply with the scheduled study visits, treatment plans, laboratory tests, and other
procedures |
|
| E.4 | Principal exclusion criteria |
1. Drug-induced SLE, rather than "idiopathic" SLE
2. Other systemic autoimmune disease (eg, erosive arthritis, rheumatoid
arthritis [RA], multiple sclerosis [MS], systemic sclerosis, or vasculitis
not related to SLE)
a. RA-Lupus overlap (Rupus), and secondary Sjögren syndrome are
allowed
3. Any major surgery within 6 weeks of study drug administration, (Day
0), or any elective surgery planned during the course of the study
4. Any history or risk for tuberculosis (TB) -please see the details in the
protocol
5. 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
6. Severe proliferative lupus nephritis, (WHO Class III, IV), which
requires or may require induction treatment with cytotoxic agents or
high dose CS
7. 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
a. However, treatment for asthma with inhalational CS therapy is
allowed
8. 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
9. 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
10. A history of opportunistic infection, or a history of recurrent or
severe disseminated herpes zoster or disseminated herpes simplex
within the last 3 years
11. Chronic viral hepatitis including hepatitis B (HBV) and hepatitis C
(HCV) unless patient received curative treatment for HCV and has a
documented negative viral load, known human immunodeficiency virus
(HIV), or acquired immunodeficiency syndrome (AIDS)-related illness
12. Cryptosporidium in the stool sample at screening
13. White blood cells (WBC) < 1,200/mm3 (1.2 × 109/L) at screening
14. Absolute neutrophil count (ANC) < 500/mm3 at screening
15. CD4+ count < 150/μL at screening
16. Platelets < 50,000/mm3 (50 × 109/L) or < 35,000/ mm3 (35 ×
109/L) if related to SLE, at screening
17. Hemoglobin < 8 g/dL or < 7 g/dL at screening if related to SLE
18. Proteinuria > 3.0 g/day (3000 mg/day) at screening or equivalent
level of proteinuria as assessed by protein/creatinine ratio (3 mg/mg or
339 mg/mmol)
19. Serum creatinine > 2.0 mg/dL at screening or creatinine clearance
(CrCL) < 40 ml/minute based on Cockcroft-Gault calculation
20. Serum alanine aminotransferase (ALT) and/or serum aspartate
aminotransferase (AST) > 2 × the upper limit of normal (ULN) at
screening, unless explicitly related to lupus based on the investigator's
judgment
21. Creatinine kinase (CK) > 3.0 × ULN at screening unless related to
lupus myositis
22. Total bilirubin > 1.5 × ULN at screening (unless related to Gilbert's
syndrome)
23. Any other laboratory test results that, in the opinion of the
Investigator or the sponsor or sponsor's designee, might place a patient
at unacceptable risk for participating in this study
24. History of allergic or anaphylactic reaction to any therapeutic or
diagnostic mAb (eg, IgG protein) or molecules made of components of
mAbs
25. History substance and/or alcohol abuse, or dependence within the
past 1 year, at the investigator's judgment
26. History of cancer within the last 5 years (see protocol)
27. 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 patient inappropriate for entry into this study
28. 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 patients who are employees of the
sponsor or directly involved in the conduct of the trial
29. Currently participating in, or who have participated in other
interventional (drug or device) clinical study within 30 days or 5 halflives
of baseline, whichever is longer
30. Recent (within the past 12 months) or active suicidal ideation or
behavior based on patient responding "yes" to question 3, 4, or 5 on the
C-SSRS
31. Current or pending incarceration
32. Current or pending compulsory detainment for treatment of either a
psychiatric or physical (eg, infectious disease) illness
33. Currently taking a total daily dose of > 30 mg morphine or morphine
equivalent (see APPENDIX 7)
34. Body mass index (BMI) ≥ 40.0 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
POC Phase 2 Primary (Efficacy) Endpoints:
The proportion of patients with a SRI-4 response at Day 210. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Timepoints for evaluation of POC primary endpoints are listed in the endpoint description above. |
|
| E.5.2 | Secondary end point(s) |
POC Phase 2 Secondary (Efficacy) Endpoints:
• The proportion of patients with:
- SRI-4 response at each visit
- SRI-5 and SRI-6 response at each visit (Section 6.3.4.2)
- a sustained reduction from baseline of oral corticosteroid (CS) (≤ 7.5
mg/day and < Day 0 dose) between Day 150 and Day 210
- new or recurrent BILAG flares (≥ 1 qualifying BILAG A or > 1 qualifying
BILAG B) through Day 210
- PGA worsening
- a BICLA response
- a CLASI response
- medication failures
• Results and changes from baseline in:
- CLASI
- Total number of swollen joints, tender joints, and active joints
(swelling and tenderness in the same joint) in the ACR-28 joint count
- SLEDAI-2K
- SLICC/ACR damage index
• Time to medication failure
• Group mean percent reduction in corticosteroid administration from
baseline Day 0 dose through Day 210 in patients receiving ≥ 7.5 mg/day
prednisone equivalent at Day 0
• Duration of longest SRI-4 response
• Time to first SRI-4 response
• Time to first BILAG flare (≥ 1 new or recurrent BILAG A or > 1 new or
recurrent BILAG B) relative to baseline through Day 210 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Timepoints for evaluation of POC secondary endpoints are listed in the endpoint description above. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Bulgaria |
| Colombia |
| Georgia |
| Hungary |
| Mexico |
| Peru |
| Philippines |
| Poland |
| Romania |
| Ukraine |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| End of trial will be when last patient completes the safety follow-up visit at Day 270. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
Print
