| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061664 |
| E.1.2 | Term | Autoimmune disorder |
| E.1.2 | System Organ Class | 10021428 - Immune system 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 |
Safety and tolerability of anti-BLyS / anti-CD 20 coadministration therapy and anti-BLyS and anti-CD 20
monotherapies |
|
| E.2.2 | Secondary objectives of the trial |
-Clinical efficacy of anti-BLyS / anti-CD 20 co-administration therapy and anti-BLyS and anti-CD 20 monotherapies
-Assessment of anti-BLyS / anti-CD 20 co-administration therapy and anti-BLyS and anti-CD 20
monotherapies on tissue B-cells. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
AGE
1. Age ≥18 years, at the time of signing the informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Documented Primary Sjögren’s Syndrome by American European Consensus Group criteria including:
- either SS-A or SS-B positive.
3. Baseline unstimulated salivary flow >0.0 mL/min or evidence of glandular reserve function (stimulated baseline salivary flow >0.05 mL/min).
4. Symptomatic oral dryness (≥5/10 on subject completed Numeric Response Scale)
5. Systemically active disease, ESSDAI ≥5 points.
OR (for sites in ITALY ONLY)
Systemically active disease, ESSDAI≥5 points and with at least:
a) 1 extraglandular domain moderate,
OR
b) 2 extraglandular domains low.
SEX
6. Male and female subjects; females of child bearing potential are eligible if using effective contraception:
Female subject is eligible to participate if she is not pregnant (as confirmed by a negative urine human chorionic gonadotropin (hCG) test), not lactating, and at least one of the following conditions applies:
a. Non-reproductive potential defined as:
-Pre-menopausal females with one of the following:
-Documented tubal ligation
-Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion
-Hysterectomy
-Documented Bilateral Oophorectomy
- Postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause (refer to laboratory reference ranges for confirmatory levels)]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study; otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment.
b. Reproductive potential and agrees to follow one of the options listed below in the GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) requirements from 30 days prior to the first dose of study medication up to Week 68 after Day 0.
GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP)
This list does not apply to FRP with same sex partners, when this is their preferred and usual lifestyle or for subjects who are and will continue to be abstinent from penilevaginal intercourse on a long term and persistent basis.
-Contraceptive subdermal implant that meets the SOP effectiveness
criteria including a <1% rate of failure per year, as stated in the product
label
-Intrauterine device or intrauterine system that meets the SOP
effectiveness criteria including a <1% rate of failure per year, as stated
in the product label
-Combined estrogen and progestogen oral contraceptive
-Injectable progestogen
-Contraceptive vaginal ring
-Percutaneous contraceptive patches
-Male partner sterilization with documentation of azoospermia prior to
the female subject's entry into the study, and this male is the sole
partner for that subject.
These allowed methods of contraception are only effective when used consistently, correctly and in accordance with the product label.
The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.
OTHER CRITERIA
8. For FRANCE ONLY, a subject will be eligible for inclusion in this study
if he /she is either affiliated to or beneficiary of a social security
category. It is the investigator's responsibility to ensure and to
document (in source document - patient notes) that the patient is either
affiliated to or beneficiary of a social security category. |
|
| E.4 | Principal exclusion criteria |
CONCURRENT CONDITIONS/MEDICAL HISTORY
1. Diagnosis of secondary Sjögren’s syndrome.
2. Active life-threatening or organ-threatening complications of SS disease at the time of screening based on treating physician evaluation including but not restricted to (a) vasculitis with renal, digestive, cardiac, pulmonary or CNS involvement characterized as severe, (b) active CNS or PNS involvement requiring high dose steroids, (c) severe renal involvement defined by objective measures, (d) lymphoma.
3. History of major organ transplant
4. History of malignancy within past 5 years [with the exception of adequately treated: (a)cervical carcinoma Stage 1B or less, (b)non-invasive basal cell and squamous cell skin carcinoma].
5. History of infection requiring long term systemic therapy including: (a)history of positive HIV serology, (b)positive serology for Hepatitis C (HCV), (c)positive serology for Hepatitis B (HB), defined as: (i) HB surface antigen positive (HBsAg+) OR (ii) HB core antibody positive (HBcAb+).
6. Previous serious opportunistic or atypical infections or hospitalization for treatment of infection within 364 days of Day 0 or use of parenteral (IV or IM) antibacterials, antivirals, anti-fungals, or anti-parasitic agents within 364 days of prior to Day 0.
7. Patients in a severely immunocompromised state.
8. History of an anaphylactic reaction to parenteral administration of contrast agents, human or murine proteins or monoclonal antibodies.
9. History of significant medical illness which in the opinion of the investigator would interfere with the study procedures and/or assessments - including but not limited to IgG4 disease or prior head or neck irradiation.
10. Severe heart failure or other severe, uncontrolled cardiac disease.
11. Tuberculosis (TB), defined as: (a)prior history of TB infection, (b)suspicion of TB infection or (c) current TB infection
12. At risk of suicide, as indicated by a lifetime history of attempted suicide or significant suicidal ideation over the 6 months prior to the screening visit; or, if in the Investigator’s judgment, the subject is at risk for a suicide attempt.
13. Neurological findings consistent with Progressive Multifocal Leukoencephalopathy (PML) - not otherwise explained - or confirmed PML.
14. Electrocardiogram (ECG) showing a clinically significant abnormality at Screening or showing an average QTcB or QTcF interval ≥450 msec over 3 consecutive ECGs (refer to Section 7.4.5)
15. ALT >2xULN and bilirubin >1.5xULN
16. Current or chronic history of liver disease, or known hepatic or biliary abnormalities.
CONCOMITANT MEDICATIONS
17. Use of systemic immunosuppressive or immunomodulatory agents including methotrexate, azathioprine, leflunomide, mycophenolate, mizoribine, calcineurin inhibitors, sirolimus, 6-mercaptopurine, or thalidomide) within 60 days prior to Day 0.
18. Have received cyclophosphamide within 180 days prior to Day 0.
19. Have received anti-BLyS, anti-CD 20, anti-CD22 or anti-CD52 or any other B-cell depleting agent within 364 days prior to Day 0.
20. Have received abatacept or any biologic agent within 180 day prior to Day 0
21. Have received IVIG or plasmapheresis within 90 days prior to Day 0.
22. Have received oral steroid >10 mg prednisone equivalent/day within 30 days prior to Day 0 or oral steroid >20 mg prednisone equivalent / day for a minimum of two consecutive weeks within 60 days prior to Day 0. Have received parenteral steroid within 60 days prior to Day 0.
23. Have received a live vaccine within 30 days of Day 0.
24. Current participation in any other interventional trial.
25. Planned blood donation during the treatment and follow up periods of the study.
RELEVANT HABITS
26. Subjects who are unable or unwilling to administer, or to have a caregiver administer subcutaneous injections.
27. Drug or alcohol abuse or dependence.
CONTRAINDICATIONS
28. History of hypersensitivity to belimumab and/or rituximab or known to have titers of human anti-mouse antibody or human anti-chimeric antibody or history of
hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal antibodies.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
29. Have an IgA deficiency (IgA level <10 mg/dL).
30. Any of the following screening laboratory values:
-White blood cells (WBC) <2 x 109/L -Neutrophils <1.5 x 109/L -Circulating IgG <550mg/dl -Aspartate aminotransferase (AST) >2.0 times the upper limit of normal -Alkaline phosphatase (ALP) >1.5 times the upper limit of normal -Bilirubin >1.5 times the upper limit of normal -CD19+ B-lymphocyte counts <0.1 x 109/L (applies only to subjects previously exposed to B cell depleting therapies)
31. For FRANCE ONLY, subjects with legal or administrative guardianship ("tutelle" or "curatelle"),or subjects deprived of liberty, or subjects receiving psychiatric care, or subjects hospitalized in an Health and Social Establishment for purposes other than participation in this study |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| ESSDAI score; stimulated salivary flow; oral dryness numeric response scale; B cell quantification within the salivary gland |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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 | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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 |
| transcriptomic and proteonomic analyses |
|
| 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 | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 26 |
| 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 |
| Canada |
| France |
| Germany |
| Italy |
| Netherlands |
| Norway |
| Spain |
| Sweden |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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