A Phase 2, randomized, double blind, placebo controlled study to evaluate the safety and efficacy of belimumab and rituximab co-administration in subjects with primary Sjögren’s syndrome

• Register: EUCTR
• Last refreshed on: 13 July 2020
• Main ID: EUCTR2015-000400-26-SE
• Date of registration: 08/09/2015
• Prospective Registration: Yes
• Primary sponsor: GlaxoSmithKline R&D Ltd
• Public title: A Phase 2, randomized, double blind, placebo controlled study to evaluate the safety and efficacy of belimumab and rituximab co-administration in subjects with primary Sjögren’s syndrome
• Scientific title: A randomized, double blind (sponsor open), comparative, multicenter study to evaluate the safety and efficacy of subcutaneous belimumab (GSK1550188) and intravenous rituximab coadministration in subjects with primary Sjögren’s syndrome.
• Date of first enrolment: 15/12/2015
• Target sample size: 120
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-000400-26
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: no Other: yes Other trial design description: Sponsor unblinded If controlled, specify comparator, Other Medicinial Product: yes Placebo: yes Other: no Number of treatment arms in the trial: 4
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Canada, France, Germany, Italy, Netherlands, Norway, Spain, Sweden, United Kingdom

Contacts

• Name: GSK Clinical Support Help Desk
• Affiliation: GlaxoSmithKline Research & Development Ltd

• Name: GSK Clinical Support Help Desk
• Affiliation: GlaxoSmithKline Research & Development Ltd

Key inclusion & exclusion criteria

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 FRAN
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 t

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Immune System Diseases [C20]

Primary Sjogrens disease
MedDRA version: 20.0 Level: PT Classification code 10061664 Term: Autoimmune disorder System Organ Class: 10021428 - Immune system disorders

Intervention(s)

Trade Name: MabThera (Rituximab)
Product Name: MabThera (Rituximab)
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: RITUXIMAB
CAS Number: 174722-31-7
Other descriptive name: MABTHERA
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Concentrate for solution for injection
Route of administration of the placebo: Intravenous use

Trade Name: Benlysta (Belimumab)
Product Name: Benlysta (Belimumab)
Pharmaceutical Form:
INN or Proposed INN: BELIMUMAB
CAS Number: 356547-88-1
Current Sponsor code: GSK1550188
Other descriptive name: HGS1006, LymphoStat-B, monoclonal anti-BLyS, LSB, BENLYSTA
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 200-
Pharmaceutical form of the placebo: Solution for injection in pre-filled syringe
Route of administration of the placebo: Subcutaneous use

Primary Outcome(s)

Primary end point(s): Safety and tolerability

Secondary Objective: -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.

Main Objective: Safety and tolerability of anti-BLyS / anti-CD 20 coadministration therapy and anti-BLyS and anti-CD 20 monotherapies

Timepoint(s) of evaluation of this end point: Weeks 24 and 52

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Weeks 24 and 52

Secondary end point(s): ESSDAI score; stimulated salivary flow; oral dryness numeric response scale; B cell quantification within the salivary gland

Secondary ID(s)

201842

Source(s) of Monetary Support

GlaxoSmithKline R&D

Ethics review

Status: Approved
Approval date: 15/12/2015
Contact: