A Phase 3/4, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, 52-Week Study to Evaluate the Efficacy and Safety of Belimumab (HGS1006) in Adult Subjects of Black Race with Systemic Lupus Erythematosus (SLE).
This is a Phase 3/4, multi-center, international, randomized, double-blind, placebo-controlled, 52-week study to evaluate the efficacy and safety of belimumab in adult black subjects with active SLe.
approximately 816 SLe subjects will be randomized with a target of about 544 subjects treated with belimumab and 272 subjects receiving placebo.
in addition to receiving stable standard therapy, subjects will be randomized in a 2:1 ratio to treatment with either 10 mg/kg belimumab or placebo. at randomization, subjects will be stratified by their screening SeLena SLeDai score (8-9 vs [GreaterThanorequalTo] 10), complement level (C3 and/or C4 low vs other), and region (uS/Canada vs rest of the world).
Subjects will be dosed with study agent on Days 0, 14, 28, and then every 28 days through 48 weeks, with a final evaluation at Week 52 (4 weeks after the last dose).
Study agent will be administered iV over 1 hour. Subjects will remain under clinical supervision for 3 hours after completion of the first 2 infusions during the 52-week double-blind phase and 6-month open-label extension.
all subjects will continue the stable standard therapy they were receiving during the screening period.
Subjects who complete dosing up to 48 weeks will return for a Day 364/Week 52 (final evaluation) visit.
Subjects who successfully complete the initial 52 week double-blind phase may enter into a 6-month open-label extension. The Day 364/Week 52 visit will serve as the Day 0 visit for subjects entering the 6-month open-label extension. Subjects on active drug or placebo will receive belimumab 10 mg/kg iV every 28 days for 6 months in the open-label extension. The 1st dose on the 6-month open-label extension will be given on Day 364 (Week 52) of the double-blind treatment phase following the completion of all Day 364 (Week 52) assessments.
Subjects participating in the 6-month open-label extension will continue to be monitored for safety and more latitude will be permitted for background medication changes.
Subjects who complete the 52-week double-blind phase, but do not enter the 6-month open-label extension will be required to return for an additional follow up visit 8 weeks after the last dose of study agent.
Subjects who withdraw early will be required to return for an exit visit (4 weeks after the last dose of study agent) and a follow-up visit approximately 8 weeks after their last dose of study agent
in the event that a subject discontinues study agent at any time during the study or withdraws consent, an attempt will be made to ascertain survival status approximately 52 weeks after the first dose of study agent.
at the end of the 6-month open-label period, subjects who wish to continue treatment may do so by being prescribed commercially available product. if belimumab is not commercially available in a subject's country of participation, subjects may continue to receive belimumab under a separate continuation protocol. a separate informed consent will need to be provided for the continuation protocol.
Primary efficacy endpoint
The primary efficacy endpoint is the systemic lupus erythematosus responder index (SRi) at
a SRi response is defined as:
* [GreaterThanorequalTo] 4 point reduction from baseline in SeLena SLeDai score, anD
* no worsening (increase of [Less Than] 0.30 points from baseline) in Physician's Global assessment(PGa),anD
* no new BiLaG a organ domain score or 2 new BiLaG B organ domain scores compared with baseline at the time of assessment (ie, at Week 52).
Secondary efficacy endpoints
The major secondary efficacy endpoints include:
1. Time to first severe flare (as measured by the modified SLe Flare index).
2. Percent of subjects whose average prednisone dose has been reduced by [GreaterThanorequalTo] 25% from baseline to [LessThanorequalTo] 7.5 mg/day during Weeks 40 through 52, in subjects receiving greater than 7.5 mg/day at baseline
Subjects enrolled in the study must meet the following inclusion criteria:
1. Are at least 18 years of age.
2. Are self-identified black race.
3. Have a clinical diagnosis of SLE according to the American College of Rheumatology (ACR) criteria
4. Have active SLE disease defined as a SELENA SLEDAI score >= 8 at screening
5. Have unequivocally positive autoantibody test results defined as an ANA titer >= 1:80 and/or a positive anti-dsDNA (>= 30 IU/mL) serum antibody test from 2 independent time points as follows:
* Positive test results from 2 independent time points within the study screening period. Screening results must be based on the study[Single Quote]s central laboratory results.
* One positive historical test result and 1 positive test result during the screening period.
- Historical documentation of a positive test of ANA (eg, ANA by HEp-2 titer ) or anti-dsDNA (eg, anti-dsDNA by Farr assay) must include the date and type of the test, the name of the testing laboratory, numerical reference range, and a key that explains values provided as positive vs negative OR negative, equivocal/borderline positive). Only unequivocally positive values as defined in the laboratory[Single Quote]s reference range are acceptable; borderline values will not be accepted.
6. Are on a stable SLE treatment regimen consisting of any of the following medications (alone or in combination) for a period of at least 30 days prior to Day 0 (ie, day of 1st dose of study agent)
* Corticosteroids (prednisone or prednisone equivalent, up to 40 mg/day):
- For subjects on SLE combination therapy, their stable steroid dose must be fixed within the range of 0 to 40 mg/day (prednisone or prednisone equivalent).
- For subjects whose only SLE treatment is steroids, their stable steroid dose must be fixed within the range of 7.5 to 40 mg/day (prednisone or prednisone equivalent).
- For those subjects on alternating day doses of steroids, use the average of 2 daily doses to calculate the average daily steroid dose.
* Other immunosuppressive or immunomodulatory agents including methotrexate, azathioprine, leflunomide, mycophenolate (including mycophenolate mofetil, mycophenolate mofetil hydrochloride, and mycophenolate sodium), calcineurin inhibitors (eg, tacrolimus, cyclosporine), sirolimus, oral cyclophosphamide, 6- mercaptopurine, mizoribine, or thalidomide.
* Anti-malarials (eg, hydroxychloroquine, chloroquine, quinacrine).
* Non-steroidal anti-inflammatory drugs (NSAIDs).
* Pre-existing SLE medications must be stable for at least 30 days prior to Day 0.
* Corticosteroids may be added as new medication or their doses adjusted only up to 30 days prior to Day 0 (see Exclusion Criterion #6).
* New SLE therapy other than corticosteroids must not be added within 60 days of Day 0.
7. A female subject is eligible to enter the study if she is:
* Not pregnant or nursing;
* Of non-childbearing potential (ie, women who had a hysterectomy, are postmenopausal which is defined as 1 year without menses, have both ovaries surgically removed, or have current documented tubal ligation or any other permanent female sterilization procedure); or
* Of childbearing potential (ie, women with functional ovaries and no documented impairment of oviductal or uterine function that would cause sterility). This category includes women with oligomenorrhoea [even severe], women who are perimenopausal, or have just begun to menstruate. These women must have a negative serum pregnancy test at screening, and agree to 1 of the following:
- Complete abstinence from intercourse from 2 weeks prior to administration of the 1st dose of study agent until 16 weeks after the last dose of study agent; or
- Consistent and correct use of 1 of the following acceptable methods of birth control for 1 month prior to the start of the study agent, during the study, and 16 weeks after the last dose of study agent:
* Implants of levonorgestrel or etonogestrel;
* Ethinyl estradiol/Etonogestrel vaginal ring;
* Injectable progesterone;
* Any intrauterine device (IUD) with a documented failure rate of less than 1% per year;
* Oral contraceptives (either combined or progesterone only);
* Double barrier method: condom and occlusive cap (diaphragm or cervical/vault
caps) with spermidical foam/gel/film/cream/suppository;
* Transdermal contraceptive patch;
* Male partner who is sterile prior to the female subject[Single Quote]s entry into the study and is the sole sexual partner for the female subject.
NOTE: MMF and other forms of mycophenolate affect the metabolism of oral contraceptives and may reduce their effectiveness. As such, women receiving mycophenolate who are using oral contraceptives for birth control should employ an additional method (eg, barrier method).
8. Have the ability to understand the requirements of the study, provide written informed consent (including consent for the use and disclosure of research-related health information), and comply with the study protocol procedures (including required study visits).