Pediatric Lupus Trial of Belimumab Plus Background Standard Therapy (PLUTO)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Glaxosmithkline Research & Development Limited

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

14 Sep 2012 → 30 Sep 2025

Decision date (initial)

2024-06-20

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

GSK Research and Development

External identifiers

EU CT number

2024-512730-15-00

EudraCT number

2011-000368-88

ClinicalTrials.gov

NCT01649765

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Efficacy

"Evaluate the efficacy of belimumab in the pediatric SLE population.
Evaluate the pharmacokinetics of belimumab in the pediatric SLE population.
Evaluate the safety and tolerability of belimumab in the pediatric SLE population.
Evaluate the effects of belimumab on the quality of life in the pediatric SLE population.
"

Secondary objectives 2

1. To evaluate the sustained efficacy and safety of belimumab in the pediatric SLE population.
2. Evaluate the effects of belimumab on the quality of life and fatigue in the pediatric SLE population.

Conditions and MedDRA coding

Systemic Lupus Erythematosus

Study design 1 period

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-000520-PIP01-08

Plan to share IPD

Yes

IPD plan description

Qualified researchers may request access to anonymized individual patient-level data (IPD) and related study documents of the eligible studies via the Data Sharing Portal. Details on GSK's data sharing criteria can be found at: https://www.gsk.com/en- gb/innovation/trials/data-transparency/

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Are 5 to 17 years of age.
2. Have or have had in series, 4 or more of the American College of Rheumatology (ACR) 11 criteria for the classification of SLE.
3. Have active SLE disease defined as a SELENA SLEDAI score ≥ 6 at screening.
4. "Have unequivocally positive autoantibody test results defined as an ANA titre ≥ 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's central laboratory results. OR - One positive historical test result and 1 positive test result during the screening period. Historical documentation of a positive test of ANA (e.g., ANA by HEp-2 titre) or anti-dsDNA (e.g., 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's reference range are acceptable; borderline values will not be accepted."
5. "Are on a stable SLE treatment regimen. "" Stable treatment at baseline"" consists of any of the following medications (alone or in combination) at a fixed dose for a period of at least 30 days prior to Day 0: - Corticosteroids (prednisone or prednisone equivalent up to 0.5 mg/kg/day): -For subjects on SLE combination therapy, their stable steroid dose must be fixed within the range of 0 to 0.5mg/kg/day (prednisone or prednisone equivalent) - For subjects whose only SLE treatment is steroids, their stable steroid dose must be fixed within the range of 0.1-0.5mg/kg/day. - 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 (e.g. tacrolimus, cyclosporine), sirolimus, oral cyclophosphamide, 6-mercaptopurine or thalidomide. - Anti-malarials (e.g. hydroxychloroquine, chloroquine, quinacrine) - Non-steroidal anti-inflammatory drugs (NSAIDs) Note: - Pre-existing SLE medications must be stable for at least 30 days prior to Day 0. - Corticosteroids may be added as new medications or their doses adjusted only up to 30 days prior to Day 0. - New SLE therapy other than corticosteroids must not be added within 60 days of Day 0. "
6. "A sexually active female subject is eligible to enter the study if she is: - Not pregnant or nursing; - Of non-childbearing potential. Non-childbearing potential is defined as a premenarcheal female who has not yet entered puberty as evidenced by lack of breast development (palpable glandular breast tissue); or a female who has documentation (medical report verification) of a hysterectomy, has both ovaries surgically removed or tubal ligation; or - Of childbearing potential (i.e., with functional ovaries and no documented impairment of oviductal or uterine function that would cause sterility). This category includes those with oligomenorrhoea [even severe]. These 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 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 spermicidal foam/gel/film/cream/suppository; - Transdermal contraceptive patch; - Male partner who is sterile prior to the female subject's entry into the study and is the sole sexual partner for the female subject. Note: Mycophenolate mofetil (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)."
7. Subject signs and dates a written age appropriate assent form (in accordance with applicable regulations) and the parent or legal guardian (or emancipated minor) that has the ability to understand the requirements of the study, provides written informed consent (including consent for the use and disclosure of research-related health information) that the subject will comply with the study protocol procedures (including required study visits).

Exclusion criteria 26

1. Have received treatment with belimumab (BENLYSTA™) at any time.
2. "Have an estimated glomerular filtration rate (eGFR) as calculated by Schwartz Formula of less than 30 ml/min."
3. "Have acute severe nephritis defined as a significant worsening of renal disease (e.g., the presence of urinary sediments and other lab abnormalities) that, in the opinion of the study investigator, may lead to the subject requiring induction therapy with IV cyclophosphamide, MMF or high dose corticosteroids during the first 6 months of the trial. Note: clinically stable lupus nephritis which can be managed with medications allowed in the study will not exclude subjects from participating in the trial (nor will any maximum level of proteinuria exclude subjects). Clinical assessment and medical management of nephritis will be at the discretion of the study investigator."
4. "Have a history of a major organ transplant (e.g., heart, lung, kidney, liver) or hematopoietic stem cell/marrow transplant."
5. "Have clinical evidence of significant, unstable or uncontrolled, acute or chronic diseases not due to SLE (i.e., cardiovascular, pulmonary, hematologic, gastrointestinal, hepatic, renal, neurological, malignancy or infectious diseases) which, in the opinion of the principal investigator, could confound the results of the study or put the subject at undue risk."
6. "Have a planned surgical procedure or a history of any other medical disease (e.g., cardiopulmonary), laboratory abnormality, or condition (e.g., poor venous access) that, in the opinion of the principal investigator, makes the subject unsuitable for the study."
7. Have a history of malignant neoplasm within the last 5 years.
8. "Have received any of the following within 364 days of Day 0: - Treatment with any B-cell targeted therapy (e.g., rituximab, other anti- CD20 agents, anti- CD22 [epratuzumab], anti-CD52 [alemtuzumab], BLyS-receptor fusion protein [BR3], TACI-Fc) - Abatacept. - A biologic investigational agent"
9. Have required 3 or more courses of systemic corticosteroids for concomitant conditions (e.g., asthma, atopic dermatitis) within 364 days of Day 0 (Topical or inhaled steroids are permitted).
10. Have received intravenous (IV) cyclophosphamide within 60 days of Day 0.
11. "Have received any of the following within 90 days of Day 0: - Anti-TNF therapy (e.g., adalimumab, etanercept, infliximab). - Interleukin-1 receptor antagonist (anakinra). - Intravenous immunoglobulin (IVIG). - Plasmapheresis."
12. "Have received any of the following within 60 days of Day 0: - A non-biologic investigational agent. - Any new immunosuppressive/immunomodulatory agent, anti-malarial, NSAID, (See Inclusion Criteria #5) Note: New inhaled steroids and new topical immunosuppressive agents (e.g., eye drops, topical creams) are allowed. Any NSAID use for less than 1 week is allowed. - High dose prednisone or equivalent (> 1.5 mg/kg/day) or any steroid injection (intramuscular, intraarticular or intravenous). "
13. "Have received any of the following within 30 days of Day 0: - A live vaccine. - A change in dose of a corticosteroid, other immunosuppressive/ immunomodulatory agent, anti-malarial, NSAID, (See Inclusion Criteria #5)"
14. "Have active central nervous system (CNS) lupus (including seizures, psychosis, organic brain syndrome, cerebrovascular accident [CVA], cerebritis or CNS vasculitis) requiring therapeutic intervention within 60 days of Day 0."
15. Have required renal replacement therapy (e.g. hemodialysis, peritoneal dialysis) within 90 days of Day 0 or be currently on renal replacement therapy
16. Subjects 12 years of age and older who have evidence of serious suicide risk including any history of suicidal behavior in the last 6 months and/or any suicidal ideation of type 4 or 5 on the Columbia Suicide Severity Rating Scale (Refer to Appendix 12) in the last 2 months or who in the investigator's judgment, pose a significant suicide risk.
17. Have a history of a primary immunodeficiency
18. Have an IgA deficiency (IgA level < 10 mg/dL).
19. "Have acute or chronic infections requiring management, as follows: - Currently on any suppressive therapy for a chronic infection (such as tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical mycobacteria). - Hospitalization for treatment of infection within 60 days of Day 0. - Use of parenteral (IV or IM) antibiotics (antibacterials, antivirals, anti-fungals, or anti-parasitic agents) for infection within 60 days of Day 0."
20. Have current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or dependence within 364 days prior to Day 0.
21. Have a historically positive HIV test or test positive at screening for HIV.
22. "Hepatitis B: Serologic evidence of Hepatitis B (HB) infection based on the results of testing for HBsAg, anti-HBc and anti-HBs as follows: - Subjects positive for HBsAg are excluded - Subjects negative for HBsAg and anti-HBc antibody but positive for anti-HBs antibody are eligible to participate - Subjects negative for HBsAg and anti-HBs antibody but positive for anti-HBc antibody will require clarification of their status by testing for HB DNA which if positive will exclude the subject from participation. Subjects with documented vaccination against Hepatitis B (primary and secondary immunization and booster) will be considered negative."
23. Hepatitis C: Positive test for Hepatitis C antibody confirmed on an additional blood sample by RNA PCR assay. Subjects who are positive for Hepatitis C antibody and negative when the Hepatitis C RNA-PCR assay is performed on an additional sample will be eligible to participate. Subjects who are positive for Hepatitis C antibody and have a positive result for the HCV when the Hepatitis C RNA PCR assay is performed on the additional sample will not be eligible to participate. (Institution or country specific guidelines for blood sample volume limits must be followed in collection of the additional blood sample.)
24. "Have a Grade 3 or greater laboratory abnormality based on the protocol toxicity scale except for the following that are allowed: - Stable Grade 3 prothrombin time (PT) secondary to warfarin treatment. - Stable Grade 3 partial thromboplastin time (PTT) due to lupus anticoagulant and not related to liver disease or anti-coagulant therapy. - Stable Grade 3 hypoalbuminemia due to lupus nephritis, and not related to liver disease or malnutrition. - Any grade proteinuria - Stable Grade 3 gamma glutamyl transferase (GGT) elevation due to lupus hepatitis, and not related to alcoholic liver disease, uncontrolled diabetes or viral hepatitis. If present, any abnormalities in the ALT and or AST must be ≤ Grade 2. - Stable Grade 3 neutropenia; or stable Grade 3 lymphopenia; or stable Grade 3 leukopenia, due to SLE "
25. Have a history of an anaphylactic reaction to parenteral administration of contrast agents, human or murine proteins or monoclonal antibodies.
26. Children in Care: A Child in Care (CiC) is a child who has been placed under the control or protection of an agency, organisation, institution or entity by the courts, the government or a government body, acting in accordance with powers conferred on them by law or regulation. The definition of a CiC can include a child cared for by foster parents or living in a care home or institution, provided that the arrangement falls within the definition above. The determination of whether a child meets the definition of CiC should be made with the study centre staff in consultation with the responsible IRB/Ethics Committee.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. "SLE Responder Index (SRI) response rate at Week 52 which is defined as: I. ≥ 4-point reduction from baseline in SELENA SLEDAI score AND II. No worsening (increase of < 0.30 points from baseline) in Physician's Global Assessment (PGA) AND II. No new British Isles Lupus Assessment Group (BILAG) A organ domain score or 2 new BILAG B organ domain scores compared with baseline."

Secondary endpoints 14

1. "Proportion of subjects meeting PRINTO/ACR Juvenile SLE response evaluation criteria for improvement in juvenile SLE defined as at least 50% improvement in 2 of 5 endpoints (at week 52) below and no more than 1 of the remaining worsening by more than 30%: I. Percent change in Parent's Global Assessment II. Percent change from baseline in PGA III. Percent change from baseline in SELENA SLEDAI score IV. Percent change from baseline in Pediatric V. Percent change in 24-hour proteinuria"
2. "Proportion of subjects meeting PRINTO/ACR Juvenile SLE response evaluation criteria for improvement in juvenile SLE defined as at least 30% improvement in 3 of 5 endpoints (at week 52) below and no more than 1 of the remaining worsening by more than 30%: I. Percent change in Parent's Global Assessment II. Percent change from baseline in PGA III. Percent change from baseline in SELENA SLEDAI score IV. Percent change from baseline in Pediatric V. Percent change in 24-hour proteinuria"
3. Percent change from baseline in Parent Global Assessment at week 52
4. Percent change from baseline in PGA at week 52
5. Percent change from baseline in SELENA SLEDAI at week 52
6. Percent change from baseline in PedsQL Physical Functioning Domain Score at Week 52
7. Percent change from baseline in proteinuria at Week 52
8. Proportion of subjects with a sustained SRI response
9. Proportion of subjects with a sustained Parent Global Assessment response
10. Safety of belimumab
11. Observed serum concentrations of belimumab
12. PK comparison with adult PK
13. Quality of life evaluated using Pediatric Quality of Life Inventory - Generic Core (PedsQL-GC) and PedsQL Multidimensional Fatigue Scale (PedsQL - Fatigue)
14. evaluation of biological markers

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Glaxosmithkline Research & Development Limited

Sponsor organisation

Glaxosmithkline Research & Development Limited

Address

G S K House, 980 Great West Road 980 Great West Road

City

Brentford

Postcode

TW8 9GS

Country

United Kingdom

Scientific contact point

Organisation

Glaxosmithkline Research & Development Limited

Contact name

EU GSK Clinical Trials Call Center

Public contact point

Organisation

Glaxosmithkline Research & Development Limited

Contact name

EU GSK Clinical Trials Call Center

Third parties 13

Locations

1 EU/EEA country · 3 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 39 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications