A Phase III, Randomized, Double-blind, Parallel-group, Placebo controlled Study to Evaluate the Pharmacokinetics, Pharmacodynamics, Efficacy, and Safety of IV Anifrolumab in Pediatric Participants 5 to < 18 Years of Age with Moderate to Severe Active Systemic Lupus Erythematosus While on Background Standard of Care Therapy
- Trial ID
- 2022-502289-25-00
- Protocol
- D3461C00030
- Sponsor
- AstraZeneca AB
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to **characterize the pharmacokinetics (PK)** and define the appropriate dose of **anifrolumab** in pediatric participants with moderate to severe active **Systemic Lupus Erythematosus (SLE)**. Additionally, the study aims to evaluate the efficacy of anifrolumab compared to placebo on the BICLA response in this population. Understanding the PK and determining the correct dosing is crucial for optimizing therapeutic outcomes and ensuring safety in pediatric patients with SLE.
Secondary objectives include:
- Characterizing the efficacy of anifrolumab versus placebo on the SRI(4) response in pediatric participants with moderate to severe active SLE.
- Assessing the efficacy of anifrolumab versus placebo on the time to first flare in these participants.
- Characterizing the pharmacokinetics (PK), immunogenicity, and pharmacodynamics (PD) of anifrolumab in the pediatric population with moderate to severe active SLE.
- Evaluating the efficacy of anifrolumab versus placebo on the PRINTO/ACR cSLE response in pediatric participants.
- Assessing the efficacy of anifrolumab versus placebo on the oral corticosteroid (OCS) background dose in pediatric participants with moderate to severe active SLE.
These secondary objectives aim to provide a comprehensive understanding of the therapeutic potential and safety profile of anifrolumab in managing pediatric SLE, which is essential for improving clinical outcomes in this vulnerable population.
Participants
The clinical trial involves a total of **80 participants** diagnosed with **Moderate to Severe Active Systemic Lupus Erythematosus**. The study population comprises both male and female subjects aged between **5 to less than 18 years**. Participants were selected based on specific inclusion criteria, including a confirmed diagnosis of systemic lupus erythematosus according to the 2019 EULAR/ACR criteria for at least six months prior to enrollment. All participants are required to have a body weight of at least 15 kg at screening. The trial includes individuals who are auto-antibody positive and are receiving stable standard of care regimens, such as oral prednisone, antimalarials, or immunosuppressants. Participants must have moderate to severe active disease as adjudicated by the Central Adjudication Committee. The trial population is characterized by a vulnerable group, given the pediatric nature of the study. Lifestyle considerations such as diet and physical activity are not specified in the provided data. The selection process ensures that participants meet all necessary health and safety criteria, including negative SARS-CoV-2 test results and no active or latent tuberculosis. The trial aims to evaluate the pharmacokinetics and efficacy of anifrolumab in this specific pediatric population.
Plans and Procedures
The clinical trial is a **Phase III**, randomized, double-blind, parallel-group, placebo-controlled study designed to evaluate the pharmacokinetics, pharmacodynamics, efficacy, and safety of intravenous **anifrolumab** in pediatric participants aged 5 to less than 18 years with moderate to severe active **systemic lupus erythematosus** (SLE). The trial aims to define the appropriate dose of anifrolumab and assess its efficacy compared to a placebo, which contains no active ingredient. The study is expected to last until September 2029, with participant recruitment starting in October 2024.
Participants will be involved in the study for a maximum treatment period of 104 weeks. The trial includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to assess final outcomes. The screening visit will ensure participants meet all inclusion criteria, such as a body weight of at least 15 kg, a diagnosis of SLE according to the 2019 EULAR/ACR criteria, and a negative SARS-CoV-2 test result. Participants must also be on a stable standard of care regimen for SLE.
Follow-up visits will occur at regular intervals to monitor the participants' response to treatment and any adverse events. The primary endpoints include pharmacokinetic parameters such as Cmax and AUC, and the proportion of BICLA responders at week 52. Secondary endpoints include SRI(4) responders at week 52, time to first flare, and changes in anifrolumab serum concentration and other biomarkers. Participants may be withdrawn from the study if they experience significant adverse events, fail to comply with the study protocol, or if the investigator deems it in their best interest.
Treatment
The clinical trial involves the administration of **Saphnelo**, a 300 mg **concentrate for solution for infusion** containing the active substance **anifrolumab**. Anifrolumab is a protein-based therapeutic agent, specifically classified under the ATC code L04AA51. The pharmaceutical form of Saphnelo is a concentrate intended for intravenous infusion. The maximum daily and total dose is 300 mg, administered via intravenous infusion. The treatment period extends up to 104 weeks. The product is manufactured by AstraZeneca AB and is authorized for use in the European Union under the marketing authorization number EU/1/21/1623/001. The administration of Saphnelo is conducted in a controlled clinical setting to ensure adherence to the dosing schedule and to monitor participant compliance.
The study also includes a **placebo** group, which receives an infusion containing no active ingredient. The placebo formulation consists of L-histidine, L-histidine hydrochloride monohydrate, L-lysine hydrochloride, trehalose dihydrate, and polysorbate 80. It does not contain any preservatives or novel excipients. The placebo is administered in the same manner as the experimental treatment, ensuring blinding and maintaining the integrity of the study design. The placebo serves as a comparator to evaluate the efficacy and safety of anifrolumab in pediatric participants with moderate to severe active systemic lupus erythematosus (SLE) while on background standard-of-care therapy.
Efficacy
Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary efficacy endpoint is the proportion of participants who are BICLA responders at Week 52. A BICLA responder is defined by the reduction of all baseline BILAG A scores to B/C/D and B scores to C/D, with no worsening in other organ systems, no worsening from baseline in SLEDAI-2K scores, and no increase of ≥ 0.30 points on a PGA 3-point VAS. Secondary endpoints include the proportion of SRI(4) responders at Week 52, time to first flare through Week 52, and changes from baseline through Week 52 in various biomarkers such as anifrolumab serum concentration, anti-dsDNA antibodies, and complement levels (C3, C4, CH50). Additionally, the trial will evaluate the reduction of oral corticosteroid (OCS) background dose from baseline through Week 52 and the proportion of participants who are PRINTO/ACR cSLE responders at Week 52, defined as at least 50% improvement in any two of five core set outcome measures.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participant’s parent/caregiver/legally authorized representative and participant (if required per local country regulation) capable of giving signed informed consent as described in Appendix A which includes compliance with the requirements and restrictions listed in the ICF and in this protocol. Informed assent is to be provided by the participant per local country regulation.
- At Screening, body weight ≥ 15 kg
- Male participants: All fertile males who are sexually active must use a condom from Day 1 until at least 16 weeks after receipt of the last dose of study intervention. Tanner staging (Section 1.3 and Section 8.3.3) is required to allow the investigator to assess when male participants may achieve potential fertility (ie, Tanner stage 3 and above) NOTE: It is strongly recommended that the female partner of a male participant also use an effective method of contraception from Table 10 throughout this period.
- Female participants of childbearing potential* must meet all the following requirements: (a) Must have negative serum β-human chorionic gonadotropin test result at Screening (b) Must have negative urine pregnancy test result prior to administration of study intervention at randomization (DAY 1) (c) If sexually active, must use one highly effective method of contraception, plus a male condom, from Screening until 16 weeks after the last dose of study intervention (Table 10). Participants who are not sexually active, ie, true sexual abstinence in line with the preferred and usual lifestyle choice of the participant, are not required to use contraception. *A female is considered of childbearing potential if she is capable of conceiving. While this is typically the case following first menarche, adolescents can ovulate prior to first menarche. Assessment of female adolescents for the development of secondary sexual characteristics (Tanner stage) should be assessed at Screening to assist in determining childbearing potential. Assessment of female participants (Tanner staging – Sections 1.3 and 8.3.3 and Appendix P) for the development of secondary sexual characteristics, is mandatory during Screening and should be used by the investigator along with assessment of menarcheal status, for judging potential fertility. Female participants will be considered of childbearing potential if they have had first menarche or achieved Tanner stage 3 or higher. Highly effective methods of contraception (those that can achieve a failure rate of less than 1% per year when used consistently and correctly) include those listed in Table 10.
- Completion of Screening procedures within 30 days after signing the ICF.
- At the time of signing the ICF, males or females ≥ 5 to < 18 years of age.
- Diagnosis of SLE according to the 2019 EULAR/ACR criteria, for at least 3 months (≥ 12 weeks) prior to signing the ICF.
- Auto-antibody positivity for ANA immunofluorescent assay test (titer ≥ 1:80), at Screening, as determined by the central laboratory. NOTE: Retesting of ANA is allowed once during Screening.
- Must be receiving at least one of the following stable SoC regimens: (a) Oral prednisone (OCS) or equivalent monotherapy: (i) Start date ≥ 6 weeks prior to signing the ICF (ii) Dose must be stable for ≥ 2 weeks before Day 1 (randomization) (iii) TDD between 0.5 – 1.0 mg/kg/day to a maximum dose of 40 mg/day (iv) For participants on OCS monotherapy, documented intolerance, lack of therapeutic benefit, or contraindication to other SoC treatments described in inclusion criterion 6b—or confirmation that study participation is in the participant’s best interest per the investigator’s judgment—is required. (b) Antimalarials and/or immunosuppressant(s) with or without OCS: (i) Permitted antimalarials include: hydroxychloroquine, chloroquine, quinacrine. (ii) Permitted immunosuppressants include azathioprine, mycophenolate mofetil/mycophenolic acid, methotrexate, mizoribine, and tacrolimus NOTE: Immunosuppressant medications are not permitted in combination. Only OCS and/or antimalarials may be used in combination with immunosuppressants. (iii) Start date ≥ 12 weeks prior to signing the ICF (iv) Dose must be stable for ≥ 8 weeks prior to signing the ICF and remain stable throughout the Screening period (v) Maximum allowed daily dose: a. Azathioprine: ≤ 200 mg/day b. Mycophenolate mofetil: ≤ 3 g/day or mycophenolic acid ≤ 2.16 g/day c. Oral, SC, or IM methotrexate: ≤ 25 mg/week d. Mizoribine: ≤ 150 mg/day e. Tacrolimus: ≤ 0.2 mg/kg/day NOTES: a. For OCS, a maximum TDD of 40 mg/day applies to all participants receiving OCS as monotherapy or in combination with other therapies. b. A minimum 8 week period on a stable dose of each immunosuppressant is required even if a participant on dual immunosuppressants has discontinued one prior to Screening. c. For guidance regarding eligibility of participants previously treated with biologics, please refer to exclusion criteria 20, 23, 24 and 25.
- At Screening, participant must have moderate to severe active SLE disease, as adjudicated by the Central Adjudication Committee, defined as: (a) SLEDAI-2K activity of: (i) ≥ 6 points with at least 4 points (≥ 4 points) coming from the following clinical components (‘Clinical’ SLEDAI-2K score): arthritis, myositis, rash, alopecia, mucosal ulcers, pleurisy, pericarditis, or vasculitis and excluding points attributed to a fever, SLE headache, and organic brain syndrome (ii) Clinical SLEDAI score of ≥ 4 points must also be verified at Day 1 NOTE: a. If the minimum Clinical SLEDAI (≥ 4 points) is solely due to mucocutaneous manifestations (oral/nasopharyngeal ulcers, alopecia, rash), or if > 50% of the total points are due to mucocutaneous manifestations, a rash must be present as part of the score. (b) BILAG-2004 activity of: (i) ≥ 1 BILAG A score; or (ii) ≥ 2 BILAG B scores (c) PGA score ≥ 1.0 on a 0 to 3 VAS
- Meets all the following TB criteria prior to signing ICF or at any time during the Screening period: (a) No signs or symptoms of active TB (b) No medical history or past physical examinations suggestive of active TB (c) No recent contact with a person with active TB or if there has been such contact, referral to a TB specialist for evaluation and initiation of treatment for latent TB, if warranted, prior to the first administration of study intervention in accordance with local SoC (d) No history of latent TB without documented completion of treatment prior to initial Screening Visit
- Must undergo an IGRA (eg, QFT-G) test for TB obtained from the central laboratory at Screening with any of the following results: (a) Negative result (b) Positive result: referral to a TB specialist for evaluation and for which active TB has been ruled out (as described in the protocol definition; Section 8.4.8.5), and initiation of treatment for latent TB prior to the first administration of study intervention in accordance with local SoC (c) Indeterminate result that has been confirmed indeterminate upon immediate retesting: (i) If in an endemic region (Appendix I), referral to a TB specialist for evaluation and initiation of treatment for latent TB, if warranted, prior to the first administration of study intervention in accordance with local SoC. If treatment is not warranted, the participant may enter the study but must be administered a retest at least every 12 months and will complete the TB questionnaire at every on site study visit. If upon retest the result is indeterminate or negative, the participant may continue in the study without treatment and with routine TB testing. (ii) If in a non-endemic region, it is recommended but not required that the participant be referred to a TB specialist for evaluation. The participant may enter the study without referral to a TB specialist and without latent TB treatment but must be administered a retest at least every 12 months and will complete the TB questionnaire at every on site study visit. If, upon retest the result is indeterminate or negative, the participant may continue in the study without treatment and with routine TB testing. NOTES: a. A participant with a positive IGRA test result upon retest (after an initial indeterminate result) should follow the criteria above for a positive test result. b. A participant with a negative IGRA test result upon retest (after an initial indeterminate result) should follow the criteria above for a negative test result. c. All participants who begin treatment for latent TB must commit to completing the full course of therapy. d. A participant with an indeterminate IGRA test result in a non endemic region, can defer immediate retesting during Screening for a retest at Visit 1, immediately before effective randomization and study intervention administration, and conditional to available clinical evidence for rule out of latent TB provided by the investigator.
Exclusion Criteria
- Known diagnosis of an IFN-mediated autoinflammatory interferonopathy (eg, AG, SAVI, CANDLE, COPA).
- Receipt of any live or attenuated vaccine within 8 weeks prior to signing the ICF: (a) Administration of killed, inactivated, or recombinant vaccines is acceptable (b) AstraZeneca recommends investigators ensure all participants are up to date on required/recommended vaccinations including influenza (inactivated/recombinant) vaccine prior to study entry) (Section 6.9.5).
- A known history of allergy or reaction to any component of the study intervention formulation or history of anaphylaxis to any human gamma globulin therapy, human proteins, or monoclonal antibodies.
- Known history of a primary immunodeficiency, splenectomy, or any underlying condition that predisposes the participant to infection, or a positive result for HIV infection confirmed by central laboratory at Screening: (a) An HIV test must be performed during Screening, and the result should be available before randomization. The participant is ineligible to participate in the study when positive for HIV antibody or infection (ie, positive nucleic acid test) performed by the central laboratory. Participants refusing HIV testing during the Screening period will not be eligible for study participation.
- At Screening (within 4 weeks of randomization), any of the following (NOTE: retesting of central laboratory test results during Screening may be repeated once): (a) eGFR < 35 mL/min/1.73m2 by modified Schwartz formula (b) AST or ALT > 2.0 × ULN (c) Alkaline phosphatase > 5.0 × ULN (d) TBL > ULN (unless due to Gilbert’s syndrome) (e) Serum creatinine > 2.5 mg/dL (f) Urine protein/creatinine ratio > 2.0 mg/mg (or > 226.30 mg/mmol) (g) Neutrophil count < 1000/μL (or < 1.0 × 10⁹/L) (h) Platelet count < 50000/μL (or < 50 × 10⁹/L) (i) Hemoglobin < 8 g/dL (or < 80 g/L), or < 7 g/dL (or < 70 g/L) if related to participant’s SLE such as in active hemolytic anemia (j) Any other laboratory value in the Screening panel that, in the opinion of the investigator, is clinically significant or might confound analysis of study results.
- At Screening, 12-lead ECG with clinically significant abnormalities.
- In participants aged ≥ 11 years, a history or evidence of suicidal ideation (severity of 4 [active: method and intent, but no plan] or 5 [active: method, intent, and plan]) within the past 6 months; or any suicidal behavior within the past 12 months or recurrent suicidal behavior in the lifetime of the participant based on an assessment with the C-SSRS at Screening or at baseline.
- Concurrent enrollment in another clinical study with a study intervention.
- Individuals involved with the conduct of the study, their employees, or immediate family members of such individuals.
- For females of childbearing potential: Currently lactating, breastfeeding, pregnant (confirmed with a positive serum pregnancy test) or intending to become pregnant or begin breastfeeding anytime from initiation of Screening until 16 weeks following the last dose of study intervention.
- Spontaneous or induced abortion, still or live birth, or pregnancy ≤ 4 weeks prior to signing the ICF.
- COVID-19: (a) Any history of severe COVID-19 infection (eg, requiring prolonged hospitalization [hospitalization for observational purposes is not exclusionary], intensive care unit care, or assisted ventilation) or any prior COVID-19 infection with documented long COVID and/or clinically significant unresolved sequelae. (b) Within 2 weeks prior to Day 1, any mild/asymptomatic COVID-19 infection (laboratory confirmed or suspected based on clinical symptoms). Note: In case of positive COVID-19 RT-PCR or rapid antigen test result at Screening, rescreening may be allowed after 4 weeks of mild/asymptomatic infection or at the discretion of the investigator, provided there has been no development of severe COVID-19 infection or sequelae. Participants may also be rescreened a second time following rescreening procedures, if the reason for screen failure was due to positive COVID-19 test.
- History of or current alcohol, drug, or chemical abuse prior to signing the ICF.
- Major surgery within 8 weeks before signing the ICF or elective major surgery planned during the study period.
- Active hepatitis B infection, as per central laboratory, defined as: (a) Positive HBsAg; or (b) Positive HBcAb and HBV DNA detected above the lower limit of quantification by reflex testing by the central laboratory. NOTE: Participants who are HBcAb positive at Screening will be tested at least every 12 weeks for HBV DNA. To remain eligible for the study, the participant’s HBV DNA levels must remain below the LLOQ as per the central laboratory.
- Active severe or unstable neuropsychiatric SLE including, but not limited to: aseptic meningitis; cerebral vasculitis; myelopathy; demyelination syndromes (ascending, transverse, acute inflammatory demyelinating polyradiculopathy); acute confusional state; impaired level of consciousness; psychosis; acute stroke or stroke syndrome; cranial neuropathy; status epilepticus; cerebellar ataxia; and mononeuritis multiplex.
- Active, severe SLE-driven renal disease (ISN/RPS or WHO: Class III or IV plus/minus Class V) with significant proteinuria at Screening or randomization in whom protocol specified standard therapy is insufficient in the opinion of the investigator or the Sponsor. In such participants it would be expected that more intensive SLE treatment is indicated that is not permitted in the protocol. Examples of more intensive immunosuppression include increase of mycophenolate dose (unless stable per Table 12), and/or adding IV cyclophosphamide, and/or biologic immunosuppressants, and/or CNI (except tacrolimus monotherapy per Table 12), and/or administering high-dose IV pulse corticosteroid therapy or other treatments prohibited by the protocol. Participants with controlled renal disease with serum creatinine under the ULN and mild to moderate residual proteinuria with a UPCR of 2 mg/mg or less are allowed to participate in the study. Control of renal disease must be documented with at least 2 stable measurements of proteinuria or UPCR over the past 6 months, at least 4 weeks apart.
- History of, or current diagnosis of, catastrophic APS within one year prior to signing the ICF. Participants with other degrees of adequately controlled APS can be recruited to the study.
- History of any non-SLE disease that has required treatment with oral or parenteral corticosteroids for more than a total of 2 weeks within the last 24 weeks prior to signing the ICF.
- Any other significant disease, disorder, or finding that, in the opinion of the investigator or AstraZeneca, may significantly increase the risk to the participant because of participation in the study, affect their ability to participate in the study, or interfere with the evaluation of study intervention and/or interpretation of the participant’s safety and the study data.
- History of recurrent infection requiring hospitalization and IV antibiotics (eg, 3 or more of the same type of infection over the previous 52 weeks).
- Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.
- Prior receipt of anifrolumab
- Active hepatitis C infection, as per central laboratory, defined as positive HCV antibody and detectable HCV RNA.
- Any active or recent case of HZ including: (a) Any HZ infection that has not completely resolved within 12 weeks prior to signing the ICF. (b) Any case of HZ emerging between ICF signature and randomization (Day 1).
- Any clinical cytomegalovirus or Epstein-Barr virus infection that has not completely resolved within 12 weeks prior to signing the ICF.
- Opportunistic infection (Section 8.4.8.3) requiring hospitalization or IV antimicrobial treatment within 3 years of randomization.
- Any of the following: (a) Clinically significant, chronic infection (ie, osteomyelitis, bronchiectasis, etc) within 8 weeks prior to signing the ICF (chronic nail infections are allowed) (b) Any infection requiring hospitalization or treatment with IV anti-infectives not completed at least 4 weeks prior to signing the ICF (c) Any infection requiring oral anti-infectives (including antivirals) within 2 weeks prior to Day 1. NOTE: Oral anti-infectives for chronic nail infections, recurrent UTIs, and acne are permitted.
- History of cancer, apart from: (a) Squamous or basal cell carcinoma of the skin treated with documented success of curative therapy ≥ 3 months prior to Week 0 (Day 1).
- History of, or current diagnosis of, clinically significant non-SLE-related vasculitides (Appendix F). Vasculitides due to SLE are allowed in the study.
- Any change in route of administration of oral, SC, or IM methotrexate anytime within the 8 weeks prior to signing the ICF through Day 1.
- Receipt of intra-articular, IM or IV glucocorticoids within 2 weeks (≤ 2 weeks) prior to signing ICF.
- Receipt of any commercially available biologic agent within 5 half-lives or specified washout period (whichever is longer, see Appendix G for a complete list) prior to signing the ICF.
- Receipt of any investigational agent (small molecule or biologic agent) within 5 half-lives prior to signing the ICF.
- Receipt of any prohibited medication listed in Appendix G unless the required washout period is met prior to signing ICF.
- Any history of severe or recurrent HZ including: (a) Any case of non-cutaneous HZ, herpes encephalitis, or ophthalmic herpes involving the retina at any time prior to signing of the ICF. (b) Any case of recurrent HZ defined as 2 or more episodes prior to signing of the ICF.
- Prior treatment with directly acting cytotoxic B-cell depleting therapeutics (eg, rituximab) < 26 weeks prior to ICF signature. NOTE: For participants treated with directly acting cytotoxic B-cell depleting therapeutics ≥ 26 weeks prior to ICF signature, B-cell levels measured at Screening must be above LLN or above baseline value prior to receipt of cytotoxic B-cell depleting therapy, whichever is lower.
- Blood transfusion or receipt of blood products except albumin within 4 weeks prior to signing the ICF.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 04 Oct 2024 | 3 |
 Germany | Recruiting | 04 Oct 2024 | 3 |
 Italy | Recruiting | 04 Oct 2024 | 4 |
 Poland | Recruiting | 04 Oct 2024 | 3 |
 Portugal | Not Yet Recruiting | 04 Oct 2024 | 2 |
 Spain | Recruiting | 04 Oct 2024 | 5 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
No active ingredient. The Placebo contains L-histidine, L-histidine hydrochloride monohydrate, L-lysine hydrochloride, trehalose dihydrate, and polysorbate 80. There are no preservatives or novel excipients included in the Placebo. | Placebo | N/A | — | — | — | N/A |
Saphnelo 300 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 300 | 104 | PRD9504474 |