A study of anifrolumab in children and adolescents (5 to < 18 years old) with moderate to severe lupus to find the appropriate anifrolumab dose for those participants and to confirm anifrolumab is safe and works in this population

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AstraZeneca AB

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

28 Aug 2024 → ongoing

Decision date (initial)

2023-11-10

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

AstraZeneca AB

External identifiers

EU CT number

2022-502289-25-00

ClinicalTrials.gov

NCT05835310

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Dose response, Efficacy, Pharmacodynamic

To characterize the PK profile and to define the dose of anifrolumab in pediatric participants with moderate to severe active SLE. To characterize the efficacy of anifrolumab versus placebo on BICLA response in pediatric participants with moderate to severe active SLE

Secondary objectives 5

1. To characterize the efficacy of anifrolumab versus placebo on SRI(4) response in pediatric participants with moderate to severe active SLE
2. To characterize the efficacy of anifrolumab vs placebo on time to first flare in pediatric participants with moderate to severe active SLE
3. To characterize the PK, immunogenicity, and PD of anifrolumab in pediatric participants with moderate to severe active SLE
4. To characterize the efficacy of anifrolumab versus placebo on PRINTO/ACR cSLE response in pediatric participants with moderate to severe active SLE
5. To characterize the efficacy of anifrolumab versus placebo on OCS background dose in pediatric participants with moderate to severe active SLE

Conditions and MedDRA coding

Moderate to Severe Active Systemic Lupus Erythematosus

Study design 5 periods

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-001435-PIP02-16

Plan to share IPD

Yes

IPD plan description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com /ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared. When a request has been approved AstraZeneca will provide access to the de-identified individual patientlevel data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at:https://astrazenecagrouptrials.pharmacm.com /ST/Submission/Disclosure. IPD Sharing Url https://astrazenecagroup-dt.pharmacm.com/DT/Home

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. 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.
2. At Screening, body weight ≥ 15 kg
3. 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.
4. 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.
5. Completion of Screening procedures within 30 days after signing the ICF.
6. At the time of signing the ICF, males or females ≥ 5 to < 18 years of age.
7. Diagnosis of SLE according to the 2019 EULAR/ACR criteria, for at least 3 months (≥ 12 weeks) prior to signing the ICF.
8. 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.
9. 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.
10. 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
11. 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
12. 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 38

1. Known diagnosis of an IFN-mediated autoinflammatory interferonopathy (eg, AG, SAVI, CANDLE, COPA).
2. 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).
3. 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.
4. 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.
5. 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.
6. At Screening, 12-lead ECG with clinically significant abnormalities.
7. 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.
8. Concurrent enrollment in another clinical study with a study intervention.
9. Individuals involved with the conduct of the study, their employees, or immediate family members of such individuals.
10. 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.
11. Spontaneous or induced abortion, still or live birth, or pregnancy ≤ 4 weeks prior to signing the ICF.
12. 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.
13. History of or current alcohol, drug, or chemical abuse prior to signing the ICF.
14. Major surgery within 8 weeks before signing the ICF or elective major surgery planned during the study period.
15. 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.
16. 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.
17. 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.
18. 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.
19. 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.
20. 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.
21. History of recurrent infection requiring hospitalization and IV antibiotics (eg, 3 or more of the same type of infection over the previous 52 weeks).
22. 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.
23. Prior receipt of anifrolumab
24. Active hepatitis C infection, as per central laboratory, defined as positive HCV antibody and detectable HCV RNA.
25. 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).
26. Any clinical cytomegalovirus or Epstein-Barr virus infection that has not completely resolved within 12 weeks prior to signing the ICF.
27. Opportunistic infection (Section 8.4.8.3) requiring hospitalization or IV antimicrobial treatment within 3 years of randomization.
28. 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.
29. 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).
30. History of, or current diagnosis of, clinically significant non-SLE-related vasculitides (Appendix F). Vasculitides due to SLE are allowed in the study.
31. 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.
32. Receipt of intra-articular, IM or IV glucocorticoids within 2 weeks (≤ 2 weeks) prior to signing ICF.
33. 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.
34. Receipt of any investigational agent (small molecule or biologic agent) within 5 half-lives prior to signing the ICF.
35. Receipt of any prohibited medication listed in Appendix G unless the required washout period is met prior to signing ICF.
36. 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.
37. 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.
38. Blood transfusion or receipt of blood products except albumin within 4 weeks prior to signing the ICF.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. After single dose or after dose adjustment: • Serum PK concentrations PK parameters: Cmax, AUC, Cmin after the first dose or after dose adjustment
2. BICLA responders at W52 (Y/N), defined as follow: Reduction of all baseline BILAG A to B/C/D & B to C/D & no BILAG worsening in other organ systems (≥ 1 new BILAG A or ≥ 2 new BILAG B) No worsening from baseline S-2K (increase of > 0 points) No worsening from baseline in SLE activity (increase ≥ 0.30 points on a PGA 3-point VAS)

Secondary endpoints 5

1. SRI(4) responders at Wk. 52 (Y/N): meet all the following: Minimum 4-point reduction from baseline (BL) SLEDAI2K score No new BILAG-2004 (BILAG) scores from BL (≥ 1 new A or ≥ 2 new BILAG B scores) No worsening in BL lupus disease activity (increase ≥ 0.30 points on a PGA 3-point VAS)
2. Time to first flare through Week 52, where flare is defined as either ≥ 1 new BILAG-2004 A, or ≥ 2 new BILAG-2004 B items compared with the previous visit.
3. • PK: Anifrolumab serum concentrations • Immunogenicity: ADA • PD: Change from baseline through Week 52 in: o Anti-dsDNA antibodies o C3, C4, and CH50 complement levels o Type I IFN 21-gene signature
4. Participants who are PRINTO/ACR cSLE responders (Y/N) at W52, defined as at least 50% improvement from baseline in any 2 of 5 core set outcome measures and no more than one of the remaining worsening > 30%
5. Reduction of OCS background dose from baseline through Week 52

Investigational products

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

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AstraZeneca AB

Sponsor organisation

AstraZeneca AB

Address

Astraallen Gartuna, Karlebyhus Byggnad 674 Karlebyhus Byggnad 674

City

Sodertalje

Postcode

151 85

Country

Sweden

Scientific contact point

Organisation

AstraZeneca AB

Contact name

Clinical Study Information Centre

Public contact point

Organisation

AstraZeneca AB

Contact name

Clinical Study Information Centre

Third parties 1

Locations

6 EU/EEA countries · 22 investigational sites

By country

Investigational sites

Country notifications

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

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Corrective measures 1 · Art. 77 CTR

Results and documents

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

Documents 119 files

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

Application history

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