A Study to Investigate the Efficacy and Safety of Anifrolumab Administered as Subcutaneous Injection and Added to Standard of Care Compared with Placebo Added to Standard of Care in Adult Participants with Idiopathic Inflammatory Myopathies (Polymyositis and Dermatomyositis)

Phase 3

Not yet recruiting

• Conditions: Polymyositis, (2) ICD-10 Condition: M331||Other dermatomyositis,

• Registration Number: CTRI/2024/11/077478
• Lead Sponsor: AstraZeneca AB

Brief Summary

This is a multicentre, randomized, double-blind,placebo-controlled, Phase III study to evaluate the efficacy and safety ofanifrolumab in adult participants with moderate to severe active Polymyositis(PM), while receiving stable standard-of-care therapy. The study designincludes a double-blind, placebo-controlled treatment period of 24 weeks; 162eligible participants will be randomized in a 1:1 ratio to receive anifrolumab120 mg SC QW or placebo SC QW for 24 weeks (Week 0 Day 1 to Week 23 Day 162).At Week 24, all participants will rollover to an open-label period of 28 weeksin which they will receive anifrolumab 120 mg SC QW.

 The studyintervention (anifrolumab or placebo) will be administered on top of standardof care treatments, which are allowed at stable regimens and doses as per thespecifications described in Section 6.9.2 of the Clinical Study Protocol. To

minimize the risk of baseline imbalances betweenanifrolumab and placebo for potentially confounding variables, therandomization will be stratified on the following factors at baseline: anti-ARSantibodies or antibodies associated with overlap myositis by myositis autoantibodytest (positive versus negative); MMT-8 (< 125/150 versus ≥ 125/150); andoral prednisone dose (< 10 mg/day versus ≥ 10 mg/day). To be eligible forthe study, participants must have moderate to severe active PM and be receivingSoC with oral corticosteroid and/or immunosuppressant therapy.Since no biological or small-molecule therapy is currently approvedspecifically in Polymyositis, it is assumed that the placebo group’s treatmentcorresponds to the current accepted standard of care. The use of placebo for 24weeks is considered the minimal duration to allow for a proper double-blindedtreatment period and the unbiased assessment of the efficacy and safety ofAnifrolumab necessary for a registrational Phase 3 study in PM. Assessment oflong-term efficacy and safety beyond Week 24 up to Week 52 will be possible,but with all participants receiving Anifrolumab

Detailed Description

Not available

Study Timeline

• Last Update Posted: 2024-05-12
• Study Start: 2024-09-12

Recruitment & Eligibility

• Status: Not Yet Recruiting
• Sex: All
• Target Recruitment: 162

Inclusion Criteria

• Body weight ≥ 40 kg at screening Disease Characteristics Disease diagnosis, severity, and activity (inclusion criteria 2, 3, and 4 must be confirmed by the Disease Adjudication Committee.
• 2 Must have “probable†or “definite†diagnosis of PM according to the 2017 EULAR/ACR classification criteria for adult myositis (Lundberg et al 2017).
• Participants are eligible if: a.
• Positive for anti-ARS antibodies or antibodies associated with OM by myositis autoantibody test performed at screening; or b.
• b PtGA ≥ 2.0 cm (VAS 10-cm scale).
• c HAQ-DI ≥ 0.25.
• d One or more muscle enzyme elevation (CK, AST, ALT, aldolase, LDH) ≥ 1.3 × ULN.
• e Global extra-muscular disease activity (MDAAT) ≥ 2.0 cm (VAS 10-cm scale).
• 4 Fulfill one of the following criteria of active disease at screening: a Muscle enzyme elevation of CK ≥ 4 × ULN.
• b Muscle enzyme elevation of CK ≥ 1 × ULN and < 4 × ULN with at least one of the following: i.
• Report from MRI performed within 6 months prior to Day 1 (randomization) with evidence of muscle inflammation.
• Report from muscle biopsy performed within 6 months prior to Day 1 (randomization) that demonstrates active inflammation.
• Note: Results of muscle biopsy performed during screening may be used only if collected for inclusion 3(b).
• No muscular biopsy should be performed during screening for activity confirmation only.
• Report from electromyography performed within 6 months prior to Day 1 (randomization) that exhibits irritable myopathic pattern.
• 5 Currently receiving at least one of the following, unless the participant is intolerant to one or both (a) and (b), defined as the inability to continue treatment due to adverse effects, regardless of treatment dose: a An oral prednisone dose of ≤ 20 mg/day (or prednisone equivalent) for a minimum of 2 weeks prior to signing the ICF and at a stable dose for a minimum of 4 weeks prior to Day 1 (randomization).
• b Not more than one of the following medications administered for a minimum of 12 weeks prior to signing the ICF and at a stable dose for a minimum of 8 weeks prior to Day 1 (randomization): i.
• Azathioprine ≤ 200 mg/day.
• Mycophenolate mofetil ≤ 3 g/day or mycophenolic acid ≤ 1.44 g/day.
• Methotrexate ≤ 25 mg/week oral, SC, or IM.
• Mizoribine ≤ 150 mg/day.
• Tacrolimus ≤ 0.2 mg/kg/day; where local practice guidelines mandate or in case of safety concerns, monitoring of serum tacrolimus concentration may be performed at the discretion of investigator, with an aim of keeping a stable tacrolimus concentration targeting 5-10 ng/mL.
• Any abnormal cervical cancer screening result documented within 2 years prior to Day 1 (randomization) must be repeated to confirm eligibility.
• Note: Females < 25 years of age, who have never been sexually active or have well documented HPV vaccination records may not require a cervical cancer screening test.
• Tuberculosis 7 Must meet all the following TB criteria: a No medical history or signs or symptoms of active TB prior to or during the screening period.
• b A chest CT scan obtained at screening with no evidence of active or signs of prior TB infection.
• If a CT scan cannot be performed during screening, a recent chest x-ray or CT scan performed within 12 weeks of screening, or a chest x-ray performed during the screening period may be acceptable.
• c No recent contact with a person with active TB, or if there has been such contact, referral to a physician specializing in TB to undergo additional evaluation prior to Day 1 (randomization), documented comprehensively in source, and, if warranted, receipt of appropriate treatment for latent TB initiated before the first administration of study intervention.
• d No history of latent TB prior to signing the ICF, except latent TB with documented completion of appropriate treatment.
• 8 Must undergo an IGRA test (eg, QFT-G test) for TB obtained from the central laboratory at screening with any of the following results: a Negative test result.
• b Positive test result: referral to a TB specialist for evaluation and for which active TB has been ruled out, and initiation of treatment for latent TB prior to the first administration of study intervention in accordance with local SoC.
• c Indeterminate test result confirmed by repeat test using the same assay: i.
• If in an endemic region, the participant must be referred to a TB specialist for evaluation (with assessment and treatment recommendation comprehensively documented in source) and initiation of appropriate latent TB treatment, if warranted, prior to the first administration of study intervention.
• If in a non-endemic region, the participant may enter the study without referral to a TB specialist and latent TB treatment.
• See Note: Endemic region is defined based on WHO lists of high burden countries for TB and multidrug-resistant TB (World Health Organization Global TB Report 2020) Coronavirus Disease 2019 1Any negative SARS-CoV-2 RT-PCR or antigen test result (central or local laboratory, as appropriate) as per local policies at screening, in addition to no known or suspected COVID-19 exposure within 2 weeks prior to signing the ICF based on the COVID-19 questionnaire.
• If there is a known or suspected exposure, the participant must be negative upon retest obtained after 2 weeks and must remain asymptomatic to be eligible for the study.
• Note: Participants positive at screening may be rescreened after 6 weeks of mild/asymptomatic infections or at the discretion of the investigator, provided there has been no development of severe COVID-19 infection or sequelae.
• Sex and Contraceptive/Barrier Requirements Contraceptive use by participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• Female Participants: 2 Females of non-childbearing potential must be postmenopausal or have been surgically sterilized (eg, bilateral oophorectomy or complete hysterectomy), which should be documented in the participant’s medical records.
• 3 Females of childbearing potential: a Must have a negative serum β-hCG test at screening.
• c Must use one highly effective method of contraception, plus a male condom, from screening until 16 weeks after the final dose of study intervention unless the participant is surgically sterile (eg, bilateral oophorectomy or complete hysterectomy), has a sterile/non-fertile male partner, is at least 12 months postmenopausal, or practices sustained abstinence consistent with the participant’s customary lifestyle.

Exclusion Criteria

• 1 Participants with documented DM, IBM, IMNM, juvenile myositis, drug-induced myositis, cancer-associated myositis (myositis diagnosed within 2 years of a diagnosis of cancer), and non-inflammatory myopathies (eg, muscular dystrophies).
• a Participants with clinically significant fibromyalgia or with muscle symptoms that may interfere with study efficacy assessments in the opinion of the investigator are excluded.
• 2 Wheelchair-bound within 3 months prior to Day 1 (randomization) due to severe muscle involvement caused by PM.
• 3 Signs of severe uncontrolled extra-muscular disease damage related to PM as determined by any of the following: a Interstitial lung disease that requires oxygen supplementation/therapy (of any type) or FVC < 55% of predicted.
• b Severe cardiac manifestations such as congestive heart failure, arrhythmias, or conduction abnormalities requiring treatment, or myocardial infarction within 6 months prior to Day 1 (randomization).
• c Severe dysphagia manifested as severely altered eating or swallowing, use of feeding tube or total parenteral nutrition, or hospitalization indicated.
• 4 Severe muscle damage in the opinion of the investigator or as per muscle MRI (if available).
• 5 Permanent weakness due to a non-PM cause (eg, stroke) in the opinion of the investigator.
• 6 History or evidence of suicidal ideation (severity of 4 [active: method and intent, but no plan] or 5 [active: method, intent, and plan]) within 6 months prior to signing the ICF, or any suicidal behavior within 12 months prior to signing the ICF or recurrent suicidal behavior in the lifetime of the participant based on an assessment with the C-SSRS at screening.
• Infection and Malignancy Risk Factors 7 Any severe case, as defined by study guidelines, of herpes zoster infection at any time prior to Day 1 (randomization) including but not limited to: a Non-cutaneous herpes, herpes encephalitis, or ophthalmic herpes involving the retina.
• b Recurrent herpes zoster defined as 2 or more episodes within 2 years.
• c Any herpes zoster infection that has not completely resolved within 12 weeks prior to signing the ICF.
• 8 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 Day 1 (randomization) b Cervical cancer in situ treated with apparent success with curative therapy ≥ 1 year prior to Day 1 (randomization).
• 9 Known history of a primary immunodeficiency, splenectomy, or any underlying condition that predisposes the participant to infection.
• 10 Positive test result for HIV antibody or infection (ie, positive nucleic acid test) by central laboratory at screening.
• 11 Positive test result for hepatitis B serology, as confirmed by central laboratory at screening for: a Hepatitis B surface antigen; or b Hepatitis B core antibody and HBV DNA detected above the LLOQ by reflex testing.
• Note: Participants who are positive for hepatitis B core antibody at screening will be tested every 12 to 16 weeks (Table 2) 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.
• See Appendix M for Japan.
• 12 Active hepatitis C infection, defined as positive HCV antibody and detectable HCV RNA, as confirmed by central laboratory at screening.
• Participants with positive anti-HCV antibodies can be eligible if HCV-RNA is undetectable at screening and remains undetectable during study (test will be repeated every 24 to 28 weeks [Table 2]).
• 13 Any clinical cytomegalovirus or Epstein-Barr virus infection that has not completely resolved within 12 weeks prior to signing the ICF.
• 14 Opportunistic infection (Section 8.4.4.3) requiring hospitalization or IV antimicrobial treatment within 3 years prior to Day 1 (randomization).
• 15 Clinically significant chronic infection (eg, osteomyelitis, bronchiectasis, etc) within 8 weeks prior to signing the ICF (chronic nail infections are allowed).
• 16 Any infection requiring hospitalization or treatment with IV anti-infective medications not completed at least 4 weeks prior to signing the ICF.
• 18 Must not meet any of the following COVID-19 infection criteria: a Any history of severe COVID-19 infection (eg, prolonged hospitalization [hospitalization for observational purposes is not exclusionary]) or any prior COVID-19 infection with documented long COVID and/or clinically significant unresolved sequelae.
• Hypersensitivity, Including Anaphylaxis 19 Known history of allergy or reaction to any component of the study intervention formulation or history of anaphylaxis to any human gamma globulin therapy.
• 20 Any history of an anaphylactic reaction to human proteins or mAbs.
• Prior/Concomitant Therapy 21 Prior receipt of anifrolumab.
• 22 Any change in route of administration of oral, SC, or IM methotrexate anytime within 8 weeks prior to signing the ICF through Day 1 (randomization).
• 23 Receipt of any commercially available biologic agent within 5 half-lives (see Appendix H for a complete list) prior to signing the ICF.
• 24 Receipt of any of the prohibited medications listed in Appendix H if the required discontinuation or washout time prior to signing the ICF is not met: a B cell depleting therapy (eg, rituximab) within 26 weeks prior to signing the ICF or if administered more than 26 weeks prior to signing the ICF, absolute B cell count below lower limit of normal or below baseline value prior to receipt of B cell- depleting therapy (whichever is lower).
• 25 Receipt of any of the following: a Intra-articular, IM, or IV glucocorticosteroids within 4 weeks prior to Day 1 (randomization).
• b Any live or attenuated vaccine within 8 weeks prior to signing the ICF.
• Note: Administration of killed vaccines is acceptable.
• The sponsor recommends the investigators ensure that the participant is up to date on vaccinations, including COVID-19, pneumonia, varicella zoster, and influenza (inactivated/recombinant) vaccines prior to screening.
• c Blood transfusion or receipt of blood products within 4 weeks prior to signing the ICF.
• 26 Cannabinoid use that is not at a stable regimen for at least 8 weeks prior to signing the ICF.
• Any new medicinal cannabinoid should not be started during the study (Section 6.9.4) Prior/Concurrent Clinical Study Experience 27 Receipt of > 2 investigational products for the disease under study (PM) since time of diagnosis and through signing the ICF.
• 28 Receipt of any investigational product (small molecule or biologic agent), including licensed drugs that are not approved for the treatment of myositis (Appendix H), within 4 weeks or 5 half-lives prior to signing the ICF, whichever is longer.
• 29 Concurrent enrollment in another clinical study with an investigational product.

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
To demonstrate the superiority of anifrolumab to placebo on moderate improvement in disease activity at Week 24	Participants who have at least moderate improvement in disease activity TIS ≥ 40 at Week 52, where a responder (yes/no) for moderate improvement is defined as a participant who meets the following criteria: | - TIS ≥ 40 points at Week 52 and | - Has not met “confirmed deterioration†criteria at 2 consecutive visits up to and including Week 52

Secondary Outcome Measures

Name	Time	Method
To assess the efficacy of anifrolumab compared with placebo on 5-D itch	- 5-D itch change from baseline at Week 8
To assess the efficacy of anifrolumab compared with placebo on early onset of action on minimal improvement in disease activity at Week 8	Participants who have at least minimal improvement in disease activity TIS ≥ 20 at Week 8, where a responder (yes/no) for minimal improvement is defined as a participant who meets the following criteria:
To assess the efficacy of anifrolumab compared with placebo on cumulative corticosteroid dose	- Cumulative corticosteroids use as determined by the normalized standardized AUC from baseline up to & including Week 24
To assess the safety & tolerability anifrolumab compared with placebo	Safety & tolerability will be evaluated in terms of AEs, vital signs, clinical laboratory tests, 12-lead ECGs, physical examination, & C SSRS.
To demonstrate the superiority of anifrolumab to placebo on muscle improvement at Week 52	MMT-8 (CSM) change from baseline at Week 52
To demonstrate the superiority of anifrolumab to placebo on moderate improvement in disease activity in PM participants at Week 52	Participants who have at least moderate improvement in disease activity TIS ≥ 40 at Week 52, where a responder (yes/no) for moderate improvement is defined as a participant who meets the following criteria:
To demonstrate the superiority of anifrolumab to placebo on improving skin activity at Week 8	CDASI-activity change from baseline at Week 8.
To assess the safety & tolerability of anifrolumab compared with placebo	Safety & tolerability will be evaluated in terms of AEs, vital signs, clinical laboratory tests, 12-lead ECGs, physical examination, & C SSRS.
To demonstrate the superiority of anifrolumab to placebo on OCS dose reduction at Week 52	Participants who achieve OCS dose ≤ 7.5 mg/day at Week 52 (yes/no).
To demonstrate the superiority of anifrolumab to placebo on moderate improvement in disease activity in DM participants at Week 52	Participants who have at least moderate improvement in disease activity TIS ≥ 40 at Week 52, where a responder (yes/no) for moderate improvement is defined as a participant who meets the following criteria:
To assess the efficacy of anifrolumab compared with placebo on disease activity at Week 52	Change from baseline at Week 52 in CSMs:
To assess the efficacy of anifrolumab compared with placebo on cutaneous dermatomyositis activity investigator global assessment	- Participants who achieve CDA-IGA score ≤ 1 at Week 8 (yes/no)
To assess the efficacy of anifrolumab compared with placebo on major improvement in disease activity at Week 52	Participants who have major improvement in disease activity TIS ≥ 60 at Week 52, where a responder (yes/no) for major improvement is defined as a participant who meets the following criteria:

Trial Locations

Locations (9)

Fortis Hospitals Limited, Mulund; 🇮🇳 Mumbai, MAHARASHTRA, India

IPGME&R and SSKM Hospital; 🇮🇳 Kolkata, WEST BENGAL, India

JSS Medical College,JSS Hospital; 🇮🇳 Mysore, KARNATAKA, India

Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute; 🇮🇳 Mumbai, MAHARASHTRA, India

Krishna Institute of Medical Sciences Limited; 🇮🇳 Hyderabad, TELANGANA, India

Medanta Hospital, Lucknow; 🇮🇳 Lucknow, UTTAR PRADESH, India

Medanta The Medicity; 🇮🇳 Gurgaon, HARYANA, India

Nizams Institute of Medical Sciences; 🇮🇳 Hyderabad, TELANGANA, India

Sheth Vadilal Sarabhai General Hospital; 🇮🇳 Ahmadabad, GUJARAT, India

Fortis Hospitals Limited, Mulund

🇮🇳Mumbai, MAHARASHTRA, India

Dr Bhojani Kaushik Shashikant

Principal investigator

9619177718

kaushik.bhojani@fortishealthcare.com