2.1.1.1 Clinical trial identifiers

EU trial number:

2025-522857-20-00

Full title (English):

An open label, phase I/II study investigating the safety and efficacy of the bispecific T-cell engaging antibody cizutamig (BCMAxCD3) in patients with immune-mediated inflammatory diseases – the SPLENDID Trial

Public title (English):

An open label, phase I/II study investigating the safety and efficacy of the bispecific T-cell engaging antibody cizutamig (BCMAxCD3) in patients with immune-mediated inflammatory diseases – the SPLENDID Trial

Protocol code:

TMP-23062025-2

2.1.1.2 Secondary identifying numbers

WHO universal trial number (UTN):

ClinicalTrials.gov identifier (NCT number):

ISRCTN number:

2.1.1.3 Additional registries

2.1.2.1 Transition Trial

EudraCT number:

2.1.2.2 Trial Category

Trial phase:

Phase I and Phase II (Integrated)- Other

Trial category:

2

Justification for trial category:

Phase I and phase II integrated clinical trial

2.1.2.3 Medical Conditions

Medical condition(s) (English):

Severe, treatment refractory primary Sjögren’s disease (pSjD)

Is the medical condition considered to be a rare disease:

No

Medical condition(s) (English):

Severe, treatment refractory idiopathic inflammatory myopathy (IIM)

Is the medical condition considered to be a rare disease:

No

Medical condition(s) (English):

Severe, treatment refractory systemic sclerosis (SSc)

Is the medical condition considered to be a rare disease:

No

Medical condition(s) (English):

Severe, treatment-refractory, seropositive (anti-citrullinated protein antibody (ACPA) and/or rheumatoid factor positive) rheumatoid arthritis (RA)

Is the medical condition considered to be a rare disease:

No

Therapeutic area:

Diseases [C] - Immune System Diseases [C20]

2.1.2.4 Medical condition(s) MedDRA information

Version	Level	Classification code	Term name	System organ class
21.0	LLT	10042953	Systemic sclerosis	10028395
24.1	PT	10085970	Idiopathic inflammatory myopathy	100000004859
23.1	PT	10039073	Rheumatoid arthritis	100000004859
21.0	LLT	10040766	Sjogren's disease	10028395

2.1.2.5 Main objective

Trial scope:

Safety, Efficacy

Main objective (English):

Primary objective (Safety): To assess the safety of the BCMAxCD3 TCE cizutamig in participants with severe, treatment refractory IMIDs

2.1.2.6 Secondary objective

Secondary objective number	Secondary objective (English)
1	Clinical Efficacy: To assess the general and disease specific clinical efficacy after BCMAxCD3 TCE (cizutamig) therapy
2	Cellular and humoral response: To assess the cellular and humoral response after BCMAxCD3 TCE therapy
3	Safety: To assess AEs and SAEs including those not encompassed by the primary endpoint

2.1.2.7 Principal inclusion criteria

Inclusion criteria number	Principal inclusion criteria (English)
1	Written informed consent and data protection declaration obtained prior to the initiation of any protocol required procedures
10	Disease specific inclusion criteria (RA): a. Fulfilment of the 2010 ACR/EULAR classification criteria for RA b. Rheumatoid factor (RF) and/or ACPA positivity at screening c. Disease Activity Score DAS28-CRP>3.2 at screening d. Tender joint count (TJC) ≥ 3/68 and swollen joint count (SJC) ≥ 3/66 at screening e. Failure (defined as inadequate response after at least 3 months of therapy or intolerance) of at least one conventional DMARD and at least two tsDMARD/bDMARDs with different mechanisms
2	Willing and able to comply to study procedures and study protocol
3	Age ≥ 18 years at time of consent
4	Male participants unless surgically sterile, must agree to use two acceptable methods for contraception (e.g. spermicide and condom) during the trial and refrain from fathering a child starting from the time of signing the Informed Consent Form (ICF) throughout the trial
5	Females of childbearing potential (FCBP) must have a negative serum pregnancy test at screening and must agree to use a highly effective contraceptive method (Pearl index <1) starting from the time of signing the ICF and throughout the trial. If they take oral contraceptives, the patients must also agree to use two other acceptable methods for contraception (e.g. spermicide and condom) during the trial.
6	Updated vaccination record according to the Standing Committee on Vaccination (STIKO) recommendations for immunocompromised patients
7	Disease specific inclusion criteria (SSC): a. Fulfillment of the 2013 ACR/EULAR classification criteria for SSc b. Positivity for at least one SSc-specific or associated antibody c. Diffuse cutaneous disease d. Severe disease defined as at least one of the following: i. Skin disease with screening mRSS ≥ 10 AND skin disease progression by ≥ 3 mRSS points or involvement of 1 new body area, or mRSS increase ≥ 2 units in 1 body area within the last 6 months and/or new tendon friction rubs ii. SSc-associated interstitial lung disease with either reduction of FVC of ≥ 5% and/or reduction of DLCO of ≥ 10% within the last 12 months before screening and/or presence of ILD with signs of alveolitis on HRCT with FVC < 85% iii. SSc-associated cardiac involvement with Troponin T elevation e. Failure (defined as inadequate response after at least 3 months of therapy or intolerance) of at least two of the following treatments with different mechanisms: glucocorticoids, methotrexate, azathioprine, mycophenolate mofetil, tocilizumab, rituximab, cyclophosphamide, tacrolimus, cyclosporine, nintedanib, hydroxychloroquine
8	Disease specific inclusion criteria (IIM): a. Diagnosis of IIMs including DM, PM (including antibody-positive immune-mediated necrotizing myopathy [IMNM]), anti-synthetase syndrome according to the 2017 American College of Rheumatology [ACR]/European Alliance of Associations for Rheumatology [EULAR] classification criteria (including probable or definite diagnosis; > 55%) b. Positivity for at least one myositis specific or associated antibody c. Severe, active disease defined as at least one of the following: i. Myositis with • Recent (within the last 6 months) evidence of myositis in muscle biopsy and/or muscle MRI and/or EMG and/or PET/CT • AND/OR at least two of the following: Manual Muscle Testing-8 (MMT-8) score ≤142; extra-muscular activity ≥2 cm; health Assessment Questionnaire ≥0.25; at least one muscle enzyme >1.5 times upper limit of normal; VAS of patient global assessment ≥ 2 cm; VAS of physician global assessment ≥ 2cm ii. IIM-associated interstitial lung disease with reduction of FVC of ≥ 5% and/or reduction of DLCO of ≥ 10% within the last 12 months and/or presence of ILD with signs of alveolitis on HRCT with FVC < 85% d. Failure (defined as inadequate response after at least 3 months of therapy or intolerance) of at least two of the following treatments with different mechanisms: glucocorticoids, methotrexate, azathioprine, mycophenolate mofetil, rituximab, cyclophosphamide, intravenous immunoglobulins, tacrolimus, cyclosporin A, nintedanib, janus kinase inhibitors, hydroxychloroquine
9	Disease specific inclusion criteria (pSjD): a. Fulfillment of the 2016 ACR/EULAR classification criteria for SjD b. Positivity for SSA antibodies in serum c. Moderate to severe disease defined as ESSDAI and/or ESSPRI ≥ 5 d. Failure (defined as inadequate response after at least 3 months of therapy or intolerance) of at least two of the following treatments with different mechanisms: glucocorticoids, hydroxychloroquine, methotrexate, azathioprine, leflunomide, rituximab, abatacept, belimumab, tacrolimus, cyclosporine A, mycophenolate mofetil, cyclophosphamide, intravenous immunoglobulins.

2.1.2.8 Principal exclusion criteria

Exclusion criteria number	Principal exclusion criteria (English)
1	ANC < 500/µl, hemoglobin < 6/dl, absolute CD3+T cell count < 500/µl at screening
10	Life-threatening allergies, hypersensitivity, or intolerance to cizutamig or its excipients or tocilizumab
11	Pregnancy or lactation
12	Females who are intending to conceive during the study
13	Malignancy in the last 5 years before screening (except basal or squamous cell skin cancer)
14	Requirement for immunization with live vaccine during the study period
15	Participants who are younger than 18 years or are incapable to understand the aim, importance and consequences of the study and to give legal informed consent
16	Participants who have a history of alcohol or substance abuse within the preceding 6 months that, in the opinion of the Investigator, may increase the risks associated with study participation or study agent administration, or may interfere with interpretation of results
17	Participants who possibly are dependent on the sponsor, the Principal Investigator or Investigator (e.g. family members)
18	Patients who are institutionalized by court order or regulatory action
19	Subjects participating in another clinical trial with an investigational medicinal product or medical device (there must be at least 3 months since the last IMP administration before this trial)
2	Severely impaired liver (Child Pugh C), cardiac or pulmonory (NYHA IV) function and need for supplemental oxygen
3	Patients with known selective IgA deficiency
4	IgG level below 4g/l at screening
5	Any condition, including the presence of laboratory abnormalities, which places the participants at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study, including active infections and within 1 week of completing anti-infective treatment, neurologic conditions, primary immunodeficiency and history of splenectomy
6	Patients will be excluded if they are known to have any of the following: a. Severe infection requiring hospitalization within the last two weeks. b. Any known human immunodeficiency virus (HIV) infection or positive HIV-1 or -2 antibody at screening c. Positive hepatitis B surface antigen (HBsAg). Patients with positive hepatitis B core antibody (HBcAb) must be tested for hepatitis B virus (HBV)-DNA to determine their status; if HBV DNA is positive, patients should be excluded; if HBV-DNA is negative, the patient may participate in the study. d. Patients with positive hepatitis C virus (HCV) antibody must be tested for HCV ribonucleic acid (RNA); if HCV RNA is also positive, patients should be excluded; if HCV RNA is negative, the patient may participate in the study at the investigator’s discretion. e. Active tuberculosis (TB) or lack of documentation of completion of treatment for active TB. If the TB test (QuantiFERON® Gold Test) is positive, patients may be allowed to enroll if chest CT is negative for active TB and treatment according to local guidelines has been initiated or completed prior to enrollment. If the test result is indeterminate, the site should repeat the test. A positive test result or 2 successive indeterminate results should be considered as a positive result. An indeterminate test result followed by a negative test result should be considered as a negative test result.
7	Receipt of or inability to discontinue any of the following excluded therapies at screening: a. Anti-metabolites: MMF/mycophenolate sodium, azathioprine, methotrexate b. Calcineurin inhibitors: e.g., but not limited to cyclosporine, tacrolimus, voclosporin c. Alkylating agent: cyclophosphamide d. Janus kinase (JAK) inhibitors, Bruton tyrosine kinase (BTK) inhibitors, Tyrosine kinase 2 (TYK2) inhibitors: e.g., but not limited to tofacitinib, upadacitinib, baricitinib, deucravacitinib e. Complement inhibitors: e.g., but not limited to eculizumab, ravulizumab, zilucoplan, avacopan f. Plasmapheresis or intravenous immunoglobulin (IVIg) g. FcRn inhibitors: including but not limited to efartigimod, rozanolixizumab h. Any of the following (including biosimilars): Tumor necrosis factor (TNF) inhibitors: e.g., but not limited to infliximab, adalimumab or anti-cytokine (IL-1, IL-6, IL-17, IL-12/23): e.g., but not limited to anakinra, tocilizumab, secukinumab, ustekinumab, risankizumab i. Anti-B-cell activating factor (BAFF) or anti-a proliferation inducing ligand (APRIL): e.g., but not limited to belimumab, telitacicept j. Thalidomide or thalidomide derivatives k. CD19 inhibitor: e.g., but not limited to inebilizumab l. CD20 inhibitors: e.g., but not limited to rituximab, ocrelizumab, obinutuzumab m. Other cell depleting therapy, anti-CD3, anti-CD4, anti-CD5
8	Prior chimeric antigen receptor (CAR)-T or TCE therapy directed at any antigen or BCMA-targeted therapy at any time
9	Inability to taper glucocorticoids to a maximun of 20mg prednisolone equivalent per day until enrolment

2.1.2.9 Primary end points

End point criteria number	Primary end point (English)
1	Primary endpoint (Safety): Incidence and grading of severity of Cytokine Release Syndrome (CRS), Immune Cell Associated Neurotoxicity Syndrome (ICANS) and treatment-emergent adverse events (TEAE) and serious adverse events (SAE) due to IMP until 28 days after the last administration of BCMAxCD3 TCE cizutamig

2.1.2.10 Secondary end points

Secondary end point number	Secondary end point (English)
1	Main disease specific clinical efficacy (SSc): rCRISS30/5 response at Week 16
2	Main disease specific clinical efficacy (IIM): moderate or major total improvement score (TIS) response at week 16
3	Main disease specific clinical efficacy (pSjD): change from baseline in European Alliance of Associations for Rheumatology (EULAR) Sjögren's syndrome disease activity index (ESSDAI) at week 16
4	Main disease specific clinical efficacy (RA): American College of Rheumatology (ACR) 20 response at week 16
5	Main disease specific clinical efficacy (ONLY for those with interstitial lung disease [ILD] at baseline for all IMIDs): Change in forced vital capacity (FVC) and diffusion capacity of the lungs for carbon monoxide (DLCO) at 16 and 52 weeks compared to baseline
6	Further disease specific clinical efficacy (SSc): rCRISS 20/30/50 response at week 16 and 52
7	Further disease specific clinical efficacy (SSc): Change in modified Rodnan skin score (mRSS) at 16, 24 and 52 weeks compared to baseline
8	Further disease specific clinical efficacy (SSc): Change in Troponin T levels at 16, 24 and 52 weeks compared to baseline
9	Further disease specific clinical efficacy (SSc): Change in EULAR SSc Impact Score (Sclero-ID) over time compared to baseline
10	Further disease specific clinical efficacy (SSc): Change in digital ulcer count at 16, 24 and 52 weeks compared to baseline
11	Further disease specific clinical efficacy (IIM): Minimal, moderate or major TIS response at 16, 24 and 52 weeks
12	Further disease specific clinical efficacy (IIM): Change in TIS score from baseline at 16, 24 and 52 weeks
13	Further disease specific clinical efficacy (IIM): Change in muscle memory test 8 (MMT8) at 16, 24 and 52 weeks compared to baseline
14	Further disease specific clinical efficacy (IIM): Change in physician’s global assessment of extramuscular activity at 16, 24 and 52 weeks compared to baseline
15	Further disease specific clinical efficacy (IIM): Change in cutaneous disease area and severity index (CDASI) at 16, 24 and 52 weeks (in case of DM) compared to baseline
16	Further disease specific clinical efficacy (IIM): Change in CK, aldolase and Troponin T levels over time compared to baseline
17	Further disease specific clinical efficacy (pSjD): Change from baseline in ESSDAI at week 24 and 52
18	Further disease specific clinical efficacy (pSjD): Change from baseline in EULAR Sjögren’s syndrome patient reported index (ESSPRI) at week 16, 24 and 52
19	Further disease specific clinical efficacy (pSjD): Percentage (%) of participants with decrease in ESSPRI ≥1 or 15% from baseline at 16, 24 and 52 weeks
20	Further disease specific clinical efficacy (pSjD): Percentage (%) of participants with decrease in ESSDAI ≥3 points from baseline at 16, 24 and 52 weeks
21	Further disease specific clinical efficacy (pSjD): Percentage (%) of participants with ESSDAI <5 at 16, 24 and 52 weeks
22	Further disease specific clinical efficacy (pSjD): Change from baseline in oral and ocular dryness numerical rating scale (NRS) at 16 and 52 weeks
23	Further disease specific clinical efficacy (pSjD): Percentage (%) of participants with increase of Schirmer's test ≥ 5 mm if abnormal baseline at 16 and 52 weeks
24	Further disease specific clinical efficacy (RA): American College of Rheumatology (ACR) 50/70 response at 16, 24 and 52 weeks.
25	Further disease specific clinical efficacy (RA): ACR 20 response at week 24 and 52 weeks.
26	Further disease specific clinical efficacy (RA): Disease acitivity score 28 (DAS28)-CRP / DAS28-ESR / simplified disease acitivity index (SDAI) / Boolean remission at 16, 24, and 52 weeks.
27	Further disease specific clinical efficacy (RA): Proportion of patients with DAS28-CRP<3.2 at week 16, 24 and 52
28	Further disease specific clinical efficacy (RA): Change in DAS28-CRP / SDAI / clinical disease activity index (CDAI) at 16, 24, and 52 weeks compared to baseline.
29	Further disease specific clinical efficacy (RA): Change in ESR values over time compared to baseline
30	General clinical response and patient reported outcomes in all IMID groups: Duration without disease-modifying antirheumatic drug (DMARD) therapy from week 5 to week 52
31	General clinical response and patient reported outcomes in all IMID groups: Time until clinical relapse or flare observed between week 5 and week 52
32	General clinical response and patient reported outcomes in all IMID groups: Number of flares from week 5 through week 52
33	General clinical response and patient reported outcomes in all IMID groups: Cumulative steroid dosage from week 5 to week 52
34	General clinical response and patient reported outcomes in all IMID groups: Change in levels of CRP over time compared to baseline
35	General clinical response and patient reported outcomes in all IMID groups: Change in hand strength over time compared to baseline
36	General clinical response and patient reported outcomes in all IMID groups: Change in patient’s global assessment (PtGA) of disease activity (VAS 0-100mm) over time compared to baseline
37	General clinical response and patient reported outcomes in all IMID groups: Change in physician’s global assessment (PhGA) of disease activity (VAS 0-100mm) over time compared to baseline
38	General clinical response and patient reported outcomes in all IMID groups: Change in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) over time compared to baseline
39	General clinical response and patient reported outcomes in all IMID groups: Change in Short Form 36 (SF-36, quality of life questionnaire) over time compared to baseline
40	General clinical response and patient reported outcomes in all IMID groups: Change in Health Assessment Questionnaire Disability Index (HAQ-DI) over time compared to baseline

2.1.2.11 Individual Participant Data (IPD) Sharing statement

Plan to share IPD:

No

Plan description:

2.1.2.12 Participants

Gender:

Male and Female

Age range:

65+ years, 18-64 years

Age range secondary identifier:

Clinical trial group:

Patients

Vulnerable population:

No

2.1.3.1 Study design

Period details:

Number	Period title	Period description	Allocation method	Blinding used	Roles blinded	Blinding implementation details	Arm details

2.2.1.1 Product: Cizutamig

Type

Product

Excluded MSCs

2.2.1.1.1 Product details

Medicinal product name:

Cizutamig

EU medicinal product number/medicinal product unique ID:

PRD12768911

Pharmaceutical form:

SOLUTION FOR INFUSION

Strength:

Medicinal product other name:

Is this a specific paediatric formulation:

No

Product authorisation status:

Not Authorised

Medicinal product role in trial:

Test

Sponsors product code:

2.2.1.1.2 Products characteristics

Medicinal product characteristics:

Immunological

Other medicinal product:

2.2.1.1.3 Dosage and administration Details

Route of administration:

INTRAVENOUS INFUSION

Maximum duration of treatment:

undefined undefined

Maximum daily dose allowed:

Daily dose unit of measure:

Maximum total dose allowed:

Total dose unit of measure:

2.2.1.1.4 Information about the modification of the medicinal product

Has the medicinal product been modified in relation to its Marketing Authorisation:

No

Description of the modification:

2.2.1.1.5 Product classification

Anatomical Therapeutic Chemical (ATC) Codes:

ATC name:

ATC level:

2.2.1.1.6 Product authorisation details

MA holder

CANDID THERAPEUTICS INC.

MA authorisation country

Marketing authorisation number

Centralised procedure/MRP/DCP/registration procedure number

2.2.1.1.7 Orphan designation

Does this product have an orphan drug designation:

No

Designation number for orphan drug:

2.2.1.1.8 Active substance

Classification:

Protein - Other

Active Substance name:

CIZUTAMIG

Active substance name synonyms:

Bispecific monoclonal antibody against tumor necrosis factor receptor superfamily member 17 and CD3E,EMB-06

Active Substance other descriptive name:

EU Active Substance Code:

SUB405024

Strength:

Status:

Not Authorised

2.2.1.1.9 Advanced therapy medicinal product

2.2.1.1.10 Device associated with medicinal product

Product used in combination with a device	Product ID	Device trade name	Description of the device	Type of device	Device has CE mark	Device notified body

2.2.1.1 Compliance with (GMP) for the medicinal product

Authorisation number of manufacturing and import: