Daratumumab in Primary Antiphospholipid Syndrome

• Register: ClinicalTrials.gov
• Last refreshed on: 9 December 2024
• Main ID: NCT05671757
• Date of registration: 20/12/2022
• Prospective Registration: Yes
• Primary sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Public title: Daratumumab in Primary Antiphospholipid Syndrome DARE-APS
• Scientific title: Targeting CD38 With Daratumumab in Primary Antiphospholipid Syndrome: A Phase 1b Dose Escalation Safety Trial (ITN093AI)
• Date of first enrolment: May 26, 2023
• Target sample size: 22
• Recruitment status: Recruiting
• URL: https://clinicaltrials.gov/ct2/show/NCT05671757
• Study type: Interventional
• Study design: Allocation: Non-Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 1/Phase 2

Countries of recruitment

United States

Contacts

• Name: Doruk Erkan, M.D., M.P.H.
• Affiliation: Hospital for Special Surgery, New York: Division of Rheumatology

• Name: Jason Knight, M.D., Ph.D.
• Affiliation: University of Michigan Health System: Department of Internal Medicine, Division of Rheumatology

Key inclusion & exclusion criteria

Inclusion Criteria:

1. Adults 18 to 70 years of age, inclusive.

2. The completion of the following vaccinations at least 14 days prior to Visit 0:

1. At least one dose of the most recently updated COVID-19 vaccine, and

2. At least one dose of the herpes zoster vaccination series, and

3. Current seasonal influenza vaccine, if available.

3. History of APS according to the updated 2006 Sapporo classification criteria,
including at least one of the following:

a. Arterial thrombosis, except transient ischemic attack, confirmed by objective
validated criteria such as imaging, or b. Venous thrombosis, except superficial
thrombophlebitis, confirmed by objective validated criteria such as imaging, or c.
Pregnancy morbidity, based on the updated 2006 Sapporo APS classification criteria,
or d. Microvascular APS, with at least one of the following: i. Renal biopsy
documentation of aPL-associated nephropathy, or ii. Lung biopsy or bronchoalveolar
lavage documentation of diffuse alveolar hemorrhage (DAH), or iii. Skin biopsy
documentation of livedoid vasculopathy.

4. History of triple positive aPL within the prior 5 years and at least 12 weeks prior
to enrollment, including all of the following:

1. aCL IgG level > Upper Limit of Normal (ULN), and

2. aß2GPI IgG level > ULN, and

3. Positive LA test.

5. Confirmation of triple positive aPL at screening, including all of the following:

1. aCL IgG level = 40 GPL, and

2. aß2GPI IgG level = 40 SGU, and

3. Positive LA test.

6. Undergoing anticoagulation with warfarin or low molecular weight heparin (LMWH), if
there is a history of arterial or venous thrombosis.

Exclusion Criteria:

1. Inability or unwillingness to give written informed consent.

2. Inability or unwillingness to comply with study protocol.

3. Systemic autoimmune diseases other than APS, including but not limited to:

1. Systemic lupus erythematosus (SLE) meeting the EULAR/ACR classification
criteria.

2. Rheumatoid arthritis meeting the ACR/EULAR classification criteria.

3. Small, medium, and large vessel vasculitis meeting ACR classification criteria.

4. Catastrophic APS classification within the prior 90 days.

5. Acute arterial or venous thrombosis within the prior 30 days.

6. Use of the following medications:

1. Any prior treatment with CD38 targeting monoclonal antibodies, including
daratumumab or isatuximab-irfc.

2. Administration of the Janssen COVID-19 vaccine within the prior 14 days.

3. The following within the prior 30 days:

i. Corticosteroids > 10 mg/day prednisone or equivalent. ii. Direct oral
anticoagulants (DOACs). iii. Live attenuated vaccines. iv. IVIG or other
supplemental immunoglobulin. d. Azathioprine, methotrexate, mycophenolate mofetil,
mycophenolate sodium, lefluonomide, or calcineurin inhibitors within the prior 90
days.

e. Cyclophosphamide within the prior 90 days. f. Immunomodulatory or
immunosuppressive biologic agents, including belimumab, within the prior 90 days or
5 half-lives, whichever is greater.

g. Investigational agents within the prior 90 days or 5 half-lives, whichever is
greater, except for COVID-19 vaccines and medications for prevention or treatment of
COVID-19 per FDA Emergency Use Authorization (EUA).

h. Biologic B cell depleting agents including rituximab with any of the following:
i. Treatment within the prior 180 days, or ii. CD19+ absolute count < 40/ µl, or
iii. Serum IgG <500 mg/dL.

7. Plasma exchange within the prior 90 days.

8. Hemodialysis within the prior 90 days.

9. Major surgical procedure within the prior 60 days.

10. Known allergy, hypersensitivity, or intolerance to boron, malitol, sorbitol,
corticosteroids, monoclonal antibodies including daratumumab, human proteins, or
their excipients.

11. Allergy, intolerance, or contraindication to acyclovir, valacyclovir, and
famciclovir.

12. Active or chronic infection, including the following:

1. Active bacterial, viral, fungal, or opportunistic infection.

2. Chronic infection requiring suppressive antibiotic treatment.

3. Intravenous antibiotics or hospitalization for infection within the prior 30
days.

4. Evidence of current or prior Mycobacterium tuberculosis infection.

5. Human immunodeficiency virus (HIV).

6. Current or prior infection with hepatitis B virus (HBV).

7. Current or prior infection with hepatitis C virus (HCV), except adequately
treated HCV with sustained virologic response = 12 weeks.

8. History of recurrent herpes zoster, or history of herpes zoster ophthalmicus,
disseminated herpes zoster, or disseminated herpes simplex.

13. The following laboratory abnormalities:

ITN093AI: DARE-APS Version 3.0 September 12, 2023 Daratumumab in Primary
Antiphospholipid Syndrome

1. Absolute neutrophil count < 1500/mm3.

2. Platelets < 100,000/mm3.

3. Hemoglobin (Hgb) < 10 g/dL.

4. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), or alkaline
phosphatase > 2x the Upper Limit of Normal (ULN).

5. Total bilirubin > 2x ULN, except in the case of congenital bilirubinemia then
direct bilirubin > 2x ULN.

6. eGFR < 45 ml/min/1.73 m2.

14. History of primary immunodeficiency.

15. History of solid organ or hematopoietic stem cell transplantation.

16. Comorbidities requiring systemic corticosteroid therapy, including those which have
required three or more courses of systemic corticosteroids within the 12 months
prior to Visit 0.

17. Any of the following conditions with FEV1 < 70% predicted within the prior 90 days:

1. Asthma.

2. Chronic obstructive pulmonary disease (COPD).

3. DAH.

18. Pulmonary hypertension.

19. Adrenal insufficiency.

20. Poorly controlled diabetes mellitus defined as hemoglobin A1c (HbA1c) = 8.0%.

21. Concomitant malignancy or history of malignancy, except adequately treated or
excised nonmetastatic squamous cell carcinoma, basal cell skin carcinoma, or
cervical carcinoma in situ.

22. Clinically significant cardiac disease, including but not limited to:

1. Myocardial infarction within the prior 6 months, or

2. Unstable or uncontrolled disease or condition related to or affecting cardiac
function, including but not limited to:

i. Unstable angina, or ii. Congestive heart failure, New York Heart Association
Class II-IV, or iii. Uncontrolled cardiac arrhythmia.

23. Current diagnosed mental illness or current diagnosed or self-reported drug or
alcohol abuse which, in the opinion of the investigator, would interfere with the
participant's ability to comply with study requirements.

24. Severe, progressive, or uncontrolled renal, hepatic, hematological,
gastrointestinal, pulmonary, cardiac, or neurological disease.

25. Past or current medical problems or findings from physical examination or la


Age minimum: 18 Years
Age maximum: 65 Years
Gender: All

Health Condition(s) or Problem(s) studied

Autoimmune Disorders

Intervention(s)

Biological: Daratumumab

Primary Outcome(s)

The proportion of participants in the dose escalation phase with at least one Dose Limiting Toxicity (DLT) [Time Frame: At or before week 9]

Secondary Outcome(s)

Change in Anticardiolipin antibodies Immunoglobulin M (aCL IgM) levels [Time Frame: From week 0 to weeks 4, 9, 12, 18, 24, 36 and 48]

The proportion of participants with at least 50% reduction in Anti-beta2-glycoprotein test Immunoglobulin G (abeta2GPI IgG) levels [Time Frame: At week 9 compared to week 0]

The proportion of participants with at least 50% reduction in Anti-beta2-glycoprotein test Immunoglobulin G (abeta2GPI IgG) levels [Time Frame: At week 48 compared to week 0]

The proportion of participants with at least 50% reduction in Anticardiolipin antibodies Immunoglobulin G (aCL IgG) levels [Time Frame: At week 24 compared to week 0]

The proportion of participants with a negative Lupus Anticoagulant (LA) test [Time Frame: At week 24]

The proportion of participants with a negative Lupus Anticoagulant (LA) test [Time Frame: At week 48]

The proportion of participants with at least 50% reduction in Anticardiolipin antibodies Immunoglobulin G (aCL IgG) [Time Frame: At week 9 compared to week 0]

The proportion of participants with negative Lupus Anticoagulant (LA) test [Time Frame: At week 9]

The proportion of Grade 2 or higher serious adverse event (SAEs) related to daratumumab [Time Frame: At or before weeks 9, 24, and 48]

The proportion of participants with a negative Lupus Anticoagulant (LA) test [Time Frame: At weeks 4, 9, 12, 18, 24, 36 and 48]

The proportion of participants with the following Grade 3 or higher adverse events (AEs) related to daratumumab [Time Frame: At or before weeks 9, 24, and 48.]

Change in Anti-beta2-glycoprotein test Immunoglobulin G (abeta2GPI IgG) levels [Time Frame: From weeks 0 to weeks 4, 9, 12, 18, 24, 36 and 48]

The proportion of Grade 2 or higher adverse event (AEs) related to daratumumab [Time Frame: At or before weeks 9, 24, and 48]

The proportion of participants with at least 50% reduction in Anti-beta2-glycoprotein I antibodies (a-beta2GPI IgG) compared to week 0 [Time Frame: At week 9]

The proportion of participants with at least 50% reduction in Anticardiolipin antibodies Immunoglobulin G (aCL IgG) levels [Time Frame: At week 48 compared to week 0]

Secondary ID(s)

DAIT ITN093AI

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Secondary Sponsor(s)

PPD DEVELOPMENT, LP

Rho Federal Systems Division, Inc.

Immune Tolerance Network (ITN)