IgG4 Related Disease
Conditions
Brief summary
The aim of this clinical trial is to evaluate the safety and efficacy of zanubrutinib in treating patients with IgG4-related disease
Detailed description
This will be a single-site, open-label study in symptomatic patients with IgG4-related disease affecting the submandibular and/or lacrimal glands. All patients will receive zanubrutinib orally at a dose of 80mg BID for 24 weeks. The primary objective of this study is to demonstrate that zanubrutinib treatment reduces reduces the volume of the submandibular and/or lacrimal glands on PET/MRI at week 24 compared to baseline.
Interventions
DRUGZanubrutinib 80 MG
Zanubrutinib 80 MG for 24 weeks
Sponsors
Matthew C. Baker
Stanford University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open-label study in symptomatic subjects with histopathologically confirmed IgG4-related disease affecting the submandibular and/or lacrimal glands. Ten subjects will be included in the study. All eligible subjects will receive zanubrutinib 80mg BID over a period of 24 weeks and will be followed up for an additional 8 weeks after the last dose.
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Men or women aged 18 to 85, inclusive, at the time of initial screening * Have histopathologically confirmed IgG4-RD in the submandibular gland and/or the lacrimal gland confirmed by international consensus pathology criteria * Presence of a lymphoplasmacytic infiltrate with 10 IgG4+ plasma cells per high-power field and/or an IgG4+/IgG+ plasma cell ratio of 40% * All women must test negative for pregnancy and agree to use a reliable method of birth control * No current treatment with immunosuppressive medications other than prednisone 40mg daily (or other glucocorticoid equivalent) with stable dosing for 28 days
Exclusion criteria
* Unstable prescribed dose of glucocorticoids within 28 days prior to baseline * Any treatment with a synthetic DMARD including but not limited to hydroxychloroquine, methotrexate, leflunomide, or sulfasalazine within 28 days prior to baseline * Any treatment with a cytotoxic or immunosuppressive drug including but not limited to cyclophosphamide, mycophenolic acid, azathioprine, cyclosporine, sirolimus, or tacrolimus within 28 days prior to baseline * Any treatment with a BTK inhibitor within 6 months before baseline * Any treatment with a JAK inhibitor within 28 days prior to baseline * Use of biologic agents including infliximab, abatacept, or tocilizumab within 56 days prior to baseline * Use of a B cell depleting therapy (such as rituximab) within 12 months prior to baseline * A history of, or current, inflammatory or autoimmune disease (that could affect the interpretation of safety or efficacy outcomes) other than IgG4-related disease * Evidence of active tuberculosis, HIV, or hepatitis B or C infection * History of cancer other than non-melanoma skin cancer, cervical dysplasia or carcinoma in situ (cured \>1 year), prostate cancer (cured \>5 years), or colon cancer (cured \>5 years)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Volume of the Submandibular Glands on PET-MRI | Baseline and Week 24 | To demonstrate that zanubrutinib treatment reduces the volume of the submandibular glands on PET-MRI at week 24 compared to Baseline. |
| Volume of the Lacrimal Glands on PET-MRI | Baseline and Week 24 | To demonstrate that zanubrutinib treatment reduces the volume of the lacrimal glands on PET-MRI at Week 24 compared to Baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| FDG Avidity (SUVmax) of the Submandibular Glands on PET | Baseline, Week 12, and Week 24 | Effect of zanubrutinib on change in FDG avidity (SUVmax) of the submandibular glands on PET at Weeks 12 and 24 compared to Baseline. |
| FDG Avidity (SUVmax) of the Lacrimal Glands on PET | Baseline, Week 12, and Week 24 | Effect of zanubrutinib on change in FDG avidity (SUVmax) of the lacrimal glands on PET at Week 24 compared to Baseline. |
| Change in Total Metabolic Lesion Volume (tMLV) of Lacrimal Glands, Submandibular Glands, Parotid Glands, and Lymph Notes on PET | Baseline, Week 12, and Week 24 | — |
| Change in Total Lesion Glycolysis (TLG) of Submandibular and/or Lacrimal Glands on PET | Baseline, Week 12, and Week 24 | — |
| Change in Submandibular Glands on MRI | Baseline, Week 12, and Week 24 | Change in parenchymal architecture scored 0 to 4 and sialography scored 0 to 4 where 0 is normal, healthy gland and 4 is worse outcome. |
| Change in Parotid Glands on MRI | Baseline, Week 12, and Week 24 | Change in parenchymal architecture scored 0 to 4 and sialography scored 0 to 4, where 0 is normal, healthy gland and 4 is worse outcome. |
| Change in Lacrimal Glands on MRI | Baseline, Week 12, and Week 24 | Change in parenchymal architecture scored 0 to 4, where 0 is normal, healthy gland and 4 is worse outcome. |
| Change in the Volume of the Parotid Glands on PET/MRI | Baseline, Week 12, and Week 24 | — |
| Change in the Volume of the Submandibular Glands on PET/MRI | Baseline and Week 12 | — |
| Change in the Volume of the Lacrimal Glands on PET/MRI | Baseline, and Week 12 | — |
| Change in Serum IgG4 Level | Baseline, Week 12, and Week 24 | — |
| Change in Plasmablast Count | Baseline, Week 12, and Week 24 | Change in percentage of CD19+ B cells in blood |
| Change in Absolute Regulatory B Cell Count | Baseline, Week 12, and Week 24 | Percentage of regulatory B cells in the blood, assessed using flow cytometry. |
| Change in the IgG4-RD Responder Index | Baseline, Week 12, and Week 24 | The IgG4-RD Responder Index detects change in disease activity and identifies improvements/worsening in the same or different organ systems. It encompasses more than 25 organs/sites and records the following for each organ/site: (i) activity trend (through a 0-3 \[normal/resolved - worsening\] organ/site score); (ii) presence of symptoms due to active disease; (iii) need for urgent care; (iv) presence of damage; and (v) presence of symptoms due to damage. The final activity score at each visit is obtained by summing all organ/site scores (i) and by doubling items needing urgent care (iii). The IgG4-RD Responder Index Total Activity Score ranges from 0 to a maximum of 162. Higher scores represent greater (i.e. worse) disease activity. A score of 0 represents no disease activity other than residual fibrosis. |
| Proportion of Patients With no Disease Flares | Week 12 to Week 24 | Number and percentage of patients who did not have an IgG4-RD flare |
| Change in Total Salivary Grey Scale Ultrasound Score (TUS) | Baseline, Week 12, and Week 24 | Each parotid and submandibular gland scored from 0 to 3 with a higher score indicating worse disease, total summed scores across all four glands will be assessed for change (overall score range: 0 to 12, with a higher score indicating worse disease) |
| Change in Highest Score Among the Salivary Glands for the Grey Scale Ultrasound Score (HSUS) | Baseline, Week 12, and Week 24 | Each parotid and submandibular gland (n=4) scored from 0 to 3 with a higher score indicating worse disease, highest score will be assessed for change (overall score range: 0 to 12, with a higher score indicating worse disease) |
| Change in Glandular Inflammation Total Ultrasound Score (iTUS) | Baseline, Week 12, and Week 24 | Each parotid and submandibular gland (n=4) scored from 0 to 3 with a higher score indicating worse disease, total summed scores across all four glands will be assessed for change (overall score range: 0 to 12, with a higher score indicating worse disease) |
| Change in Highest Score Among the Salivary Glands for the Glandular Inflammation Ultrasound Score (iHSUS) | Baseline, Week 12, and Week 24 | Each parotid and submandibular gland (n=4) scored from 0 to 3 with a higher score indicating worse disease, highest score will be assessed for change (overall score range: 0 to 12, with a higher score indicating worse disease) |
| Change in Physician Global Assessment of Disease | Baseline, Week 12, and Week 24 | Symptoms rated on a 100 mm visual analog scale (VAS). Score range: 0 to 100, higher scores correspond to worse disease state. |
| Change in Patient Global Assessment of Disease | Baseline, Week 12, and Week 24 | Symptoms rated on a 100 mm VAS. Score range: 0 to 100, higher scores correspond to worse disease state. |
| Change in VAS for Ocular Symptoms - Dryness | Baseline to Week 24 | Symptoms rated on a 100 mm VAS. Score range: 0 to 100, higher scores correspond to worse disease state. |
| Change in VAS for Dryness Symptoms | Baseline, Week 12, Week 24 | Symptoms rated on a 100 mm VAS. Score range: 0 to 100, higher scores correspond to more dryness. Participants were asked to assess their dryness, taking into account all areas, including ocular and salivary symptoms. |
| Change in FACIT-F Fatigue Score | Baseline, Week 12, and Week 24 | Total score range: 0-52, lower scores correspond with more fatigue. FACIT = Functional Assessment of Chronic Illness Therapy. |
| Change in RAND Short Form-36 | Baseline, Week 12, and Week 24 | The summary scores range from 0 to 100, with higher scores indicating better levels of function and/or better health. |
| Change in C3 Lab | Baseline, Week 12, and Week 24 | Complement component 3 (C3) level in blood |
| Change in C4 Lab | Baseline, Week 12, and Week 24 | Complement component 4 (C4) level in blood |
| Change in Total IgG Lab | Baseline, Week 12, and Week 24 | — |
| Change in IgE Lab | Baseline, Week 12, and Week 24 | — |
| Change in IgG1 Lab | Baseline, Week 12, and Week 24 | — |
| Change in ESR Lab | Baseline, Week 12, and Week 24 | Change in erythrocyte sedimentation rate (ESR) |
| Change in CRP Lab | Baseline, Week 12, and Week 24 | Change in serum C-reactive protein (CRP) level |
| Incidence of Safety Parameters Including Adverse Events | Baseline to Week 32 | Number of participants with treatment-emergent adverse events (TEAEs). |
| Incidence of Safety Parameters Including Abnormal Laboratory Results | Baseline to Week 32 | Number of participants with any grade 3 or 4 treatment-emergent laboratory abnormality |
Countries
United States
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 58.2 years STANDARD_DEVIATION 11.4 |
| Age, Customized <50 years | 3 Participants |
| Age, Customized >=50 years | 7 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized Asian | 6 Participants |
| Race/Ethnicity, Customized Black | 1 Participants |
| Race/Ethnicity, Customized Other | 1 Participants |
| Race/Ethnicity, Customized White | 2 Participants |
| Region of Enrollment United States | 10 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 10 |
| other Total, other adverse events | 10 / 10 |
| serious Total, serious adverse events | 1 / 10 |
Outcome results
None listed