Abatacept for the Treatment of Common Variable Immunodeficiency With Interstitial Lung Disease

Interstitial Lung Disease Clinical Trial

— ABCVILD  

Official title:

Abatacept for the Treatment of Common Variable Immunodeficiency With Interstitial Lung Disease

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04925375
• Other study ID #: 2020-0876
• Secondary ID: R01FD007267
• Status: Recruiting
• Phase: Phase 2
• Start date: July 14, 2021
• Est. completion date: July 2025

Study information

• Verified date: March 2024
• Source: Children's Hospital Medical Center, Cincinnati
• Contact: Michael Jordan
• Phone: 513-803-9063
• Email: Michael.Jordan.[@]cchmc.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

There is no standard of care therapy for patients with granulomatous-lymphocytic interstitial lung disease (GLILD) seen in common variable immunodeficiency (CVID). Abatacept has recently looked promising for the treatment of patients with complex CVID. This study is a multi-site, phase II, randomized, blinded/placebo-controlled clinical trial in pediatric and adult subjects to determine the efficacy of abatacept compared to placebo for treatment of subjects with GLILD in the context of CVID.

Funding Source - FDA OOPD

Description:

There is no standard of care therapy for patients with granulomatous-lymphocytic interstitial lung disease (GLILD) seen in common variable immunodeficiency (CVID). Abatacept is a recombinant, human fusion protein of cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and human IgG1 that blocks T cell activation by binding to CD80 and CD86, thereby blocking CD28 engagement- the "second signal" needed for T cell activation. Abatacept has recently looked promising for the treatment of patients with complex CVID.

This study is a multi-site, phase II, randomized, blinded/placebo-controlled clinical trial in pediatric subjects ≥50 kg and adult subjects (cohort 1), with an additional cohort (#2) of pediatric subjects <50 kg tested as a single arm, receiving open-label abatacept. Cohort 1 utilizes a 'delayed-start' design to obtain maximum statistical power from this cohort. Cohort 2 will be open label due to the lack of a suitable placebo for pediatric dose abatacept syringes. A total of 21-30 evaluable subjects will be treated in cohort 1 and 8 evaluable subjects in cohort 2.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 38
• Est. completion date: July 2025
• Est. primary completion date: July 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 4 Years and older

Eligibility

Inclusion Criteria:

1. Diagnosis of CVID according to the international consensus document (ICON)

1. Age 4 years or above

2. Serum IgG at least 2 standard deviations below the age adjusted normal

3. Decreased serum IgA and/or serum IgM

4. Abnormal specific antibody response to immunization

5. Exclusion of secondary immunodeficiency

2. On replacement immunoglobulin for at least 6 months and willing to maintain throughout study

3. Granulomatous-lymphocytic interstitial lung disease with a lymphocytic component diagnosed by lung biopsy prior to study entry, wedge biopsy preferred.

4. Persistence or worsening of interstitial lung disease measured on serial CT imaging of the lung at least 6 months apart, with the latest assessment within 3 months of study entry.

5. Signed written informed consent

6. Willing to allow storage of biological specimens for future use in medical research.

7. Female subjects of childbearing potential must agree to an effective form of birth control such as hormone based contraceptive, intrauterine device, condoms/barrier, surgically sterile partner, or abstinence.

8. Fertile, non-vasectomized males with a female partner of childbearing potential should use condoms throughout the study and for 3 months after the last dose

Exclusion Criteria:

1. History of hypersensitivity to abatacept or any of its components

2. Has received any lymphocyte depleting agents including anti-CD20 monoclonal antibodies, alemtuzumab, ATG in the preceding 6 months

3. Has received abatacept, cyclophosphamide, tumor necrosis factor inhibitors, or pulse steroids (defined as >15mg/kg/day of methylprednisone or corticosteroid equivalent) within the past 3 months

4. Have started or increased any of the following immune modulating drugs within 3 months of enrolling and 3 months from initial CT chest: azathioprine, cyclosporine, tacrolimus, mercaptopurine, methotrexate, mycophenolate mofetil, or sirolimus

5. History of HIV infection (positive PCR)

6. Chronic untreated hepatitis B or C (positive PCR)

7. Active tuberculosis (TB) by positive QuantiFERON gold. If history of latent TB, then must supply evidence of completing treatment.

8. Persistent Epstein-Barr Virus (EBV) load = 1,000 units/mL blood checked twice at least 1 month apart

9. Other uncontrolled infections

10. Live vaccine given within 6 weeks of the start of the trial

11. Malignancy or treated for malignancy within the past year

12. Currently pregnant or breast feeding

13. Life expectancy less than 1 month

14. Subjects unwilling to self-administer or have a parent/caregiver self-administer subcutaneous injections at home

15. Other conditions that the investigators feel contraindicate participation in the study

Related Conditions & MeSH terms

• Common Variable Immunodeficiency
• Immunologic Deficiency Syndromes
• Interstitial Lung Disease
• Lung Diseases
• Lung Diseases, Interstitial

Intervention

Drug:
• Abatacept
Abatacept is a selective costimulation modulator, inhibiting T lymphocyte activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Orencia solution supplied in a prefilled syringe should be refrigerated at 2C to 8C (36F to 46F). Orencia should not be used beyond the expiration date on the prefilled syringe. The product should be protected from light by storing in the original package until time of use. The prefilled syringe should not be frozen.

Other:
• Placebo
The composition of the placebo for Orencia is the same as the active study drug without the abatacept. The placebo will be packaged and labeled as described above for the Orencia prefilled syringes. To maintain the blind, injection volumes will be the same as the active treatment.

Locations

Country	Name	City	State
United States	Lahey Hospital and Medical Center	Burlington	Massachusetts
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Duke University Health System	Durham	North Carolina
United States	Mayo Clinic	Rochester	Minnesota
United States	University of California, San Francisco	San Francisco	California
United States	University of South Florida	Tampa	Florida

Sponsors (2)

Lead Sponsor	Collaborator
Children's Hospital Medical Center, Cincinnati	Bristol-Myers Squibb

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	High Resolution CT Scan of the chest (HRCT)	Proportion of subjects achieving a significant response (defined as >30 percent change in lung tissue disease burden by GLILD) on HRCT after 6 months of abatacept therapy.	6 months
Secondary	Forced vital capacity (FVC)	Forced vital capacity (FVC)	6 months, 12 months
Secondary	Forced expiratory volume (FEV)	Forced expiratory volume (FEV)	6 months, 12 months
Secondary	Diffusion capacity of carbon monoxide (DLCo)	Diffusion capacity of carbon monoxide (DLCo)	6 months, 12 months
Secondary	Incidence	Incidence of new onset autoimmune/inflammatory diseases while on abatacept or placebo	6 months, 12 months
Secondary	Resolution	Resolution of existing autoimmune/inflammatory diseases while on abatacept or placebo	6 months, 12 months
Secondary	Change in Short Form-36 scores	Short Form-36: scoring ranges from 0-100 where a higher score denotes better health	6 months, 12 months
Secondary	Change in PedsQL (Pediatric Quality of Life) Generic Core scores	PedsQL Generic Core Scales: items are reversed scored and linearly transformed to a 0-100 scale, so that higher scores indicate better HRQOL. Range of 0-2300 for ages above 4, range of 0-2100 for 4 years old	6 months, 12 months
Secondary	Change in King's Interstitial Lung Disease scores	King's Interstitial Lung Disease: scoring ranges from 0-100 where a higher score denotes better health	6 months, 12 months
Secondary	Steroid usage	Cumulative number of steroids used after 6 months and 12 months	6months, 12 months
Secondary	Survival	Survival at 12 months	6 months, 12 months
Secondary	Pediatric growth - change in height	Change in height at 6 and 12 months.	6 months, 12 months
Secondary	Pediatric growth - change in weight	Change in weight at 6 and 12 months.	6 months, 12 months
Secondary	Additional Immune Agents	Rate of discontinuation of additional immune agents while on study agent	6 months, 12 months
Secondary	Adverse Events/Serious Adverse Events	Incidence of adverse events and severe adverse events, compared to placebo	6 months, 12 months
Secondary	Dropout rate	Study dropout rate	6 months, 12 months
Secondary	Incidence of concurrent infections	Incidence of concurrent infections while on study	6 months, 12 months
Secondary	Treatment of concurrent infections	Number of infections per patient which require treatment with antibiotics	6 months, 12 months
Secondary	Complications of concurrent infections	Complications of concurrent infections while on study	6 months, 12 months