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

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

Study Overview

• Status: Recruiting
• Conditions: Common Variable Immunodeficiency; Interstitial Lung Disease
• Intervention / Treatment: Drug: Abatacept; Other: Placebo

Detailed 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.

• Study Type: Interventional
• Enrollment (Estimated): 38
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Michael Jordan; Phone Number: 513-803-9063; Email: Michael.Jordan.@cchmc.org
• Study Contact Backup: Name: Erinn Kellner; Phone Number: 513-517-2188; Email: Erinn.Kellner@cchmc.org

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143
      • Recruiting
      • University of California, San Francisco
      • Contact: Alma Andrade; Phone Number: 415-476-7054; Email: Alma.Andrade@ucsf.edu
      • Principal Investigator: Michele Pham, MD
  • Florida
    • Tampa, Florida, United States, 33620
      • Recruiting
      • University of South Florida
      • Contact: Jolan Walter; Phone Number: 727-553-1258; Email: jolanwalter@usf.edu
      • Principal Investigator: Jolan Walter, MD
  • Massachusetts
    • Burlington, Massachusetts, United States, 01805
      • Recruiting
      • Lahey Hospital and Medical Center
      • Contact: Jocelyn Farmer, MD; Email: Jocelyn.Farmer@lahey.org
      • Contact: Ahmed Sanousi; Email: Ahmed.Sanousi@lahey.org
      • Principal Investigator: Jocelyn Farmer, MD
  • Minnesota
    • Rochester, Minnesota, United States, 55902
      • Recruiting
      • Mayo Clinic
      • Contact: Kawser Iguel; Phone Number: 507-422-5291; Email: iguel.kawser@mayo.edu
      • Principal Investigator: Avni Joshi, MD
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Recruiting
      • Duke University Health System
      • Contact: Katherine Prince; Phone Number: 919-681-8931; Email: katherine.prince@duke.edu
      • Principal Investigator: Patricia Lugar, MD
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Recruiting
      • Cincinnati Children's Hospital Medical Center
      • Contact: Michael Jordan; Phone Number: 513-803-9063; Email: Michael.Jordan@cchmc.org
      • Principal Investigator: Erinn Kellner, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Abatacept; Pediatric subjects weighing <50 kg will be placed in an single arm with abatacept with dosing based on weight. Pediatric subjects weighing ≥50kg and adult subjects will enter a double blinded, randomization in a 1:2 ratio of subjects to the abatacept treatment group (arm 1) or to the placebo group (arm 2) treated weekly through weekly 26. Pediatric dosing: Abatacept subcutaneous every week: 10-25 kg: 50 mg; 25-50 kg: 87.5 mg; >50 kg: 125 mg Adult dosing: Abatacept: 125 mg subcutaneous every week	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 Names: Orencia
Placebo Comparator: Placebo; Pediatric subjects weighing ≥50kg and adult subjects will enter a double blinded, randomization in a 1:2 ratio of subjects to the abatacept treatment group (arm 1) or to the placebo group (arm 2) treated weekly through weekly 26. The composition of the placebo is the same as the active study drug without the abatacept. To maintain the blind, injection volumes will be the same as the active treatment.	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Forced vital capacity (FVC)	Forced vital capacity (FVC)	6 months, 12 months
Forced expiratory volume (FEV)	Forced expiratory volume (FEV)	6 months, 12 months
Diffusion capacity of carbon monoxide (DLCo)	Diffusion capacity of carbon monoxide (DLCo)	6 months, 12 months
Incidence	Incidence of new onset autoimmune/inflammatory diseases while on abatacept or placebo	6 months, 12 months
Resolution	Resolution of existing autoimmune/inflammatory diseases while on abatacept or placebo	6 months, 12 months
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
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
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
Steroid usage	Cumulative number of steroids used after 6 months and 12 months	6months, 12 months
Survival	Survival at 12 months	6 months, 12 months
Pediatric growth - change in height	Change in height at 6 and 12 months.	6 months, 12 months
Pediatric growth - change in weight	Change in weight at 6 and 12 months.	6 months, 12 months
Additional Immune Agents	Rate of discontinuation of additional immune agents while on study agent	6 months, 12 months
Adverse Events/Serious Adverse Events	Incidence of adverse events and severe adverse events, compared to placebo	6 months, 12 months
Dropout rate	Study dropout rate	6 months, 12 months
Incidence of concurrent infections	Incidence of concurrent infections while on study	6 months, 12 months
Treatment of concurrent infections	Number of infections per patient which require treatment with antibiotics	6 months, 12 months
Complications of concurrent infections	Complications of concurrent infections while on study	6 months, 12 months

Collaborators and Investigators

• Sponsor: Children's Hospital Medical Center, Cincinnati
• Collaborators: Bristol-Myers Squibb

Study record dates

Study Major Dates

• Study Start (Actual): July 14, 2021
• Primary Completion (Estimated): July 1, 2025
• Study Completion (Estimated): July 1, 2025

Study Registration Dates

• First Submitted: May 11, 2021
• First Submitted That Met QC Criteria: June 7, 2021
• First Posted (Actual): June 14, 2021

Study Record Updates

• Last Update Posted (Actual): March 15, 2024
• Last Update Submitted That Met QC Criteria: March 13, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Immunologic Deficiency Syndromes; Lung Diseases, Interstitial; Common Variable Immunodeficiency; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Abatacept
• Other Study ID Numbers: 2020-0876; R01FD007267 (U.S. FDA Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No