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Lung TransplantPhase 2NCT02266888

B Cell Induction in Pediatric Lung Transplantation

A Phase 2 study testing Rituximab (Rituxan®) in people with Lung Transplant, run by National Institute of Allergy and Infectious Diseases (NIAID) at 7 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

In this study, doctors are trying to see if a study drug called rituximab (Rituxan®) will lower the number of B cells in the body. Doctors are also trying to see if decreasing B cells with rituximab (Rituxan®) can prevent injury to the transplanted lung. Read more about this study

Who is it for?
Ages Up to 21 years
Conditions the study is for
Lung Transplant
What is being tested?
Rituximab (Rituxan®)
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
45 participants
Where
7 sitesUnited States
Study dates
22 Jan 2015to 30 Jun 2019
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages Up to 21 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • Enrollment:
  • Subject and/or parent guardian must be able to understand and provide informed consent;
  • Candidate for a primary lung transplant (listed for lung transplant);
  • Female and male subjects with reproductive potential must agree to use FDA approved methods of birth control for 12-months after completion of treatment.
  • Adequate bone marrow functions based on the following criteria:
  • Absolute neutrophil count (ANC): >1000mm^3
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  • Platelets: >100,000/mm^3
  • Hemoglobin: >7 gm/dL
  • AST or ALT< 2x Upper Limit of Normal unless related to primary disease
  • Randomization:
  • Individuals who meet all of the following criteria are eligible for randomization:
  • Serum IgG immunoglobulin level greater than lower level of normal for age based on local laboratory ranges or 400mg/dL within 90 days prior to randomization;
  • Female subjects of childbearing potential must have a negative pregnancy test within 4 hours of transplant;
  • Negative for Hepatitis B infection (if at time of transplant, participant does not exhibit effective immunization, the participant should be re-tested).

Who cannot join

  • Enrollment:
  • Individuals who meet any of these criteria are not eligible for enrollment as study participants:
  • Inability or unwillingness of a participant to give written informed consent or comply with study protocol;
  • Multi-organ transplant;
  • Previous treatment with rituximab (Rituxan®);
  • History of severe allergic anaphylactic reactions to humanized or murine monoclonal antibodies;
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  • History of severe reaction to previous therapy with intravenous immunoglobulin (IVIG);
  • History of Burkholderia cenocepacia;
  • History of anti-CD20 therapy;
  • Persistent hypogammaglobulinemia (IgG < lower level of normal for age based on local laboratory ranges or 400 gm/dL for >2 months) and/or IVIG replacement therapy;
  • Positive blood culture, sepsis or other disease process with hemodynamic instability at time of enrollment;
  • Any history of serologic positivity to HIV, HBsAg, HBcAb and HCV Ab;
  • History of malignancy less than 2 years in remission of malignancy (any history of adequately treated in-situ cervical carcinoma, or adequately treated basal or squamous cell carcinoma of the skin will be permitted);
  • Any condition, including psychiatric disorders, that in the opinion of the investigator would interfere with the subject's ability to comply with study requirements;
  • Participation in another investigational trial within 4 weeks of enrollment;
  • Currently lactating or plans to become pregnant during the timeframe of the study follow-up period;
  • Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study.
  • Randomization:
  • Individuals who meet any of these criteria are not eligible for randomization:
  • Use of an induction agent other than Thymoglobulin®;
  • Renal insufficiency requiring hemodialysis or ultrafiltration;
  • Inability to obtain intravenous access;
  • Positive blood culture, sepsis or other disease process with hemodynamic instability at time of transplant;
  • Use of investigational agent(s) within 5 half-lives of the investigational drug or 4 weeks, whichever is longer;
  • Receipt of a MMR vaccine within 30 days prior to randomization;
  • Any condition that, in the opinion of the investigator, would interfere with the subject's ability to comply with study requirements.

Trial locations and contacts

7 sites in 1 country.

7 sites in 1 country

United States7 sites

  • Children's Hospital Boston

    Boston, Massachusetts, 02115

  • Cincinnati Children's Hospital Medical Center

    Cincinnati, Ohio, 45229

  • Nationwide Children's Hospital

    Columbus, Ohio, 43205

  • Texas Children's Hospital

    Houston, Texas, 77030

  • Stanford University

    Palo Alto, California, 94305

  • Children's Hospital of Philadelphia

    Philadelphia, Pennsylvania, 19104

  • Washington University

    St Louis, Missouri, 63110

Other trials in United States

About this study

Official title: B Cell Targeted Induction to Improve Outcomes in Pediatric Lung Transplantation (CTOTC-08)

In this study, doctors are trying to see if a study drug called rituximab (Rituxan®) will lower the number of B cells in the body. Doctors are also trying to see if decreasing B cells with rituximab (Rituxan®) can prevent injury to the transplanted lung. This treatment has been studied in other types of solid organ transplants.

Read the detailed description

Patients who receive a lung transplant are at risk for rejection of the transplanted lung(s). Rejection occurs when the new lung triggers the body's defense (immune) system. When the immune system is triggered special cells are sent out to destroy the new lung and eventually the lung may not be able to function as it should. These special cells include B cells. B cells are an important part of the immune system and help the body fight infection. One way B cells fight infection is by producing antibodies. B cells and the antibodies they produce are involved in some kinds of rejection after organ transplantation.

Conditions
Lung Transplant
Being tested
Rituximab (Rituxan®), Placebo
Keywords
B cells, lung transplant recipient, rituximab, placebo, standard of care

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Rituximab (Rituxan®)Biological

    Also called Rituxan®

    2 Doses: 375 mg/m^2 on Day 0 (within 12 hours of return to ICU following transplant) and Day 12 (+/-2 days).

  • PlaceboBiological

    Placebo for Rituximab (Rituxan®). 2 Doses: 375 mg/m^2 on Day 0 (within 12 hours of return to ICU following transplant) and Day 12 (+/-2 days).

Study groups in NCT02266888
Study groupRoleWhat they receive
Rituximab InductionExperimentalRituximab (Rituxan®) Induction Therapy Plus Standard of Care Immunosuppression (thymoglobulin induction, tacrolimus or equivalent, mycophenolate mofetil (MMF) or equivalent, and steroids)
Receives: Biological: Rituximab (Rituxan®)
Placebo InductionPlacebo comparatorPlacebo Induction Therapy Plus Standard of Care Immunosuppression (Thymoglobulin® induction, tacrolimus or equivalent, mycophenolate mofetil (MMF) or equivalent, and steroids)
Receives: Biological: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Earliest Time to Any of the Following Events: Chronic Allograft Dysfunction, Listed for Retransplant or Death

    This composite outcome measures is defined as the earliest time post-transplant to any of the following events during the follow-up period:

    • Chronic Allograft Dysfunction (defined as the occurrence of confirmed Bronchiolitis Obliterans Syndrome (BOS) grade 0-p or higher or a diagnosis of Obliterative Bronchiolitis (OB)),
    • Listed for re-transplant (e.g., second lung transplant), or
    • Death.

    Measured: Up to 35 months post-transplant

Secondary outcomes (12)

  1. Percent of Participants Diagnosed With Chronic Allograft Dysfunction

    Chronic allograft dysfunction is defined as Bronchiolitis Obliterans Syndrome (BOS) ≥Grade 0p according to the International Society for Heart and Lung Transplantation (ISHLT) criteria, or biopsy proven histologic evidence of obliterans bronchiolitis.

    BOS is an indicator of post-transplant loss of lung function, a sign of allograft dysfunction that presents as a persistent decline in forced expiratory volume in 1 second (FEV1) or forced expiratory flow (FEF) 25-75% (often accompanied by evidence of airway obstruction) that is not the result of other causes such as acute rejection, acute infection, and/or airway stenosis.

    • BOS grade: Spirometry % of baseline
    • 0: FEV1 >90% and FEF25-75% >75%
    • 0-p: FEV1 81-90% and FEF25-75% ≤75%
    • 1: FEV1 66-80%
    • 2: FEV1 51-65%
    • 3: FEV1 ≤50%

    Measured: Up to 35 months post-transplant

  2. Percent of Participants Listed for Re-Transplant During the Study Follow-Up Period

    Participants with a reported date of listing for a second lung transplant during the study follow-up period.

    Measured: Up to 35 months post-transplant

  3. Percent of Participants Who Died During the Study Follow-Up Period

    Participants with a reported date of death were considered to have met this outcome.

    Measured: Up to 35 months post-transplant

  4. Percent of Participants With Primary Graft Dysfunction (PGD)

    The International Society for Heart and Lung Transplantation's (ISHLT) grading for Primary Graft Dysfunction (PGD) was used. The severity of PGD is graded 0 - 3 based on the presence or absence of diffuse opacities on chest radiograph and the ratio of arterial oxygen pressure to inspired oxygen concentration. The grading system predicts post-lung transplant outcomes with Grade 3 being the worse.

    Participants were classified as having PGD if graded as 2 or 3 at any time during the first 72 hours post-transplant.

    Measured: Up to 72 hours post-transplant

  5. Percent of Participants With Occurrence of Grade A Acute Rejection

    Pulmonary allograft rejection was defined according to the 2007 International Society for Heart and Lung Transplantation's (ISHLT). Each transbronchial biopsy (TBBx) was evaluated by the local center's pathologist and graded as described below.

    Acute Cellular Rejection (ACR) Grade Classification:

    • A0: None
    • A1: Minimal
    • A2: Mild
    • A3: Moderate
    • A4: Severe

    Participants met this outcome if at any point in time their biopsy was classified as A2, A3, or A4.

    Measured: Up to 24 months post-transplant

  6. Percent of Participants With Occurrence of Antibody Mediated Rejection

    Antibody Mediated Rejection (AMR) was defined based on the revision of the 1996 Working Formulation for the Standardization of Nomenclature in the Diagnosis of Lung Rejection, the Pathology of pulmonary AMR and the 2012 update from the Pathology Council of the International Society for Heart and Lung Transplantation (ISHLT).

    AMR was diagnosed locally and graded as:

    • Grade I: Latent humoral response - Donor Specific Antibody (DSA) or autoantibody present and absence of both abnormal histology and unexplained graft dysfunction
    • Grade II: Subclinical humoral rejection - DSA or autoantibody present and abnormal histology present with an absence of unexplained graft dysfunction
    • Grade III: Humoral rejection - DSA or autoantibody present and abnormal histology present and unexplained graft dysfunction present.

    Higher grades indicate more severe AMR.

    Participants were considered to have met this outcome if at any point in time their biopsy was classified as Grade II or III.

    Measured: Up to 24 months post-transplant

  7. Percent of Participants Meeting Tacrolimus Variability Threshold

    Tacrolimus trough levels are generally collected post-transplant to allow clinicians to monitor transplant recipients' adherence to prescribed tacrolimus dosing. This outcome was designed for research purposes as an indicator of adherence to tacrolimus over time.

    Beginning at 3 months post-transplant, a rolling standard deviation (SD) was estimated for each participant who had at least 3 outpatient trough levels collected and recorded. The estimated SD could derive from up to 1 year worth of trough levels at any given time. The larger the SD (variation) of tacrolimus levels, the greater the nonadherence of participant(s) taking tacrolimus as prescribed. Nonadherence is a major reason for post-transplant morbidity.

    Participants were considered to have met this outcome, the tacrolimus variability threshold, if their estimated SD of tacrolimus medication levels at any time was 2.0 ng/mL or greater.

    Measured: Up to 24 months post-transplant

  8. Percent of Participants Meeting Tacrolimus Variability Threshold Who Completed Tacrolimus Variability Intervention

    For participants who met the Tacrolimus Variability Threshold and agreed to participate in the Tacrolimus Variability Intervention (TVI), a series of calls with the participant, parent(s)/guardian(s), and trained call center personnel were conducted to address barriers to adherence.

    Refer to Outcome Measure 8 for a description of tacrolimus variability threshold methodology.

    Measured: Up to 27 months post-transplant

  9. Magnitude of Change in Standard Deviation of Tacrolimus Levels Following Intervention

    Standard deviation (SD) is a number that describes how a group of measurements are spread out around the average value for that group. A low SD value means the numbers are close to the average; a high SD means the numbers are more spread out. The change in SD of tacrolimus levels was calculated by subtracting each participant's pre-intervention SD from their SD 180 days after enrollment into the intervention (i.e., value of SD 180 days after enrollment minus value of SD before enrollment). A change less than zero (i.e., a negative number) would indicate a decrease in SD, which is good, possibly as a result of the intervention.

    Measured: Up to 19 months post-transplant

  10. Percent of Participants Experiencing an Infection Episode

    Defined by:

    • A local report of bacterial, fungal, or viral infection through either the organism specific case report form (CRF) or adverse event reporting; or
    • Presence of symptoms at the time of a study visit without a local report of infection but with a corresponding Core Lab identified viral infection
    • All symptoms reported at the time of a study visit were evaluated for any Epstein-Barr Virus (EBV) and Cytomegalovirus (CMV) infections identified by the Core Lab
    • For any other infections identified in Core Lab Nasopharyngeal (NP) and Bronchoalveolar Lavage (BAL) biospecimens: shortness of breath, new x-ray or other imaging finding, new supplemental oxygen requirement, cough with sputum, and decreased spirometry were evaluated signs/symptoms.

    Participants were considered to have met this outcome if at any point in time they had an infection meeting the referenced criteria.

    Measured: Up to 24 months post-transplant

  11. Number of Participants With Severity of Infection Episodes

    The severity of infection episodes was determined by the site Principal Investigator (PI) using the adverse event (AE) scale of mild to moderate (Grade <3), severe (Grade 3), life-threatening (Grade 4), or fatal (Grade 5).

    Since the protocol restricted AE reporting to only those events which met National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 grading criteria of Grade 3 (moderate) or higher, any infection not reported as an AE was assigned a severity of Grade <3 (effectively combining Grades 1 and 2); all other infections utilized the assigned CTCAE severity grade of the corresponding AE. A higher severity grade indicates a more severe event.

    Measured: Up to 24 months post-transplant

  12. Percent of Participants Experiencing a Serious Adverse Event (SAE) Related to Rituximab

    The percentage of participants with Serious Adverse Events (SAEs) as determined by the trial's medical monitor to be related to rituximab is reported.

    Measured: Up to 35 months post-transplant

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 Oct 2014 (estimated)
  2. Study start22 Jan 2015
  3. Primary completion30 Jun 2019
  4. Study completion30 Jun 2019

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Triple blind
Who is masked
Participant, Care provider, Investigator
Enrolment
45 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02266888
Sponsor's protocol ID
DAIT CTOTC-08
Other IDs
NIAID CRMS ID#: 20181
Status last verified
Oct 2021
First submitted
8 Oct 2014
Last updated
26 Oct 2021
Data monitoring committee
Yes
Individual data sharing
Yes: The plan is to share data upon completion of the study in: Immunology Database and Analysis Portal (ImmPort), a long-term archive of clinical and mechanistic data from DAIT-funded grants and contracts.

Publications

  • Sweet SC, Armstrong B, Blatter J, Chin H, Conrad C, Goldfarb S, Hayes D Jr, Heeger PS, Lyou V, Melicoff-Portillo E, Mohanakumar T, Odim J, Ravichandran R, Schecter M, Storch GA, Visner G, Williams NM, Danziger-Isakov L. CTOTC-08: A multicenter randomized controlled trial of rituximab induction to reduce antibody development and improve outcomes in pediatric lung transplant recipients. Am J Transplant. 2022 Jan;22(1):230-244. doi: 10.1111/ajt.16862. Epub 2021 Nov 5.

    PubMed 34599540

  • Duncan-Park S, Dunphy C, Becker J, D'Urso C, Annunziato R, Blatter J, Conrad C, Goldfarb SB, Hayes D Jr, Melicoff E, Schecter M, Visner G, Armstrong B, Chin H, Kesler K, Williams NM, Odim JN, Sweet SC, Danziger-Isakov L, Shemesh E. Remote intervention engagement and outcomes in the Clinical Trials in Organ Transplantation in Children consortium multisite trial. Am J Transplant. 2021 Sep;21(9):3112-3122. doi: 10.1111/ajt.16567. Epub 2021 Apr 12.

    PubMed 33752251

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Rituximab (Rituxan®) in people with Lung Transplant, run by National Institute of Allergy and Infectious Diseases (NIAID) at 7 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 14 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 26 Oct 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 7 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 16 Jul 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Earliest Time to Any of the Following Events: Chronic Allograft Dysfunction, Listed for Retransplant or Death (time frame: Up to 35 months post-transplant). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02266888, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Oct 2021.

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