Preservation and Transfer of HBV Immunity After Allogeneic HSCT for SCD (PROTECT)

June 7, 2023 updated by: Erfan Nur, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Preservation and Transfer of Hepatitis B Virus Immunity After Non-Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation in Adult Sickle Cell Disease Patients (Protect Study)

Sickle cell disease (SCD) patients ending with mixed mononuclear chimerism after non-myeloablative HSCT with alemtuzumab/TBI conditioning will probably preserve their immune response to vaccinations administered prior to the transplantation and will therefore not need to be revaccinated. Furthermore, SCD patients after haploidentical HSCT might benefit from adoptive transfer of immunity from their donors.

To test the first hypothesis, patients undergoing alemtuzumab/TBI HSCT will be vaccinated with a hepatitis B virus (HBV) vaccine before the transplant. To test the second hypothesis, haploidentical and matched related donors will be vaccinated prior to stem cell donation against HBV. Neither the patient nor the donor may previously have been immunized against HBV in all cohorts. Post-transplantation, the investigators will be able to evaluate whether SCD patients preserve their pre-transplant immune response in the post-transplantation period. Furthermore, the investigators will determine whether donors transfer their immunity to HSCT recipients with SCD disease.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Rationale: Sickle cell disease (SCD) is an inherited hemoglobinopathy, characterized by chronic hemolytic anemia and microvascular occlusions leading to pain attacks and progressive deterioration of organ function. As a result, SCD patients have a significantly reduced life expectancy. Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only available curative treatment for SCD. Recently, a mild non-myeloablative conditioning regimen for HSCT with alemtuzumab (1mg/kg) and low dose (3Gy) total body irradiation (TBI) has been developed for adult SCD patients with a matched sibling donor (MSD) and been implemented in the Netherlands since 2018. The post-transplant setting of SCD patients treated with the alemtuzumab/TBI regimen differs greatly from that in other transplantation regimens usually used as treatment for malignant hematological diseases. Because of its mild character, the conditioning regimen typically results in mixed chimerism. In most patients, stable T-cell donor chimerism of around 50% is achieved. Thus, approximately half of the adaptive immunity is still patient-derived. However, whether these patients preserve their immune response after the transplantation, is not known.

Another promising development is the improvement of HSCT conditioning regimens for adult SCD patients with an haploidentical related donor. At the Amsterdam UMC, haploidentical HSCT has been implemented in 2020 using antithymocyte globulin, fludarabine, cyclophosphamide, thiotepa and low-dose (2Gy) TBI as conditioning regimen and post-transplantation cyclophosphamide (PTCy) as in vivo T-cell depletion. Besides improved engraftment rates, this conditioning regimen is also associated with a reasonably swift immune reconstitution. Unlike the conditioning with alemtuzumab/TBI in MSD HSCT, the above-mentioned conditioning for haploidentical HSCT results in full donor chimerism. Patients losing their immune response due to HSCT might benefit from the transfer of protective immunity from the stem cell donor. Two previous studies have demonstrated the adoption of immunity against hepatitis B virus (HBV) by transplant recipients. However, transplant recipients are also at high risk of gradual disappearance of protective antibodies. In contrast to our study patient population, these studies were conducted in mostly heavily pretreated patients with malignant hematological diseases undergoing myeloablative conditioning regimens.

Currently, it is common practice to revaccinate all patients post-transplant according to the revaccination schedules used for other allogeneic HSCT recipients. However, revaccinating might not be necessary in SCD patients undergoing non-myeloablative HSCT, as they might either preserve their immunity (mixed chimerism after alemtuzumab/TBI conditioning) or benefit from transfer of immunity (haploidentical HSCT)).

The investigators hypothesize, that patients ending with mixed mononuclear chimerism after HSCT will preserve their immune response to vaccinations administered prior to the transplantation and will therefore not need to be revaccinated. Furthermore, the investigators hypothesize, that SCD patients after haploidentical HSCT can benefit from adoptive transfer of immunity from their donors.

To test the first hypothesis, the investigators will vaccinate patients undergoing the alemtuzumab/TBI HSCT with a hepatitis B virus (HBV) vaccine before the transplant. To test the second hypothesis, the investigators will vaccinate haploidentical and matched related donors prior to stem cell donation against HBV. Neither the patient nor the donor may previously have been immunized against HBV in all cohorts. Post-transplantation, the investigators will be able to evaluate whether SCD patients preserve their pre-transplant immune response in the post-transplantation period. Furthermore, the investigators will determine whether donors transfer their immunity to HSCT recipients with SCD disease.

Objectives: Primarily, to investigate whether recipient immunity is preserved and how fast it reconstitutes after non-myeloablative MSD HSCT resulting in mixed chimerism in adult SCD patients. Secondly, to investigate whether donor immunity is transferred to SCD patients after non-myeloablative haploidentical and MSD HSCT.

Study design: Prospective interventional cohort study. Six SCD patients per cohort will be vaccinated with a recombinant HBV vaccine before allogeneic MSD HSCT (cohort 1a) and haploidentical HSCT (cohort 1b). Six SCD patients not undergoing allogeneic HSCT will be vaccinated as controls (cohort 2). Six haploidentical donors and six matched sibling donors of unvaccinated receivers will be vaccinated against HBV before stem cell donation (cohort 3a and 3b, respectively). All vaccinated patients and the receivers of stem cells of vaccinated donors will receive a booster vaccination at 12 months post-transplantation. Follow-up will be until 2 years post-transplantation.

Study population: Adult SCD patients undergoing a matched sibling donor or haploidentical non-myeloablative allogeneic HSCT. HBV naive SCD patients not undergoing HSCT will serve as controls.

Main study parameters/endpoints: Primary endpoint: proportion of SCD patients with a preserved anti-HBs response following non-myeloablative HSCT with an HBV naive MSD. Secondary endpoints: proportion of SCD patients with a preserved HBV specific cellular immune response following non-myeloablative HSCT with an HBV naive MSD. Proportion of SCD patients with a preserved anti-HBs and/or HBV-specific cellular immune response following non-myeloablative HSCT with an haploidentical donor. Proportion of SCD patients adopting their donors anti-HBs and/or HBV-specific cellular immune response following non-myeloablative HSCT. Immune reconstitution as expressed by serum total IgG levels and peripheral blood T-lymphocyte subset counts (CD3+, CD4+, CD8+), B-lymphocyte subset counts (CD19+) and Natural Killer (NK) cell counts at 3-, 6-, 12- and 24-months post-transplantation as compared to baseline (pre-transplantation) values.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
30

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

  • Netherlands
      • Amsterdam, Netherlands, 1105AZ
        • Recruiting
        • Amsterdam Medical Centre
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

16 years to 60 years (Child, Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Age 18 or older
  • High performance liquid chromatography (HPLC) confirmed diagnosis of SCD (not applicable to participating donors).
  • An indication for and a planned matched sibling or haploidentical donor non-myeloablative HSCT at the Amsterdam UMC, location AMC (not applicable to patients in cohort 2 (control group) and participating donors)
  • Written informed consent

Exclusion Criteria:

  • History of either cleared, chronic or active HBV infection (positive HBsAg, anti-HBs, anti-HBc and/or HBV DNA)
  • History of auto-immune diseases and/or use of immunosuppressive drugs
  • History of HIV infection
  • Known hypersensitivity to yeast of any vaccine constituent
  • Donor with a history of HBV infection

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Other
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Other: Cohort 1a
SCD patients that are vaccinated against hepatitis B virus before matched sibling donor allogeneic SCT.
Drug: Engerix-B
Subjects are vaccinated with an accelerated scheme at 0, +1, +2 months with a booster at +12 months.
Other: Cohort 1b
SCD patients that are vaccinated against hepatitis B virus before haploidentical donor allogeneic SCT.
Drug: Engerix-B
Subjects are vaccinated with an accelerated scheme at 0, +1, +2 months with a booster at +12 months.
Other: Cohort 2
SCD patients that are vaccinated against hepatitis B virus without undergoing allogeneic SCT (control group).
Drug: Engerix-B
Subjects are vaccinated with an accelerated scheme at 0, +1, +2 months with a booster at +12 months.
Other: Cohort 3a
SCD patients undergoing matched sibling donor allogeneic SCT whose donor is vaccinated against hepatitis B virus before stem cell collection.
Drug: Engerix-B
Subjects are vaccinated with an accelerated scheme at 0, +1, +2 months with a booster at +12 months.
Other: Cohort 3b
SCD patients undergoing haploidentical donor allogeneic SCT whose donor is vaccinated against hepatitis B virus before stem cell collection.
Drug: Engerix-B
Subjects are vaccinated with an accelerated scheme at 0, +1, +2 months with a booster at +12 months.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
The proportion of SCD patients with a preserved anti-HBs response and HBV-specific cellular response following non-myeloablative allogeneic HSCT with an HBV naive MSD at 12 months post-transplantation as compared to SCD patients without HSCT.
Time Frame: +1 year post-transplantation
An antibody titer (anti-HBsAg) of >10IU/l is considered protective.
+1 year post-transplantation

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Time Frame
The proportion of SCD patients with a preserved anti-HBs response and HBV-specific cellular response following non-myeloablative allogeneic HSCT with an HBV naive MSD at 3-, 6-, and 24 months post-transplantation as compared to SCD patients without HSCT.
Time Frame: 3-, 6-, and 24 months post-transplantation
3-, 6-, and 24 months post-transplantation
The proportion of SCD patients with a preserved anti-HBs response and HBV-specific cellular response following non-myeloablative allogeneic HSCT with an HBV naive haploidentical donor (cohort 1b) at 3-, 6-, 12- and 24 months post-transplantation.
Time Frame: 3-, 6-, 12- and 24 months post-transplantation
3-, 6-, 12- and 24 months post-transplantation
The proportion of SCD patients with an adoptive transfer of anti-HBs response and HBV-specific cellular response following non-myeloablative haploidentical HSCT with an HBV vaccinated donor at 3-, 6-, 12- and 24- months post-transplantation (cohort 3a).
Time Frame: 3-, 6-, 12- and 24 months post-transplantation
3-, 6-, 12- and 24 months post-transplantation
Serum total IgG level and peripheral blood T-lymphocyte subset counts (CD3+, CD4+, CD8+), B-lymphocyte subset counts (CD19+) and NK cell count, at 3-, 6-, 12- and 24-months post-transplantation as compared to counts before the start of (pre-)conditioning
Time Frame: 3-, 6-, 12- and 24-months post-transplantation
3-, 6-, 12- and 24-months post-transplantation

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Erfan Nur, MD, PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
June 8, 2021

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
January 1, 2024

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 1, 2024

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
January 6, 2022

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 6, 2022

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
January 20, 2022

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
June 8, 2023

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 7, 2023

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
June 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • METC 2021_091

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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