Gene Transfer for Patients With Sickle Cell Disease

April 10, 2024 updated by: Children's Hospital Medical Center, Cincinnati

Gene Transfer For Patients With Sickle Cell Disease Using A Gamma Globin Lentivirus Vector: An Open-Label Phase 1 / 2 Pilot Study

The purpose of this Phase 1/2 study is to determine the feasibility and safety of stem cell collection and gamma-globin gene transfer, and success of gene correction in subjects with sickle cell disease

Study Overview

Status

Status

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

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

This study will assess the feasibility, safety and efficacy of gene transfer using ARU-1801 (CD34+ cells transduced with the gamma-globin lentiviral vector). Gene transfer will occur ex-vivo into CD34+ enriched human bone marrow or plerixafor-mobilized peripheral blood hematopoietic stem cells (HSC) collected from subjects with severe sickle cell disease (SCD). Subjects will undergo reduced intensity chemotherapy conditioning with single-dose melphalan to facilitate engraftment of ex-vivo ARU-1801 via IV infusion. Subjects will return to the study site at regular intervals for follow-up for 2 years after the ARU-1801 infusion. It is anticipated that a separate long-term follow-up (LTFU) clinical study will be initiated, in which all subjects completing the 2 year study visit will be asked to consent and enroll, and will followed for a further 13 years.

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 (Actual)

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.
7

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.
  • Phase 2
  • Phase 1

Contacts and Locations

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

Study Locations

  • United States
    • Ohio
      • Cincinnati, Ohio, United States, 45229
        • Cincinnati Children's Hospital Medical Center

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

18 years to 45 years (Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria

  • Signed informed consent form.
  • Has confirmed diagnosis of sickle cell disease (SCD)

  • Has severe sickle cell disease, defined as one or more of the following:

    1. Minimum of two episodes of clinically diagnosed acute chest syndrome (ACS) requiring hospital admission, or one life threatening episode of ACS requiring intensive care unit (ICU) admission for exchange transfusion and/or intubation, or frequent ACS episodes which necessitate treatment with chronic transfusion therapy.
    2. Frequent painful vaso-occlusive episodes (VOEs) which significantly interfere with normal life activities, defined as a history of 2 or more severe acute sickle pain events per year requiring additional treatment at a medical facility outside of home pain management over the preceding 2-year period prior to study enrollment, or that necessitate chronic transfusion therapy.
    3. Subjects on chronic transfusion therapy for severe disease symptoms other than those listed above, and which interfere with normal life activities.
  • Has failed hydroxyurea therapy, was unable to tolerate hydroxyurea therapy, or has actively made the choice to not take the recommended daily hydroxyurea advised for severe disease (Note: must be off hydroxyurea therapy for 2 months prior to stem cell collection). If refusing hydroxyurea, the subject must document that they have been educated about the benefits and continue to refuse the treatment. Patients placed on chronic transfusion therapy instead of hydroxyurea for severe disease are eligible. Subjects unable to take hydroxyurea due to financial or safety monitoring constraints are eligible.
  • Has adequate functional status and organ function as determined at Screening.

Exclusion Criteria

  • Female subjects who are pregnant or lactating/breastfeeding.
  • Female subjects who are not surgically sterile, postmenopausal or who refuse to practice effective method of birth control as determined by the Investigator for one year after receiving the study drug. Women must also agree not to breastfeed for 1 year after receiving the study drug.
  • Any participant of reproductive potential who refuses to agree to use an appropriate contraceptive method determined by the Investigator, for 1 year after receiving the study drug.
  • Patients with an active malignant disease or receiving treatment for any type of cancer (except squamous cell carcinoma, basal cell carcinoma, or carcinoma in situ of the skin).
  • Current diagnosis or history of hepatitis B, hepatitis C, or HIV.
  • Has received another study drug within 30 days, or 5 half-lives of the last dose (whichever is longer), prior to screening.
  • Has severe obstruction, restriction or diffusion defect on pulmonary function tests.
  • Has uncontrolled bacterial, viral or fungal infections within 1 month prior to starting the conditioning part of the study. Subjects with fever should wait for symptoms to resolve before starting the conditioning part of the study.
  • Has a history of stroke or is at moderate to high risk of primary stroke (eg receiving chronic transfusions or hydroxyurea for primary prevention of stroke; has severe cerebral vasculopathy defined as moderate stenosis in >2 arterial segments; and/or has sever stenosis/occlusion in ≤2 segments in the polygon of Willis or presence of Moyamoya-like disease).
  • Patients with alpha thalassemia sickle cell disease.
  • Has previous liver biopsy showing cirrhosis, bridging hepatic fibrosis, or active hepatitis; or has received chronic transfusions and has previous evidence of iron overload and evidence of liver fibrosis by noninvasive liver imaging.
  • Has a matched sibling donor, unless the subject has declined this option or this option is not feasible. Documentation must be included as part of the informed consent process for subjects who decline this option.
  • Has a known hypersensitivity to any study treatments (e.g. melphalan, plerixafor).

Other protocol-defined inclusion-exclusion criteria may apply.

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: Supportive Care
  • Allocation: N/A
  • Interventional Model: Single Group 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.
Experimental: ARU-1801
Autologous CD34+ hematopoietic stem cells transduced ex-vivo with gamma-globin lentiviral vector. Administered via IV infusion.
Genetic: ARU-1801

Autologous CD34+ hematopoietic stem cells transduced ex-vivo with a gamma-globin lentiviral vector

  • Subjects with sickle cell anemia will undergo hematopoietic stem cell procurement by bone marrow harvest or apheresis after mobilization with plerixafor
  • Reduced intensity chemotherapy conditioning with single dose melphalan will be used to facilitate engraftment of ex-vivo transduced cells.

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
Incidence of Grade 3 allergic reaction
Time Frame: From infusion (Day 0) to 15 years
Incidence of Grade 3 allergic reaction associated with infusion of transduced cell product
From infusion (Day 0) to 15 years
Incidence of Grade 4 infection
Time Frame: From infusion (Day 0) to 15 years
Incidence of Grade 4 infection following infusion of transduced cell product uncontrolled for ≥14 days
From infusion (Day 0) to 15 years
Incidence of Grade 4 neutropenia
Time Frame: From date of chemotherapy clearance visit to 15 years post-infusion of transduced cells
Incidence of Grade 4 neutropenia lasting >1 month following melphalan
From date of chemotherapy clearance visit to 15 years post-infusion of transduced cells
Incidence of Grade 3 or 4 organ toxicity
Time Frame: From screening to 15 years post-infusion of transduced cells
Incidence of Grade 3 or 4 organ toxicity attributable to study procedures
From screening to 15 years post-infusion of transduced cells
Incidence of Adverse Events (AEs)
Time Frame: From screening to 15 years post-infusion of transduced cells
From screening to 15 years post-infusion of transduced cells
Incidence of Serious Adverse Events (SAEs)
Time Frame: From screening to 15 years post-infusion of transduced cells
From screening to 15 years post-infusion of transduced cells
Incidence of death due to study procedures
Time Frame: From screening to 15 years post-infusion of transduced cells
From screening to 15 years post-infusion of transduced cells
Incidence of hematological malignancy
Time Frame: From infusion (Day 0) to 15 years
Incidence of hematological malignancy due to vector insertion
From infusion (Day 0) to 15 years
Incidence of hematological cancer
Time Frame: From screening to 15 years post-infusion of transduced cells
Incidence of hematological cancer related to investigational product or study medications/procedures
From screening to 15 years post-infusion of transduced cells
Time to neutrophil recovery
Time Frame: From ≥36 hours before Day 0 to 2 years post-infusion of transduced cells
Number of days from melphalan-induced nadir to the first of 3 consecutive absolute neutrophil counts ≥500 cells/µL
From ≥36 hours before Day 0 to 2 years post-infusion of transduced cells
Time to platelet recovery
Time Frame: From ≥36 hours before Day 0 to 2 years post-infusion of transduced cells
Number of days from melphalan-induced nadir to the first of 3 consecutive platelet counts >50,000 cells/µL and independent of platelet transfusion for ≥7 days consecutive days.
From ≥36 hours before Day 0 to 2 years post-infusion of transduced cells
≥8x10⁶kg viable CD34+ cells
Time Frame: Up to Year 2
Number of subjects with a total number of CD34+ cells recovered from all collections combined (mobilized peripheral blood and bone marrow) of at least ≥8x10⁶kg viable CD34+ cells
Up to Year 2
≥4x10⁶ CD34+ cells/kg body weight transduced
Time Frame: Up to Year 2
Proportion of subjects for which a minimum of 4x10⁵ CD34+ cells/kg body weight from all collections combined have been successfully transduced
Up to Year 2
Bone marrow aspirates with ≥1% gene-marked cells
Time Frame: Infusion (Day 0) to 1 year
Number of subjects with bone marrow aspirates at 1-year post-infusion with ≥1% gene-marked cells
Infusion (Day 0) to 1 year

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
Measure Description
Time Frame
Quantity of Hb (hemoglobin) subtypes
Time Frame: Months 6, 12, 18, 24 and year 3, 4, 5
Quantification of HbF^G16D and other Hb subtypes, including HbF (endogenous), HbS, adult Hb (HbA), HbA2 and, if applicable, HbC and HbE
Months 6, 12, 18, 24 and year 3, 4, 5
Change in proportion of antisickling/sickling hemoglobin
Time Frame: Baseline to Month 6 through 12
Change in the proportion of antisickling/sickling hemoglobin ([HbF+HbF^G16D+HbA2]/HbS) in months 6-12 post-transplantation compared to baseline
Baseline to Month 6 through 12
Percentage of F-RBC (fetal hemoglobin content in red blood cells)
Time Frame: Months 6, 12, 18, 24, 36
Measured by flow cytometry
Months 6, 12, 18, 24, 36
Percentage of F-retics (fetal hemoglobin content in reticulocytes)
Time Frame: Months 6, 12, 18, 24, 36
Measured by flow cytometry
Months 6, 12, 18, 24, 36
Presence of vector copies in white blood cell fraction
Time Frame: Days 30, 60, 90, Months 4, 5, 6, 9, 12, 18, 21, 24
Days 30, 60, 90, Months 4, 5, 6, 9, 12, 18, 21, 24
Presence of vector copies in bone marrow
Time Frame: Prior to ARU-1801 infusion, month 6, 12, 18, 24 and 36
Measured by qPCR and DNA
Prior to ARU-1801 infusion, month 6, 12, 18, 24 and 36
Presence of gene-marked colony-forming unit cells (CFU-c) in bone marrow (BM) indicting gene transfer
Time Frame: Prior to ARU-1801 infusion, month 6, 12, 18, 24 and 36
Measured by CFU-c assay by qPCR on individual CFU-c
Prior to ARU-1801 infusion, month 6, 12, 18, 24 and 36
Number of annualized vaso-occlusive episodes (VOEs) pre-transplant versus post-transplant
Time Frame: Baseline to year 15
Change in disease severity
Baseline to year 15
Frequency of opioid use pre-transplant versus post-transplant
Time Frame: Baseline to year 15
Change in disease severity
Baseline to year 15
Change in QoL (Quality of Life)
Time Frame: Baseline, month 4, 5, 6, 12 and 24 and year 3, 4, 5
Measured by adult sickle cell quality of life measurement (ASCQ-Me®)
Baseline, month 4, 5, 6, 12 and 24 and year 3, 4, 5

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.
Children's Hospital Medical Center, Cincinnati

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.
  • Study Chair: Stella M. Davies, MB BS, PhD, MRCP, Children's Hospital Medical Center, Cincinnati

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.
July 1, 2014

Primary Completion (Actual)

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.
October 31, 2022

Study Completion (Actual)

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.
October 31, 2022

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).
June 30, 2014

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.
July 9, 2014

First Posted (Estimated)

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.
July 10, 2014

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.
April 12, 2024

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.
April 10, 2024

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.
July 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.
  • ARU-1801_Ph1_01

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

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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