- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04774536
Transplantation of Clustered Regularly Interspaced Short Palindromic Repeats Modified Hematopoietic Progenitor Stem Cells (CRISPR_SCD001) in Patients With Severe Sickle Cell Disease
Transplantation of CRISPRCas9 Corrected Hematopoietic Stem Cells (CRISPR_SCD001) in Patients With Severe Sickle Cell Disease
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Study Type
Enrollment (Estimated)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Contact
- Name: Mark Walters, MD
- Phone Number: (510) 428-3374
- Email: Mark.Walters@ucsf.edu
Study Contact Backup
- Name: Christina Chun, MPH
- Phone Number: (415) 502-2558
- Email: Christina.Chun@ucsf.edu
Study Locations
-
-
California
-
Los Angeles, California, United States, 90095
- University of California, Los Angeles
-
Contact:
- Augustine Fernandes, PhD
- Email: afernandes@mednet.ucla.edu
-
Principal Investigator:
- Donald B Kohn, MD
-
Oakland, California, United States, 94609
- UCSF Benioff Children's Hospital
-
Contact:
- Cyrus Bascon
- Phone Number: 6953 510-428-3885
- Email: Cyrus.Bascon@ucsf.edu
-
Principal Investigator:
- Mark Walters, MD
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
Male or female 12.00 - 34.99 years of age (at time of consent) who have one or more of the following:
- History of two or more episodes of acute chest syndrome (ACS) in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. asthma therapy and/or hydroxyurea);
- History of at least 4 severe vaso-occlusive pain events in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. a pain management plan and/or treatment with hydroxyurea); painful episodes related to or any sickle-related acute event are acceptable; a severe painful vaso-occlusive event is defined as receiving analgesic treatment (opioid or other analgesic) for longer than 24 -hours in a hospital or emergency room (ER) observation unit visit or at least 2 visits in a day unit or ER over 72 hours with both visits requiring intravenous analgesics.
Participants must have adequate physical function as measured by all of the following:
- Karnofsky performance score ≥60.
- Cardiac function: Left ventricular ejection fraction (LVEF) >40%; or LV shortening fraction > 26% by cardiac echocardiogram or by (multiple-gated acquisition) MUGA scan.
- Pulmonary function: Pulse oximetry with a baseline O2 saturation of ≥85% and diffusion capacity of lung for carbon monoxide(DLCO) > 40% (corrected for hemoglobin).
- Renal function: Serum creatinine ≤ 1.5 x upper limit of normal for age and estimated or measured creatinine clearance ≥ 70 mL/min/1.73 m2.
- Hepatic function:
i. Serum conjugated (direct) bilirubin < 2x upper limit of normal for age as per local laboratory. Participants with hyperbilirubinemia as the result of hyperhemolysis, or a severe drop in hemoglobin post blood transfusion, are not excluded.
ii. Alanine aminotransferase (ALT) and aspartate aminotransferase (AS < 5 times upper limit of normal as per local laboratory.
f. Liver MRI using a validated methodology per institutional preference (T2* or R2* or by ferriscan [R2 MRI]) for estimation of hepatic iron content is required for participants who are currently receiving ≥8 packed red blood cell transfusions per year for ≥1 year or have received ≥20 packed red blood cell transfusions (lifetime cumulative). Participants who have hepatic iron content ≥ 8 mg Fe/g liver dry weight by liver MRI must have a Gastroenterology/hepatology consultation with liver biopsy and histological examination including documentation of the absence of cirrhosis, bridging fibrosis[1], and active hepatitis.
- Written informed consent or assent obtained from subject or subject's legal representative and ability for subject to comply with the requirements of the study.
Exclusion Criteria:
- Participants with uncontrolled bacterial, viral or fungal infection in the 6 weeks before enrollment (currently taking medication with evidence of progression of clinical symptoms or radiologic findings).
- Participants with evidence of HIV infection or seropositivity for HIV or active hepatitis B or C.
- Participants who have received a Hematopoietic Cell Transplant (HCT)
- Participants who have received a solid organ transplant.
- Participants who have participated in another clinical trial in which the participant received an investigational or off-label use of a drug or device within 3 months prior to enrollment.
- Females who are pregnant or breast feeding.
- Females of child bearing potential (to include all female participants > 10 years of age, unless postmenopausal for a minimum of 1 year before the time of consent or surgically sterilized) who do not agree to practice two (2) effective methods of contraception at the same time, or who do not agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject, from the time of signing of informed consent through 12 months post-stem cell infusion.
- Males (even if surgically sterilized) who do not agree to practice effective barrier contraception, or who do not agree to practice true abstinence from the time of signing informed consent through 12 months post-stem cell infusion.
- Participants who have had a stroke OR who are receiving red blood cell (RBC) transfusions to prevent primary stroke or silent cerebral infarction.
- Patients who have a human leukocyte antigen identical (HLA-ID) sibling donor
- Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data.
- Any non-homozygous sickle hemoglobin (HbSS) genotype of SCD
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: CRISPR_SCD001 Drug Product
CRISPR_SCD001 Drug Product (autologous CD34+ cell-enriched population that contains cells modified by the CRISPR-Cas9 ribonucleoprotein) dose will be ≥3.0×106
CD34+ cells/kg recipient weight for each subject and the upper limit cell dose is 20 ×106 CD34+ cells/kg.
|
CRISPR_SCD001 is administered by IV infusion following myeloablative conditioning with busulfan.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Incidence of adverse events and grade 3 or higher serious adverse events, using the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE)
Time Frame: 24 months post-transplant
|
The adverse event rate will be summarized using descriptive statistics, together with 95% confidence intervals where appropriate.
No formal statistical hypothesis testing will be performed.
Adverse events defined: failure of engraftment, malignant clonal expansion related to genomic editing or death.
|
24 months post-transplant
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in the annualized vaso-occlusive pain event (VOE) rates.
Time Frame: 24 months pre-transplant to 24 months post-transplant
|
Change in the annualized vast-occlusive pain event (VOE) rates comparing the 24 months before with 24 months after the infusion of drug product.
|
24 months pre-transplant to 24 months post-transplant
|
Graft rejection defined as having an absolute neutrophil count (ANC) < 500 at 42 days post-infusion
Time Frame: 42 days post-transplant
|
A delay in platelet and/or neutrophil engraftment will be captured.
|
42 days post-transplant
|
Time to neutrophil recovery defined as the first of 3 measurements on different days when the patient has an absolute neutrophil count (ANC) of ≥500/µL after transplant.
Time Frame: 24 months post-transplant
|
Neutrophil recovery as part of the overall hematological recovery.
|
24 months post-transplant
|
Time to platelet recovery is defined as the first day of a minimum of 3 measurements on different days that the patient has achieved a platelet count > 50,000/µL AND did not receive a platelet transfusion in the previous 7 days.
Time Frame: baseline, through 24 months post-transplant
|
Platelet recovery as part of the overall hematological recovery.
|
baseline, through 24 months post-transplant
|
Rate of improvement in Hemoglobin S (HbS) fraction as measured by hemoglobin electrophoresis, as percent of total.
Time Frame: baseline, through 24 months post-transplant
|
Hemolysis markers.
|
baseline, through 24 months post-transplant
|
Rate of normalization in hemoglobin (hgb) level as measured by clinical hematology (laboratory) test.
Time Frame: baseline, through 24 months post-transplant
|
Hemolysis markers.
|
baseline, through 24 months post-transplant
|
Rate of normalization of lactate dehydrogenase (LDH), reticulocyte count, and haptoglobin, as measured by clinical hematology and serum chemistry (laboratory) tests.
Time Frame: baseline, through 24 months post-transplant
|
Hemolysis markers.
|
baseline, through 24 months post-transplant
|
Frequency of hepatic veno-occlusive disease (VOD) as measured by Seattle or Baltimore Criteria for VOD Diagnosis.
Time Frame: 24 months post-transplant
|
Hematologic and non-hematologic toxicities of autologous transplantation with CRISPR-Cas9 sickle-corrected HSPCs.
|
24 months post-transplant
|
Frequency of hepatic idiopathic pneumonia syndrome (IPS) as measured by the Idiopathic pneumonia syndrome (IPS) criteria.
Time Frame: 24 months post-transplant
|
Hematologic and non-hematologic toxicities of autologous transplantation with CRISPR-Cas9 sickle-corrected HSPCs.
|
24 months post-transplant
|
Frequency of central nervous system (CNS) toxicity (reversible posterior leukoencephalopathy syndrome [RPLS] or posterior reversible encephalopathy syndrome [PRES], hemorrhage, and seizures).
Time Frame: 24 months post-transplant
|
Hematologic and non-hematologic toxicities of autologous transplantation with CRISPR-Cas9 sickle-corrected HSPCs.
|
24 months post-transplant
|
Frequency of cytomegalovirus (CMV) infection, invasive fungal infection, and any other serious viral or bacterial infection
Time Frame: 24 months post-transplant
|
Hematologic and non-hematologic toxicities of autologous transplantation with CRISPR-Cas9 sickle-corrected HSPCs.
|
24 months post-transplant
|
Frequency of sickle gene-editing (correction and insertion/deletion) and off-target site-1 editing in marrow and peripheral blood mononuclear cells.
Time Frame: 3 months, 1 and 2 years post-transplant
|
Stability of gene-editing in hematopoietic cells by genotyping studies.
|
3 months, 1 and 2 years post-transplant
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Rate of sickle-related events other than severe VOE and end organ function.
Time Frame: 24 months post-infusion
|
Rate of sickle-related complications after infusion
|
24 months post-infusion
|
Patient-reported quality of life (pain and fatigue domains) as measured by the use of Patient Reported Outcome Measurement Information System (PROMIS) modules.
Time Frame: baseline, and 1 and 2 years post-transplant
|
Change in quality of life score at baseline (prior to the initiation of hydroxyurea), 1 year and 2 years post-stem cell infusion accessed using Patient Reported Outcome Measurement Information System (PROMIS) modules. The PROMIS modules rate the following areas:
|
baseline, and 1 and 2 years post-transplant
|
Change from baseline in cardiac-pulmonary function via pulmonary function tests
Time Frame: Through 1 and 2 years post-transplant
|
Through 1 and 2 years post-transplant
|
|
Change from baseline in cardiac-pulmonary function via echocardiogram (tricuspid regurgitant jet velocity [TRJV], LVEF).
Time Frame: Through 1 and 2 years post-transplant
|
Through 1 and 2 years post-transplant
|
|
Change from baseline in meters walked during 6-minute walk test (6MWD)
Time Frame: Through 1 and 2 years post-transplant
|
Through 1 and 2 years post-transplant
|
|
Event-free survival defined as survival without clinical and hematological evidence of the underlying Sickle Cell Disease (SCD)
Time Frame: 1 and 2 years post-transplant
|
1 and 2 years post-transplant
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Mark Walters, MD, UCSF Benioff Children's Hospital Oakland
Study record dates
Study Major Dates
Study Start (Estimated)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 21-33287
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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.
Clinical Trials on Sickle Cell Disease
-
Klein Buendel, Inc.National Institute on Minority Health and Health Disparities (NIMHD); Hilton...CompletedSickle Cell Disease | Sickle Cell Anemia in Children | Sickle Cell Thalassemia | Sickle Cell SC DiseaseUnited States
-
SangartCompletedSickle Cell Disease | Anemia, Sickle Cell | Sickle Cell Anemia | Hemoglobin SC Disease | Sickle Cell Disorders | Sickle Cell Hemoglobin C DiseaseUnited Kingdom, France, Jamaica, Lebanon
-
Nova Laboratories LimitedCompletedSickle Cell Disease | Sickle Cell Hemoglobin C | Sickle Cell-beta-thalassemia | Sickle-Cell; Hemoglobin Disease, ThalassemiaUnited Kingdom, Jamaica
-
SangartWithdrawnSickle Cell Disease | Anemia, Sickle Cell | Sickle Cell Anemia | Hemoglobin SC Disease | Sickle Cell Disorders | Sickle Cell Hemoglobin C DiseaseFrance, United Kingdom, Netherlands, Turkey, Bahrain, Belgium, Brazil, Lebanon, Qatar
-
University of British ColumbiaCompletedSickle Cell Disease | Beta-Thalassemia | Sickle Cell Trait | Sickle Cell-Beta Thalassemia | Sickle Cell-SS DiseaseCanada, Nepal
-
Sidney Kimmel Cancer Center at Thomas Jefferson...National Heart, Lung, and Blood Institute (NHLBI)TerminatedSickle Cell Anemia | Sickle Cell-hemoglobin C Disease | Sickle Cell-β0-thalassemiaUnited States
-
University of RegensburgRecruitingSickle Cell Disease | Sickle Cell Anemia | Sickle Cell Disorders | HbS Disease | Hemoglobin S Disease | Sickling Disorder Due to Hemoglobin SGermany, Austria
-
Centre Hospitalier Intercommunal CreteilRecruitingSickle-Cell Disease Nos With CrisisFrance
-
HemaQuest Pharmaceuticals Inc.TerminatedSickle Cell Disease | Sickle Cell Anemia | Sickle Cell Disorders | Hemoglobin S Disease | Sickling Disorder Due to Hemoglobin SUnited States, Lebanon, Egypt, Canada, Jamaica
-
HemaQuest Pharmaceuticals Inc.CompletedSickle Cell Disease | Sickle Cell Anemia | Sickle Cell Disorders | Hemoglobin S Disease | Sickling Disorder Due to Hemoglobin SUnited States, Lebanon, Canada, Egypt, Jamaica