While stifled for many decades, the clinical trials arena for sickle cell disease (SCD) is currently a rich field with many diverse trials. Novel drugs are being developed to reduce the number of vaso-occlusive events, meanwhile other trials are pursuing a cure with cutting-edge gene therapeutics.
The STAND trial is a phase III, multicenter, randomized, double-blind study currently in the recruiting phase. The trial aims to recruit 240 participants aged 12 years and older with SCD to assess the efficacy and safety of 2 doses of crizanlizumab versus placebo in patients either receiving or not receiving hydroxyurea or hydroxycarbamide therapy. The study will consist of 2 treatment arms and 1 control arm. Patients in the first treatment arm will receive crizanlizumab at a dose of 5.0 mg/kg, and those in the second treatment arm will receive a dose of 7.5 mg/kg. Patients in the control arm will receive a placebo. The primary outcome of the study is the rate of vaso-occlusive crisis events leading to healthcare visits over a 1-year period. The proposed completion date is July 2027.1
More information on the eligibility criteria for this study can be found at https://clinicaltrials.gov/ct2/show/NCT03814746.
The STEADFAST trial is a phase II, multicenter, randomized, open-label study in the recruiting phase that will compare the effects of crizanlizumab plus standard of care to those of standard of care alone on renal function in patients with chronic kidney disease caused by SCD. The trial aims to recruit 148 participants over 16 years of age with chronic kidney disease secondary to SCD. Participants will be randomized to receive either crizanlizumab (5 mg/kg) plus standard of care or standard of care alone. The primary outcome of the study is the percentage of patients with a ≥30% decrease in albuminuria over a 1-year period. The proposed date of completion is January 2024.2
More information on the eligibility criteria for this study can be found at https://clinicaltrials.gov/ct2/show/NCT04053764.
The HIBISCUS trial is an adaptive, randomized, placebo-controlled, double-blind, multicenter study in the recruiting phase that aims to evaluate the effects of FT-4202, a pyruvate kinase activator, on patients with SCD. FT-4202 is an experimental drug that appears to decrease 2,3-diphosphoglyceric acid in erythrocytes and increase their affinity for oxygen, which in theory may improve hemoglobin concentration and reduce the frequency of vaso-occlusive episodes. The study aims to recruit 344 participants aged 12 to 65 years with SCD and randomize participants in a 1:1:1 ratio to receive either placebo, 200 mg of FT-4202, or 400 mg of FT-4202. After interim analysis, patients will be randomized again for a phase 3 trial to receive either FT-4202 or placebo. The primary outcomes are hemoglobin response rate at week 24 and annualized vaso-occlusive crisis rate during the 52-week blinded treatment period. The expected date of completion is December 2026.3
More information on the eligibility criteria for this study can be found at https://clinicaltrials.gov/ct2/show/NCT04624659.
Gene therapy has gathered the most attention in the SCD research space and is showing promise. It appears that further investigation and research in this relatively new field of medicine might be the haystack hiding the cure for SCD. Below are 2 examples of such trials.
Gene Transfer for Patients With Sickle Cell Disease
This is an open-label, phase 1/2 trial in the recruitment phase that aims to determine the feasibility, safety, and efficacy of gene transfer using ARU-1801 (CD34+ cells transduced with the gamma-globin lentiviral vector). Participants will volunteer blood samples for ex vivo gene transfer and will be subsequently reinfused with the CD34+ enriched human bone marrow or plerixafor-mobilized peripheral blood hematopoietic stem cells. Before receiving the infusion, participants must undergo intensive chemotherapy. The primary outcomes are numerous and revolve around safety and adverse events. Some of the main outcome measures include the incidences of allergic reactions, infection, neutropenia, organ toxicity, and hematological cancer. The expected date of completion is June 2035.4 According to the American Journal of Managed Care, the trial is showing promise.5
For more information on eligibility criteria and objectives, visit https://clinicaltrials.gov/ct2/show/NCT02186418.
Gene Transfer for Sickle Cell Disease
This is an open-label, non-randomized, single-center, pilot and feasibility, single-arm cohort study. Similar to the above trial, this study will use a lentivirus vector encoding a small hairpin (sh) RNA targeting the γ-globin gene repressor, BCL11A, in CD34+ hematopoietic stem cells for reinfusion back into the host. BCL11A is a downregulator of γ-globin expression and fetal hemoglobin (HbF) production, and its suppression using this technique should, in theory, increase the amount of HbF production. The study is currently recruiting patients.6 Results from 6 patients who have undergone this therapy have been reported. All patients that were followed up experienced robust increases in HbF and had a reduction or complete resolution of SCD symptoms.7 Currently, this study has been suspended due to adverse events related to an unrelated gene therapy trial with a similar design.6
For more information on eligibility criteria and objectives, visit https://clinicaltrials.gov/ct2/show/NCT03282656.
1. Study of two doses of crizanlizumab versus placebo in adolescent and adult sickle cell disease patients (STAND). ClinicalTrials.gov. January 24, 2019. Updated November 17, 2021. Accessed November 29, 2021.
2. Study exploring the effect of crizanlizumab on kidney function in patients with chronic kidney disease caused by sickle cell disease (STEADFAST). ClinicalTrials.gov. August 12, 2019. Updated November 4, 2021. Accessed November 29, 2021.
3. A study of FT-4202 in adults and adolescents with sickle cell disease (HIBISCUS). ClinicalTrials.gov. November 12, 2020. Updated November 10, 2021. Accessed November 29, 2021.
4. Gene transfer for patients with sickle cell disease. ClinicalTrials.gov. July 10, 2014. Updated August 26, 2021. Accessed November 29, 2021.
5. Shaw ML. Revolutionary treatment for sickle cell disease shows promise in clinical trial. The American Journal of Managed Care. January 16, 2020. Accessed November 29, 2021.
6. Gene transfer for sickle cell disease. ClinicalTrials.gov. September 14, 2017. Updated September 5, 2021. Accessed November 29, 2021.
7. Esrick EB, Lehmann LE, Biffi A, et al. Post-transcriptional genetic silencing of BCL11A to treat sickle cell disease. N Engl J Med. 2021;384(3):205-215. doi:10.1056/NEJMoa2029392
Reviewed by Harshi Dhingra, MD, on 11/29/2021.