A Phase II Trial to Compare Allogeneic Transplant Vs. Standard of Care for Severe Sickle Cell Disease: Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Protocol 1503

Background: Allogeneic hematopoietic cell transplantation (HCT) is a curative treatment for sickle cell disease (SCD). A pilot trial confirmed the suitability of a myeloablative conditioning regimen (busulfan/fludarabine/r-ATG) for HLA-matched sibling and unrelated donor HCT for severe SCD. This led to the current phase II trial funded by the NHLBI. The primary aim is to determine the efficacy of treatment options (HCT vs. standard of care) for adolescents and young adults with severe SCD (NCT02766465).

Study design and Treatment: This is a "biologic assignment" trial in which subjects with an HLA-matched sibling or HLA-matched unrelated donor are assigned to a donor arm (expected to receive HCT). Those without a suitable donor are assigned to a no-donor arm and expected to receive current therapies for SCD at the discretion of their provider. Although randomization is the gold standard for comparing treatments, such an approach for a rare disease is not feasible for the following reasons: 1) timely completion of the trial (~30% expected to identify a matched sibling and ~20%, a matched unrelated donor) and 2) accrual is challenging when the two arms of a randomized trial have markedly disparate treatments (i.e., one arm is an intervention with about 10-20% upfront mortality vs. the other arm also expected to have mortality risks but accepted as a consequence of disease). While we expect some to decline HCT (donor arm) or proceed to a mismatched related or unrelated donor HCT (no-donor arm), through education /counselling prior to consent, we anticipate <5% cross-over.

Major Inclusion Criteria: Age 15 - 40 years with SCD (stroke or neurologic deficit, recurrent vaso-occlusive crisis, acute chest syndrome, high impact chronic pain or tricuspid regurgitant jet velocity ≥2.7m/second. Subjects who already have a suitable donor are excluded.

Statistical Methods: Subjects are screened for eligibility and enrolled without knowing their biological assignment. HLA typing of the subject and donor search can be undertaken only after enrollment. Treatment arm assignment, (donor or no-donor arm) has to occur within 6 months of enrollment. We hypothesize that subjects on the donor arm will exert an early impact on survival and that survival will plateau by 1-year. Those on the no-donor arm are expected to follow the natural history of their disease with risk of premature mortality. A non-inferiority framework was chosen to test the non-inferiority of the donor arm compared to the no donor arm. The non-inferiority margin of 0.20 was chosen to establish that the difference in the proportion of subjects surviving at 2 years between the donor arm is no more than 0.20 worse than the no donor arm. If we reject the non-inferiority null hypothesis with a one-sided test, we will declare that the non-inferiority margin is met and that the difference in the probability of 2-year survival between the donor and no-donor arm is no more than 20%.

Endpoints: The primary endpoint is the estimate of overall survival at 2-years after enrollment. Regardless of treatment received subjects will remain in their assigned treatment arm for analysis of survival (intent-to-treat principle). Secondary endpoints include comparison of occurrence of sickle related events in both treatment groups over 2 years (pulmonary hypertension, cerebrovascular, renal, avascular necrosis, leg ulcer), and functional assessment (6-minute walk distance test, 28-day e-pain diary [mean pain intensity] and HRQoL. Exact logistic regression will be used to estimate an odds ratio of such events, assuming that at least one such event occurs on study in each of the treatment arms, controlling for other patient-related characteristics and individual history of the event of interest.

The trial is on-going and has met ~55% of projected accrual. Obstacles to accrual include: physician bias, subjects were not aware of a curative option for their disease, payment for HCT on a clinical trial in some US states despite meeting the Center for Medicare/Medicaid Services (CMS) requirement for coverage with evidence determination (CED), prior HLA typing and knowledge regarding donor availability, competing treatment options and the fact that substantial numbers of potentially eligible subjects are followed in the community and lack access to academic sites. Overcoming obstacles took ~2 years. The trial is now at "steady state accrual" and expected to complete accrual in ~18-24 months.