To the Editor,
To date, all phase-3 randomized controlled trials (RCTs) for vaso-occlusive pain episodes (VOE) among patients with sickle cell disease (SCD) have failed to meet their primary outcome of shortening time-to-crisis resolution after promising phase-2 RCTs. The Sickle Cell Disease Treatment with Arginine Therapy (STArT) trial was recently added to the list of RCTs closed early [1–3]. STArT was a multi-center, double-blind, phase-3 RCT to assess the efficacy of intravenous arginine therapy on time-to-crisis resolution, defined as the time in hours from study drug delivery to the last dose of parenteral opioids in children and young adults with SCD failing outpatient management for VOE [2]. Leveraging the high-quality research infrastructure in the Pediatric Emergency Care Applied Research Network (PECARN) [4], STArT aimed to enroll 360 subjects. Unlike prior RCTs for SCD-VOE that have been closed early due to insufficient patient accrual [1–3], STArT was closed early after the enrollment of 274 participants, surpassing enrollment milestones nearly a year ahead of schedule, following an interim analysis that identified futility to demonstrate reduced time to crisis resolution in the intervention arm.
Despite its premature closure, STArT is one of the largest RCTs for pediatric SCD-VOE to date and provides the ideal platform to answer crucial questions regarding clinical trial design to further discourse on appropriate outcomes for SCD-VOE. Thus, our objective was to determine the association between patient and hospital characteristics and time-to-crisis resolution, hospital length of stay (LOS), and total opioid use (TPO) for SCD-VOE.
We conducted a cross-sectional analysis of data collected on patients age 3–21 years with SCD-VOE requiring parenteral opioid analgesic therapy who were randomized to placebo in the STArT trial at 10 participating sites (Supplemental Table 1). Univariable analysis and a multivariable linear regression model were constructed to identify patient and enrollment site variables at ED presentation that were associated with time-to-crisis-resolution. Detailed methodology and exclusion criteria of STArT have been previously described [2]. For the purposes of this analysis, we limited our population to participants randomized to placebo to avoid any potential impact that intravenous arginine would have on key outcomes evaluated in this secondary analysis.
The STArT trial primary outcome was time-to-crisis-resolution. Hospital LOS stay was also analyzed, measured as time between ED presentation and the time of order placement for hospital discharge. We also included TPO usage in intravenous morphine equivalents (mg/kg) from the time of study drug delivery until hospital discharge. Chronic pain was defined as patient-reported SCD-related pain on ≥ 15 days per month for the prior 6 months [5]. Prior surgeries were collected per patient/family report and chart review. Statistical analyses are summarized in the Supplemental Methods.
Of 274 subjects enrolled, 142 were randomized to placebo (mean age 14.2 ± 4.6 years; 56% male; 67.4% with hemoglobin-SS genotype; Supplemental Figure 1; Supplemental Table 2) and 141 were included in this analysis. One participant had a time-to-crisis-resolution of 1724 h and was excluded as an outlier. Mean time-to-crisis-resolution was 77.0 ± 64.0 h, with a median (IQR) of 65.6 (31.1, 110.1) hours.
Time-to-crisis-resolution strongly correlated with hospital LOS and TPO (Supplemental Figure 2). Younger children had longer time-to-crisis-resolution than older children (Figure 1A). In contrast, data from a prior single-center phase-2 trial suggested that older children had longer time-to-crisis-resolution (Figure 1B) [6]. The established association between age and LOS [6–8] was diluted when analyzing single-institution vs. multicenter data.
FIGURE 1 |.
Variations in clinical trial outcomes across different age groups. (A) Time-to-crisis-resolution (diagonal striped bars) and length of hospital stay (black bars) across different age groups in patients randomized to the placebo arm of the STArT trial (mean and SEM) and (B) Time-to-crisis-resolution (diagonal striped bars) and length of hospital stay (black bars) for all patients enrolled in an intravenous arginine phase-2 randomized controlled trial for children admitted to the hospital with sickle cell disease and vaso-occlusive pain. (2B is modified with permission from Morris CR, Hatabah D, Korman R et al. Arginine Therapy for Pain in Sickle Cell Disease: A Phase-2 Randomized, Placebo-Controlled Trial.) [6] Time-to-crisis-resolution and length of hospital stay were longest in the age group 3–4 years and shortest in the age group 16–21 years the STArT trial placebo group in 2A, in contrast to 2B that exhibited the opposite pattern, where time-to-crisis-resolution and length of stay significantly increased with age.
Time-to-crisis-resolution varied substantially by site of enrollment (Figure 2A). The median and mean time-to-crisis-resolution varied by site as much as 114 h and 80 h, respectively. Inpatient clinical care was provided by inpatient hematology subspeciality services in all but one participating hospital (n = 9/10, 90%). No sites used a day hospital. All patients presented to the emergency department. In unadjusted comparisons, participants who had zero ED visits within the prior 12 months not resulting in hospitalization had over 29 h longer time-to-crisis-resolution compared to participants with > 1 prior ED visit not resulting in hospitalization (Table 1). A total of 82% (n = 37/45) of participants in the zero ED visits category required hospitalization every time they visited the ED. Participants with a history of bacteremia had time-to-crisis-resolution that was, on average, 34 h longer than those who did not have prior positive blood culture results. Additionally, participants who experienced chronic pain, depression, or prior surgeries experienced longer time-to-crisis-resolution compared to those without these. While only 19.0% of patients with chronic pain reported depression, 57.9% of patients with depression reported chronic pain. Subjects with current VOE lasting ≥ 24 h prior to ED presentation also experienced significantly longer time-to-crisis-resolution compared to those with pain < 24 h. However, in adjusted comparisons, the only factors that remained independently associated with longer time-to-crisis-resolution were the number of prior ED visits not resulting in hospitalization and a history of prior surgeries (Table 1). The most common surgeries included cholecystectomy (38%) and splenectomy (27%), with 10 patients (13%) having had both (Supplemental Table 3). Factors associated with TPO are summarized in Supplemental Results, (Supplemental Table 4) and discussed in Supplemental Discussion. In adjusted comparisons, the presence of fever, acute chest syndrome at presentation and site remained significantly associated with TPO use. Complications that were not present at the time of ED arrival but developed during hospital admission and their association with time-to-crisis-resolution and TPO are summarized in (Supplemental Tables 5–6).
FIGURE 2 |.
Variations in clinical trial outcomes by site. Distribution of median (A) Time-to-crisis-resolution (in hours) and (B) Total parenteral opioids administered (in mg/kg intravenous morphine equivalents) by site of enrollment in patients randomized to placebo (N = 141). Each bar represents a site, with the number of participants enrolled per site displayed below the corresponding site. Substantial variation is observed across sites, with differing patterns in time-to-crisis-resolution compared to total parenteral opioids. Variations in practice across sites resulted in differences in median time-to-crisis resolution by up 114 h (site J vs. D).
TABLE 1 |.
Factors associated with time-to-crisis-resolution (in hours) for vasoocclusive pain episodes among children, adolescents and young adults with sickle cell disease randomized to the STArT placebo arm (N = 141).a
| Summaries |
Univariable |
Multivariableb |
||||
|---|---|---|---|---|---|---|
| Mean (SD) | Median [IQR] | Effect (95% CI) | P value | Effect (95% CI) | P value | |
|
| ||||||
| Age | −0.96 (−3.26, 1.34) | 0.411 | −0.93 (−3.31, 1.44) | 0.437 | ||
| Sex at birth | 0.164 | 0.427 | ||||
| Male | 83.6 (67.1) | 66.0 [38.2, 124.7] | Reference | Reference | ||
| Female | 68.6 (59.4) | 60.5 [22.6, 97.8] | −15.03 (−36.25, 6.19) | −8.66 (−30.13, 12.82) | ||
| Genotype | 0.065 | 0.163 | ||||
| Hb-SS and S-Beta Zero Thal | 83.7 (67.9) | 65.6 [38.7, 115.5] | Reference | Reference | ||
| All others | 62.4 (52.4) | 65.4 [14.4, 90.7] | −21.27 (−43.89, 1.34) | −16.13 (−38.90, 6.64) | ||
| Number of ED visits that did not result in hospitalization in the past 12 months | 0.049 | 0.035 | ||||
| 0 | 94.9 (75.3) | 85.2 [38.7, 133.0] | 29.53 (6.05, 53.02) | 29.53 (5.25, 53.82) | ||
| 1 | 77.9 (60.5) | 71.7 [41.1, 97.8] | 12.48 (−16.18, 41.15) | 25.31 (−4.40, 55.03) | ||
| > 1 | 65.4 (55.1) | 50.9 [22.6, 86.4] | Reference | Reference | ||
| Readmission within 28 days | ||||||
| No | Reference | |||||
| Yes | 0.02 (−0.01, 0.04) | 0.158 | ||||
| Fever at presentation | 0.608 | |||||
| No | 76.2 (61.8) | 66.0 [32.1, 106.7] | Reference | |||
| Yes | 86.1 (87.7) | 48.2 [12.2, 141.1] | 9.87 (−28.10, 47.84) | |||
| Positive blood culture | 0.036 | 0.457 | ||||
| No | 73.5 (62.1) | 63.2 [27.3, 106.7] | Reference | Reference | ||
| Yes | 107.6 (76.0) | 102.2 [45.8, 182.6] | 34.01 (2.19, 65.83) | 11.81 (−19.55, 43.18) | ||
| ACS at presentation | 0.130 | |||||
| No | 75.3 (62.7) | 63.2 [30.9, 110.1] | Reference | |||
| Yes | 115.5 (87.6) | 90.2 [84.7, 158.4] | 40.20 (−11.91, 92.31) | |||
| Prescribed Hydroxyurea | 0.406 | |||||
| No | 69.3 (73.2) | 41.5 [14.5, 106.6] | Reference | |||
| Yes | 79.6 (60.9) | 66.9 [36.6, 113.9] | 10.33 (−14.16, 34.82) | |||
| Bronchodilator use | 0.308 | |||||
| No | 69.9 (51.3) | 63.4 [37.4, 95.0] | Reference | |||
| Yes | 81.2 (70.4) | 66.2 [26.4, 122.2] | 11.32 (−10.58, 33.22) | |||
| Experienced sickle cell-related pain on 15 or more days of the month for the last 6 months | 0.032 | 0.057 | ||||
| No | 67.4 (57.1) | 62.0 [21.9, 90.7] | Reference | Reference | ||
| Yes | 90.7 (70.9) | 70.9 [39.4, 133.5] | 23.26 (2.07, 44.46) | 21.40 (−0.63, 43.43) | ||
| Depression | 0.037 | 0.175 | ||||
| No | 73.5 (61.2) | 61.9 [30.9, 108.0] | Reference | Reference | ||
| Yes | 106.6 (78.5) | 93.7 [41.2, 182.2] | 33.03 (2.10, 63.96) | 21.74 (−9.80, 53.28) | ||
| Duration of current pain crisis prior to ED presentation | 0.023 | 0.186 | ||||
| < 24 h | 64.3 (51.5) | 54.0 [27.3, 97.0] | Reference | Reference | ||
| ≥ 24 h | 88.6 (72, 0) | 70.6 [38.7, 115.9] | 24.30 (3.45, 45.14) | 14.44 (−7.05, 35.92) | ||
| Prior Surgeries | 0.002 | 0.035 | ||||
| No | 59.1 (56.6) | 50.2 [15.1, 84.8] | Reference | Reference | ||
| Yes | 91.5 (66.4) | 77.7 [40.8, 134.1] | 32.41 (11.77, 53.05) | 22.94 (1.62, 44.25) | ||
| Site | 0.129 | |||||
| A | 84.0 (73.5) | 66.2 [38.2, 111.1] | Reference | |||
| B | 67.5 (53.9) | 52.6 [40.9, 86.4] | −16.52 (−62.67, 29.63) | |||
| C | 89.2 (34.9) | 96.0 [65.6, 115.5] | 5.21 (−40.94, 51.36) | |||
| D | 64.3 (91.6) | 28.0 [8.5, 89.3] | −19.65 (−64.03, 24.74) | |||
| E | 55.5 (54.0) | 39.9 [13, 81.2] | −28.52 (−60.86, 3.82) | |||
| F | 76.5 (62.8) | 64.9 [27.8, 134.1] | −7.44 (−50.32, 35.45) | |||
| G | 83.2 (65.9) | 67.9 [34.5, 158.1] | −0.75 (−39.36, 37.86) | |||
| H | 68.9 (37.5) | 54.0 [41.5, 85.2] | −15.07 (−50.97, 20.84) | |||
| I | 79.6 (71.7) | 99.7 [0, 139.1] | −4.38 (−77.35, 68.59) | |||
| J | 135.1 (79.5) | 142.0 [114.4, 182.2] | 51.09 (6.71, 95.48) | |||
All variance inflation factors were < 5 and all Condition indices were > 30, indicating no collinearity of included factors.
Variables included in the multivariable model are those where the p-value for the variable is less than or equal to 0.10 in the univariable models with age, sex, and genotype forced into the model.
This study identified key patient and site-level factors present at the time of trial enrollment that were independently associated with longer time-to-crisis-resolution and greater total parenteral opioid use. We also found that patients with ED encounters that nearly always resulted in hospitalization versus those with ED encounters discharged home, and those with prior surgeries, experienced significantly longer time-to-crisis-resolution. Patients with pain typically requiring admission from the ED may represent a group at risk for longer hospitalizations. Additionally, since cholecystectomy represented the majority of surgeries encountered, this variable may be reflective of a more severe clinical phenotype experiencing a higher hemolytic rate. We also observed substantial variation in time-to-crisis-resolution by site of enrollment. Prior studies have described large variations in LOS by age reproduced across different institutions and patient cohorts, where the youngest patients have had the shortest LOS while the oldest experience the longest LOS [6, 7, 9]. However, in the STArT trial, we observed the opposite, with the youngest experiencing the longest LOS, and site rather than age demonstrating a stronger association. While variations in SCD-VOE treatment practices by hospital are recognized [10], our study extends these findings by elucidating site-specific variation in time-to-crisis-resolution. Although not measured in our study, this may be due, in part, to hospital-level practices. This is critically important to note when designing multicenter clinical trials as variations in hospital LOS may depend on the site and not just patient-level factors, which may potentially obscure the impact of treatments on outcomes like time-to-crisis-resolution.
Chronic pain, depression, and duration of pain before ED presentation > 24 h were all significantly associated with a longer time-to-crisis-resolution in univariable comparisons and are likely measuring overlapping patient characteristics. To our knowledge, this is the first SCD-VOE study to assess for chronic pain based on patient-reported SCD-related pain on ≥ 15 days per month for the prior six months [5]. This feature may identify patients likely to remain in the hospital for an extended duration. Chronic pain is discussed further in the Supplement.
Potential confounders in clinical outcomes based on age, sex, genotype, and hydroxyurea use were a priori assumptions considered in our statistical analysis plan; however, it was surprising that none of these variables achieved statistical significance. This study highlights additional previously unrecognized confounders to be considered for successful SCD-VOE study design. Furthermore, hospital LOS for SCD-VOE has decreased significantly over the last 20 years, from over a week to < 72 h [6]. Median time-to-crisis-resolution among our placebo cohort was only 65.6 h, with notable interpatient variability. As sites implement SCD-VOE guidelines [11, 12], treatment becomes more standardized and interventions are unlikely to significantly influence these outcomes within such a short time period [6]. It may be more feasible to impact time-to-crisis-resolution in patients with longer hospital stays, like those with acute chest syndrome or patients outside the US where hospitalizations remain longer than a week [13, 14].
These findings are crucial to consider in the design of future RCTs. If there are certain populations with inherently longer time-to-crisis-resolution, then adjustments for these populations must be made in both the study design and the sample size determination. In fact, in a post hoc sample size calculation noting these differences in time-to-crisis-resolution, it was estimated that > 900 participants would need to be enrolled to detect a 17-h difference in time-to-crisis-resolution. The results of our analyses should be interpreted in the context of their limitations (Supplemental Discussion). Ultimately, larger-than-expected outliers and standard deviations, numerous confounders and site-based practice variations have been identified in this placebo cohort that are difficult to control for. Given the inherent differences in time-to-crisis-resolution and TPO among some patient populations, these outcomes may not be ideal for SCD-VOE trials. Failure to recognize site and patient level factors that contribute to differences in these outcomes may be contributing to suboptimal phase-3 clinical trial results. At a minimum, these differences should be accounted for in the design of future therapeutic trials. Dialog between stakeholders including the FDA, American Society of Hematology, and investigators is urgently needed to identify more ideal outcome measures beyond time-to-crisis-resolution, which is currently the FDA-preferred outcome for orphan drug regulatory approval for acute SCD-VOE.
Supplementary Material
Supporting Information
Additional supporting information can be found online in the Supporting Information section. Data S1: ajh70129-sup-0001-Supinfo.docx.
Acknowledgments
We would like to thank the site investigators and research coordinators who conducted this study. We are also grateful the patients with SCD and their parents and guardians for their participation, without whom none of this work would be possible.
Funding:
This work was supported by National Center for Complementary and Integrative Health, AT009893; National Heart, Lung, and Blood Institute, 1K23HL140142, 1K23HL140142–03S1, 5UH3HL148560, K23HL173694; Doris Duke Charitable Foundation COVID19 Fund to Retain Clinical Scientists-PeRSEVERE Program at Emory University School of Medicine, and the Georgia Clinical and Translational Science Alliance, 5U24HL148563, UL1-TR002378; Maternal and Child Health Bureau, U03MC00001, U03MC00007, U03MC22684, U03MC28844, U03MC33154, U03MC33156, U03MC49671, UJ5MC30824.
Footnotes
Conflicts of Interest
The authors of this manuscript have no competing interests and nothing to declare related to this manuscript. Orphan designation was awarded by the FDA to Claudia R. Morris in May 2024. CRM is the inventor or co-inventor of several UCSF-Benioff Children’s Hospital Oakland patents that include nutritional supplements and is an inventor/co-inventor of several Emory University School of Medicine patents/patent-pending applications for nutritional supplements for autism, coronaviruses, and pain, is a consultant for CSL Behring, F. Hoffmann-La Roche LTD, and Pfizer, is on the Scientific Advisory Board of TRILITY, is an editor of the Sickle Cell Disease-Fever and Sickle Cell Disease-Pain reference for UpToDate, is the Founder and Executive Director for Food as Medicine Therapeutics LLC and Sigma Spero LLC, is a member of American Society of Hematology (ASH) Sickle Cell Disease Research Priorities working group since February 2024 till present, and has received research support from the United States Food and Drug Administration, Health Resources & Services Administration (HRSA, agency of the US Department of Health and Human Services) and the National Institutes of Health. Carlton Dampier, MD has received research support from Pfizer.
Elliott P. Vichinsky is a committee member of Highlights of ASH Presentation, section editor for UpToDate, and a consultant for Global Blood Therapeutics Inc., Genesis Therapeutics and Vindico Medical Education—GBT CME event. Melanie E. Fields has received research grants from NIH (R01HL157188, R01HL169591); consulting fees from Dedham Group, Guidepoint, Pfizer; participation on an Advisory Board for Pfizer; equity ownership of Proclara Biosciences.
Ethics Statement
The STArT study was conducted under an active Investigational New Drug application (IND# 66943) with the U.S. Food and Drug Administration (FDA) and was approved by the University of Utah Institutional Review Board (IRB) on May 3, 2021 (IRB# 00136000), which served as the single IRB of record for all participating sites, which relied on the single IRB. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Oversight was provided by an independent Data and Safety Monitoring Board (DSMB) by NIH/NHLBI. The corresponding author had full access to all data in the study and had final responsibility for the decision to submit the manuscript for publication.
Consent
Patients were enrolled in the STArT study if they met eligibility criteria while receiving clinical care for sickle cell disease–related vaso-occlusive episodes (SCD-VOE) in participating emergency departments. After receiving information about the study verbally and/or electronically, patients were invited to participate. Written or electronic informed consent was obtained from all participants aged 18 years or older. For participants under 18 years of age, written or electronic permission was obtained from a parent or legal guardian, and verbal or written assent was obtained from participants aged 6–17 when appropriate.
Data Availability Statement
Individual participant data that underlies the results reported in this article, after de-i dentification can be made available upon reasonable request after June 2027. Proposals and requests should be directed to claudia.r.morris@emory.edu. Data requestors will need to sign a data access and confidentiality agreement.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Individual participant data that underlies the results reported in this article, after de-i dentification can be made available upon reasonable request after June 2027. Proposals and requests should be directed to claudia.r.morris@emory.edu. Data requestors will need to sign a data access and confidentiality agreement.