Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2018 Aug 14;2(15):1969-1979.
doi: 10.1182/bloodadvances.2018021444.

Double-blind, randomized, multicenter phase 2 study of SC411 in children with sickle cell disease (SCOT trial)

Ahmed A Daak  1 , Carlton D Dampier  2 , Beng Fuh  3 , Julie Kanter  4 , Ofelia A Alvarez  5 , L Vandy Black  6 , Melissa A McNaull  7 , Michael U Callaghan  8 , Alex George  9 , Lynne Neumayr  10 , Lee M Hilliard  11 , Fredrick Sancilio  1 , Adrian L Rabinowicz  1 , Matthew M Heeney  12
Affiliations
Clinical Trial

Double-blind, randomized, multicenter phase 2 study of SC411 in children with sickle cell disease (SCOT trial)

Ahmed A Daak et al. Blood Adv. .

Abstract

Blood cell membranes in sickle cell disease (SCD) have low docosahexaenoic acid (DHA). DHA treatment reduces sickle cell crisis (SCC) rate and ameliorates the inflammation, oxidative stress, and hypercoagulable state of SCD. SC411 is a novel DHA ethyl ester formulation with a proprietary delivery platform (Advanced Lipid Technology) that enhances DHA bioavailability. The SCOT trial investigated the effect of 3 different doses of SC411 on clinical and biochemical endpoints in 67 children with SCD (5-17 years old). Seventy-six percent of subjects were also receiving hydroxyurea. After 4 weeks of treatment with SC411 at 20, 36, and 60 mg DHA/kg per day or placebo a statistically significant (P < .001) mean percentage increase of blood cell membrane DHA and eicosapentaenoic acid was seen vs baseline: 109.0% (confidence interval [CI], 46.7-171.3), 163.8% (CI, 108.3-219.2), 170.8% (CI, 90.2-251.4), and 28.6% (CI, 250.1 to 107.3), respectively. After 8 weeks of treatment, statistically significant changes vs placebo were also observed in D-dimer (P = .025) and soluble E-selectin (P = .0219) in subjects exposed to 36 mg/kg. A significant increase in hemoglobin was observed against placebo in subjects receiving 20 mg DHA/kg per day (P = .039). SC411 significantly reduced electronic diary recorded SCC, analgesic use at home, and days absent from school because of sickle cell pain. The lower rate of clinical SCC observed in the pooled active groups vs placebo did not reach statistical significance (rate ratio, 0.47; 95% CI, 0.20-1.11; P = .07). All tested doses were safe and well tolerated. This trial was registered at www.clinicaltrials.gov as #NCT02973360.

PubMed Disclaimer

Conflict of interest statement

Conflict-of-interest disclosure: A.A.D. and A.L.R. are employees of SCI. O.A.A. has been an advisory board member for Novartis. C.D.D. has been an advisory board member for Novartis, Pfizer, and SCI; worked as a consultant for Novartis, Pfizer, GBT, Epizyme, and Prolong Therapeutics, and Data and Safety Monitoring Committee chair for Ironwood; and obtained research funding for Pfizer, SCI, Lilly, Novartis, Katz Foundation, and the National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development. J.K. has worked as a consultant for Bluebird Bio, Novartis, CRISPR, and AstraZeneca (steering committee), as well as participated in the National Heart, Lung, and Blood Institute Sickle Cell Advisory Committee. L.V.B. has worked as a consultant for Prolong Pharmaceuticals and Mast Therapeutics; been a paid member of the American Society of Pediatric Hematology/Oncology; participated in the advisory committee of Bioverativ; and obtained research funding from the National Institutes of Health, Pfizer, and Mast Therapeutics. M.U.C. participated in the Advisory Board of Shire, Octapharma, Grifols, Pfizer, Bayer, Roche, Bioverativ, and Hema; has been part of the Speakers Bureau of Shire, Roche/Genentech, Bayer, and Novo Nordisk; has obtained research support from Shire and Pfizer; has participated as site investigator for Pfizer, Roche/Genentech, Novo Nordisk, Global Blood Therapeutics, SCI, and Amgen; and holds stocks in Alnylum Pharmaceuticals. L.N. worked as a consultant for Emmaus, Bayer, CTD Holdings, and Pfizer; is currently on a Data and Safety Monitoring Committee for ApoPharma; is a site principal investigator for Pfizer, Sancilio, and PCORI; is a co-investigator for ApoPharma, Novartis, Bluebird Bio, Sangamo Therapeutics, Global Blood Therapeutics, Silarus, Celgene, Terumo, La Jolla Pharmaceuticals, and Imara; and also is an investigator on National Heart, Lung, and Blood Institute, Agency for Healthcare Research and Quality, US Food and Drug Administration, Health Resources and Services Administration, Centers for Disease Control and Prevention, Doris Duke, the State of California, University of California Office of the President, and Seattle Children's Research grants. F.S. has worked as a consultant for Clearway Global, LLC; and is a member of the Board of Directors of SCI; and participated in the Advisory Committees of Noble Financial Company. M.M.H. has worked as a consultant for SCI and AstraZeneca; is part of the Advisory Committees of SCI and Novartis; and received research support from SCI, Pfizer, and Intrinsic Life Sciences. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Flowchart of patient enrollment, randomization assignments and follow-up.
Figure 2.
Figure 2.
Percentage change of DHA+EPA blood cell membrane levels from baseline at week 4. After 4 weeks of treatment, blood cell membrane DHA and EPA levels were significantly increased in all SC411 doses (P < .001) vs baseline; 36 mg/kg, 60 mg/kg, and pooled treatments were also significantly increased vs placebo (P < .01).
Figure 3.
Figure 3.
Effect of SC411 on selected biomarkers of adhesion, coagulation, and hemolysis. After 8 weeks of treatment, statistically significant reductions were observed in soluble E-selectin (A) (P = .0219), and D-dimer (B) (P = .025) in patients exposed to the 36 mg DHA/kg dose of SC411 vs placebo. Hemoglobin was significantly increased compared with baseline at doses 20 and 36 mg/kg and against placebo at 20 mg DHA/kg vs placebo (C) (P < .001). No significant difference was observed lactate dehydrogenase (D). *Significance vs placebo.
Figure 4.
Figure 4.
Ratio of the clinical SCC. The clinical sickle cell crisis rate ratio was calculated in all patients (A), patients receiving HU treatment at baseline (B), and patients not receiving HU treatment at baseline (C). The analysis of the sum of events for each subject was performed using Poisson regression (Proc Genmod). The model statement included covariates for either treatment (all doses vs placebo) or for the 4 dose levels vs placebo. Each analysis was adjusted for disease severity at baseline, the subject’s age group, and the subject’s use of HU at the time of the baseline evaluation. The model was standardized to an annual rate, using a SAS offset variable. Each table shows the estimate, its standard error, the risk ratio, and the 95% CI for the risk ratio, which was done by exponentiation of the lower and upper CIs for the treatment β coefficients.
Figure 5.
Figure 5.
eDiary-recorded endpoints. The rate ratio (active vs placebo) of pain crises (A), analgesic use at home (B), and opioid analgesic use at home (C) were calculated using a Poisson regression model with a log-link and with treatment, baseline disease severity, age group, and HU use as covariates. The model used the log of (days in the study/365) as the offset variable to produce the annualized rates. P values were testing to see whether the rate ratio is different from placebo. The odds of absence from school because of SCD pain (D) were calculated as the number of days missed (eDiary Q7 response of “Yes”) divided by the number of days available to be missed (eDiary Q7 response of “Yes,” “No, went to school,” or “No, other”). Least squares proportion estimates, CIs, and comparison P values are from a logistic regression with treatment, baseline disease severity, age group, and HU use as covariates. P values are testing to see whether the odds ratio is different from 1.
See this image and copyright information in PMC

References

    1. Piel FB, Steinberg MH, Rees DC. Sickle cell disease. N Engl J Med. 2017;376(16):1561-1573. - PubMed
    1. Piel FB, Hay SI, Gupta S, Weatherall DJ, Williams TN. Global burden of sickle cell anaemia in children under five, 2010-2050: modelling based on demographics, excess mortality, and interventions. PLoS Med. 2013;10(7):e1001484. - PMC - PubMed
    1. Hassell KL. Population estimates of sickle cell disease in the U.S. Am J Prev Med. 2010;38(4 Suppl):S512-S521. - PubMed
    1. Rahimy MC, Gangbo A, Ahouignan G, et al. . Effect of a comprehensive clinical care program on disease course in severely ill children with sickle cell anemia in a sub-Saharan African setting. Blood. 2003;102(3):834-838. - PubMed
    1. Molineaux L, Fleming AF, Cornille-Brøgger R, Kagan I, Storey J. Abnormal haemoglobins in the Sudan savanna of Nigeria. III. Malaria, immunoglobulins and antimalarial antibodies in sickle cell disease. Ann Trop Med Parasitol. 1979;73(4):301-310. - PubMed

Publication types

Associated data