Sickle cell anemia - null regimens

The purpose of this page is to provide references to "null therapy" such as placebo and observation. These references provide further insight into the historical development of the treatment landscape. See the main sickle cell anemia page for regimens that include active treatment.

All lines of therapy

Observation

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
DeBaun et al. 2014 (SIT)	2004-2010	Phase 3 (C)	RBC transfusions	Seems to have more cerebral infarcts (primary endpoint)

No treatment.

References

1. SIT: DeBaun MR, Gordon M, McKinstry RC, Noetzel MJ, White DA, Sarnaik SA, Meier ER, Howard TH, Majumdar S, Inusa BP, Telfer PT, Kirby-Allen M, McCavit TL, Kamdem A, Airewele G, Woods GM, Berman B, Panepinto JA, Fuh BR, Kwiatkowski JL, King AA, Fixler JM, Rhodes MM, Thompson AA, Heiny ME, Redding-Lallinger RC, Kirkham FJ, Dixon N, Gonzalez CE, Kalinyak KA, Quinn CT, Strouse JJ, Miller JP, Lehmann H, Kraut MA, Ball WS Jr, Hirtz D, Casella JF. Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia. N Engl J Med. 2014 Aug 21;371(8):699-710. link to original article link to PMC article PubMed NCT00072761

Placebo

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Dampier et al. 2023 (RESET)	2015-06 to 2019-06	Phase 3 (C)	Rivipansel	Did not meet primary endpoint of TTRFD
Heeney et al. 2022 (HESTIA3)	2018-09-26 to 2019-10-18	Phase 3 (C)	Ticagrelor	Did not meet primary endpoint of reduced VOC rate

No active treatment.

References

1. MSH: Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, Eckert SV, McMahon RP, Bonds DR; Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. N Engl J Med. 1995 May 18;332(20):1317-22. link to original article contains dosing details in abstract PubMed
   1. Update: Steinberg MH, Barton F, Castro O, Pegelow CH, Ballas SK, Kutlar A, Orringer E, Bellevue R, Olivieri N, Eckman J, Varma M, Ramirez G, Adler B, Smith W, Carlos T, Ataga K, DeCastro L, Bigelow C, Saunthararajah Y, Telfer M, Vichinsky E, Claster S, Shurin S, Bridges K, Waclawiw M, Bonds D, Terrin M. Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment. JAMA. 2003 Apr 2;289(13):1645-51. Erratum in: JAMA. 2003 Aug 13;290(6):756. link to original article PubMed
   2. HRQoL analysis: Ballas SK, Barton FB, Waclawiw MA, Swerdlow P, Eckman JR, Pegelow CH, Koshy M, Barton BA, Bonds DR. Hydroxyurea and sickle cell anemia: effect on quality of life. Health Qual Life Outcomes. 2006 Aug 31;4:59. link to original article link to PMC article PubMed
2. BABY HUG: Wang WC, Ware RE, Miller ST, Iyer RV, Casella JF, Minniti CP, Rana S, Thornburg CD, Rogers ZR, Kalpatthi RV, Barredo JC, Brown RC, Sarnaik SA, Howard TH, Wynn LW, Kutlar A, Armstrong FD, Files BA, Goldsmith JC, Waclawiw MA, Huang X, Thompson BW; BABY HUG investigators. Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG). Lancet. 2011 May 14;377(9778):1663-72. link to original article link to PMC article PubMed NCT00006400
3. SUSTAIN: Ataga KI, Kutlar A, Kanter J, Liles D, Cancado R, Friedrisch J, Guthrie TH, Knight-Madden J, Alvarez OA, Gordeuk VR, Gualandro S, Colella MP, Smith WR, Rollins SA, Stocker JW, Rother RP. Crizanlizumab for the prevention of pain crises in sickle cell disease. N Engl J Med. 2017 Feb 2;376(5):429-439. Epub 2016 Dec 3. link to original article link to PMC article contains dosing details in abstract PubMed NCT01895361
4. GLUSCC09-01: Niihara Y, Miller ST, Kanter J, Lanzkron S, Smith WR, Hsu LL, Gordeuk VR, Viswanathan K, Sarnaik S, Osunkwo I, Guillaume E, Sadanandan S, Sieger L, Lasky JL, Panosyan EH, Blake OA, New TN, Bellevue R, Tran LT, Razon RL, Stark CW, Neumayr LD, Vichinsky EP; Investigators of the Phase 3 Trial of l-Glutamine in Sickle Cell Disease. A phase 3 trial of l-glutamine in sickle cell disease. N Engl J Med. 2018 Jul 19;379(3):226-235. link to original article contains dosing details in abstract PubMed NCT01179217
5. HOPE: Vichinsky E, Hoppe CC, Ataga KI, Ware RE, Nduba V, El-Beshlawy A, Hassab H, Achebe MM, Alkindi S, Brown RC, Diuguid DL, Telfer P, Tsitsikas DA, Elghandour A, Gordeuk VR, Kanter J, Abboud MR, Lehrer-Graiwer J, Tonda M, Intondi A, Tong B, Howard J; HOPE Trial Investigators. A Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease. N Engl J Med. 2019 Aug 8;381(6):509-519. Epub 2019 Jun 14. link to original article contains dosing details in abstract PubMed NCT03036813
   1. Update: Howard J, Ataga KI, Brown RC, Achebe M, Nduba V, El-Beshlawy A, Hassab H, Agodoa I, Tonda M, Gray S, Lehrer-Graiwer J, Vichinsky E. Voxelotor in adolescents and adults with sickle cell disease (HOPE): long-term follow-up results of an international, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Haematol. 2021 May;8(5):e323-e333. Epub 2021 Apr 7. link to original article PubMed
6. HESTIA3: Heeney MM, Abboud MR, Githanga J, Inusa BPD, Kanter J, Michelson AD, Nduba V, Musiime V, Apte M, Inati A, Taksande AM, Andersson M, Åstrand M, Maklad N, Niazi M, Himmelmann A, Berggren AR. Ticagrelor vs placebo for the reduction of vaso-occlusive crises in pediatric sickle cell disease: the HESTIA3 study. Blood. 2022 Sep 29;140(13):1470-1481. link to original article link to PMC article PubMed NCT03615924
7. RESET: Dampier CD, Telen MJ, Wun T, Brown RC, Desai P, El Rassi F, Fuh B, Kanter J, Pastore Y, Rothman J, Taylor JG, Readett D, Sivamurthy KM, Tammara B, Tseng LJ, Lozier JN, Thackray H, Magnani JL, Hassell KL. A randomized clinical trial of the efficacy and safety of rivipansel for sickle cell vaso-occlusive crisis. Blood. 2023 Jan 12;141(2):168-179. link to original article PubMed NCT02187003