Design of the DOVE (Determining Effects of Platelet Inhibition on Vaso‐Occlusive Events) trial: A global Phase 3 double‐blind, randomized, placebo‐controlled, multicenter study of the efficacy and safety of prasugrel in pediatric patients with sickle cell anemia utilizing a dose titration strategy

Hoppe, Carolyn; Styles, Lori; Heath, Lori E.; Zhou, Chunmei; Jakubowski, Joseph A.; Winters, Kenneth J.; Brown, Patricia; Rees, David C.; Heeney, Matthew M.

doi:10.1002/pbc.25771

Cited by 13 publications

(18 citation statements)

References 45 publications

(43 reference statements)

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“…A phase III study of 341 children with SCD did not show a significant reduction in vaso-occlusive events per person-year in children taking Prasugrel compared with those taking placebo. It also did not show a significant reduction in diary-reported pain events [85,86].…”

Section: Agents That Reduce Cell Adhesion To Activated Microvascular mentioning

confidence: 73%

Sickle Cell Disease—Genetics, Pathophysiology, Clinical Presentation and Treatment

Inusa

Hsu

Kohli

et al. 2019

IJNS

120

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Sickle cell disease (SCD) is a monogenetic disorder due to a single base-pair point mutation in the β-globin gene resulting in the substitution of the amino acid valine for glutamic acid in the β-globin chain. Phenotypic variation in the clinical presentation and disease outcome is a characteristic feature of the disorder. Understanding the pathogenesis and pathophysiology of the disorder is central to the choice of therapeutic development and intervention. In this special edition for newborn screening for haemoglobin disorders, it is pertinent to describe the genetic, pathologic and clinical presentation of sickle cell disease as a prelude to the justification for screening. Through a systematic review of the literature using search terms relating to SCD up till 2019, we identified relevant descriptive publications for inclusion. The scope of this review is mainly an overview of the clinical features of pain, the cardinal symptom in SCD, which present following the drop in foetal haemoglobin as young as five to six months after birth. The relative impact of haemolysis and small-vessel occlusive pathology remains controversial, a combination of features probably contribute to the different pathologies. We also provide an overview of emerging therapies in SCD.

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Section: Agents That Reduce Cell Adhesion To Activated Microvascular mentioning

confidence: 73%

Sickle Cell Disease—Genetics, Pathophysiology, Clinical Presentation and Treatment

Inusa

Hsu

Kohli

et al. 2019

IJNS

120

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“…Subjects aged 2 to 16 years with abnormal or conditional transcranial Doppler within the past year were excluded. Other selection criteria have been described previously [8,9].…”

Section: Methodsmentioning

confidence: 99%

“…In each country, the study was approved by national regulatory authorities and by local ethics committees, institutional review boards, or both, and abided by local regulations. The design [8] and outcomes [9] of DOVE have been described previously.…”

Section: Introductionmentioning

confidence: 99%

Geographic Differences in Phenotype and Treatment of Children with Sickle Cell Anemia from the Multinational DOVE Study

Inusa

Colombatti

Rees

et al. 2019

JCM

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Background: DOVE (Determining Effects of Platelet Inhibition on Vaso-Occlusive Events) was a Phase 3, randomized, double-blind, placebo-controlled study conducted in children with sickle cell anemia at 51 sites in 13 countries across four continents. Procedure: Data from DOVE were assessed for regional differences in subject phenotype and treatment. Demographics, baseline clinical and laboratory data, hydroxyurea (HU) use, vaso-occlusive crisis (VOCs; composite endpoint of painful crisis or acute chest syndrome (ACS)), serious adverse events (SAEs), hospitalization, and treatments were compared across the Americas, Europe, North Africa/Middle East, and Sub-Saharan Africa (SSA). Results: Race, body mass index, and blood pressures differed by region. Pre-enrollment VOCs were highest in the Americas. For subjects not on HU, baseline hemoglobin was lowest in SSA; reticulocyte count was lowest in the Americas. Within SSA, Kenya subjects presented higher baseline hemolysis. Painful crisis was the most common SAE, followed by ACS in the Americas and infections in other regions. VOC rate and percentage of VOC hospitalizations were highest in Europe. Regardless of region, most VOCs were treated with analgesics; approximately half were treated with intravenous fluids. The proportion of VOC-related transfusions was greatest in Europe. Lengths of hospital stay were similar across regions. Conclusions: Overall differences in SAEs and hospitalization for VOCs may be due to cultural diversities, resource utilization, disease severity, or a combination of factors. These data are of importance for the planning of future trials in SCA in a multinational setting.

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“…For example, several recent studies with the third-generation P2Y12 antagonist, prasugrel, have been disappointing. While no major bleeding complications were seen with prasugrel in four trials, 142–146 including one large randomized placebo controlled multicenter trial, 143 these showed a non-significant decrease in VOC despite significant platelet inhibition.…”

Section: [H1] Developing New Scd Therapiesmentioning

confidence: 96%

Therapeutic strategies for sickle cell disease: towards a multi-agent approach

Telen

Malik

Vercellotti

2018

Nat Rev Drug Discov

143

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For over 100 years, clinicians and scientists have been unraveling the consequences of the A to T substitution in the beta globin gene that produces hemoglobin S, which leads to the systemic manifestations of sickle cell disease (SCD), including vaso-occlusion, anemia, hemolysis, organ injury and pain. However, despite growing understanding of the mechanisms of hemoglobin S polymerization and its effects on red blood cells, only two therapies for SCD — hydroxyurea and L-glutamine — are approved by the US Food and Drug Administration. Moreover, these treatment options do not fully address the manifestations of SCD. The pathophysiology of SCD suggests a complex network of interdependent processes, and in this article, we review efforts to develop new drugs targeting these processes, including agents that reactivate fetal hemoglobin, anti-sickling agents, anti-adhesive agents, modulators of inflammation, ischemia/reperfusion and oxidative stress, anti-thrombotics, anti-platelet agents and agents that counteract free hemoglobin/heme. We also discuss gene therapy, which holds promise of a cure, although its widespread application is currently limited by technical challenges and the expense of treatment. We thus propose that developing systems-oriented multi-agent strategies based on SCD pathophysiology is needed to improve to improve the quality of life and survival of people with SCD.

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Abstract: DOVE presents a unique opportunity to determine whether antiplatelet therapy reduces frequency of patient-reported VOC and daily vaso-occlusive pain in a global study of children with SCA.

Cited by 13 publications

References 45 publications

Sickle Cell Disease—Genetics, Pathophysiology, Clinical Presentation and Treatment

Sickle Cell Disease—Genetics, Pathophysiology, Clinical Presentation and Treatment

Geographic Differences in Phenotype and Treatment of Children with Sickle Cell Anemia from the Multinational DOVE Study

Therapeutic strategies for sickle cell disease: towards a multi-agent approach

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