A Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease.

BACKGROUND: Deoxygenated sickle hemoglobin (HbS) polymerization drives the pathophysiology of sickle cell disease. Therefore, direct inhibition of HbS polymerization has potential to favorably modify disease outcomes. Voxelotor is an HbS polymerization inhibitor. METHODS: In a multicenter, phase 3, double-blind, randomized, placebo-controlled trial, we compared the efficacy and safety of two dose levels of voxelotor (1500 mg and 900 mg, administered orally once daily) with placebo in persons with sickle cell disease. The primary end point was the percentage of participants who had a hemoglobin response, which was defined as an increase of more than 1.0 g per deciliter from baseline at week 24 in the intention-to-treat analysis. RESULTS: A total of 274 participants were randomly assigned in a 1:1:1 ratio to receive a once-daily oral dose of 1500 mg of voxelotor, 900 mg of voxelotor, or placebo. Most participants had sickle cell anemia (homozygous hemoglobin S or hemoglobin Sß0-thalassemia), and approximately two thirds were receiving hydroxyurea at baseline. In the intention-to-treat analysis, a significantly higher percentage of participants had a hemoglobin response in the 1500-mg voxelotor group (51%; 95% confidence interval [CI], 41 to 61) than in the placebo group (7%; 95% CI, 1 to 12). Anemia worsened between baseline and week 24 in fewer participants in each voxelotor dose group than in those receiving placebo. At week 24, the 1500-mg voxelotor group had significantly greater reductions from baseline in the indirect bilirubin level and percentage of reticulocytes than the placebo group. The percentage of participants with an adverse event that occurred or worsened during the treatment period was similar across the trial groups. Adverse events of at least grade 3 occurred in 26% of the participants in the 1500-mg voxelotor group, 23% in the 900-mg voxelotor group, and 26% in the placebo group. Most adverse events were not related to the trial drug or placebo, as determined by the investigators. CONCLUSIONS: In this phase 3 randomized, placebo-controlled trial involving participants with sickle cell disease, voxelotor significantly increased hemoglobin levels and reduced markers of hemolysis. These findings are consistent with inhibition of HbS polymerization and indicate a disease-modifying potential. (Funded by Global Blood Therapeutics; HOPE ClinicalTrials.gov number, NCT03036813.).

Medication adherence assessment: high accuracy of the new Ingestible Sensor System in kidney transplants.

BACKGROUND: This open-label single-arm exploratory study evaluated the accuracy of the Ingestible Sensor System (ISS), a novel technology for directly assessing the ingestion of oral medications and treatment adherence. METHODS: ISS consists of an ingestible event marker (IEM), a microsensor that becomes activated in gastric fluid, and an adhesive personal monitor (APM) that detects IEM activation. In this study, the IEM was combined to enteric-coated mycophenolate sodium (ECMPS). Twenty stable adult kidney transplants received IEM-ECMPS for a mean of 9.2 weeks totaling 1227 cumulative days. RESULTS: Eight patients prematurely discontinued treatment due to ECMPS gastrointestinal symptoms (n=2), skin intolerance to APM (n=2), and insufficient system usability (n=4). Rash or erythema due to APM was reported in 7 (37%) patients, all during the first month of use. No serious or severe adverse events and no rejection episode were reported. IEM detection accuracy was 100% over 34 directly observed ingestions; Taking Adherence was 99.4% over a total of 2824 prescribed IEM-ECMPS ingestions. ISS could detect accurately the ingestion of two IEM-ECMPS capsules taken at the same time (detection rate of 99.3%, n=2376). CONCLUSIONS: ISS is a promising new technology that provides highly reliable measurements of intake and timing of intake of drugs that are combined with the IEM.

A digital health solution for using and managing medications: wirelessly observed therapy.

Taking oral medication on a prescribed schedule can be a nuisance, especially for elderly individuals and busy people with lots of things on their minds. Nonetheless, taking medication as prescribed is important for maintaining health and well-being. In cases where medication use is part of a clinical trial, taking prescribed medication is important to the entire investigation and outcome of the study, including the determination of whether a drug is effective and safe.

A novel method to quantify histochemical changes throughout the mediolateral axis of the substantia gelatinosa after spared nerve injury: characterization with TRPV1 and substance P.

UNLABELLED: Nerve injury dramatically increases or decreases protein expression in the spinal cord dorsal horn. Whether the spatial distribution of these changes is restricted to the central innervation territories of injured nerves or could spread to adjacent territories in the dorsal horn is not understood. To address this question, we developed a simple computer software-assisted method to precisely distinguish and efficiently quantify immunohistochemical staining patterns across the mediolateral axis of the dorsal horn 2 weeks after transection of either the tibial and common peroneal nerves (thus sparing the sural branch, spared nerve injury, [SNI]), the tibial nerve, or the common peroneal and sural nerves. Using thiamine monophosphatase (TMP) histochemistry, we determined that central terminals of the tibial, common peroneal, sural, and posterior cutaneous nerves occupy the medial 35%, medial-central 20%, central-lateral 20%, and lateral 25% of the substantia gelatinosa, respectively. We then used these calculations to show that SNI reduced the expression of SP and TRPV1 immunoreactivity within the tibial and peroneal innervation territories in the L4 dorsal horn, without changing expression in the uninjured, sural sector. We conclude that SNI-induced loss of SP and TRPV1 in central terminals of dorsal horn is restricted to injured fibers. Our new method enables direct comparison of injured and uninjured terminals in the dorsal horn so as to better understand their relative contributions to mechanisms of chronic pain. PERSPECTIVE: A simple computer software-assisted algorithm was developed to precisely distinguish and efficiently quantify immunohistochemical staining patterns across the mediolateral axis of the dorsal horn after distal sciatic-branch transection. This method will facilitate a better understanding of the relative contribution of injured and uninjured terminals to mechanisms of chronic pain.