REALM-DCM: A Phase 3, Multinational, Randomized, Placebo-Controlled Trial of ARRY-371797 in Patients With Symptomatic LMNA-Related Dilated Cardiomyopathy

BACKGROUND LMNA (lamin A/C)-related dilated cardiomyopathy is a rare genetic cause of heart failure. In a phase 2 trial and long-term extension, the selective p38 alpha MAPK (mitogen-activated protein kinase) inhibitor, ARRY-371797 (PF-07265803), was associated with an improved 6-minute walk test at 12 weeks, which was preserved over 144 weeks. METHODS REALM-DCM (NCT03439514) was a phase 3, randomized, double-blind, placebo-controlled trial in patients with symptomatic LMNA-related dilated cardiomyopathy. Patients with confirmed LMNA variants, New York Heart Association class II/III symptoms, left ventricular ejection fraction <= 50%, implanted cardioverter-defibrillator, and reduced 6-minute walk test distance were randomized to ARRY-371797 400 mg twice daily or placebo. The primary outcome was a change from baseline at week 24 in the 6-minute walk test distance using stratified Hodges-Lehmann estimation and the van Elteren test. Secondary outcomes using similar methodology included change from baseline at week 24 in the Kansas City Cardiomyopathy Questionnaire-physical limitation and total symptom scores, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) concentration. Time to a composite outcome of worsening heart failure or all-cause mortality and overall survival were evaluated using Kaplan-Meier and Cox proportional hazards analyses. RESULTS REALM-DCM was terminated after a planned interim analysis suggested futility. Between April 2018 and October 2022, 77 patients (aged 23-72 years) received ARRY-371797 (n=40) or placebo (n=37). No significant differences (P>0.05) between groups were observed in the change from baseline at week 24 for all outcomes: 6-minute walk test distance (median difference, 4.9 m [95% CI, -24.2 to 34.1]; P=0.82); Kansas City Cardiomyopathy Questionnaire-physical limitation score (2.4 [95% CI, -6.4 to 11.2]; P=0.54); Kansas City Cardiomyopathy Questionnaire-total symptom score (5.3 [95% CI, -4.3 to 14.9]; P=0.48); and NT-proBNP concentration (-339.4 pg/mL [95% CI, -1131.6 to 452.7]; P=0.17). The composite outcome of worsening heart failure or all-cause mortality (hazard ratio, 0.43 [95% CI, 0.11-1.74]; P=0.23) and overall survival (hazard ratio, 1.19 [95% CI, 0.23-6.02]; P=0.84) were similar between groups. No new safety findings were observed. CONCLUSIONS Findings from REALM-DCM demonstrated futility without safety concerns. An unmet treatment need remains among patients with LMNA-related dilated cardiomyopathy

Is exposure to formaldehyde in air causally associated with leukemia?—A hypothesis-based weight-of-evidence analysis

Recent scientific debate has focused on the potential for inhaled formaldehyde to cause lymphohematopoietic cancers, particularly leukemias, in humans. The concern stems from certain epidemiology studies reporting an association, although particulars of endpoints and dosimetry are inconsistent across studies and several other studies show no such effects. Animal studies generally report neither hematotoxicity nor leukemia associated with formaldehyde inhalation, and hematotoxicity studies in humans are inconsistent. Formaldehyde's reactivity has been thought to preclude systemic exposure following inhalation, and its apparent inability to reach and affect the target tissues attacked by known leukemogens has, heretofore, led to skepticism regarding its potential to cause human lymphohematopoietic cancers. Recently, however, potential modes of action for formaldehyde leukemogenesis have been hypothesized, and it has been suggested that formaldehyde be identified as a known human leukemogen. In this article, we apply our hypothesis-based weight-of-evidence (HBWoE) approach to evaluate the large body of evidence regarding formaldehyde and leukemogenesis, attending to how human, animal, and mode-of-action results inform one another. We trace the logic of inference within and across all studies, and articulate how one could account for the suite of available observations under the various proposed hypotheses. Upon comparison of alternative proposals regarding what causal processes may have led to the array of observations as we see them, we conclude that the case fora causal association is weak and strains biological plausibility. Instead, apparent association between formaldehyde inhalation and leukemia in some human studies is better interpreted as due to chance or confounding

Proceedings : 1973 Divers' Gas Purity Symposium, November 27 & 28, 1973, held at Battelle-Columbus /

Mode of access: Internet

Effects of Cement on Moisture Migration in Concrete Phase A: Laboratory Study of Moisture Migration in Hardened Cement Paste

The Columbus Laboratories of Battelle Memorial Institute is currently conducting a study of the effect of cement on moisture migration in concrete as related to the problem of D-cracking of portland cement concrete pavements. The study began on December 31, 1970, and is planned as a 3-year program. The work plan, approved by the policy committee of the members of the Iowa, Kansas, and Missouri highway departments and the Federal Highway Administration, is composed of four parts. This report presents the results of the first part, Part A - Laboratory Study of Moisture Migration in Hardened Cement Paste. This first phase of the investigation concerned the movement of moisture into and from hardened cement pastes and the dimensional changes accompanying the moisture changes. Small slab specimens of hardened neat cement pastes were prepared from 32 different cements which were prepared at the same water/cement ratio and hydrated to the same maturity factor. For each cement the .following data were obtained: (1) Maturity factor at time of testing; (2) Total evaporable water content of the saturated specimens at time of testing (2 specimens each cement); (3)The total evaporable water list in isothermally (74 \ub0F) drying from initial saturation to equilibrium at each of two conditions of lower relative humidity, viz. (2 specimens each cement): 75 percent relative humidity and 25 percent relative humidity; (4) The rate of moisture loss under conditions of Item (3); (5) The total evaporable water gained when the partially dried specimens of Item (3) were reexposed (at 74 \ub0F) to 100 percent relative humidity; (6) The rate of moisture absorption under conditions of Item (5); (7) Data as in Item (3) for second cycle of drying at 74 \ub0F; (8) Data as in Item (4) for second cycle of drying; (9) The total evaporable water lost in isothermally (100 \ub0F) drying from initial saturation to equilibrium at 75 percent relative humidity (2 specimens each cement); (10) The rate of moisture loss under the conditions of Item (9); and (11) After equilibrium was attained in Item (9) the specimen temperature was decreased to 74 \ub0F and Steps (5) through (8) were carried out. Statistical techniques were used to identify significant differences in the moisture migration behavior of the cement pastes

Evaluation of Economic Development Administration planning grants : field reports and final report /

Mode of access: Internet