Phase 2 Trial of Baxdrostat for Treatment-Resistant Hypertension.

BACKGROUND: Aldosterone synthase controls the synthesis of aldosterone and has been a pharmacologic target for the treatment of hypertension for several decades. Selective inhibition of aldosterone synthase is essential but difficult to achieve because cortisol synthesis is catalyzed by another enzyme that shares 93% sequence similarity with aldosterone synthase. In preclinical and phase 1 studies, baxdrostat had 100:1 selectivity for enzyme inhibition, and baxdrostat at several dose levels reduced plasma aldosterone levels but not cortisol levels. METHODS: In this multicenter, placebo-controlled trial, we randomly assigned patients who had treatment-resistant hypertension, with blood pressure of 130/80 mm Hg or higher, and who were receiving stable doses of at least three antihypertensive agents, including a diuretic, to receive baxdrostat (0.5 mg, 1 mg, or 2 mg) once daily for 12 weeks or placebo. The primary end point was the change in systolic blood pressure from baseline to week 12 in each baxdrostat group as compared with the placebo group. RESULTS: A total of 248 patients completed the trial. Dose-dependent changes in systolic blood pressure of -20.3 mm Hg, -17.5 mm Hg, -12.1 mm Hg, and -9.4 mm Hg were observed in the 2-mg, 1-mg, 0.5-mg, and placebo groups, respectively. The difference in the change in systolic blood pressure between the 2-mg group and the placebo group was -11.0 mm Hg (95% confidence interval [CI], -16.4 to -5.5; P<0.001), and the difference in this change between the 1-mg group and the placebo group was -8.1 mm Hg (95% CI, -13.5 to -2.8; P = 0.003). No deaths occurred during the trial, no serious adverse events were attributed by the investigators to baxdrostat, and there were no instances of adrenocortical insufficiency. Baxdrostat-related increases in the potassium level to 6.0 mmol per liter or greater occurred in 2 patients, but these increases did not recur after withdrawal and reinitiation of the drug. CONCLUSIONS: Patients with treatment-resistant hypertension who received baxdrostat had dose-related reductions in blood pressure. (Funded by CinCor Pharma; BrigHTN ClinicalTrials.gov number, NCT04519658.).

Task-Specific Perturbation Training Improves the Recovery Stepping Responses by Women With Knee Osteoarthritis Following Laboratory-Induced Trips.

Trip-specific training improves the kinematics of trip-specific compensatory stepping response (CSR) in the laboratory and reduces prospectively measured trip-related fall-rate of middle age and older women. We examined whether one session of trip-specific perturbation training could improve recovery step kinematics in women with knee osteoarthritis (OA), a condition known to increase fall risk. Seventeen women with self-reported symptomatic knee OA (age 61.1 ± 7.7 years, body mass index [BMI] 29.7 ± 5.9 kg/m2 ) and 22 control women (age 59.5 ± 6.8 years, BMI 28.4 ± 6.2 kg/m2 ) completed a brief training protocol consisting of 20 trials of treadmill-delivered trip-specific perturbations. We assessed pre- and post-training recovery step length and trunk kinematics at the instant of recovery step completion. Repeated-measures analysis of variance was used to determine the significance of between-group differences following the training protocol, and to evaluate the significance of within-group pre-to-post changes in the variables of interest. The group by training interaction effects for step length (p = 0.466), trunk flexion angle (p = 0.751), and trunk angular velocity (p = 0.413) were not significant and the pre-to-post changes in step length were not significant (p = 0.286). However, pre-to-post trunk flexion angle improved by 26% and 34% in the OA and control groups, respectively (p < 0.001) and trunk flexion angular velocity decreased by 193% in the OA group and by 32% in the control group, respectively (p < 0.001), often reflecting a transition to the direction of extension. The results suggest that trip-specific training can improve CSR kinematics in women with knee OA. It is important to determine, the effectiveness of trip-specific training in decreasing trip-specific fall-rate by women with knee OA. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:663-669, 2020.

Trip-specific training enhances recovery after large postural disturbances for which there is NO expectation.

PURPOSE: Informed consent usually provides foreknowledge of experimental methods that can potentially increase expectation of stimuli and, therefore, influence the response. We determined the effects of increased expectation and trip-specific training on the recovery response following a treadmill-delivered, trip-specific disturbance. To deliver unexpected disturbances, subjects were deceived during the informed consent process. The primary hypothesis was that the recovery response following an expected postural disturbance would be characterized by trunk kinematics that have been shown to decrease the likelihood of a fall, compared to following an unexpected postural disturbance. We further hypothesized that following an unexpected postural disturbance, the recovery response of the subjects who had completed a trip-specific training protocol would be more biomechanically favorable to recovery compared to those of subjects who had not received the training. METHODS: Young adults were randomized into Untrained or Trained groups. During the informed consent process, the purpose of the study was explained to subjects in both groups as being to determine the effect of trip-specific training on postural sway while performing an attention-demanding task. Untrained subjects completed two trials during which they minimized their postural sway. During the second trial, an unexpected disturbance was delivered while they performed the attention-demanding task. Trained subjects performed a pre-training postural sway trial, followed by the delivery of a series of expected, training disturbances. Finally, an unexpected disturbance was delivered while they minimized postural sway and performed the attention-demanding task. RESULTS: Expectation significantly improved trunk kinematics (p < .05). In addition, participation in the trip-specific training protocol following the unexpected disturbance the trunk kinematics of the Trained subjects were more biomechanically favorable to recovery than those of the Untrained subjects (p < .01). CONCLUSION: Improved trunk kinematics following trip-specific training may be independent of the extent to which the disturbance is expected.

Knee osteoarthritis negatively affects the recovery step following large forward-directed postural perturbations.

The reasons for higher fall risk of people with osteoarthritis (OA) compared to people without OA are not known. It is possible that following a loss of balance OA may negatively affect the recovery stepping response. Stepping responses have not been reported for people with knee OA. Here, we compared recovery step kinematics following laboratory-induced trip and following a large treadmill-delivered perturbation simulating a trip between a group of women with and without self-reported knee OA. We hypothesized that knee OA would significantly impair recovery step kinematics compared to those of a control group. Following the laboratory-induced trip, step length and trunk flexion velocity at recovery step completion of women with OA were significantly impaired and more so for the women who fell. Following the treadmill-delivered perturbation, the recovery step kinematics of women with OA were not significantly impaired. For both perturbations, the women who fell had significantly impaired recovery step kinematics compared to those who did not fall, regardless of OA. The results are consistent with previous work on healthy middle aged and older women and suggest that the same biomechanical risk factors for trip-related falls are shared by middle age and older women regardless of the presence of knee OA. The results support the need to determine whether training protocols which have been shown to improve recovery step kinematics and reduce prospective falls by healthy older women can have similar outcomes for people with knee OA.

Expectation of an upcoming large postural perturbation influences the recovery stepping response and outcome.

Tripping during locomotion, the leading cause of falls in older adults, generally occurs without prior warning and often while performing a secondary task. Prior warning can alter the state of physiological preparedness and beneficially influence the response to the perturbation. Previous studies have examined how altering the initial "preparedness" for an upcoming perturbation can affect kinematic responses following small disturbances that did not require a stepping response to restore dynamic stability. The purpose of this study was to examine how expectation affected fall outcome and recovery response kinematics following a large, treadmill-delivered perturbation simulating a trip and requiring at least one recovery step to avoid a fall. Following the perturbation, 47% of subjects fell when they were not expecting the perturbation whereas 12% fell when they were aware that the perturbation would occur "sometime in the next minute". The between-group differences were accompanied by slower reaction times in the non-expecting group (p < 0.01). Slower reaction times were associated with kinematics that have previously been shown to increase the likelihood of falling following a laboratory-induced trip. The results demonstrate the importance of considering the context under which recovery responses are assessed, and further, gives insight to the context during which task-specific perturbation training is administered.