In this single-arm, multicenter, combined phase 1 and phase 2 study, patients with metastatic prostate adenocarcinoma with progression on prior androgen receptor pathway inhibitors and taxane-based chemotherapy were treated with ODM-208. A decrease in prostate-specific antigen levels of 50% or more occurred in 16/42 (38.1%) and 24/45 (53.3%) in phase 1 and 2 respectively. Responses mainly occurred in patients with androgen receptor mutations. Adrenal insufficiency was the dose-limiting toxicity.
Rare events can sometime arise in clinical development of treatments. For example, CYPIDES was a single-arm study of the CYP11A1 inhibitor ODM-208 to treat metastatic prostate cancer.1 Preclinical testing of the compound identified elevated thyroid-stimulating hormone (TSH) and bilirubin in rats and dogs. Unusual findings in preclinical testing focus attention and magnify evidence if similar results occur in humans. By analogy, imagine a murder trial in which the only evidence against the defendant arose from a database search of DNA matching the partial profile found at the crime scene. Multiple people could match, so without other evidence, the perpetrator could be any of them.
Multiple therapeutic advances in recent years have significantly improved outcomes for patients with metastatic prostate cancer, including utilization of combination androgen receptor (AR) pathway inhibitors and/or taxane chemotherapy in earlier, hormone-sensitive disease.1 Unfortunately, patients typically still develop metastatic castration-resistant prostate cancer (mCRPC), the lethal form of disease with limited prognosis. Despite castration resistance, the majority of patients with mCRPC continue to have AR-dependent disease through a variety of mechanisms, including emergence of AR mutations, amplifications, splice variants, and persistent AR activation via alternative pathways of androgen production.2
In a trial of 352 patients with embolic stroke of undetermined source, 5 mg of apixaban administered twice daily was compared with 100 mg of aspirin administered once daily for the prevention of recurrent ischemic strokes. At 12 months, 13.6% of patients given apixaban had new ischemic lesions on magnetic resonance imaging compared with 16.0% of patients given aspirin, and the rates of clinically relevant bleeding were also comparable.
Adaptive clinical trials allow researchers to make preplanned modifications based on accumulating data from an ongoing trial while preserving the trial’s integrity and validity. These modifications may include early termination in cases of successes or lack of efficacy, refining the sample size, altering treatments or doses, or focusing recruitment efforts on individuals most likely to benefit. In this issue of NEJM Evidence, Geisler et al.1 report results from the Apixaban for Treatment of Embolic Stroke of Undetermined Source (ATTICUS) trial, a multicenter randomized trial of apixaban compared with aspirin in patients with cardioembolism risk factors.
Hearing impairment is the most common sensory deficit. It affects 2 to 3 of 1000 newborns and nearly 50% of adults 75 years of age and older in the United States.1 Idiopathic sudden sensorineural hearing loss (ISSNHL) is characterized by an abrupt hearing loss requiring immediate diagnosis and treatment. Systemic glucocorticoids are widely used as the primary treatment for ISSNHL,2 but no head-to-head comparisons of the effectiveness and risk profiles of high doses over a more commonly used lower dose of glucocorticoids have been conducted to inform standard-of-care practice.
This trial compared courses of high-dose intravenous prednisolone or high-dose oral dexamethasone versus standard-dose oral prednisone in adults with idiopathic sudden sensorineural hearing loss. At 30 days, systemic high-dose glucocorticoid therapy was not superior to a lower-dose regimen with respect to change in hearing threshold, and it was associated with a higher risk of side effects.
Using the primary results of 23,551 randomized clinical trials from the Cochrane Database, van Zwet et al. provide an empirical guide for the interpretation of an observed P value from a “typical” clinical trial in terms of the degree of overestimation of the reported effect, the probability of the effect’s sign being wrong, and the predictive power of the trial.
Randomized encouragement trials randomize to an opportunity to receive treatment instead of to the treatment. Here, Johansen and colleagues combine randomized encouragement trials with several advantages inherent in the Danish health system.
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A total of 4017 patients with acute myocardial infarction, but no diabetes or chronic heart failure, were randomly assigned 10 mg of dapagliflozin or placebo. The primary outcome was a composite of death, hospitalization for heart failure, and five cardiometabolic outcomes analyzed using the win ratio method. There were significantly more wins for dapagliflozin than for placebo (win ratio, 1.34; 95% confidence interval, 1.20 to 1.50), which was driven by the cardiometabolic outcomes. The composite of time to cardiovascular death/hospitalization for heart failure was not different between the two groups.
A 14-year-old girl presented for evaluation of shortness of breath and chest pain after recent travel to the Caribbean. How do you approach the evaluation, and what is the diagnosis?
Choosing the right antibiotic is challenging. Unnecessarily broad-spectrum antibiotic treatment promotes antimicrobial resistance; inappropriately narrow-spectrum antibiotic use can lead to treatment failure. A cluster-randomized trial of a model-informed clinical decision support tool is proposed for guiding empiric antibiotic therapy for hospitalized patients with suspected infection.
Asthma is a highly prevalent disease. Although most people with asthma can be treated effectively with certain inhaled medicines, accessing affordable care near their homes is a challenge for many people in low- and middle-income countries. We present stories from six men, women, and children living with asthma in such countries.
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