Aims and MethodsThis was a 6-month, open label, multinational, observational study in hypogonadal men treated with daily titrated dose of 50, 75, or 100 mg 1% testosterone gel (AndroGel®) in community practice. Primary outcome was effect of treatment on hypogonadal symptoms and quality of life as assessed by Aging Males’ Symptoms (AMS) scale. Secondary objectives included erectile dysfunction (International Index of Erectile Function [IIEF]), fatigue (Multidimensional Fatigue Inventory [MFI]), and surrogates for body composition (waist circumference, body mass index [BMI]).ResultsSeven hundred and ninety-nine of the 1053 men enrolled had follow-up data at 6 months, 81.2% had ≥1 testosterone value in the normal range during the study. Substantial and significant improvements were observed in mean AMS score (−29%), IIEF score (+115.7%), and MFI scores (−21.5%). Further beneficial effects were significant decreases in mean BMI (−0.8 kg/m2) and waist circumference (−3.3 cm). Younger age quartiles showed greater improvements in AMS, MFI, BMI, and waist circumference than older quartiles. IIEF scores, however, did not differ significantly by age category.ConclusionsSubstantial improvements in hypogonadal symptoms, quality of life, fatigue, erectile dysfunction, and libido/sexual desire were observed. Adverse drug reactions were experienced by 7.5% of the safety population over the 6-month study period.

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Introduction Factors influencing prostate-specific antigen (PSA) changes in men undergoing testosterone (T) therapy have not been well studied. Aim The aim of this study was to assess the influence of selected variables on PSA changes in hypogonadal men administered with 1.62% testosterone gel (T-gel) for 6 months. Methods A double-blind, placebo-controlled study of 274 (234 T-gel, 40 placebo) hypogonadal men >18 years of age, with baseline T concentrations <300 ng/dL, PSA ≤2.5 ng/mL, and negative digital rectal examination. Subjects received once-daily T-gel for T therapy. Main Outcome Measures Changes in mean serum PSA, percentage of free PSA (%fPSA), and T from baseline to 6 months (182 days). Results Mean age was 53.5 years and baseline mean values were total T 247 ng/dL, PSA 0.9 ng/mL, and %fPSA 24.6%. Among men treated with T-gel, T increased to 499 ng/dL and PSA increased by 0.1 ng/mL (P = 0.0012). PSA increased ≥0.3 ng/mL in 26.3%, <0.3 ng/mL in 73.7%, including a decline from baseline in 33.0%. In the placebo group, T increased 29 ng/dL to 274 ng/dL, and PSA decreased 0.1 ng/mL, compared with baseline. A greater increase in PSA was noted in men ≥60 years old than in men <60 years old (0.4 vs. 0.05 ng/mL, respectively; P = 0.0006). Mean PSA did not change in men with baseline serum T >250 ng/dL, whereas it increased by 0.2 ng/mL in men with T ≤250 ng/dL (P = 0.0031). PSA increased 0.3 ng/mL in men with baseline %fPSA <20% and 0.1 ng/mL in men with %fPSA ≥20%. Conclusions Overall, T-gel treatment was associated with a minor increase in PSA, of questionable clinical significance. Factors predicting greater PSA increases included age ≥60 years, baseline T ≤250 ng/dL, and %fPSA <20%. Men with T >250 ng/dL and age <60 years demonstrated minimal or no PSA change.

An addendum of the ICH E9 guideline on Statistical Principles for Clinical Trials was released in November 2019 introducing the estimand framework. This new framework aims to align trial objectives and statistical analyses by requiring a precise definition of the inferential quantity of interest, that is, the estimand. This definition explicitly accounts for intercurrent events, such as switching to new anticancer therapies for the analysis of overall survival (OS), the gold standard in oncology. Traditionally, OS in confirmatory studies is analyzed using the intention-to-treat (ITT) approach comparing treatment groups as they were initially randomized regardless of whether treatment switching occurred and regardless of any subsequent therapy (treatment-policy strategy). Regulatory authorities and other stakeholders often consider ITT results as most relevant.

Adaptive design clinical trial methodologies offer both opportunities and challenges for observing basic ethical principles in human subject research. Using both published and unpublished adaptive design clinical trials, we have selected and reviewed examples of clinical trials with different design adaptations to discuss the ethical obstacles presented and often successfully resolved by these approaches, including (1) confirmatory trials for treatments widely accepted on the basis of uncontrolled case series or open-label trials (clinical equipoise and "justice" in the sense of which trial groups will "receive the benefits of research and bear its burdens") (infantile hemangioma/propranolol); (2) interim results analysis by unblinded data monitoring committees ("withholding information necessary to make a considered judgment" ["respect for persons"] versus compromising the trial's scientific basis) (BIG 1-98); (3) adaptations involving sample size reassessment or dose adjustment via dropping or adding treatment arms, allowing fewer subjects to produce statistically significant results, fewer subjects treated with ineffective/toxic doses, and more subjects given doses showing tolerance and treatment activity ("beneficence" or "protecting from harm and making efforts to secure wellbeing") (ECMO, Neuromyelitis Optica); (4) adaptive randomization inferential problems balanced against ethical benefits (trastuzumab vs taxane in advanced gastric cancer; ADVENT); (5) more efficient allocation of societal resources for research, in both public and commercial realms, versus uncertain regulatory acceptance (indicaterol; VALOR); and (6) platform, umbrella, and basket trials offering additional efficiencies (I-SPY II, BATTLE, Lung-MAP). The importance of careful design, meticulous planning, and rigorous ethical review of adaptive design trials on a case-by-case basis cannot be overemphasized.