No abstract

Historical controls (HCs) can be used for model parameter estimation at the study design phase, adaptation within a study, or supplementation or replacement of a control arm. Currently on the latter, there is no practical roadmap from design to analysis of a clinical trial to address selection and inclusion of HCs, while maintaining scientific validity. This paper provides a comprehensive roadmap for planning, conducting, analyzing and reporting of studies using HCs, mainly when a randomized clinical trial is not possible. We review recent applications of HC in clinical trials, in which either predominantly a large treatment effect overcame concerns about bias, or the trial targeted a life-threatening disease with no treatment options. In contrast, we address how the evidentiary standard of a trial can be strengthened with optimized study designs and analysis strategies, emphasizing rare and pediatric indications. We highlight the importance of simulation and sensitivity analyses for estimating the range of uncertainties in the estimation of treatment effect when traditional randomization is not possible. Overall, the paper provides a roadmap for using HCs.

Data are lacking on correlations between changes in nerve conduction (NC) studies and treatment response in chronic inflammatory demyelinating polyneuropathy (CIDP). This report examined data from a randomized, double-blind trial of immune globulin intravenous, 10% caprylate/chromatography purified (IGIV-C [Gamunex]; n = 59) versus placebo (n = 58) every 3 weeks for up to 24 weeks in CIDP. Motor NC results and clinical measures were assessed at baseline and endpoint/week 24. Improvement from baseline in adjusted inflammatory neuropathy cause and treatment score correlated with improvement in proximally evoked compound muscle action potential (CMAP) amplitudes (r = -0.53; P < 0.001) of all nerves tested and with improvement in CMAP amplitude of the most severely affected motor nerve (r = -0.36; P < 0.001). Correlations were observed between improvement in averaged CMAP amplitudes and dominant-hand grip strength (r = 0.44; P < 0.001) and Medical Research Council sum score (r = 0.38; P < 0.001). Overall, the change in electrophysiologic measures of NC in CIDP correlated with clinical response to treatment.

Formula-fed infants are more susceptible to infectious diseases because they lack the maternal immune factors transferred from breast milk, while their own immune system is still immature. As timely probiotic administration was suggested to promote immune system development in formula-fed infants, this study aimed at assessing the safety and the effects of a probiotic supplement (Bifidobacterium infantis R0033, Bifidobacterium bifidum R0071, and Lactobacillus helveticus R0052) on mucosal immune competence and digestive function in formula-fed infants. Healthy infants (3.5-6 months old) were randomised to receive either probiotic- (n=66) or placebo-supplemented (n=66) formula once a day for four weeks. In the probiotics group, faecal secretory immunoglobulin A (SIgA) levels remained similar between visit 2 (baseline; V2) and visit 3 (end-of-treatment; V3), but decreased in the placebo group. Changes in SIgA levels following treatment (log10ΔV3-V2 [95%CI]) between the probiotic and placebo groups were statistically significant (23 ng/dl [-57;102] and -137 ng/dl [-212;-62], respectively (P=0.0044; ANCOVA)). While log10ΔV3-V2 [95%CI] for salivary SIgA levels increased in both groups, this trend was more pronounced in the probiotics than in the placebo group with an increase of 123 ng/dl [9;236] and 37 ng/dL [-72;147], respectively (P=0.2829; ANCOVA). The weekly average number of stools/day was significantly higher in the probiotics group compared to placebo during the last week of treatment for the per protocol population. There was no difference in microbiota composition or anthropometric parameters between groups. No serious adverse event was reported, and all adverse events were mild and unrelated to the product or study. Our results show that formula-fed infants receiving probiotics maintained higher faecal SIgA levels at the end of the four-week treatment period, suggesting a positive effect of probiotics on SIgA production. This study demonstrates the safety of this probiotic formulation in infants. Formula-fed infants may benefit from probiotics supplementation to sustain the development of mucosal immunity.

Background: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a common inflammatory neuropathy that can be progressive, stepwise progressive, or relapsing and remitting.Objectives: To further evaluate the long-term safety and tolerability of immune globulin intravenous, 10% caprylate-chromatography purified immune globulin intravenous in CIDP.Design: Randomized multicenter trial.Setting: Hospitals and outpatient clinics.Patients: Adults with CIDP (n = 113).Interventions: Immune globulin intravenous, 10% caprylate-chromatography purified (2 g/kg of body weight) or placebo was infused as a baseline loading dose, followed by a maintenance dose (1 g/kg) every 3 weeks for up to 24 weeks. Patients who responded were rerandomized into a double-blind extension phase of immune globulin intravenous, 10% caprylate-chromatography purified (1 g/kg) or placebo every 3 weeks for up to 24 weeks. Patients who relapsed during the extension phase were withdrawn from the study. Main Outcome Measures: Additional analyses of safety and tolerability. Results: Overall, 113 patients and 95 patients were exposed to immune globulin intravenous, 10% caprylate-Author Affiliations are listed at the end of this article. Group Information: The IGIV-C CIDP Efficacy (ICE) Study Group Members are listed on page 1087.