Evaluation of Clinical Meaningfulness of Fortasyn Connect in Terms of "Time Saved".

Assessment of meaningfulness in randomized clinical trials (RCTs) in Alzheimer's disease (AD) is challenging, particularly in early disease. Converting clinical outcomes to disease progression time allows assessment of treatment effects using a metric that is understandable and meaningful: time. We demonstrate time savings assessments using meta time component tests (TCTs) in the LipiDiDiet multinutrient RCT. Dietary patterns are important for dementia prevention, likely due to individual cumulative nutrient effects. LipiDiDiet used a multinutrient (Fortasyn Connect) formulation in patients with prodromal AD, benefitting cognition (5-item composite NTB, effect 0.089), cognition and function (CDR-SB, -0.605), and slowing hippocampal atrophy (0.122 cm3). Meaningfulness of point differences is unclear. However, a combination TCT showed 9-month disease time savings at 24 months (38% slowing of disease time): 9.0, 10.5, and 7.2 months for NTB, CDR-SB, and hippocampal volume, underscoring the value of TCTs in AD RCTs and the need for continued validation of this approach.

"Time Saved" Calculations to Improve Decision-Making in Progressive Disease Studies.

BACKGROUND: Disease modifying therapies (DMTs) may be most beneficial in early disease, when progression is slow and changes small, with clinical relevance difficult to interpret. OBJECTIVES: Time component tests (TCTs) translate differences between treatments from mean change, vertical distance between longitudinal trajectories, into intuitively understood time saved, horizontal distance between trajectories, which can be readily combined across endpoints in a global TCT (gTCT). DESIGN: The value of composites, time savings estimates, and combination scores to optimize measurement and interpretation of DMTs are demonstrated, along with construction details and simulation studies. SETTING: TCT methods were applied to a randomized phase II clinical trial. PARTICIPANTS: Patients with early Alzheimer's disease (N=332). INTERVENTION: Three treatment groups with AFFITOPE® AD02 and two control groups with aluminum oxyhydroxide, AD04. MEASUREMENTS: The co-primary efficacy outcomes were an adapted ADAS-Cog (aADAS) and adapted ADCS-ADL (aADL), which were optimized composite scales specific to cognitive and functional domains. A composite based on these two scores was the study's prespecified primary outcome. The CDR-sb and standard non-adapted ADCS-ADL and ADAS-Cog scales were prespecified secondary outcomes. RESULTS: The AD04 2 mg group showed some statistically significant effects compared with other study arms. It is unclear whether the observed 3.8-point difference on the composite is clinically meaningful. TCT results show a time savings of 11 months in an 18-month study with AD04 2 mg. CONCLUSION: The relevance of 11 months saved is more universally understood than a mean difference of 3.8 points in the composite outcome. These results suggest that a combination of a composite approach and a time savings interpretation offers a powerful approach for detecting and interpreting disease modifying effects.

Colchicine lack of effectiveness in symptom and inflammation modification in knee osteoarthritis (COLKOA): a randomized controlled trial.

OBJECTIVES: Uric acid may activate an innate immune response in osteoarthritis (OA), contributing to disease pathology and progression. We evaluated the effectiveness of colchicine on pain and function in symptomatic knee OA (KOA) and the underlying mechanism of action. METHODS: Colchicine effectiveness in symptoms and inflammation modification in knee osteoarthritis (COLKOA) was a double-blind, placebo-controlled, randomized trial comparing 16 weeks of treatment with 0.5 mg twice-daily oral colchicine to placebo for knee osteoarthritis (KOA). The primary endpoint was ≥30% improvement in total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score at week 16. Secondary endpoints included improvement in pain (0-10 Likert scales); WOMAC pain; patient global assessment (0-100); physical function; the OARSI-OMERACT response; quality of life; and change in serum, urine, synovial fluid (SF) biomarkers of cartilage metabolism and inflammation, and plasma/SF colchicine concentrations. RESULTS: Of 109 randomly assigned participants, 39% (95% confidence interval (CI) 27-52%) and 49% (95% CI 36-62%) in the colchicine and placebo arms respectively met the primary endpoint at study end (P = 0.284, odds ratio 0.66, 95% CI 0.31-1.41). No strong evidence of treatment differences was identified on clinical secondary endpoints. Treatment significantly reduced mean serum hs-CRP (P = 0.008) and SF CTXI (P = 0.002); treatment tended to reduce inflammatory markers (SF IL-6, IL8, TNFα, CD14 and IL-18), but these differences were not statistically significant. CONCLUSION: Colchicine (0.5 mg twice-daily orally) reduced inflammation and high bone turnover biomarkers known to be associated with OA severity and progression risk, but did not reduce KOA symptoms over a 16-week study period. A longer-term study to evaluate for slow-acting disease modifying effects is warranted. TRIAL REGISTRATION: The trial has been registered at clinicaltrials.gov as NCT02176460. Date of registration: June 26, 2014.

Synovial fluid pro-inflammatory profile differs according to the characteristics of knee pain.

OBJECTIVE: The role of inflammation and pain in osteoarthritis (OA) is not fully understood. We evaluated the association between pro-inflammatory biomarkers and pain. METHODS: We used baseline data and samples from a randomized controlled trial of colchicine for symptomatic knee OA. Severity of pain of the more symptomatic knee was assessed by National Health and Nutrition Examination Survey-I (NHANES-I) criterion and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain index. Pains on movement and at rest were self-reported on an 11-point Likert scale. Severity of radiographic tibiofemoral OA was assessed by Kellgren and Lawrence (KL) grade. Concentrations of synovial fluid (sf) IL-1ß, IL-6, IL-8, TNFα, C-terminal telopeptides of Type I collagen (CTXI) and C-telopeptide of Type II collagen (CTXII), as well as urinary (u) CTXII were measured. RESULTS: Of the 109 patients enrolled in the study, 70 patients (70% women) with synovial fluid obtained by direct aspiration were included for analysis. The mean ± SD age and body mass index (BMI) of the patients were 57.6 ± 8.3 years and 28.8 ± 5.2 kg/m2. After adjustment for age, sex, and BMI, sf IL-6 and IL-8 were statistically significantly associated with 11-point pain on movement, but not with pain at rest. No significant associations were observed with WOMAC pain scores. sf IL-1ß (analyzed as detectable/non-detectable) was inversely associated with pain. In contrast, after adjustment, Sf TNFα was associated with WOMAC total pain and both pain on movement and at rest. sf/u CTXII was associated with radiographic severity, but not with knee pain. CONCLUSIONS: This study provides indication that OA pain mechanisms may differ according to the characteristics of the pain.

Is intravenous contrast necessary for detection of clinically significant extracolonic findings in patients undergoing CT colonography?

OBJECTIVE: To determine whether intravenous contrast (IVC) is necessary for detection of extracolonic findings (ECFs) in patients undergoing CT colonography (CTC). METHODS: We performed a retrospective review of CT findings in 179 cases of CTC studies performed over 18 months where both pre-contrast (NECT) and post-contrast (CECT) scans were performed in the prone and supine positions, respectively, in the same patients. All ECFs were recorded on a per patient basis and graded according to the colonography reporting and data system classification. RESULTS: There was no significant change in E grade for the cohort (p = 0.171) between the NECT and CECT scans. On the CECT scans, additional findings were detected in 49.1% of patients. Overall, there were 27/179 (15.1%) patients graded E3 and 18/179 (10.1%) patients graded E4 on the CECT study. Compared with the NECT study, there was a decrease of 12.9% of patients graded E3 and no change in the number of patients graded E4. CONCLUSION: With IVC administration, additional ECFs are detected in nearly half of all patients. However, there was no increase in the number of patients with clinically significant lesions. The risk-benefit ratio of routine IVC administration for CTC in symptomatic patients thus requires further evaluation. ADVANCES IN KNOWLEDGE: This study reviews the utility of IVC in CTC and is thus relevant to current clinical practice at many institutions.