Outcome measures in placebo-controlled trials of osteoarthritis: responsiveness to treatment effects in the REPORT database.

INTRODUCTION: Treatment response in randomized clinical trials (RCT) of osteoarthritis (OA) has been assessed by multiple primary and secondary outcomes, including pain, function, patient and clinician global measures of status and response to treatment, and various composite and responder measures. Identifying outcome measures with greater responsiveness to treatment is important to increase the assay sensitivity of RCTs. OBJECTIVE: To assess and compare the responsiveness of different outcome measures used in placebo-controlled RCTs of OA. SEARCH STRATEGY: The Resource for Evaluating Procedures and Outcomes of Randomized Trials database includes placebo-controlled clinical trials of pharmacologic treatments (oral, topical, or transdermal) for OA identified from a systematic literature search of RCTs published or publicly available before August 5, 2009, which was conducted using PubMed, the Cochrane collaboration, publicly-available websites, and reference lists of retrieved publications. DATA COLLECTION AND ANALYSIS: Data collected included: (1) pain assessed with single-item ratings and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale; (2) patient and clinician global measures of status, improvement, and treatment response; (3) function assessed by the WOMAC function subscale; (4) stiffness assessed by the WOMAC stiffness subscale; and (5) the WOMAC and Lequesne Algofunctional Index composite outcomes. Measures were grouped according to the total number of response categories (i.e., <10 categories or ≥10 categories). The treatment effect (difference in mean change from baseline between the placebo and active therapy arms) and standardized effect size (SES) were estimated for each measure in a meta-analysis using a random effects model. RESULTS: There were 125 RCTs with data to compute the treatment effect for at least one measure; the majority evaluated non-steroidal anti-inflammatory drugs (NSAIDs), followed by opioids, glucosamine and/or chondroitin, and acetaminophen. In general, the patient-reported pain outcome measures had comparable responsiveness to treatment as shown by the estimates of treatment effects and SES. Treatment effects and SESs were generally higher for patient-reported global measures compared with clinician-rated global measures but generally similar for the WOMAC and Lequesne composite measures. CONCLUSIONS: Comparing different outcome measures using meta-analysis and selecting those that have the greatest ability to identify efficacious treatments may increase the efficiency of clinical trials of treatments for OA. Improvements in the quality of the reporting of clinical trial results are needed to facilitate meta-analyses to evaluate the responsiveness of outcome measures and to also address other issues related to assay sensitivity.

Production responses of dairy cows fed various amounts of rumen-protected methionine and lysine.

A 3 x 3 factorial response surface design was used to study the effects of feeding rumen-protected methionine and lysine to dairy cows between 22 and 305 d of lactation. A total of 130 dairy cows at three universities were individually fed a corn silage and corn grain-based diet that contained either soybean meal or corn gluten meal and urea. An unsupplemented control diet plus nine treatment combinations of three amounts of rumen-protected DL-methionine (3.4, 7.8, and 12.2 g/d) and three amounts of rumen-protected L-lysine (5.9, 13.5, and 21.1 g/d) were fed at all locations. Plasma concentrations of methionine and lysine were increased when rumen-protected methionine and lysine were supplemented to the diets. Rumen-protected methionine and lysine did not affect feed intake by cows fed either by soybean meal or corn gluten meal and urea based diets. Milk protein percentage was increased, but milk and milk protein yields were not improved when diets containing soybean meal were supplemented with rumen-protected methionine and lysine. In contrast, milk and milk protein yields were improved when a diet that contained corn gluten meal and urea was supplemented with rumen-protected methionine and lysine. Health and reproduction measurements were similar for cows receiving all treatments.

Supplementation of dairy cow diets with ammonium salts of volatile fatty acids.

The objective was to determine the efficacy of a blend of ammonium salts of the volatile fatty acids, isobutyric, 2-methylbutyric, isovaleric, and valeric as a supplement to diets for dairy cows. Treatments of 0 (control) or 120 (supplemented) g/cow of the blend were fed daily from approximately 3 wk prepartum through a complete lactation. Five trials were conducted concurrently with a total of 116 multiparous Holstein cows. Dietary ingredients or combinations of ingredients differed in each of the trials. Diets contained either 1) corn gluten meal and urea, 2) soybean meal, or 3) cottonseed meal as the primary grain source of crude protein. The forage portion of the diets contained corn silage in combination with one or more of the following: alfalfa hay, alfalfa haylage, or wheat silage. Cows fed the supplement produced more milk and fat-corrected milk than the control cows for the 305-d lactation on four of the five diets, resulting in an average increase of 1.7 kg/d or 7%. Feed intake of cows on the supplemented diet was generally similar or lower than intake of the control cows throughout lactation, indicating that increased milk yield was associated with improved feed utilization. Percent milk fat was similar for cows on the supplemented diet, but fat yield was higher. Percent milk protein was lower for supplemented cows, but protein yield was about the same for both treatments because of higher milk yield. Health and reproduction were similar for all cows.

Effect of rumen-protected methionine on plasma free amino acids and production by dairy cows.

The effectiveness of an encapsulated rumen-protected methionine compound (RPMet) for delivering methionine postruminally and its effect on plasma amino acid concentrations, milk production and milk composition were evaluated. Thirty multiparous Holstein cows in early lactation were randomly assigned to five levels of RPMet. RPMet was supplied at 0, 550, 1100, 1650 or 3300 mg/kg of concentrate resulting in an intake of 0, 6.9, 12.9, 19.6 or 40.2 g of supplemental DL-methionine/day for each cow. The basal diet was alfalfa-bromegrass hay and a 15.8% crude protein corn- and soybean meal-based concentrate mixture. The experiment was divided into pretreatment and treatment periods, each consisting of 21 days. Feed intake and milk production were measured daily, milk composition weekly and plasma amino acid concentrations twice daily on days 17 and 20 of the pretreatment period and on days 4, 10 and 21 of the treatment period. RPMet was effective in delivering methionine postruminally, which increased concentrations of methionine in plasma. Dry matter intake, milk production, milk composition and body weight were not significantly affected by RPMet.