Chronic Illness Therapy-Fatigue Score Research Articles

Effect of Filgotinib vs Placebo on Clinical Response in Patients With Moderate to Severe Rheumatoid Arthritis Refractory to Disease-Modifying Antirheumatic Drug Therapy

Patients with active rheumatoid arthritis (RA) despite treatment with biologic disease-modifying antirheumatic drug (bDMARD) therapy need treatment options. To evaluate the effects of filgotinib vs placebo on the signs and symptoms of RA in a treatment-refractory population. A 24-week, randomized, placebo-controlled, multinational phase 3 trial conducted from July 2016 to June 2018 at 114 sites internationally, randomizing 449 adult patients (and treating 448) with moderately to severely active RA and inadequate response/intolerance to 1 or more prior bDMARDs. Filgotinib, 200 mg (n = 148); filgotinib, 100 mg (n = 153); or placebo (n = 148) once daily; patients continued concomitant stable conventional synthetic DMARDs (csDMARDs). The primary end point was the proportion of patients who achieved 20% improvement in the American College of Rheumatology criteria (ACR20) at week 12. Secondary outcomes included week 12 assessments of low disease activity (disease activity score in 28 joints-C-reactive protein [DAS28-CRP] ≤3.2) and change in Health Assessment Questionnaire-Disability Index, 36-Item Short-Form Health Survey Physical Component, and Functional Assessment of Chronic Illness Therapy-Fatigue scores, as well as week 24 assessment of remission (DAS28-CRP <2.6) and adverse events. Among 448 patients who were treated (mean [SD] age, 56 [12] years; 360 women [80.4%]; mean [SD] DAS28-CRP score, 5.9 [0.96]; 105 [23.4%] with ≥3 prior bDMARDs), 381 (85%) completed the study. At week 12, more patients receiving filgotinib, 200 mg (66.0%) or 100 mg (57.5%), achieved ACR20 response (placebo, 31.1%; difference vs placebo: 34.9% [95% CI, 23.5%-46.3%] and 26.4% [95% CI, 15.0%-37.9%], respectively; both P < .001), including among patients with prior exposure to 3 or more bDMARDs (70.3%, 58.8%, and 17.6%, respectively; difference vs placebo: 52.6% [95% CI, 30.3%-75.0%] for filgotinib, 200 mg, and 41.2% [95% CI, 17.3%-65.0%] for filgotinib, 100 mg; both P < .001). The most common adverse events were nasopharyngitis (10.2%) for filgotinib, 200 mg; headache, nasopharyngitis, and upper respiratory infection (5.9% each) for filgotinib, 100 mg; and RA (6.1%) for placebo. Four uncomplicated herpes zoster cases and 1 retinal vein occlusion were reported with filgotinib; there were no opportunistic infections, active tuberculosis, malignancies, gastrointestinal perforations, or deaths. Among patients with active RA who had an inadequate response or intolerance to 1 or more bDMARDs, filgotinib, 100 mg daily or 200 mg daily, compared with placebo resulted in a significantly greater proportion achieving a clinical response at week 12. However, further research is needed to assess longer-term efficacy and safety. ClinicalTrials.gov Identifier: NCT02873936.

Clinical response beyond the Systemic Lupus Erythematosus Responder Index: post-hoc analysis of the BLISS-SC study

ObjectiveThe Systemic Lupus Erythematosus (SLE) Responder Index (SRI), developed as a primary outcome measure for use in clinical trials, captures improvement in SLE disease activity without concomitant worsening in disease...

Muscle mass as a target to reduce fatigue in patients with advanced cancer.

BackgroundCancer‐related fatigue (CRF) reduces quality of life and the activity level of patients with cancer. Cancer related fatigue can be reduced by exercise interventions that may concurrently increase muscle mass. We hypothesized that low muscle mass is directly related to higher CRF.MethodsA total of 233 patients with advanced cancer starting palliative chemotherapy for lung, colorectal, breast, or prostate cancer were studied. The skeletal muscle index (SMI) was calculated as the patient's muscle mass on level L3 or T4 of a computed tomography scan, adjusted for height. Fatigue was assessed with the Functional Assessment of Chronic Illness Therapy‐fatigue questionnaire (cut‐off for fatigue <34). Multiple linear regression analyses were conducted to study the association between SMI and CRF adjusting for relevant confounders.ResultsIn this group of patients with advanced cancer, the median fatigue score was 36 (interquartile range 26–44). A higher SMI on level L3 was significantly associated with less CRF for men (B 0.447, P 0.004) but not for women (B − 0.401, P 0.090). No association between SMI on level T4 and the Functional Assessment of Chronic Illness Therapy‐fatigue score was found (n = 82).ConclusionsThe association between SMI and CRF may lead to the suggestion that male patients may be able to reduce fatigue by exercise interventions aiming at an increased muscle mass. In women with advanced cancer, CRF is more influenced by other causes, because it is not significantly related to muscle mass. To further reduce CRF in both men and women with cancer, multifactorial assessments need to be performed in order to develop effective treatment strategies.

Fatigue in patients with neuromyelitis optica spectrum disorder and its impact on quality of life.

Fatigue is a prevalent symptom and major burden in neuroimmunological diseases. In neuromyelitis optica spectrum disorder (NMOSD), a severe autoimmune central nervous system (CNS) inflammatory disease with autoantibodies reactive to aquaporin-4, there are few reports about fatigue and quality of life (QOL). We aimed to evaluate the severity of fatigue and its relationship with QOL in patients with NMOSD. We prospectively studied patients with NMOSD who were in remission and seropositive for anti-aquaporin-4 antibody, and they were divided into 2 groups based on the presence of fatigue assessed using the Functional Assessment of Chronic Illness Therapy-fatigue score. Sleep quality, depression, pain, and QOL were also evaluated. A total of 35 patients were enrolled (mean age, 46.5 ± 14.1 years; female: male = 29:6), and the median Expanded Disability Status Scale (EDSS) score was 2.0 (range, 0 to 8.0). The patients with fatigue (N = 25, 71.4%) had poorer sleep quality and more severe depression than those without fatigue (p = 0.009 and p = 0.001). Both the physical and mental QOL scores were lower in patients with fatigue than in those without fatigue (p = 0.033 and p = 0.004). Multiple linear regression analyses showed that the degree of fatigue with EDSS score and pain were independent predictors of physical aspects of QOL (B = 0.382, p = 0.001), whereas depression was the only predictor of the mental components of QOL (B = -0.845, p = <0.001). Fatigue is a common symptom and an important predictor of QOL in patients with NMOSD.

The effect of increasing physical activity and/or omega-3 supplementation on fatigue in inflammatory bowel disease

This study tested the effect of individualised advice to increase physical activity and/or omega-3 fatty acid suppleme ntation on fatigue in inactive inflammatory bowel disease (IBD). Patients in remission were recruited to a pilot study using a randomised controlled 2x2 factorial design comparing baseline and post-intervention fatigue scores. Interventions (12 weeks) were 15-minute exercise consultation and/or 2970 mg/day omega-3 supplementation and controls were general health discussion and/or placebo. From n=656 screened patients, n=74 who met the eligibility criteria were random ised, n=60 commenced and n=52 completed the study. Fatigue measured with Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) score was worse with omega-3 supplementation and unchanged with exercise advice. Fatigue, measured by Inflammatory Bowel Disease-Fatigue (IBD-F) score, was reduced with exercise advice. Advice to increase physical activity and omega-3 supplementation, singly or in combination, was shown to be well-tolerated in IBD patients in remission. There was no evidence of exercise-related adverse effects on gut symptoms. Fatigue (IBD-F score) was reduced with exercise advice, but fatigue (FACIT-F score) was unchanged. Increasing fatigue with omega-3 supplementation is unexplained. Regular exercise may be a self-management option in IBD-related fatigue.

Tu1247 Unplanned Hospital Readmission: Rates and Causes in Patients With Inflammatory Bowel Disease: A Critical Analysis

Patients complete Functional Assessment of Chronic Illness Therapy-Fatigue score (FACITCF) as well as psychological scores (Beck for depression, Stai for anxiety, Epworth for sleep disturbances and IBDQ-9 for quality of life) and IBD activity scores. Biological parameters (Interleukin 5, 8, 12, complete blood count, ferritin, C-reactive protein, erythrocyte sedimentation rate and micronutrients) were tested by appropriate blood tests. Results: A total of 219 were studied and at the end of the study 177 patients (mean age, 39 ± 12 years, 28% ulcerative colitis and 72% crohn's disease) were included for the analysis. The median Fatigue score (38, range (1-52)) was lower that than in general population. Twenty-eight (16%) patients had moderate-to-severe fatigue determined as fatigue score of 22 or lower. In the univariate analysis, fatigue differed significatively with gender, type of IBD, Harvey and Mayo score, articular disease, body mass Index (BMI), psychological tests, thiopurine and biological treatment. All these variables were included in the multivariate analysis. Female gender (β-6.61, p<0.001), BMI (β -0.61, p<0.001) and higher depression (β-0.43, p<0.001) and anxiety (β -0.18, p<0.001) scores were predictors of increased fatigue. IBDQ9 (β0.51, p<0.001) was independently related to lower fatigue. Conclusion: Fatigue was prevalent in our IBD patients and was related to high levels of anxiety and depression and low quality of life. None of the biological factors evaluated including pro-inflammatory interleukins or micronutrient deficiencies was associated with fatigue.

Clinical, laboratory and health-related quality of life correlates of Systemic Lupus Erythematosus Responder Index response: a post hoc analysis of the phase 3 belimumab trials

ObjectiveCorrelates of systemic lupus erythematosus (SLE) Responder Index (SRI) response with clinical trial end points were examined using pooled data from the Study of Belimumab in Subjects with SLE (BLISS)...

Assessment of Fatigue in Rheumatoid Arthritis (by Functional Assessment of Chronic Illness Therapy–Fatigue Score) and Its Relation to Disease Activity and Anemia

Patients with rheumatoid arthritis (RA) mention fatigue as one of their most annoying problems. Measuring fatigue, understanding its contributory factors, and treating it as a feasible target lead to better patient outcome and improved quality of life. The Functional Assessment of Chronic Illness Therapy (FACIT) Measurement System is a collection of health-related quality-of-life questionnaires targeted to the management of chronic illness. The objective of this study was to evaluate fatigue using FACIT-Fatigue (FACIT-F) score and its relation to disease activity (using Disease Activity Score [DAS28] and Clinical Disease Activity Index [CDAI] score) and anemia in RA patients. A total of 100 RA patients were evaluated for fatigue using FACIT-F score, for disease activity using DAS28 and CDAI scores, for anemia using hemoglobin levels. Correlation studies were done using Pearson test. Functional Assessment of Chronic Illness Therapy-Fatigue showed positive association with DAS28 (P < 0.001; r = -0.80) and CDAI (P < 0.001; r = -0.83). Considering various components of DAS28 and CDAI, FACIT-F showed significant correlation with tender joint count (P < 0.001; r = -0.73), swollen joint count (P < 0.001; r = -0.76), patient global assessment (P < 0.001; r = -0.72), and evaluator global assessment (P < 0.001; r = -0.75). Erythrocyte sedimentation rate had no association with the fatigue (P = 0.217). No association was observed between fatigue and hemoglobin levels (P = 0.203). The fatigue experienced by the patients with RA is strongly associated with the severity of disease activity and is independent of anemia.

Low‐ Versus High‐Dose Rituximab for Rheumatoid Arthritis: A Systematic Review and Meta‐Analysis

The approved dose of rituximab (RTX) for rheumatoid arthritis (RA) is 2 × 1,000 mg infusions given 2 weeks apart. There is contradictory evidence regarding the effectiveness of a lower-dose regimen (2 × 500 mg) of RTX. Our aim was to compare the efficacy and safety of low- and high-dose RTX and to test the noninferiority of the low-dose regimen. A systematic literature review searching for randomized controlled trials (RCTs) and cohort studies comparing low- and high-dose RTX for RA was conducted using the Embase, PubMed, Cochrane Library, and Web of Science databases. The primary end points were the American College of Rheumatology criteria for 20% improvement (ACR20), ACR50, and ACR70 responses and the Disease Activity Score in 28 joints (DAS28) at 24 and 48 weeks. The secondary end points were patient-reported outcomes (PROs; Health Assessment Questionnaire, Short Form 36, and Functional Assessment of Chronic Illness Therapy-Fatigue scores) and adverse events. Noninferiority of low-dose RTX was tested using different approaches, one of which was based on the fixed margin method. In total, 6 RCTs and 2 cohort studies were identified. Four RCTs were included in the meta-analysis of efficacy outcomes, which showed no significant differences in the primary outcomes between low- and high-dose RTX. Noninferiority criteria of low-dose RTX were met for the ACR20, ACR50, DAS28, and PROs (at 24 and 48 weeks). Serious adverse events did not differ significantly. The results of 2 additional RCTs and a meta-analysis of 2 cohort studies corroborated the results of the meta-analysis of RCTs. Low-dose RTX has similar effectiveness and met noninferiority criteria for most primary outcomes. Considering the lower cost, it should be the standard RTX regimen for RA.

Efficacy and safety of IV ferumoxytol for adults with iron deficiency anemia previously unresponsive to or unable to tolerate oral iron

Although oral iron is the initial treatment approach for iron deficiency anemia (IDA), some patients fail to respond to or cannot tolerate oral iron. This double-blind safety and efficacy study of the intravenous (IV) iron, ferumoxytol, randomized patients with a history of unsatisfactory oral iron therapy, or in whom oral iron could not be used, to ferumoxytol (n = 609) or placebo (n = 203). The proportion of patients achieving the primary endpoint (hemoglobin increase ≥2.0 g/dL at Week 5) was 81.1% with ferumoxytol versus 5.5% with placebo (P < 0.0001). The mean increase in hemoglobin from Baseline to Week 5, a secondary endpoint (also the alternative preplanned primary efficacy endpoint for other health authorities), was 2.7 versus 0.1 g/dL (P < 0.0001). Achievement of a hemoglobin ≥12 g/dL, time to a hemoglobin increase ≥2.0 g/dL, and improvement in the Functional Assessment of Chronic Illness Therapy Fatigue score also significantly favored ferumoxytol over placebo at Week 5 (P < 0.0001). Ferumoxytol treatment-emergent adverse events were mainly mild to moderate. Ferumoxytol was effective and well tolerated in patients with IDA of any underlying cause in whom oral iron was ineffective or could not be used. This trial was registered at http://www.clinicaltrials.gov as #NCT01114139. Am. J. Hematol. 89:7–12, 2014. © 2013 Wiley Periodicals, Inc.

Comparisons of health status scores with MRC grades in COPD: implications for the GOLD 2011 classification

The 2011 Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy document recommends assessment of chronic obstructive pulmonary disease (COPD) using symptoms and future exacerbation risk, employing two score cut-points: COPD Assessment Test (CAT) score ≥ 10 or modified Medical Research Council dyspnoea scale (mMRC) grade ≥ 2. To explore the equivalence of these two symptom cut-points, the relationship between the CAT and the mMRC and St George's Respiratory Questionnaire (SGRQ), the Short-form Health Survey and the Functional Assessment of Chronic Illness Therapy Fatigue scores were retrospectively analysed using a primary care dataset. Data from 1817 patients (mean ± SD forced expiratory volume in 1 s 1.6 ± 0.6 L) showed a significant association between mMRC grades and all health status scores (ANOVA p<0.0001). mMRC grade 1 was associated with significant levels of health status impairment (SGRQ 39.4 ± 15.5 and CAT 15.7 ± 7.0); even patients with mMRC grade 0 had modestly elevated scores (SGRQ 28.5 ± 15.1 and CAT 11.7 ± 6.8). An mMRC grading ≥ 2 categorised 57.2% patients with low symptom (groups A and C) versus 17.2% with the CAT. Using the mMRC cut-point (≥ 1) resulted in similar GOLD group categorisations as the CAT (18.9%). The mMRC showed a clear relationship with health status scores; even low mMRC grades were associated with health status impairment. Cut-points of mMRC grade ≥ 1 and CAT score ≥ 10 were approximately equivalent in determining low-symptom patients. The GOLD assessment framework may require refinement.

Ferumoxytol Treatment Results in Robust Hemoglobin Increases in Iron Deficiency Anemia Patients with a History of Unsatisfactory Oral Iron Therapy in a Phase III, Randomized, Placebo-Controlled Trial.

AbstractAbstract 2098▪▪This icon denotes a clinically relevant abstract Background:Although oral iron therapy is often the initial approach to the treatment of iron deficiency anemia (IDA), many patients fail to adequately respond or do not tolerate oral iron. Unfortunately for these patients, approved treatment options are limited in the US and Canada to only the IV iron dextrans, which have boxed safety warnings and inconvenient dosing regimens. Many of these patients, therefore, do not get IV iron, and remain inadequately treated and symptomatic. Ferumoxytol (FER), a new IV iron approved for the treatment of IDA in patients with chronic kidney disease (CKD), is being investigated to treat IDA patients without CKD who have a history of unsatisfactory oral iron therapy or in whom oral iron cannot be used. This randomized, placebo-controlled, double blind trial was designed to assess the efficacy and safety of FER for the treatment of these IDA patients. Methods:Key inclusion criteria included a Baseline hemoglobin (Hgb) less than 10 g/dL and >7 g/dL, and transferrin saturation (TSAT) <20%. Subjects were randomized 3:1 to receive 2 injections of either FER (510 mg, 5±3 days apart) or placebo (IV normal saline). Efficacy assessments included comparisons of the change in Hgb, TSAT and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) score in the 2 treatment groups between Baseline and Week 5. Results:A total of 808 subjects were randomized to the 2 treatment arms (FER, n=608; placebo, n=200). FER demonstrated superiority to placebo with 81.1% of subjects achieving an increase in Hgb of >2.0 g/dL from Baseline to Week 5 compared to only 5.5% in the placebo group (treatment difference: 75.6%, p<0.0001). At each post-FER treatment time point, a larger percentage of FER-treated subjects had a >2.0 g/dL increase in Hgb compared with those treated with placebo. The superiority of FER was also demonstrated for the mean change in Hgb from Baseline to Week 5 with a robust 2.7 g/dL increase compared to only 0.1 g/dL in the placebo group (treatment difference: 2.54 g/dL, p<0.0001). An increase in TSAT from Baseline to Week 5 was only observed in FER-treated subjects (mean change: FER, 11.0%; placebo −0.1%). In addition, a statistically significant improvement in fatigue from Baseline to Week 5, as measured by the FACIT-Fatigue, was shown for FER-treated subjects compared to placebo (p<0.0001).The rates of adverse events (AEs) and related AEs were higher in the FER group, although no pattern or safety trend was observed to suggest a specific safety signal. The overall rate of serious adverse events (SAEs) was comparable between the 2 treatment groups (FER, 2.6%; placebo, 3.0%), and treatment-related SAEs associated with the class of IV iron products were reported in 4 (0.7%) FER-treated subjects. As expected, protocol-defined AEs of Special Interest (signs/symptoms of hypotension or hypersensitivity associated with IV iron use) were noted at a higher rate in FER-treated subjects (FER, 3.6%; placebo, 1.0%). All cardiovascular AEs were considered unrelated by the investigators. Overall, FER was well tolerated and no new safety signals were identified. [Display omitted] Summary of Efficacy and Safety Results by Treatment GroupFER (n=608)Placebo (n=200)p-valueEfficacy Results: (ITT Population)% Subjects with Increase Hgb >2 g/dL181.15.5<0.0001Mean Change in Hgb2 (g/dL)2.70.1<0.0001Mean Change in TSAT2 (%)11.0−0.1<0.0001Safety Results: (Safety Population)All Treatment Emergent AEs49.2%43.0%Related AEs14.6%7.5%All SAEs2.6%3.0%Related SAEs0.7%0%AEs of Special Interest33.6%1.0%Cardiovascular AEs0.8%0%AEs Resulting in Study Discontinuation0.5%1.0%1at any time from Baseline to Week 5.2Least Square Mean change from Baseline to Week 5.3includes protocol-defined signs/symptoms of hypotension and hypersensitivity. Conclusion:In this randomized, placebo-controlled Phase III trial, 2 doses of FER were shown to be highly effective in raising hemoglobin and iron parameters in non-CKD patients with IDA who had a history of unsatisfactory oral iron therapy. FER also significantly reduced fatigue, and was generally well tolerated with no new safety signals being identified. Therefore, FER could provide an important, new treatment option for IDA patients with a history of unsatisfactory oral iron therapy or in whom oral iron could not be used. Disclosures:Vadhan Raj:AMAG Pharmaceuticals, Inc.: Research Funding. Off Label Use: Feraheme (ferumoxytol) injection. For treatment of iron deficiency anemia in non-CKD patients. Cressman:AMAG Pharmaceuticals, Inc.: Employment. Strauss:AMAG Pharmaceuticals, Inc.: Employment. Bernard:AMAG Pharmaceuticals, Inc.: Employment. Li:AMAG Pharmaceuticals, Inc.: Employment. Allen:AMAG Pharmaceuticals, Inc.: Employment.

Low-dose prednisone chronotherapy for rheumatoid arthritis: a randomised clinical trial (CAPRA-2)

ObjectiveTo assess the efficacy and safety of low-dose prednisone chronotherapy using a new modified-release (MR) formulation for the treatment of rheumatoid arthritis (RA).MethodsIn this 12-week, double-blind, placebo-controlled study, patients with...

Effect of rituximab on physical function and quality of life in patients with rheumatoid arthritis previously untreated with methotrexate

To assess the effect of rituximab plus methotrexate (MTX) compared with MTX alone on patient-reported outcomes (PROs) and health-related quality of life (HRQOL) in patients with active early rheumatoid arthritis (RA) previously untreated with MTX. Patients with active early RA were randomized to groups receiving placebo, rituximab 500 mg, or rituximab 1,000 mg. Rituximab was given by intravenous infusion on days 1 and 15. From week 24, patients with a Disease Activity Score in 28 joints-erythrocyte sedimentation rate of ≥2.6 were eligible for retreatment. Physical function was assessed by Health Assessment Questionnaire (HAQ) disability index (DI) and Short Form 36 (SF-36) scores. Patients achieving a minimal clinically important difference (MCID) for PROs were determined. Additional PROs, including fatigue and pain, were assessed. A total of 748 patients were randomized and received the study drug. Patient characteristics were well balanced. At week 52, treatment with rituximab in both dose groups showed significant improvements in the HAQ DI compared to the MTX alone group (-0.905 and -0.916 in the rituximab 500 mg plus MTX and 1,000 mg plus MTX groups, respectively, versus -0.628 in the MTX alone group; P < 0.0001). Higher proportions of patients achieved MCID in the HAQ DI in the rituximab plus MTX groups compared to MTX alone. Treatment with rituximab plus MTX led to a significant reduction in the SF-36 physical component summary for both rituximab dose groups, but did not show statistically significant differences in the SF-36 mental component summary. Compared to the MTX alone group, both doses of rituximab plus MTX were associated with significant reductions in the patient global assessment of disease activity and pain, and a significantly higher improvement in Functional Assessment of Chronic Illness Therapy-Fatigue scores from baseline to 52 weeks. Rituximab plus MTX was associated with significant improvement in physical function and HRQOL outcomes compared with MTX alone in patients previously untreated with MTX.

Placebo and nocebo effects in randomized double-blind clinical trials of agents for the therapy for fatigue in patients with advanced cancer.

A significant response to placebo in randomized controlled trials of treatments for cancer-related fatigue (CRF) had been reported. A retrospective study was conducted to determine the frequency and predictors of response to placebo effect and nocebo effects in patients with CRF treated in those trials. The records of 105 patients who received placebo in 2 previous randomized clinical trials conducted by this group were reviewed. The proportion of patients who demonstrated clinical response to fatigue, defined as an increase in Functional Assessment of Chronic Illness Therapy-Fatigue score of > or = 7 from baseline to Day 8, and the proportion of patients with a nocebo effect, defined as those reporting >2 side effects, were determined. Baseline patient characteristics and symptoms recorded using the Edmonton Symptom Assessment Scale (ESAS) were analyzed to determine their association with placebo and nocebo effects. Fifty-nine (56%) patients had a placebo response. Worse baseline anxiety and well-being subscale score (univariate) and well-being (multivariate) were significantly associated with placebo response. Commonly reported side effects were insomnia (79%), anorexia (53%), nausea (38%), and restlessness (34%). Multivariate analysis indicated that worse baseline (ESAS) sleep, appetite, and nausea were associated with increased reporting of the corresponding side effects. Greater than half of advanced cancer patients enrolled in CRF trials had a placebo response. Worse baseline physical well-being score was associated with placebo response. Patients experiencing specific symptoms at baseline were more likely to report these as side effects of the medication. These findings should be considered in the design of future CRF trials.