A randomized sequential trial of creatine in amyotrophic lateral sclerosis. Creatine monohydrate in ALS: effects on strength, fatigue, respiratory status and ALSFRS. A clinical trial of creatine in ALS. Supplemented very low protein diet ameliorates responsiveness to erythropoietin in chronic renal failure. CINRG randomized controlled trial of creatine and glutamine in Duchenne muscular dystrophy. Creatine supplementation in chronic heart failure increases skeletal muscle creatine phosphate and muscle performance. Creatine supplementation in Huntington's disease: a placebo-controlled pilot trial. Creatine supplementation improves muscle strength in patients with congestive heart failure. A randomized controlled trial of resistance exercise in individuals with ALS.
Amyotrophic lateral sclerosis (ALS) is a fatal disease with no cure. In a transgenic mouse model of ALS, creatine monohydrate showed a promising increase in survival. We performed a double-blind, placebo-controlled, sequential clinical trial to assess the effect of creatine monohydrate on survival and disease progression in patients with ALS. Between June 2000 and December 2001, 175 patients with probable, probable-laboratory supported, or definite ALS were randomly assigned to receive either creatine monohydrate or placebo 10 gm daily. A sequential trial design was used with death, persistent assisted ventilation, or tracheostomy as primary end points. Secondary outcome measurements were rate of decline of isometric arm muscle strength, forced vital capacity, functional status, and quality of life. The trial was stopped when the null hypothesis of indifference was accepted. Creatine did not affect survival (cumulative survival probability of 0.70 in the creatine group vs 0.68 in the placebo group at 12 months, and 0.52 in the creatine group vs 0.47 in the placebo group at 16 months), or the rate of decline of functional measurements. Creatine intake did not cause important adverse reactions. This placebo-controlled trial did not find evidence of a beneficial effect of creatine monohydrate on survival or disease progression in patients with ALS. Our objective was to determine the effect of creatine monohydrate on disease progression in patients with amyotrophic lateral sclerosis (ALS). One hundred and seven patients with the diagnosis of probable or definite ALS, of less than five years duration from symptom onset, were randomized to either treatment with daily creatine monohydrate (5 g/d) or placebo. In this multicenter, double-blinded study we followed changes in disease progression: using quantitative measures of strength via maximal isometric voluntary contraction, forced vital capacity, ALSFRS, quality of life, fatigue and survival. Patients were followed for nine months. The results showed that creatine monohydrate did not significantly improve motor, respiratory or functional capacity in this patient population. The drug was well tolerated and the study groups well balanced, especially considering the absence of forced vital capacity criteria for entrance into the study. There was a trend toward improved survival in patients taking daily creatine monohydrate and this was identical to the trend seen in another recently published report of creatine in ALS patients 1. In conclusion, creatine monohydrate (5 g/d) did not have an obvious benefit on the multiple markers of disease progression measured over nine months. We measured fatigue during isometric contraction and found no significant improvement despite anecdotal patient reports prior to and during the study. The trend toward improved survival was also found in another recently completed blinded trial using creatine monohydrate. Further investigation on the possible survival benefit of creatine in this patient population is ongoing. Mitochondrial dysfunction occurs early in the course of ALS, and the mitochondria may be an important site for therapeutic intervention. Creatine stabilizes the mitochondrial transition pore, and is important in mitochondrial ATP production. In a transgenic mouse model of ALS, administration of creatine prolongs survival and preserves motor function and motor neurons.
                The authors conducted a randomized double-blind, placebo controlled trial on 104 patients with ALS from 14 sites to evaluate the efficacy of creatine supplementation in ALS. The primary outcome measure was maximum voluntary isometric contraction of eight upper extremity muscles, with secondary outcomes including grip strength, ALS Functional Rating Scale-Revised, and motor unit number estimates. Patients were treated for 6 months, and evaluated monthly.
                Creatine was tolerated well, but no benefit of creatine could be demonstrated in any outcome measure. CI analysis showed that the study, although powered to detect a 50% or greater change in rate of decline of muscle strength, actually made an effect size of greater than 23% unlikely. It was also demonstrated that motor unit number estimation was performed with acceptable reproducibility and tolerability, and may be a useful outcome measure in future clinical trials.
                Any beneficial effect of creatine at 5 g per day in ALS must be small. Other agents should be considered in future studies of therapeutic agents to address mitochondrial dysfunction in ALS. In addition, motor unit number estimation may be a useful outcome measure for future clinical trials in ALS. The aim of this study was to evaluate the relationship between uremic state and erythropoiesis in patients with predialytic chronic renal failure (CRF).
                We monitored for 2 years the erythropoietin (EPO) requirement in patients with advanced CRF (creatinine clearance < or =25 mL/min), randomized to either low protein diet (LPD) group (0.6 g/kg body weight/day, N = 10) or very low protein diet (VLPD) group (0.3 g/kg body weight/day, N = 10) supplemented with a mixture of ketoanalogs and essential amino acids, both kept at target hemoglobin levels.
                The achieved protein intake after 6 months was 0.79 +/- 0.02 g/kg body weight/day and 0.50 +/- 0.02 g/kg body weight/day in LPD and VLPD, respectively; such a difference was maintained up to the end of follow up. The final hemoglobin values did not differ from the basal values in either group (11.5 +/- 0.2 g/dL and 11.5 +/- 0.3 g/dL). EPO dose, that was similar at baseline (62.4 +/- 9.6 UI/kg body weight/week and 61.8 +/- 8.8 UI/kg body weight/week subcutaneously), remained unchanged in LPD but progressively decreased in VLPD down to the final value of 41.2 +/- 7.0 UI/kg body weight/week (P < 0.0001 vs. basal and LPD). VLPD was associated with a decrease of urinary excretion and serum levels of urea nitrogen and phosphate; however, EPO requirement was not correlated with the changes of these parameters. On the contrary, the variation of EPO dose directly correlated with the modification of parathyroid hormone (PTH) levels, that diminished from 229 +/- 55 pg/mL to 118 +/- 16 pg/mL (P < 0.0001) in VLPD and did not change in LPD.
                In patients with advanced CRF, an effective decrease of protein intake of 0.3 g/kg body weight/day induces a reduction of about 35% of the EPO dose required to maintain the target hemoglobin levels. This effect appears dependent on the correction of a moderate secondary hyperparathyroidism. We tested the efficacy and safety of glutamine (0.6 gm/kg/day) and creatine (5 gm/day) in 50 ambulant boys with Duchenne muscular dystrophy in a 6-month, double-blind, placebo-controlled clinical trial. Drug efficacy was tested by measuring muscle strength manually (34 muscle groups) and quantitatively (10 muscle groups). Timed functional tests, functional parameters, and pulmonary function tests were secondary outcome measures. Although there was no statistically significant effect of either therapy based on manual and quantitative measurements of muscle strength, a disease-modifying effect of creatine in older Duchenne muscular dystrophy and creatine and glutamine in younger Duchenne muscular dystrophy cannot be excluded. Creatine and glutamine were well tolerated. Cardiac creatine levels are depressed in chronic heart failure. Oral supplementation of creatine to healthy volunteers has been shown to increase physical performance.
                To evaluate the effects of creatine supplementation on ejection fraction, symptom-limited physical endurance and skeletal muscle strength in patients with chronic heart failure.
                With a double-blind, placebo-controlled design 17 patients (age 43-70 years, ejection fraction < 40) were supplemented with creatine 20 g daily for 10 days. Before and on the last day of supplementation ejection fraction was determined by radionuclide angiography as was symptom-limited 1-legged knee extensor and 2-legged exercise performance on the cycle ergometer. Muscle strength as unilateral concentric knee extensor performance (peak torque, Nm at 180 degrees/s) was also evaluated. Skeletal muscle biopsies were taken for the determination of energy-rich phosphagens.
                Ejection fraction at rest and at work did not change. Performance before creatine supplementation did not differ between placebo and creatine groups. While no change was seen in the placebo group compared to baseline, creatine supplementation increased skeletal muscle total creatine and creatine phosphate by 17 +/- 4% (P < 0.05) and 12 +/- 4% (P < 0.05), respectively. Increments were seen only in patients with < 140 mmol total creatine/kg d.w. (P < 0.05). One-legged performance (21%, P < 0.05), 2-legged performance (10%, P < 0.05), and peak torque, Nm (5%, P < 0.05) increased. Both peak torque and 1-legged performance increased linearly with increased skeletal muscle phosphocreatine (P < 0.05). The increments in 1-legged, 2-legged and peak torque were significant compared to the placebo group, (P < 0.05).
                One week of creatine supplementation to patients with chronic heart failure did not increase ejection fraction but increased skeletal muscle energy-rich phosphagens and performance as regards both strength and endurance. This new therapeutic approach merits further attention. To evaluate the effect of creatine (Cr) supplementation (5 g/day) in Huntington's disease (HD).
                A 1-year double-blind placebo-controlled study was performed in 41 patients with HD (stage I through III). At baseline and after 6 and 12 months, the functional, neuromuscular, and cognitive status of the patients was assessed by a test battery that consisted of 1) the Unified Huntington's Disease Rating Scale (UHDRS), 2) an exercise test on an isokinetic dynamometer to assess strength of the elbow flexor muscles, 3) a maximal exercise test on a bicycle ergometer to evaluate cardiorespiratory fitness, and 4) a test to assess bimanual coordination ability. Following the baseline measurements, the subjects were assigned to either a creatine (n = 26) or a placebo group (n = 15).
                Scores on the functional checklist of the UHDRS (p < 0.05), maximal static torque (p < 0.05), and peak oxygen uptake (p < 0.05) decreased from the start to the end of the study, independent of the treatment received. Cognitive functioning, bimanual coordination ability, and general motor function (total motor scale, UHDRS) did not change from baseline to 1 year in either group.
                One year of Cr intake, at a rate that can improve muscle functional capacity in healthy subjects and patients with neuromuscular disease (5 g/day), did not improve functional, neuromuscular, and cognitive status in patients with stage I to III HD. Both, cardiac and skeletal muscle creatine levels are depressed in patients with congestive heart failure (CHF). Oral supplementation of creatine (Cr) could increase physical performance in healthy volunteers. We therefore hypothesized that oral creatine supplementation improves skeletal muscle strength, quality of live and symptom-limited performance in patients with CHF.
                In a double-blind, placebo-controlled and crossover-designed study, 20 patients suffering from congestive heart failure more than 6 months and a peak oxygen uptake (peak VO2) below 20 ml/min/kg received 4 x 5 g Cr daily vs. placebo for 6 weeks and were crossed over for the following 6 weeks. Peak VO2, VO2 at the anaerobic threshold (VO2AT), ejection fraction (EF), distance in 6-minute-walk-test (6 min W), and muscle strength (Modified Sphygmomanometer (MS)) were determined at baseline, after 6, and after 12 weeks. Dyspnoea after 6-minute-walk-test was measured using the Borg Scale. Quality of live was assessed with the Minnesota Living with Heart Failure Questionnaire (MLHFQ).
                13 of 20 Patients finished the study. After 6 weeks of creatine supplementation there was a significant increase in body weight and muscle strength compared to baseline and placebo (p < 0.05). However, there was no significant change in peak VO2, VO2AT, walking distance, quality of life assessment and EF.
                Short-term creatine supplementation inaddition to standard medication in patients with CHF leads to an increase in body weight and an improvement of muscle strength. This effect is restricted to the time of supplementation. To determine the effects of resistance exercise on function, fatigue, and quality of life in individuals with ALS.
                Subjects with a diagnosis of clinically definite, probable, or laboratory-supported ALS, forced vital capacity (FVC) of 90% predicted or greater, and an ALS Functional Rating Scale (ALSFRS) score of 30 or greater were randomly assigned to a resistance exercise group that received a home exercise program consisting of daily stretching and resistance exercises three times weekly or to a usual care group, who performed only the daily stretching exercises. ALSFRS, the Fatigue Severity Scale (FSS), and Short Form-36 (SF-36) were completed at baseline and monthly for 6 months. FVC and maximum voluntary isometric contraction (MVIC) were monitored monthly throughout the study.
                Of 33 subjects screened, 27 were randomly assigned (resistance = 13; usual care = 14). Eight resistance exercise subjects and 10 usual care subjects completed the trial. At 6 months, the resistance exercise group had significantly higher ALSFRS and SF-36 physical function subscale scores. No adverse events related to the intervention occurred, MVIC and FVC indicated no negative effects, and less decline in leg strength measured by MVIC was found in the resistance exercise group.
                Our study, although small, showed that the resistance exercise group had significantly better function, as measured by total ALS Functional Rating Scale and upper and lower extremity subscale scores, and quality of life without adverse effects as compared with subjects receiving usual care.
In patients already diagnosed with clinically probable or definite ALS, creatine at doses ranging from 5 to 10 g per day did not have a statistically significant effect on survival, ALSFRS-R progression or percent predicted FVC progression.