A placebo-controlled trial of gabapentin in spinal muscular atrophy. A phase 1 trial of riluzole in spinal muscular atrophy. SMA CARNI-VAL trial part I: double-blind, randomized, placebo-controlled trial of L-carnitine and valproic acid in spinal muscular atrophy. Randomized, double-blind, placebo-controlled trial of hydroxyurea in spinal muscular atrophy. Open-label randomized trial of oral trimethoprim-sulfamethoxazole, doxycycline, and chloramphenicol compared with trimethoprim-sulfamethoxazole and doxycycline for maintenance therapy of melioidosis. The efficacy of self-monitoring of blood glucose in the management of patients with type 2 diabetes treated with a gliclazide modified release-based regimen. A multicentre, randomized, parallel-group, 6-month evaluation (DINAMIC 1 study). Ofloxacin versus trimethoprim/sulfamethoxazole in the treatment of uncomplicated urinary tract infection. Impact of glucose self-monitoring on non-insulin-treated patients with type II diabetes mellitus. Randomized controlled trial comparing blood and urine testing. A randomized, double-blind study of the efficacy of fleroxacin versus trimethoprim-sulfamethoxazole in men with culture-proven chancroid.
To evaluate the efficacy of gabapentin in increasing muscle strength of patients with spinal muscular atrophy (SMA).
                Preclinical data in experimental models of motor neuron disease suggest a neuroprotective effect of gabapentin.
                Gabapentin (1200 mg), or placebo, was administered three times daily in a randomized, double-blind trial for 12 months. The primary outcome measure was the average percent change from baseline, based on the measurement of strength in four muscles (elbow flexion and hand grip bilaterally) for each patient. Drug efficacy was examined by comparing the percent change in strength for patients on drug vs. placebo. Secondary efficacy variables included: forced vital capacity (FVC), SMA functional rating scale (SMAFRS), and mini-Sickness Impact Profile (SIP).
                Eighty-four patients, with type II or III SMA, were enrolled at eight sites across the United States. There were no differences in baseline features. There was no difference between the placebo and drug groups in any outcome measure.
                This study demonstrates the feasibility of this trial design and provides data for the design of future clinical trials in SMA. Severe spinal muscular atrophy (SMA) (Werdnig-Hoffmann disease, acute SMA, and SMA I) is a disease of the motor neuron characterized by onset before 6 months of age, failure ever to achieve sitting without support, and a life expectancy of 2 years or less. There is no known treatment for SMA, and, until recently, no therapeutic trials have been attempted. There is reason to believe that glutamate, an excitatory neurotransmitter, enhances programmed cell death of anterior horn cells. Riluzole, a glutamate inhibitor, has been shown to slow the rate of decline in patients with amyotrophic lateral sclerosis, another form of motor neuron disease.
                To determine whether a glutamate inhibitor might be tolerated by infants with SMA and, furthermore, whether this medication could have a positive effect on life expectancy.
                Subjects with homozygous deletions of the survival motor neuron gene were recruited from pediatric neuromuscular clinics and randomized in a 2:1 ratio, 2 riluzole to 1 placebo. Neurologic examination was performed at the first visit by one of the investigators. Complete blood count, hepatic and renal screens, and urinalysis were performed at baseline, 2 weeks, 1 month, 2 months, 3 months, 6 months, and 9 months after drug or placebo was started. An electrocardiogram was done at baseline, 3 months, 6 months, and 12 months. Treatment was stopped after 9 months, and blood work was repeated at 12 months. Treatment was reinstituted at 1 year if requested by the parents. The enrollment goal was 30 patients; however, support from the pharmaceutical company was withdrawn when Rhone-Poulenc Rorer was taken over by Aventis. The investigational review boards of the participating centers approved the protocol and consent forms.
                Seven patients received riluzole and 3 received placebo medication. All 3 patients in the placebo group died (mean age, 9 months). Three of 7 who received active drug are still living at ages 513 years, 4 years, and 30 months. None of the 10 subjects experienced adverse effects or changes in laboratory test results. None showed any change in motor abilities.
                Riluzole appears to be safe in young children. This was a limited study with insufficient power to show a difference between the 2 groups. Because there is a suggestion of possible benefit in treated subjects, we recommend further study of riluzole in pediatric patients with SMA. Valproic acid (VPA) has demonstrated potential as a therapeutic candidate for spinal muscular atrophy (SMA) in vitro and in vivo.
                Two cohorts of subjects were enrolled in the SMA CARNIVAL TRIAL, a non-ambulatory group of "sitters" (cohort 1) and an ambulatory group of "walkers" (cohort 2). Here, we present results for cohort 1: a multicenter phase II randomized double-blind intention-to-treat protocol in non-ambulatory SMA subjects 2-8 years of age. Sixty-one subjects were randomized 1:1 to placebo or treatment for the first six months; all received active treatment the subsequent six months. The primary outcome was change in the modified Hammersmith Functional Motor Scale (MHFMS) score following six months of treatment. Secondary outcomes included safety and adverse event data, and change in MHFMS score for twelve versus six months of active treatment, body composition, quantitative SMN mRNA levels, maximum ulnar CMAP amplitudes, myometry and PFT measures.
                At 6 months, there was no difference in change from the baseline MHFMS score between treatment and placebo groups (difference = 0.643, 95% CI = -1.22-2.51). Adverse events occurred in >80% of subjects and were more common in the treatment group. Excessive weight gain was the most frequent drug-related adverse event, and increased fat mass was negatively related to change in MHFMS values (p = 0.0409). Post-hoc analysis found that children ages two to three years that received 12 months treatment, when adjusted for baseline weight, had significantly improved MHFMS scores (p = 0.03) compared to those who received placebo the first six months. A linear regression analysis limited to the influence of age demonstrates young age as a significant factor in improved MHFMS scores (p = 0.007).
                This study demonstrated no benefit from six months treatment with VPA and L-carnitine in a young non-ambulatory cohort of subjects with SMA. Weight gain, age and treatment duration were significant confounding variables that should be considered in the design of future trials.
                Clinicaltrials.gov NCT00227266. The purpose of this study was to evaluate the safety and efficacy of hydroxyurea (HU) in spinal muscular atrophy (SMA) in a randomized, double-blind, placebo-controlled trial.
                Twenty-eight patients with type 2 SMA and 29 patients with type 3 SMA were randomly assigned (2:1) to receive HU or matching placebo for 18 months. HU was initiated at 10 mg/kg/day with an 8-week titration to 20 mg/kg/day. Subjects were assessed at baseline (T0) and monthly for the first 2 months (T1-T2) and then every 2 months throughout treatment (T3-T10) and posttreatment periods (T11-T13). The primary outcome measures were the Gross Motor Function Measure (GMFM), Manual Muscle Test (MMT), and serum full-length survivor motor neuron (flSMN) mRNA. The secondary outcome measures were Modified Hammersmith Functional Motor Scale and forced vital capacity (FVC).
                Fifty-five patients completed this trial, which lasted from March 2007 to June 2009. Except for neutropenia, we found no differences in adverse events between the 2 groups. Compared with the placebo group, the HU group had -1.88 for GMFM (p = 0.11), -0.55 for MMT (p = 0.49), and 2.17 for flSMN mRNA (p = 0.13). Similarly, we found no difference in mean improvement of the secondary endpoints. Both groups had a trend toward a decline in FVC with little change in strength and motor function.
                Under the current regimen and schedule, HU brought about no improvement in patients with type 2 and 3 SMA, and its main side effect was neutropenia. Classification of evidence: This trial provides Class I evidence that HU 20 mg/kg/day does not effectively treat SMA. Melioidosis (infection caused by Burkholderia pseudomallei) requires a prolonged course of oral antibiotics following initial intravenous therapy to reduce the risk of relapse after cessation of treatment. The current recommendation is a four-drug regimen (trimethoprim [TMP], sulfamethoxazole [SMX], doxycycline, and chloramphenicol) and a total treatment time of 12 to 20 weeks. Drug side effects are common; the aim of this study was to compare the efficacy and tolerance of the four-drug regimen with a three-drug regimen (TMP-SMX and doxycycline). An open-label, randomized trial was conducted in northeast Thailand. A total of 180 adult Thai patients were enrolled, of which 91 were allocated to the four-drug regimen and 89 to the three-drug regimen. The trial was terminated early due to poor drug tolerance, particularly of the four-drug regimen. The culture-confirmed relapse rates at 1 year were 6.6% and 5.6% for the four- and three-drug regimens, respectively (P = 0.79). The three-drug regimen was better tolerated than the four-drug regimen; 36% of patients receiving four drugs and 19% of patients receiving three drugs required a switch in therapy due to side effects (P = 0.01). The duration of oral therapy was significantly associated with relapse; after adjustment for confounders, patients receiving less than 12 weeks of oral therapy had a 5.7-fold increase of relapse or death. A combination of TMP-SMX and doxycycline is as effective as and better tolerated than the conventional four-drug regimen for the oral treatment phase of melioidosis. To determine if therapeutic management programmes for type 2 diabetes that include self-monitoring of blood glucose (SMBG) result in greater reductions in glycated haemoglobin (HbA1c) compared with programmes without SMBG in non-insulin requiring patients.
                Multicentre, randomized, parallel-group trial. A total of 610 patients were randomized to SMBG or non-SMBG groups. Patients in both groups received the same oral antidiabetic therapy using a gliclazide modified release (MR)-based regimen for 27 weeks. The primary efficacy end-point was the difference between groups in HbA1c at the end of observation.
                A total of 610 patients were randomized: 311 to the SMBG group and 299 to the non-SMBG group. HbA1c decreased from 8.12 to 6.95% in the SMBG group and from 8.12 to 7.20% in the non-SMBG group; between-group difference was 0.25% (95% CI: 0.06, 1.03; p = 0.0097). Symptoms suggestive of mild to moderate hypoglycaemia was the most commonly reported adverse event, reported by 27 (8.7%) and 21 (7.0%) patients in the SMBG and non-SMBG groups, respectively; the incidence of symptomatic hypoglycaemia was lower in the SMBG group.
                In patients with type 2 diabetes, the application of SMBG as an adjunct to oral antidiabetic agent therapy results in further reductions in HbA1c. A multicenter randomized study was conducted to compare the efficacy and safety of ofloxacin with that of trimethoprim/sulfamethoxazole (TMP/SMX) in the treatment of uncomplicated urinary tract infection in adults. Patients were randomized to receive either oral ofloxacin 200 mg daily for three days (102 patients), or oral TMP/SMX 160 mg/800 mg twice daily for seven days (100 patients). The pathogen was eradicated in 73 (97.3%) of the 75 evaluable patients receiving ofloxacin and in 66 (97.1%) of the 68 evaluable patients receiving TMP/SMX. The most frequently isolated pathogens were Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis. More urinary pathogens were susceptible to ofloxacin than to TMP/SMX, although this difference was not statistically significant. The clinical cure rate for patients receiving ofloxacin was 93.3%, with 4% improved and 2.7% failed. For patients receiving TMP/SMX, the clinical cure rate was 86.4%, with 12.1% improved and 1.5% failed. Side effects were reported by 29.7% of the patients receiving ofloxacin and by 40.4% of the patients receiving TMP/SMX. Drug-related adverse experiences, as determined by the investigators, occurred in 5% of the ofloxacin patients and in 15.2% of the TMP/SMX patients, a statistically significant difference. No patients receiving ofloxacin, compared with three patients receiving TMP/SMX, discontinued therapy because of an adverse reaction. These results indicate that short-course ofloxacin is as effective as TMP/SMX in the treatment of uncomplicated urinary tract infection. Ofloxacin therapy is also better tolerated than TMP/SMX. The goal of this study was to compare the relative efficacy and cost of self-monitoring of blood glucose (SMBG) with routine urine testing in the management of patients with type II (non-insulin-dependent) diabetes mellitus not treated with insulin. Fifty-four patients with type II diabetes mellitus, not treated with insulin, who had inadequate glucose control on diet alone or diet and oral hypoglycemic agents were studied. Patients performed SMBG or urine glucose testing as part of a standardized treatment program that also included diet and exercise counseling. During the 6-mo study, both the urine-testing and SMBG groups showed similar improvement in glycemic control; within each group, there were significant improvements in fasting plasma glucose (reduction of 1.4 +/- 3.2 mM, P less than 0.03) and glycosylated hemoglobin (reduction of 2.0 +/- 3.4%, P less than 0.01) levels. Seventeen (31%) of 54 patients actually normalized their glycosylated hemoglobin values, 9 in the urine-testing group and 8 in the SMBG group. Comparisons between the urine-testing and SMBG groups showed no significant differences in mean fasting plasma glucose (P greater than 0.86), glycosylated hemoglobin (P greater than 0.95), or weight (P greater than 0.19). In patients with type II diabetes mellitus not treated with insulin, SMBG is no more effective, but is 8-12 times more expensive, than urine testing in facilitating improved glycemic control. Our results do not support widespread use of SMBG in diabetic patients not treated with insulin. Chancroid is linked to the spread of human immunodeficiency virus type 1 (HIV-1) in East Africa. Effective, easily administered therapy is a priority for the control of Haemophilus ducreyi. The efficacy of a single oral dose of fleroxacin, 400 mg, was compared to a 3-day oral course of trimethoprim-sulfamethoxazole (TMP-SMZ), 160/800 mg, twice daily for the treatment of chancroid in 98 HIV-1-seronegative men in Nairobi, Kenya. No differences were noted between the two groups with respect to demographic characteristics, sexual behavior, and clinical characteristics. Culture-proven failure occurred in 1 (3%) of 36 fleroxacin-treated patients and in 11 (30%) of 37 TMP-SMZ-treated patients (P = .005). Fleroxacin, as a single oral dose, is an effective treatment for culture-proven chancroid in patients who are HIV-1 seronegative. TMP-SMZ is no longer predictably effective due to the recent emergence of resistance to both sulfonamides and to trimethoprim.
No drug treatment for SMA type I has been proven to have significant efficacy.