Efficacy and tolerability of a prolonged release ferrous sulphate formulation in iron deficiency anaemia: a non-inferiority controlled trial.

BACKGROUND: Iron deficiency anaemia (IDA) is the last stage of iron deficiency, consecutive to an imbalance between iron supply through food intake and iron loss through physiological or pathological processes. As well as by haemoglobin levels, IDA is diagnosed by measuring biomarkers of iron stores. Women are most affected by IDA since their teenage years, as menstruation constitutes a chronic iron loss. Oral supplementation with ferrous sulphate is an effective therapy, but gastrointestinal side effects may impair treatment compliance. METHODS: The present multicentric randomised controlled trial was designed to assess the non-inferiority of a ferrous sulphate prolonged release formulation called V0355 with the referential ferrous sulphate Ferrograd® in a population of Italian women aged 18-50 years diagnosed for IDA. Three hundred and ninety-nine patients were randomised to receive V0355 (80 mg Fe/day) or Ferrograd® (105 mg Fe/day). RESULTS: After 12 weeks of treatment, the difference in the mean haemoglobin level between the two groups was 0.081 g/dL ([-2.986;1.361], p = 0.54), which confirmed the hypothesis of non-inferiority. All the other biochemical parameters (serum iron, serum ferritin, transferrin, and soluble transferrin receptor) and haematological parameters (erythrocytes count, reticulocytes count, haematocrit, and mean corpuscular volume), as well as patient's anaemia-related symptoms, were not different between treatment groups throughout the study. Furthermore, the incidence of gastrointestinal adverse events of moderate and severe intensity was significantly lower (p = 0.007) in the V0355 group (5.6%) than in the Ferrograd® group (13.9%). CONCLUSION: V0355 was as efficient as Ferrograd® in the treatment of anaemia and exhibited a better gastrointestinal tolerance profile.

Effects of iron supplementation on attention deficit hyperactivity disorder in children.

Iron deficiency has been suggested as a possible contributing cause of attention deficit hyperactivity disorder (ADHD) in children. This present study examined the effects of iron supplementation on ADHD in children. Twenty-three nonanemic children (aged 5-8 years) with serum ferritin levels <30 ng/mL who met DSM-IV criteria for ADHD were randomized (3:1 ratio) to either oral iron (ferrous sulfate, 80 mg/day, n = 18) or placebo (n = 5) for 12 weeks. There was a progressive significant decrease in the ADHD Rating Scale after 12 weeks on iron (-11.0 +/- 13.9; P < 0.008), but not on placebo (3.0 +/- 5.7; P = 0.308). Improvement on Conners' Parent Rating Scale (P = 0.055) and Conners' Teacher Rating Scale (P = 0.076) with iron supplementation therapy failed to reach significance. The mean Clinical Global Impression-Severity significantly decreased at 12 weeks (P < 0.01) with iron, without change in the placebo group. Iron supplementation (80 mg/day) appeared to improve ADHD symptoms in children with low serum ferritin levels suggesting a need for future investigations with larger controlled trials. Iron therapy was well tolerated and effectiveness is comparable to stimulants.

Efficacy of Propranolol Between 6 and 12 Months of Age in High-Risk Infantile Hemangioma.

BACKGROUND AND OBJECTIVES: There is no consensus on optimal treatment duration for propranolol in infantile hemangioma (IH). We evaluated the efficacy and safety of oral propranolol solution administered for a minimum of 6 months up to a maximum of 12 months of age in high-risk IH. METHODS: This single-arm, open-label, phase 3 study was conducted in patients aged 35 to 150 days with high-risk IH in 10 hospitals between 2015 and 2017. The study comprised a 6-month initial treatment period (ITP) plus continuation up to 12 months of age if complete success was not achieved, a follow-up, and a retreatment period. Patients received oral propranolol twice daily (3 mg/kg per day). The primary end point was the success rate at the end of the ITP. Furthermore, the persistence of IH response and efficacy of retreatment was evaluated. RESULTS: The success rate after 6 months of treatment was 47%, increasing to 76% at the end of the ITP. Of the patients who achieved success, 68% sustained success for 3 months without treatment, and 24% required retreatment. Of the 8 patients who were retreated, 7 achieved success. Adverse events, reported by 80% of patients, were mild, which were expected in this population or known propranolol side effects. CONCLUSIONS: Oral propranolol administered beyond 6 months and up to 12 months of age meaningfully increases the success rate in high-risk IH. Success was sustained in most patients up to 3 months after stopping treatment. Retreatment was efficacious, and the safety profile satisfactory.

Comparative efficacy and safety study of two chondroitin sulfate preparations from different origin (avian and bovine) in symptomatic osteoarthritis of the knee.

INTRODUCTION: Some argued that clinical efficacy of Chondroitin Sulfate (CS) could vary upon the product origin. The objective of this trial is to compare the effect of 2 CS medicinal products from different origin: Structum(®) (avian, 1000mg/day) and Chondrosulf(®) (bovine, 1200mg/day). METHODS: This was a randomized, double-blind, double placebo, active-controlled, parallel-group study using a non-inferiority design. Symptomatic osteoarthritis of the knee patients, according to American College of Rheumatology criteria, aged 50-80 years received either Structum(®) (500mg BID) or Chondrosulf(®) (400mg TID) during 24 weeks. Inclusion criteria were: global pain in the target knee ≥ 40mm on a Visual Analog Scale (VAS 0-100), a Lequesne's Algofunctional Index (LFI) score ≥ 7 (range: 0-24) and a radiological Kellgren-Lawrence grade 2 or 3. Primary outcome was the mean change over 24 weeks of pain VAS and LFI score. Secondary outcomes were patient's and physician's global assessments, Outcome Measures in Rheumatology Clinical Trials and Osteoarthritis Research Society International responders rate, analgesics intake and Medical Outcomes Survey Short-Form 12 (SF-12). Safety was assessed by recording adverse events. A non-inferiority test was performed on the Structum(®)-Chondrosulf(®) difference for VAS and LFI score changes. Predefined non inferiority limit was settled as the lower limit of the 95% CI above -5mm and -1pt for pain VAS and LFI score respectively. RESULTS: 837 patients were randomized: 817 available for the full analysis dataset (FAS), 692 for the per protocol (PP) analysis. No statistical and clinical differences were observed for demographics and disease characteristics between the 2 groups. PP analysis showed no difference between groups on mean variations of pain VAS or LFI scores over 24 weeks. Mean Pain VAS decreased by 23.9mm (17.5) in Structum(®) group and 23.8mm (17.2) in Chondrosulf(®) group (difference: 0.012 [CI95%: -2.6 ; 2.6]). Mean LFI score decreased by 3.2 (2.4) and 3.1 (2.4) respectively (difference: 0.139 [CI95%: -0.2 ; 0.5]). The lower limits of the 2 CI were above predefined non inferiority margin, which demonstrated the non inferiority of Structum(®) in comparison with Chondrosulf(®). FAS analysis gave similar results. Secondary efficacy outcomes analysis showed the same trends. Responders rate were 76.3% and 73.8% respectively (PP, W24). Treatments were well tolerated: 2.4% in Structum(®) group and 4.5% in Chondrosulf(®) group withdrew from the study for safety reasons. CONCLUSION: Structum(®) and Chondrosulf(®) were equally effective in reducing functional impairment and relieving pain over 6 months in knee osteoarthritis patients, without any safety concerns. TRIAL REGISTRATION: http://www.controlled-trials.com Number: ISRCTN04305346.

Effect of six months of treatment with V0191 in patients with suspected prodromal Alzheimer's disease.

New criteria related to prodromal Alzheimer's disease (AD) have been proposed to overcome the issue of heterogeneity of patients with mild cognitive impairment (MCI) and to better define patients in early stage AD. Only few therapeutic trials, if any, have been reported using this newly defined population. The objective of this study was to assess the clinical efficacy and safety of a novel pro-cholinergic drug (V0191) in patients with prodromal AD. Two hundred forty two (242) patients with a diagnosis of prodromal AD were randomized in an approximately 1 : 1 ratio to receive either 1500 mg V0191 or matching placebo once daily for 24 weeks. Changes in global cognitive functioning were assessed using the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog; responder rate as primary efficacy measure). Standardized measures of memory, executive function, attention, functional capacity, and apathy were also obtained. Despite some interesting trends at week 12 and conversion rates favoring V0191, no statistically significant differences in cognitive function between V0191 and placebo were noted. In addition to the absence of drug efficacy on this population, several design features may have hindered this study, including insufficient powering to assess changes in cognition over time, a relatively short duration of treatment, and the lack of validated clinical trial measures designed to assess the prodromal AD population. Lessons learned in AD study design optimization, including those presented in this paper, could be valuable for further investigation with pro-cholinergic drugs such as V0191.

Effects of dimethylaminoethanol pyroglutamate (DMAE p-Glu) against memory deficits induced by scopolamine: evidence from preclinical and clinical studies.

RATIONALE: Dimethylaminoethanol pyroglutamate (DMAE p-Glu) is a compound resulting from the reaction between dimethylaminoethanol (an indirect precursor of acetylcholine) and pyroglutamic acid (a cyclic derivative of glutamic acid having procholinergic properties and promnesic effects in both animals and man). OBJECTIVES: The present study undertook preclinical and clinical evaluations to test a potential therapeutic utility for DMAE p-Glu in cognitive impairments related to central cholinergic deficit. MATERIALS AND METHODS: In preclinical study, DMAE p-Glu was studied in rats by intracerebral microdialysis in conscious freely moving animals, on performance of rats in the Morris water maze test of spatial memory, and on the deficit in passive avoidance behavior induced by scopolamine. The clinical study examined the effect of DMAE p-Glu on cognitive deficits induced by an intravenous injection of scopolamine in healthy young male subjects. RESULTS: In rat experiments, DMAE p-Glu increased the extracellular levels of choline and acetylcholine in the medial prefrontal cortex, as assessed by intracerebral microdialysis, improved performance in a test of spatial memory, and reduced scopolamine-induced memory deficit in passive avoidance behavior. Clinical study results show that scopolamine induced a memory deficit and that DMAE p-Glu produced a significant positive effect on scores in the Buschke test, as well as a slight but significant difference on choice reaction time. CONCLUSION: These results indicate that DMAE p-Glu reduces the deleterious effect of scopolamine on long-term memory in healthy volunteers and suggest that DMAE p-Glu might be effective in reducing memory deficits in patients with cognitive impairment.

Effect of chondroitin sulphate in symptomatic knee osteoarthritis: a multicentre, randomised, double-blind, placebo-controlled study.

OBJECTIVE: To evaluate the efficacy and tolerability of chondroitin sulphate (chondroitin sulphate) in knee osteoarthritis. PATIENTS AND METHODS: A 24-week, randomised placebo-controlled trial of chondroitin sulphate (1 g/day) in patients with symptomatic knee osteoarthritis as measured on a visual analogue scale. Pain on daily activities and Lequesne's Index were the primary efficacy criteria. Secondary outcomes included the rate of responders according to the outcome measures in rheumatoid arthritis clinical trials of the Osteoarthritis Research Society International (OMERACT-OARSI) criteria, quality of life, patient's/physician's global assessments and carry-over effect after treatment. Biochemical markers of bone (CTX-I), cartilage (CTX-II) and synovium (hyaluronic acid) metabolism were also measured. Safety was assessed by recording adverse events (AEs). Statistical analysis was performed on the inter-group differences in the intention-to-treat population. RESULTS: 307 patients were included in the study. 28 (9%) patients discontinued the study because of lack of efficacy or AEs. At the end of treatment, the decrease in pain was -26.2 (24.9) and -19.9 (23.5) mm and improved function was -2.4 (3.4) (-25%) and -1.7 (3.3) (-17%) in the chondroitin sulphate and placebo groups, respectively (p = 0.029 and 0.109). The OMERACT-OARSI responder rate was 68% in the chondroitin sulphate and 56% in the placebo group (p = 0.03). The investigator's assessments and short form 12 (SF-12) physical component reported improvement more frequently in the chondroitin sulphate than in the placebo group (p = 0.044 and 0.021, respectively). No significant difference was observed between treatment groups for changes in biomarkers over 24 weeks. However, there was a significant difference between non-responders and responders according to the OARSI criteria for 24-week changes of CTX-I (p = 0.018) and CTX-II (p = 0.014). Tolerance was considered to be satisfactory. CONCLUSION: This study failed to show an efficacy of chondroitin sulphate on the two primary criteria considered together, although chondroitin sulphate was slightly more effective than placebo on pain, OMERACT-OARSI response rate, investigator's assessment and quality of life.