Fluconazole in hypercalciuric patients with increased 1,25(OH)2D levels: the prospective, randomized, placebo-controlled, double-blind FLUCOLITH trial.

BACKGROUND: Hypercalciuria is one of the most frequent metabolic disorders associated with nephrolithiasis and/or nephrocalcinosis possibly leading to chronic kidney disease (CKD) and bone complications in adults. Orphan diseases with different underlying primary pathophysiology share inappropriately increased 1,25(OH)2D levels and hypercalciuria, e.g., hypersensitivity to vitamin D and renal phosphate wasting. Their management is challenging, typically based on hyperhydration and dietary advice. The antifungal azoles are known to inhibit the 1α-hydroxylase and therefore decrease 1,25(OH)2D levels; they are commonly used, with well described pharmacokinetic and tolerability data. Fluconazole has been successfully reported to reduce calciuria in patients with CYP24A1 or SLC34A3 mutations, with no safety warnings. Thus, based on these case reports, we hypothesize that fluconazole is effective to decrease and normalize calciuria in patients with hypercalciuria and increased 1,25(OH)2D levels. METHODS: The FLUCOLITH trial is a prospective, interventional, randomized in parallel groups (1:1), placebo-controlled, double-blind trial. A total of 60 patients (10-60 years) with nephrolithiasis and/or nephrocalcinosis history, hypercalciuria (> 0.1 mmol/kg/day), increased 1,25(OH)2D levels (> 150 pmol/L), and 25-OH-D levels >20 nmol/L will be included. Inclusions will be performed only from mid-September to the beginning of February to avoid bias due to sunlight-induced vitamin D synthesis. The primary endpoint will be the proportion of patients with normalization of 24-h calciuria between baseline and 16 weeks, or with a relative decrease of at least 30% of 24-h calciuria in patients who still display at W16 a 24-h hypercalciuria. DISCUSSION: The current challenge is to propose an efficient treatment to patients with hypercalciuria and increased 1,25(OH)2D levels in order to prevent later complications and notably CKD that can ultimately lead to end-stage renal disease. Based on improvement of knowledge in phosphate/calcium metabolism, pathophysiology and genetics, the "off-label" use of fluconazole was recently reported to be useful in hypercalciuric patients with increased 1,25(OH)2D levels. Thus, the FLUCOLITH study is a unique opportunity to develop a new indication of a well-known and not expensive drug in orphan renal diseases, the ultimate objective being the secondary prevention of CKD worsening in these patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT04495608 . Registered on July 23, 2020.

Adherence to cysteamine in nephropathic cystinosis: A unique electronic monitoring experience for a better understanding. A prospective cohort study: CrYSTobs.

INTRODUCTION: In nephropathic cystinosis (NC), adherence to cysteamine remains challenging; poor adherence is worsening the disease progression with a decline of kidney function and increase of extrarenal morbidities. Our objective was to describe adherence to cysteamine in NC patients, using electronic monitoring systems. METHODS: Patients with confirmed NC, aged > 4 years and receiving oral cysteamine (short acting or delayed release formulation as standard of care) from 3 French reference centers, were included. Adherence to treatment was primarily assessed as the percentage of days with a good adherence score, adherence score rating from 0 (poor) to 2 (good). A descriptive analysis was performed after 1-year follow-up. RESULTS: Seventeen patients (10 girls, median age: 13.9 (5.4-33.0) years) were included. Median age at diagnosis was 17.0 (3.0-76.9) months and age at start of cysteamine was 21.0 (15.5-116.3) months. Median daily dose of cysteamine was 1.05 (0.55-1.63) g/m2/day. Over the year, the median percentage of days with a good adherence score was 80 (1-99)% decreasing to 68 (1-99)% in patients > 11 years old. The median of average number of hours covered by treatment in a day was 22.5 (6.1-23.9) versus 14.9 (9.2-20.5) hours for delayed release versus short acting cysteamine. CONCLUSION: Our data are the first describing a rather good adherence to cysteamine, decreasing in adolescents and adults. We described a potential interest of the delayed release formulation. Our data highlight the need for a multidisciplinary approach including therapeutic education and individualized approaches in NC patients transitioning to adulthood. Graphical abstract.

Patterns of hip migration in non-ambulant children with cerebral palsy: A prospective cohort study.

BACKGROUND: In children with cerebral palsy (CP), we have little information on when hip migration (HM) starts, what causes hip displacement, how HM changes over time, and how to halt this migration to avoid surgery. OBJECTIVES: We aimed to estimate the prevalence of HM percentage (HMP)>40% in a homogeneous population of non-ambulant children with CP and model the changes in HMP over a 2.6-year mean follow-up. METHODS: From September 2009 to September 2015, this observational, prospective, multicenter cohort study recruited 235 children from 51 centers who were 3 to 10 years old and had levels IV and V of the Gross Motor Function Classification System for CP. The outcomes were yearly HMP measurements by the Reimers index. Only children with at least one hip with HMP≤40% at baseline were included in trajectory modeling. Comparisons of chidren's characteristics between trajectory groups were adjusted by the false discovery rate method. RESULTS: The prevalence of children with at least one hip with HMP>40% was estimated at 24.3% (95% confidence interval 18.6-30.0). Pelvic obliquity was observed in 51.4% and 24.4% of children with asymmetric and symmetric HMP (P=0.002). The trajectory modelling identified 3 types of MP changes over time. Many children (67.4% and 79.3% for the right and left hip) could be assigned to the "stable" trajectory group. CONCLUSIONS: In non-ambulant children with CP, the prevalence of HM requiring surgery is low and most hips remain practically stable over time.

A double-blind placebo-controlled randomised trial of omega-3 supplementation in children with moderate ADHD symptoms.

OBJECTIVE: Clinical trials and inconclusive meta-analyses have investigated the effects of omega-3 supplements in children with Attention-Deficit Hyperactivity Disorder (ADHD). We performed a randomised placebo-controlled trial to evaluate the efficacy of omega-3 fatty acids. METHODS: Children aged 6-15 years with established diagnosis of ADHD were randomised 1:1 to receive either supplements containing docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) or a placebo for 3 months. Psychotropic or omega-3-containing treatments were not authorised during the study. The primary outcome was the change in the Attention-Deficit Hyperactivity Disorder Rating Scale version 4 (ADHD-RS-IV). Other outcomes included safety, lexical level (Alouette test), attention (Test of Attentional Performance for Children-KiTAP), anxiety (48-item Conners Parent Rating Scale-Revised-CPRS-R), and depression (Children's Depression Inventory-CDI). RESULTS: Between 2009 and 2011, 162 children were included in five French child psychiatry centres. The mean age was 9.90 (SD 2.62) years and 78.4% were boys. The inclusion ADHD-RS-IV at was 37.31 (SD 8.40). The total ADHD-RS-IV score reduction was greater in the placebo group than in the DHA-EPA group: -19 (-26, -12)  % and -9.7 (-16.6, -2.9) %, respectively, p = 0.039. The other components of the Conners score had a similar variation but the differences between groups were not significant. Two patients in the DHA-EPA group and none in the placebo group experienced a severe adverse event (hospitalisation for worsening ADHD symptoms). CONCLUSION: This study did not show any beneficial effect of omega-3 supplement in children with mild ADHD symptoms.

Management of adolescents with very poorly controlled type 1 diabetes by nurses: a parallel group randomized controlled trial.

BACKGROUNDS: Fluctuation in glycemia due to hormonal changes, growth periods, physical activity, and emotions make diabetes management difficult during adolescence. Our objective was to show that a close control of patients' self-management of diabetes by nurse-counseling could probably improve metabolic control in adolescents with type 1 diabetes. METHODS: We designed a multicenter, randomized controlled, parallel group, clinical trial. Seventy seven adolescents aged 12-17 years with A1C >8% were assigned to either an intervention group (pediatrician visit every 3 months + nurse visit and phone calls) or to the control group (pediatrician visit every 3 months). The primary outcome was the evolution of the rate of A1C during the 12 months of follow-up. Secondary outcomes include patient's acceptance of the disease (evaluated by visual analog scale), the number of hypoglycemic or ketoacidosis episodes requiring hospitalization, and evaluation of A1C rate over time in each group. RESULTS: Seventy-seven patients were enrolled by 10 clinical centers. Seventy (89.6%) completed the study, the evolution of A1C and participants satisfaction over the follow-up period was not significantly influenced by the nurse intervention. CONCLUSION: Nurse-led intervention to improve A1C did not show a significant benefit in adolescents with type 1 diabetes because of lack of power. Only psychological management and continuous glucose monitoring have shown, so far, a slight but significant benefit on A1C. We did not show improvements in A1C control in teenagers by nurse-led intervention. TRIAL REGISTRATION: Clinical Trials.gov registration number: NCT00308256, 28 March 2006.