The clinical profile of ibandronate as add‐on to calcitriol and calcium was studied in this double‐blind, placebo‐controlled trial of 129 renal transplant recipients with early stable renal function (≤ 28 days posttransplantation, GFR ≥ 30 mL/min). Patients were randomized to receive i.v. ibandronate 3 mg or i.v. placebo every 3 months for 12 months on top of oral calcitriol 0.25 mcg/day and calcium 500 mg b.i.d. At baseline, 10 weeks and 12 months bone mineral density (BMD) and biochemical markers of bone turnover were measured. The primary endpoint, relative change in BMD for the lumbar spine from baseline to 12 months was not different, +1.5% for ibandronate versus +0.5% for placebo (p = 0.28). Ibandronate demonstrated a significant improvement of BMD in total femur, +1.3% versus −0.5% (p = 0.01) and in the ultradistal radius, +0.6% versus −1.9% (p = 0.039). Bone formation markers were reduced by ibandronate, whereas the bone resorption marker, NTX, was reduced in both groups. Calcium and calcitriol supplementation alone showed an excellent efficacy and safety profile, virtually maintaining BMD without any loss over 12 months after renal transplantation, whereas adding ibandronate significantly improved BMD in total femur and ultradistal radius, and also suppressed biomarkers of bone turnover. Ibandronate was also well tolerated.

Background: OligoG is a low molecular-weight alginate oligosaccharide that improves the viscoelastic properties of cystic fibrosis (CF) mucus and disrupts biofilms, thereby potentiating the activity of antimicrobial agents. The efficacy of inhaled OligoG was evaluated in adult patients with CF.Methods: A randomised, double-blind, placebo-controlled multicentre crossover study was used to demonstrate safety and efficacy of inhaled dry powder OligoG. Subjects were randomly allocated to receive OligoG 1050 mg per day (10 capsules three times daily) or matching placebo for 28 days, with 28-day washout periods following each treatment period. The primary end-point was absolute change in percentage predicted forced expiratory volume in 1 s (FEV₁) at the end of 28-day treatment. The intention-to-treat (ITT) population (n=65) was defined as randomised to treatment with at least one administration of study medication and post-dosing evaluation.Results: In this study, 90 adult subjects were screened and 65 were randomised. Statistically significant improvement in FEV₁was not observed in the ITT population. Adverse events included nasopharyngitis, cough and pulmonary exacerbation. The number and proportions of patients with adverse events and serious adverse events were similar between OligoG and placebo group.Conclusions: Inhalation of OligoG-dry powder over 28 days was safe in adult CF subjects. Statistically significant improvement of FEV₁was not reached. The planned analyses did not indicate a significant treatment benefit with OligoG compared to placebo.Post hocexploratory analyses showed subgroup results that indicate that further studies of OligoG in this patient population are justified.

Cardiovascular complications are common in kidney transplant patients and calcification propensity of blood, measured as T50, is associated with cardiovascular outcomes. Paricalcitol supplementation affects calcium/phosphate homeostasis and may affect calcification propensity. To assess this hypothesis we measured T50 in kidney transplant recipients participating in a randomized study comparing paricalcitol versus no treatment during the first year after kidney transplantation. Stored serum samples from 76 kidney transplant recipients (paricalcitol n = 37, no treatment n = 39) were analyzed. Analyses were performed at inclusion (8 weeks after transplantation) and repeated one year after transplantation. There were no statistically significant differences in T50 between the paricalcitol and placebo groups, neither at baseline (p = 0.56) nor at 1 year (p = 0.61). Also, there were no significant changes in T50 over time in either group or when pooling all data (p < 0.20). In multivariate regression analysis, out of 16 potentially relevant covariates, comprising clinical and biochemical parameters, only plasma PTH and T50 at baseline were significantly correlated to T50 after one year. (p < 0.03 and p < 0.01, respectively). Calcium propensity measured as T50 score remained unchanged with paricalcitol treatment in kidney transplant recipients, and was not changed over time during the study period of one year. ClinicalTrials.gov, NCT01694160 , registered 23 September 2012.

Background. Trabecular bone score (TBS) is a new tool to assess trabecular bone microarchitecture based on standard dual-energy x-ray absorptiometry (DXA) of lumbar spine images. TBS may be important to assess bone quality and fracture susceptibility in kidney transplant recipients (KTRs). This study aimed to investigate the effect of different bone therapies on TBS in KTRs. Methods. We reanalyzed DXA scans to assess TBS in 121 de novo KTRs at baseline, 10 wk, and 1 y. This cohort, between 2007 and 2009, participated in a randomized, placebo-controlled trial evaluating the effect of ibandronate versus placebo in addition to vitamin D and calcium. Results. Although bone mineral density (BMD) Z scores showed a subtle decrease in the first weeks, TBS Z scores increased from baseline to 10 wk for both treatment groups, followed by a slight decline at 12 mo. When comparing treatment groups and adjusting for baseline TBS, there were no differences found in TBS at 12 mo (P = 0.419). Correlation between TBS and BMD at baseline was weak (Spearman’s ρ = 0.234, P = 0.010), and change in TBS was not correlated with changes in lumbar spine BMD in either of the groups (ρ = 0.003, P = 0.973). Conclusions. Treatment with ibandronate or vitamin D and calcium did not affect bone quality as measured by TBS in de novo KTRs, but TBS increased early, irrespective of intervention. Changes in TBS and BMD during the study period were not correlated, indicating that these measurements reflect different aspects of bone integrity. TBS may complement BMD assessment in identifying KTRs with a high fracture risk. Export

Purpose Evaluating the safety and tolerability of 5-FU-miR-15a (CR-001) in adults with relapsed or refractory acute myeloid leukemia (R/R AML) in a phase I dose-escalation study (EudraCT number: 2021-006332-46). Patients and Methods A standard 3+3 dose-escalation study design was employed. Patients received intravenous (IV) administrations of the synthetic double-stranded mimic of miR-15a (miRNA) CR-001 of 7.5 mg, 11.25 mg, 15 mg and 18.75 mg/administration, weekly dosing. Each patient was dosed on a single dose level. The formulation included a fixed dose of GMP-grade linear polyethyleneimine (PEI; α-Methyl-ω-hydroxy-poly[(iminioethylene)chloride]; Poly[imino(1,2-ethanediyl)]; CAS Number 26913-06-4; EC Number 608-018-6) as the excipient: 15 mg of PEI with 7.5 mg CR-001, and 20 mg of PEI with all higher dose levels. Glucose was added to stabilize the miRNA/PEI complexes. Biomarker analysis was performed using mass cytometry (CyTOF) on peripheral blood and bone marrow samples to quantify surface and intracellular protein expression at the single-cell level. Results A total of 11 patients with R/R AML (median age: 74 years; all classified as adverse risk per ELN 2022) received a cumulative 66 intravenous doses of CR-001 (range: 1–16 doses; median: 5) across the four dose levels. The treatment was well-tolerated. One patient demonstrated a partial clinical response, with resolution of extramedullary pericardial AML after four doses. Among the 10 evaluable patients, six achieved stable disease (SD) according to ELN criteria after four infusions. Single-cell profiling mass cytometry revealed molecular activity of CR-001 on known targets of miR-15a (e.g., BMI1, WEE1 and MCL-1) beginning at the lowest dose level (7.5 mg). Concurrently, an increase in BAX, a pro-apoptotic marker, was observed following treatment. Conclusions CR-001 was well tolerated and demonstrated biological activity as evidenced by target modulation and disease stabilization in R/R AML patients. Biological activity was observed starting at the lowest dose level (7.5 mg/administration), with initial signs of clinical efficacy at 11.25 mg per administration. This trial was closed prematurely due to funding constraints, however, based on these findings further development is warranted, possibly in therapy combinations.