Xevinapant or placebo plus chemoradiotherapy in locally advanced squamous cell carcinoma of the head and neck: TrilynX phase III study design.

Xevinapant is a first-in-class antagonist of inhibitor of apoptosis proteins, which enhances cancer cell sensitivity to chemotherapy and radiotherapy. In a phase II randomized study in patients with unresected locally advanced squamous cell carcinoma of the head and neck (LA SCCHN), xevinapant plus standard-of-care cisplatin-based chemoradiotherapy (CRT) showed superior efficacy versus placebo plus CRT. Here, we describe the design of TrilynX (NCT04459715), a randomized, double-blind, phase III study. In total, 700 patients with unresected LA SCCHN will be randomized 1:1 to receive xevinapant or placebo plus standard-of-care CRT followed by xevinapant monotherapy or placebo. The primary end point is event-free survival by blinded independent review committee. Secondary end points include progression-free survival, locoregional control, overall survival and safety.

Xevinapant is being developed as a new type of cancer treatment. Xevinapant works by enhancing the effects of chemotherapy and radiotherapy (chemoradiotherapy), which are standard anticancer treatments. Researchers are studying whether adding xevinapant to these treatments could be helpful for people with head and neck cancers that have not spread to other parts of the body and cannot be removed by surgery. In a study of 96 people with this disease, those treated with chemoradiotherapy plus xevinapant on average lived longer than people treated with chemoradiotherapy plus placebo (liquid that looked the same but did not contain any medicine). To confirm the results, researchers have started a larger study, called TrilynX, that will compare the same treatments in around 700 people worldwide. This study will show if adding xevinapant to chemoradiotherapy can help to keep the cancer from progressing, control symptoms better and help people live longer. Clinical trial registration: NCT04459715 (ClinicalTrials.gov).

Effect of slow-release ß-alanine tablets on absorption kinetics and paresthesia.

Oral ß-alanine (ßA) doses larger than 800 mg commonly result in unpleasant sensory symptoms (paresthesia). However, the association of form (pure vs. slow-release) with side-effects has not been fully described. The aim of this single-blinded, randomized three-arm clinical trial was to compare plasma kinetics and symptoms following ßA bolus administration in solution or in slow-release tablet form. Eleven healthy adults ingested 1.6 g of a pure ßA reference solution (REF), 1.6 g in slow-release ßA tablets (TAB) or a placebo (PLA) after an overnight fast. During the next 6 h, urinary and plasma ßA concentrations were measured and questionnaires about intensity, nature (pins and needles, itching, flushing, irritation, numbness, soreness), and spatial distribution of unusual sensations were filled in. TAB resulted in a smaller peak plasma concentration than REF (82 vs. 248 µmol L(-1), p<0.001), delayed time to peak (1.0 vs. 0.5 h, p<0.01) no difference in area under the curve, reduced loss in urine (202 vs. 663 µmol, p<0.0001), and improved retention (98.9 vs. 96.3%, p<0.001). Symptoms described as "pins and needles" were perceived rapidly on the skin of the arms and trunk after REF (Tmax=15 min) and their time course nearly mimicked plasma concentrations. Maximum intensity scores were weaker with TAB ("very low") than with REF ("low", p<0.001), while TAB and PLA did not differ with respect to side-effects. In summary, ingesting 1.6 g ßA in slow-release tablets rather than pure in solution results in slower absorption kinetics, improved whole body retention and sensory side-effects that cannot be differentiated from PLA.

Influence of the consumption pattern of magnesium from magnesium-rich mineral water on magnesium bioavailability.

It is generally considered that the absorption of Mg is inversely related to the ingested dose. The objective of the present study was to determine if the mode of administration (bolus v. consumption throughout the day) could influence Mg bioavailability from Mg-rich natural mineral water comparing the same nutritional Mg amount (126 mg). Using a 2 d cross-over design, twelve healthy men were asked to drink 1·5 litres Mg-rich mineral water either as 2 × 750 ml or 7 × 212 ml throughout the day. Two stable isotopes ((25)Mg and (26)Mg) were used to label the water in order to distinguish both regimens. Fractional apparent Mg absorption was determined by faecal monitoring and Mg retention was determined by measuring urinary excretion of Mg isotopes. Higher Mg absorption (50·7 (SD 12·7) v. 32·4 (SD 8·1) %; P = 0·0007) and retention (47·5 (SD 12·9) v. 29·0 (SD 7·5) %; P = 0·0008) from Mg-rich mineral water were observed when it was consumed in seven servings compared with larger servings. Thus, regular water consumption throughout the day is an effective way to increase Mg bioavailability from Mg-rich mineral water.

Absorption, conjugation and excretion of the flavanones, naringenin and hesperetin from alpha-rhamnosidase-treated orange juice in human subjects.

We have determined the absorption, conjugation and excretion of naringenin-7-O-rutinoside (narirutin) compared to the corresponding glucoside in an orange juice matrix in human subjects. Healthy volunteers (eight men and eight women), in a double blind, randomised, crossover study, consumed orange juice with (1) natural content of naringenin-7-O-rutinoside; (2) alpha-rhamnosidase-treated to yield naringenin-7-O-glucoside. Blood was sampled at twelve time points and three fractions of urine were collected over 24 h. The area under the plasma-time curve of naringenin from (2) alpha-rhamnosidase-treated orange juice was increased about 4-fold (P < 0.0001), peak plasma concentration (Cmax) was 5.4-fold higher (P < 0.0001) and Tmax was decreased from 311 to 92 min (P = 0.002) compared to untreated orange juice (1), indicating a change in absorption site from the colon to the small intestine. Furthermore, the amount in urine was increased from 7 to 47 % (P < 0.0001) of the dose after consumption of the alpha-rhamnosidase-treated orange juice (2). All urine samples contained both naringenin-7- and -4'-O-glucuronides. In addition, to examine the effect of dose and alpha-rhamnosidase treatment on hesperetin conjugate profiles, a further treatment where (3) orange juice fortified with three times the original content of hesperetin-7-O-rutinoside was used. Five hesperetin metabolites (3'-O-glucuronide; 7-O-glucuronide; 5,7-O-diglucuronide; 3',7-O-diglucuronide; 3'-O-sulphate) were present after all treatments (1-3), with the same profile of the conjugates. The present data show that bioavailability of naringenin is increased by conversion from rutinoside to glucoside, but the profile of the conjugates of flavanones formed and excreted in urine is neither affected by the absorption site nor by a 3-fold change in dose.

Antisense oligonucleotide eluforsen is safe and improves respiratory symptoms in F508DEL cystic fibrosis.

BACKGROUND: Eluforsen is an antisense oligonucleotide designed to bind to the mRNA region around the F508-encoding deletion and restore the cystic fibrosis transmembrane conductance regulator (CFTR) protein function in the airway epithelium. We assessed the safety and tolerability, pharmacokinetics and exploratory measures of efficacy of inhaled eluforsen in cystic fibrosis (CF) patients homozygous for the F508del-CFTR mutation. METHODS: This randomised, double-blind, placebo-controlled, dose escalation 1b study recruited adult CF subjects with a FEV1 > 70% predicted in four single ascending dose cohorts and four multiple ascending dose cohorts. Primary objectives were safety and tolerability. Secondary endpoints included pharmacokinetics, percent predicted forced expiratory volume in 1 s (ppFEV1), and Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Symptom Score (RSS). RESULTS: Single and multiple doses of inhaled eluforsen up to 50 mg were safe and well tolerated. A maximum tolerated dose was not established. Systemic exposure was low in all cohorts and lung function remained stable throughout the study. Three of four eluforsen-treated groups in the MAD study demonstrated an improvement in CFQ-R RSS at end of treatment with adjusted mean change from baseline values ranging from 6.4 to 12.7 points. In comparison, there was a mean decrease of 6.5 points in the placebo group from baseline to end of treatment. CONCLUSIONS: Inhaled eluforsen up to 50 mg dosed 3 times per week for 4 weeks was safe and well tolerated, showed low systemic exposure, and demonstrated improvement in CFQ-R RSS, a relevant measure of clinical benefit in CF patients.

Antisense oligonucleotide eluforsen improves CFTR function in F508del cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. In this study we assessed the effect of antisense oligonucleotide eluforsen on CFTR biological activity measured by Nasal Potential Difference (NPD) in patients with the most common mutation, F508del-CFTR. METHODS: This multi-centre, exploratory, open-label study recruited adults with CF homozygous or compound heterozygous for the F508del-CFTR mutation. Subjects received intranasal eluforsen three times weekly for 4 weeks. The primary endpoint was the within-subject change from baseline in total chloride transport (Cl-free+iso), as assessed by NPD. Secondary endpoints included within-subject change from baseline in sodium transport. RESULTS: In the homozygous cohort (n = 7; per-protocol population), mean change (90% confidence interval) in Cl-free+iso was -3.0 mV (-6.6; 0.6) at day 15, -4.1 mV (-7.8; -0.4, p = .04) at day 26 (end of treatment) and - 3.7 mV (-8.0; 0.6) at day 47. This was supported by improved sodium transport as assessed by an increase in average basal potential difference at day 26 of +9.4 mV (1.1; 17.7, p = .04). The compound heterozygous cohort (n = 7) did not show improved chloride or sodium transport NPD values. Eluforsen was well tolerated with a favourable safety profile. CONCLUSIONS: In F508del-CFTR homozygous subjects, repeated intranasal administration of eluforsen improved CFTR activity as measured by NPD, an encouraging indicator of biological activity.

Improved growth of toddlers fed a milk containing synbiotics.

Bifidobacterium longum (BL999), Lactobacillus rhamonosus (LPR), prebiotics (inulin and fructo-oligosaccharides), and long-chain polyunsaturated fatty acids (LCPUFA) are believed to have health benefits. In a randomized, double-blind, controlled trial we compared growth and development of toddlers fed milk containing synbiotics (BL999, LPR, and prebiotics) and LCPUFA or a control milk. Three hundred and ninety three healthy, 12 month-old toddlers were fed approximately 400 mL/day for 12 months. Anthropometric measurements were taken at 12, 14, and 16 months. Toddlers' response to measles and hepatitis A vaccine was measured at 16 months, and Bayley scale for motor, cognitive, and behavioral functions made at 24 months. The primary outcome was weight gain between 12 and 16 months. Secondary outcomes were gain in length, head circumference, and body mass index, gastrointestinal tolerance (stool characteristics), stool bacterial counts, safety, anti-vaccine IgG, and neurodevelopment. Weight gain was greater in the synbiotics group (mean±SD, 7.57±4.13 g/day) compared with the control group (6.64±4.08 g/day). The difference of 0.93 g/day (with a 95% confidence interval of 0.12 to 1.75) is significant (p=0.025). The gain in the synbiotics group resulted in a change in z-score weight-for-age closer to WHO Child Growth Standard. There was a significant increase in lactobacilli and enterococci counts between 12 months and 16 months in the synbiotic group. We conclude that in healthy toddlers milk containing synbiotics and LCPUFA provides better growth and promotes favorable gut colonization, as shown by higher Lactobacillus counts.