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Long-Term Outcomes of Radical Radiation Therapy with Hypoxia Modification with Biomarker Discovery for Stratification: 10-Year Update of the BCON (Bladder Carbogen Nicotinamide) Phase 3 Randomized Trial (ISRCTN45938399).
Song, YP, Mistry, H, Irlam, J, Valentine, H, Yang, L, Lane, B, West, C, Choudhury, A, Hoskin, PJ
International journal of radiation oncology, biology, physics. 2021;(5):1407-1415
Abstract
PURPOSE Many muscle-invasive bladder cancers are hypoxic, which limits the efficacy of radiation therapy. Hypoxia modification using carbogen and nicotinamide has been tested in a phase 3 trial, Bladder Carbogen Nicotinamide. We present mature follow-up data with biomarker predictions of outcomes. METHODS AND MATERIALS Bladder Carbogen Nicotinamide is a prospective, phase 3, multicenter, randomized, 2-arm, nonblinded clinical trial. Participants were randomized to receive radical radiation therapy (RT; control arm) alone or with the addition of carbogen (98% O2; 2% CO2) and nicotinamide (CON). Patients with muscle-invasive or high-grade non-muscle invasive bladder cancer were included. Tumor tissue was collected at entry and was analyzed for tumor necrosis, hypoxia (24-gene signature), and basal and luminal tumor molecular subtypes. Overall survival (OS) and disease-free survival and relationships with biomarker status outcomes are analyzed using multivariable Cox regression and log-rank analysis. RESULTS We analyzed 333 patients with a median follow-up of 10.3 years. The 10-year OS rates were 30% (95% confidence interval [CI], 0.23-0.39) in RT + CON patients and 24% (95% CI, 0.18-0.33) in the RT-alone patients (hazard ratio [HR], 0.80; 95% CI, 0.61-1.04; P = .08). The greatest benefit from CON was seen in patients with tumor necrosis (n = 79; 5-year OS, 53% vs. 33% in patients without tumor necrosis; HR, 0.59; 95% CI, 0.36-0.99; P = .04). Cases with a high hypoxia gene score (n = 75) had a 5-year OS rate of 51%, compared to 34% for a low score (HR, 0.64; 95% CI, 0.38-1.08; P = .09); those with the basal molecular subtype (n = 70) had a 5-year OS rate of 58%, compared to 38% for those with the luminal subtype (HR, 0.58; 95% CI, 0.32-1.06; P = .08). CONCLUSIONS Although the improvement in long-term OS in the whole population is not statistically significant, patients selected by necrosis and high hypoxia gene score benefitted from hypoxia modification.
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Effects of Nicotinamide and Lanthanum Carbonate on Serum Phosphate and Fibroblast Growth Factor-23 in CKD: The COMBINE Trial.
Ix, JH, Isakova, T, Larive, B, Raphael, KL, Raj, DS, Cheung, AK, Sprague, SM, Fried, LF, Gassman, JJ, Middleton, JP, et al
Journal of the American Society of Nephrology : JASN. 2019;(6):1096-1108
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Abstract
BACKGROUND Higher serum phosphate and fibroblast growth factor-23 (FGF23) levels may be modifiable to prevent cardiovascular disease in CKD. Short-term studies have reported modest efficacy in phosphate and FGF23 reduction with intestinal phosphate binders in CKD. METHODS To investigate effects of lanthanum carbonate (LC; a phosphate binder) and/or nicotinamide (NAM; an inhibitor of active intestinal phosphate transport) on serum phosphate and FGF23 in stage 3b/4 CKD, we conducted a randomized trial among individuals with eGFR 20-45 ml/min per 1.73 m2 to NAM (750 mg twice daily) plus LC (1000 mg thrice daily), NAM plus LC placebo, LC plus NAM placebo, or double placebo for 12 months. Dual primary end points were change from baseline in serum phosphate and intact FGF23 concentrations. RESULTS Mean eGFR for the 205 participants was 32ml/min per 1.73 m2. At baseline, serum phosphate was 3.7 mg/dl and median FGF23 was 99 pg/ml (10th, 90th percentiles: 59, 205). Mean rates of change in phosphate increased slightly over 12 months in all groups and did not differ significantly across arms. Similarly, percent changes in FGF23 per 12 months increased for all arms except LC plus placebo, and did not differ significantly across arms. Gastrointestinal symptoms limited adherence. Adverse events rates were similar across arms. CONCLUSIONS LC and/or NAM treatment did not significantly lower serum phosphate or FGF23 in stage 3b/4 CKD over 12 months. Although these agents appeared safe, intestinal symptoms limited adherence. Reducing phosphate and FGF23 in nondialysis CKD will require new approaches.
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Efficacy and safety of nicotinamide in haemodialysis patients: the NICOREN study.
Lenglet, A, Liabeuf, S, El Esper, N, Brisset, S, Mansour, J, Lemaire-Hurtel, AS, Mary, A, Brazier, M, Kamel, S, Mentaverri, R, et al
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2017;(5):870-879
Abstract
BACKGROUND Nicotinamide (NAM) has been proposed as an alternative treatment to phosphate binders for hyperphosphataemia in chronic kidney disease. METHODS The NICOREN multicentre, open-label and randomized study was designed to examine non-inferiority and safety of NAM when compared with sevelamer (SEV) in chronic haemodialysis patients. One hundred patients were randomized to either NAM or SEV treatment for 24 weeks. Serum biochemistry and NAM's main metabolite, N -methyl-2-pyridone-5-carboxamide (2PY), were measured to assess compliance, efficacy and safety. RESULTS After 24 weeks, we observed a comparable decrease in serum phosphorus in the NAM and SEV treatment arms, from 2.1 ± 0.4 to 1.8 ± 0.5 and 2.3 ± 0.5 to 1.7 ± 0.5 mM (P = not significant), respectively. The criterion for non-inferiority was, however, not met due to a more limited number of patients being included than planned. Treatment discontinuation due to adverse events was 1.6 times higher in the NAM than in the SEV group with only 55% of study completers in the NAM arm versus 90% in the SEV arm. Thrombocytopenia was observed in four NAM-treated patients. Serum 2PY levels were comparable at baseline, but increased markedly in the NAM group, but not in the SEV group, at 24 weeks (P < 0.0001). CONCLUSIONS Thus, both drugs are equally effective in lowering serum phosphorus, but patients' tolerance of NAM was largely inferior to that of SEV. Extremely high 2PY levels may contribute to NAM's side effects.
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Oral nicotinamide reduces transepidermal water loss: a randomized controlled trial.
Chen, AC, Martin, AJ, Dalziell, RA, Halliday, GM, Damian, DL
The British journal of dermatology. 2016;(6):1363-1365
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[Performance evaluation of integrated cytoprotective therapy of different duration in patients with cerebral infarction].
Chichanovskaia, LV, Tsukurova, LA, Kovalenko, AL, Nazarov, MV, Lukin, DI, Rumiantseva, SA, Silina, EV, Stupin, VA, Nedorostkova, TIu, Kabaeva, EN, et al
Eksperimental'naia i klinicheskaia farmakologiia. 2015;(1):21-6
Abstract
The paper reviews the preliminary results of a multicenter randomized clinical research. The aim of the study was to determine the optimal duration of different types of energy-correction therapy. 99 case report forms of patients with cerebral infarction were reviewed with their prior envelope randomization into three groups. Patients in the first group (experimental group), consisting of 32 patients, as part of combined therapy received ascorbic acid (5% solution twice a day in a recommended dosage of 20 ml/day for 20 days); the second group (37 patients) received 10 ml of cytoflavin intravenously by drop infusion twice a day for 10 days; the third group received cytoflavin for 20 days (from day 1 to day 10 - 20 ml a day, from day 11 to day 20 - 10 ml a day). The average NIH scale score on admission was 14.9 ± 2.6. Prescription of cytoflavin came with average 1.7 - 1.8 time regression (p < 0.05) of the volumes of cerebral ischemia in the of cases of the 10- and 20-day courses of treatment, while there were no significant morphologic changes in the ascorbic acid group. These results correlated with the best dynamics and outcomes of the neurological and performance status of patients receiving cytoflavin. Despite the lack of significant general differences in the clinical and morphological data of the second and third groups, the patients with underlying grave medical condition in the 20-day cytoflavin group (with NIH score of 14-20 points on admission) tended to have improved neurologic status parameters in comparison with the experimental group and the 10-day cytoflavin group. These results attest to the advantages of personalized antioxidant energy-correction therapy.