scholarly journals An open label, adaptive, phase 1 trial of high‐dose oral nitazoxanide in healthy volunteers: an antiviral candidate for SARS‐CoV‐2

2021 ◽  
Author(s):  
Lauren E Walker ◽  
Richard FitzGerald ◽  
Geoffrey Saunders ◽  
Rebecca Lyon ◽  
Michael Fisher ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Phase 1 ◽  
High Dose ◽  
Open Label ◽  
Phase 1 Trial ◽  
Dose Oral

scholarly journals An open label, adaptive, phase 1 trial of high-dose oral nitazoxanide in healthy volunteers: an antiviral candidate for SARS-CoV-2

2021 ◽  
Author(s):  
Lauren E Walker ◽  
Richard FitzGerald ◽  
Geoffrey Saunders ◽  
Rebecca Lyon ◽  
Michael Fisher ◽  
...  
Keyword(s):  
Phase 1 ◽  
Optimum Dose ◽  
Drug Discontinuation ◽  
High Dose ◽  
Open Label ◽  
Pbpk Modelling ◽  
Health Crisis ◽  
Phase 1 Trial

AbstractRepurposing approved drugs may rapidly establish effective interventions during a public health crisis. This has yielded immunomodulatory treatments for severe COVID-19, but repurposed antivirals have not been successful to date because of redundancy of the target in vivo or suboptimal exposures at studied doses. Nitazoxanide is an FDA approved antiparasitic medicine, that physiologically-based pharmacokinetic (PBPK) modelling has indicated may provide antiviral concentrations across the dosing interval, when repurposed at higher than approved doses. Within the AGILE trial platform (NCT04746183) an open label, adaptive, phase 1 trial in healthy adult participants was undertaken with high dose nitazoxanide. Participants received 1500mg nitazoxanide orally twice-daily with food for 7 days. Primary outcomes were safety, tolerability, optimum dose and schedule. Intensive pharmacokinetic sampling was undertaken day 1 and 5 with Cmin sampling on day 3 and 7. Fourteen healthy participants were enrolled between 18th February and 11th May 2021. All 14 doses were completed by 10/14 participants. Nitazoxanide was safe and well tolerated with no significant adverse events. Moderate gastrointestinal disturbance (loose stools) occurred in 8 participants (57.1%), with urine and sclera discolouration in 12 (85.7%) and 9 (64.3%) participants, respectively, without clinically significant bilirubin elevation. This was self-limiting and resolved upon drug discontinuation. PBPK predictions were confirmed on day 1 but with underprediction at day 5. Median Cmin was above the in vitro target concentration on first dose and maintained throughout. Nitazoxanide administered at 1500mg BID with food was safe and well tolerated and a phase 1b/2a study is now being initiated in COVID-19 patients.

scholarly journals High-dose oral and intravenous rifampicin for the treatment of tuberculous meningitis in predominantly HIV-positive Ugandan adults: a phase II open-label randomised controlled trial

2021 ◽  
Author(s):  
Fiona V Cresswell ◽  
David B Meya ◽  
Enock Kagimu ◽  
Daniel Grint ◽  
Lindsey te Brake ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Tuberculous Meningitis ◽  
Geometric Mean ◽  
Standard Of Care ◽  
Hiv Positive ◽  
High Dose ◽  
Open Label ◽  
Dose Oral ◽  
Csf Levels

Abstract Background High-dose rifampicin may improve outcomes of tuberculous meningitis (TBM). Little safety or pharmacokinetic (PK) data exist on high-dose rifampicin in HIV co-infection, and no cerebrospinal fluid (CSF) PK data exist from Africa. We hypothesized that high-dose rifampicin would increase serum and CSF concentrations without excess toxicity. Methods In this phase II open-label trial, Ugandan adults with suspected TBM were randomised to standard-of-care control (PO-10, rifampicin 10mg/kg/day), intravenous rifampicin (IV-20, 20mg/kg/day), or high-dose oral rifampicin (PO-35, 35mg/kg/day). We performed PK sampling on day 2 and 14. The primary outcomes were total exposure (AUC0-24), maximum concentration (Cmax), CSF concentration and grade 3-5 adverse events. Results We enrolled 61 adults, 92% were HIV-positive, median CD4 count was 50cells/µL (IQR 46–56). On day 2, geometric mean plasma AUC0-24hr was 42.9h.mg/L with standard-of-care 10mg/kg dosing, 249h.mg/L for IV-20 and 327h.mg/L for PO-35 (P<0.001). In CSF, standard-of-care achieved undetectable rifampicin concentration in 56% of participants and geometric mean AUC0-24hr 0.27mg/L, compared with 1.74mg/L (95%CI 1.2–2.5) for IV-20 and 2.17mg/L (1.6–2.9) for PO-35 regimens (p<0.001). Achieving CSF concentrations above rifampicin minimal inhibitory concentration (MIC) occurred in 11% (2/18) of standard-of-care, 93% (14/15) of IV-20, and 95% (18/19) of PO-35 participants. Higher serum and CSF levels were sustained at day 14. Adverse events did not differ by dose (p=0.34) Conclusion Current international guidelines result in sub-therapeutic CSF rifampicin concentration for 89% of Ugandan TBM patients. High-dose intravenous and oral rifampicin were safe, and respectively resulted in exposures ~6- and ~8-fold higher than standard-of-care, and CSF levels above the MIC

Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial

2020 ◽  
Vol 21 (7) ◽  
pp. 935-946 ◽  
Author(s):  
Michael C Heinrich ◽  
Robin L Jones ◽  
Margaret von Mehren ◽  
Patrick Schöffski ◽  
César Serrano ◽  
...  
Keyword(s):  
Phase 1 ◽  
Gastrointestinal Stromal Tumour ◽  
Stromal Tumour ◽  
Open Label ◽  
Phase 1 Trial ◽  
Open Label Phase

scholarly journals Open-Label Clinical Trials of Oral Pulse Dexamethasone for Adults with Idiopathic Nephrotic Syndrome

2019 ◽  
Vol 49 (5) ◽  
pp. 377-385 ◽  
Author(s):  
Monique E. Cho ◽  
Mary H. Branton ◽  
David A. Smith ◽  
Linda Bartlett ◽  
Lilian Howard ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Adverse Events ◽  
Idiopathic Nephrotic Syndrome ◽  
High Dose ◽  
Open Label ◽  
Serious Adverse Events ◽  
Oral Dexamethasone ◽  
Dose Oral ◽  
Pulse Dexamethasone ◽  
Daily Prednisone

Background: In adults with primary focal segmental glomerulosclerosis (FSGS), daily prednisone may induce complete remissions (CR) and partial remissions (PR), but relapses are frequent and adverse events are common. Methods: We carried out 2 open-label, uncontrolled trials to explore the efficacy and tolerability of pulse oral dexamethasone as an alternative to daily prednisone. We enrolled adult patients with proteinuria > 3.5 g/day despite the use of renin-angiotensin-aldosterone blockade. In the first trial, we enrolled 14 subjects with FSGS and administered 4 dexamethasone doses (25 mg/m2) daily for 4 days, repeated every 28 days over 32 weeks. The second trial involved a more intensive regimen. Eight subjects received 4 dexamethasone doses of 50 mg/m2 every 4 weeks for 12 weeks, followed by 4 doses of 25 mg/m2 every 4 weeks for 36 weeks; subjects were randomized to 2 doses every 2 weeks or 4 doses every 4 weeks. Results: In the first trial, we enrolled 13 subjects with FSGS and 1 with minimal change disease and found a combined CR and PR rate of 36%. In the second trial, we enrolled 8 subjects. The combined CR and PR rate was 29%. Analysis combining both trials showed a combined CR and PR rate of 33%. Adverse events were observed in 32% of subjects, with mood symptoms being most common. There were no serious adverse events related to the study. Conclusion: We conclude that high dose oral dexamethasone is well tolerated by adults with idiopathic nephrotic syndrome and may have some efficacy.

Phase-1 trial of high-dose intravenous cisplatin with simultaneous intravenous sodium thiosulfate

1991 ◽  
Vol 117 (2) ◽  
pp. 151-155 ◽  
Author(s):  
Maurie Markman ◽  
Robert D'Acquisto ◽  
Nicholas Iannotti ◽  
Mark Kris ◽  
Thomas Hakes ◽  
...  
Keyword(s):  
Phase 1 ◽  
Sodium Thiosulfate ◽  
High Dose ◽  
Phase 1 Trial ◽  
Intravenous Sodium
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