scholarly journals Favipiravir for treatment of outpatients with asymptomatic or uncomplicated COVID-19: a double-blind randomized, placebo-controlled, phase 2 trial

2021 ◽  
Author(s):  
Marisa Holubar ◽  
Aruna K Subramanian ◽  
Natasha Purington ◽  
Haley Hedlin ◽  
Bryan Bunning ◽  
...  
Keyword(s):  
Symptom Duration ◽  
Phase 2 ◽  
Double Blind ◽  
Intention To Treat ◽  
Phase 2 Trial ◽  
Polymerase Inhibitor ◽  
The Impact ◽  
To Receive ◽  
Higher Doses

Background: Favipiravir is an oral, RNA–dependent RNA polymerase inhibitor with in vitro activity against SARS–CoV2. Despite limited data, favipiravir is administered to patients with COVID-19 in several countries. Methods: We conducted a phase 2 double–blind randomized controlled outpatient trial of favipiravir in asymptomatic or mildly symptomatic adults with a positive SARS–CoV2 RT–PCR within 72 hours of enrollment. Participants were randomized 1:1 to receive placebo or favipiravir (1800 mg BID Day 1, 800mg BID Days 2–10). The primary outcome was SARS–CoV2 shedding cessation in a modified intention-to-treat (mITT) cohort of participants with positive enrollment RT–PCRs. Using SARS–CoV2 deep sequencing, we assessed the impact of favipiravir on mutagenesis. Results: From July 8, 2020 to March 23, 2021, we randomized 149 participants with 116 included in the mITT cohort. The mean age was 43 years (SD 12.5) and 57 (49%) were women. We found no difference in time to shedding cessation by treatment arm overall (HR 0.76 favoring placebo, 95% confidence interval [CI] 0.48 – 1.20) or in sub-group analyses (age, sex, high-risk comorbidities, seropositivity or symptom duration at enrollment). We observed no difference in time to symptom resolution (initial: HR 0.84, 95% CI 0.54 – 1.29; sustained: HR 0.87, 95% CI 0.52 – 1.45). We detected no difference in accumulation of transition mutations in the viral genome during treatment. Conclusions: Our data do not support favipiravir use at commonly used doses in outpatients with uncomplicated COVID-19. Further research is needed to ascertain if higher doses of favipiravir are effective and safe for patients with COVID-19.

scholarly journals In VitroActivity and Microbiological Efficacy of Tedizolid (TR-700) against Gram-Positive Clinical Isolates from a Phase 2 Study of Oral Tedizolid Phosphate (TR-701) in Patients with Complicated Skin and Skin Structure Infections

2012 ◽  
Vol 56 (9) ◽  
pp. 4608-4613 ◽  
Author(s):  
Philippe Prokocimer ◽  
Paul Bien ◽  
Carisa DeAnda ◽  
Chris M. Pillar ◽  
Ken Bartizal
Keyword(s):  
Clinical Efficacy ◽  
Phase 2 ◽  
Coagulase Negative Staphylococci ◽  
Gram Positive ◽  
Double Blind ◽  
Content Type ◽  
Skin Structure ◽  
Phase 2 Trial ◽  
Complicated Skin

ABSTRACTTedizolid (TR-700, formerly torezolid) is the active moiety of the prodrug tedizolid phosphate (TR-701), a next-generation oxazolidinone, with high potency against Gram-positive species, including methicillin-resistantStaphylococcus aureus(MRSA). A recently completed randomized, double-blind phase 2 trial evaluated 200, 300, or 400 mg of oral tedizolid phosphate once daily for 5 to 7 days in patients with complicated skin and skin structure infections. This report examines thein vitroactivity of tedizolid and Zyvox (linezolid) against Gram-positive pathogens isolated at baseline and describes the microbiological and clinical efficacy of tedizolid. Of 196 isolates tested, 81.6% wereS. aureus, and of these, 76% were MRSA. The MIC50and MIC90of tedizolid against both methicillin-susceptibleS. aureus(MSSA) and MRSA were 0.25 μg/ml, compared with a MIC50of 1 μg/ml and MIC90of 2 μg/ml for linezolid. For coagulase-negative staphylococci (n= 7), viridans group streptococci (n= 15), and beta-hemolytic streptococci (n= 3), the MICs ranged from 0.03 to 0.25 μg/ml for tedizolid and from 0.12 to 1 μg/ml for linezolid. The microbiological eradication rates at the test-of-cure visit (7 to 14 days posttreatment) in the microbiologically evaluable population (n= 133) were similar in all treatment groups, with overall eradication rates of 97.7% for all pathogens, 97.9% for MRSA, and 95.7% for MSSA. The clinical cure rates for MRSA and MSSA infections were 96.9% and 95.7%, respectively, across all dose groups. This study confirms the potentin vitroactivity of tedizolid against pathogenic Gram-positive cocci, including MRSA, and its 4-fold-greater potency in comparison with linezolid. All dosages of tedizolid phosphate showed excellent microbiological and clinical efficacy against MRSA and MSSA.

High-dose erythropoietin in patients with progressive multiple sclerosis: A randomized, placebo-controlled, phase 2 trial

2016 ◽  
Vol 23 (5) ◽  
pp. 675-685 ◽  
Author(s):  
Karen Schreiber ◽  
Melinda Magyari ◽  
Finn Sellebjerg ◽  
Pernille Iversen ◽  
Ellen Garde ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Primary Outcome ◽  
Progressive Multiple Sclerosis ◽  
High Dose ◽  
Phase 2 ◽  
Double Blind ◽  
Intention To Treat ◽  
Phase 2 Trial ◽  
Hand Dexterity ◽  
Magnetic Resonance Imaging Mri

Background: Erythropoietin (EPO) is a part of an endogenous neuroprotective system in the brain and may address pathophysiological mechanisms in progressive multiple sclerosis (MS). Objective: To evaluate a treatment effect of EPO on progressive MS. Methods: This was a single-center, randomized, double-blind, placebo-controlled phase 2 trial, in which 52 patients with secondary or primary progressive MS were allocated to treatment with recombinant EPO (48,000 IU) or placebo, administered intravenously 17 times during 24 weeks. Patients had an Expanded Disability Status Score (EDSS) from 4 to 6.5 and clinical progression without relapses in the 2 preceding years. The primary outcome was the change in a composite measure of maximum gait distance, hand dexterity, and cognition from baseline to 24 weeks. Results: A total of 50 patients completed the study. Venesection was performed often but no thromboembolic events occurred. We found no difference in the primary outcome between the EPO and the placebo group using the intention-to-treat principle ( p = 0.22). None of the secondary outcomes, neither clinical nor magnetic resonance imaging (MRI) measures showed any significant differences. Conclusion: This study provides class II evidence that treatment with high-dose EPO is not an effective treatment in patients with moderately advanced progressive MS.

scholarly journals Immunogenicity and Safety of a SARS-CoV-2 Inactivated Vaccine (KCONVAC) in Healthy Adults: Two Randomized, Double-blind, and Placebo-controlled Phase 1/2 Clinical Trials

2021 ◽  
Author(s):  
Hong-Xing Pan ◽  
Jian-Kai Liu ◽  
Bao-Ying Huang ◽  
Gui-Fan Li ◽  
Xian-Yun Chang ◽  
...  
Keyword(s):  
Antibody Response ◽  
Cellular Response ◽  
Phase 1 ◽  
Healthy Adults ◽  
Phase 2 ◽  
Double Blind ◽  
Live Virus ◽  
Phase 1 Trial ◽  
Phase 2 Trial ◽  
To Receive

Background The significant morbidity and mortality resulted from the infection of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) call for urgent development of effective and safe vaccines. We report the immunogenicity and safety of a SARS-CoV-2 inactivated vaccine, KCONVAC, in healthy adults. Methods Two phase 1 and phase 2 randomized, double-blind, and placebo-controlled trials of KCONVAC were conducted in Chinese healthy adults aged 18 through 59 years. The phase 1 trial was conducted in a manner of dosage escalation. The first 30 participants were randomized in a ratio of 4:1 to receive two doses of either KCONVAC at 5 μg per dose or placebo on Day 0 and Day 14, and the second 30 participants were randomized to receive either KCONVAC at 10 μg per dose or placebo following the same procedures. The participants in the phase 2 trial were randomized in a ratio of 2:2:1 to receive either KCONVAC at 5 μg or 10 μg per dose, or placebo on Day 0 and Day 14, or Day 0 and Day 28. In the phase 1 trial, the primary safety endpoint was the proportion of participants experiencing adverse reactions/events within 28 days following each vaccination. Antibody response and cellular response were assayed in the phase 1 trial. In the phase 2 trial, the primary immunogenicity endpoint was the seroconversion and titre of neutralization antibody, and the seroconversion of receptor binding domain (RBD)-IgG 28 days after the second dose. Findings In the phase 1 trial, 60 participants were enrolled and received at least one dose of 5-μg vaccine (N=24), 10-μg vaccine (N=24), or placebo (N=12). In the phase 2 trial, 500 participants were enrolled and received at least one dose of 5-μg vaccine (N=100 for 0/14 or 0/28 regimens), 10-μg vaccine (N=100 for each regimen), or placebo (N=50 for each regimen). In the phase 1 trial, 13 (54%), 11(46%), and 7 (58%) participants reported at least one adverse event (AE), of whom 10 (42%), 6 (25%), and 6 (50%) participants reported at least one vaccination-related AE after receiving 5-μg vaccine, 10-μg vaccine, or placebo, respectively. In the phase 2 trial, 16 (16%), 19 (19%), and 9 (18%) participants reported at least one AE, of whom 13 (13%), 17 (17%), and 6 (12%) participants reported at least one vaccination-related AE after receiving 5-μg vaccine, 10-μg vaccine, or placebo at the regimen of Day 0/14, respectively. Similar results were observed in the three treatment groups of Day 0/28 regimen. All the AEs were grade 1 or 2 in intensity. No AE of grade 3 or more was reported. One SAE (foot fracture) was reported in the phase 1 trial. KCONVAC induced significant antibody response. 87.5% (21/24) to 100% (24/24) of participants in the phase 1 trial and 83.0% (83/100) to 100% (99/99) of participants in the phase 2 trial seroconverted for neutralising antibody to live virus, neutralising antibody to pseudovirus, and RBD-IgG after receiving two doses. Across the treatment groups in the two trials, the geometric mean titres (GMTs) of neutralising antibody to live virus ranged from 29.3 to 49.1 at Day 0/14 regimen and from 100.2 to 131.7 at Day 0/28 regimen, neutralising antibody to pseudovirus ranged from 69.4 to 118.7 at Day 0/14 regimen and from 153.6 to 276.6 at Day 0/28 regimen, and RBD-IgG ranged from 605.3 to 1169.8 at Day 0/14 regimen and from 1496.8 to 2485.5 at Day 0/28 regimen. RBD-IgG subtyping assay showed that a significant part of RBD-IgG was IgG1. The vaccine induced obvious T-cell response with 56.5% (13/23) and 62.5% (15/24) of participants in 5-μg and 10-μg vaccine groups showed positive interferon-γ enzyme-linked immunospot responses 14 days after the second dose in the phase 1 trial, respectively. Interpretation KCONVAC is well tolerated and able to induce robust antibody response and cellular response in adults aged 18 to 59 years, which warrants further evaluation with this vaccine in the upcoming phase 3 efficacy trial. Funding Guandong Emergency Program for Prevention and Control of COVID-19 (2020A1111340002) and Shenzhen Key Research Project for Prevention and Control of COVID-19.

scholarly journals Phase 2 trial to assess lebrikizumab in patients with idiopathic pulmonary fibrosis

2020 ◽  
pp. 1902442
Author(s):  
Toby M. Maher ◽  
Ulrich Costabel ◽  
Marilyn K. Glassberg ◽  
Yasuhiro Kondoh ◽  
Takashi Ogura ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Primary Endpoint ◽  
Safety Profile ◽  
Controlled Trial ◽  
Phase 2 ◽  
Double Blind ◽  
Phase 2 Trial ◽  
Treatment Naïve ◽  
To Receive

This phase 2, randomised, double-blind, placebo-controlled trial evaluated the efficacy and safety of lebrikizumab, an interleukin-13 monoclonal antibody, alone or with background pirfenidone therapy, in patients with idiopathic pulmonary fibrosis (IPF).Patients with IPF aged ≥40 years with % predicted forced vital capacity (%FVC) 40%–100% and diffusing capacity for carbon monoxide 25%–90% and who were treatment-naive (Cohort A) or receiving pirfenidone (2403 mg·day−1; Cohort B) were randomised 1:1 to receive lebrikizumab 250 mg or placebo subcutaneously every 4 weeks. The primary endpoint was annualised rate of %FVC decline over 52 weeks.In Cohort A, 154 patients were randomised to receive lebrikizumab (n=78) or placebo (n=76). In Cohort B, 351 patients receiving pirfenidone were randomised to receive lebrikizumab (n=174) or placebo (n=177). Baseline demographics were balanced across treatment arms in both cohorts. The primary endpoint (annualised rate of %FVC decline) was not met in Cohort A (lebrikizumab versus placebo, −5.2% versus −6.2%; p=0.456) or Cohort B (lebrikizumab versus placebo, −5.5% versus −6.0%; p=0.557). In Cohort B, a non-statistically significant imbalance in mortality favouring combination therapy was observed (hazard ratio, 0.42 [95% CI, 0.17–1.04]). Pharmacodynamic biomarkers indicated lebrikizumab activity. The safety profile was consistent with that in previous studies of lebrikizumab and pirfenidone as monotherapies.Lebrikizumab alone or with pirfenidone was not associated with reduced %FVC decline over 52 weeks despite evidence of pharmacodynamic activity. Lebrikizumab was well tolerated with a favourable safety profile. These findings suggest that blocking IL-13 may not be sufficient to achieve a lung function benefit in patients with IPF.

scholarly journals CTNI-18. FINAL RESULTS OF A PHASE 2 STUDY OF EFFICACY, SAFETY AND INTRATUMORAL PHARMACOKINETICS (PK) OF SELINEXOR MONOTHERAPY IN RECURRENT GLIOBLASTOMA (rGBM)

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii46-ii46
Author(s):  
Andrew Lassman ◽  
Patrick Wen ◽  
Martin van den Bent ◽  
Scott Plotkin ◽  
Annemiek Walenkamp ◽  
...  
Keyword(s):  
Nuclear Export ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Median Number ◽  
Recurrent Glioblastoma ◽  
Phase 2 ◽  
Nuclear Retention ◽  
Phase 2 Trial ◽  
Human Gbm

Abstract BACKGROUND Selinexor is an FDA-approved first-in-class, oral selective nuclear export inhibitor which forces nuclear retention of many tumor suppressor proteins. METHODS We conducted a phase 2 trial of selinexor monotherapy for adults with recurrent GBM including a surgical arm to explore intratumoral PK and 3 medical arms to optimize dosing. Prior treatment with radiotherapy and temozolomide was required; prior bevacizumab was exclusionary. The primary endpoint was 6-month progression-free survival (6mPFS) rate. RESULTS Selinexor administered ~2 hours pre-operatively yieleded average intratumoral concentration (136 nM, n=6) comparable to the in vitro IC50 (130 nM) from 7 primary human GBM cell lines. Among all 68 patients accrued to 3 medical arms (~85 mg BIW, n=24; 60 mg BIW, n=14; 80 mg QW, n=30), median age was 56 years (21–78). Median number of prior lines of therapies was 2 (1–7). At 80 mg QW, 28% patients were progression-free at the end of cycle 6; the 6mPFS was 17%; disese control rate by RANO was 37% (1 CR, 2 PRs, 7 SD) among 27 evaluable patients; responses were durable (median 11.1 months), and treatment lasted for 442, 547 and 1282 days in 3 responders, as of data lock, with one responder remaining on treatment off study; median overall survival was 10.2 months with 95% CI (7.0, 15.4). The ~85 mg BIW-schedule was abandoned due to poor tolerability. The related adverse events (all grades) in patients on ~85 mg BIW/60 mg BIW/80 mg QW were nausea (41.7%/64.3%/66.7%), fatigue (70.8%/71.4%/50.0%), neutropenia (29.2%/14.3%/33.3%), decreased appetite (45.8%/71.4%/26.7%), thrombocytopenia (66.7%/28.6%/23.3%) and weight loss (16.7%,/42.9%/6.7%). CONCLUSION Selinexor monotherapy demonstrated encouraging intratumoral penetration and efficacy, with durable disease control in rGBM. Monotherapy dose at 80 mg QW is recommended for further development in rGBM. A phase 1/2 study of combination therapy for newly diagnosed or rGBM has been initiated (NCT04421378).

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