Favipiravir In Adults with Moderate to Severe COVID-19: A Phase 3 Multicentre, Randomized, Double-Blind, Placebo-Controlled Trial.

Aim: To assess the efficacy and safety of favipiravir in adults with moderate to severe coronavirus disease 2019 (COVID-19). Methods: In this randomized, double-blind, multicenter, phase 3 trial, adults (21 80 years) with real-time reverse transcriptase polymerase chain reaction (rRT-PCR) confirmed SARS CoV 2 infection and presenting with moderate to severe COVID-19 and requiring hospitalization were randomized 1:1 to oral favipiravir (day 1: 1800 mg BID and days 2-10: 800 mg BID) (FPV) plus standard supportive care (SoC) versus placebo plus SoC (placebo). The primary endpoint was time to resolution of hypoxia. Results: In total, 353 patients were randomized to receive either FPV or placebo (175 and 178 in the FPV and placebo groups, respectively). Overall, 76% of the patients (240/315, 78% in FPV vs. 75% in placebo group) reached resolution of hypoxia on or before day 28. The median time to resolution of hypoxia was 7 days in the FPV group and 8 days in the placebo group. Treatment effect was not significant [Hazard ratio (HR) (95% CI): 0.991 (0.767, 1.280) (p=0.94)]. Patients in the lower NEWS-2 clinical risk subgroup were more likely to achieve shorter time to resolution of hypoxia with the median time to resolution of hypoxia of 6 days in FPV and 7 days in placebo group [HR (95% CI): 1.21 (0.847, 1.731) (p=0.29)]; shorter time to hospital discharge with a median time to discharge of 8 and 10 days in the FPV and placebo group, respectively [HR (95% CI): 1.47 (1.081, 1.997) (p=0.014)]; and shorter time to improvement by 1-point improvement over baseline in WHO 10-point clinical status score with the median time to improvement by 1-point from baseline of 6 and 7 days in the FPV and placebo group, respectively [HR (95% CI): 1.16 (0.830, 1.624) (p=0.38)] than higher NEWS-2 clinical risk subgroup. Treatment emergent adverse event (TEAEs) were experienced by 62/334 (19%) patients [35/168 (21%) patients in FPV and 27/166 (16%) in placebo group]. Hyperuricaemia/increased blood uric acid was reported in 9 (3%)/2 (1%) patients [8 (5%)/1(1%) patients in FPV and 1 (1%)/1(1%) in placebo group] ,which were of mild intensity and transient. Overall, 36 serious adverse events (SAEs) were reported, 20 in FPV and 16 in placebo group. Conclusion: The trial did not find favipiravir to be effective in moderate to severe, hospitalized COVID-19 patients; favourable clinical trends were observed in patients with lower NEWS-2 risk when early administration of favipiravir could be achieved.

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Efficacy of a nasal spray containing Iota-Carrageenan in the prophylaxis of COVID-19 in hospital personnel dedicated to patients care with COVID-19 disease. A pragmatic multicenter, randomized, double-blind, placebo-controlled trial (CARR-COV-02)

10.1101/2021.04.13.21255409 ◽

2021 ◽

Author(s):

Juan Manuel Figueroa ◽

Monica Lombardo ◽

Ariel Dogliotti ◽

Luis Flynn ◽

Robert P. Giugliano ◽

...

Keyword(s):

Placebo Group ◽

Nasal Spray ◽

Controlled Trial ◽

Hospital Personnel ◽

Culture Methods ◽

Double Blind ◽

Double Blind Placebo ◽

Significant Efficacy ◽

To Receive

Background Iota-Carrageenan (I-C) is a sulfate polysaccharide synthesized by red algae, with demonstrated antiviral activity and clinical efficacy as nasal spray in the treatment of common cold. In vitro, I-C inhibits SARS-CoV-2 infection in cell culture. Methods This is a pragmatic multicenter, randomized, double-blind, placebo-controlled trial assessing the use of a nasal spray containing I-C in the prophylaxis of COVID-19 in hospital personnel dedicated to care of COVID-19 patients. Clinically healthy physicians, nurses, kinesiologists and others medical providers were assigned in a 1:1 ratio to receive four daily doses of I-C spray or placebo for 21 days. The primary end point was clinical COVID-19, as confirmed by reverse-transcriptase-polymerase-chain-reaction testing, over a period of 21 days. The trial is registered at ClinicalTrials.gov (NCT04521322). Findings A total of 394 individuals were randomly assigned to receive I-C or placebo. Both treatment groups had similar baseline characteristics. The incidence of COVID-19 was significantly lower in the I-C group compared to placebo (1.0% vs 5.0%) (Odds Ratio 0.19 (95% confidence interval 0.05 to 0.77; p= 0.03). Workday loss in placebo group compared to I-C were 1.6% days / person (95% CI, 1.0 to 2.2); p <0.0001 There were no differences in the incidence of adverse events across the two groups (17.3% in the I-C group and 15.2% in the placebo group, p= 0.5). Interpretation I-C showed significant efficacy in preventing SARS-CoV-2 infection in hospital personnel dedicated to care patients with COVID-19 disease.

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Effect of a Fermented Milk CombiningLactobacillus AcidophilusCL1285 andLactobacillus Caseiin the Prevention of Antibiotic-Associated Diarrhea: A Randomized, Double-Blind, Placebo-Controlled Trial

Canadian Journal of Gastroenterology ◽

10.1155/2007/720205 ◽

2007 ◽

Vol 21 (11) ◽

pp. 732-736 ◽

Cited By ~ 98

Author(s):

Mélanie Beausoleil ◽

Nadia Fortier ◽

Stéphanie Guénette ◽

Amélie L’Ecuyer ◽

Michel Savoie ◽

...

Keyword(s):

Placebo Group ◽

Controlled Trial ◽

Randomized Study ◽

Fermented Milk ◽

Daily Basis ◽

Hospitalized Patients ◽

Double Blind ◽

Antibiotic Associated Diarrhea ◽

Potential Measure ◽

To Receive

BACKGROUND: Antibiotic-associated diarrhea is an important problem in hospitalized patients. The use of probiotics is gaining interest in the scientific community as a potential measure to prevent this complication. The main objective of the present study was to assess the efficacy and safety of a fermented milk combiningLactobacillus acidophilusandLactobacillus caseithat is widely available in Canada, in the prevention of antibiotic-associated diarrhea.METHODS: In this double-blind, randomized study, hospitalized patients were randomly assigned to receive either a lactobacilli-fermented milk or a placebo on a daily basis.RESULTS: Among 89 randomized patients, antibiotic-associated diarrhea occurred in seven of 44 patients (15.9%) in the lactobacilli group and in 16 of 45 patients (35.6%) in the placebo group (OR 0.34, 95% CI 0.125 to 0.944; P=0.05). The median hospitalization duration was eight days in the lactobacilli group, compared with 10 days in the placebo group (P=0.09). Overall, the lactobacilli-fermented milk was well tolerated.CONCLUSION: The daily administration of a lactobacilli-fermented milk was safe and effective in the prevention of antibiotic-associated diarrhea in hospitalized patients.

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Safety and immunogenicity of anti-SARS CoV-2 conjugate vaccine SOBERANA 02 in a two-dose or three-dose heterologous scheme in adults: Phase IIb Clinical Trial

10.1101/2022.01.01.21268271 ◽

2022 ◽

Author(s):

Maria Eugenia-Toledo-Romani ◽

Mayra Garcia-Carmenate ◽

Leslyhana Verdecia-Sanchez ◽

Suzel Perez-Rodriguez ◽

Meybis Rodriguez-Gonzalez ◽

...

Keyword(s):

Clinical Trial ◽

Placebo Group ◽

Neutralizing Antibodies ◽

Seroconversion Rate ◽

Serious Adverse Events ◽

Double Blind ◽

The Third ◽

Functional Antibodies ◽

Dose Trial ◽

To Receive

Background: We report results of immunogenicity, safety and reactogenicity of SOBERANA 02 in a two-dose or three-dose heterologous scheme in adults in a phase IIb clinical trial. Method: This phase IIb trial was designed as parallel, multicentre, adaptive, double blind, randomized and placebo-controlled. Subjects (N=810) aged 19-80 years were randomized to receive two doses of the recombinant SARS CoV-2 receptor binding domain (RBD) conjugated to tetanus toxoid (SOBERANA 02) and a third dose of dimeric RBD (SOBERANA Plus) 28 days apart; two production batches of active ingredient of SOBERANA 02 were evaluated. Primary outcome was the percentage of seroconverted subjects with ≥4-fold the anti-RBD IgG concentration. Secondary outcomes were safety, reactogenicity and neutralizing antibodies. Results: Seroconversion rate in vaccinees was respectively 76.3 and 96.8% after two or three doses, compared with 7.3% in placebo group. Anti-RBD IgG increased significantly after first and second dose of SOBERANA 02 respect to placebo group; and the third dose with SOBERANA Plus boosts the response compared to the second dose. Neutralizing IgG antibodies were detected against D614G and VOCs α, β and δ. Specific and functional antibodies were detected until 7-8 months after the third dose. The frequency of serious adverse events (AEs) associated with vaccination was very low (0.1%); with only one serious AE consistent with vaccination. Local pain was the most frequent AE. Conclusions: Two doses of SOBERANA 02 were well tolerated, safe an immunogenic in adults aged 19-80 years old. The heterologous combination with a third dose of SOBERANA Plus increased neutralizing antibodies, detectable 7-8 months after the third dose. Trial registry: https://rpcec.sld.cu/trials/RPCEC00000347

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The effect of nadolol on heart rate in hyperthyroidism. A controlled trial

Acta Endocrinologica ◽

10.1530/acta.0.1140102 ◽

1987 ◽

Vol 114 (1) ◽

pp. 102-106

Author(s):

J. H. Lazarus ◽

J. C. Kingswood ◽

R. John

Keyword(s):

Heart Rate ◽

Placebo Group ◽

Controlled Trial ◽

Circadian Variation ◽

Maximum Heart Rate ◽

Double Blind ◽

Early Management ◽

The Mean ◽

To Receive ◽

Hyperthyroid Patients

Abstract. Twenty hyperthyroid patients were randomly assigned in a double-blind fashion to receive either nadolol 80 mg/day or placebo for 2 weeks; all patients then took carbimazole as well from 2–6 weeks. Twenty-four hour Holter ECG recordings at 0, 2 and 6 weeks showed that nadolol reduced the mean maximum heart rate by 19.9% (P < 0.0005) at 2 weeks and by 30.3% (P < 0.0005) at 6 weeks compared to 5.2% (ns) and 18.3% (P < 0.0005) in patients taking placebo. There was no alteration of the normal circadian variation of heart rate by nadolol. The minimum heart rate before therapy was significantly correlated with FT4 (r = 0.52) and with FT3 (r = 0.44). The percentage of time per hour during which the heart rate was greater than 100 was reduced by 79% at week 2 by nadolol compared to 22% in the placebo group. At the 6 week point the placebo group still had a tachycardia (mean maximum heart rate 101.6 beats/min ± 15.2 sd) compared to the nadolol group (80.4 ± 7.7). Nadolol did not cause excessive bradycardia. It is effective in the early management of hyperthyroidism and should be given for at least the first 4–6 weeks.

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Onset of analgesia by a topically administered flurbiprofen lozenge: a randomised controlled trial using the double stopwatch method

British Journal of Pain ◽

10.1177/2049463718756152 ◽

2018 ◽

Vol 12 (4) ◽

pp. 208-216 ◽

Cited By ~ 3

Author(s):

Bernard Schachtel ◽

Sue Aspley ◽

Adrian Shephard ◽

Emily Schachtel ◽

Mary Beth Lorton ◽

...

Keyword(s):

Pain Relief ◽

Sore Throat ◽

Median Time ◽

Controlled Trial ◽

Moderate Intensity ◽

Onset Of Action ◽

Serious Adverse Events ◽

Double Blind ◽

Kaplan Meier ◽

Randomised Controlled

Background: The double stopwatch (DSW) method for determining the onset of analgesic activity has been implemented extensively by investigators studying orally administered drugs. Objective: The aim of this randomised, placebo-controlled trial was to use the DSW method to determine the time to onset of analgesia of a single dose of a topically administered non-steroidal anti-inflammatory drug, flurbiprofen 8.75 mg lozenge. Methods: Adults with acute sore throat (n = 122) were examined to confirm the presence of tonsillopharyngitis (Tonsillo-Pharyngitis Assessment) and sore throat pain of at least moderate intensity (≥6 on a 0–10 Sore Throat Scale). Lozenges containing flurbiprofen 8.75 mg or inert ingredients (identically flavoured) were administered under double-blind conditions in the clinic while patients assessed pain and pain relief over 3 hours. Onset of analgesia was determined using the DSW method and reported as the Kaplan–Meier median time to meaningful relief. The median time to first perceived relief was also documented. Results: About 78% of flurbiprofen-treated patients reported meaningful pain relief compared with 48% of placebo-treated patients (p < 0.01); median time to meaningful relief for flurbiprofen-treated patients was 43 minutes (placebo-treated patients were right-censored due to non-responsivity; p = 0.01). Median time to first perceived pain relief was 11 minutes for flurbiprofen-treated patients and 19 minutes for placebo-treated patients (p = 0.03). Flurbiprofen lozenge was well tolerated, with no serious adverse events occurring and no patient discontinuing due to an adverse event. Conclusion: These results indicate that the DSW method can be successfully applied to the evaluation of the onset of action of a locally administered analgesic in patients with acute sore throat, demonstrating that the onset of action (time to meaningful pain relief) of flurbiprofen lozenge was <45 minutes.

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A Randomized Placebo-Controlled Trial of Sarilumab in Hospitalized Patients with Covid-19

10.1101/2021.05.13.21256973 ◽

2021 ◽

Author(s):

Sumathi Sivapalasingam ◽

David Lederer ◽

Rafia Bhore ◽

Negin Hajizadeh ◽

Gerard Criner ◽

...

Keyword(s):

Relative Risk ◽

Controlled Trial ◽

Statistical Significance ◽

Clinical Status ◽

Hospitalized Patients ◽

Phase 2 ◽

Primary Analysis ◽

Phase 3 ◽

Double Blind ◽

Critical Patients

BACKGROUND Sarilumab (anti-interleukin-6 receptor-alpha; monoclonal antibody) may attenuate the inflammatory response in Covid-19. METHODS We performed an adaptive, phase 2/3, randomized, double-blind, placebo-controlled trial of intravenous sarilumab 200 mg or 400 mg in adults hospitalized with Covid-19. The phase 3 primary analysis population (cohort 1) was patients with critical Covid-19 receiving mechanical ventilation (MV) randomized to sarilumab 400 mg or placebo. The primary end point for phase 3 was the proportion of patients with ≥1-point improvement in clinical status from baseline to day 22. RESULTS Four-hundred fifty-seven (457) and 1365 patients were randomized and treated in phases 2 and 3, respectively. Among phase 3 critical patients receiving MV (n=289; 34.3% on corticosteroids), the proportion with ≥1-point improvement in clinical status (alive not receiving MV) at day 22 was 43.2% in sarilumab 400 mg and 35.5% in placebo (risk difference [RD] +7.5%; 95% confidence interval [CI], − 7.4 to 21.3; P=0.3261), representing a relative risk improvement of 21.7%. Day 29 all-cause mortality was 36.4% in sarilumab 400 mg versus 41.9% in placebo (RD − 5.5%; 95% CI, −20.2 to 8.7; relative risk reduction 13.3%). In post hoc analyses pooling phase 2 and 3 critical patients receiving MV, the hazard ratio (HR) for death in sarilumab 400 mg compared with placebo was 0.76 (95% CI, 0.51 to 1.13) overall, improving to 0.49 (95% CI, 0.25 to 0.94) in patients receiving corticosteroids at baseline. CONCLUSION In hospitalized patients with Covid-19 receiving MV, numerical benefits with sarilumab did not achieve statistical significance, but benefit may be greater in patients receiving corticosteroids. A larger study is required to confirm this observed numerical benefit.

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Fostamatinib for the treatment of hospitalized adults with COVD-19 A randomized trial

Clinical Infectious Diseases ◽

10.1093/cid/ciab732 ◽

2021 ◽

Author(s):

Jeffrey R Strich ◽

Xin Tian ◽

Mohamed Samour ◽

Christopher S King ◽

Oksana Shlobin ◽

...

Keyword(s):

Immune Response ◽

Adverse Events ◽

Kinase Inhibitor ◽

Controlled Trial ◽

Standard Of Care ◽

Serious Adverse Events ◽

Double Blind ◽

Reactive Protein ◽

To Receive ◽

Confirmatory Trials

Abstract Background Coronavirus Disease 2019 (Covid-19) requiring hospitalization is characterized by robust antibody production, dysregulated immune response and immunothrombosis. Fostamatinib, is a novel spleen tyrosine kinase inhibitor we hypothesize will ameliorate Fc activation and attenuate harmful effects of the anti-COVID-19 immune response. Methods We conducted a double-blind, randomized, placebo-controlled trial in hospitalized adults requiring oxygen with Covid-19 where patients receiving standard of care were randomized to receive fostamatinib or placebo. The primary outcome was serious adverse events by day 29. Results A total of 59 patients underwent randomization (30 to fostamatinib and 29 to placebo). Serious adverse events occurred in 10.5% of patients in the fostamatinib group compared to 22% in placebo (P = .2). Three deaths occurred by day 29, all receiving placebo. The mean change in ordinal score at day 15 was greater in the fostamatinib group (-3.6 ± 0.3 vs. -2.6 ± 0.4, P = .035) and the median length in the ICU was 3 days in the fostamatinib group vs. 7 days in placebo (P = .07). Differences in clinical improvement were most evident in patients with severe or critical disease (median days on oxygen, 10 vs. 28, P = .027). There were trends towards more rapid reductions in C-reactive protein, D-dimer, fibrinogen and ferritin levels in the fostamatinib group. Conclusion For COVID-19 requiring hospitalization, the addition of fostamatinib to standard of care was safe and patients were observed to have improved clinical outcomes compared to placebo. These results warrant further validation in larger confirmatory trials.

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A Double-Blind Trial of Intramuscular Stanozolol in the Prevention of Postoperative Deep Vein Thrombosis Following Elective Abdominal Surgery

Thrombosis and Haemostasis ◽

10.1055/s-0038-1661023 ◽

1984 ◽

Vol 51 (01) ◽

pp. 071-074 ◽

Cited By ~ 20

Author(s):

S L Blarney ◽

B M McArdle ◽

P Burns ◽

D C Carter ◽

G D O Lowe ◽

...

Keyword(s):

Deep Vein Thrombosis ◽

Placebo Group ◽

Controlled Trial ◽

Double Blind Trial ◽

Double Blind ◽

Vein Thrombosis ◽

Postoperative Deep Vein Thrombosis ◽

Deep Vein ◽

To Receive

SummaryFibrinolytic shutdown may be important in the development of postoperative deep vein thrombosis (DVT). We have previously shown that stanozolol 50 mg, given intramuscularly 24 hr before surgery, prevents the decrease in plasminogen activator activity (PA) seen on the first postoperative day in patients at high risk of DVT. To investigate the role of fibrinolytic shutdown in causation of DVT, sixty patients were randomised in a double-blind controlled trial to receive stanozolol or placebo intramuscularly, and DVT was detected by leg scanning and confirmed by venography. Scan positive DVT occurred in IT of 31 placebo patients (35%) and 12 of 29 who received stanozolol (41%). A significant decrease in PA was confirmed in the placebo group, while stanozolol caused a significant increase in PA on the first postoperative day. Patients in either group who did not develop DVT showed minimal changes in PA. We conclude that prevention of fibrinolytic shutdown by this regimen of stanozolol does not prevent postoperative DVT, and that further studies are required to clarify the relationships of postoperative fibrinolysis and DVT.

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A Double-Blind Placebo-Controlled Trial of Intranasal Capsaicin for Cluster Headache

Cephalalgia ◽

10.1046/j.1468-2982.1993.1302114.x ◽

1993 ◽

Vol 13 (2) ◽

pp. 114-116 ◽

Cited By ~ 69

Author(s):

David R Marks ◽

Alan Rapoport ◽

Dennis Padla ◽

Randall Weeks ◽

Robert Rosum ◽

...

Keyword(s):

Placebo Group ◽

Cluster Headache ◽

Sensory Neurons ◽

Therapeutic Option ◽

Controlled Trial ◽

Nerve Terminals ◽

Double Blind ◽

Headache Severity ◽

Topical Capsaicin ◽

To Receive

It has been suggested that treatment of cluster headache (CH) patients with topical capsaicin may desensitize sensory neurons by depleting the nerve terminals of substance P. We attempted to determine whether capsaicin is effective in aborting CH attacks. Patients in acute cluster were randomized to receive either capsaicin or placebo in the ipsilateral nostril for 7 days. Patients recorded the severity of each headache for 15 days. Headaches on days 8–15 of the study were significantly less severe in the capsaicin group vs the placebo group. There was also a significant decrease in headache severity in the capsaicin group on days 8–15 compared to days 1–7, but not in the placebo group. Episodic CH patients appeared to benefit more than chronic CH patients. These results indicate that intranasal capsaicin may provide a new therapeutic option for the treatment of this disease.

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Efficacy and Safety of a Naphthoquine-Azithromycin Co-Formulation for Malaria Prophylaxis in Southeast Asia: A Phase 3, Double-Blind, Randomized, Placebo-Controlled Trial

Clinical Infectious Diseases ◽

10.1093/cid/ciaa1018 ◽

2020 ◽

Author(s):

Henglin Yang ◽

Jingyan Wang ◽

Hui Liu ◽

Yan Zhao ◽

Seetha Lakshmi ◽

...

Keyword(s):

Single Dose ◽

Placebo Group ◽

Protective Efficacy ◽

Controlled Trial ◽

Fixed Dose ◽

Phase 3 ◽

Double Blind ◽

Intent To Treat ◽

Transient Elevation ◽

Double Blinded

Abstract Background A prophylactic antimalarial drug that is both effective for protection and improves compliance is in high demand. Methods We conducted a randomized, placebo-controlled, double-blinded, phase-3 trial to evaluate the 1:1 fixed-dose combination of naphthoquine-azithromycin (NQAZ) for safety and protection against Plasmodium infections in villages along the China-Myanmar border. A total of 631 residents, 5–65 years old, were randomized into the drug group (319) and the placebo group (312) to receive NZAQ and placebo, respectively, as a single-dose monthly treatment. Follow-ups were conducted weekly to monitor for adverse events and malaria infections. Results Of the 531 subjects completing the trial, there were 46 and 3 blood smear-positive Plasmodium infections in the placebo and treatment groups, respectively. For the intent-to-treat analysis, the single-dose monthly NQAZ treatment had 93.62% protective efficacy (95% confidence interval [CI]: 91.72–95.52%). For the per-protocol analysis, NQAZ treatment provided a 93.04% protective efficacy (95% CI: 90.98–95.1%). Three smear-positive cases in the NQAZ group were all due to acute falciparum malaria. In comparison, NQAZ treatment provided 100% protection against the relapsing malaria Plasmodium vivax and Plasmodium ovale. The treatment group had 5.6% of participants experiencing transient elevation of liver transaminases as compared to 2.2% in the placebo group (P > 0.05). Conclusions Monthly prophylaxis with NQAZ tablets was well tolerated and highly effective for preventing Plasmodium infections. It may prove useful for eliminating P. vivax in areas with a high prevalence of glucose-6-phosphate dehydrogenase deficiency in the population.

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