Favipiravir, lopinavir-ritonavir, or combination therapy (FLARE): A randomised, double-blind, 2 × 2 factorial placebo-controlled trial of early antiviral therapy in COVID-19.

BACKGROUND: Early antiviral treatment is effective for Coronavirus Disease 2019 (COVID-19) but currently available agents are expensive. Favipiravir is routinely used in many countries, but efficacy is unproven. Antiviral combinations have not been systematically studied. We aimed to evaluate the effect of favipiravir, lopinavir-ritonavir or the combination of both agents on Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) viral load trajectory when administered early. METHODS AND FINDINGS: We conducted a Phase 2, proof of principle, randomised, placebo-controlled, 2 × 2 factorial, double-blind trial of ambulatory outpatients with early COVID-19 (within 7 days of symptom onset) at 2 sites in the United Kingdom. Participants were randomised using a centralised online process to receive: favipiravir (1,800 mg twice daily on Day 1 followed by 400 mg 4 times daily on Days 2 to 7) plus lopinavir-ritonavir (400 mg/100 mg twice daily on Day 1, followed by 200 mg/50 mg 4 times daily on Days 2 to 7), favipiravir plus lopinavir-ritonavir placebo, lopinavir-ritonavir plus favipiravir placebo, or both placebos. The primary outcome was SARS-CoV-2 viral load at Day 5, accounting for baseline viral load. Between 6 October 2020 and 4 November 2021, we recruited 240 participants. For the favipiravir+lopinavir-ritonavir, favipiravir+placebo, lopinavir-ritonavir+placebo, and placebo-only arms, we recruited 61, 59, 60, and 60 participants and analysed 55, 56, 55, and 58 participants, respectively, who provided viral load measures at Day 1 and Day 5. In the primary analysis, the mean viral load in the favipiravir+placebo arm had changed by -0.57 log10 (95% CI -1.21 to 0.07, p = 0.08) and in the lopinavir-ritonavir+placebo arm by -0.18 log10 (95% CI -0.82 to 0.46, p = 0.58) compared to the placebo arm at Day 5. There was no significant interaction between favipiravir and lopinavir-ritonavir (interaction coefficient term: 0.59 log10, 95% CI -0.32 to 1.50, p = 0.20). More participants had undetectable virus at Day 5 in the favipiravir+placebo arm compared to placebo only (46.3% versus 26.9%, odds ratio (OR): 2.47, 95% CI 1.08 to 5.65; p = 0.03). Adverse events were observed more frequently with lopinavir-ritonavir, mainly gastrointestinal disturbance. Favipiravir drug levels were lower in the combination arm than the favipiravir monotherapy arm, possibly due to poor absorption. The major limitation was that the study population was relatively young and healthy compared to those most affected by the COVID-19 pandemic. CONCLUSIONS: At the current doses, no treatment significantly reduced viral load in the primary analysis. Favipiravir requires further evaluation with consideration of dose escalation. Lopinavir-ritonavir administration was associated with lower plasma favipiravir concentrations. TRIAL REGISTRATION: Clinicaltrials.gov NCT04499677 EudraCT: 2020-002106-68.

Early antiviral treatment in outpatients with COVID-19 (FLARE): a structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: The objective of this trial is to assess whether early antiviral therapy in outpatients with COVID-19 with either favipiravir plus lopinavir/ritonavir, lopinavir/ritonavir alone, or favipiravir alone, is associated with a decrease in viral load of SARS-CoV-2 compared with placebo. TRIAL DESIGN: FLARE is a phase IIA randomised, double-blind, 2x2 factorial placebo-controlled, interventional trial. PARTICIPANTS: This trial is being conducted in the United Kingdom, with Royal Free Hospital, London as the lead site. Participants are non-hospitalised adults with highly suspected COVID-19 within the first 5 days of symptom onset, or who have tested positive with SARS-CoV-2 causing COVID-19 within the first 7 days of symptom onset, or who are asymptomatic but tested positive for SARS-CoV-2 for the first time within the last 48 hours. Inclusion criteria are as follows: 1. Any adult with the following: Symptoms compatible with COVID-19 disease (Fever >37.8°C on at least one occasion AND either cough and/ or anosmia) within the first 5 days of symptom onset (date/time of enrolment must be within the first 5 days of symptom onset) OR ANY symptoms compatible with COVID-19 disease (may include, but are not limited to fever, cough, shortness of breath, malaise, myalgia, headache, coryza) and tested positive for SARS-CoV-2 within the first 7 days of symptom onset) (date/time of enrolment must be within the first 7 days of symptom onset) OR no symptoms but tested positive for SARS-CoV-2 within the last 48 hours (date/time of test must be within 48 hours of enrolment) 2. Male or female aged 18 years to 70 years old inclusive at screening 3. Willing and able to take daily saliva samples 4. Able to provide full informed consent and willing to comply with trial-related procedures Exclusion criteria are as follows: 1. Known hypersensitivity to any of the active ingredients or excipients in favipiravir and matched placebo, and in lopinavir/ritonavir and matched placebo (See Appendix 2) 2. Chronic liver disease at screening (known cirrhosis of any aetiology, chronic hepatitis (e.g. autoimmune, viral, steatohepatitis), cholangitis or any known elevation of liver aminotransferases with AST or ALT > 3 X ULN)* 3. Chronic kidney disease (stage 3 or beyond) at screening: eGFR < 60 ml/min/1.73m2 * 4. HIV infection, if untreated, detectable viral load or on protease inhibitor therapy 5. Any clinical condition which the investigator considers would make the participant unsuitable for the trial 6. Concomitant medications known to interact with favipiravir and matched placebo, and with lopinavir/ritonavir and matched placebo, and carry risk of toxicity for the participant 7. Current severe illness requiring hospitalisation 8. Pregnancy and/ or breastfeeding 9. Eligible female participants of childbearing potential and male participants with a partner of childbearing potential not willing to use highly effective contraceptive measures during the trial and within the time point specified following last trial treatment dose. 10. Participants enrolled in any other interventional drug or vaccine trial (co-enrolment in observational studies is acceptable) 11. Participants who have received the COVID-19 vaccine *Considering the importance of early treatment of COVID-19 to impact viral load, the absence of known chronic liver/ kidney disease will be confirmed verbally by the participant during pre-screening and Screening/Baseline visit. Safety blood samples will be collected at Screening/Baseline visit (Day 1) and test results will be examined as soon as they become available and within 24 hours. INTERVENTION AND COMPARATOR: Participants will be randomised 1:1:1:1 using a concealed online minimisation process into one of the following four arms: Arm 1: Favipiravir + Lopinavir/ritonavir Oral favipiravir at 1800mg twice daily on Day 1, followed by 400mg four (4) times daily from Day 2 to Day 7 PLUS lopinavir/ritonavir at 400mg/100mg twice daily on Day 1, followed by 200mg/50mg four (4) times daily from Day 2 to Day 7. Arm 2: Favipiravir + Lopinavir/ritonavir placebo Oral favipiravir at 1800mg twice daily on Day 1, followed by 400mg four (4) times daily from Day 2 to Day 7 PLUS lopinavir/ritonavir matched placebo at 400mg/100mg twice daily on Day 1, followed by 200mg/50mg four (4) times daily from Day 2 to Day 7. Arm 3: Favipiravir placebo + Lopinavir/ritonavir Oral favipiravir matched placebo at 1800mg twice daily on Day 1, followed by 400mg four (4) times daily from Day 2 to Day 7 PLUS lopinavir/ritonavir at 400mg/100mg twice daily on Day 1, followed by 200mg/50mg four (4) times daily from Day 2 to Day 7. Arm 4: Favipiravir placebo + Lopinavir/ritonavir placebo Oral favipiravir matched placebo at 1800mg twice daily on Day 1, followed by 400mg four (4) times daily from Day 2 to Day 7 PLUS lopinavir/ritonavir matched placebo at 400mg/100mg twice daily on Day 1, followed by 200mg/50mg four (4) times daily from Day 2 to Day 7. MAIN OUTCOMES: The primary outcome is upper respiratory tract viral load at Day 5. SECONDARY OUTCOMES: Percentage of participants with undetectable upper respiratory tract viral load after 5 days of therapy Proportion of participants with undetectable stool viral load after 7 days of therapy Rate of decrease in upper respiratory tract viral load during 7 days of therapy Duration of fever following commencement of trial medications Proportion of participants with hepatotoxicity after 7 days of therapy Proportion of participants with other medication-related toxicity after 7 days of therapy and 14 days post-randomisation Proportion of participants admitted to hospital with COVID-19 related illness Proportion of participants admitted to ICU with COVID-19 related illness Proportion of participants who have died with COVID-19 related illness Pharmacokinetic and pharmacodynamic analysis of favipiravir Exploratory: Proportion of participants with deleterious or resistance-conferring mutations in SARS-CoV-2 RANDOMISATION: Participants will be randomised 1:1:1:1 using a concealed online minimisation process, with the following factors: trial site, age (≤ 55 vs > 55 years old), gender, obesity (BMI <30 vs ≥30), symptomatic or asymptomatic, current smoking status (Yes = current smoker, No = ex-smoker, never smoker), ethnicity (Caucasian, other) and presence or absence of comorbidity (defined as diabetes, hypertension, ischaemic heart disease (including previous myocardial infarction), other heart disease (arrhythmia and valvular heart disease), asthma, COPD, other chronic respiratory disease). BLINDING (MASKING): Participants and investigators will both be blinded to treatment allocation (double-blind). NUMBERS TO BE RANDOMISED (SAMPLE SIZE): 240 participants, 60 in each arm. TRIAL STATUS: Protocol version 4.0 dated 7th January 2021. Date of first enrolment: October 2020. Recruitment is ongoing, with anticipated finish date of 31st March 2021. TRIAL REGISTRATION: The FLARE trial is registered with Clinicaltrials.gov, trial identifying number NCT04499677 , date of registration 4th August 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Belimumab after B cell depletion therapy in patients with systemic lupus erythematosus (BEAT Lupus) protocol: a prospective multicentre, double-blind, randomised, placebo-controlled, 52-week phase II clinical trial.

INTRODUCTION: Few treatment options exist for patients with systemic lupus erythematosus (SLE) who fail conventional therapy. Although widely used to treat lupus, the efficacy of B cell depletion therapy using rituximab has not been demonstrated in randomised clinical trials. Following rituximab, elevated levels of serum B cell activating factor (BAFF) have been associated with failure to remit or subsequent lupus relapse. The administration of belimumab, a monoclonal antibody specific for BAFF and approved for lupus therapy, could potentiate the efficacy of rituximab and enable longer periods of disease remission. The aim of this trial is to assess the safety and efficacy of belimumab following rituximab in patients with SLE. METHODS AND ANALYSIS: BEAT Lupus is a double-blind, randomised, placebo controlled, phase II clinical trial. Patients with SLE commencing a treatment cycle of rituximab (two 1g infusions, 2 weeks apart) as standard of care will be randomised to receive belimumab or placebo, 4 to 8 weeks following the first rituximab infusion. Belimumab or placebo infusions are administered for 52 weeks. The primary outcome measure is anti-double stranded DNA (anti-dsDNA) antibody levels at 52 weeks. Secondary outcomes include measures of adverse events, lupus disease activity and cumulative steroid dose. The kinetics of B cell repopulation will be assessed in a subgroup of participants. Belimumab administration after rituximab may provide a novel therapeutic pathway for patients with active lupus if safety is demonstrated in this proof of concept study, and lower anti-dsDNA antibodies levels are achieved in those patients treated with belimumab compared with placebo. ETHICS AND DISSEMINATION: The protocol has been reviewed and approved by the Hampstead Research Ethics Committee - London (reference 16/LO/1024). Trial information is available at https://www.isrctn.com/ISRCTN47873003, and the results of this trial will be submitted for publication in relevant peer-reviewed journals. Key findings will also be presented at national and international conferences. TRIAL REGISTRATION NUMBER: ISRCTN47873; date assigned to the registry: 28 November 2016. The stage is pre-results.

Repeatability of Spectralis OCT measurements of macular thickness and volume in diabetic macular edema.

PURPOSE: We estimated coefficients of repeatability for Spectralis optical coherence tomography (OCT)-derived automated retinal thickness and volume measurements in subjects with center-involving diabetic macular edema (DME). METHODS: A total of 50 eyes of 50 consecutive patients with center-involving DME underwent four consecutive "fast" volume scans at a single session using one OCT device operated by one of two experienced operators. Bland-Altman coefficients of repeatability (CR) were calculated for automated retinal thickness measurements in the nine Early Treatment of Diabetic Retinopathy Study (ETDRS) subfields, center point thickness, and total macular volume. Scans were evaluated for significant automated retinal boundary detection error and revised estimates for CR calculated with these scans excluded. RESULTS: CR in the central subfield was 8.03 µm (95% confidence interval [CI] 7.70-8.35 µm). In other subfields, CR ranged from 6.54 to 18.25 µm. Scan sets from 13 subjects had significant boundary detection error; reanalysis with these excluded yielded a CR for the central subfield of 7.44 µm with CR for all other subfields <8 µm. CONCLUSIONS: Retinal thickness measurements in subjects with DME obtained using Spectralis OCT are considerably less variable than has been reported with other devices. Changes in central subfield thickness >8 µm can be considered more indicative of true clinical change rather than measurement variability. This finding informs clinical practice and clinical trial design.

Intersession repeatability of optical coherence tomography measures of retinal thickness in early age-related macular degeneration.

PURPOSE: To determine the intersession repeatability of Stratus optical coherence tomography (OCT) measures of retinal thickness in patients with age-related macular degeneration (AMD). METHODS: Measurement of retinal thickness was performed over four sessions over 12 weeks using a standardized OCT protocol with the fast macular thickness map in 67 non-treated eyes of 67 patients with AMD enrolled in a clinical trial. The intrapatient standard deviation (S(w) ) and 95% coefficient of repeatability (CR) (1.96×√2×S(w)), expressed in µm and as a percentage of mean retinal thickness, were calculated to estimate intersession repeatability. RESULTS: The CR was 32 µm for the average retinal thickness in the central 1 mm A1 subfield [95% confidence interval (CI) 31-33 µm] and 53 µm (95% CI 51-55 µm) for the centre-point thickness (CPT). When expressed as a percentage, the CR was 15% (95% CI 14-16) for the central 1 mm A1 subfield and 29% (95% CI 27-30) for the CPT measure. CONCLUSION: The average central 1 mm (A1) subfield retinal thickness measure shows good intersession repeatability in patients with stable, early AMD with poorer repeatability for the CPT measure. The results suggest that a change in Stratus OCT retinal thickness of more than 32 µm in the central A1 subfield is more indicative of true clinical change in these patients.

Intrasession repeatability of optical coherence tomography measures in active neovascular age-related macular degeneration.

OBJECTIVES: To determine the repeatability of Stratus optical coherence tomography fast macular thickness map analysis in patients with active neovascular age-related macular degeneration (nAMD). METHODS: Consecutive pairs of scans from 112 eyes of 112 consecutive patients with active nAMD were analyzed. The Bland-Altman coefficient of repeatability (CR) was calculated for each retinal thickness or volume measure. RESULTS: The CR for the central 1 mm macular subfield was 59 µm (18% of retinal thickness) and did not exceed 69 µm in any subfield. There was much poorer repeatability for the center-point thickness (CPT) measure (CR of 78 µm; 24%). However, in the subgroup of 38 patients with no Stratus software low analysis confidence message on either analysis map, the revised CR (42 µm) for the CPT measure and the A1 subfield (40 µm) were similar. CONCLUSION: Optical coherence tomography-derived retinal thickness measurements are subject to measurement variability in patients with active nAMD. The results suggest a change criterion of more than 59 µm in central 1 mm (A1) subfield macular thickness is necessary to distinguish true clinical change from measurement variability in these patients.

Effects of retinal morphology on contrast sensitivity and reading ability in neovascular age-related macular degeneration.

PURPOSE: To investigate the effect of changes in retinal morphology on contrast sensitivity and reading ability in patients with neovascular age-related macular degeneration (AMD) in the Avastin (bevacizumab; Genentech, South San Francisco, CA) for choroidal neovascularization (ABC) Trial. METHODS: Contrast sensitivity obtained with Pelli-Robson charts, reading ability assessed with Minnesota Reading charts, and Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) obtained by protocol refraction, were recorded. Raw Stratus optical coherence tomography (OCT; Carl Zeiss Meditec, Inc., Dublin, CA) images were analyzed with the publicly available software OCTOR, which allows precise delineation of any retinal compartment of interest. Thickness and volume were calculated for neurosensory retina, subretinal fluid (SRF), subretinal tissue, and pigment epithelium detachment, and the resulting measurements were correlated with each visual function parameter. RESULTS: One hundred twenty-two patients with newly diagnosed neovascular AMD and enrolled in the ABC Trial, were evaluated. Increased subretinal tissue volume correlated with decreased contrast sensitivity (Pearson's correlation coefficient, r = -0.4944, P = 0.001). A modest correlation was detected between SRF volume and contrast sensitivity (r = -0.2562, P = 0.004). Increased retinal thickness at the foveal center also correlated with decreased visual function (ETDRS VA: r = -0.4530, P < 0.001). CONCLUSIONS: The strongest correlation detected between the functional parameters assessed and any of the OCT-derived morphologic parameters was that between decreased contrast sensitivity and increased subretinal tissue. In the future, assessment of contrast sensitivity and reading ability, in combination with quantitative subanalysis of retinal compartments, may lead to the identification of parameters relevant to functional improvement and ultimate prognosis in patients with newly diagnosed neovascular AMD (www.controlled-trials.com number, ISRCTN83325075).

Quantitative assessment of the effects of pupillary dilation on aqueous flare in eyes with chronic anterior uveitis using laser flare photometry.

The purpose of this study is to determine whether pupillary dilation has any effect on anterior chamber flare measurements using a Kowa laser flare meter (FM-500) in patients with chronic anterior uveitis (CAU). Twenty-five eyes of 25 consecutive patients with CAU were assessed for anterior chamber inflammation by an experienced operator using the Kowa laser flare meter. Ten measurements were taken in total, with the highest and the lowest measurements deducted. The mean value and standard deviation was then recorded. One drop of tropicamide 1% and phenylephrine 2.5% was then applied and after 30 min the measurements were repeated and the results recorded. Sixteen women (64%) and nine men (36%) were recruited. The majority of patients were white Caucasian (68%). Fifteen left and ten right eyes were studied and the median (interquartile range: IQR) visual acuity was 6/9 (6/6-6/18). Iris colour was classified as brown, blue, grey/hazel and hazel. Thirteen eyes (52%) had brown irises, eight (32%) had blue, two had grey and the remainder were grey/hazel and hazel. The mean (SD) age was 50.8 (12.59) years. The median (IQR) flare reading before dilation was 17.93 (8.33-29.93) and after dilation was 15.97 (10.17-29.4). The mean change was -0.74 which was not a statistically significantly different to 0 (P=0.25) and the 95% limits of agreements ranged from -6.91 to 5.43. This study showed little evidence of any systematic difference between dilated and undilated flare measurements. The measurement of flare was not affected by the dilation of the pupil and measurements could be taken before or after papillary dilation for the purpose of patient follow-up data and clinical studies.

Posterior hyaloid changes following intravitreal triamcinolone and macular laser for diffuse diabetic macular edema.

PURPOSE: To compare the effects of intravitreal triamcinolone and macular grid laser photocoagulation on the vitreomacular relationship in diffuse diabetic macular edema. METHODS: Review of optical coherence tomography images gathered in a prospective, interventional randomized clinical trial. SETTING: Institutional Practice. PROCEDURES: Seventy-seven optical coherence tomography images of 88 consecutive patients entered into a randomized clinical trial of the treatment of persistent diffuse diabetic macular edema were reviewed by two independent observers. All patients in the trial had diabetic macular edema following at least two macular grid laser treatments and were randomized to intravitreal injections of 4 mg triamcinolone or to further macular grid laser. Optical coherence tomography images were recorded at baseline, 4, 8, and 12 months and the patterns of vitreomacular relationship were classified into six categories. MAIN OUTCOME MEASURES: The patterns of vitreomacular relationship in the two groups were compared and correlated with the response to treatment. Outcome measures were defined as changes in best-corrected visual acuity Early Treatment Diabetic Retinopathy Study letters and central macular thickness on optical coherence tomography. RESULTS: Six eyes had peri-foveal vitreous detachment with or without traction in each group at baseline. At 12 months, the prevalence of peri-foveal vitreous detachment was significantly higher after intravitreal triamcinolone (n = 11) than macular grid laser (n = 8). These patients had poorer visual outcome (P = 0.01) and increased central macular thickness (P = 0.002). The development of complete posterior vitreous detachment was associated with significantly decreased central macular thickness (P = 0.001) but not better visual outcome (P = 0.72). CONCLUSION: These results suggest that posterior hyaloid changes may play a more influential role in the response to intravitreal triamcinolone than laser treatment for diffuse diabetic macular edema.

Repeatability of stratus optical coherence tomography measures in neovascular age-related macular degeneration.

PURPOSE: To determine the repeatability of Stratus optical coherence tomography (OCT) measures of retinal thickness and volume in patients with neovascular age-related macular degeneration (nAMD) METHOD: Fifty-one eyes of 51 consecutive patients with nAMD underwent an OCT imaging session in which two fast macular thickness map (FMTM) protocol scans sets were acquired by a single experienced operator certified for clinical trials work. Coefficients of repeatability for each of nine Early Treatment of Diabetic Retinopathy Study (ETDRS)-like regions, foveolar center-point retinal thickness (CPT) and total macular volume (TMV), were calculated. Scans were analyzed retrospectively for errors in retinal boundary placement by two observers, with revised coefficients of repeatability calculated after excluding any scan sets with significant segmentation error. RESULTS: The coefficient of repeatability for the central 1-mm macular subfield was 67 mum (23%) and was less than 75 mum for all macular subfields. There was much larger variability in the center-point thickness measure, with a coefficient of repeatability of 88 mum (32%) for the automated center-point thickness (ACPT). After excluding nine scan set pairs with significant segmentation error, the coefficient of repeatability for the central 1-mm macular subfield was reduced to 50 mum (19%). CONCLUSIONS: OCT-derived retinal thickness measurements are subject to considerable measurement variability in patients with nAMD. Changes in central macular thickness of more than 50 mum may better reflect true clinical change in scan sets without significant segmentation error and may be used to guide the retreatment of patients with nAMD in clinical trials and clinical practice.

Tomographic assessment of therapeutic response to uveitic macular oedema.

PURPOSE: To evaluate the therapeutic effects on the different morphological patterns of uveitic macular oedema and central macular thickness using optical coherence tomography (OCT). METHODS: Retrospective observational case series. Fifty consecutive patients with a clinical diagnosis of new or recurrent macular oedema due to uveitis were examined with serial OCTs for 1 year. The correlation between different patterns of macular oedema (diffuse macular oedema, inner cystoid oedema, outer cystoid oedema, oedema involving both inner and outer layers of retina and serous retinal detachment) and change in logMAR visual acuity and the recorded variables including age, gender, systemic disease associated with uveitis, location and duration of uveitis, and duration of macular oedema were examined. Response to treatment was measured as change in logMAR visual acuity and evolution of patterns of macular oedema. RESULTS: Diffuse macular oedema, external cystoid and serous retinal detachment responded well to treatment. Cysts in the inner retinal layers were more resistant to treatment. The cysts in the outer layers disappeared faster than cysts in the inner layers in patients with cysts in both layers at baseline. Multivariate analysis showed that cystoid macular oedema (all types) (P = 0.03) and inner cystoid oedema (P = 0.031) were the variables significantly associated with final visual acuity. CONCLUSION: Assessment of patterns of uveitic macular oedema by OCT gives useful information on the prognosis. Inner retinal cystoid oedema is more resistant to treatment than any other patterns of oedema.