PROphylaxis for paTiEnts at Risk of COVID-19 infecTion
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 2,240
- 试验地点
- 45
- 主要终点
- Confirmed symptomatic COVID-19 infection during treatment
研究概览
简要总结
COVID-19 (SARS-CoV2 virus) was declared a global pandemic by the WHO on 11th March 2020. Currently there are no drugs proven to prevent COVID-19 or to reduce the severity of illness if given as prophylaxis. Although vaccines are now available, there remains a need for other prophylactic agents until vaccine use becomes widespread globally and effectiveness and durability is established, particularly in immunocompromised individuals, for whom vaccine responses may be suboptimal. Efforts are underway to repurpose established drugs with well understood drug interactions and safety profiles.
PROTECT-V is a platform trial to test prophylactic interventions against SARS-CoV2 infection in vulnerable patient populations at particularly high risk of COVID-19 and its complications, seeking to identify treatments that either might prevent the disease from occurring or may reduce the number of cases where the disease becomes serious or life-threatening.
In PROTECT-V, multiple agents can be evaluated on the same platform across vulnerable populations, with the option of adding additional treatments at later time points as these become available. The expectation is for as many sites as possible to recruit to all available trial treatments at any time, however, the platform structure and randomisation/data collection systems allow sites to open the trial treatment arms according to their capacity.
The trial opened with intranasal niclosamide and matched placebo, aiming to recruit 1500 vulnerable renal patients in February 2021. A parallel study protocol, was conducted in India, sponsored by The George Institute. Recruitment of around 750 Indian patients was completed in with the rest of the study arm recruitment in November 2022. The Niclosamide arm of the study was completed in June 2023.
The second agent, intranasal and inhaled ciclesonide and matched placebo, was meant to be added to the platform in mid-2022 in the same renal patient population however it was unable to be included due to other factor.
Sotrovimab and matched placebo have been added to the platform in August 2022 which aim to recruit approximately 800-1000 patients from the main study population with additional patient groups with primary immunodeficiency, any Haematology or Oncology patient who is currently receiving or has received chemotherapy or who is immunocompromised as a result of their disease or treatment, those with a diagnosis of an autoimmune or inflammatory disease receiving immunosuppression and also haematopoietic stem cell transplant recipients.
详细描述
Part 1: Inhaled repurposed agents The trial commenced with the first intervention, nasal niclosamide and matched placebo from February 2021. The intended second intervention is nasal and inhaled ciclesonide. Participants are being randomised in a 1:1 ratio until the second intervention is introduced. Once ciclesonide is introduced, participants who are eligible for ciclesonide will be randomised to niclosamide, ciclesonide, niclosamide matching placebo or ciclesonide matching placebo in a 2:2:1:1 ratio. The net result will be a 1:1:1 distribution between niclosamide, ciclesonide and placebo, with niclosamide-matching placebo and ciclesonide-matching placebo pooled for the analysis.
Three vulnerable patient populations were enrolled initially: dialysis patients, kidney transplant recipients and those with vasculitis or other auto-immune kidney disease such as systemic lupus erythematosus (SLE) or glomerulonephritis (GN) These patient groups are noted to be particularly vulnerable to COVID-19 infection by virtue of demographics, underlying co-morbidities or as a consequence of treatments for these conditions, and they are at exceptionally high risk of adverse outcomes. Additionally these groups are known to mount sub-optimal responses to vaccination.
Approximately 1500 participants will be randomised to active treatment or placebo, stratified by PROTECT sub-population, age and participating sites. Enrolment to the trial will be via an online platform following informed consent with a face to face screening visit. The screening visit will include assessment of eligibility (which will include liver function tests and COVID-19 PCR test), randomisation, baseline data collection and research serum sample collection to detect anti SARS-COV-2 antibodies. Subsequent assessments, aside from an in person end of trial visit, will be done via email or telephone together with utilising the routine collected health data thus reducing the burden to participants as well as reducing their exposure to COVID-19. Telephone consultations will be carried out at weeks 1, 2, 3, 4 and 6, followed by two weekly self-reporting at week 8 onwards.
If a participant has not submitted data for a period of approximately 6 weeks, they will be contacted by the local study team for a telephone interview to minimise loss to follow up. Failure to follow up a participant for more than 6 consecutive weeks will halt their trial treatment dispensation until communication has been restored. Failure to follow up a participant for more than 12 consecutive weeks will be considered loss of follow up and conclude their participation in the trial.
If a participant develops symptoms suggestive of COVID-19 infection they should arrange an urgent COVID-19 test. They should notify their trial physician. Participants should continue taking trial medication (if self-administering medication) until advised to stop by a member of the trial team or admitted to hospital. Any participant testing positive for SARS-CoV-2 will be required to complete a COVID-19 symptom assessment at least weekly for 4 weeks after diagnosis, unless hospitalised.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Triple (Participant, Care Provider, Investigator)
盲法说明
PROTECT-V will be a double blind placebo controlled study where neither the participant nor clinician will be aware of treatment allocation.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Be aged 18 years or older
- •Have given written informed consent
- •Be a member of one of the following vulnerable patients populations
- •Dialysis - including in centre haemodialysis, home haemodialysis and peritoneal dialysis
- •Kidney transplant receiving at least one of the immunosuppressive medications listed below
- •Vasculitis (according to Chapel Hill Consensus Conference 2012 definitions) or systemic lupus erythematosus (SLE) receiving at least one of the immunosuppressive medications listed below
- •Glomerulonephritis (includes prior histological confirmation of any of the following conditions - minimal change nephropathy, focal segmental glomerulosclerosis (FSGS), IgA nephropathy, primary membranous nephropathy, membranoproliferative glomerulonephritis or lupus nephritis) receiving at least one of the immunosuppressive medications listed below Ciclosporin Tacrolimus Azathioprine Mycophenolate Mofetil or Mycophenolic Acid Belatacept Methotrexate Tocilizumab Abatacept Leflunomide Sirolimus Prednisolone (current dose) > 20mg daily for 8 weeks Anti-TNF (infliximab, adalimumab, etanercept) Belimumab Cyclophosphamide (within the last 6 months) Rituximab (in the last 12 months) or Rituximab in the last 5 years and IgG level <5g/l Alemtuzumab (in the last 12 months)
排除标准
- •Inability to provide informed consent or to comply with trial procedures
- •COVID-19 at time of enrolment - either positive SARS CoV-2 swab (PCR) or symptoms highly suggestive of COVID-19 infection
- •Known chronic liver disease or hepatic dysfunction as evidenced by ALT or AST > 3x upper limit of the normal range
- •Allergy or hypersensitivity to any of the active IMPs, or to any of the excipients used
- •Pregnant, trying to conceive, unwilling to use contraception or breastfeeding
- •Current participation in another interventional prophylactic or vaccine trial* against COVID-
- •Patients remain eligible for enrolment if they have received SARS-COV-2 vaccination as part of routine care.
- •NICLOSAMIDE ARM Additional exclusion criteria
- •Significant structural nasal disease in the opinion of the investigator
- •Prior participation in the niclosamide arm of the trial (if being re-screened for participation in a second interventional arm).
- •CICLESONIDE ARM Additional Exclusion Criteria
- •In addition to the core exclusion criteria in the master protocol, the presence of any of the following will preclude participant inclusion:
- •Significant structural nasal disease in the opinion of the investigator
- •Prior participation in the ciclesonide arm of the trial (if being re-screened for participation in a second interventional arm).
- •Currently taking inhaled corticosteroids - beclometasone dipropionate (aerosol inhaler and dry powder inhaler), budesonide (dry powder inhaler and single-dose units for nebulization), ciclesonide (aerosol inhaler), fluticasone propionate (dry powder inhaler, aerosol inhaler, and single-dose units for nebulization), mometasone furoate (dry powder inhaler).
- •Received a live vaccine within last 14 days - ciclesonide increases risk of generalised infection: influenza, MMR, rotavirus, typhoid, varicella-zoster (shingles), yellow fever.
- •Taking one of the following medications ○ Systemic Ketoconazole, itraconazole, ritanovir, nelfinavir
- •SOTROVIMAB ARM Additional Inclusion Criteria
- •Be a member of an immunocompromised population, which includes but is not limited to those groups listed in the core protocol as well as the following:
- •Primary immunodeficiency
- •Any Oncology, Haematology-Oncology or Haematology patient who is currently receiving or has received chemotherapy or who is immunocompromised as a result of their disease or treatment
- •Have a diagnosis of an autoimmune/inflammatory disease currently receiving immunosuppression including those individuals currently on Prednisolone ≥20mg daily for at least 4 weeks. Those who have received Rituximab or Alemtuzumab within the last 12 months would also be eligible.
- •Solid organ and haematopoietic stem cell transplant recipients
- •Additional Exclusion Criteria
- •In addition to the core exclusion criteria in the master protocol, the presence of any of the following will preclude participant inclusion:
- •If in the opinion of the PI it is not in the best interests of the participant to take part in the study - for example due to limited life expectancy (≤12 months) due to pre-existing co-morbidities
- •History of hypersensitivity reaction to sotrovimab, one of its excipients or any other monoclonal antibody targeting SARS CoV-2
- •History of receiving any monoclonal antibody targeting SARS CoV-2 within the last 6 months
- •Admission to hospital for acute, unplanned care at the time of randomisation or in the two weeks prior to screening
- •History of receiving chimeric antigen receptor T-cell (CAR-T) therapy less than 4 weeks prior to consenting to take part in the study
研究组 & 干预措施
Niclosamide
INN: Niclosamide Ethanolamine Chemical name (IUPAC): 5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide.2 aminoethanol CAS registry number: 1420-04-8 Lab code: UNI911
The IMPs niclosamide Nasal Spray 1% and matching Nasal Spray Placebo will be provided in 20 mL amber glass vials with nasal spray pumps, containing 8.5 mL of the respective solution, delivering 140 μL per spray shot. It is an isotonic and euhydric aqueous solution with red colour.
干预措施: Niclosamide (Drug)
Placebo niclosamide
Placebo to match niclosamide will be supplied, stored, labelled, dispensed and dosed as for the active formulation. The placebo product is formulated to have the same appearance as the active solution.
干预措施: Placebo (Drug)
Ciclesonide
Chemical name (IUPAC): 2-[(1S,2S,4R,8S,9S,11S,12S,13R)-6-cyclohexyl-11-hydroxy-9,13-dimethyl-16-oxo-5,7-dioxapentacycloicosa-14, 17-dien-8-yl]- 2-oxoethyl 2-methylpropanoate CAS registry number: 141845-82-1
It is a pressurised solution, intended for inhalation use and commercialised under the brand Alvesco. The recommended dose of ciclesonide is 160μg once daily, which leads to asthma control in the majority of patients. However, this may be increased if necessary to 320μg twice daily, in severe asthma.
干预措施: Ciclesonide (Drug)
Placebo ciclesonide
Matched placebo contains the same solvent and propellant as the active product but no drug substance.
干预措施: Placebo (Drug)
Sotrovimab
Sotrovimab, VIR-7831, GSK4182136 Sterile solution for intravenous infusion, 62.5 mg/mL, intravenous infusion Colourless or yellow to brown, liquid solution 20 mM histidine, 7% sucrose (w/v), 0.04% PS80 (w/v), 5 mM L-methionine at pH 6.0
干预措施: Sotrovimab (Drug)
Placebo sotrovimab
This will be in the form of 0.9% sodium chloride 100mL for infusion and will be sourced from commercially available stock by the site. It may be procured and stored as per sites usual procedures and only requires handling as an IMP upon dispensing and labelling.
干预措施: Placebo (Drug)
结局指标
主要结局
Confirmed symptomatic COVID-19 infection during treatment
时间窗: 6-9 months. Reported at 24 weeks for niclosamide and ciclesonide arms and 12 weeks for sotrovimab arm from date of IMP administration.
The primary outcome for PROTECT is confirmed symptomatic COVID-19 infection during treatment. The primary outcome event is defined as the presence of both * PCR confirmed SARS-CoV2 and * One or more symptoms in keeping with COVID-19, including: * Respiratory (Cough +/- sputum and shortness of breath) * Constitutional (Pyrexia/chills, myalgia/arthralgia, fatigue, rash, headache, confusion) * Gastrointestinal (nausea/vomiting, diarrhoea, abdominal pain, loss of appetite) The date (time) of the primary outcome event is defined as the date of the confirmed COVID-19 test.
次要结局
- Time to confirmed SARS-Cov-2 infection from the date of randomisation including asymptomatic cases. In addition, confirmed symptomatic COVID-19 infection at 16, 24, 36, and 48 weeks from date of IMP administration.(6-9 months)
- Safety and seriousness of the event(9 months)
- All-cause mortality(9 months)
- Severity of COVID-19 disease(28 days after date of positive test)
研究者
Dr. Rona Smith
Senior Research Associate
Cambridge University Hospitals NHS Foundation Trust