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PROphylaxis for paTiEnts at Risk of COVID-19 infecTion -V (PROTECT-V)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04870333
Recruitment Status : Recruiting
First Posted : May 3, 2021
Last Update Posted : March 8, 2022
Sponsor:
Collaborators:
LifeArc
Kidney Research UK (KRUK)
UNION therapeutics
Addenbrookes Charitable Trust
GlaxoSmithKline
National Institute for Health Research, United Kingdom
Information provided by (Responsible Party):
Dr. Rona Smith, Cambridge University Hospitals NHS Foundation Trust

Brief Summary:

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, will be conducted in India, sponsored by The George Institute. Recruitment of approximately 750 Indian patients will commence in February 2022.

The second agent, intranasal and inhaled ciclesonide and matched placebo, will be added to the platform in early 2022 in the same renal patient population.

Sotrovimab and matched placebo will be added to the platform in early 2022 in patients who have mounted sub-optimal vaccine responses to vaccines against SARS CoV-2.


Condition or disease Intervention/treatment Phase
Covid19 Drug: Niclosamide Drug: Placebo Drug: Ciclesonide Drug: Sotrovimab Phase 2 Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 5000 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

The following populations will be defined for efficacy and safety analyses:

  • Intent-to-treat population (ITT) The ITT population is defined as all participants randomised in the trial, regardless of whether they actually received trial treatment. The treatment group will be analysed as randomised.
  • Safety population The safety population comprises all participants randomised and having received as least one dose of trial treatment. The treatment group will be analysed as treated.
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description: PROTECT-V will be a double blind placebo controlled study where neither the participant nor clinician will be aware of treatment allocation.
Primary Purpose: Prevention
Official Title: PROphylaxis for paTiEnts at Risk of COVID-19 infecTion
Actual Study Start Date : February 19, 2021
Estimated Primary Completion Date : July 2023
Estimated Study Completion Date : October 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: 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.

Drug: Niclosamide
140μL of a 1% niclosamide ethanolamine solution in each nostril twice daily, equivalent to 1.4mg of niclosamide ethanolamine salt per nostril twice daily, approximately 12 hours apart. Total daily dose 5.6mg niclosamide ethanolamine salt (4.7mg free niclosamide acid). Treatment duration will be 6-9 months or up to 28 days after COVID-19 diagnosis unless hospitalised. Participants hospitalised with a diagnosis of COVID-19 should stop the randomised treatment immediately.

Placebo Comparator: 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.
Drug: Placebo
140μL of a matching placebo solution in each nostril twice daily. Treatment duration will be 6-9 months or up to 28 days after COVID-19 diagnosis unless hospitalised. Participants hospitalised with a diagnosis of COVID-19 should stop the randomised treatment immediately.

Active Comparator: 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.

Drug: Ciclesonide

Participants will be prescribed ciclesonide once daily, administered as follows:

Two puffs (320 μg) inhaled via mouth sequentially One puff (160 μg) inhaled via nose Treatment duration will be 6-9 months or up to 28 days after COVID-19 diagnosis unless hospitalised. Participants hospitalised with a diagnosis of COVID-19 should stop the randomised treatment immediately.


Placebo Comparator: Placebo ciclesonide
Matched placebo contains the same solvent and propellant as the active product but no drug substance.
Drug: Placebo

Matched placebo: two puffs inhaled via mouth sequentially and one puff inhaled via nose.

Treatment duration will be 6-9 months or up to 28 days after COVID-19 diagnosis unless hospitalised. Participants hospitalised with a diagnosis of COVID-19 should stop the randomised treatment immediately.


Experimental: 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
Drug: Sotrovimab

There will be a single infusion of sotrovimab administered at the beginning of the study.

500mg of sotrovimab solution (8mL) will be diluted in 42mL of 0.9% sodium chloride and administered by intravenous infusion. 50mLs to be infused over 30 minutes with a 0.2 micrometre inline filter.


Placebo Comparator: Placebo sotrovimab
This will be in the form of 0.9% sodium chloride 50mL 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.
Drug: Placebo
There will be a single infusion placebo, in the form of 50mL 0.9% sodium chloride, administered at the beginning of the study.




Primary Outcome Measures :
  1. Confirmed symptomatic COVID-19 infection during treatment [ Time Frame: 6-9 months. Reported at 24 weeks for niclosamide and ciclesonide arms and 16 weeks for sotrovimab arm ]

    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.


Secondary Outcome Measures :
  1. Time to confirmed SARS-Cov-2 infection from the date of randomisation including asymptomatic cases [ Time Frame: 6-9 months ]
  2. Safety [ Time Frame: 9 months ]
    SAE and SAR since consent until end of follow-up. Safety will be assessed weekly for the first 4 weeks and then 2-weekly from 6th week onwards using a questionnaire that includes common COVID symptoms and all expected reactions to the trial. Investigators will also report any SAE or SAR within 24 hours of awareness.

  3. All-cause mortality [ Time Frame: 9 months ]
  4. Severity of COVID-19 disease [ Time Frame: 28 days after date of positive test ]
    Severity of COVID-19 disease (assessed by PI 28 days after date of positive test following current guidelines)


Other Outcome Measures:
  1. Occurrence of other infections [ Time Frame: 6-9 months ]
    Occurrence of other influenza infection (swab confirmed) - niclosamide arm only Occurrence of other respiratory viral infections (aside from COVID-19 and influenza) Staphylococcus aureus infections (dialysis population only)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Core protocol

Inclusion Criteria:

- 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)

Exclusion Criteria:

  • 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-19.

    • 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:

  1. Significant structural nasal disease in the opinion of the investigator
  2. Prior participation in the ciclesonide arm of the trial (if being re-screened for participation in a second interventional arm).
  3. 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).
  4. Received a live vaccine within last 14 days - ciclesonide increases risk of generalised infection: influenza, MMR, rotavirus, typhoid, varicella-zoster (shingles), yellow fever.
  5. Taking one of the following medications

    ○ Systemic Ketoconazole, itraconazole, ritanovir, nelfinavir

    SOTROVIMAB ARM Additional Inclusion Criteria

    • Absent or suboptimal response (Roche Elecsys® Anti-SARS-CoV-2 assay result <400 AU/mL) to COVID-19 vaccination (sub-optimal/absent vaccination response to be confirmed via centralised COVID-19 antibody assay as part of screening visit prior to randomisation; central lab will report the result of the assay to site as either 'positive' or 'negative' using the pre-specified threshold)

    AND

    • 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:

    • Antibody response to COVID-19 vaccination above the pre-specified threshold, as measured by the central laboratory antibody assay
    • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04870333


Contacts
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Contact: Rona Smith, Dr +44 1223336817 ronasmith@doctors.org.uk

Locations
Show Show 35 study locations
Sponsors and Collaborators
Cambridge University Hospitals NHS Foundation Trust
LifeArc
Kidney Research UK (KRUK)
UNION therapeutics
Addenbrookes Charitable Trust
GlaxoSmithKline
National Institute for Health Research, United Kingdom
Investigators
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Principal Investigator: Rona Smith, Dr Cambridge University Hospitals NHS Foundation Trust
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Responsible Party: Dr. Rona Smith, Senior Research Associate, Cambridge University Hospitals NHS Foundation Trust
ClinicalTrials.gov Identifier: NCT04870333    
Other Study ID Numbers: CCTU0307
2020-004144-28 ( EudraCT Number )
First Posted: May 3, 2021    Key Record Dates
Last Update Posted: March 8, 2022
Last Verified: February 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Dr. Rona Smith, Cambridge University Hospitals NHS Foundation Trust:
dialysis
solid organ transplant
vasculitis
glomerulonephritis
systemic lupus erythematosus
haematopoietic stem cell transplant
oncology or haematology patient who is or has received chemotherapy or who is immunocompromised as a result of their disease or treatment
diagnosis of an autoimmune/inflammatory disease currently receiving immunosuppression
primary immunodeficiency
Additional relevant MeSH terms:
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COVID-19
Infections
Respiratory Tract Infections
Pneumonia, Viral
Pneumonia
Virus Diseases
Coronavirus Infections
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Lung Diseases
Respiratory Tract Diseases
Ciclesonide
Niclosamide
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Anti-Allergic Agents
Anticestodal Agents
Antiplatyhelmintic Agents
Anthelmintics
Antiparasitic Agents
Anti-Infective Agents
Antinematodal Agents