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Efficacy and Safety of Novel Treatment Options for Adults With COVID-19 Pneumonia (CCAP)

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: NCT04345289
Recruitment Status : Recruiting
First Posted : April 14, 2020
Last Update Posted : May 29, 2020
Sponsor:
Information provided by (Responsible Party):
Thomas Benfield, Hvidovre University Hospital

Brief Summary:

CCAP is an investigator-initiated multicentre, randomized, double blinded, placebo-controlled, multi-stage trial, which aims to assess the safety and efficacy of novel treatment option of moderate-severe COVID-19.

Participants will be randomized 1:1:1:1:1:1 to parallel treatment arms: Convalescent plasma, sarilumab, hydroxychloroquine, baricitinib, intravenous and subcutaneous placebo, or oral placebo.

Primary outcome is a composite endpoint of all-cause mortality or need of invasive mechanical ventilation up to 28 days.


Condition or disease Intervention/treatment Phase
COVID Corona Virus Infection Viral Pneumonia Biological: Convalescent anti-SARS-CoV-2 plasma Drug: Sarilumab Drug: Baricitinib Drug: Hydroxychloroquine Other: Injective placebo Other: Oral placebo Phase 3

Detailed Description:

The study is a randomized, double blinded, placebo-controlled, multicenter, multi-stage study with six parallel treatment arms consisting of either convalescent plasma, sarilumab, hydroxychloroquine, baricitinib, intravenous and subcutaneous placebo, or oral placebo. We plan to enroll 250 patients in each arm, with a total of 1500 patients yielding a statistical power of 81 % to show a 40% relative reduction in risk of mechanical ventilation or death at day 28. Patients with confirmed COVID-19 infection and signs compatible with pneumonia will be enrolled in the study. The participants will be randomized 1:1:1:1:1:1 to the parallel treatment arms, and depending on the randomization receive either single dose injection/infusion treatment or oral treatment for 7 days.

The primary outcome is a composite endpoint of all-cause mortality or need of invasive mechanical ventilation up to 28 days. Interim analysis will be performed frequently. We will apply a win ratio matched approach to evaluate the primary endpoint

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1500 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Adaptive multi-arm trial comparing several different experimental treatments against two control groups. Interim analyses are included at 75 and 175 matched participants to compare the effect and safety of each experimental treatment to control (placebo). The results of the interim analyses are used to decide if one or more treatments should be discontinued due to either futility or harm. An arm is discontinued if either of the predefined stopping criteria are met. For the remaining arms, further patients are recruited until a decision has been reached or until a maximum number of patients is reached.

Additional experimental treatments may be added as they become available. Any efficacious treatment identified in this or any other high-quality RCT may become the new SOC after consensus by national and international societies, and, thus, the control arm will change accordingly and in parallel.

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

Infusion treatment (convalescent plasma and placebo) will be administered via a colored intravenous line with a colored sleeve disguising the fluid bag. Injective treatment (sarilumab and placebo) will be administered in a prepared syringe. Oral treatment (hydroxychloroquine, baricitinib placebo and active treatment) will be prepared in non-identifiable and identical capsules.

In order to achieve blinding of participants and treating personnel, patients randomized to active treatment will also receive placebo treatment.

Primary Purpose: Treatment
Official Title: Efficacy and Safety of Novel Treatment Options for Adults With COVID-19 Pneumonia. A Double-blinded, Randomized, Multi-stage, 6-armed Placebo-controlled Trial in the Framework of an Adaptive Trial Platform
Actual Study Start Date : May 1, 2020
Estimated Primary Completion Date : June 15, 2021
Estimated Study Completion Date : June 15, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Pneumonia

Arm Intervention/treatment
Active Comparator: Convalescent plasma
Will receive active treatment with convalescent anti-SARS-CoV-2 plasma (600 ml) as a single dose iv infusion + placebo treatment with saline 0.9% (1.14 mL) as a single sc injection, in addition to standard care.
Biological: Convalescent anti-SARS-CoV-2 plasma
Single infusion of convalescent anti-SARS-CoV-2 plasma (2 x 300 mL)
Other Name: Convalescent plasma

Active Comparator: Sarilumab
Will receive active treatment with sarilumab (200 mg) as a single sc injection + placebo treatment with saline 0.9% (600 ml) as a single dose iv infusion, in addition to standard care.
Drug: Sarilumab
Pre-filled syringe 200 mg (1.14 mL) as a single dose
Other Name: Kevazara

Placebo Comparator: Injective placebo
Will receive placebo treatment with saline 0.9% (600 ml) as an iv single dose infusion + placebo treatment with saline 0.9% (1.14 mL) as a single sc injection, in addition to standard care.
Other: Injective placebo
Saline 0.9% (600 ml) as an iv single dose infusion + placebo treatment with saline 0.9% (1.14 mL) as a single sc injection

Active Comparator: Hydroxychloroquine
Will receive active treatment with hydroxychloroquine (600 mg) as a daily oral administration for 7 days in addition to standard care.
Drug: Hydroxychloroquine
Tablets 600 mg/day for 7 days
Other Name: Plaquenil

Active Comparator: Baricitinib
Will receive active treatment with baricitinib (4 mg) as oral administration for 7 days + oral placebo treatment for 7 days, in addition to standard care.
Drug: Baricitinib
Tablets 4 mg/day for 7 days
Other Name: Olumiant

Placebo Comparator: Oral placebo
Will receive placebo treatment with three glucose monohydrate placebo capsules daily for 7 days, in addition to standard care.
Other: Oral placebo
Three glucose monohydrate placebo capsules daily for 7 days




Primary Outcome Measures :
  1. All-cause mortality or need of invasive mechanical ventilation [ Time Frame: 28 days ]
    Composite outcome


Secondary Outcome Measures :
  1. Frequency of adverse events [ Time Frame: 90 days ]
    Number of participants with adverse events with possible relation to study drug

  2. Frequency of severe adverse events [ Time Frame: 90 days ]
    Number of participants with serious adverse events according to International Council of Harmonisation-Good Clinical Practice (ICH-GCP) guidelines

  3. Time to improvement of at least 2 categories relative to baseline on a 7-category ordinal scale of clinical status [ Time Frame: 90 days ]
    Number of days to improvement of at least 2 categories relative to baseline on the ordinal scale. Categories are as follows: Death; Hospitalized, in intensive care requiring Extracorporeal Membrane Oxygenation (ECMO) or mechanical ventilation; Hospitalized, on non-invasive ventilation or high-flow oxygen device; Hospitalized, requiring supplemental oxygen; Hospitalized, not requiring supplemental oxygen; Not hospitalized, limitation on activities and/or requiring home oxygen; Not hospitalized, no limitations on activities

  4. Ventilator-free days [ Time Frame: 28 days ]
    Number of days without mechanical ventilation

  5. Organ failure-free days [ Time Frame: 28 days ]
    Number of days without organ-failure

  6. Duration of ICU stay [ Time Frame: 90 days ]
    Number of days in ICU

  7. Mortality rate [ Time Frame: 7, 14, 21, 28 and 90 days ]
    Number of deaths by any cause

  8. Length of hospital stay [ Time Frame: 90 days ]
    Days from the date of hospital admission for COVID-19 to the date of discharge

  9. Duration of supplemental oxygen [ Time Frame: 90 days ]
    Days requiring supplement oxygen



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

Inclusion Criteria:

  • ≥18 years of age
  • Confirmed COVID-19 infection by presence of SARS-CoV-2 nucleic acid by polymerase chain reaction (PCR)
  • Evidence of pneumonia given by at least one of the following: SpO2 ≤93% on ambient air or PaO2/FiO2 <300 mmHg/40 kPa OR Radiographic findings compatible with COVID-19 pneumonia
  • Onset of first experienced symptom, defined as one respiratory symptom or fever, no more than 10 days before admission
  • For women of childbearing potential: Negative pregnancy test and willingness to use contraceptive (consistent with local regulations) during study period
  • Signed Informed Consent Form by any patient capable of giving consent, or, when the patient is not capable of giving consent, by his or her legal/authorized representatives

Exclusion Criteria:

  • In the opinion of the investigator, progression to death is imminent and inevitable within the next 24 hours, irrespective of the provision of treatment
  • History of allergic reaction to study drug (as judged by the site investigator)
  • Participating in other drug clinical trials (participation in COVID-19 antiviral trials may be permitted if approved by sponsor)*
  • Pregnant or breastfeeding, positive pregnancy test in a pre-dose examination or patients family planning within three months after receiving study agent
  • Estimated glomerular filtration (eGFR) <30 ml/min
  • Severe liver dysfunction (Child Pugh score C)
  • Known history of the following medical conditions: Active or latent tuberculosis (TB) or history of incompletely treated TB; Chronic hepatitis B or C infection; Retinopathy or maculopathy; Neurogenic hearing impairment
  • Presence of any of the following abnormal laboratory values at screening: Absolute neutrophil count (ANC) less than 1000 mm3 (= 1,0 x 10⁹ /L); Alanine aminotransferase (ALT) greater than 5 x upper limit of normal (ULN); Platelet count <50,000 per mm3 (= 50 x 10⁹ /L)
  • Immunosuppression, defined as following: Treatment with immunosuppressive agents, chemotherapy or immunomodulatory drugs within 30 days prior to inclusion; Use of chronic oral corticosteroids for a non-COVID-19-related condition in a dose higher than prednisolone 20 mg or equivalent per day for 4 weeks; Ongoing chemotherapy
  • Any serious medical condition or abnormality of clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of 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): NCT04345289


Contacts
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Contact: Thomas Benfield, MD, DMSc +45 38622302 thomas.lars.benfield@regionh.dk

Locations
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Denmark
Aalborg University Hospital Not yet recruiting
Aalborg, Denmark
Contact: Henrik Nielsen, MD, DMSc         
Contact       henrik.nielsen@rn.dk   
Aarhus University Hospital Not yet recruiting
Arhus, Denmark
Contact: Lars Østergaard, MD, DMSc         
Contact       larsoest@rm.dk   
Bispebjerg Hospital Not yet recruiting
Copenhagen, Denmark
Contact: Stine Johnsen, MD, PhD       stine.johnsen.01@regionh.dk   
Rigshospitalet Not yet recruiting
Copenhagen, Denmark
Contact: Jan Gerstoft, MD, DMSc         
Contact       jan.gerstoft@regionh.dk   
Herlev Gentofte Hospital Not yet recruiting
Herlev, Denmark
Contact: Kasper Iversen, MD, DMSc       kasper.karmark.iversen@regionh.dk   
Herning Hospital Not yet recruiting
Herning, Denmark
Contact: Rajesh Mohey, MD, PhD       rajemohe@rm.dk   
Nordsjællands Hospital Not yet recruiting
Hillerød, Denmark
Contact: Birgitte Lindegaard Madsen, MD, PhD       birgitte.lindegaard.madsen@regionh.dk   
Hvidovre Hospital Recruiting
Hvidovre, Denmark
Contact: Thomas Benfield, MD, DMSc    +4538622302    thomas.lars.benfield@regionh.dk   
Kolding Hospital Not yet recruiting
Kolding, Denmark
Contact: Janne Jensen, MD, PhD       janne.jensen@rsyd.dk   
Odense University Hospital Not yet recruiting
Odense, Denmark
Contact: Isik Johansen, MD, DMSc       isik.somuncu.johansen@rsyd.dk   
Roskilde Hospital Not yet recruiting
Roskilde, Denmark
Contact: Lothar Wiese, MD, PhD       low@regionsjaelland.dk   
Vejle Hospital Not yet recruiting
Vejle, Denmark
Contact: Ole Hilberg, MD, DMSc       ole.hilberg@rsyd.dk   
Sponsors and Collaborators
Thomas Benfield
Investigators
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Study Director: Sandra Hansen, MD Hvidovre University Hospital
Study Director: Simone Bastrup Israelsen, MD Hvidovre University Hospital
Study Director: Louise Thorlacius-Ussing, MD Hvidovre University Hospital
Study Director: Karen Brorup Heje Pedersen, MD Hvidovre University Hospital
Study Director: Clara Clausen, MD Hvidovre University Hospital
Study Director: Michaela Tinggaard, MD Hvidovre University Hospital
Study Director: Nichlas Hovmand, MD Hvidovre University Hospital
Publications:
World Health Organization. Coronavirus disease 2019 (COVID-19) - Situation Report 67. https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200327-sitrep-67-covid-19.pdf?sfvrsn=b65f68eb_4.

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Responsible Party: Thomas Benfield, Professor, Hvidovre University Hospital
ClinicalTrials.gov Identifier: NCT04345289    
Other Study ID Numbers: 25032020
2020-001367-88 ( EudraCT Number )
First Posted: April 14, 2020    Key Record Dates
Last Update Posted: May 29, 2020
Last Verified: May 2020
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
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Coronavirus Infections
Severe Acute Respiratory Syndrome
Pneumonia, Viral
Pneumonia
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Virus Diseases
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Hydroxychloroquine
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antirheumatic Agents