Clinical trial NCT04427098: Enoxaparin in COVID-19 Moderate to Severe Hospitalized Patients
Official title: Intermediate Dose Enoxaparin in Hospitalized Patients With Moderate-severe COVID19: A Pilot Phase II Single-arm Study, INHIXACOVID19
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: COVID-19
Lead sponsor: IRCCS Azienda Ospedaliero-Universitaria di Bologna
Sponsor class: OTHER
First posted: 2020-06-11
Enrollment: 301
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The study consists of two parts:

* a phase II single-arm interventional prospective study including all patients treated with the study drug;
* an observational prospective cohort study including all patients screened for receiving the study drug but not included in the phase II study.
Primary purpose: TREATMENT

Brief summary: General objective of the study To assess the efficacy and safety of enoxaparin in hospitalized patients with moderate to severe COVID-19 (Coronavirus Disease 2019) infection.

Study Design

The study consists of two parts:

* a phase II single-arm interventional prospective study including all patients treated with the study drug;
* an observational prospective cohort study including all patients screened for receiving the study drug but not included in the phase II study.

Patients will be enrolled from "date of study approval" for 1 month. Each patient will be followed-up for a minimum of 90 days after COVID19 diagnosis.

Detailed description: General objective of the study To assess the efficacy and safety of enoxaparin in hospitalized patients with moderate to severe COVID-19 infection.

Specific objectives Primary Endpoints To investigate the efficacy of enoxaparin in improving the clinical outcome of hospitalized patients with moderate to severe COVID-19.

* All-cause in-hospital, 30-day and 90-day mortality rates.
* Evolution of the clinical severity during treatment.
* ICU admission and length of ICU stay.
* Length of hospital stay.

Secondary Endpoints To analyse the safety of enoxaparin in hospitalized patients with with moderate to severe COVID-19.

* Rate of adverse events (AEs) during treatment, at the end of treatment (EOT) and at 30 days after EOT.
* Severity of AEs classified according to common terminology criteria for adverse events (CTCAE). The worst degree ever suffered will be considered.

To describe the rates and the types of thromboembolic events among hospitalized patients with confirmed diagnosis of COVID-19.

* Occurrence of thromboembolic event at 90 days after COVID-19 diagnosis.
* Description of the type, distribution and severity of thromboembolic events.

Study Design Overall Design

The study consists of two parts:

* a phase II single-arm interventional prospective study including all patients treated with the study drug;
* an observational prospective cohort study including all patients screened for receiving the study drug but not included in the phase II study.

Patients will be enrolled from "date of study approval" for 1 month. Each patient will be followed-up for a minimum of 90 days after COVID19 diagnosis.

End of Study Definition A participant is considered to have completed the study if he/she has completed the last scheduled procedure shown in the Schedule of assessments. The end of the study is defined as the date of the last scheduled procedure shown in the Schedule of assessments for the last participant in the trial.

Study Population

Definitions

Clinical severity of COVID-19 will be assessed at the diagnosis of COVID19, during the treatment with the study drug, and at the end of treatment according to the following criteria (1):

* Mild patients: only show mild symptoms without radiographic features
* Moderate patients: have fever, respiratory symptoms, and radiographic signs of pneumonia
* Severe patients: have fever, respiratory symptoms, and radiographic signs of pneumonia plus at least one of three criteria: (1) RR (respiratory rate) \>30 times/min, (2) oxygen saturation \<93% on ambient air, (3) PaO2/FiO2 (Oxygen partial pressure/inspired oxygen fraction ) \<300 mmHg.
* Critical patients: meet one of three criteria: (1) respiratory failure needing invasive ventilation, (2) septic shock, (3) multiple organ failure.

Major bleeding will be defined according to the ISTH (International Society of Thrombosis and Haemostasis) criteria as one of the following:

* Fatal bleeding
* Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome
* Bleeding causing a fall in haemoglobin level of 2 g/dL or more, or leading to transfusion of two or more units of whole blood or red cells (11).

Treatments Administration and monitoring of study drug

All patients screened for being included in the study will receive standard thrombo-prophylaxis with LMWH (low molecular weight heparin) (e.g. enoxaparin 40 mg/die). Patients included in the observational cohort will continue on standard thrombo-prophylaxis, while patients included in the interventional study will receive subcutaneous enoxaparin in a single daily dose of:

* 60 mg once daily in case of body weight of 45 to 60 kg
* 80 mg per day in case of weight from 61 to 100 kg or
* 100 mg once daily in case of bodyweight \>100 kg Enoxaparin will be started on the first day of COVID19 diagnosis and continued for 14 days, after determination of baseline PT (prothrombin time), aPTT (activated partial thromboplastin time), complete blood cell count and creatinine levels.

After reaching the steady state (usually after the third dose), heparin levels will be measured with the determination of anti-Xa activity on a blood sample obtained at 4 hours after the morning injection. LMWH dose may be then increased or reduced on the basis of target anti-Xa activity (0.4-0.6 antiFXa (Anti Factor X activated) UI/ml (International Unit/ml) for intermediate doses). The determination of anti-Xa activity will be repeated on the fifth or sixth day to monitor any drug accumulation.

Complete blood cell count will be obtained every second day to monitor for heparin induced thrombocytopenia.

Single low dose antiplatelet agents will be allowed. In all patients, RT-PCR (reverse transcription-polymerase chain reaction) nasopharyngeal swabs will be performed every 7 days to assess virus clearance and blood samples will be collected at baseline and on day 7 and will be retrospectively analysed to measure viral load.

Follow up procedures Patients will be followed-up to 90 days after study drug initiation. Follow-up information will be collected via telephone calls, patient medical records and/or clinical visits according to clinical evolution.

This is a pilot study and an initial sample of 100 patients for the phase II single-arm interventional trial is established. Even if currently precise data are not available, it can be assumed that the composite endpoint is around 30% in patient treated with the standard thromboprophylaxis dose of enoxaparin. To verify the hypothesis that the experimental treatment may produce a halving of this endpoint (from 30% to 15%), 300 patients (200 for the observational cohort and 100 for the phase II cohort; ratio 2:1) are needed with a 80% power and a 0,05 bilateral alpha error. As stated above a first safety analysis after enrolling the first 50 patients in the interventional study arm is planned and it will be done by an independent committee. According to safety and efficacy data obtained, using as control the observational cohort, a large study with a more robust design is planned.

Eligibility criteria: Inclusion Criteria:

* For both interventional study and observational cohort, hospitalized patients are eligible to be included if the following criteria apply:

Inclusion criteria:

* Age \>=18 y
* Microbiologically confirmed COVID-19 infection
* Patients with moderate to severe disease according to study definitions (see below)
* Informed consent to participate and to use data for interventional study, only to use data for observational cohort

Exclusion Criteria:

* Participants are excluded from the interventional study if any of the following criteria apply:

  * Thrombocytopenia (platelet count \< 50.000 mm3)
  * Coagulopathy: INR (International normalized ratio) \>1.5, aPTT ratio \>1.4
  * Impaired renal function (clearance to creatinine less than 15 ml/min)
  * Known hypersensitivity to heparin
  * History of heparin induced thrombocytopenia
  * Presence of an active bleeding or a pathology susceptible of bleeding in presence of anticoagulation (e.g. recent haemorrhagic stroke, peptic ulcer, malignant tumors at hig risk of haemorrhages, recent neurosurgery or ophthalmic surgery, vascular aneurysms, arteriovenous malformations)
  * Body weight \<45 or \> 150 kg
  * Concomitant anticoagulant treatment for other indications ( eg atrial fibrillation, venous thromboembolism , prosthetic heart valves).
  * Dual antiplatelet therapy
  * Pregnant or breast-feeding women

Primary outcomes:
measure: Mortality
timeFrame: 30 days and 90 days from the first LMWH subcutaneous injection
measure: Effectivness of enoxaparin on the outcome of COVID 19.
timeFrame: This evaluation will be performed at 30 days and 90 days from the first LMWH subcutaneous injection
measure: ICU admission and length of ICU stay
timeFrame: This evaluation will be performed at 14 days (the last day of treatment adminstration), at 30 days and 90 days from the first LMWH subcutaneous injection
measure: Lenght of hospital stay
timeFrame: This evaluation will be performed at 90 days from admission
Secondary outcomes:
measure: To describe the rates and the types of thromboembolic events among hospitalized patients with confirmed diagnosis of COVID-19.
timeFrame: 90 days
measure: Advers Events
timeFrame: 45 days
Other outcomes:
Locations:
city: Bologna
country: Italy
facility: Policlinico S. Orsola Malpighi Dipartimento Malattie Infettive
state: Emilia Romagna
city: Parma
country: Italy
facility: Azienda Ospedaliero-Universitaria di Parma Anestesia e Rianimazione Dipartimento di Medicina e Chirurgia
state: Emilia Romagna
city: San Giovanni Rotondo
country: Italy
facility: I.R.C.C.S. "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG) UOVD Emostasi e trombosi- Poliambulatorio Giovanni Paolo II Viale Padre Pio n.7 San Giovanni Rotondo (FG)
state: Foggia
city: Brescia
country: Italy
facility: Fondazione Poliambulanza Chirurgia Vascolare
city: Brescia
country: Italy
facility: Piazzale Spedali Civili, 1, 25123 Brescia BS Medicina Interna UniBS 2° Medicina ASST Spedali Civili
city: Catania
country: Italy
facility: Azienda Ospedaliero-Universitaria "Policlinico - V. Emanuele", Catania Anestesia e Rianimazione UO Malattie Infettive
city: Cremona
country: Italy
facility: ASST Cremona Unità Operativa di Chirurgia Vascolare Dipartimento di Medicina di Laboratorio e di Radiologia- Centro Emostasi e Trombosi
city: Forlì
country: Italy
facility: Ospedale Morgagni Pierantoni U.O.C. Malattie Infettive
city: Mantova
country: Italy
facility: Ospedale Carlo Poma di Mantova MALATTIE INFETTIVE Padiglione 37 Str. Lago Paiolo, 10, 46100 Mantova
city: Matera
country: Italy
facility: AZIENDA OSPEDALIERA Regionale S CARLO POTENZA Struttura Complessa Interaziendale "Malattie Infettive"
city: Milano
country: Italy
facility: Ospedale San Raffaele Unità Funzionale dell'Unità Operativa di Malattie Infettive Osp. San Raffaele
city: Torino
country: Italy
facility: Ospedale Amedeo di Savoia Torino Università di Torino Malattie Infettive
city: Verona
country: Italy
facility: Azienda Ospedaliera Universitaria Integrata Verona UOC Malattie Infettive e Tropicali
Study officials:
affiliation: Infectious Diseases Unit, Dep. Med. and Surg. Science University of Bologna
name: Pierluigi Viale, MD
role: PRINCIPAL_INVESTIGATOR
References: