Enoxaparin in COVID-19 Moderate to Severe Hospitalized Patients

COVID-19 Clinical Trial

— INHIXACOV19  

Official title:

Intermediate Dose Enoxaparin in Hospitalized Patients With Moderate-severe COVID19: A Pilot Phase II Single-arm Study, INHIXACOVID19

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04427098
• Other study ID #: 2020-001308-40
• Status: Recruiting
• Phase: Phase 2
• Start date: May 22, 2020
• Est. completion date: October 30, 2020

Study information

• Verified date: June 2020
• Source: Azienda Ospedaliera Universitaria di Bologna Policlinico S. Orsola Malpighi
• Contact: Andrea Romagnoli, MD
• Phone: 0039 050 0984040
• Email: aromagnoli[@]ricerchenuove.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 (Oxigen 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 300
• Est. completion date: October 30, 2020
• Est. primary completion date: October 30, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 90 Years

Eligibility

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

Related Conditions & MeSH terms

• COVID-19

Intervention

Drug:
• Enoxaparin 40 Mg/0.4 mL Injectable Solution
Subcutaneous enoxaparin 40 mg once daily for 14 days.
• Enoxaparin
Subcutaneous enoxaparin for 14 days: 60 mg once daily in case of body weight of 45 to 60 kg; 80 mg once daily in case of weight from 61 to 100 kg; 100 mg once daily in case of bodyweight >100 kg

Locations

Country	Name	City	State
Italy	Policlinico S. Orsola Malpighi Dipartimento Malattie Infettive	Bologna	Emilia Romagna
Italy	Fondazione Poliambulanza Chirurgia Vascolare	Brescia
Italy	Piazzale Spedali Civili, 1, 25123 Brescia BS Medicina Interna UniBS 2° Medicina ASST Spedali Civili	Brescia
Italy	Azienda Ospedaliero-Universitaria "Policlinico - V. Emanuele", Catania Anestesia e Rianimazione UO Malattie Infettive	Catania
Italy	ASST Cremona Unità Operativa di Chirurgia Vascolare Dipartimento di Medicina di Laboratorio e di Radiologia- Centro Emostasi e Trombosi	Cremona
Italy	Ospedale Morgagni Pierantoni U.O.C. Malattie Infettive	Forlì
Italy	Ospedale Carlo Poma di Mantova MALATTIE INFETTIVE Padiglione 37 Str. Lago Paiolo, 10, 46100 Mantova	Mantova
Italy	AZIENDA OSPEDALIERA Regionale S CARLO POTENZA Struttura Complessa Interaziendale "Malattie Infettive"	Matera
Italy	Ospedale San Raffaele Unità Funzionale dell'Unità Operativa di Malattie Infettive Osp. San Raffaele	Milano
Italy	Azienda Ospedaliero-Universitaria di Parma Anestesia e Rianimazione Dipartimento di Medicina e Chirurgia	Parma	Emilia Romagna
Italy	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)	San Giovanni Rotondo	Foggia
Italy	Ospedale Amedeo di Savoia Torino Università di Torino Malattie Infettive	Torino
Italy	Azienda Ospedaliera Universitaria Integrata Verona UOC Malattie Infettive e Tropicali	Verona

Sponsors (1)

Lead Sponsor	Collaborator
Azienda Ospedaliera Universitaria di Bologna Policlinico S. Orsola Malpighi

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To investigate the efficacy of enoxaparin in improving the clinical outcome of hospitalized patients with moderate-severe COVID-19.	Rates of hospitalized patients dead for all-cause within 30 days and 90 days from the first LMWH subcutaneous injection	30 days and 90 days from the first LMWH subcutaneous injection
Primary	To investigate the efficacy of enoxaparin in improving the clinical outcome of hospitalized patients with moderate-severe COVID-19.	Based on the four levels scale of severity of symptoms. Any change from one level to another will be detected for all the enrolled patients, in order to evalutate the clinical efficacy of enoxaparin on the outcome of COVID 19.	This evaluation will be performed at 30 days and 90 days from the first LMWH subcutaneous injection
Primary	To investigate the efficacy of enoxaparin in improving the clinical outcome of hospitalized patients with moderate-severe COVID-19.	Evolution of the clinical severity during treatment, based on the number and rate of patients admitted to ICU and the length of their ICU stay	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
Primary	To investigate the efficacy of enoxaparin in improving the clinical outcome of hospitalized patients with moderate-severe COVID-19.	Difference between groups in number of days of hospitalization from admission to discharge	This evaluation will be performed at 90 days from admission
Secondary	To analyse the safety of enoxaparin in hospitalized patients with moderatesevere 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.	45 days
Secondary	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.	90 days