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Cyproheptadine

Histamine H1 Antagonists

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Phase 1: Cyproheptadine 4 mg three time a day for 10 days, per oral administration associated to Standard care of COVID 19 patient currently recommend by WHO

Phase 2: Cyproheptadine 8 mg three time a day for 10 days, per oral administration associated to Standard care of COVID 19 patient currently recommend by WHO

The dose will be adjusted according to the renal function.

Cyproheptadine Hydrochloride 4 MG

This is a Pilot study for evaluating the feasibility, security and efficacy of the use of Cypropheptadine, an antihistaminic and antiserotonin drug, as an adjunct of the standardized treatment in a population of patient who are hospitalized and requiring oxygen therapy for COVID-19.

Background :

Biochemical studies have revealed a significant increase in plasma serotonin levels in patients suffering from COVID-19 multi-organ disease, which appears to be a consequence of platelet hyperreactivity and dysfunction.

Among the several potential therapeutic pathways available to modulate this serotonin dysregulation is the use of cyproheptadine, an Anti-serotonergic antihistamine that can potentially improve organ dysfunction related to elevated plasma serotonin levels.

The investigators hypothesize that treatment with cyproheptadine will improve clinical course in these patients.

Objectives:

Primary objective

Compare the clinical course according to the WHO ordinal severity score for COVID-19, between a retrospective and a prospective interventional cohort of patient hospitalized in the same hospital.

Secondary objectives

Evaluate the safety of the use of the cyproheptadine hospitalized patients presenting COVID 19.

Evaluate the study in term of Feasibility Recruitment rate and Study completion rate.

Evaluate the outcome in term of Death, Needs of Non-invasive and/or invasive mechanical ventilation and Total Length of hospitalization Evaluate the evolution of clinical indicators of oxygenation and blood parameters of inflammation, renal function, hepatic cytolysis and platelet count.

Design:

This pilot trial is a non-blinded clinical designed to access the feasibility, the security and the efficacy of the use of Cyproheptadine in patient hospitalized in a single center for Covid-19 with comparison between:

A retrospective cohort study of patient and treated by standard care according to WHO international guidelines.

A prospective study of a cohort of patients hospitalized for covid 19 taking oral Cyproheptadine during 10 days in addition to standard care according to WHO international guidelines. The prospective study will be divided into two different phases in which two different doses of cyproheptadine will be administered.

Pilot Study for Cyproheptadine in Hospitalized Patient for COVID-19

Pilot Study for Cyproheptadine in Hospitalized Patient for COVID-19: a Single-center, Observational Retrospective-prospective Comparative Study.

World Health Organisation Clinical Progression Scale for COVID 19 Minimal value 0 (uninfected) to maximal value 10 (Dead)

Safety evaluation, as measured by suspected as related to cyproheptadine during the first 28 days after inclusion in the study:

Adverse events

Adverse drug reactions

Serious adverse event and adverse drug reaction

Worst value of ROX ratio (SPO2/FiO2/Respiratory Rate) at D3,5,7,10,14,28

Worst value of Laboratory assessment of Creatinine at Days 3,5,7,10,14,28 after inclusion in the study

Worst value of Laboratory assessment of Alanine amino transferase at Days 3,5,7,10,14,28 after inclusion in the study

Worst value of Laboratory assessment of CRP at Days 3,5,7,10,14,28 after inclusion in the study

Worst value of Laboratory assessment of D-Dimere at Days 3,5,7,10,14,28 after inclusion in the study

Worst value of Laboratory assessment of platelet count at Days 3,5,7,10,14,28 after inclusion in the study

Ciusss de L'Est de l'Île de Montréal

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Cola

Patients undergoing elective glioma resection

Patients undergoing elective colon cancer resection

The following blood samples will be drawn for hemostasis evaluation: 1. Conventional clotting tests, 2. Rotational thromboelastometry (ROTEM), including EXTEM and FIBTEM; 3. Platelet function as assessed by PFA-200 for; and 4. Platelet function as assessed by ara-tem, adp-tem and trap-tem. All the analyses will be performed before (within a period 24-h before surgery) and after (within of the following periods: 2 h, 24 h and 48 h after surgery).

Exposure to glioma resection surgery

Exposure to colon resection surgery

Santiago R. Leal-Noval, MD Ph.D

Santiago R Leal-Noval, MD

Prospective, observational study aimed to investigate the specific hemostatic alterations in patients undergoing glial tumor resection.

Brain parenchyma express tissue factor and other coagulation factors in high concentrations. In addition, neuro critical patients (NCP) may present platelet dysfunction, hyperfibrinolysis, hypo coagulation and / or hyper coagulation status, early after the injury. It is not known whether these alterations of hemostasis are due to a specific brain response to aggression, or they are included into a systemic response. This prospective, observational study is aimed to investigate the coagulation disorders specifically associated with cerebral aggression.

This is a prospective, cohort study including (calculated sample size) a study group of patients undergoing elective surgery (glial tumors) and other one undergoing colo rectal surgery. Alterations of the hemostasis will be evaluated by clotting tests, thromboelastometry and tests for platelet function. Samples will be drawn before and after surgical procedures. Multiple statistical comparisons intra and inter groups will be performed.

Hemostasis Alterations in Neurosurgical Patients

Prospective Study on Hemostasis Alterations in Patients Undergoing Neuro Surgical Glioma Resection Acronym: (ABCD Study: Acute Brain Coagulopathy Development Study)

Blood samples for assessing INR (clotting tests) will be drawn in these periods of time "t": "t0" (before surgery) and t1 (2-hour after surgery), t2 (24-hour after surgery) and t3 (48-hour after surgery). Changes from t0 to t1, t2 and / or t3 will be considered.

Blood samples for assessing aPTT (clotting tests) will be drawn in these periods of time "t": "t0" (before surgery) and t1 (2-hour after surgery), t2 (24-hour after surgery) and t3 (48-hour after surgery). Changes from t0 to t1, t2 and / or t3 will be considered.

Blood samples for assessing CT / EXTEM (measured by thromboelastometry test) will be drawn in these periods of time "t": "t0" (before surgery) and t1 (2-hour after surgery), t2 (24-hour after surgery) and t3 (48-hour after surgery). Changes from t0 to t1, t2 and / or t3 will be considered.

Blood samples for assessing MCF / EXTEM (measured by thromboelastometry test) will be drawn in these periods of time "t": "t0" (before surgery) and t1 (2-hour after surgery), t2 (24-hour after surgery) and t3 (48-hour after surgery). Changes from t0 to t1, t2 and / or t3 will be considered.

Blood samples for assessing ML (measured by thromboelastometry test) will be drawn in these periods of time "t": "t0" (before surgery) and t1 (2-hour after surgery), t2 (24-hour after surgery) and t3 (48-hour after surgery). Changes from t0 to t1, t2 and / or t3 will be considered.

Blood samples for assessing col EPI (measured by platelet function analyzer : PFA-200 test) will be drawn in these periods of time "t": "t0" (before surgery) and t1 (2-hour after surgery), t2 (24-hour after surgery) and t3 (48-hour after surgery). Changes from t0 to t1, t2 and / or t3 will be considered.

Blood samples for assessing A6 (amplitude at 6 minutes, ohm), MS (maximum slope, ohm/min), and AUC (area under curve, ohm\* min), all of then measured by platelet function analyzer ROTEM will be drawn in these periods of time "t": "t0" (before surgery) and t1 (2-hour after surgery), t2 (24-hour after surgery) and t3 (48-hour after surgery). Changes from t0 to t1, t2 and / or t3 will be considered.

Blood samples for assessing CT / FIBTEM (measured by thromboelastometry test) will be drawn in these periods of time "t": "t0" (before surgery) and t1 (2-hour after surgery), t2 (24-hour after surgery) and t3 (48-hour after surgery). Changes from t0 to t1, t2 and / or t3 will be considered.

Blood samples for assessing MCF / FIBTEM (measured by thromboelastometry test) will be drawn in these periods of time "t": "t0" (before surgery) and t1 (2-hour after surgery), t2 (24-hour after surgery) and t3 (48-hour after surgery). Changes from t0 to t1, t2 and / or t3 will be considered.

Any bleeding occurring during this period.

Instituto de Salud Carlos III

Santiago R. Leal-Noval

Santiago R. Leal-Noval, MD, PhD, Critical Care specialist

Start Cyproheptadine 8mg three times a day during 5 days. Dose will be reduced to 4mg three times a day if GFR inferior to 30ml/min/1.73m²

Standard management of COVID-19 infection according to current international guidelines

Standard management of COVID-19 infection according to current international guidelines

Cyproheptadine associated to standard care

Philippe Rola, MD

Alexandre Noel, MD

This randomized controled open label clinical trial is to evaluate the effect of Cyproheptadine on the clinical course of patients presenting a severe SARS-COV 2 pneumonia.

Observational and biochemical studies have identified an interesting pathway in the pathophysiology of certain clinical-biological characteristics of COVID-19, linked to an excess of serotonin. We hypothesize that the antagonism of the action of serotonin could improve the clinical course of patients most severely affected by COVID-19.

One such antagonist of serotonin with a long track record of safety and tolerability is cyproheptadine. Cyproheptadine acts as an antagonist of 5-hydroxytryptamine (5HT=serotonin) receptor subtype 2 as well as histamine-1 receptor. Many of the potent effects of serotonin on lung vascular tone, respiratory rate, and systemic vascular beds are mediated by 5-HT receptor subtype 2.

Investigators will randomize approximately 200 participants, aged 18 and older, who have tested positive for COVID-19 and who will be hospitalized at Santa Cabrini Hospital in Montreal, Quebec, Canada, presenting a severe form of covid-pneumonia-19 requiring supplemental oxygen.

Study eligibility of all participants will be assessed first. Once a participant is confirmed eligible and consented, they will participate in the study.

Participants will be randomly assigned (1: 1) to either take cyproheptadine 8 mg by mouth three times a day for 5 days and receive standard care or receive standard care alone.

The dose will be adjusted according to the glomerular filtration rate.

On D1, D3, D5, D7 and D10 since randomization, participant's vital signs (including SpO2, respiratory rate, FiO2 or oxygen flow, heart rate, blood pressure and temperature), blood creatinine, bilirubin, CRP, LDH, Dimers and platelets the count will be evaluated. Any adverse event will be assessed daily and documented.

Cyproheptadine in Severe COVID-19 : A Unblinded Randomized Trial

Sequential Organ Failure Min Score 0-Max score 24 Higher scores mean a worse outcome

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Pilot Study for Cyproheptadine in Hospitalized Patient for COVID-19	NCT04876573	Viral Pneumonia COVID-19 Pneumo... Serotonin Syndr... Platelet Dysfun...	Cyproheptadine ...	18 Years -	Ciusss de L'Est de l'Île de Montréal
Hemostasis Alterations in Neurosurgical Patients	NCT02652897	Glioma Coagulopathy Acquired Platel... Thromboelastome... Surgery	Exposure to gli... Exposure to col...	18 Years -	Hospitales Universitarios Virgen del Rocío
Cyproheptadine in Severe COVID-19 : A Unblinded Randomized Trial	NCT04820751	Viral Pneumonia Serotonin Syndr... Platelet Dysfun...	Cyproheptadine ...	18 Years - 99 Years	Ciusss de L'Est de l'Île de Montréal
Hemostasis Alterations in Neurosurgical Patients	NCT02652897	Glioma Coagulopathy Acquired Platel... Thromboelastome... Surgery	Exposure to gli... Exposure to col...	18 Years -	Hospitales Universitarios Virgen del Rocío

Spots Global Cancer Trial Database for platelet dysfunction