Mild COVID-19 outpatients managed by General Practitioners in Northern Italy (Lombardy)

Mild, moderate and severe inpatients managed in different Italian Hospitals, mostly in Northern Italy (Lombardy)

COVID-19

Cardiovascular Risk Factor

Istituto Auxologico Italiano

Predictors of Cardiovascular Risk in Covid-19 Patients During Acute Disease and at Short Term Follow-up

Cardiovascular Risk in COVID-19 Patients: Metabolic, Prothrombotic and Proinflammatory Mechaninsms Associated With Outcome and With Cardiorespiratory Features During the Acute Viral Disease and at Short Term Follow-up

To obtain a multivariable model based on anthropometric, clinical and therapeutic variables that will allow to predict the development of severe COVID-19 and its complications

To Identify the role of selected clinical, pathophysiological and molecular mechanisms in the development of COVID-19 disease and its clinical manifestations of different severity

To Identify the clinical, immunological, inflammatory, viral, cardiorespiratory consequences of COVD-19 that may persist a few months after discharge and may affect mid- and long-term prognosis

Sharing individual participants data that underlie the results included in published articles, after deidentification

"Lifestyle modifications" group (Control) will consist of a 1,000-calorie/day diet and to maintain proper sleep hygiene and habits (avoid supine decubitus position, maintain regular sleep habits and exercise, not take sedatives, stimulants, alcohol, tobacco or heavy meals within four hours before bedtime). Oxygen therapy can be prescribed by the treating team using standard criteria (awake PaO2 <55 mmHg or room air oxygen saturation below 88% (Masa JF et al. J Clin Sleep Med. 2016 ;12:1379-88)

Automatic NIV: In addition to lifestyle modification and oxygen (if required), the ventilator will be adjusted to a range of predetermined parameters with the intelligent ventilation mode (pressure of intelligent support with guaranteed volume with automatic backup frequency) with the following adjustment: maximum pressure: 35 cmH2O; respiratory rate: automatic; maximum pressure support: 20 cm H2O; minimum pressure support: 4 cmH2O; maximum EPAP pressure: 15 cmH2O; minimum EPAP pressure: 4 cmH2O; and tidal volume (Vt) based on 8-10 ml/kg of predicted body weight. These parameters may be modified according to patient tolerance or non-compensated leak.

In-laboratory polysomnographic NIV titration will be performed according to published guidelines (Berry R et al JCSM 2010). In addition to lifestyle modification and oxygen (if required), home NIV therapy with fixed pressures will be started. The ventilator mode will be a bilevel PAP with backup respiratory rate (BIPAP S/T mode). The ventilator adjustment will be firstly performed in awake situation and then during sleep by means of a PSG.

In-laboratory polysomnographic CPAP titration will be performed according to published guidelines (SEPAR guideline or AASM guideline). In addition to lifestyle modification and oxygen (if required), home CPAP therapy at a fixed pressure will be initiated.

Acute on Chronic Hypercapnic Respiratory Failure

Obesity Hypoventilation Syndrome (OHS)

It will consist of a 1,000-calorie/day diet and to maintain proper sleep hygiene and habits (avoid supine decubitus position, maintain regular sleep habits and exercise, not take sedatives, stimulants, alcohol, tobacco or heavy meals within four hours before bedtime). Oxygen therapy can be prescribed by the treating team using standard criteria (awake PaO2 <55 mmHg or room air oxygen saturation below 88% (Masa JF et al. J Clin Sleep Med. 2016 ;12:1379-88). The treatment period will be three months.

"Lifestyle modifications" group (Control)

In addition to lifestyle modification and oxygen (if required), the ventilator will be adjusted to a range of predetermined parameters with the intelligent ventilation mode (pressure of intelligent support with guaranteed volume with automatic backup frequency) with the following adjustment: maximum pressure: 35 cmH2O; respiratory rate: automatic; maximum pressure support: 18 cm H2O; minimum pressure support: 4 cmH2O; maximum EPAP pressure: 15 cmH2O; minimum EPAP pressure: 4 cmH2O; and tidal volume (Vt) based on 8-10 ml/kg of predicted body weight, being able to be modified according to tolerance.The treatment period will be three months.

Automatic NIV

In-laboratory polysomnographic CPAP titration will be performed according to published guidelines for CPAP titration (SEPAR guideline or AASM guideline).In addition to lifestyle modification and oxygen (if require), a home titrated CPAP therapy will be initiated.The treatment period will be three years.

CPAP treatment group

In-laboratory polysomnographic NIV titration will be performed according to published guidelines In addition to lifestyle modification and oxygen (if required) home NIV therapy with fixed pressures will be started. The ventilator mode will be a bilevel pressure in S/T mode. The ventilator adjustment will be firstly performed in awake situation and then during sleep by means of a PSG. The treatment period will be three years.

NIV treatment groups

"Post-acute Pickwick Study" (Postacute-Pick-2020)

"Mid- and Long-term Effectiveness of Positive Airway Pressure in OHS After an Acute-on-chronic Hypercapnic Respiratory Failure"

Primary (medium-term from the first phase or RCT): the medium-term efficacy of automatic NIV treatment versus "lifestyle modifications" treatment in OHS measuring as primary outcome a composite including hospital and ICU admissions, emergency department visits for any cause, and all-cause mortality measured as the number of events/year

Primary (long-term from the second phase or RCT): the long-term efficacy of titrated CPAP therapy versus titrated NIV therapy in OHS measuring as primary outcome a composite including hospital and ICU admissions, emergency department visits for any cause, and all-cause mortality measured as the number of events/year

Separately the components of the primary outcome: hospital admissions measured as the number of events/year

Separately the components of the primary outcome: ICU admissions measured as the number of events

Separately the components of the primary outcome: emergency department visits for any cause measured as the number of events/year

Separately the components of the primary outcome: All-cause mortality number

Duration of hospital admissions measured in days of hospital admission

Duration of ICU admissions measured in days of ICU admission

Number of patients who change of the allocated arms

Number of patients with lower extremity edema classified into four levels of intensity (from 1 to 4)

Number of patients with unrefreshing sleep classified into four levels of intensity (from 1 to 4)

Number of patients with morning fatigue classified into four levels of intensity (from 1 to 4)

Number of patients with nocturia classified into four levels of intensity (from 1 to 4)

Number of patients with headache classified into four levels of intensity (from 1 to 4)

Number of patients with morning confusion classified into four levels of intensity (from 1 to 4)

Number of patients with dysnea according to the Medical Research Council scale classified into four levels of intensity (from 1 to 4)

Level of perceived sleepiness measured by the Epworth Sleepiness Scale

Scoring of Functional Outcomes of Sleep Questionnaire-- FOSQ---

Scoring of European health-related quality of life questionnaire (EuroQol) EQ-5D-5L

Scoring of Subjective state of illness on a visual analogical scale: Visual Analogical Well-being Scale -VAWS (Masa JF et al. Sleep Breath. 2011;15:549-59) measured in percentage.

Systolic and diastolic blood pressure measured in mmHg

Incidence of new hypertension diagnosis or initiation of a new anti-hypertensive treatment

Incidence of new atrial fibrillation diagnosis

Incidence of new hospitalization for nonfatal myocardial infarction

Incidence of new hospitalization for nonfatal angina

Incidence of new hospitalization for coronary percutaneous interventions

Incidence of new hospitalization for nonfatal stroke or transient ischemic attack

Incidence of new hospitalization for acute heart failure episode

Number of adverse events according to Treatment-Related Adverse Events as assessed by CTCAE v4.0

Differences in within trial costs will be related with the differences in effectiveness (primary outcome and QALY) between arms using a probabilistic Bayesian approach to calculate the cost-effectiveness plane.

Efficacy of automatic NIV treatment versus "lifestyle modifications" treatment measuring a composite outcome including hospital and ICU admissions, emergency department visits for any cause, and all-cause mortality measured as the number of events/year comparing adherent vs. non-adherent to PAP therapy subgroups (lower and higher of a mean of 4 h/day)

Efficacy of automatic NIV treatment versus CPAP treatment measuring a composite outcome including hospital and ICU admissions, emergency department visits for any cause, and all-cause mortality measured as the number of events/year comparing adherent vs. non-adherent to PAP therapy subgroups (lower and higher of a mean of 4 h/days)

Comparative efficacy between treatment arms measuring a composite outcome including hospital and ICU admissions, emergency department visits for any cause, and all-cause mortality measured as the number of events/year in the subgroups with PaCO2 higher or lower of 45 mmHg at the end of follow-up

Comparative efficacy between treatment arms measuring a composite outcome including hospital and ICU admissions, emergency department visits for any cause, and all-cause mortality measured as the number of events/year in the subgroups with or without supplemental oxygen therapy at baseline

Comparative efficacy between treatment arms measuring a composite outcome including hospital and ICU admissions, emergency department visits for any cause, and all-cause mortality measured as the number of events/year in the subgroups with higher and lower hypercapnia at baseline (above and below of the median PaCO2 measured in mmHg)

Comparative efficacy between treatment arms measuring a composite outcome including hospital and ICU admissions, emergency department visits for any cause, and all-cause mortality measured as the number of events/year in the subgroups with higher and lower apnea-hypopnea index at baseline (above and below of the median apnea-hypopnea index at baseline)

Comparative efficacy between treatment arms measuring a composite outcome including hospital and ICU admissions, emergency department visits for any cause, and all-cause mortality measured as the number of events/year in the subgroups with or without hypertension diagnosis at baseline

Comparative efficacy between treatment arms measuring a composite outcome including hospital and ICU admissions, emergency department visits for any cause, and all-cause mortality measured as the number of events/year in the subgroups with different home care providers (i.e. AirLiquide)

To perform a validity analysis of EQ 5D-5L test

Additional related documents such as study protocol, statistical analysis plan, and informed consent form will be available upon request from the Project principal investigator (Dr. Juan Fernando Masa). Deidentified patients' data can be requested by researchers for use in independent scientific research and will be provided following review and approval of the research proposal (including statistical analysis plan) and completion of a data sharing agreement with the Project Publications Committee. Investigator Data requests can be made anytime from 1 to 2 years after the publication of this trial. Requests should be sent to the corresponding author (Dr. Juan Fernando Masa- fmasa@separ.es).

Juan F. Masa

Principal Investigator

Prospective, randomized, double arm, open in two sequential randomized controlled trias of phases

Patients with snoring and OSAS. Therapy with MAD type H-MAD with lateral hinges according to Herbst.
Bite elevation 2 mm interocclusal distance with a lower jaw advancement of 5 mm

Patients with snoring and OSAS,Fusion MAD with sliding side wings (F-MAD). Bite elevation 5 mm interocclusal distance with a lower jaw advancement of 5 mm

Obstructive Sleep Apnea Syndrome

Temporomandibular Disorders

The randomized grouping into blocks at a ratio of 1: 1 takes place over sealed envelopes containing the allocation key for the respective MAD. The assignment is stratified according to gender because gender is a strong predictor of sleep disorders and also temporomandibular dysfunctions Integration of the MAD (start of treatment) The laboratory-made MAD (F-MAD / H-MAD) is integrated and checked for a comfortable fit. The patient is instructed to always wear the splint during sleep.
All patients receive an extended guide to jaw gymnastics with the instruction to do it in the morning after waking up and in the evening before falling asleep.
Four weeks after incorporation, the titration phase begins, the slow adjustment of mandibular advancement to optimize sleep medical parameters while minimizing unwanted side effects.
Control appointments take place after four weeks, six months, one year and two years after insertion of the MAD

H-MAD with a hinge system according to Herbst

Dental Office Dr. Krumholz

Dental Office Dr. Schlieper

Dental Office Dr. Hauschild

Zahnarztpraxis Weststadt

Dental Office Dr. Kares

Dental Office Dr. Heckmann

Dental Office Dr. Meyer

Dental Office Dr. Nauert

Mund-Zahn-Kiefer-Klinik

Side Effects of Mandibular Advancement Devices

Side Effects of Two Different Mandibular Advancement Devices (MAD) in the Treatment of Snoring and Obstructive Sleep Apnea Syndrome (OSAS)

change of orofacial pain after applying the MAD measured by numeric rating scale (NRS; 0-10, 0: no pain, 10: worst imaginable pain)

number of pressure pain points on palpation of the masticatory muscles and in the area of the temporomandibular joints according to the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD)

change of the number of occluding posterior teeth

change in sleep quality after applying the MAD measured by Pittsburgh Sleep Quality Index retrospectively asks for a four-week period the incidence of sleep disturbing events, sleep quality assessment, sleep habits, sleep latency and sleep duration, sleeping medication use.

Change in daytime sleepiness measured by Epworth Sleepiness Scale. ESS is a short questionnaire for the detection of daytime sleepiness. (ESS, 0-24, <11 no daytime sleepiness)

Oral Health Impact profile (OHIP-5) is a measurement tool for assessing the oral health-related quality of life in adults. It consists of 5 questions for functional limitation, physical pain, psychological discomfort, physical disability, social disability

Graded Chronic Pain Scale (GCPS) questionnaire records pain intensity and the presence of functional or dysfunctional chronic pain. Three subscale scores (characteristic pain intensity, disability score, and the disability points score) are used to classify subjects into 1 of the 5 pain severity grades: grade 0 for no pain, grade 1displays low disability, low intensity, grade 2 displays low disability but high intensity, grade 3 displays high disability,moderately limiting and grade 4 displays high disability and severely limiting.

University Medicine Greifswald

Multicenter, randomized two-arm study with active control group, stratified by gender.

Unblinded with respect to the examiner, blinded to the patient and statisticians in the evaluation.

hypoventilation/infarkts

Predictors of Cardiovascular Risk in Covid-19 Patients During Acute Disease and at Short Term Follow-up

"Post-acute Pickwick Study" (Postacute-Pick-2020)

Side Effects of Mandibular Advancement Devices

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