key: cord-0254248-4gbz9ovg
authors: Dupuis, J.; Laurin, P.; Tardif, J.-C.; Hausermann, L.; Rosa, C.; Guertin, M.-C.; Thibaudeau, K.; Gagnon, L.; Cesari, F.; Robitaille, M.; Moran, J. E.
title: Fourteen-days Evolution of COVID-19 Symptoms During the Third Wave in Non-vaccinated Subjects and Effects of Hesperidin Therapy: A randomized, double-blinded, placebo-controlled study.
date: 2021-10-05
journal: nan
DOI: 10.1101/2021.10.04.21264483
sha: 79e73b90ebb5d3245ad6060c4912b18144be9502
doc_id: 254248
cord_uid: 4gbz9ovg

COVID-19 symptoms can cause substantial disability, yet no therapy can currently reduce their frequency or duration. We conducted a double-blind placebo-controlled trial of hesperidin 1000 mg once-daily for 14 days in 216 symptomatic non-vaccinated COVID-19 subjects. Thirteen symptoms were recorded after 3, 7, 10 and 14 days. The primary endpoint was the proportion of subjects with any of four cardinal (group A) symptoms: fever, cough, shortness of breath or anosmia. At baseline, symptoms in decreasing frequency were: cough (53.2%), weakness (44.9%), headache (42.6%), pain (35.2%), sore throat (28.7%), runny nose (26.9%), chills (22.7%), shortness of breath (22.2%), anosmia (18.5%), fever (16.2%), diarrhea (6.9%), nausea/vomiting (6.5%) and irritability/confusion (3.2%). Group A symptoms in the placebo vs hesperidin group was 88.8% vs 88.5% (day 1) and reduced to 58.5 vs 49.4 % at day 14 (OR 0.69, 95% CI 0.38-1.27, p = 0.23). At day 14, 15 subjects in the placebo group and 28 in the hesperidin group failed to report their symptoms. In an attrition bias analysis imputing ''no symptoms'' to missing values, the hesperidin group shows reduction of 14.5 % of group A symptoms from 50.9% to 36.4% (OR: 0.55, 0.32-0.96, p = 0.03). Anosmia, the most frequent persisting symptom (29.3%), was lowered by 7.3% at 25.3 % in the hesperidin group vs 32.6% in the placebo group (p = 0.29). Mean number of symptoms in placebo and hesperidin was 5.10 {+/-} 2.26 vs 5.48 {+/-} 2.35 (day 1) and 1.40 {+/-} 1.65 vs 1.38 {+/-} 1.76 (day 14) (p = 0.92). In conclusion, most non-vaccinated COVID-19 infected subjects remain symptomatic after 14 days with anosmia being the most frequently persisting symptom. Hesperidin 1g daily may help reduce group A symptoms. Earlier treatment of longer duration and/or higher dosage should be tested.

Since the end of December 2019, the COVID-19 pandemic led to important worldwide morbidity 51 and mortality. Despite the success of vaccination, a substantial proportion of the world 52 population is still awaiting immunization and therefore at risk of getting infected with the 53 inherent risk of viral mutations that could lead to vaccine resistant strains of the virus. Most 54 infected subjects report symptoms of varying severity that can become debilitating and persist for 55 prolonged periods in a substantial proportion. Currently, no therapy that has been shown to 56 reduce the burden and length of COVID-19 symptoms in non-hospitalized subjects. 57

This was a no-contact study with the screening, randomization and follow-ups at day 3, 7, 122 10 and 14 done exclusively by phone. All randomized subjects signed an electronic informed 123 consent form using the DocuSign online service. The study medication and material were 124 delivered to the patients' home and included an oral electronic thermometer (Physio logic © 125 Acuflex Pro) and a daily symptoms log. Allocation was performed through a randomization list 126 generated by the MHICC (blocks sequence was fixed with block size of 4) and provided to the 127 MHI pharmacists who dispensed the medication (hesperidin or placebo) according to the list after 128 randomization of the participants by the study coordinators, keeping participants, investigators 129 and staff blinded to drug assignment for the whole study duration. The symptoms log listed 13 130 COVID-19 symptoms including the temperature readings in degrees Celsius. Participants were 131 asked to take two capsules (500 mg each) of study medication once daily at bedtime on an empty 132 stomach. They were requested to record their symptoms and temperature daily in the symptoms 133 log and return it to the study team at the end of their participation. At each follow-up call, the 134 information recorded in the symptoms log was captured in an electronic case report form (InForm 135 V 6.0, Oracle Health Sciences) by the study team. The trial ended according to protocol, namely 136 after last patient last visit. The hesperidin capsules and matching placebo were kindly provided 137 by Valeo Pharma (Kirkland, Quebec, Canada) . 138 139 Outcomes 140

The primary endpoint was the proportion of subjects with any of the following cardinal 141 COVID-19 symptoms: fever, cough, shortness of breath or anosmia at day 3, 7, 10 and 14. These 142 symptoms are referred to as group A symptoms in the province of Quebec, Canada. The 143 secondary endpoints were: 1) The mean number of all COVID-19 symptoms (range 0-13) at day 144 3, 7, 10 and 14; 2) Duration of COVID-19 symptoms, defined as the number of days between 145 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 5, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 first symptom and complete disappearance of any symptom; 3) For each 13 COVID-19 146 symptoms listed in the symptoms log (recent cough of aggravation of chronic cough, fever,  147   chills, sore throat, runny nose, shortness of breath, nausea/vomiting, headache, general weakness,  148 pain, irritability/confusion, diarrhea and anosmia defined as sudden loss of smell), the proportion 149 of subjects with the symptom at day 3, 7, 10 and 14. Fever was defined as a temperature of > 38.0 150 ˚C by oral temperature using the supplied electronic thermometer. 151

The study also included two exploratory endpoints: 1) For each COVID-19 listed in the 152 symptoms log, proportion of subjects with the symptom on a daily basis; and: 2) Composite of 153 COVID-19 related hospitalization, mechanic ventilation or death in the 14 days following 154 randomization. 155

The safety data were reviewed by a fully independent 3-member Data and Safety 156

Monitoring Board (DSMB) after randomization of 50 subjects. Serious adverse events were 157 reported to the DSMB on a weekly basis after their first meeting. 158 159

Sample size was based on the proportion of subjects with any of the following group A COVID-161 19 symptoms: fever, cough, shortness of breath or anosmia at day 7. We assumed that 50% of 162 placebo subjects would be symptomatic at this time point. These symptoms, referred to as group 163 A symptoms in Quebec, are among the most frequent COVID-19 symptoms and are more 164 objectively assessable. These symptoms were used as a diagnostic criterion in the 165 epidemiological definition of COVID-19 prior to the widespread use and availability of PCR 166 testing. Using a two-sided 0.05 significance level, considering achieving an 80% power to detect 167 an absolute difference of 20% between both groups in the proportion of symptomatic 168 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted October 5, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 participants, and factoring in a 15% drop out rate, we determined that 216 participants (108 per 169 group) were required to complete the study. 170

Efficacy analyses were based on an intent-to-treat (ITT) principle. All participants who 171 received the medication were included in the ITT population. The primary analysis compared the 172 proportions of subjects between both treatment groups using a generalized linear mixed model 173 (GLMM), more precisely, a repeated binary logistic regression model with terms for treatment 174 group (placebo, hesperidin), time (3, 7, 10 and 14 days) and treatment group x time interaction. 175 Contrasts under this model allowed for the comparisons of the proportions at each time point. 176

Then, for secondary analyses, number of COVID-19 symptoms was compared between treatment 177 groups using another GLMM, namely a repeated Poisson regression model with similar terms for 178 group, time and interaction. Rate ratios are presented with 95% confidence intervals and p-179 values. Duration of COVID-19 symptoms were compared using a log rank test with Meier curves. Subjects who still had at least one symptom at their last assessment were censored 181 at the day of this last assessment. The statistical approach used for primary endpoint was also 182 used to compare individual COVID-19 symptoms over time. Composite of COVID-19-related 183 hospitalization, mechanic ventilation or death were compared between both groups using a chi-184 square test. Statistical analyses were described in a statistical analysis plan that was approved 185 prior to database lock and unblinding. 186

Safety of hesperidin was evaluated with descriptive statistics on adverse events and 187 serious adverse events broken down by groups and presented on the safety population of all 188 subjects who took at least one dose of the study medication. 189

To account for a possible attrition bias and evaluate its impact, two post-hoc sensitivity 190 analyses on the primary endpoint were conducted. Both imputed data in subjects who stopped 191 reporting symptoms prior to day 14. The first analysis used the last observation carried forward 192 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 5, 2021. ; https://doi.org/10.1101/2021.10.04.21264483 doi: medRxiv preprint as a worst-case scenario to impute missing symptoms while the second imputed "no symptom" 193 when symptoms were missing as a best-case scenario. All statistical tests were two-sided and 194 conducted at the 0.05 significance level. Statistical analyses were done using SAS version 9.4. 195 196 197 RESULTS 198 The study flow-chart is shown in figure 1. 217 subjects were enrolled and there was one screen-199 fail due to administration of COVID-19 vaccine prior to randomization. 216 subjects were 200 randomized into the study with 109 assigned to placebo and 107 to hesperidin. All participants 201 who received the placebo completed the study, but there was one lost to follow-up in the 202 hesperidin group. (Table 1)  207 The demographics as well as the clinical profile at randomization are shown in table 1. 208

For the whole study population, mean age was 40.98 ± 12.14 years with a proportion of males of 209 44.9%. The delay between the beginning of symptoms and randomization in the placebo group 210 and the hesperidin group was similar at 3.78 ± 1.81 and 3.88 ± 1.89 days respectively. The mean 211 delay between COVID-19 diagnosis and randomization was 1.10 ± 0.43 days in the placebo and 212

1.10 ± 0.39 days in the hesperidin group. The most common COVID-19 symptoms in decreasing 213 frequency were: cough (53.2%), general weakness (44.9%), headache (42.6%), pain (35.2%), 214 sore throat (28.7%), runny nose (26.9%), chills (22.7%), shortness of breath (22.2%), anosmia 215 (18.5%), fever (16.2%), diarrhea (6.9%), nausea/vomiting (6.5%) and irritability/confusion 216 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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Primary endpoint: proportion of participants with group A symptoms at day 3, 7, 10 and 14 222 (Table 2) . 223 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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The proportion of subjects presenting with any of the four selected group A symptoms 224 (fever, cough, shortness of breath and anosmia) in the hesperidin group compared to the placebo 225 group were, respectively, 88.5% vs 88.8% (day 1), 91.2% vs 87.4% (day 3), 81.3% vs 75.2% 226 (day 7), 64.4% vs 60.6% (day 10) and 49.4% vs 58.5% (day 14). At 14 days, there was a 9.1% 227 absolute reduction in group A symptoms in the hesperidin group (OR: 0.69, p = 0.2328). There 228 was progressive attrition in the number of participants that reported their symptoms between day 229 1 and day 14, with 15 missing in the placebo group and 28 in the hesperidin group. In the first 230 post-hoc sensitivity analysis using the last observation carried forward imputation, there was also 231 no statistically significant difference in the primary endpoint at each time point (S2 table). In this 232 worst-case analysis, we still observed a reduction at day 14 in the hesperidin subjects from 59.3% 233 to 52.3%, a 7.0 % difference (OR 0.75, p = 0.3098). In the second post-hoc sensitivity analysis 234 imputing "no symptom" to any missing value (S2 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 5, 2021. that greatly varies depending on the symptom. For the whole duration of the study, the most 278 prominent symptoms for their frequency and duration were cough and anosmia, two group A 279 symptoms which affected 60.8% and 43.9% of participants at day 1 and persisted in 28.7% and 280 29.3% of them, respectively, at day 14. Some other symptoms such as runny nose, shortness of 281 breath/difficulty breathing, headache and general weakness were still present in more than 10% 282 of the whole population at the end of the study. All other symptoms were markedly reduced with 283 time and only affected a small proportion of patient at day 14. For each time point, hesperidin had 284 no statistically significant impact on the proportion of patients with each of these thirteen 285 COVID-19 symptoms compared to the placebo group. Anosmia, the most frequently persisting 286 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 5, 2021. infection. AE led to study drug withdrawal in 5 placebo subjects and 8 hesperidin subjects. There 308 was 1 TESAE in the placebo group and 4 in the hesperidin group and none were related to study 309 treatment. 310 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 5, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 

Commonly reported COVID-19 symptoms are cough, fever, malaise and anosmia [3, 4] . 313

More severe cases present an exaggerated inflammatory response depicted as a cytokine storm 314 that can lead to respiratory distress [6, 7] . Because SARS-CoV-2 is an evolutive virus with 315 possible emergence of new variants that may not respond to current vaccines, it remains 316 imperative to find treatments to reduce disease severity. Symptoms associated with COVID-19 in 317 non-hospitalized subjects can be responsible for substantial disability, absenteeism, and loss of 318 productivity [16] . During the first and second waves of the pandemic, availability of COVID-19 319 PCR diagnosis was limited and restricted to more symptomatic subjects, therefore introducing a 320 selection bias in studies evaluating symptoms. During the recent third wave of the pandemic, 321 PCR testing for COVID-19 became widely available and testing was strongly encouraged for all 322 symptomatic subjects and contacts. There has been no prospective evaluation of COVID-19 323 symptoms in non-hospitalized and non-vaccinated subjects during the third wave. Here, we 324 prospectively evaluated COVID-19 symptoms and the effects of 14-days hesperidin therapy, a 325 flavonoid naturally present in citrus fruits, in 216 non-hospitalized and non-vaccinated 326 symptomatic subjects who tested positive for 328 Frequency and evolution of COVID-19 symptoms during the third wave. Subjects in this trial 329 were randomized a mean of 3.83 ± 1.84 days after the beginning of symptoms and a mean of 1.10 330 ± 0.41 days after PCR diagnosis and followed for 14 days. Therefore, at the end of the study, the 331 participants were at about 18 days since the beginning of symptoms. At randomization the most 332 frequent symptoms, present in more than 1/3 of subjects, were cough, general weakness, 333 headache and pain. In 20%-30% there was sore throat, runny nose, chills and shortness of breath. 334 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 5, 2021. ; https://doi.org/10. 1101 /2021 Anosmia was present in 18.5% and fever in only 16.2%. Other symptoms, diarrhea, 335 nausea/vomiting and irritability/confusion were present in only a minority of patients in a 336 proportion of less than 7% each. With the notable exception of anosmia, all symptoms steadily 337 decreased in frequency with time as the mean number of symptoms went from about 5.3 to 1.4 338 from day 1 to day 14. Still, most subjects, about 70%, remained symptomatic at day 14. The 339

proportion of subjects with anosmia tripled from randomization to day 3 when it reached a 340 proportion of 54.1%. At day 14, anosmia was the most frequent persisting symptom (29.3%). 341

Considering the previous reports on the importance of persisting anosmia after COVID-19 and its 342 impact on quality of life, our study confirms that anosmia occurs in about 50% of infected 343 subjects and persists more than 14 days in about 30%. Clearly, because of its clinical importance, 344 new sudden onset anosmia represents the best objective symptomatic target for COVID-19 345 therapeutic studies. 346

The incidence of fever found in this study is much lower that what has been previously 347 reported early in the pandemic [17], but confirms later reports in non-hospitalized COVID-19 348 subjects that found comparable incidence [18] . Indeed, in 4066 outpatient adults with COVID-19 349 diagnosis and a mean age of 43, 10.3% reported fever [18] . This rate is similar to the 16.2% 350 found at randomization in our study as self-reported by the participants. Our study further 351 emphasizes the discrepancy in self-reported fever and mandatory measured temperature since we 352 provided the subjects with a thermometer and required daily temperature measurements. Baseline 353 temperature at randomization was inquired by phone, while day 1 temperature was measured 354 with the provided electronic thermometer and entered in the symptoms log. Fever measured on 355 day 1 in our study (defined as greater than 38.0 by oral thermometer) was present in only 3.9% of 356

subjects, yet 32% reported chills on day 1 in the symptoms log. Our study therefore shows that 357 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 5, 2021. Despite repeated recalls by phone and emails, there was progressive attrition in the 370 number of participants reporting symptoms, greater in the hesperidin group (28/107) than in the 371 placebo group (15/109). To account and explore the extremes of a possible attrition bias, we 372 performed a worst-case and best-case imputation analysis to missing values. In the worst-case 373 analysis, we imputed the "last observation carried forward" approach and symptomatic subjects 374 were therefore considered symptomatic for all subsequent missing days. In the best-case analysis, 375

we imputed the absence of symptom to all missing values. In the worst-case analysis, we found 376 no statistically significant difference in group A symptoms at all time points, but still observed a 377 reduction at day 14 in the hesperidin group from 59.3% to 52.3%, a 7.0 % difference (OR 0.75, p 378 = 0.3098). In the best-case analysis, the difference at day 14 became significant with a reduction 379 of 14.5% from 50.9% in the placebo group to 36.4% in the hesperidin group (OR 0.55, p = 380 0.0343). Although speculative, the reason for the greater attrition rate in the reporting of 381 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 5, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 symptoms in the hesperidin group may be due to symptomatic improvement and decreased 382 willingness to cooperate for the participants that felt better. The attrition rate increased with study 383 duration, a recognized factor of poorer compliance. Our study, powered to detect a 20% absolute 384 difference in symptoms at Day 7, did not find statistically significant differences between 385 treatments. A smaller absolute reduction, especially for anosmia, could however be highly 386 clinically significant. Based on the attrition bias analysis and a best-case scenario where non-387 compliant subjects have no symptom, we cannot exclude that hesperidin could have beneficial 388 effects and further studies are encouraged. Because of its clinical importance, persistence, and 389 more subjective evaluation, new onset anosmia should be a primary therapeutic target in COVID-390 19 therapeutic studies. 391

The rationale and interest for using hesperidin in the treatment and even in the prevention 393 of COVID-19 has been highlighted by others, both for its anti-oxidant and anti-inflammatory 394 properties, and for its ability to block the entry and replication of 20] . The 395 current phase 2 study does not close the chapter on hesperidin therapy for COVID-19 with a 396 signal of possible benefit on selected symptoms driven by a reduction of anosmia. Furthermore, 397 since we did not grade the severity of each symptom in the design of this trial, we cannot exclude 398 a potential benefit of treatment on this important component. Besides the attrition bias discussed 399 above, there are several limitations that need to be considered in the planning of future phase 3 400 studies: delay of treatment, dosing, and duration of treatment and follow-up. The mean delay of 401 3.83 ± 1.84 days before enrollment into the trial may certainly mitigate the benefits of therapy as 402 it has been largely reported that viral load peaks at symptoms onset and for the few following 403 days, which is concordant with the infectiousness profile of . The optimal 404 therapeutic dosage of hesperidin has not previously been reported in human subjects. Participants 405 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 5, 2021. ; https://doi.org/10.1101/2021.10.04.21264483 doi: medRxiv preprint were asked to take 2 capsules of 500 mg each once daily, the maximal allowable daily dose by 406 the Non-Prescription and Natural Health Products Directorate (NNHPD) of Canada. Higher 407 dosage more than once a day may be necessary to obtain optimal therapeutic effects. Finally, the 408 duration of therapy and of follow-up may need to be longer to provide maximal benefit and better 409 detect improvement of persisting symptoms, especially anosmia. 410

Our study showed good safety of hesperidin with no evidence for greater drug-related AE 411 compared to placebo and no drug-related SAE. This concords with previous pre-clinical 412 observations in Sprague Dawley rats, with low observed adverse effects at a dosage of 1000 413 mg/kg in a sub-chronic oral toxicity study [22] During the third wave of the COVID-19 pandemic, only 30% of initially symptomatic 426 non-hospitalized and non-vaccinated subjects were asymptomatic about 18 days after symptom 427 onset. Anosmia affected 50% of subjects and was the most frequently persisting symptom in 428 30%. Hesperidin therapy is safe and may help reduce a composite of selected COVID-19 429 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted October 5, 2021. ; https://doi.org/10.1101/2021.10.04.21264483 doi: medRxiv preprint symptoms including fever, cough, shortness of breath and anosmia. Further trials with this agent 430 are encouraged. 431 432 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted October 5, 2021. for providing the study drug and placebo free of charge. 451 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted October 5, 2021. ; https://doi.org/10.1101/2021.10.04.21264483 doi: medRxiv preprint

A Novel Coronavirus from 453 Patients with Pneumonia in China

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically 458 Proven Protease Inhibitor

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PubMed Central PMCID: PMCPMC7392393 Journal Editors form 513 for disclosure of potential conflicts of interest. Christopher J. Lindsell reports grants from 514 National Institutes of Health and Department of Defense

outside the 516 submitted work. Daniel J. Henning reports personal fees from CytoVale and grants from Baxter, 517 outside the submitted work

Brown reports grants from National Institutes of Health, Department of Defense, Intermountain 520 Research and Medical Foundation, and Janssen, consulting fees paid to his employer from Faron 521 and Sedana, and royalties from

Peltan reports grants from National Institutes of Health

Rice reports 524 personal fees from Cumberland Pharmaceuticals, Inc., Cytovale, Inc., and Avisa, LLC, outside 525 the submitted work. No other potential conflicts of interest were disclosed

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Citrus polyphenol 550 hesperidin stimulates production of nitric oxide in endothelial cells while improving endothelial 551 function and reducing inflammatory markers in patients with metabolic syndrome

The 555 citrus flavonoids hesperidin and naringin do not affect serum cholesterol in moderately 556 hypercholesterolemic men and women

First 559 epidemiological data for venotonics in pregnancy from the EFEMERIS database

The authors would like to thank: The Montreal Heart Institute Foundation for providing 435 funding for this study; Sarah Samson RN, Denis Fortin RN, Cyntia Pennestri RN, Colette Morin 436