Hydroxychloroquine in the treatment of adult patients with Covid-19 infection in a primary care setting (LIBERTY): A structured summary of a study protocol for a randomised controlled trial

Objectives: The primary objective of this study is to evaluate the therapeutic potential of hydroxychloroquine (HCQ) in the treatment of adult patients with PCR-confirmed Covid-19 infection in a primary open-care setting, as compared to placebo. The study hypothesis is that treatment with HCQ will reduce the risk of hospitalization because of Covid-19 infection, and the sample size estimate of the study is based on the need to test this hypothesis.The secondary objectives of the study are:to evaluate the safety and tolerability of HCQ in the treatment of adult patients with PCR-confirmed Covid-19 infection in a primary open-care setting, as compared to placebo;to collect experience of the use of HCQ in the treatment of Covid-19 infection in outpatients, in order to be able to identify patient characteristics that predict specific treatment responses (favourable or unfavourable); this objective will also be addressed by post-hoc subgroup analysis of the study results and by meta-analysis of pooled patient data from other clinical trials of HCQ in outpatients; andto evaluate the impact of Covid-19 infection and its treatment on the mental health and well-being of the study participants.In addition, if the data allow, the study has the following exploratory objectives:to evaluate the extent and duration of SARS-CoV-2 viral shedding by PCR testing of nasopharyngeal swab samples in study subjects treated with HCQ, as compared to placebo;to evaluate the extent and time course of SARS-CoV-2 virus-specific antibody responses in serum of study subjects treated with HCQ, as compared to placebo;to evaluate other possible biomarker changes in blood in study subjects treated with HCQ, as compared to placebo;to explore the possible effects of genetic variation in drug metabolizing enzymes on HCQ-related outcomes in the study population;to explore the associations of HCQ-related outcome variables with other patient characteristics, e.g. HLA haplotypes, HCQ concentrations, demographic variables, disease history and concomitant medications.Trial design: This is a phase 2, placebo-controlled, double-blind, randomized, parallel-group treatment trial comparing HCQ with placebo in outpatients with Covid-19 infection. Participants will be randomized in a 1:1 ratio to the two treatment arms.Participants:Main inclusion criteria: 1. Males and females >40 years of age, or 18-40 years of age with one or both of the following: i. diabetes mellitus (type 1 or type 2); ii. BMI > 35 kg/m(2);2. Valid independent informed consent obtained;3. Symptoms typical of Covid-19 infection, according to criteria specified in the study protocol. The onset of symptoms must be within 5 days of enrolment;4. Positive SARS-CoV-2 PCR test result of a nasopharyngeal swab sample.Main exclusion criteria:1. Suspected severe or moderately severe pneumonia, presenting with any of the following: respiratory rate > 26 breaths/min; significant respiratory distress; or SpO(2) <= 94% on room air;2. Requiring treatment in the hospital, according to the treating physician's judgement;3. Any contraindication to treatment with HCQ;4. Pregnancy or lactation.The trial will be conducted at seven study sites in a primary public health care setting in the region of Satakunta, Finland.Intervention and comparator: Participants will be randomized to receive either HCQ capsules at 300 mg twice a day for one day and then 200 mg twice a day for 6 days, or placebo capsules for 7 days.Main outcomes: The primary endpoint of the study is the number of hospitalizations due to Covid-19 infection within four weeks of entry into the study.The secondary endpoints of the study include the following:duration and severity of Covid-19-related symptoms, as reported by daily self-assessments;number of Intensive Care Unit treatment episodes due to Covid-19 infection within four weeks of entry into the study;number of deaths due to Covid-19 infection within four weeks of entry into the study;number of treatment-related adverse events (AEs) and serious AEs (SAEs);all-cause hospitalizations and mortality within six months of entry into the study; andself-assessed symptoms of anxiety, as assessed with repeated administration of the Generalized Anxiety Disorder 7-item scale (GAD-7).The exploratory endpoints of the study include the following:extent and duration of SARS-CoV-2 viral shedding and virus-specific antibody responses in serum; andpossible other blood biomarker changes.Randomisation: Eligible study participants are randomly allocated into two treatment arms (1:1 ratio). The randomization list has been generated using Viedoc (TM) (Viedoc Technologies AB, Uppsala, Sweden) that is used as an electronic data capture system for this study.Blinding (masking): The participants and all study personnel remain blinded to the treatment allocation by having both IMPs packed in identical containers. Masking of the treatments was performed by re-formulation of the IMPs so that the HCQ capsules and the placebo capsules have identical appearance.Numbers to be randomised (sample size): 600 participants are to be randomised with 300 in each arm.Trial Status: Protocol version 2, dated 14 July 2020; recruitment is expected to start in December, 2020, and to be completed in June, 2021.Trial registration: EudraCT 2020-002038-33, registered 26 June 2020Full protocol: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). The protocol has been redacted to conform with privacy regulations by deleting the names and contact information of individuals mentioned in the protocol but not listed as authors in this communication. In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol

Behavioral and economic aspects of caries control

Abstract The aim was to determine the association between baseline factors, such as oral health-related behavior, attitudes, knowledge and beliefs in relation to caries increment during a randomized clinical trial (RCT). A further aim was to evaluate treatment costs and health outcomes during and after the RCT. In Pori Finland, 11- to 12-year-old children with active initial caries lesion(s) participated in the RCT in 2001–05. The experimental group (n=250) received multiple measures for controlling caries. The control group (n=247) received standard dental care. In 2005–08, all received standard dental care. Regression analyses were used to study the associations between behavioral factors and caries increment. Cost-effectiveness analysis was conducted (trial period), and costs and health outcomes as well as dental service utilization were evaluated (post-trial period). In the experimental group, brushing teeth twice a day was indicative of developing no new caries lesions, whereas eating candy at least once a day, predicted new lesions. In the experimental and control groups, lack of concern about cavities and lack of knowledge about mother’s dental health predicted new caries lesions. The average incremental cost for averting one DMF surface was €34. The experimental regimen was more effective and more costly than the standard dental care. The total costs decreased year after year. The mean total cost per adolescent was lower and the clinical outcome was better among the former participants in the experimental group. The utilization of dental services was significantly more regular among the former participants in this group. It may be feasible to control caries more effectively by affecting toothbrushing, candy eating and oral health-related attitudes, as preventive procedures may be ineffective if those factors are not in order. It is important to discuss oral health-related topics in families, because this may improve the oral health-related behavior of children. Cost-effectiveness of regimen used for the experimental group may be improved by division of work or by selective reduction of preventive procedures. Well-timed caries control can decrease treatment cost and yield long-term improvement of dental health.Tiivistelmä Tutkimuksen tarkoituksena oli selvittää satunnaistetun kliinisen kokeen alussa rekisteröityjen suunterveyteen liittyvien tapojen, tietojen, asenteiden, uskomusten ja karieskertymän välisiä yhteyksiä. Lisäksi arvioitiin hoitokustannuksia ja hoidollisia tuloksia sekä kokeen ajalta että kokeen jälkeiseltä ajalta. Ne 11–12-vuotiaat lapset, joilla oli ainakin yksi alkava aktiivinen kariesvaurio, osallistuivat kokeeseen Porissa vuosina 2001–05. Koeryhmän lapset (n=250) saivat tehostettua ehkäisevää hoitoa ja kontrolliryhmän lapset (n=247) tavanomaista hammashoitoa. Kaikki saivat tavanomaista hammashoitoa vuosina 2005–08. Käyttäytymisellisten tekijöiden ja karieskertymän välisiä yhteyksiä tutkittiin regressioanalyysien avulla. Kustannusvaikuttavuusanalyysi tehtiin kokeen ajalta. Hoitokustannuksia ja hoidollisia tuloksia sekä palveluiden käyttöä arvioitiin kokeen jälkeiseltä ajalta. Lapsilla, jotka harjasivat vähintään kaksi kertaa päivässä, oli yleensä ehjät hampaat, kun taas lapsilla, jotka söivät päivittäin makeisia, oli useasti reikiä. Huolettomuus reikiintymistä kohtaan ja tietämättömyys äidin hampaiden kunnosta näkyi lasten hampaiden reikiintymisenä. Yhden hammaspinnan säästyminen paikkaukselta maksoi keskimäärin 34 €. Koeryhmän saama hoito oli vaikuttavampaa, mutta kalliimpaa kuin kontrolliryhmän saama hoito. Kokonaiskustannukset laskivat vuosi vuodelta. Keskimääräiset hoitokustannukset olivat pienemmät ja hammasterveys parempi entisen koeryhmän jäsenillä kuin kontrolliryhmäläisillä. Myös palveluiden käyttö oli säännöllisempää koeryhmässä. Karieksen hallintaa voidaan todennäköisesti tehostaa vaikuttamalla hampaiden harjaukseen, makeisten syöntiin ja suunterveyteen liittyviin asenteisiin. On tärkeää varmistaa, että nämä asiat ovat kunnossa, koska ehkäisevät toimenpiteet saattavat muuten jäädä tehottomiksi. Suunterveyteen liittyvistä asioista olisi hyvä keskustella perheissä, koska asioiden esillä pitäminen voi vaikuttaa suotuisasti lasten terveystapoihin. Koeryhmän saaman hoito-ohjelman kustannusvaikuttavuutta voisi todennäköisesti parantaa muuttamalla suunterveydenhuollon henkilöstön työnjakoa tai karsimalla valikoiden ehkäisevien toimenpiteiden määrää. Oikea-aikainen karieksen hallinta voi vähentää hoitokustannuksia ja lisätä hammasterveyttä pitkällä aikavälillä

Self-assessed medication risk factors as part of comprehensive health screening in home-dwelling older adults

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