Performance of four centralized statistical monitoring methods for early detection of an atypical center in a multicenter study.

Background: Ensuring the quality of data is essential for the credibility of a multicenter clinical trial. Centralized Statistical Monitoring (CSM) of data allows the detection of a center in which the distribution of a specific variable is atypical compared to other centers. The ideal CSM method should allow early detection of problem and therefore involve the fewest possible participants. Methods: We simulated clinical trials and compared the performance of four CSM methods (Student, Hatayama, Desmet, Distance) to detect whether the distribution of a quantitative variable was atypical in one center in relation to the others, with different numbers of participants and different mean deviation amplitudes. Results: The Student and Hatayama methods had good sensitivity but poor specificity, which disqualifies them for practical use in CSM. The Desmet and Distance methods had very high specificity for detecting all the mean deviations tested (including small values) but low sensitivity with mean deviations less than 50%. Conclusion: Although the Student and Hatayama methods are more sensitive, their low specificity would lead to too many alerts being triggered, which would result in additional unnecessary control work to ensure data quality. The Desmet and Distance methods have low sensitivity when the deviation from the mean is low, suggesting that the CSM should be used alongside other conventional monitoring procedures rather than replacing them. However, they have excellent specificity, which suggests they can be applied routinely, since using them takes up no time at central level and does not cause any unnecessary workload in investigating centers.

Therapeutic Patient Education for Fibromyalgia during Spa Therapy: The FiETT Randomized Controlled Trial.

Spa therapy is known to improve quality of life and diminish pain. We assessed the efficacy (Fibromyalgia Impact Questionnaire-FIQ) and safety at 6 months of a fibromyalgia-specific therapeutic patient education (TPE) program added to fibromyalgia-specific standardized spa therapy (SST), compared to SST alone, in a controlled randomized trial. We enrolled 157 patients, mostly women, attending spa centers in Southwest France in 2015-2016, and randomized them to SST + TPE (79) or SST (78). The intention-to-treat with "missing as failure" analysis showed a tendency toward a higher, though non-significant, benefit with TPE than without for FIQ (-9 vs. -3; p = 0.053) or pain intensity (-0.9 vs. -1.1; p = 0.58). In addition, pain relief (+3.2 vs. +4.3; p = 0.03) and fatigue (-1.6 vs. -3.7; p = 0.02) were significantly improved, and 87% patients in the SST + TPE arm still regularly practiced the physical exercises taught to them at 6 months. We suspect significant and lasting improvement from spa therapy, as well as our already well-informed and well-managed participants, to have prevented the demonstration of a significant benefit of TPE on FIQ.

Inhaled ciclesonide for outpatient treatment of COVID-19 in adults at risk of adverse outcomes: a randomised controlled trial (COVERAGE).

OBJECTIVES: To assess the efficacy of inhaled ciclesonide in reducing the risk of adverse outcomes in COVID-19 outpatients at risk of developing severe illness. METHODS: COVERAGE is an open-label, randomized controlled trial. Outpatients with documented COVID-19, risk factors for aggravation, symptoms for ≤7 days, and absence of criteria for hospitalization are randomly allocated to either a control arm or one of several experimental arms, including inhaled ciclesonide. The primary efficacy endpoint is COVID-19 worsening (hospitalization, oxygen therapy at home, or death) by Day 14. Other endpoints are adverse events, maximal follow-up score on the WHO Ordinal Scale for Clinical Improvement, sustained alleviation of symptoms, cure, and RT-PCR and blood parameter evolution at Day 7. The trial's Safety Monitoring Board reviewed the first interim analysis of the ciclesonide arm and recommended halting it for futility. The results of this analysis are reported here. RESULTS: The analysis involved 217 participants (control 107, ciclesonide 110), including 111 women and 106 men. Their median age was 63 years (interquartile range 59-68), and 157 of 217 (72.4%) had at least one comorbidity. The median time since first symptom was 4 days (interquartile range 3-5). During the 28-day follow-up, 2 participants died (control 2/107 [1.9%], ciclesonide 0), 4 received oxygen therapy at home and were not hospitalized (control 2/107 [1.9%], ciclesonide 2/110 [1.8%]), and 24 were hospitalized (control 10/107 [9.3%], ciclesonide 14/110 [12.7%]). In intent-to-treat analysis of observed data, 26 participants reached the composite primary endpoint by Day 14, including 12 of 106 (11.3%, 95% CI: 6.0%-18.9%) in the control arm and 14 of 106 (13.2%; 95% CI: 7.4-21.2%) in the ciclesonide arm. Secondary outcomes were similar for both arms. DISCUSSION: Our findings are consistent with the European Medicines Agency's COVID-19 task force statement that there is currently insufficient evidence that inhaled corticosteroids are beneficial for patients with COVID-19.

Home Treatment of Older People with Symptomatic SARS-CoV-2 Infection (COVID-19): A structured Summary of a Study Protocol for a Multi-Arm Multi-Stage (MAMS) Randomized Trial to Evaluate the Efficacy and Tolerability of Several Experimental Treatments to Reduce the Risk of Hospitalisation or Death in outpatients aged 65 years or older (COVERAGE trial).

OBJECTIVES: To assess the efficacy of several repurposed drugs to prevent hospitalisation or death in patients aged 65 or more with recent symptomatic SARS-CoV-2 infection (COVID-19) and no criteria for hospitalisation. TRIAL DESIGN: Phase III, multi-arm (5) and multi-stage (MAMS), randomized, open-label controlled superiority trial. Participants will be randomly allocated 1:1:1:1:1 to the following strategies: Arm 1: Control arm Arms 2 to 5: Experimental treatment arms Planned interim analyses will be conducted at regular intervals. Their results will be reviewed by an Independent Data and Safety Monitoring Board. Experimental arms may be terminated for futility, efficacy or toxicity before the end of the trial. New experimental arms may be added if new evidence suggests that other treatments should be tested. A feasibility and acceptability substudy as well as an immunological substudy will be conducted alongside the trial. PARTICIPANTS: Inclusion criteria are: 65-year-old or more; Positive test for SARS-CoV-2 on a nasopharyngeal swab; Symptoms onset within 3 days before diagnosis; No hospitalisation criteria; Signed informed consent; Health insurance. Exclusion criteria are: Inability to make an informed decision to participate (e.g.: dementia, guardianship); Rockwood Clinical Frailty Scale ≥7; Long QT syndrome; QTc interval > 500 ms; Heart rate <50/min; Kalaemia >5.5 mmol/L or <3.5 mmol/L; Ongoing treatment with piperaquine, halofantrine, dasatinib, nilotinib, hydroxyzine, domperidone, citalopram, escitalopram, potent inhibitors or inducers of cytochrome P450 CYP3A4 isoenzyme, repaglinide, azathioprine, 6-mercaptopurine, theophylline, pyrazinamide, warfarin; Known hypersensitivity to any of the trial drugs or to chloroquine and other 4-aminoquinolines, amodiaquine, mefloquine, glafenine, floctafenine, antrafenine, ARB; Hepatic porphyria; Liver failure (Child-Pugh stage ≥B); Stage 4 or 5 chronic kidney disease (GFR <30 mL/min/1.73 m²); Dialysis; Hypersentivity to lactose; Lactase deficiency; Abnormalities in galactose metabolism; Malabsorption syndrome; Glucose-6-phosphate dehydrogenase deficiency; Symptomatic hyperuricemia; Ileus; Colitis; Enterocolitis; Chronic hepatitis B virus disease. The trial is being conducted in France in the Bordeaux, Corse, Dijon, Nancy, Paris and Toulouse areas as well as in the Grand Duchy of Luxembourg. Participants are recruited either at home, nursing homes, general practices, primary care centres or hospital outpatient consultations. INTERVENTION AND COMPARATOR: The four experimental treatments planned in protocol version 1.2 (April 8th, 2020) are: (1) Hydroxychloroquine 200 mg, 2 tablets BID on day 0, 2 tablets QD from day 1 to 9; (2) Imatinib 400 mg, 1 tablet QD from day 0 to 9; (3) Favipiravir 200 mg, 12 tablets BID on day 0, 6 tablets BID from day 1 to 9; (4) Telmisartan 20 mg, 1 tablet QD from day 0 to 9. The comparator is a complex of vitamins and trace elements (AZINC Forme et Vitalité®), 1 capsule BID for 10 days, for which there is no reason to believe that they are active on the virus. In protocol version 1.2 (April 8th, 2020): People in the control arm will receive a combination of vitamins and trace elements; people in the experimental arms will receive hydroxychloroquine, or favipiravir, or imatinib, or telmisartan. MAIN OUTCOME: The primary outcome is the proportion of participants with an incidence of hospitalisation and/or death between inclusion and day 14 in each arm. RANDOMISATION: Participants are randomized in a 1:1:1:1:1 ratio to each arm using a web-based randomisation tool. Participants not treated with an ARB or ACEI prior to enrolment are randomized to receive the comparator or one of the four experimental drugs. Participants already treated with an ARB or ACEI are randomized to receive the comparator or one of the experimental drugs except telmisartan (i.e.: hydroxychloroquine, imatinib, or favipiravir). Randomisation is stratified on ACEI or ARBs treatment at inclusion and on the type of residence (personal home vs. nursing home). BLINDING (MASKING): This is an open-label trial. Participants, caregivers, investigators and statisticians are not blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 1057 participants will be enrolled if all arms are maintained until the final analysis and no additional arm is added. Three successive futility interim analyses are planned, when the number of participants reaches 30, 60 and 102 in the control arm. Two efficacy analyses (interim n°3 and final) will be performed successively. TRIAL STATUS: This describes the Version 1.2 (April 8th, 2020) of the COVERAGE protocol that was approved by the French regulatory authority and ethics committee. The trial was opened for enrolment on April 15th, 2020 in the Nouvelle Aquitaine region (South-West France). Given the current decline of the COVID-19 pandemic in France and its unforeseeable dynamic in the coming months, new trial sites in 5 other French regions and in Luxembourg are currently being opened. A revised version of the protocol was submitted to the regulatory authority and ethics committee on June 15th, 2020. It contains the following amendments: (i) Inclusion criteria: age ≥65 replaced by age ≥60; time since first symptoms <3 days replaced by time since first symptoms <5 days; (ii) Withdrawal of the hydroxychloroquine arm (due to external data); (iii) increase in the number of trial sites. TRIAL REGISTRATION: The trial was registered on Clinical Trials.gov on April 22nd, 2020 (Identifier: NCT04356495): and on EudraCT on April 10th, 2020 (Identifier: 2020-001435-27). FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). 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. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

PMTCT care cascade and factors associated with attrition in the first four years after Option B+ implementation in Mozambique.

OBJECTIVE: To evaluate the effectiveness of the prevention of mother-to-child transmission (PMTCT) Option B+ programme in two provinces with high human immunodeficiency virus (HIV) burden in Mozambique over the first four years of programme implementation. METHODS: We assessed the PMTCT cascade in antenatal care (ANC) from July 2013 to December 2017 using facility-level data and performed a retrospective cohort analysis with patient-level data. We compared the 12-month antiretroviral therapy (ART) retention rates between women with HIV infection who initiated ART under Option B+ ('B+ pregnant') and those who initiated ART for their own health ('own health'). RESULTS: A total of 916 280 pregnant women enrolled in ANC. The proportion of women with a documented HIV status increased from 93% in 2013 to 96% in 2017. The proportion of those tested HIV-positive decreased from 8% to 6% while that of those HIV-positive on ART increased from 42% to 95%. Of the 44 377 HIV-positive women included in the analysis, 35% were lost to care. 'B+ pregnant' women initiating ART in 2015 were less likely to have no follow-up (NFU) compared with 'own health' women starting ART during the same period (adjusted odds ratio: 0.77, 95% confidence interval [CI]: 0.64-0.94, P = 0.01). There was no statistical difference between the two groups during the other years in which ART was initiated. Of those returning for care after their first visit (N = 39 801), the 'B+ pregnant' women showed a higher risk of non-retention than the other group (adjusted hazard ratio: 1.14, 95% CI: 1.03-1.25) when ART was initiated in 2013. The risk decreased during the subsequent years, with no difference observed between the groups. CONCLUSION: PMTCT Option B+ programme scale-up has yielded positive results, including the maintenance of high HIV testing and ART initiation rates in ANC. Challenges still remain, however, in improving immediate engagement in care and long-term retention. Seeking alternative service delivery models to support existing health systems and prevent defaulters is required to achieve the UNAIDS 95-95-95 targets for PMTCT in Mozambique.

OBJECTIF: Evaluer l'efficacité du programme de la prévention de la transmission mère-enfant (PTME) Option B+ dans deux provinces avec une charge élevée du virus de l' immunodéficience humaine (VIH) au Mozambique, au cours des quatre premières années de la mise en œuvre du programme. MÉTHODES: Nous avons évalué la cascade PTME dans les soins des cliniques prénatales (SCP) de juillet 2013 à décembre 2017 à l'aide de données à l'échelle de l'établissement et avons effectué une analyse de cohorte rétrospective avec des données à l'échelle du patient. Nous avons comparé les taux de rétention à 12 mois de la thérapie antirétrovirale (ART) entre les femmes infectées par le VIH qui ont commencé l'ART dans le cadre de l'option B+ (''enceintes B+'') et celles qui ont commencé l'ART pour leur propre santé (''propre santé''). RÉSULTATS: Au total, 916.280 femmes enceintes ont été inscrites dans les SCP. La proportion de femmes avec un statut VIH documenté est passée de 93% en 2013 à 96% en 2017. La proportion de celles testées positives pour le VIH est passée de 8% à 6% tandis que celle des femmes positives au VIH sous ART est passée de 42% à 95%. Sur les 44.377 femmes séropositives incluses dans l'analyse, 35% ont été perdues au cours des soins. Les femmes ''enceintes B+'' qui ont commencé l'ART en 2015 étaient moins susceptibles de ne pas avoir de suivi (NFU) que les femmes ''propre santé'' ayant commencé l'ART au cours de la même période (rapport de cotes ajusté: 0,77 ; intervalle de confiance à 95% [IC]: 0,64-0,94 ; P = 0,01). Il n'y avait aucune différence statistique entre les deux groupes durant les autres années au cours desquelles l'ART a été initiée. Parmi celles retournant pour des soins après leur première visite (N = 39.801), les femmes ''enceintes B+'' présentaient un risque plus élevé de non-rétention que l'autre groupe (rapport de risque ajusté: 1,14 ; IC95%: 1,03-1,25) lorsque l'ART a été initiée en 2013. Le risque diminuait au cours des années suivantes, sans différence observée entre les groupes. CONCLUSION: Le déploiement du programme PTME Option B+ a donné des résultats positifs, notamment le maintien de taux élevés de dépistage du VIH et d'initiation de l'ART dans les SCP. Il reste cependant des défis à relever pour améliorer l'engagement immédiat dans les soins et la rétention à long terme. La recherche de modèles de prestation de services alternatifs pour soutenir les systèmes de santé existants et prévenir les défaillances est nécessaire pour atteindre les objectifs de l'ONUSIDA 95-95-95 pour la PTME au Mozambique.

Mefloquine Versus Sulfadoxine-Pyrimethamine for Intermittent Preventive Treatment in Pregnancy: A Joint Analysis on Efficacy and Tolerability.

Since there is no ideal candidate to replace sulfadoxine-pyrimethamine (SP) for intermittent preventive treatment (IPTp), alternatives need to be evaluated on basis of their benefit-risk ratio. We reanalyzed the first Beninese trial on mefloquine (MQ) versus SP for IPTp using a multiple outcome approach, which allowed the joint assessment of efficacy and tolerability. Overall superiority of MQ to SP was defined as superiority on at least one efficacy outcome (low birth weight [LBW], placental malaria, or maternal anemia), non-inferiority on all of them as well as on tolerability defined as cutaneous or neuropsychiatric adverse events (AEs) or low compliance with the treatment. The analysis included 1,601 women. MQ was found to be overall superior to SP (P = 0.004). Performing several sensitivity analyses to handle both missing data and stillbirths provided similar results. Using MQ for IPTp as an example, we show that a multiple outcome analysis is a pragmatic way to assess the benefits/disadvantages of one drug compared with another. In the current context of a lack of antimalarials that could be used for IPTp, such a statistical approach could be widely used by institutional policy makers for future recommendations regarding the prevention of malaria in pregnancy (MiP).

Viremia copy-years as a predictive marker of all-cause mortality in HIV-1-infected patients initiating a protease inhibitor-containing antiretroviral treatment.

BACKGROUND: Viremia copy-years (VCY) has been reported as a short-term predictor of mortality. We evaluated the association of this parameter with 10-year outcome within the APROCO-COPILOTE cohort. METHODS: Prospective data from 1281 HIV-1-infected patients who started a first protease inhibitor-containing regimen in 1997-1999 were analyzed. Patients with baseline plasma viral load (pVL) > 500 copies per milliliter and at least 2 pVL measures from the eighth month of follow-up were selected. VCY was calculated individually over the follow-up as the area under the pVL curve. Multivariate Cox models analyzed the relation between all-cause mortality and the following variables: age, sex, geographical origin, transmission group, HIV infection duration, ART-naive, pVL at baseline, time-dependent CD4 count, and VCY. RESULTS: Nine hundred seventy-nine patients were followed up for a median of 10 years (interquartile range: 5-11.5). At baseline, median (interquartile range) values for duration of HIV infection, pVL, and CD4 cell count were 43 (4-95) months, 4.6 (3.9-5.2) log10 copies per milliliter, and 278 (125-416) cells per cubic millimeter, respectively. At censoring date, 77 patients (8%) had died. VCY >1.4 log10 copies × yrs/mL was an independent predictor of death (hazard ratio: 2.0; 95% confidence interval: 1.2 to 3.5), which was no longer the case after adjustment for the latest pVL value [risk ratio (RR): 1.2 for 1 additional log10 copies per milliliter; 95% confidence interval: 1.1 to 1.4]. CONCLUSIONS: VCY was associated with mortality in HIV-infected patients under combined antiretroviral therapy but did not overweigh the predictive value of the latest pVL. VCY might be more useful as a marker of persistent viral replication than for routine clinical care.

[Public clinical trials: which kind of monitoring should be used?]. / Essais cliniques institutionnels : quel monitoring ?

OBJECTIVE: Sponsors must take responsibility for the quality of trials at the best possible cost. Our objective was to describe the most frequent quality failures, how they impact trial results, and identify the most efficient monitoring strategies using published articles and reports. RESULTS: Errors affecting clinical trials include conception, procedures, data management, and data analysis. The consequences are usually an overestimation of the treatment effect. No study shows that monitoring reduces the risk of errors, and there is no comparison of monitoring methods. Many research organisations advocate for monitoring based on risk analysis and recommend an extensive use of centralised monitoring. CONCLUSIONS: Trial quality depends on trial conception and design. Study conduct should guarantee a maximum level of quality level. This should be done using risk management and extensive centralised monitoring.

Preserving participant anonymity during remote preenrollment consent form checking.

BACKGROUND: In biomedical research, the consent form must comply with regulatory requirements. Checking for compliance typically has been performed on-site and most frequently after a participant's final enrollment. We use a procedure for remote preenrollment checking of consent forms that protects participant identities. This procedure requires a copy of the consent form that partially masks the fields for participant's name and signature; this copy is faxed to the clinical trials unit for checking. PURPOSE: To describe our efforts to identify an appropriate printed masking pattern. We tried several patterns that permit ascertainment of the presence of signatures and names and evaluated each one with respect to degree of masking participant identities. METHODS: We assessed the efficiency of a satisfactory pattern through an experiment. We created forms with variants of the masking pattern on the copy to be faxed. We completed the forms with fictitious identities before copies were faxed and checked by clinical research associates. We measured the rate of empty and filled fields detected and the rate of letters and names correctly read. The target was defined as 100% for the rate of empty and filled fields detected and 0% for the rate of letters and names correctly read. RESULTS: The best masking pattern allowed the detection of 100% empty and filled fields and the reading of 0% names and 19% letters. Consequently, the consent form with the selected masking pattern has been used routinely in our clinical trials unit. LIMITATIONS: We tested only five fictitious identities, five individuals who completed forms, and three who checked forms. Also, we initially considered only four patterns and variations in them. CONCLUSIONS: We defined a masking pattern that satisfactorily fulfilled our needs for confidentiality. This and other procedures for remote preenrollment checking of consent form can be a key component of a risk-based monitoring strategy.

Remote preenrollment checking of consent forms to reduce nonconformity.

BACKGROUND: In biomedical research, the signed consent form must be checked for compliance with regulatory requirements. Checking usually is performed on site, most frequently after a participant's final enrollment. PURPOSE: We piloted a procedure for remote preenrollment consent forms checking. We applied it in five trials and assessed its efficiency to reduce form nonconformity before participant enrollment. METHODS: Our clinical trials unit (CTU) routinely uses a consent form with an additional copy that contains a pattern that partially masks the participant's name and signature. After completion and signatures by the participant and investigator, this masked copy is faxed to the CTU for checking. In case of detected nonconformity, the CTU suspends the participant's enrollment until the form is brought into compliance. We checked nonconformities of consent forms both remotely before enrollment and on site in five trials conducted in our CTU. We tabulated the number and nature of nonconformities by location of detection: at the CTU or on site. We used these data for a pseudo before-and-after analysis and estimated the efficiency of this remote checking procedure in terms of reduction of nonconformities before enrollment as compared to the standard on-site checking procedure. We searched for nonconformity determinants among characteristics of trials, consent forms, investigator sites, and participants through multivariate logistic regression so as to identify opportunities for improvement in our procedure. RESULTS: Five trials, starting sequentially but running concurrently, with remote preenrollment and on-site checking of consent forms from 415 participants screened in 2006-2009 led to 518 consent forms checked; 94 nonconformities were detected in 75 forms, 75 (80%) remotely and 19 more (20%) on site. Nonconformities infrequently concerned dates of signatures (7%) and information about participants (12%). Most nonconformities dealt with investigator information (76%), primarily contact information (54%). The procedure reduced nonconformities by 81% (95% confidence interval (CI): 73%-89%) before enrollment. Nonconforming consent forms dropped from 25% to 0% over the period, indicating a rapid learning effect between trials. Fewer nonconformities were observed for participants screened later in a trial (odds ratio (95% CI): 0.5 (0.3-0.8); p = 0.004), indicating a learning effect within trials. Nonconformities were more common for participants enrolled after screening (2.4 (1.1-5.3); p = 0.03), indicating a stricter scrutiny by form checkers. LIMITATIONS: Although our study had a pseudo before-and-after design, no major bias was identified. Power and generalizability of our findings were sufficient to support implementation in future trials. CONCLUSIONS: This procedure substantially limited nonconformity of consent forms with regulatory requirements before enrollment, thus proving a key component of a risk-based monitoring strategy that has been recommended to optimize resources for clinical research.

Validation of a risk-assessment scale and a risk-adapted monitoring plan for academic clinical research studies--the Pre-Optimon study.

CONTEXT: Good Clinical Practice regulates monitoring activities in clinical research. Due to question and design diversity, and limited resources, on-site monitoring is often less intensive in the academic context, and variable. Standardization is needed, and relies on definition and validation of tools accounting for risk. OBJECTIVE: To define, and validate tools, to implement a risk-based monitoring strategy for academic clinical research. METHODS: Working groups of experienced professionals searched the literature, and built a consensus risk-assessment scale (RAS), and a risk-adapted monitoring plan (RAMP). We allocated 200 protocols to 49 assessors. We assessed the RAS relevance vs. a visual analogue scale (VAS), and its reproducibility through Kraemer's kappa, and intraclass correlation coefficient (ICC) from a random proportional odds model. We identified sources of disagreement through a logistic regression. We described assessors' difficulties during assessment. We applied the RAMP to 10 protocols per risk level, and rated its feasibility (0 = easy to 4 = impossible). RESULTS: RAS and RAMP were defined in 4 levels. RAS relevance was good: RAS-risk levels were evenly distributed on VAS-risk (0.6, 2.6, 5.6, and 7.9). Reproducibility was moderate to good: kappa=0.48, ICC=0.70. Major disagreements (36%) arose from decision-makers, rather than hands-on managers. Most difficulties occurred in ill-written protocols (17%). RAMP was easily feasible for most protocols (mean score: 0.2 to 0.9). We proposed a standard synopsis for evaluation purpose. CONCLUSION: We defined, and validated risk-based tools. This risk-adapted strategy will be compared to an intensive one in a randomized trial, Optimon, to define a standard of practice for academic clinical research.

Four year follow-up of simplification therapy with once-daily emtricitabine, didanosine and efavirenz in HIV-infected patients (ALIZE ANRS 099 trial).

BACKGROUND: once-daily combinations of efavirenz and two nucleoside analogues are recommended for the treatment of HIV infection. Long-term efficacy and safety data are scarce for the combination of efavirenz, emtricitabine and didanosine. METHODS: the ALIZE ANRS 099 trial enrolled 355 adults with plasma HIV RNA levels of <400 copies/mL under a protease inhibitor-based regimen, who were randomized to remain on this regimen or to switch to a once-daily regimen of emtricitabine, didanosine and efavirenz for 48 weeks. An extended 4 year follow-up was available for the 178 patients who switched to the efavirenz-containing regimen, and assessed plasma HIV RNA levels, CD4 cell counts, safety and tolerability. RESULTS: after a median follow-up of 42 months, 121 patients (68%) remained on an efavirenz-based regimen, and 62% and 57% had plasma HIV RNA levels of <400 and <50 copies/mL, respectively, in an intent-to-continue analysis with missing data and treatment discontinuation considered as failure. There was a significant increase in CD4 cell count of 41 cells/mm(3). Drug-related adverse events were the main reason for treatment discontinuation in 26 patients (15%), and 15 were reported during the first year of therapy (58%). There was no emergence of clinically defined lipodystrophy, and lipid and glucose profiles were favourable with a significant increase from baseline of high-density lipoprotein cholesterol levels (median increase 12 mg/dL, P < 10(-4)). CONCLUSIONS: a once-daily regimen of emtricitabine, didanosine and efavirenz provided a durable antiretroviral response and was well tolerated through 4 years of therapy.

About the necessity to manage events coded with MedDRA prior to statistical analysis: proposal of a strategy with application to a randomized clinical trial, ANRS 099 ALIZE.

BACKGROUND: Since 2003, the Medical Dictionary for Regulatory Activities (MedDRA) is the regulatory standard for safety report in clinical trials in the European Community. Yet, we found no published example of a practical experience for a scientifically oriented statistical analysis of events coded with MedDRA. We took advantage of a randomized trial in HIV-infected patients with MedDRA-coded events to explain the difficulties encountered during the events analysis and the strategy developed to report events consistently with trial-specific objectives. METHODS: MedDRA has a rich hierarchical structure, which allows the grouping of coded terms into 5 levels, the highest being "System Organ Class" (SOC). Each coded term may be related to several SOCs, among which one primary SOC is defined. We developed a new general 5-step strategy to select a SOC as trial primary SOC, consistently with trial-specific objectives for this analysis. We applied it to the ANRS 099 ALIZE trial, where all events were coded with MedDRA version 3.0. We compared the MedDRA and the ALIZE primary SOCs. RESULTS: In the ANRS 099 ALIZE trial, 355 patients were recruited, and 3,722 events were reported and documented, among which 35% had multiple SOCs (2 to 4). We applied the proposed 5-step strategy. Altogether, 23% of MedDRA primary SOCs were modified, mainly from MedDRA primary SOCs "Investigations" (69%) and "Ear and labyrinth disorders" (6%), for the ALIZE primary SOCs "Hepatobiliary disorders" (35%), "Musculoskeletal and connective tissue disorders" (21%), and "Gastrointestinal disorders" (15%). CONCLUSIONS: MedDRA largely enhanced in size and complexity with versioning and the development of Standardized MedDRA Queries. Yet, statisticians should not systematically rely on primary SOCs proposed by MedDRA to report events. A simple general 5-step strategy to re-classify events consistently with the trial-specific objectives might be useful in HIV trials as well as in other fields.

Phase I study of a candidate vaccine based on recombinant HIV-1 gp160 (MN/LAI) administered by the mucosal route to HIV-seronegative volunteers: the ANRS VAC14 study.

One goal of HIV vaccination is to achieve high mucosal levels of specific secretory IgA (SIgA). In order to elicit specific SIgA antibodies against human immunodeficiency virus type-1 (HIV-1), a vaccine must be administered by the mucosal route, to the nasal or vaginal mucosa for example. We report here the results of the first phase I, randomized, open-label trial designed to assess the mucosal tolerability and immunogenicity of a candidate vaccine (recombinant protein HIV-1 gp160MN/LAI with or without DC-Chol adjuvant) administered by the nasal or vaginal route. Thirty-four female volunteers with a mean age of 46 years were vaccinated. There were 465 adverse events, of which 65 were considered related to the vaccine. No severe adverse events were related to the vaccine, and no difference in terms of tolerability was observed between the sites of vaccination or between the vaccine formulations. None of the volunteers reported that study participation affected their intimate or broader social relationships. No anti-gp160 activity was found between week 4 and week 48 in serum, saliva, or cervicovaginal and nasal secretions. These results show that a mucosal HIV vaccine can be well tolerated when administered by the nasal or vaginal route.

Five-year follow up of once-daily therapy with emtricitabine, didanosine and efavirenz (Montana ANRS 091 trial).

BACKGROUND: Once-daily combination therapy with emtricitabine, didanosine and efavirenz has been highly effective in clinical trials but its long-term efficacy and safety has not been previously reported. METHODS: This multicentre, single-arm, open-label trial enrolled 40 antiretroviral-naive HIV-1-infected patients who received a once-daily regimen of emtricitabine, didanosine and efavirenz. The objective was to assess the long-term effects of this combination on plasma HIV RNA levels, CD4+ T-cell counts, safety and tolerability. RESULTS: After 5 years, 73% and 68% of patients had plasma HIV RNA levels < 400 and < 50 copies/ml, respectively, in an intent-to-treat, missing-equals-failure analysis. Genotypic resistance on treatment emerged in six patients. There was a significant increase in CD4+ T-cell count of 294 x 10(6) cells/l. Only six patients discontinued study treatment, because of non-severe adverse events. Lipodystrophy was infrequent, and lipid and glucose profiles were favourable with a significant increase in high-density lipoprotein cholesterol. CONCLUSION: A convenient once-daily regimen of emtricitabine, didanosine and efavirenz provided durable antiretroviral response and was well tolerated through 5 years of therapy.

Changes in the peripheral blood mtDNA levels in naive patients treated by different nucleoside reverse transcriptase inhibitor combinations and their association with subsequent lipodystrophy.

Nucleoside reverse transcriptase inhibitors (NRTIs) differ in the type and severity of adverse effects resulting from mitochondrial abnormalities. mtDNA in peripheral blood mononuclear cells (PBMCs) was measured during the first 12 months of different NRTIs combinations and its association with clinical lipodystrophy was estimated. Extended follow-up of a randomized trial, ALBI-ANRS 070, including antiretroviral naive patients was conducted. Total DNA was extracted from available cryopreserved PBMCs at baseline and months 6 and 12. Nuclear and mitochondrial genes were amplified using a real-time PCR assay. Clinical lipodystrophy was assessed 30 months after randomization using a standardized questionnaire. A logistic regression analysis assessed the value of mtDNA to predict lipodystrophy. Mean mtDNA level (copies/cell) significantly decreased from 5847 at baseline to 3176 at month 12 (p < 0.0001). In the zidovudine + lamivudine (ZDV + 3TC) arm (n = 37), the mean mtDNA was 6098, 6807, and 3725 copies/cell for baseline, month 6, and month 12, respectively. In the stavudine + didanosine (d4T + ddI) arm (n = 40), the mean values were 5616, 5731, and 2648 copies/cell, respectively. The proportion of patients in the lowest quartile of mtDNA (<1421 copies/cell) at month 12 was higher in 18 patients with lipodystrophy (44%) than in 28 without lipodystrophy (7%) (p = 0.008). At 12 months, a larger reduction of mtDNA from baseline was observed in those started on the d4T + ddI arm. Furthermore, a low mtDNA level at month 12 was associated with the subsequent development of lipodystrophy. This marker may be of value for the early prevention of lipodystrophy in treated HIV-infected patients.

Use of efavirenz is not associated with a higher risk of depressive disorders: a substudy of the randomized clinical trial ALIZE-ANRS 099.

BACKGROUND: Efavirenz (EFV) is a highly active antiretroviral drug, use of which is associated with frequent (although transient) neurosensorial adverse reactions. Whether the use of EFV is associated with the risk of depression or suicide remains controversial. METHODS: ALIZE-ANRS (Agence Nationale de Recherches sur le SIDA et les Hepatites Virales) 099 was a 48-week randomized trial involving virologically suppressed, human immunodeficiency virus (HIV)-infected patients that compared the maintenance of a treatment regimen that contained protease inhibitors (177 subjects) with a switch to a once-daily combination of EFV, didanosine, and emtricitabine (178 subjects). We used the trial's adverse events reporting system and a self-administered Center for Epidemiologic Studies-Depression Scale questionnaire to assess depressive disorders. Determinants were studied using a multivariate proportional hazards model adjusted for antiretroviral treatment, sex, age, HIV risk factor, history of depression, hepatic disorder, alcohol abuse, and HIV-related or non-HIV-related events. RESULTS: Thirty cases of depressive disorder (26 cases of depression and 4 suicide attempts) occurred during treatment in 27 patients (12 patients [7%] and 15 patients [8%] in the protease inhibitor-based and EFV-based treatment arms, respectively; P = .56). In the proportional hazards model, only age (hazard ratio, 1.6 per 10 years younger; 95% confidence interval, 1.0-2.6) and a history of depressive disorder (hazard ratio, 5.0; 95% confidence interval, 2.1-12.0) were associated with a risk of depressive disorders. The proportion of depressive patients (24%), as determined on the basis of the Center for Epidemiologic Studies-Depression Scale data, was stable during the follow-up period, without difference between treatment groups. Patients with a history of depressive disorder were more frequently depressed (53%) than were those without such history (22%; P = .03). CONCLUSIONS: The frequency of depressive disorders was high in this population, but the disorders were not related to EFV treatment. Younger age and a history of depression are important determinants for depression and should be considered for early detection and case management.

Simplification therapy with once-daily emtricitabine, didanosine, and efavirenz in HIV-1-infected adults with viral suppression receiving a protease inhibitor-based regimen: a randomized trial.

BACKGROUND: We assessed a once-daily combination to simplify therapy in patients infected with human immunodeficiency virus type 1 (HIV-1). METHODS: A total of 355 adults with plasma HIV-1 RNA levels <400 copies/mL were randomly assigned to either switch to once-daily emtricitabine, didanosine, and efavirenz (n=178) or maintain their protease inhibitor (PI)-based regimens (n=177). The primary end point was sustained suppression of plasma HIV-1 RNA levels to <400 copies/mL. RESULTS: At week 48, the proportion of patients meeting the end point was 87.6% in the PI group and 90.5% in the once-daily group, with a treatment difference of -2.9% (upper bound of the 1-tailed 95% confidence interval, 2.6%). The proportion of patients with HIV-1 RNA levels <50 copies/mL was higher in the once-daily group (87%) than in the PI group (79%) (P<.05). Resistance mutations to efavirenz and emtricitabine were detected in all patients in the once-daily group who experienced virologic failure while receiving study medication. The proportion of patients discontinuing study medication because of adverse events was similar between the once-daily group (9%) and the PI group (10%) (P=.8). CONCLUSIONS: Substituting a convenient once-daily combination of emtricitabine, didanosine, and efavirenz for a PI-based regimen was well tolerated and associated with sustained virologic suppression.

Incidence of and risk factors for adverse drug reactions in a prospective cohort of HIV-infected adults initiating protease inhibitor-containing therapy.

Risk factors associated with the occurrence of protease inhibitor (PI)-related severe and serious adverse drug reactions (SADRs) were analyzed in a prospective cohort of 1155 patients who initiated PI-containing therapy. During a total follow-up of 2037 patient-years, 169 SADRs were reported, yielding a rate of 8 incidents per 100 patient-years (95% confidence interval [CI], 6.8-8.6). The most frequent SADRs were elevated transaminase levels (in 49 events); renal colic (27); abnormal hematological findings (23); and metabolic (18), neuromuscular (7), pancreatic (6), cutaneous (6), cardiovascular (5), and psychiatric disorders (5). Among baseline characteristics, plasma human immunodeficiency virus RNA levels of >or=5 log(10) copies/mL (hazard ratio [HR], 1.5; 95% CI, 1.1-2.2), elevated aspartate aminotransferase levels (HR, 1.1 for each 20 IU of elevation; 95% CI, 1.1-1.2), creatinine clearance levels of <70 mL/min (HR, 2.1; 95% CI, 1.2-3.7), test results positive for hepatitis C virus antibodies or hepatitis B surface antigenemia (HR, 2.6; 95% CI, 1.8-3.7), and receipt of indinavir (HR, 1.7; 95% CI, 1.2-2.4) were independently predictive of a SADR. SADRs were frequent in the first 4 months after initiation of highly active antiretroviral therapy but continued to occur after that time period.

Plasma levels of indinavir and nelfinavir at time of virologic response may have a different impact on the risk of further virologic failure in HIV-infected patients.

Indinavir and nelfinavir plasma levels were studied in 407 patients having plasma HIV RNA <500 copies/mL after 4 months of treatment with these drugs. For each drug, an observed/predicted (O/P) ratio was calculated between individual and mean time-adjusted population plasma drug levels. The relationship between the O/P ratio and the risk of rebound of plasma HIV RNA >500 copies/mL beyond month 4 was studied using Cox proportional hazard models. Median follow-up was 20 months. There was no association between indinavir plasma levels and risk of virologic rebound, whereas low nelfinavir + M8 (active nelfinavir metabolite) plasma levels were associated with a higher risk of virologic rebound. In multivariate analysis, the adjusted relative hazard of virologic rebound for patients with an O/P ratio of nelfinavir + M8 metabolite <0.8 compared with others was 2.2 (P = 0.01). In some patients, plasma levels of nelfinavir sufficient to achieve early viral response may not be sufficient to maintain it in the long term. This may be related to insufficient compliance with dietary recommendations. Monitoring of nelfinavir plasma levels thus seems useful, even in patients having early virologic response.