This systematic review and meta-analysis of individual patient data will be conducted of interventional, prospective, double-blind, randomized, placebo-controlled trials with an independent duloxetine arm. According to a protocol registered on PROSPERO (systematic review registration—2019 CRD42019130488), we have conducted a systematic literature review of relevant trials underwent on participants with an age < and ≥ to 65 years old, in population suffering from a condition having an EMA or FDA approval for duloxetine. In this report we describe all eligible studies and present the outcomes that will be extracted for the individual patient data and the methods that will be used for data synthesis following the PRISMA-P recommendations (Additional file 1). The anticipated end date of study is November 2021.
Eligibility criteria
We used the following eligibility criteria:
- Types of studies: RCTs with both participants ≥ and < to 65 years of age;
- Types of participants: subjects suffering from a disorder with a known approval for duloxetine by the FDA and the EMA, namely: depression, anxiety, diabetic neuropathic pain, fibromyalgia, chronic musculoskeletal pain and stress urinary incontinence;
- Types of interventions: duloxetine whatever the dosage, the administration frequency, the route of administration;
- Type of comparator: placebo;
- Types of outcome measures: report of SAE for each participant under duloxetine and placebo arms and/or non-serious adverse events and/or efficacy and or quality of life;
The research was restricted to trials written in English, whatever their publication status (published/unpublished).
Information sources
Searches were conducted in PubMed (to identify individual studies from published systematic reviews and meta-analyses of duloxetine), ClinicalTrials.gov, Clinicaltrialsregister.eu, data sharing platforms (ClinicalStudyDataRequest.com, YODA and Vivli), FDA drug approval packages and on European public assessment report and withdrawn applications from EMA website. The review was performed on studies available on electronic databases from their date of inception to May 31, 2019.
Search strategy
Trials identification was systematic with different search strategies depending on the source. First, we search PubMed for all systematic reviews and meta-analyses involving duloxetine in an approved indication. Then, individual trials were identified from these systematic reviews and meta-analyses. The search terms were as follows: “(Duloxetine AND Meta-Analysis[ptyp])". In ClinicalTrials.gov, the search was restricted to all interventional studies with adults and older adults, using “duloxetine” as search term. In Clinicaltrialsregister.eu and in data sharing platforms, the search term was “duloxetine” with no filter applied. In FDA website, FDA drug approval packages were downloaded from FDA Approved drug product, entering “duloxetine” as search term. In EMA website, European public assessment reports and withdrawn applications were selected, limited to reports on human with no restriction on the authorization status, using “duloxetine” as search term. The list of included studies, as the list of meta-analyses and of systematic reviews, are reported on additional file 2 and additional file 3, respectively.
Data management, selection and collection processes
Selection and coding of the different study characteristics were performed by two independent reviewers (JCR and AJ) in a blinded manner. A third reviewer (FN) arbitrated in case of disagreement. Studies appearing to duplicate authors, treatment comparisons, sample sizes and outcomes were checked one against another to avoid double-counting and integrating data from several reports on the same study and in contact with the studies sponsors. A data extraction sheet based on the Cochrane Handbook for Systematic Reviews of Interventions guidelines was developed. In case of missing data, the sponsor of the study and/or corresponding authors were contacted.
Collecting IPD
A data sharing request was sent to all sponsors which trials were spontaneously available on data sharing platforms. For the remaining studies, the request was sent to all correspondent authors and, if possible, a research proposal was addressed to each pharmaceutical sponsor on data sharing platforms (for Eli Lilly, Shionogi, Pfizer and AbbVie trials) or on the sponsor website (for Lundbeck, Takeda and Merck Sharp & Dohme trials). For willing collaborators, the terms of the collaboration will be specified in a data transfer agreement, signed by representatives of the data provider and of the recipients (Clinical Investigation Center, Department of Clinical Pharmacology, Rennes University Hospital, France). Collection of IPD is ongoing.
Participant characteristics requested are baseline age, gender, intervention arm, duloxetine dose, duration of participation in the study, number of serious adverse events from baseline to endpoint, number of non-serious adverse events from baseline to endpoint, study primary outcome and its values at baseline and at endpoint, type of quality of life scale used and its values at baseline and at endpoint. Data will be accepted in any suitable electronic format. Checks on the data will be made to ensure data are correctly coded, that missing data are correctly identified, that extreme values are genuine and to ensure that the data are consistent with published results. Data from all trials will be incorporated into a single database with fields that are consistent across trials.
Data items
For each included study, information was extracted on:
- Characteristics of the study: year, country, number of arms with duloxetine and placebo, funding, disease;
- Characteristic of trial participants: mean age (and its standard deviation), gender, number of patients included in analysis, population of analysis used in the identified report (intention to treat, per protocol, other);
- Type of administration and dose;
- Outcome measures as stated above (including exact definition of outcome/ e.g. MedDRA or other).
Outcomes and prioritization
The main outcome is the number (count) of SAE for each individual patient. In our study, SAE refers exclusively to any undesirable experience associated with the use of a medical product which results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability, or is a congenital anomaly or birth defect. This outcome has the advantages to be simple of interpretation and clinically relevant for safety estimation, containing a severity criterion from its definition.
Additionally, will be assessed as secondary outcomes:
- The number of non-serious adverse events (nsAE). nsAE refers to any untoward medical occurrence in a clinical trial subject administered a medicinal product and which does not have severity criteria for SAE nor necessarily have a causal relationship with this treatment. In a randomized placebo-controlled setting, this outcome provides a global estimate of treatment safety, without the severity feature of SAE.
- The efficacy on clinical scale in each indication (i.e. depression, anxiety, pain, urinary incontinence): different scales in the same indication will be standardized by z-scores. This outcome will evaluate the clinical benefit in patients.
- The quality of life scores in each indication: the different scales will be standardized by z-score. In studies where multiple quality of life scales were used, a hierarchy was established by selecting scales which both resume health data in one unique total score and which were the most used among the duloxetine trials. If the only available instrument in a trial did not permit to resume data into one score (e.g. SF36), its general health subscale was retained as indicator of quality of life (detailed in Additional file 4, Table S1). Quality of life scores yield a broad and ecological estimate of the well-being state of the patient.
Risk of bias in individual studies
Two researchers (JCR and AJ) assessed each trial for risk of bias independently, addressing randomization, allocation concealment, blinding of assessors and of study participants, completeness of outcome assessment, selective reporting and other potential sources of bias according to the Cochrane Collaboration tool for assessing risk of bias in its current version, RoB218 , at the study level. Discrepancies were resolved by consensus.
Data synthesis
Main analysis
As it appeared that all data were not directly downloadable together but rather provided remotely on separate interfaces, we chose a two-step procedure19 to derive incidence rate ratio (for count of binary outcomes) and mean differences (for quantitative outcomes).
The first step consists in comparing the number (count) of SAE between groups of participants arranged by age using a generalized linear mixed model (with a quasi-Poisson link function) in each individual study. Age (binary variable between “young” participants < 65 years old and “old” participants ≥ 65 years old) and intervention (binary variable between participants under duloxetine to participant under placebo) will be considered as fixed effects and their interaction will be explored as the main comparison. Incidence rate ratio as well as their variance will be extracted from the interaction between age and intervention.
In the second step, we will pool the extracted incidence rate ratios using a random effect meta-analysis. Similarly, number of non-serious adverse events (count) will be analyzed using a two-step approach based on a generalized linear mixed model (with a quasi-Poisson link function). For both SAE and nsAE, we will use meta-regressions to explore whether these interactions between age and intervention are different across the different conditions (major depressive disorder, generalized anxiety disorder, diabetic peripheral neuropathic pain, fibromyalgia, chronic musculoskeletal pain and stress urinary incontinence).
Summary measures for the analyses of efficacy and quality of life: in each condition, clinical scales (i.e. depression, pain, chronic anxiety) and quality of life scales will be analyzed separately using a similar two-step approach relying on results of a linear model. As various scales might be used across studies, we will use z-scores to standardize the different scales and populations.
Missing data will be handled by multiple imputation.
Sensitivity and subgroup analyses
A sensitivity analysis will be performed considering the occurrence of SAE in binary (Yes vs No) with the same two step approach relying on a generalized linear mixed model (with a logistic link function) in each individual study.
A subgroup analysis will be performed applying the same methodology as for adverse events, to explore differences between “young-old” participants (between 65 and 75 years old) and “old-old” participants (>75 years old) in terms of adverse events (serious and non-serious) and of efficacy.
Meta-biases
Missing trials will be explicitly reported with their characteristics and results described. Duplicate publications bias will be limited by the selection and precise identification of published and unpublished trials. If one or more trials could not be precisely identified by at least an ID number, these trials will be reported in the study results with explained attempts to obtain identification.
Countries where studies took place will be systematically assessed in the description studies table, to account for possible location bias. In addition, we clearly outline in our methods that our analysis select only studies written in English.
Confidence in cumulative evidence
We will use GRADE to rate the overall certainty (quality) of evidence that includes the evaluation of risk of bias, inconsistency, indirectness, imprecision and publication factors20.