Guidelines for Reporting Trial Protocols and Completed Trials Modified Due to the COVID-19 Pandemic and Other Extenuating Circumstances: The CONSERVE 2021 Statement.

Importance: Extenuating circumstances can trigger unplanned changes to randomized trials and introduce methodological, ethical, feasibility, and analytical challenges that can potentially compromise the validity of findings. Numerous randomized trials have required changes in response to the COVID-19 pandemic, but guidance for reporting such modifications is incomplete. Objective: As a joint extension for the CONSORT and SPIRIT reporting guidelines, CONSERVE (CONSORT and SPIRIT Extension for RCTs Revised in Extenuating Circumstances) aims to improve reporting of trial protocols and completed trials that undergo important modifications in response to extenuating circumstances. Evidence: A panel of 37 international trial investigators, patient representatives, methodologists and statisticians, ethicists, funders, regulators, and journal editors convened to develop the guideline. The panel developed CONSERVE following an accelerated, iterative process between June 2020 and February 2021 involving (1) a rapid literature review of multiple databases (OVID Medline, OVID EMBASE, and EBSCO CINAHL) and gray literature sources from 2003 to March 2021; (2) consensus-based panelist meetings using a modified Delphi process and surveys; and (3) a global survey of trial stakeholders. Findings: The rapid review yielded 41 673 citations, of which 38 titles were relevant, including emerging guidance from regulatory and funding agencies for managing the effects of the COVID-19 pandemic on trials. However, no generalizable guidance for all circumstances in which trials and trial protocols might face unanticipated modifications were identified. The CONSERVE panel used these findings to develop a consensus reporting guidelines following 4 rounds of meetings and surveys. Responses were received from 198 professionals from 34 countries, of whom 90% (n = 178) indicated that they understood the concept definitions and 85.4% (n = 169) indicated that they understood and could use the implementation tool. Feedback from survey respondents was used to finalize the guideline and confirm that the guideline's core concepts were applicable and had utility for the trial community. CONSERVE incorporates an implementation tool and checklists tailored to trial reports and trial protocols for which extenuating circumstances have resulted in important modifications to the intended study procedures. The checklists include 4 sections capturing extenuating circumstances, important modifications, responsible parties, and interim data analyses. Conclusions and Relevance: CONSERVE offers an extension to CONSORT and SPIRIT that could improve the transparency, quality, and completeness of reporting important modifications to trials in extenuating circumstances such as COVID-19.

Steroidal contraceptives: effect on carbohydrate metabolism in women without diabetes mellitus.

BACKGROUND: Many hormonal contraceptives have been associated with changes in carbohydrate metabolism. Alterations may include decreased glucose tolerance and increased insulin resistance, which are risk factors for Type 2 diabetes mellitus and cardiovascular disease. These issues have been raised primarily with contraceptives containing estrogen. OBJECTIVES: To evaluate the effect of hormonal contraceptives on carbohydrate metabolism in healthy women and those at risk for diabetes due to overweight. SEARCH METHODS: In April 2014, we searched the computerized databases MEDLINE, POPLINE, CENTRAL, and LILACS for studies of hormonal contraceptives and carbohydrate metabolism. We also searched for clinical trials in ClinicalTrials.gov and ICTRP. The initial search also included EMBASE. SELECTION CRITERIA: All randomized controlled trials were considered if they examined carbohydrate metabolism in women without diabetes who used hormonal contraceptives for contraception. Comparisons could be a placebo, a non-hormonal contraceptive, or another hormonal contraceptive that differed in drug, dosage, or regimen. Interventions included at least three cycles. Outcomes included glucose and insulin measures. DATA COLLECTION AND ANALYSIS: We assessed all titles and abstracts identified during the literature searches. The data were extracted and entered into RevMan. We wrote to researchers for missing data. For continuous variables, the mean difference (MD) was computed with 95% confidence interval (CI) using a fixed-effect model. For dichotomous outcomes, the Peto odds ratio with 95% CI was calculated. MAIN RESULTS: We found 31 trials that met the inclusion criteria. No new trials were eligible in 2014. Twenty-one trials compared combined oral contraceptives (COCs); others examined different COC regimens, progestin-only pills, injectables, a vaginal ring, and implants. None included a placebo. Of 34 comparisons, eight had any notable difference between the study groups in an outcome. Twelve trials studied desogestrel-containing COCs, and the few differences from levonorgestrel COCs were inconsistent. A meta-analysis of two studies showed the desogestrel group had a higher mean fasting glucose (MD 0.20; 95% CI 0.00 to 0.41). Where data could not be combined, single studies showed lower mean fasting glucose (MD -0.40; 95% CI -0.72 to -0.08) and higher means for two-hour glucose response (MD 1.08; 95% CI 0.45 to 1.71) and insulin area under the curve (AUC) (MD 20.30; 95% CI 4.24 to 36.36). Three trials examined the etonogestrel vaginal ring and one examined an etonogestrel implant. One trial showed the ring group had lower mean AUC insulin than the levonorgestrel-COC group (MD -204.51; 95% CI -389.64 to -19.38). Of eight trials of norethisterone preparations, five compared COCs and three compared injectables. In a COC trial, a norethisterone group had smaller mean change in glucose two-hour response than a levonorgestrel-COC group (MD -0.30; 95% CI -0.54 to -0.06). In an injectable study, a group using depot medroxyprogesterone acetate had higher means than the group using norethisterone enanthate for fasting glucose (MD 10.05; 95% CI 3.16 to 16.94), glucose two-hour response (MD 17.00; 95% CI 5.67 to 28.33), and fasting insulin (MD 3.40; 95% CI 2.07 to 4.73). Among five recent trials, two examined newer COCs with different estrogen types. One showed the group with nomegestrel acetate plus 17ß-estradiol had lower means than the levonorgestrel group for incremental AUC glucose (MD -1.43; 95% CI -2.55 to -0.31) and glycosylated hemoglobin (HbA1c) (MD -0.10; 95% CI -0.18 to -0.02). Two trials compared extended versus conventional (cyclic) regimens. With a dienogest COC, an extended-use group had greater mean change in AUC glucose (MD 82.00; 95% CI 10.72 to 153.28). In a small trial using two levonorgestrel COCs, the lower-dose group showed smaller mean change in fasting glucose (MD -3.00; 95% CI -5.89 to -0.11), but the obese and normal weight women did not differ significantly. AUTHORS' CONCLUSIONS: Current evidence suggests no major differences in carbohydrate metabolism between different hormonal contraceptives in women without diabetes. We cannot make strong statements due to having few studies that compared the same types of contraceptives. Many trials had small numbers of participants and some had large losses. Many of the earlier studies had limited reporting of methods. We still know very little about women at risk for metabolic problems due to being overweight. More than half of the trials had weight restrictions as inclusion criteria. Only one small trial stratified the groups by body mass index (obese versus normal).

CONSORT Statement for Randomized Trials of Nonpharmacologic Treatments: A 2017 Update and a CONSORT Extension for Nonpharmacologic Trial Abstracts.

Incomplete and inadequate reporting is an avoidable waste that reduces the usefulness of research. The CONSORT (Consolidated Standards of Reporting Trials) Statement is an evidence-based reporting guideline that aims to improve research transparency and reduce waste. In 2008, the CONSORT Group developed an extension to the original statement that addressed methodological issues specific to trials of nonpharmacologic treatments (NPTs), such as surgery, rehabilitation, or psychotherapy. This article describes an update of that extension and presents an extension for reporting abstracts of NPT trials. To develop these materials, the authors reviewed pertinent literature published up to July 2016; surveyed authors of NPT trials; and conducted a consensus meeting with editors, trialists, and methodologists. Changes to the CONSORT Statement extension for NPT trials include wording modifications to improve readers' understanding and the addition of 3 new items. These items address whether and how adherence of participants to interventions is assessed or enhanced, description of attempts to limit bias if blinding is not possible, and specification of the delay between randomization and initiation of the intervention. The CONSORT extension for abstracts of NPT trials includes 2 new items that were not specified in the original CONSORT Statement for abstracts. The first addresses reporting of eligibility criteria for centers where the intervention is performed and for care providers. The second addresses reporting of important changes to the intervention versus what was planned. Both the updated CONSORT extension for NPT trials and the CONSORT extension for NPT trial abstracts should help authors, editors, and peer reviewers improve the transparency of NPT trial reports.

Increasing value and reducing waste in research design, conduct, and analysis.

Correctable weaknesses in the design, conduct, and analysis of biomedical and public health research studies can produce misleading results and waste valuable resources. Small effects can be difficult to distinguish from bias introduced by study design and analyses. An absence of detailed written protocols and poor documentation of research is common. Information obtained might not be useful or important, and statistical precision or power is often too low or used in a misleading way. Insufficient consideration might be given to both previous and continuing studies. Arbitrary choice of analyses and an overemphasis on random extremes might affect the reported findings. Several problems relate to the research workforce, including failure to involve experienced statisticians and methodologists, failure to train clinical researchers and laboratory scientists in research methods and design, and the involvement of stakeholders with conflicts of interest. Inadequate emphasis is placed on recording of research decisions and on reproducibility of research. Finally, reward systems incentivise quantity more than quality, and novelty more than reliability. We propose potential solutions for these problems, including improvements in protocols and documentation, consideration of evidence from studies in progress, standardisation of research efforts, optimisation and training of an experienced and non-conflicted scientific workforce, and reconsideration of scientific reward systems.

SPIRIT 2013 Statement: defining standard protocol items for clinical trials.

The protocol of a clinical trial serves as the foundation for study planning, conduct, reporting, and appraisal. However, trial protocols and existing protocol guidelines vary greatly in content and quality. This article describes the systematic development and scope of SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2013, a guideline for the minimum content of a clinical trial protocol. The 33-item SPIRIT checklist applies to protocols for all clinical trials and focuses on content rather than format. The checklist recommends a full description of what is planned; it does not prescribe how to design or conduct a trial. By providing guidance for key content, the SPIRIT recommendations aim to facilitate the drafting of high-quality protocols. Adherence to SPIRIT would also enhance the transparency and completeness of trial protocols for the benefit of investigators, trial participants, patients, sponsors, funders, research ethics committees or institutional review boards, peer reviewers, journals, trial registries, policymakers, regulators, and other key stakeholders.

Steroidal contraceptives: effect on carbohydrate metabolism in women without diabetes mellitus.

BACKGROUND: Many hormonal contraceptives have been associated with changes in carbohydrate metabolism. Alterations may include decreased glucose tolerance and increased insulin resistance, which are risk factors for Type 2 diabetes mellitus and cardiovascular disease. These issues have been raised primarily with contraceptives containing estrogen. OBJECTIVES: To evaluate the effect of hormonal contraceptives on carbohydrate metabolism in healthy women and those at risk for diabetes due to overweight. SEARCH METHODS: In April 2014, we searched the computerized databases MEDLINE, POPLINE, CENTRAL, and LILACS for studies of hormonal contraceptives and carbohydrate metabolism. We also searched for clinical trials in ClinicalTrials.gov and ICTRP. The initial search also included EMBASE. SELECTION CRITERIA: All randomized controlled trials were considered if they examined carbohydrate metabolism in women without diabetes who used hormonal contraceptives for contraception. Comparisons could be a placebo, a non-hormonal contraceptive, or another hormonal contraceptive that differed in drug, dosage, or regimen. Interventions included at least three cycles. Outcomes included glucose and insulin measures. DATA COLLECTION AND ANALYSIS: We assessed all titles and abstracts identified during the literature searches. The data were extracted and entered into RevMan. We wrote to researchers for missing data. For continuous variables, the mean difference (MD) was computed with 95% confidence interval (CI) using a fixed-effect model. For dichotomous outcomes, the Peto odds ratio with 95% CI was calculated. MAIN RESULTS: We found 31 trials that met the inclusion criteria. No new trials were eligible in 2014. Twenty-one trials compared combined oral contraceptives (COCs); others examined different COC regimens, progestin-only pills, injectables, a vaginal ring, and implants. None included a placebo. Of 34 comparisons, eight had any notable difference between the study groups in an outcome.Twelve trials studied desogestrel-containing COCs, and the few differences from levonorgestrel COCs were inconsistent. A meta-analysis of two studies showed the desogestrel group had a higher mean fasting glucose (MD 0.20; 95% CI 0.00 to 0.41). Where data could not be combined, single studies showed lower mean fasting glucose (MD -0.40; 95% CI -0.72 to -0.08) and higher means for two-hour glucose response (MD 1.08; 95% CI 0.45 to 1.71) and insulin area under the curve (AUC) (MD 20.30; 95% CI 4.24 to 36.36).Three trials examined the etonogestrel vaginal ring and one examined an etonogestrel implant. One trial showed the ring group had lower mean AUC insulin than the levonorgestrel-COC group (MD -204.51; 95% CI -389.64 to -19.38).Of eight trials of norethisterone preparations, five compared COCs and three compared injectables. In a COC trial, a norethisterone group had smaller mean change in glucose two-hour response than a levonorgestrel-COC group (MD -0.30; 95% CI -0.54 to -0.06). In an injectable study, a group using depot medroxyprogesterone acetate had higher means than the group using norethisterone enanthate for fasting glucose (MD 10.05; 95% CI 3.16 to 16.94), glucose two-hour response (MD 17.00; 95% CI 5.67 to 28.33), and fasting insulin (MD 3.40; 95% CI 2.07 to 4.73).Among five recent trials, two examined newer COCs with different estrogen types. One showed the group with nomegestrel acetate plus 17ß-estradiol had lower means than the levonorgestrel group for incremental AUC glucose (MD -1.43; 95% CI -2.55 to -0.31) and glycosylated hemoglobin (HbA1c) (MD -0.10; 95% CI -0.18 to -0.02). Two trials compared extended versus conventional (cyclic) regimens. With a dienogest COC, an extended-use group had greater mean change in AUC glucose (MD 82.00; 95% CI 10.72 to 153.28). In a small trial using two levonorgestrel COCs, the lower-dose group showed smaller mean change in fasting glucose (MD -3.00; 95% CI -5.89 to -0.11), but the obese and normal weight women did not differ significantly. AUTHORS' CONCLUSIONS: Current evidence suggests no major differences in carbohydrate metabolism between different hormonal contraceptives in women without diabetes. We cannot make strong statements due to having few studies that compared the same types of contraceptives. Many trials had small numbers of participants and some had large losses. Many of the earlier studies had limited reporting of methods.We still know very little about women at risk for metabolic problems due to being overweight. More than half of the trials had weight restrictions as inclusion criteria. Only one small trial stratified the groups by body mass index (obese versus normal).

Oral contraceptives for functional ovarian cysts.

BACKGROUND: Functional ovarian cysts are a common gynecological problem among women of reproductive age worldwide. When large, persistent, or painful, these cysts may require operations, sometimes resulting in removal of the ovary. Since early oral contraceptives were associated with a reduced incidence of functional ovarian cysts, many clinicians inferred that birth control pills could be used to treat cysts as well. This became a common clinical practice in the early 1970s. OBJECTIVES: This review examined all randomized controlled trials that studied oral contraceptives as therapy for functional ovarian cysts. SEARCH METHODS: In March 2014, we searched the databases of CENTRAL, PubMed, EMBASE, and POPLINE, as well as clinical trials databases (ClinicalTrials.gov and ICTRP). We also examined the reference lists of articles. For the initial review, we wrote to authors of identified trials to seek articles we had missed. SELECTION CRITERIA: We included randomized controlled trials in any language that included oral contraceptives used for treatment and not prevention of functional ovarian cysts. Criteria for diagnosis of cysts were those used by authors of trials. DATA COLLECTION AND ANALYSIS: Two authors independently abstracted data from the articles. One entered the data into RevMan and a second verified accuracy of data entry. For dichotomous outcomes, we computed the Mantel-Haenszel odds ratio with 95% confidence interval (CI). For continuous outcomes, we calculated the mean difference with 95% CI. MAIN RESULTS: We identified eight randomized controlled trials from four countries; the studies included a total of 686 women. Treatment with combined oral contraceptives did not hasten resolution of functional ovarian cysts in any trial. This held true for cysts that occurred spontaneously as well as those that developed after ovulation induction. Most cysts resolved without treatment within a few cycles; persistent cysts tended to be pathological (e.g., endometrioma or para-ovarian cyst) and not physiological. AUTHORS' CONCLUSIONS: Although widely used for treating functional ovarian cysts, combined oral contraceptives appear to be of no benefit. Watchful waiting for two or three cycles is appropriate. Should cysts persist, surgical management is often indicated.

Steroidal contraceptives: effect on bone fractures in women.

BACKGROUND: Steroidal contraceptive use has been associated with changes in bone mineral density in women. Whether such changes increase the risk of fractures later in life is not clear. Osteoporosis is a major public health concern. Age-related decline in bone mass increases the risk of fracture, especially of the spine, hip, and wrist. Concern about bone health influences the recommendation and use of these effective contraceptives globally. OBJECTIVES: Our aim was to evaluate the effect of using hormonal contraceptives before menopause on the risk of fracture in women. SEARCH METHODS: Through April 2014, we searched for studies of fracture or bone health and hormonal contraceptives in MEDLINE, POPLINE, CENTRAL, EMBASE, and LILACS, as well as ClinicalTrials.gov and ICTRP. We examined reference lists of relevant articles for other trials. For the initial review, we wrote to investigators to find additional trials. SELECTION CRITERIA: Randomized controlled trials (RCTs) were considered if they examined fractures, bone mineral density (BMD), or bone turnover markers in women with hormonal contraceptive use prior to menopause. Eligible interventions included comparisons of a hormonal contraceptive with a placebo or with another hormonal contraceptive that differed in terms of drug, dosage, or regimen. They also included providing a supplement to one group. DATA COLLECTION AND ANALYSIS: We assessed all titles and abstracts identified through the literature searches. Mean differences were computed using the inverse variance approach. For dichotomous outcomes, the Mantel-Haenszel odds ratio (OR) was calculated. Both included the 95% confidence interval (CI) and used a fixed-effect model. Due to differing interventions, no trials could be combined for meta-analysis. We applied principles from GRADE to assess the evidence quality and address confidence in the effect estimates. In addition, a sensitivity analysis included trials that provided sufficient data for this review and evidence of at least moderate quality. MAIN RESULTS: We found 19 RCTs that met our eligibility criteria. Eleven trials compared different combined oral contraceptives (COCs) or regimens of COCs; five examined an injectable versus another injectable, implant, or IUD; two studied implants, and one compared the transdermal patch versus the vaginal ring. No trial had fracture as an outcome. BMD was measured in 17 studies and 12 trials assessed biochemical markers of bone turnover. Depot medroxyprogesterone acetate (DMPA) was associated with decreased bone mineral density (BMD). The placebo-controlled trials showed BMD increases for DMPA plus estrogen supplement and decreases for DMPA plus placebo supplement. COCs did not appear to negatively affect BMD, and some formulations had more positive effects than others. However, no COC trial was placebo-controlled. Where studies showed differences between groups in bone turnover markers, the results were generally consistent with those for BMD. For implants, the single-rod etonogestrel group showed a greater BMD decrease versus the two-rod levonorgestrel group but results were not consistent across all implant comparisons.The sensitivity analysis included 11 trials providing evidence of moderate or high quality. Four trials involving DMPA showed some positive effects of an estrogen supplement on BMD, a negative effect of DMPA-subcutaneous on lumbar spine BMD, and a negative effect of DMPA on a bone formation marker. Of the three COC trials, one had a BMD decrease for the group with gestodene plus EE 15 µg. Another indicated less bone resorption in the group with gestodene plus EE 30 µg versus EE 20 µg. AUTHORS' CONCLUSIONS: Whether steroidal contraceptives influence fracture risk cannot be determined from existing information. The evidence quality was considered moderate overall, largely due to the trials of DMPA, implants, and the patch versus ring. The COC evidence varied in quality but was low overall. Many trials had small numbers of participants and some had large losses. Health care providers and women should consider the costs and benefits of these effective contraceptives. For example, injectable contraceptives and implants provide effective, long-term birth control yet do not involve a daily regimen. Progestin-only contraceptives are considered appropriate for women who should avoid estrogen due to medical conditions.

Combination contraceptives: effects on weight.

BACKGROUND: Weight gain is often considered a side effect of combination hormonal contraceptives, and many women and clinicians believe that an association exists. Concern about weight gain can limit the use of this highly effective method of contraception by deterring the initiation of its use and causing early discontinuation among users. However, a causal relationship between combination contraceptives and weight gain has not been established. OBJECTIVES: The aim of the review was to evaluate the potential association between combination contraceptive use and changes in weight. SEARCH METHODS: In November 2013, we searched the computerized databases CENTRAL (The Cochrane Library), MEDLINE, POPLINE, EMBASE, and LILACS for studies of combination contraceptives, as well as ClinicalTrials.gov and International Clinical Trials Registry Platform (ICTRP). For the initial review, we also wrote to known investigators and manufacturers to request information about other published or unpublished trials not discovered in our search. SELECTION CRITERIA: All English-language, randomized controlled trials were eligible if they had at least three treatment cycles and compared a combination contraceptive to a placebo or to a combination contraceptive that differed in drug, dosage, regimen, or study length. DATA COLLECTION AND ANALYSIS: All titles and abstracts located in the literature searches were assessed. Data were entered and analyzed with RevMan. A second author verified the data entered. For continuous data, we calculated the mean difference and 95% confidence interval (CI) for the mean change in weight between baseline and post-treatment measurements using a fixed-effect model. For categorical data, such as the proportion of women who gained or lost more than a specified amount of weight, the Peto odds ratio with 95% CI was calculated. MAIN RESULTS: We found 49 trials that met our inclusion criteria. The trials included 85 weight change comparisons for 52 distinct contraceptive pairs (or placebos). The four trials with a placebo or no intervention group did not find evidence supporting a causal association between combination oral contraceptives or a combination skin patch and weight change. Most comparisons of different combination contraceptives showed no substantial difference in weight. In addition, discontinuation of combination contraceptives because of weight change did not differ between groups where this was studied. AUTHORS' CONCLUSIONS: Available evidence was insufficient to determine the effect of combination contraceptives on weight, but no large effect was evident. Trials to evaluate the link between combination contraceptives and weight change require a placebo or non-hormonal group to control for other factors, including changes in weight over time.

SPIRIT 2013 statement: defining standard protocol items for clinical trials.

The protocol of a clinical trial serves as the foundation for study planning, conduct, reporting, and appraisal. However, trial protocols and existing protocol guidelines vary greatly in content and quality. This article describes the systematic development and scope of SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2013, a guideline for the minimum content of a clinical trial protocol.The 33-item SPIRIT checklist applies to protocols for all clinical trials and focuses on content rather than format. The checklist recommends a full description of what is planned; it does not prescribe how to design or conduct a trial. By providing guidance for key content, the SPIRIT recommendations aim to facilitate the drafting of high-quality protocols. Adherence to SPIRIT would also enhance the transparency and completeness of trial protocols for the benefit of investigators, trial participants, patients, sponsors, funders, research ethics committees or institutional review boards, peer reviewers, journals, trial registries, policymakers, regulators, and other key stakeholders.

Methods used to develop the SPIRIT 2024 and CONSORT 2024 Statements.

OBJECTIVES: To describe, and explain the rationale for, the methods used and decisions made during development of the updated SPIRIT 2024 and CONSORT 2024 reporting guidelines. METHODS: We developed SPIRIT 2024 and CONSORT 2024 together to facilitate harmonization of the two guidelines, and incorporated content from key extensions. We conducted a scoping review of comments suggesting changes to SPIRIT 2013 and CONSORT 2010, and compiled a list of other possible revisions based on existing SPIRIT and CONSORT extensions, other reporting guidelines, and personal communications. From this, we generated a list of potential modifications or additions to SPIRIT and CONSORT, which we presented to stakeholders for feedback in an international online Delphi survey. The Delphi survey results were discussed at an online expert consensus meeting attended by 30 invited international participants. We then drafted the updated SPIRIT and CONSORT checklists and revised them based on further feedback from meeting attendees. RESULTS: We compiled 83 suggestions for revisions or additions to SPIRIT and/or CONSORT from the scoping review and 85 from other sources, from which we generated 33 potential changes to SPIRIT (n = 5) or CONSORT (n = 28). Of 463 participants invited to take part in the Delphi survey, 317 (68%) responded to Round 1, 303 (65%) to Round 2 and 290 (63%) to Round 3. Two additional potential checklist changes were added to the Delphi survey based on Round 1 comments. Overall, 14/35 (SPIRIT n = 0; CONSORT n = 14) proposed changes reached the predefined consensus threshold (≥80% agreement), and participants provided 3580 free-text comments. The consensus meeting participants agreed with implementing 11/14 of the proposed changes that reached consensus in the Delphi and supported implementing a further 4/21 changes (SPIRIT n = 2; CONSORT n = 2) that had not reached the Delphi threshold. They also recommended further changes to refine key concepts and for clarity. CONCLUSION: The forthcoming SPIRIT 2024 and CONSORT 2024 Statements will provide updated, harmonized guidance for reporting randomized controlled trial protocols and results, respectively. The simultaneous development of the SPIRIT and CONSORT checklists has been informed by current empirical evidence and extensive input from stakeholders. We hope that this report of the methods used will be helpful for developers of future reporting guidelines.

Compelling evidence from meta-epidemiological studies demonstrates overestimation of effects in randomized trials that fail to optimize randomization and blind patients and outcome assessors.

OBJECTIVES: To investigate the impact of potential risk of bias elements on effect estimates in randomized trials. STUDY DESIGN AND SETTING: We conducted a systematic survey of meta-epidemiological studies examining the influence of potential risk of bias elements on effect estimates in randomized trials. We included only meta-epidemiological studies that either preserved the clustering of trials within meta-analyses (compared effect estimates between trials with and without the potential risk of bias element within each meta-analysis, then combined across meta-analyses; between-trial comparisons), or preserved the clustering of substudies within trials (compared effect estimates between substudies with and without the element, then combined across trials; within-trial comparisons). Separately for studies based on between- and within-trial comparisons, we extracted ratios of odds ratios (RORs) from each study and combined them using a random-effects model. We made overall inferences and assessed certainty of evidence based on Grading of Recommendations, Assessment, development, and Evaluation and Instrument to assess the Credibility of Effect Modification Analyses. RESULTS: Forty-one meta-epidemiological studies (34 of between-, 7 of within-trial comparisons) proved eligible. Inadequate random sequence generation (ROR 0.94, 95% confidence interval [CI] 0.90-0.97) and allocation concealment (ROR 0.92, 95% CI 0.88-0.97) probably lead to effect overestimation (moderate certainty). Lack of patients blinding probably overestimates effects for patient-reported outcomes (ROR 0.36, 95% CI 0.28-0.48; moderate certainty). Lack of blinding of outcome assessors results in effect overestimation for subjective outcomes (ROR 0.69, 95% CI 0.51-0.93; high certainty). The impact of patients or outcome assessors blinding on other outcomes, and the impact of blinding of health-care providers, data collectors, or data analysts, remain uncertain. Trials stopped early for benefit probably overestimate effects (moderate certainty). Trials with imbalanced cointerventions may overestimate effects, while trials with missing outcome data may underestimate effects (low certainty). Influence of baseline imbalance, compliance, selective reporting, and intention-to-treat analysis remain uncertain. CONCLUSION: Failure to ensure random sequence generation or adequate allocation concealment probably results in modest overestimates of effects. Lack of patients blinding probably leads to substantial overestimates of effects for patient-reported outcomes. Lack of blinding of outcome assessors results in substantial effect overestimation for subjective outcomes. For other elements, though evidence for consistent systematic overestimate of effect remains limited, failure to implement these safeguards may still introduce important bias.

Combination injectable contraceptives for contraception.

BACKGROUND: Combination injectable contraceptives (CICs) provide a highly effective, reversible method of preventing pregnancy, and they do not require daily administration or use at the time of coitus. Although they are used in many countries, their acceptability could be limited by method characteristics, such as the need to obtain a monthly injection or bleeding pattern changes. OBJECTIVES: To assess the contraceptive efficacy, bleeding patterns, discontinuation, user preferences, and side effects of CICs. SEARCH METHODS: In January and February 2013, we searched for randomized controlled trials (RCTs) of combination injectable contraceptives.Databases include MEDLINE, POPLINE, CENTRAL, EMBASE, and LILACS.We searched for current trials in ClinicalTrials.gov and ICTRP.Earlier searches also included AIM and IMEMR. For the initial review, we also assessed the references listed in review articles and in the eligible trial reports. SELECTION CRITERIA: RCTs were eligible if they compared a combination injectable contraceptive with any other contraceptive method (e.g., a second CIC,a progestin-only injectable contraceptive, another hormonal contraceptive or a barrier method) or a placebo. We limited the review to marketed CICs. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data on contraceptive efficacy, bleeding patterns, continuation, and side effects. We calculated the Peto odds ratio or mean difference with 95% confidence interval for dichotomous or continuous outcome, respectively. Survival analysis estimates for method discontinuation were presented where available. MAIN RESULTS: Twelve trials met the inclusion criteria. Combination injectable contraceptives include depot medroxyprogesterone acetate (DMPA)25 mg plus estradiol cypionate (E(2)C) 5 mg, as well as norethisterone enanthate (NET-EN) 50 mg plus estradiol valerate (E(2)V) 5mg. These contraceptives resulted in lower rates of early study discontinuation due to amenorrhea or other bleeding problems than progestin-only contraceptives. However, rates were higher for overall discontinuation and discontinuation due to other medical reasons.Acceptability results favored the CIC in one study and the progestin-only in another.Studies comparing two CICs found that NET-EN 50 mg plus E(2)V (5)mg resulted in less overall discontinuation and less discontinuation due to amenorrhea or prolonged bleeding than DMPA 25 mg plus E(2)C 5 mg. However, these differences were not detected in all trials.The NET-EN plus E (2) V group also had more regular bleeding and fewer prolonged bleeding reference periods than the DMPA plus E(2)C group. The groups did not differ in their amenorrhea rates. AUTHORS' CONCLUSIONS: While discontinuation rates can be viewed as a measure of method acceptability, the findings should be interpreted with caution since discontinuation depends on many factors. Future research should be directed toward improving the acceptability of combination injectable contraceptives, such as providing injections in settings more convenient than clinics, methods for women to administer their own injections, and counseling about possible bleeding pattern changes.

Spermicide used alone for contraception.

BACKGROUND: Spermicides have been used as contraceptives for thousands of years. Despite this long use, only recently have studies examined the comparative efficacy and acceptability of these vaginal medications. Spermicides contain an active ingredient (most commonly nonoxynol-9) and a formulation used to disperse the product, such as foam or vaginal suppository. OBJECTIVES: This review examined all known randomized controlled trials of a spermicide used alone for contraception. SEARCH METHODS: In August 2013, we searched the following computerized databases for randomized controlled trials of spermicides for contraception: CENTRAL, MEDLINE, POPLINE, LILACS, EMBASE, ClinicalTrials.gov, and ICTRP. For the initial review, we examined the reference lists of trials found as well as those of review articles and textbook chapters. SELECTION CRITERIA: We included any trial of a commercial product used alone for contraception. Each included trial must have provided sufficient information to determine pregnancy rates. DATA COLLECTION AND ANALYSIS: Two authors independently extracted information from the trials identified. We did not conduct a meta-analysis, since most trials had large losses to follow up. We entered the data into tables and presented the results descriptively. MAIN RESULTS: We located reports from 14 trials for the initial review, but have not identified any new trials since then. In the largest trial to date, the gel (Advantage S) containing the lowest dose of nonoxynol-9 (52.5 mg) was significantly less effective in preventing pregnancy than were gels with higher doses of the same agent (100 mg and 150 mg). Probabilities of pregnancy by six months were 22% for the 52.5 mg gel, 16% for the 100 mg dose, and 14% for the 150 mg dose. In the same trial, the three different vehicles with 100 mg of nonoxynol-9 had similar efficacy. Interpretation of these figures is limited, since 39% of participants discontinued the method or were lost from the trial. Few important differences in efficacy emerged in other trials. AUTHORS' CONCLUSIONS: The probability of pregnancy varied widely in reported trials. A gel containing nonoxynol-9 52.5 mg was inferior to two other products tested in the largest trial. Aside from this finding, personal characteristics and behavior of users may be more important than characteristics of the spermicide products in determining the probability of pregnancy. Gel was liked more than the film or vaginal suppository in the largest trial. Spermicide trials have the dual challenges of difficult recruitment and high discontinuation rates; the latter threatens trial validity.

Skin patch and vaginal ring versus combined oral contraceptives for contraception.

BACKGROUND: The delivery of combination contraceptive steroids from a transdermal contraceptive patch or a contraceptive vaginal ring offers potential advantages over the traditional oral route. The transdermal patch and vaginal ring could require a lower dose due to increased bioavailability and improved user compliance. OBJECTIVES: To compare the contraceptive effectiveness, cycle control, compliance (adherence), and safety of the contraceptive patch or the vaginal ring versus combination oral contraceptives (COCs). SEARCH METHODS: Through February 2013, we searched MEDLINE, POPLINE, CENTRAL, LILACS, ClinicalTrials.gov, and ICTRP for trials of the contraceptive patch or the vaginal ring. Earlier searches also included EMBASE. For the initial review, we contacted known researchers and manufacturers to identify other trials. SELECTION CRITERIA: We considered randomized controlled trials comparing a transdermal contraceptive patch or a contraceptive vaginal ring with a COC. DATA COLLECTION AND ANALYSIS: Data were abstracted by two authors and entered into RevMan. For dichotomous variables, the Peto odds ratio (OR) with 95% confidence intervals (CI) was calculated. For continuous variables, the mean difference was computed. We also assessed the quality of evidence for this review. MAIN RESULTS: We found 18 trials that met our inclusion criteria. Of six patch studies, five examined the marketed patch containing norelgestromin plus ethinyl estradiol (EE); one studied a patch in development that contains levonorgestrel (LNG) plus EE. Of 12 vaginal ring trials, 11 examined the same marketing ring containing etonogestrel plus EE; one studied a ring being developed that contains nesterone plus EE.Contraceptive effectiveness was not significantly different for the patch or ring versus the comparison COC. Compliance data were limited. Patch users showed better compliance than COC users in three trials. For the norelgestromin plus EE patch, ORs were 2.05 (95% CI 1.83 to 2.29) and 2.76 (95% CI 2.35 to 3.24). In the levonorgestrel plus EE patch report, patch users were less likely to have missed days of therapy (OR 0.36; 95% CI 0.25 to 0.51). Of four vaginal ring trials, one found ring users had more noncompliance (OR 3.99; 95% CI 1.87 to 8.52), while another showed more compliance with the regimen (OR 1.67; 95% CI 1.04 to 2.68).More patch users discontinued early than COC users. ORs from two meta-analyses were 1.59 (95% CI 1.26 to 2.00) and 1.56 (95% CI 1.18 to 2.06) and another trial showed OR 2.57 (95% CI 0.99 to 6.64). Patch users also had more discontinuation due to adverse events than COC users. Users of the norelgestromin-containing patch reported more breast discomfort, dysmenorrhea, nausea, and vomiting. In the levonorgestrel-containing patch trial, patch users reported less vomiting, headaches, and fatigue.Of 11 ring trials with discontinuation data, two showed the ring group discontinued less than the COC group: OR 0.32 (95% CI 0.16 to 0.66) and OR 0.52 (95% CI 0.31 to 0.88). Ring users were less likely to discontinue due to adverse events in one study (OR 0.32; 95% CI 0.15 to 0.70). Compared to the COC users, ring users had more vaginitis and leukorrhea but less vaginal dryness. Ring users also reported less nausea, acne, irritability, depression, and emotional lability than COC users.For cycle control, only one trial study showed a significant difference. Women in the patch group were less likely to have breakthrough bleeding and spotting. Seven ring studies had bleeding data; four trials showed the ring group generally had better cycle control than the COC group. AUTHORS' CONCLUSIONS: Effectiveness was not significantly different for the methods compared. Pregnancy data were available from half of the patch trials but two-thirds of ring trials. The patch could lead to more discontinuation than the COC. The patch group had better compliance than the COC group. Compliance data came from half of the patch studies and one-third of the ring trials. Patch users had more side effects than the COC group. Ring users generally had fewer adverse events than COC users but more vaginal irritation and discharge.The quality of the evidence for this review was considered low for the patch and moderate for the ring. The main reasons for downgrading were lack of information on the randomization sequence generation or allocation concealment, the outcome assessment methods, high losses to follow up, and exclusions after randomization.

Strategies for communicating contraceptive effectiveness.

BACKGROUND: Knowledge of contraceptive effectiveness is crucial to making an informed choice. The consumer has to comprehend the pros and cons of the contraceptive methods being considered. Choice may be influenced by understanding the likelihood of pregnancy with each method and factors that influence effectiveness. OBJECTIVES: To review all randomized controlled trials comparing strategies for communicating to consumers the effectiveness of contraceptives in preventing pregnancy. SEARCH METHODS: Through February 2013, we searched the computerized databases of MEDLINE, POPLINE, CENTRAL, PsycINFO and CINAHL, ClinicalTrials.gov, and ICTRP. Previous searches also included EMBASE. We also examined references lists of relevant articles. For the initial review, we wrote to known investigators for information about other published or unpublished trials. SELECTION CRITERIA: We included randomized controlled trials that compared methods for communicating contraceptive effectiveness to consumers. The comparison could be usual practice or an alternative to the experimental intervention.Outcome measures were knowledge of contraceptive effectiveness, attitude about contraception or toward any particular contraceptive, and choice or use of contraceptive method. DATA COLLECTION AND ANALYSIS: For the initial review, two authors independently extracted the data. One author entered the data into RevMan, and a second author verified accuracy. For the update, an author and a research associate extracted, entered, and checked the data.For dichotomous variables, we calculated the Mantel-Haenszel odds ratio with 95% confidence intervals (CI). For continuous variables, we computed the mean difference (MD) with 95% CI. MAIN RESULTS: Seven trials met the inclusion criteria and had a total of 4526 women. Five were multi-site studies. Four trials were conducted in the USA, while Nigeria and Zambia were represented by one study each, and one trial was done in both Jamaica and India.Two trials provided multiple sessions for participants. In one study that examined contraceptive choice, women in the expanded program were more likely to choose sterilization (OR 4.26; 95% CI 2.46 to 7.37) or use a modern contraceptive method (OR 2.35; 95% CI 1.82 to 3.03), i.e., sterilization, pills, injectable, intrauterine device or barrier method. For the other study, the groups received educational interventions with differing format and intensity. Both groups reportedly had increases in contraceptive use, but they did not differ significantly by six months in consistent use of an effective contraceptive, i.e., sterilization, IUD, injectable, implant, and consistent use of oral contraceptives, diaphragm, or male condoms.Five trials provided one session and focused on testing educational material or media. In one study, knowledge gain favored a slide-and-sound presentation versus a physician's oral presentation (MD -19.00; 95% CI -27.52 to -10.48). In another trial, a table with contraceptive effectiveness categories led to more correct answers than a table based on pregnancy numbers [ORs were 2.42 (95% CI 1.43 to 4.12) and 2.19 (95% CI 1.21 to 3.97)] or a table with effectiveness categories and pregnancy numbers [ORs were 2.58 (95% CI 1.5 to 4.42) and 2.03 (95% CI 1.13 to 3.64)]. Still another trial provided structured counseling with a flipchart on contraceptive methods. The intervention and usual-care groups did not differ significantly in choice of contraceptive method (by effectiveness category) or in continuation of the chosen method at three months. Lastly, a study with couples used videos to communicate contraceptive information (control, motivational, contraceptive methods, and both motivational and methods videos). The analyses showed no significant difference between the groups in the types of contraceptives chosen. AUTHORS' CONCLUSIONS: These trials varied greatly in the types of participants and interventions to communicate contraceptive effectiveness. Therefore, we cannot say overall what would help consumers choose an appropriate contraceptive method. For presenting pregnancy risk data, one trial showed that effectiveness categories were better than pregnancy numbers. In another trial, audiovisual aids worked better than the usual oral presentation. Strategies should be tested in clinical settings and measured for their effect on contraceptive choice. More detailed reporting of intervention content would help in interpreting results. Reports could also include whether the instruments used to assess knowledge or attitudes were tested for validity or reliability. Follow-up should be incorporated to assess retention of knowledge over time. The overall quality of evidence was considered to be low for this review, given that five of the seven studies provided low or very low quality evidence.

20 µg versus >20 µg estrogen combined oral contraceptives for contraception.

BACKGROUND: Concern about estrogen-related adverse effects has led to progressive reductions in the estrogen dose in combination oral contraceptives (COCs). However, reducing the amount of estrogen to improve safety could result in decreased contraceptive effectiveness and unacceptable changes in bleeding patterns. OBJECTIVES: To test the hypothesis that COCs containing ≤ 20 µg ethinyl estradiol (EE) perform similarly as those containing > 20 µg in terms of contraceptive effectiveness, bleeding patterns, discontinuation, and side effects. SEARCH METHODS: In July 2013, we searched CENTRAL, MEDLINE, and POPLINE, and examined references of potentially eligible trials. We also searched for recent clinical trials using ClinicalTrials.gov and ICTRP. No new trials met the inclusion criteria. Previous searches included EMBASE. For the initial review, we wrote to oral contraceptive manufacturers to identify trials. SELECTION CRITERIA: English-language reports of randomized controlled trials were eligible that compare a COC containing ≤ 20 µg EE with a COC containing > 20 µg EE. We excluded studies where the interventions were designed to be administered for less than three consecutive cycles or to be used primarily as treatment for non-contraceptive conditions. Trials had to report on contraceptive effectiveness, bleeding patterns, trial discontinuation due to bleeding-related reasons or other side effects, or side effects to be included in the review. DATA COLLECTION AND ANALYSIS: One author evaluated all titles and abstracts from literature searches to determine whether they met the inclusion criteria. Two authors independently extracted data from studies identified for inclusion. We wrote to the researchers when additional information was needed. Data were entered and analyzed with RevMan. MAIN RESULTS: No differences were found in contraceptive effectiveness for the 13 COC pairs for which this outcome was reported. Compared to the higher-estrogen pills, several COCs containing 20 µg EE resulted in higher rates of early trial discontinuation (overall and due to adverse events such as irregular bleeding) as well as increased risk of bleeding disturbances (both amenorrhea or infrequent bleeding and irregular, prolonged, frequent bleeding, or breakthrough bleeding or spotting). AUTHORS' CONCLUSIONS: While COCs containing 20 µg EE may be theoretically safer, this review did not focus on the rare events required to assess this hypothesis. Data from existing randomized controlled trials are inadequate to detect possible differences in contraceptive effectiveness. Low-dose estrogen COCs resulted in higher rates of bleeding pattern disruptions. However, most trials compared COCs containing different progestin types, and changes in bleeding patterns could be related to progestin type as well as estrogen dose. Higher follow-up rates are essential for meaningful interpretation of results.

Spermicide used alone for contraception.

BACKGROUND: Spermicides have been used as contraceptives for thousands of years. Despite this long use, only recently have studies examined the comparative efficacy and acceptability of these vaginal medications. Spermicides contain an active ingredient (most commonly nonoxynol-9) and a formulation used to disperse the product, such as foam or vaginal suppository. OBJECTIVES: This review examined all known randomized controlled trials of a spermicide used alone for contraception. SEARCH METHODS: In August 2013, we searched the following computerized databases for randomized controlled trials of spermicides for contraception: CENTRAL, MEDLINE, POPLINE, LILACS, EMBASE, ClinicalTrials.gov, and ICTRP. For the initial review, we examined the reference lists of trials found as well as those of review articles and textbook chapters. SELECTION CRITERIA: We included any trial of a commercial product used alone for contraception. Each included trial must have provided sufficient information to determine pregnancy rates. DATA COLLECTION AND ANALYSIS: Two authors independently extracted information from the trials identified. We did not conduct a meta-analysis, since most trials had large losses to follow up. We entered the data into tables and presented the results descriptively. MAIN RESULTS: We located reports from 14 trials for the initial review, but have not identified any new trials since then. In the largest trial to date, the gel (Advantage S) containing the lowest dose of nonoxynol-9 (52.5 mg) was significantly less effective in preventing pregnancy than were gels with higher doses of the same agent (100 mg and 150 mg). Probabilities of pregnancy by six months were 22% for the 52.5 mg gel, 16% for the 100 mg dose, and 14% for the 150 mg dose. In the same trial, the three different vehicles with 100 mg of nonoxynol-9 had similar efficacy. Interpretation of these figures is limited, since 39% of participants discontinued the method or were lost from the trial. Few important differences in efficacy emerged in other trials. AUTHORS' CONCLUSIONS: The probability of pregnancy varied widely in reported trials. A gel containing nonoxynol-9 52.5 mg was inferior to two other products tested in the largest trial. Aside from this finding, personal characteristics and behavior of users may be more important than characteristics of the spermicide products in determining the probability of pregnancy. Gel was liked more than the film or vaginal suppository in the largest trial. Spermicide trials have the dual challenges of difficult recruitment and high discontinuation rates; the latter threatens trial validity.

Influence of reported study design characteristics on intervention effect estimates from randomized, controlled trials.

Published evidence suggests that aspects of trial design lead to biased intervention effect estimates, but findings from different studies are inconsistent. This study combined data from 7 meta-epidemiologic studies and removed overlaps to derive a final data set of 234 unique meta-analyses containing 1973 trials. Outcome measures were classified as "mortality," "other objective," "or subjective," and Bayesian hierarchical models were used to estimate associations of trial characteristics with average bias and between-trial heterogeneity. Intervention effect estimates seemed to be exaggerated in trials with inadequate or unclear (vs. adequate) random-sequence generation (ratio of odds ratios, 0.89 [95% credible interval {CrI}, 0.82 to 0.96]) and with inadequate or unclear (vs. adequate) allocation concealment (ratio of odds ratios, 0.93 [CrI, 0.87 to 0.99]). Lack of or unclear double-blinding (vs. double-blinding) was associated with an average of 13% exaggeration of intervention effects (ratio of odds ratios, 0.87 [CrI, 0.79 to 0.96]), and between-trial heterogeneity was increased for such studies (SD increase in heterogeneity, 0.14 [CrI, 0.02 to 0.30]). For each characteristic, average bias and increases in between-trial heterogeneity were driven primarily by trials with subjective outcomes, with little evidence of bias in trials with objective and mortality outcomes. This study is limited by incomplete trial reporting, and findings may be confounded by other study design characteristics. Bias associated with study design characteristics may lead to exaggeration of intervention effect estimates and increases in between-trial heterogeneity in trials reporting subjectively assessed outcomes.

A scoping review identifies multiple comments suggesting modifications to SPIRIT 2013 and CONSORT 2010.

OBJECTIVES: To identify, summarize, and analyse comments on the core reporting guidelines for protocols of randomized trials (Standard Protocol Items: Recommendations for Interventional Trials [SPIRIT] 2013) and for completed trials (Consolidated Standards of Reporting Trials [CONSORT] 2010), with special emphasis on suggestions for guideline modifications. METHODS: We included documents written in English and published after 2010 that explicitly commented on SPIRIT 2013 or CONSORT 2010. We searched four bibliographic databases (Embase and MEDLINE to June 2022; Web of Science and Google Scholar to April 2022) and other sources (e.g., the EQUATOR Network website, the BMC Blog Network, and the BMJ rapid response section). Two authors independently assessed documents for eligibility and extracted data on basic characteristics and the wording of the main comments. We categorized comments as 'suggestion for modification to the wording of an existing guideline item,' 'suggestion for a new item,' or 'reflections on challenges or strengths.' We provided a summary and examples of the proposed suggestions and categorized comments into those that were directly linked to empirical investigations, were continuations of previous methodological discussions, or reflected new methodological developments. RESULTS: We assessed full text of 2,320 potentially eligible documents and included 93 documents with 114 comments. In total, 37 comments suggested modifications to existing guideline items. The participant flow section of CONSORT 2010 received the most comments (eight comments made different suggestions, e.g., one comment suggested to add numbers on nonrandomized screened participants). There were 46 comments suggesting new items. Multiple suggestions were related to trial interventions (eight comments made different suggestions, e.g., one comment suggested to add content on cointerventions), blinding (six comments suggested to add content on risk of unblinding), statistical methods (five comments made different suggestions, e.g., one comment suggested to add content on blinding of statisticians), and participant flow (seven comments made different suggestions, e.g., three comments suggested to add content on missing data). Half (53%) of the suggestions were directly linked to empirical investigations. Six (7%) suggestions were continuations of previous methodological discussions and five (6%) suggestions reflected new methodological developments related to conflicts of interest and funding, data sharing, and patient and public involvement. CONCLUSION: The issues raised provide context to authors, peer reviewers, editors, and readers of trials using SPIRIT 2013 and CONSORT 2010 and inform the planned updates of the core guidelines.