Clinical Trials. A Practical Approach.

Seldrup, J; Pocock, Stuart J.

doi:10.2307/2987660

Cited by 36 publications

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“…With this in mind, sample size was calculated according to the literature (24) and it was verified that at least 14 patients (7 normal and 7 over-expressed BCL6) were required to have a 80% chance of detecting, as significant at the 5% level, an over-expression of BCL6 in 80% of the non-pregnant group, while BCL6 would be over-expressed in 20% in the normal (pregnant) group.…”

Section: Methodsmentioning

confidence: 99%

Endometrial BCL6 testing for the prediction of in vitro fertilization outcomes: a cohort study

Almquist

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Stone

et al. 2017

Fertility and Sterility

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Objective To evaluate endometrial BCL6 expression as a prognostic biomarker for In Vitro Fertilization (IVF) outcome in women with unexplained infertility (UI) prior to embryo transfer. Design Prospective cohort study. Setting University associated infertility clinic. Patients Women with UI for greater than 1 year. Interventions We studied women with UI who underwent testing for endometrial BCL6, in an LH-timed mid-luteal phase biopsy and completed an IVF cycle and embryo transfer. Main Outcome Measure(s) Clinical pregnancy rate (CPR) and live birth rate (LBR) per transfer was compared for women positive or negative for BCL6 expression. An abnormal BCL6 result was defined by an HSCORE (> 1.4). Results Women with normal and abnormal BCL6 and those who conceived or not had similar characteristics. Women with low levels of BCL6 expression had a significantly higher CPR (11/17; 64.7%; 95%CI: 41.3 to 82.6), compared to women with abnormal (high) BCL6 expression (9/52; 17.3%; 95%CI: 9.3 to 30.8). These results yield a relative risk (RR) of 0.267 (95%CI: 0.13 to 0.53; p = 0.0004) for those with normal BCL6 expression, an absolute benefit (AB) of 47.4% (95%CI: 22.5 to 72). LBR was also significantly higher in women with low BCL6 expression(10/17; 58.8; 95%CI: 36 to 78.4), compared to women with abnormal BCL6 expression (6/52; 11.5%; 95%CI: 5.4 to 23). The RR was 0.19 (95%CI: 0.08 to 0.45; p = 0.0002), yielding an AB of 47.3% (95%CI: 21.8 to 67.8). Conclusions Aberrant BCL6 expression (> 1.4 HSCORE) was strongly associated with poor reproductive outcomes in IVF cycles in women with UI.

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Section: Methodsmentioning

confidence: 99%

Endometrial BCL6 testing for the prediction of in vitro fertilization outcomes: a cohort study

Almquist

Likes

Stone

et al. 2017

Fertility and Sterility

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“…The number of study participants in a clinical trial is normally determined using a power calculation based on a pre‐specified change in a primary outcome measure to ensure that the study has adequate statistical power to detect meaningful treatment effects and to draw valid conclusions. Insufficient sample sizes can lead to underpowered studies, which may fail to detect clinically relevant treatment effects; meanwhile, overpowered studies result in a waste of resources and may cause ethical problems (Pocock, 2013).…”

Section: Methodsmentioning

confidence: 99%

Mesenchymal stem cell therapy in aqueous deficient dry eye disease

Møller‐Hansen

2023

Acta Ophthalmologica

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ENGLISH SUMMARYDry eye disease (DED) is characterized by ocular dryness, irritation and blurred vision and has a significant impact on the patient's quality of life. This condition can be particularly severe in patients with aqueous deficient dry eye disease (ADDE) due to Sjögren's syndrome (SS), an autoimmune disease that affects the lacrimal and salivary glands. Current treatments for ADDE are often limited to symptomatic relief. A literature review was conducted to explore the current surgical interventions used or tested in humans with ADDE (I). These interventions include procedures involving the eyelids and tear ducts, transplantation of amniotic membrane or salivary glands, injections around the tear ducts and cell‐based injections into the lacrimal gland (LG). Each treatment has its advantages and disadvantages; however, treating dry eyes in patients with SS presents a particular challenge due to the systemic nature of the disease. Moreover, there is a need for new therapeutic options. Mesenchymal stem cells (MSCs) are a type of stem cell that have shown promise in regenerating damaged tissue and reducing inflammation in various diseases. Previous studies in animal models have suggested that MSCs could be effective in treating ADDE. Thus, this thesis aims to investigate the safety and efficacy of injecting MSCs into the LG as a treatment option for patients with ADDE secondary to SS. The study also aims to see this treatment in light of existing and novel investigational treatment options. The clinical studies conducted for this thesis are the first of their kind in humans. MSCs derived from healthy donors' adipose tissue (ASCs) were cultured in a laboratory, frozen and thawed ready for use. In the safety study, we performed the first human trial involving the administration of a single injection of ASCs into the LG of one eye in seven patients suffering from severe ADDE (II). The primary objective was to test the safety of this treatment, while the secondary objective was to assess improvements in subjective and objective signs of dry eye. The results of the trial showed no serious side effects within 4 months of follow‐up after treatment. On average, there was a 40% reduction in dry eye symptoms assessed with the Ocular Surface Disease Index (OSDI) questionnaire. Additionally, in the treated eye, there was a significant decrease in tear osmolarity, an increase in tear film stability and an increase in tear production. To further investigate the efficacy of this treatment, our research group performed a clinical, randomized study aiming to compare the ASC injection into the LG with the injection of a vehicle (the excipient in which the ASCs are dissolved) and observation (no intervention) (III). The study involved 20 subjects receiving ASC injection, 20 subjects receiving vehicle injection and 14 patients being observed without intervention. The subjects were examined to assess the outcomes with a 12‐month follow‐up after treatment. Both intervention groups showed a significant reduction in subjective dry eye symptoms of approximately 40%. This improvement was evident at the 1‐week follow‐up and persisted until the 12‐month follow‐up. The observation group did not experience any change in OSDI score. The ASCs group exhibited a significant mean increase in non‐invasive tear break‐up time (NIKBUT) of 6.48 s (149%) at the four‐week follow‐up, which was significantly higher than that in the vehicle group (p = 0.04). Moreover, the ASCs group showed a significant increase in NIKBUT compared to that in the observation group at the 12‐month follow‐up (p = 0.004). In both the ASCs and vehicle group, a significant increase in Schirmer test scores at the 4‐month follow‐up and the 12‐month follow‐up was observed. In conclusion, this thesis contributes valuable findings with a new treatment option for patients with dry eye disease. Injection of ASCs into the LG was shown to be safe and to improve subjective dry eye symptoms and specifically the tear film stability in patients with ADDE due to SS. Compared to other treatment modalities of ADDE, this treatment has greater potential, as ASCs could potentially be used as an anti‐inflammatory therapeutic option for managing DED of other causes as well.RESUMÉ (DANISH SUMMARY)Tørre øjne, karakteriseret ved tørhedsfornemmelse og irritation af øjnene samt sløret syn, har en betydelig indvirkning på patientens livskvalitet. Denne tilstand kan være særligt alvorlig hos patienter med nedsat tåreproduktion (ADDE) som følge af Sjögrens syndrom (SS), en autoimmun sygdom, der påvirker tårekirtlerne og spytkirtlerne. Nuværende behandlinger for ADDE er ofte begrænset til symptomlindring. Vi gennemførte en litteraturgennemgang for at undersøge, hvilke nuværende kirurgiske behandlingsmetoder, der anvendes eller testes hos patienter med ADDE (I). Disse interventioner inkluderer procedurer, der involverer øjenlåg og tårekanaler, transplantation af amnionhinde eller spytkirtler, injektioner omkring tårekanalerne samt cellebaserede injektioner i tårekirtlen. Hver behandling har sine fordele og ulemper, men behandling af tørre øjne hos patienter med SS udgør en særlig udfordring på grund af sygdommens systemiske udbredning, og der er behov for nye behandlingsmuligheder. Mesenkymale stamceller (MSCs) er en type stamcelle, der har vist lovende resultater med hensyn til at regenerere beskadiget væv og reducere inflammation i forskellige sygdomme. Tidligere undersøgelser i dyremodeller har indikeret, at MSCs kan være en effektiv behandling af ADDE. Denne afhandling har til formål at undersøge sikkerheden og effekten af injektion af MSCs i tårekirtlen som en mulig behandling til patienter med ADDE som følge af SS. Afhandlingen sigter også mod at sammenligne denne behandling med andre eksisterende, kirurgiske behandlingsmuligheder af ADDE. Som led i dette projekt udførte vi de første kliniske forsøg af sin art i mennesker. MSCs fra raske donorers fedtvæv (ASCs) blev dyrket i et laboratorium, frosset ned og er optøet klar til brug. Det første mål var at teste sikkerheden ved denne behandling og sekundært at undersøge behandlingens effekt. For at undersøge dette modtog syv forsøgspersoner med svær ADDE én injektion med ASCs i tårekirtlen på det ene øje (II). Resultaterne af forsøget viste ingen alvorlige bivirkninger inden for fire måneders opfølgning efter behandlingen. I gennemsnit fandt vi yderligere en 40% reduktion i symptomer på tørre øjne vurderet med et spørgeskema, og en markant stigning i tåreproduktionen og af tårefilmens stabilitet i det behandlede øje. For yderligere at undersøge effekten af denne behandling udførte vi et klinisk, randomiseret forsøg med det formål at sammenligne injektion af ASCs i tårekirtlen med injektion af en kontrolopløsning (væsken, hvor stamcellerne var opløst) og observation (ingen intervention) (III). Studiet omfattede 20 forsøgspersoner, der modtog ASC‐injektion, 20 forsøgspersoner, der modtog injektion af kontrolopløsningen, og 14 forsøgspersoner i observationsgruppen. Forsøgspersonerne blev undersøgt med en opfølgningstid på 12 måneder efter behandling. Begge interventionsgrupper viste en betydelig reduktion på ca. 40% i subjektive symptomer på tørre øjne. Denne forbedring var betydelig allerede ved opfølgning efter en uge og varede ved 12 måneder efter behandling. Observationsgruppen oplevede ingen betydelig ændring i symptomer. ASCs gruppen viste desuden en signifikant stigning i tårefilmsstabiliteten (NIKBUT) på 6,48 sekunder (149%) ved opfølgning efter fire uger, hvilket var markant højere end efter injektion af kontrolopløsning (p = 0,04). Desuden viste ASCs gruppen en betydelig stigning i NIKBUT sammenlignet med observationsgruppen ved opfølgning efter 12 måneder (p = 0,004). Både injektion af ASCs og kontrolopløsning medførte en betydelig stigning i tåreproduktionen ved opfølgning fire måneder og 12 måneder efter behandling. Denne afhandling bidrager med vigtige resultater inden for en ny behandlingsmulighed af tørre øjne. Injektion af ASCs i tårekirtlen viste sig at være sikker, forbedrede subjektive symptomer på tørre øjne og øgede særligt tårfilmens stabilitet hos patienter med ADDE på grund af SS. Sammenlignet med andre behandlingsmuligheder for ADDE har denne behandling vist et stort potentiale. ASCs kan muligvis også bruges som en anti‐inflammatorisk behandling af tørre øjne af andre årsager i fremtiden.

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“…Intent-to-treat means that all eligible participants regardless of adherence with the intervention protocol should be included in the analysis of results whenever possible, in contrast to per-protocol which is an analysis of only those who adhered to or fully took up the intervention protocol. 55 Collecting data on all who were included initially in all arms allows for comparison of those who were assigned to the intervention activities (regardless of fidelity, reach, dose delivered to them or dose received by them) with those who did not. Comparison of completers and drop-outs from the data collection in all arms helps to assess attrition bias.…”

Section: Other Important Features Of Trials For Complex Interventionsmentioning

confidence: 99%

“…Since many study participants may not fully adhere, or adhere at all, to the intervention protocol, the estimates of effectiveness may be lower than the efficacy of the intervention, that is, what effects would have been achieved if the fidelity, reach, dose delivered, and dose received were ideal. Intent-to-treat means that all eligible participants regardless of adherence with the intervention protocol should be included in the analysis of results whenever possible, in contrast to per-protocol which is an analysis of only those who adhered to or fully took up the intervention protocol 55. Collecting data on all who were included initially in all arms allows for comparison of those who were assigned to the intervention activities (regardless of fidelity, reach, dose delivered to them or dose received by them) with those who did not.…”

Section: Other Important Features Of Trials For Complex Interventionsmentioning

confidence: 99%

Strengthening causal inference from randomised controlled trials of complex interventions

et al. 2022

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Researchers conducting randomised controlled trials (RCTs) of complex interventions face design and analytical challenges that are not fully addressed in existing guidelines. Further guidance is needed to help ensure that these trials of complex interventions are conducted to the highest scientific standards while maximising the evidence that can be extracted from each trial. The key challenge is how to manage the multiplicity of outcomes required for the trial while minimising false positive and false negative findings. To address this challenge, we formulate three principles to conduct RCTs: (1) outcomes chosen should be driven by the intent and programme theory of the intervention and should thus be linked to testable hypotheses; (2) outcomes should be adequately powered and (3) researchers must be explicit and fully transparent about all outcomes and hypotheses before the trial is started and when the results are reported. Multiplicity in trials of complex interventions should be managed through careful planning and interpretation rather than through post hoc analytical adjustment. For trials of complex interventions, the distinction between primary and secondary outcomes as defined in current guidelines does not adequately protect against false positive and negative findings. Primary outcomes should be defined as outcomes that are relevant based on the intervention intent and programme theory, declared (ie, registered), and adequately powered. The possibility of confirmatory causal inference is limited to these outcomes. All other outcomes (either undeclared and/or inadequately powered) are secondary and inference relative to these outcomes will be exploratory.

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Clinical Trials. A Practical Approach.

Abstract: Clinical Trials. A Practical Approach STUART J. POCOCK John Wiley, London (1983) pp. x + 266 ISBN 0 471 90155 5

Cited by 36 publications

References 0 publications

Endometrial BCL6 testing for the prediction of in vitro fertilization outcomes: a cohort study

Endometrial BCL6 testing for the prediction of in vitro fertilization outcomes: a cohort study

Mesenchymal stem cell therapy in aqueous deficient dry eye disease

Strengthening causal inference from randomised controlled trials of complex interventions

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