Accounting for Noncompliance in the Design of Clinical Trials

Albert, Jeffrey M.

doi:10.1177/009286159703100123

Cited by 3 publications

(2 citation statements)

References 29 publications

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“…Poor adherence can also jeopardize the outcome of clinical trials by reducing their power. Using data from an internal pilot can provide the anticipated adherence level of participants of a larger clinical trial and can be used to implement strategies to enhance compliance [ 71 , 72 ].…”

Section: Discussionmentioning

confidence: 99%

Optimizing early child development for young children with non-anemic iron deficiency in the primary care practice setting (OptEC): study protocol for a randomized controlled trial

Abdullah

Thorpe

Mamak

et al. 2015

Trials

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BackgroundThree decades of research suggests that prevention of iron deficiency anemia (IDA) in the primary care setting may be an unrealized and unique opportunity to prevent poor developmental outcomes in children. A longitudinal study of infants with IDA showed that the developmental disadvantage persists long term despite iron therapy. Early stages of iron deficiency, termed non-anemic iron deficiency (NAID), provide an opportunity for early detection and treatment before progression to IDA. There is little research regarding NAID, which may be associated with delayed development in young children. The aim of this study is to compare the effectiveness of four months of oral iron treatment plus dietary advice, with placebo plus dietary advice, in improving developmental outcomes in children with NAID and to conduct an internal pilot study.Methods/DesignFrom a screening cohort, those identified with NAID (hemoglobin ≥110 g/L and serum ferritin <14 μg/L) are invited to participate in a pragmatic, multi-site, placebo controlled, blinded, parallel group, superiority randomized trial. Participating physicians are part of a primary healthcare research network called TARGet Kids! Children between 12 and 40 months of age and identified with NAID are randomized to receive four months of oral iron treatment at 6 mg/kg/day plus dietary advice, or placebo plus dietary advice (75 per group). The primary outcome, child developmental score, is assessed using the Mullen Scales of Early Learning at baseline and at four months after randomization. Secondary outcomes include an age appropriate behavior measure (Children’s Behavior Questionnaire) and two laboratory measures (hemoglobin and serum ferritin levels). Change in developmental and laboratory measures from baseline to the end of the four-month follow-up period will be analyzed using linear regression (analysis of covariance method).DiscussionThis trial will provide evidence regarding the association between child development and NAID, and the effectiveness of oral iron to improve developmental outcomes in children with NAID. The sample size of the trial will be recalculated using estimates taken from an internal pilot study.Trial registrationThis trial was registered with Clinicaltrials.gov (identifier: NCT01481766) on 22 November 2011.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-015-0635-z) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Optimizing early child development for young children with non-anemic iron deficiency in the primary care practice setting (OptEC): study protocol for a randomized controlled trial

Abdullah

Thorpe

Mamak

et al. 2015

Trials

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“…According to previous research, if 40 % of the participants in a randomized trial have at least 90 % of adherence then the effectiveness assessment process remains unimpaired [ 10 ]. Data from an internal pilot study can be used to check the level of adherence in participants of clinical trials [ 11 – 13 ]. If adherence is found to be less then desired, then strategies can be implemented to improve adherence.…”

Section: Updatementioning

confidence: 99%

An internal pilot study for a randomized trial aimed at evaluating the effectiveness of iron interventions in children with non-anemic iron deficiency: the OptEC trial

Abdullah

Thorpe

Mamak

et al. 2015

Trials

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BackgroundThe OptEC trial aims to evaluate the effectiveness of oral iron in young children with non-anemic iron deficiency (NAID). The initial sample size calculated for the OptEC trial ranged from 112–198 subjects. Given the uncertainty regarding the parameters used to calculate the sample, an internal pilot study was conducted. The objectives of this internal pilot study were to obtain reliable estimate of parameters (standard deviation and design factor) to recalculate the sample size and to assess the adherence rate and reasons for non-adherence in children enrolled in the pilot study.MethodsThe first 30 subjects enrolled into the OptEC trial constituted the internal pilot study. The primary outcome of the OptEC trial is the Early Learning Composite (ELC). For estimation of the SD of the ELC, descriptive statistics of the 4 month follow-up ELC scores were assessed within each intervention group. The observed SD within each group was then pooled to obtain an estimated SD (S2) of the ELC. Correlation (ρ) between the ELC measured at baseline and follow-up was assessed. Recalculation of the sample size was performed using analysis of covariance (ANCOVA) method which uses the design factor (1- ρ2). Adherence rate was calculated using a parent reported rate of missed doses of the study intervention.ConclusionThe new estimate of the SD of the ELC was found to be 17.40 (S2). The design factor was (1- ρ2) = 0.21. Using a significance level of 5 %, power of 80 %, S2 = 17.40 and effect estimate (Δ) ranging from 6–8 points, the new sample size based on ANCOVA method ranged from 32–56 subjects (16–28 per group). Adherence ranged between 14 % and 100 % with 44 % of the children having an adherence rate ≥86 %. Information generated from our internal pilot study was used to update the design of the full and definitive trial, including recalculation of sample size, determination of the adequacy of adherence, and application of strategies to improve adherence.Trial registrationClinicalTrials.gov Identifier: NCT01481766 (date of registration: November 22, 2011).Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-015-0829-4) contains supplementary material, which is available to authorized users.

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A threshold causal model for clinical trials with departures from intended treatment

Albert

1999

Statist. Med.

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Randomized clinical trials often are planned to study a specific intervention. However, the collection of data on treatment actually received often reveals variable levels of treatment exposure (or 'dose') across subjects, due to non-compliance or other reasons. This paper presents a new method, using such 'dose' data as well as control group responses, to assess a causal dose-response relationship. The specific model utilizes a threshold function and incorporates a random effect term to allow for heterogeneous treatment responses among subjects. Further modelling of the random effects allows for reduction of error variance and control for potential confounders. The threshold dose is estimated using a residual variance criterion based on a transformed model. Estimates of standard errors and confidence intervals are obtained using a bootstrap procedure. The method is applied to data from an AIDS clinical trial. A simulation study demonstrates the adequacy of the threshold estimates for particular sample sizes and error variances. The limitations of this essentially exploratory method, as well as some possible extensions, are discussed. Published in 1999 by John Wiley & Sons, Ltd. This article is a US Government Work and is in the public domain in the United States.

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Accounting for Noncompliance in the Design of Clinical Trials

Cited by 3 publications

References 29 publications

Optimizing early child development for young children with non-anemic iron deficiency in the primary care practice setting (OptEC): study protocol for a randomized controlled trial

Optimizing early child development for young children with non-anemic iron deficiency in the primary care practice setting (OptEC): study protocol for a randomized controlled trial

An internal pilot study for a randomized trial aimed at evaluating the effectiveness of iron interventions in children with non-anemic iron deficiency: the OptEC trial

A threshold causal model for clinical trials with departures from intended treatment

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