A double-masked randomized control trial là gì

Treatment of Symptomatic Convergence Insufficiency in Children Enrolled in the Convergence Insufficiency Treatment Trial–Attention & Reading Trial: A Randomized Clinical Trial

∗

Submitted: November 14, 2018

Accepted: July 29, 2019

Funding/Support: National Eye Institute (5U10EY022599; to MMS); National Eye Institute (5U10EY022591; to ST); National Eye Institute (5U10EY022601; to GLM); National Eye Institute (5U10EY022592; to MK); National Eye Institute (5U10EY022586; to ES); National Eye Institute (United States; 5U10EY022600; to RH); National Eye Institute (5U10EY022587; to MFG); National Eye Institute (5U10EY022596; to RC); National Eye Institute (5U10EY022594; to KBH); and National Eye Institute (5U10EY022595; to SC).

Conflict of Interest Disclosure: None of the authors have reported a financial conflict of interest.

Study Registration Information:ClinicalTrials.gov identifier: NCT00338611.

Author Contributions and Acknowledgments: Conceptualization: MMS, SC, MK, GLM, EB, RH, CC, TR, LS; Data Curation: MMS, GLM; Formal Analysis: MMS, SC, MK, GLM, TR, LS, CD; Funding Acquisition: MMS, SC, GLM; Investigation: MMS, SC, MK, GLM, MFG, EB, RH, CC, ES, ST, KBH, RC, IL, TR, CD; Methodology: MMS, SC, MK, GLM, LJ-J, EB, RH, CC, TR, EA, CD; Project Administration: MMS, MK, GLM; Resources: GLM; Supervision: MMS, GLM; Validation: MMS, GLM, LJ-J; Visualization: MMS; Writing – Original Draft: MMS, TR; Writing – Review & Editing: MMS, SC, MK, GLM, LJ-J, MFG, EB, RH, CC, ES, ST, KBH, RC, IL, TR, EA, LS, CD.

The Convergence Insufficiency Treatment Trial Writing Committee: Mitchell Scheiman, OD, PhD; Susan Cotter, OD, MS; Marjean Kulp, OD, MS; G. Lynn Mitchell, MAS; Lisa Jones-Jordan, PhD; Michael Gallaway, OD; Eric Borsting, OD, MSEd, MPH; Richard Hertle, MD; Christopher Chase, PhD; Erica Schulman, OD; Susanna Tamkins, OD; Kristine Hopkins, OD, MSPH; Rachel Coulter, OD, MSEd; Ingryd Lorenzana, OD; Tawna Roberts, OD, PhD; L. Eugene Arnold, MD; Loraine Sinnott, PhD; Carolyn Denton, PhD.

The Convergence Insufficiency Treatment Trial–Attention & Reading Trial Investigator Group Clinical Sites. Sites are listed in order of the number of participants enrolled in the study, with the number enrolled listed in parentheses preceded by the clinical site name and location. Personnel are listed as PI for principal investigator, SC for coordinator, ME-ART for masked examiner or attention and reading testing, ME-VIS for masked examiner for visual function testing, VT for vision therapist, and UnM for unmasked examiners for baseline testing.

Study Center: SUNY College of Optometry (45). Jeffrey Cooper, MS, OD (PI 06/14 to 04/15); Erica Schulman, OD (PI 04/15 to present); Kimberly Hamian, OD (ME-VIS); Danielle Iacono, OD (ME-VIS); Steven Larson, OD (ME-ART); Valerie Leung, Boptom (SC); Sara Meeder, BA (SC); Elaine Ramos, OD (ME-VIS); Steven Ritter, OD (VT); Audra Steiner, OD (ME-VIS); Alexandria Stormann, RPA-C (SC); Marilyn Vricella, OD (UnM); Xiaoying Zhu, OD (ME-VIS).

Study Center: Bascom Palmer Eye Institute (44). Susanna Tamkins, OD (PI); Naomi Aguilera, OD (VT); Elliot Brafman, OD (ME-VIS); Hilda Capo, MD (ME-VIS); Kara Cavuoto, MD (ME-VIS); Isaura Crespo, BS (SC); Monica Dowling, PhD (ME-ART); Kristie Draskovic, OD (ME-VIS); Miriam Farag, OD (VT); Vicky Fischer, OD (VT); Sara Grace, MD (ME-VIS); Ailen Gutierrez, BA (SC); Carolina Manchola-Orozco, BA (SC); Maria Martinez, BS (SC); Craig McKeown, MD (UnM); Carla Osigian, MD (ME-VIS); Tuyet-Suong Pham, OD (VT); Leslie Small, OD (ME-VIS); Natalie Townsend, OD (ME-VIS).

Study Center: Pennsylvania College of Optometry (43). Michael Gallaway, OD (PI); Mark Boas, OD, MS (VT); Christine Calvert, Med (ME-ART); Tara Franz, OD (ME-VIS); Amanda Gerrouge, OD (ME-VIS); Donna Hayden, MS (ME-ART); Erin Jenewein, OD, MS (VT); Zachary Margolies, MSW, LSW (ME-ART); Shivakhaami Meiyeppen, OD (ME-VIS); Jenny Myung, OD (ME-VIS); Karen Pollack, (SC); Mitchell M. Scheiman, OD, PhD (ME-VIS); Ruth Shoge, OD (ME-VIS); Andrew Tang, OD (ME-VIS); Noah Tannen, OD (ME-VIS); Lynn Trieu, OD, MS (VT); Luis Trujillo, OD (VT).

Study Center–The Ohio State University College of Optometry (40). Marjean Kulp, OD, MS (PI); Michelle Buckland, OD, MS (ME-VIS); Allison Ellis, BS, MEd (ME-ART); Jennifer Fogt, OD, MS (ME-VIS); Catherine McDaniel, OD, MS (ME-VIS); Taylor McGann, OD (ME-VIS); Ann Morrison, OD, MS (ME-VIS); Shane Mulvihill, OD, MS (VT); Adam Peiffer, OD, MS (ME-VIS); Maureen Plaumann, OD (ME-VIS); Gil Pierce, OD, PhD (ME-VIS); Julie Preston, OD, PhD, MEd (ME-ART); Kathleen Reuter, OD (VT); Nancy Stevens, MS, RD, LD (SC); Jake Teeny, MA (ME-ART); Andrew Toole, OD, PhD (VT); Douglas Widmer, OD, MS (ME-VIS); Aaron Zimmerman, OD, MS (ME-VIS).

Study Center: Southern California College of Optometry (38). Susan Cotter, OD, MS (PI); Carmen Barnhardt, OD, MS (VT); Eric Borsting, OD, MSEd (ME-ART); Angela Chen, OD, MS (VT); Raymond Chu, OD, MS (ME-VIS); Kristine Huang, OD, MPH (ME-VIS); Susan Parker (SC); Dashaini Retnasothie (UnM); Judith Wu (SC).

Study Center: Akron Childrens Hospital (34). Richard Hertle, MD (PI); Penny Clark (ME-ART); Kelly Culp, RN (SC); Kathy Fraley CMA/ASN (ME-ART); Drusilla Grant, OD (VT); Nancy Hanna, MD (UnM); Stephanie Knox (SC); William Lawhon, MD (ME-VIS); Lan Li, OD (VT); Sarah Mitcheff (ME-ART); Isabel Ricker, BSN (SC); Tawna Roberts, OD (VT); Casandra Solis, OD (VT); Palak Wall, MD (ME-VIS); Samantha Zaczyk, OD (VT).

Study Center: UAB School of Optometry (32). Kristine Hopkins, OD (PI 12/14 to present); Wendy Marsh-Tootle, OD, MS (PI 06/14 to 2/14); Michelle Bowen, BA (SC); Terri Call, OD (ME-VIS); Kristy Domnanovich, PhD (ME-ART); Marcela Frazier, OD, MPH (ME-VIS); Nicole Guyette, OD, MS (ME-ART); Oakley Hayes, OD, MS (VT); John Houser, PhD (ME-ART); Sarah Lee, OD, MS (VT); Jenifer Montejo, BS (SC); Tamara Oechslin, OD, MS (VT); Christian Spain (SC); Candace Turner, OD (ME-ART); Katherine Weise, OD, MBA (ME-VIS).

Study Center: NOVA Southeastern University (31). Rachel Coulter, OD (PI); Deborah Amster, OD (ME-VIS); Annette Bade, OD, MCVR (SC); Surbhi Bansal, OD (ME-VIS); Laura Falco, OD (ME-VIS); Gregory Fecho, OD (VT); Katherine Green, OD (ME-VIS); Gabriela Irizarry, BA (ME-ART); Jasleen Jhajj, OD (VT); Nicole Patterson, OD, MS (ME-ART); Jacqueline Rodena, OD (ME-VIS); Yin Tea, OD (VT); Julie Tyler, OD (SC); Dana Weiss, MS (ME-ART); Lauren Zakaib, MS (ME-ART).

Study Center: Advanced Vision Care (15). Ingryd Lorenzana, OD (PI); Yesena Meza (ME-VIS); Ryan Mann (ME-ART); Mariana Quezada, OD (VT); Scott Rein, BS (ME-ART); Indre Rudaitis, OD (ME-VIS); Susan Stepleton, OD (ME-VIS); Beata Wajs (VT).

National Eye Institute, Bethesda, MD. Maryann Redford, DDS, MPH.

CITT-ART Executive Committee. Mitchell M. Scheiman, OD, PhD; G. Lynn Mitchell, MAS; Susan Cotter, OD, MS; Richard Hertle, MD; Marjean Kulp, OD, MS; Maryann Redford, DDS, MPH; Carolyn Denton, PhD; Eugene Arnold, MD; Eric Borsting, OD, MSEd; Christopher Chase, PhD.

CITT-ART Reading Center. Carolyn Denton, PhD (PI); Sharyl Wee (SC); Katlynn Dahl-Leonard (SC); Kenneth Powers (Research Assistant); Amber Alaniz (Research Assistant).

Data and Safety Monitoring Committee. Marie Diener-West, PhD, Chair; William V. Good, MD; David Grisham, OD, MS, FAAO; Christopher J. Kratochvil, MD; Dennis Revicki, PhD; Jeanne Wanzek, PhD.

CITT-ART-Study Chair. Mitchell M. Scheiman, OD, PhD (Study Chair); Karen Pollack (Study Coordinator); Susan Cotter, OD, MS (Vice Chair); Marjean Kulp, OD, MS (Vice Chair).

CITT-ART Data Coordinating Center. G. Lynn Mitchell, MAS (PI); Mustafa Alrahem (student worker); Julianne Dangelo, BS (Program Assistant); Jordan Hegedus (student worker); Ian Jones (student worker); Alexander Junglas (student worker); Jihyun Lee (Programmer); Jadin Nettles (student worker); Curtis Mitchell (student worker); Mawada Osman (student worker); Gloria Scott-Tibbs, BA (Project Coordinator); Loraine Sinnott, PhD (Biostatistician); Chloe Teasley (student worker); Victor Vang (student worker); Robin Varghese (student worker).

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Abstract

SIGNIFICANCE

These data confirm the effectiveness of office-based vergence/accommodative therapy for improving convergence in children with symptomatic convergence insufficiency. They also highlight the importance of using a primary outcome measure that is as objective as possible rather than relying solely on self-reported symptoms for studies of binocular vision in children.

PURPOSE

The purpose of this study was to report changes in clinical signs and symptoms of convergence insufficiency (secondary outcome measures) from a multicenter clinical trial (Convergence Insufficiency Treatment Trial–Attention & Reading Trial [CITT-ART]) evaluating the effectiveness of vergence/accommodative therapy for improving reading and attention in children with symptomatic convergence insufficiency.

METHODS

Three hundred eleven children aged 9 to 14 years with symptomatic convergence insufficiency were randomly assigned to 16 weeks of office-based vergence/accommodative therapy or to placebo therapy. Improvements in (1) near point of convergence (NPC), (2) positive fusional vergence (PFV), and (3) self-reported symptoms (Convergence Insufficiency Symptom Survey [CISS] score) were compared after 16 weeks of treatment.

RESULTS

Mean NPC improved 10.4 cm in the vergence/accommodative and 6.2 cm in the placebo therapy group (mean difference of −4.2 cm [95% confidence interval {CI}, −5.2 to −3.2 cm; P < .001]); mean PFV increased 23.2 and 8.8Δ in the vergence/accommodative and placebo therapy groups, respectively (mean difference of 14.4Δ [95% CI, 12.1 to 16.8Δ; P < .001]). The mean CISS score improved 11.8 and 10.4 points in the vergence/accommodative and placebo therapy groups, respectively (mean difference of 1.5 points [95% CI, −3.8 to +0.8 points; P = .21]).

CONCLUSIONS

Our results demonstrate that office-based vergence/accommodative therapy is effective for improving the NPC and PFV in children with symptomatic convergence insufficiency. However, given that both treatment groups had a similar reduction in self-reported symptoms, it may not be prudent to use the CISS alone as a measure of successful treatment.

Erratum

The authors of the articles listed below report the following errors:

CITT-ART Investigator Group. Treatment of Symptomatic Convergence Insufficiency in Children Enrolled in the Convergence Insufficiency Treatment Trial – Attention & Reading Trial: A Randomized Clinical Trial. Optom Vis Sci 2019;96(11):825–835.

CITT-ART Investigator Group. Effect of Vergence/Accommodative Therapy on Reading in Children with Convergence Insufficiency: A Randomized Clinical Trial. Optom Vis Sci 2019;96(11):836–849.

CITT-ART Investigator Group. Effect of Vergence/Accommodative Therapy on Attention in Children with Convergence Insufficiency: A Randomized Clinical Trial. Optom Vis Sci 2021;98(3):222–233.

The total sample size for the analyses in the above articles incorrectly included 10 (3.2%) children who were randomized to therapy but retrospectively determined to be ineligible (6 of 206 randomized to the vergence/accommodative therapy group and 4 of 104 assigned to placebo therapy). All 10 failed to meet the single eligibility criterion of “insufficient positive fusional vergence.”. Each child completed the 16-week primary outcome evaluation. Sensitivity analyses, as reported in the following tables, showed little to no impact of exclusion on the previously published findings.

Portion of Table 5 from Effect of Vergence/Accommodative Therapy on Reading in Children with Convergence Insufficiency: A Randomized Clinical Trial. (Optom Vis Sci 2019;96(11):836–849).

Treatment difference*,† estimates for measures of reading

Table 4 from Treatment of Symptomatic Convergence Insufficiency in Children Enrolled in the Convergence Insufficiency Treatment Trial – Attention & Reading Trial: A Randomized Clinical Trial. (Optom Vis Sci 2019;96(11):825–835).

Mean change (95% confidence interval) in outcome measures at 16 weeks by treatment group

Portion of Tables 5 & 6 from CITT-ART Investigator Group. Effect of Vergence/Accommodative Therapy on Attention in Children with Convergence Insufficiency: A Randomized Clinical Trial. (Optom Vis Sci 2021;98(3):222–233).

Cohen’s d and 95% confidence interval (CI) for between group difference‡ in each measure of attention using all participants and excluding those ineligible

Optometry and Vision Science. 99(11):834-836, November 2022.

Convergence insufficiency is a binocular vision disorder in which there is a larger exodeviation at near than at far, a receded near point of convergence, and below expected positive fusional vergence measures at near.1–6 It has an estimated prevalence of 4.2 to 17.6% in children.1,7–10 Associated symptoms are common and can include eye-related (e.g., sore eyes, headaches, blurred vision, double vision, and words moving on page) and performance-related (e.g., loss of place, loss of concentration, reading slowly, and trouble remembering what was read) symptoms.11,12 Clinical trials comparing office-based vergence/accommodative therapy with home-based pencil push-up and computer-based therapies have shown office-based vergence/accommodative therapy to be more effective than these two treatments for improving clinical signs and associated symptoms in children with symptomatic convergence insufficiency,3,4,6 with recent studies showing associated changes in brain activation after treatment.13–15

The Convergence Insufficiency Treatment Trial–Attention & Reading Trial (CITT-ART) was a multicenter, double-masked, randomized clinical trial designed to determine if office-based vergence/accommodative therapy resulted in improvements in reading16 and attention in 9- to 14-year-old children with symptomatic convergence insufficiency.17 The results showed that office-based vergence/accommodative therapy was no more effective than office-based placebo therapy for improving reading performance. The trial data also provided an opportunity to report on changes in clinical measures of convergence and subject-reported symptoms.Herein, we report on these secondary outcomes of near point of convergence, positive fusional convergence, and symptoms after 16 weeks of treatment.

PATIENTS AND METHODS

The CITT-ART was supported through a cooperative agreement with the National Eye Institute of the National Institutes of Health and conducted according to the tenets of the Declaration of Helsinki at nine optometry or ophthalmology clinical sites. The institutional review boards of participating sites approved the protocol and Health Insurance Portability and Accountability Act authorization–informed consent forms. The parent or guardian (hereafter parent) of each study participant gave written informed consent, and each participant provided written assent. Study oversight was provided by an independent data and safety monitoring committee. The study is registered at www.clinicaltrials.gov (CITT-ART: NCT02207517, accessed March 3, 2019). The CITT-ART Manual of Procedures is available at https://u.osu.edu/cittart/. Relevant portions of the protocol are summarized hereinafter.

Participant Selection

The study included children 9 to 14 years of age in grades 3 to 8 who had symptomatic convergence insufficiency defined as (1) a near exodeviation at least 4Δ greater than at distance fixation (as measured with the prism and alternate cover test), (2) a receded (≥6 cm) near point of convergence, (3) insufficient positive fusional vergence (i.e., convergence amplitudes) at near defined as failing Sheard's criterion (base-out blur [break if no blur] less than twice the near phoria)18 or minimal positive fusional vergence at near of ≤15Δ base-out break, and (4) a score of ≥16 on the Convergence Insufficiency Symptom Survey (CISS).19,20 The full eligibility and exclusion criteria are listed in Table 1. All participants presented to a CITT-ART optometrist or ophthalmologist either for routine care or seeking treatment. Data were not collected to document the primary reason the parent and child were interested in the study (e.g., visual symptoms, poor reading, inattention, etc.).

TABLE 1:

CITT-ART eligibility and exclusion criteria

Enrollment/Randomization

Using a standardized protocol (details described previously),17 study-certified optometrists and ophthalmologists administered the CISS to quantify symptoms19–22 and a sensorimotor evaluation that included the following: best-corrected visual acuity at distance and near, cover testing, near point of convergence, positive and negative fusional vergence at near (prism bar), near stereoacuity, and the other clinical tests listed in Table 3. For near point of convergence and positive fusional vergence testing, participants were instructed to “try to keep the target single for as long as possible” and “try to keep the target single and clear,” respectively. These data served as the baseline measures for the children enrolled into the study. Participants were randomly allocated using a permuted block (sizes of 3, 6, and 9) design stratified by site and parent-reported attention-deficit/hyperactivity disorder status (yes/no) in a 2:1 allocation ratio to office-based vergence/accommodative therapy (hereafter vergence/accommodative therapy) or office-based placebo therapy (hereafter placebo therapy), respectively. This was accomplished using the Research Electronic Data Capture system hosted at the Ohio State University.23

TABLE 3:

Baseline demographic and clinical characteristics for all enrolled participants by treatment group

Treatment Protocols for Both Therapy Groups

A 16-week program of weekly 60-minute in-office therapy specific to the assigned therapy (vergence/accommodative or placebo) group was administered by study-certified optometrists, with four to five therapy procedures administered in the office and 15 minutes of daily home therapy prescribed for 5 days per week. The therapy protocols, adapted from prior CITT trials,3,4,6 were extended from 12 to 16 weeks by adding new procedures and increasing the therapy time for some procedures.

Table 2 provides an overview of the vergence/accommodative therapy program.17,24 The placebo therapy program17,24 comprised pre-determined sequentially administered procedures designed to appear to be genuine therapy techniques but not to stimulate vergence, accommodation, or fine saccadic eye movements beyond normal daily visual activities. Placebo procedures included standard vergence therapy techniques that were modified to be performed monocularly rather than binocularly or had zero vergence demand. Similar to real therapy, filter glasses were often worn, and participants were told that the glasses were to help the eyes work together as a team; there were protocolized objectives and goals that were conveyed to the participants; and therapists provided encouragement, feedback, and positive reinforcement for motivational purposes. The placebo therapy is described in more detail in previous articles.25,26

TABLE 2:

Office-based vergence/accommodative therapy procedures

Follow-up Examinations and Test Procedures

Protocol-specified follow-up visits were conducted by study-certified optometrists and ophthalmologists masked to participants' treatment group after 4, 8, 12, and 16 weeks of therapy. The examiner administered the CISS and assessed eye alignment (by cover testing), near point of convergence, positive and negative fusional vergence at near, monocular accommodative amplitude, monocular accommodative facility, and near vergence facility.

Masking of Participants and Examiners

The masking protocols used in this trial were successfully implemented in previous CITT clinical trials.3,4 Examiners were asked if they became unmasked to the participant's treatment group after each examination, and participants were asked upon completion of their 16-week therapy program whether they thought they had received “real” vergence/accommodative therapy or placebo therapy.

Treatment Adherence

At each therapy visit, the therapist estimated participant adherence to the prior week's prescribed home therapy (based on electronic data from the home computer program, written home therapy logs, and participant and parental feedback) using the following five-point scale: not at all, seldom, about half the time, most of the time, and always. Responses of “most of the time” and “always” were considered adherent to the prescribed treatment regimen for the prior week. The percentage of weeks (of 16) that each participant was judged to be adherent with the prescribed therapy was calculated.

Statistical Methods

The CITT-ART's pre-planned sample size of 324 participants (216 in the vergence/accommodative therapy group and 108 in the placebo group) was chosen to provide sufficient power for the trial's primary aim of determining whether treatment improved reading comprehension; these results are reported elsewhere.16 This sample size provided >95% power with a two-sided type I error rate of 5% to detect treatment group differences in near point of convergence of ≥4 cm, CISS score of ≥10 points, positive fusional vergence of ≥10Δ, and vergence facility of ≥3 cpm.

Outcome Measures

The main analyses for this report were the between-group differences and a two-sided 95% confidence interval (CI) of the change in the near point of convergence, positive fusional vergence, and the CISS score from baseline to 16 weeks calculated using an intent-to-treat analysis that excluded participants with missing 16-week data. Mixed linear models using clinical site as a random effect were fitted for change from baseline to the 16-week outcome for each of these three outcome measures. Demographics, variables with clinically relevant treatment group differences at randomization, and potential confounders were considered for inclusion in univariate models. Once identified, interactions between these baseline factors and randomization group were assessed. Variables associated at the P < .10 level in univariate models were included in multivariable models and retained in the final multivariable model when significantly associated (P < .05) with the outcome or when determined a priori to be necessary or important for inclusion (e.g., baseline value of outcome measure).

Similar to previous CITT studies,3,4 we also evaluated four other pre-planned outcomes of success (defined herein) using chi-square tests to determine if the proportions of successful outcomes differed between the two treatment groups.

Success Criterion 1: Normal or Improved Outcome

For the near point of convergence, normal was defined as <6 cm and improved as a decrease (improvement) of ≥4 cm. For positive fusional vergence, normal was defined as passing Sheard's criterion18 and having a base-out break finding >15Δ, whereas improved was defined as an increase of ≥10Δ. A CISS score of <16 was considered normal (asymptomatic), and a decrease of ≥10 points was considered improved.

Success Criterion 2: Normal and Improved Outcome

It is possible that when using success criterion 1, a measure that just barely met the eligibility criterion at baseline could be classified as “normal” at outcome despite improving only slightly. For example, a baseline near point of convergence of 6.5 that improved only 1 cm to a distance of 5.5 cm would meet the normal criterion at outcome, although a 1-cm improvement is not considered a clinically relevant change. To address this, success criterion 2 required that both the aforementioned criterion for normal and the pre-specified amount of clinically significant improvement be met. These definitions of success were as follows: normal near point of convergence measure of <6 cm that also improved ≥4 cm, normal positive fusional vergence (met Sheard's criterion and break value >15Δ) that also improved ≥10Δ, and a normal CISS score of <16 that also improved ≥10 points.

Success Criterion 3: Composite Convergence Outcome

A successful composite convergence outcome was defined as attainment of both a normal near point of convergence and normal positive fusional vergence.

Success Criterion 4: Composite Signs and Symptoms Outcome

The composite signs and symptoms outcome was based on changes in all three outcome measures,3 with the criterion for success met when all three measures met the aforementioned criteria for normal. The outcome was considered improved when the CISS score was normal or improved in combination with a near point of convergence or positive fusional vergence that was normal or improved.

Fragility Index Assessment

The fragility index is a recently described randomized clinical trial metric used to measure the robustness of statistically significant dichotomous outcomes.27–31 It is defined as the minimal number of study participants whose status would need to change from a nonevent to an event (e.g., failure to success) to convert a statistically significant result to a nonsignificant result. The smaller the number, the more fragile and less robust the result.28 Fragility indices were calculated for the near point of convergence, positive fusional vergence, the CISS score, and both composite measures.

Basic descriptive statistics were calculated using means and standard deviations for continuous variables and frequencies for categorical variables. Reported P values for treatment group comparisons are two-tailed and considered statistically significant at P < .05. Data entry and management were completed using the Research Electronic Data Capture system hosted at the Ohio State University.23 All analyses were conducted using SAS software version 9.4 (SAS Inc., Cary, NC).

RESULTS

Enrollment and Baseline Characteristics

Between September 2014 and March 2017, 311 participants were enrolled at nine clinical sites (range of 15 to 42 participants per site; median, 37). Data from one participant found to be ineligible were excluded by institutional review board mandate, for a total of 310 participants; of these, 206 were randomly assigned to vergence/accommodative therapy and 104 to placebo therapy. The mean age was 10.8 (±1.5) years, and 171 (55%) were female. Baseline demographic and clinical characteristics were similar in both treatment groups (Table 3).

Visit Completion and Home Therapy Adherence

The 16-week primary outcome visit was completed by 199 (96.6%) of the 206 participants in the vergence/accommodative group and by 100% of the 104 participants in the placebo group (Fig. 1). Because only a few participants (n = 7) missed their 16-week outcome visit, we believe that the probability of bias is low, and thus, an imputation analysis was not conducted. Of the 4921 scheduled therapy visits, 4762 (96.8%) were completed, with no difference between the vergence/accommodative (96.8%) and the placebo (96.6%) therapy groups. There was a statistically significant difference in mean adherence with completing the prescribed home therapy most of the time or always each week between the vergence/accommodative therapy group (64.2%) and the placebo therapy group (76.3%; P < .05). No adverse events were reported.

FIGURE 1:

Flowchart of CITT-ART randomized clinical trial study visits. CITT-ART = Convergence Insufficiency Treatment Trial–Attention & Reading Trial. aOne participant was determined to be ineligible after randomization; site’s IRB stated no data collected beyond baseline could be used.

Masking of Participants and Examiners

When participants were asked, at the completion of treatment, which therapy they thought they had received, 170 (87%) of 195 assigned to vergence/accommodative therapy and 75 (73%) of 103 assigned to placebo therapy indicated vergence/accommodative therapy. One masked examiner became unmasked at a study visit and then did not perform any subsequent masked examinations for that participant.

Main Clinical Signs and Symptoms Outcome Measures

The means and 95% CIs at baseline and outcome and the treatment group comparisons for the adjusted change in near point of convergence, positive fusional vergence, and CISS scores for participants who completed their 16-week outcome visit are described hereinafter and shown in Table 4.

TABLE 4:

Change in outcomes measures at 16 weeks by treatment group

Clinical Outcome Measure of Near Point of Convergence

A significant interaction of treatment group with baseline near point of convergence was found (P = .004), so although both treatment groups experienced larger changes in near point of convergence with increasing baseline values, there was a statistically significant greater rate of change in the vergence/accommodative therapy group than in the placebo therapy group. Among participants with a near point of convergence of 14.2 cm at baseline (the study average), there was a statistically significant greater mean improvement (decrease) in near point of convergence in the vergence/accommodative group (10.4 cm) compared with the placebo therapy group (6.2 cm; adjusted difference of −4.2 cm; 95% CI, −5.2 to −3.2 cm; P < .001). If comparisons were made using a baseline near point of convergence of 10 cm, the adjusted mean treatment group difference was −3.4 cm (95% CI, −4.6 to −2.2 cm; P < .001), and when made using a baseline near point of convergence of 30 cm or greater, the adjusted mean treatment group difference was −7.2 (95% CI, −9.4 to −5.0 cm; P < .002).

A statistically significant greater proportion of participants in the vergence/accommodative therapy group than in the placebo group met both success criterion 1 for near point of convergence (normal or improved by ≥4 cm; 95.5 vs. 67.3%; P < .001; Table 5) and the stricter success criterion 2 (normal and improved ≥4 cm; 74.2 vs. 30.8%; P < .001; Table 5).

TABLE 5:

Percentage of participants in each treatment group classified as normal or improved for each outcome measure at the 16-week outcome visit

Clinical Outcome Measure of Positive Fusional Vergence at Near

The mean improvement in positive fusional vergence was 23.2 versus 8.8Δ for participants assigned to vergence/accommodative therapy and placebo therapy, respectively, with an adjusted mean treatment group difference of 14.4Δ (95% CI, 12.1 to 16.8Δ; P < .001; Table 4). Univariate models showed no covariates or interactions associated with change in vergence.

A statistically significant greater percentage of participants assigned to vergence/accommodative therapy (92.4%) as compared with placebo therapy (50%) met success criterion 1 (normal or improved ≥10Δ) for change in positive fusional vergence (P < .001; Table 5). Likewise, there were a statistically significant greater proportion of vergence/accommodative participants (80%) who achieved the stricter success criterion 2 (normal and improved ≥10Δ) compared with the proportion of placebo therapy participants (31%; P < .001; Table 5).

Symptom Outcome Measure: CISS

Because univariate analyses showed that parent-reported attention-deficit/hyperactivity disorder, baseline accommodative amplitude, and baseline accommodative facility were associated with change in the CISS score, these variables and the baseline CISS score were included in the final model as covariates. Although the adjusted within-group mean improvements (decrease) in the CISS scores were statistically significant and clinically meaningful for both the vergence/accommodative (11.8) and the placebo therapy groups (10.4; P < .001 for the improvements in both groups), there was not a statistically significant mean treatment group difference (1.5 points; 95% CI, −3.8 to +0.8 points; P = .21; Table 4).

The proportion of participants meeting CISS success criterion 1 for normal (<16) or improved (≥10-point decrease) symptoms was not statistically different (61.8 vs. 58.7%) in the vergence/accommodative and the placebo therapy groups, respectively (Table 5). Similarly, there was no statistically significant difference using the stricter success criterion 2 (normal and improved ≥10 points); 38.2 and 29.8% of participants in the vergence/accommodative therapy and the placebo therapy groups, respectively, met this criterion (P = .15; Table 5).

Composite Outcome Measures

The proportion of participants who met success criterion 3 (composite convergence outcome criterion of both a normal near point of convergence and normal positive fusional vergence) was statistically greater in the vergence/accommodative therapy group (78%) than in the placebo therapy (29%) group (P < .001).

A statistically significant greater proportion of participants in the vergence/accommodative therapy group (37%) than in the placebo therapy group (14%) were classified as successful based on success criterion 4 (composite signs and symptoms outcome classification; P < .001). Likewise, combining participants classified as successful or improved resulted in a statistically significant greater percentage (61%) of the vergence/accommodative therapy participants than placebo therapy participants (44%) meeting this criterion (P = .004).

Fragility Index Assessment

For this study, statistically significant findings were robust for near point of convergence (fragility index, 58), positive fusional vergence (fragility index, 56), the convergence composite measures (fragility index, 76), and the signs and symptoms composite measures (fragility index, 27). We also used the fragility index in a reverse form to identify the required number of vergence/accommodative participants shifting from symptomatic to asymptomatic that would result in a statistically significant finding and found a fragility index of 4. Five participants assigned to vergence/accommodative therapy had a CISS score of 16 at the outcome examination (none in the placebo therapy group scored 16). If four of those five had instead scored 15.5 (or less), the resulting chi-square analysis would have indicated a statistically significant difference between the vergence/accommodative and placebo therapy groups (P = .04). This half-point reduction in the CISS score equates to reporting 1 point lower in frequency on 1 of the 15 symptoms.

Adverse Events

No adverse events were reported.

DISCUSSION

This article reports the results for the clinical outcomes (secondary outcomes) from the CITT-ART randomized trial that compared the effectiveness of office-based vergence/accommodative therapy with office-based placebo therapy in improving reading and attention.16 After 16 weeks of treatment, office-based vergence/accommodative therapy was found to be significantly more effective than office-based placebo therapy in improving the clinical measures of near point of convergence and positive fusional vergence in 9- to 14-year-old children with symptomatic convergence insufficiency. In contrast, the improvements found in symptoms, as measured by the CISS, were not significantly different between the two treatment groups.

The mean improvements in near point of convergence in this study were similar to those found in our previous two trials for both treatment groups (Table 6),3,4 with only the vergence/accommodative group reaching a normal value (<6 cm; Table 6). The percentages of participants in the present study who met the success criterion that required both an improvement of ≥4 cm and a normal near point of convergence were 74 and 31% for the vergence/accommodative and placebo therapy groups, respectively, similar to the 78 and 20% success rates found in our last trial.3

TABLE 6:

CITT-ART outcome results compared with previous CITT studies

Similarly, the resultant changes in positive fusional vergence in this study were comparable with those found in our previous CITT studies with mean improvements in the vergence/accommodative therapy groups ranging from 19.3 to 22.2Δ across studies (Table 6). In contrast, the mean improvements in the placebo therapy groups ranged from 6.9 to 8.5Δ (Table 6) and were less than the 10Δ threshold that likely represents real change based on the coefficient of repeatability for positive fusional vergence.32

The composite convergence measure that considers the change in both the near point of convergence and positive fusional vergence may represent a more robust indication of successful treatment for convergence insufficiency. Paralleling the aforementioned results for the clinical measures alone, the proportions of participants in the vergence/accommodative and placebo therapy groups meeting this criterion in the present study were 78 and 29%, respectively, compared with the 73 and 35% found in our last trial.3

Despite consistent treatment outcomes across the CITT studies for near point of convergence and positive fusional vergence, the outcome for the CISS score in the present study was incongruent with our prior two trials. Although the mean CISS reduction of 11.8 points in the vergence/accommodative therapy group was statistically significant and clinically meaningful, it was less than the 22.6- and 14.8-point improvements found in the previous two CITT studies3,4 (Table 6).

Given that there were statistically significant differences in improvements in both clinical measures of convergence between the vergence/accommodative and placebo therapy groups in the present study and also that there was a statistically significantly greater improvement in symptoms found in the vergence/accommodative therapy group in both of our prior trials (Table 6), the lack of statistical difference between the two treatment groups in the present study is unexpected. Whether this finding is simply due to chance or whether there is another explanation is not certain. Using the CISS, a subjective survey, as a visually-related outcome measure for children has been met with skepticism by some.33–35 It has been proposed that children's responses in regard to symptom occurrence “when reading or doing close work” may depend on the type of near activity the child is envisioning when queried33 (e.g., doing homework, playing videogames, or interacting with smart devices) or whether reading is for pleasure or required for school.33 It is also possible that the increased use of electronic devices may have impacted the validity of the CISS since its development approximately 20 years ago. Finally, comorbid ocular (e.g., dry eye and allergies) or even nonocular conditions may result in positive responses on the CISS,34,35 which could account for the lack of a relationship between the severity of clinical signs and intensity of symptoms as reported by our group and others.36,37 It may be necessary to revise the CISS for use as an outcome measure in future studies of convergence insufficiency.

Although the improvements in clinical signs were significantly less in the placebo group, it could be speculated that the placebo therapy in the present study was not purely a sham treatment. Although the placebo activities did not involve saccades that imitated reading eye movements or stimulation of accommodation or vergence beyond viewing at ≥40 cm, some procedures involved directed eye movements, and keeping the target clear and single was emphasized in an attempt to mimic vergence/accommodative therapy. Thus, it is possible that both the vergence/accommodative and placebo therapies shared elements responsible for some symptom improvement in both groups.

Improved symptoms could be related to response bias, a placebo effect, or both. Response bias, a well-known phenomenon where study participants want to please the researcher by providing what they think the researcher wants them to report,38,39 can account for all or part of a subjective treatment response. In addition, it is not uncommon for participants to become attached to research team members and not want to disappoint their provider who seems invested in the outcome of the trial.40 Alternatively, there could be a genuine placebo response of symptom amelioration, which is more commonly found when outcomes are based on subjective self-reports39 and when the participant-provider relationship is supportive and has potentially placebogenic components such as compassion, reassurance, therapeutic optimism, enthusiasm, and collaborative trust.40–42 The placebo effect has also been reported to be greater when sham treatment involves a more elaborate treatment ritual such as the use of a device or more involved procedures than simply taking a pill.39,43–45 Furthermore, study participant awareness of a greater likelihood of receiving active treatment in a clinical trial, as was the case in this study, is associated with a smaller separation between treatment groups at outcome.42,46 Thus, it is possible that a greater improvement in symptoms might be found in children receiving a higher dosage (16 weeks) of one-on-one therapy including computerized and noncomputerized equipment administered by the same caring and supportive doctor. However, without having had a no-treatment group, symptom response cannot be distinguished from the natural course of the disease, regression to the mean, or the effects of other factors such as the aforementioned response bias.38,39

The fragility index, a metric that assesses the robustness of statistically significant dichotomous outcomes in randomized clinical trials,27–31 suggested that our findings were robust for near point of convergence, positive fusional vergence, the composite convergence outcome, and the composite signs and symptoms outcome. However, it suggested that the lack of difference between treatment groups in the CISS score was not robust, in that only four symptomatic participants in the vergence/accommodative group would have needed to convert to asymptomatic (e.g., change in score from 16 to 15) for the difference in the mean CISS scores between the two groups to have reached statistical significance.

Like all studies, our clinical trial had some limitations. A no-treatment group would have helped to clarify the role of natural history of the disease, regression to the mean, response bias, and various placebo effects. However, because of randomization, there is no reason to assume that any of these phenomena would have occurred unequally in our treatment groups and affected the group differences reported. Nonetheless, our placebo group had the advantage of being less susceptible to bias than an unmasked “no-treatment” control group where the participant and investigator would both know that an active treatment was not being received, which can affect self-reported outcomes and the likelihood of participants receiving treatment outside the study.

It is worthwhile to interpret our study in light of the participants enrolled into the study and the therapy regimen prescribed. Although the results apply only to 9- to 14-year-old children with symptomatic convergence insufficiency, the eligibility criteria were broad, allowing the enrollment of children with numerous comorbidities including learning disabilities, attention-deficit/hyperactivity disorder, and mild to moderate reading disorders and those taking various systemic medications.

CONCLUSIONS

Consistent with previous randomized clinical trials, office-based vergence/accommodative therapy was found to result in statistically significant and clinically relevant improvements in clinical measures of convergence ability in children with symptomatic convergence insufficiency. However, in contrast to the prior clinical trials, self-reported symptom severity as measured by the CISS did not correspond with the improvements in convergence function. Thus, the CISS, in its present form, may no longer adequately quantify the change in symptoms attributable to the change in visual function in children with convergence insufficiency.

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Randomized controlled trial là gì?

Thử nghiệm lâm sàng đối chứng ngẫu nhiên (Randomized controlled clinical trials: RCT) là loại hình nghiên cứu thực nghiệm có giá trị nhất về mặt y học thực chứng để đánh giá hiệu quả của một thuật điều trị.

MU đón là gì?

– Mù đơn: bệnh nhân bị làm mù – Mù đôi: bệnh nhân và người nghiên cứu bị làm mù – Mù ba: bệnh nhân, người nghiên cứu, người xử lý số liệu được làm mù.

Thiết kế bắt chéo là gì?

Thiết kế chéo (cross over): trong thiết kế này mỗi bệnh nhân được phân nhóm ngẫu nhiên vào các nhóm điều trị sử dụng thuốc nghiên cứu hoặc thuốc đối chiếu/placebo sau đó một thời gian được chuyển sang sử dụng phác đồ điều trị của nhóm còn lại.

Thiết kế song song là gì?

- Song song kế là 1 dụng cụ để kiểm tra và phân tích để xác định các vùng lẹm có ích đối với móc và các vùng vướng cần loại bỏ trên mẫu hàm mất răng từng phần, từ đó xác định hướng tháo lắp của hàm giả tháo lắp từng phần và xác định vị trí chính xác của móc trên răng trụ.