Glaucoma-related Adverse Events in the Infant Aphakia Treatment Study (IATS) : One Year Results

Abstract

Objective

To report the incidence of glaucoma and glaucoma suspects in the Infant Aphakia Treatment Study (IATS). To evaluate risk factors for the development of a glaucoma-related adverse event in IATS in the first year of follow-up.

Methods

114 infants with a unilateral congenital cataract were assigned to undergo cataract surgery between 1 to 6 months of age either with (IOL) or without IOL implantation (CL). Standardized definitions of glaucoma and glaucoma suspect were created and used in the IATS.

Results

Ten patients (9%) developed glaucoma and 4 patients (4%) were glaucoma suspects for a total of 14 patients (12%) with a glaucoma-related adverse event in the treated eye through the first year of follow-up. Five CL patients (9%) and 9 IOL patients (16%) developed a glaucoma-related adverse event. The odds of developing a glaucoma-related adverse event was 3.1 times higher for a child with persistent fetal vasculature (PFV), and 1.6 times higher for each month of age younger at cataract surgery.

Conclusions

Modern surgical techniques do not eliminate the early development of glaucoma following congenital cataract surgery with or without an intraocular lens. Younger patients with or without PFV seem more likely to develop a glaucoma-related adverse event in the first year of follow-up.Vigilance for the early development of glaucoma is needed following congenital cataract surgery, especially when surgery is performed during early infancy or with PFV. Five year follow-up data for the IATS will likely reveal more glaucoma-related adverse events.

Glaucoma is an important complication of pediatric cataract surgery, with a wide range of reported frequencies, depending on the definition used and the length of follow-up ^1-3. Two large, retrospective series reported 15-21% frequency of glaucoma diagnosed 5 years after cataract surgery ^4-5. Numerous risk factors for the development of glaucoma have been noted, including cataract surgery in the first year of life, postoperative complications such as secondary membrane surgery, small corneal diameters, type of cataract, a family history of aphakic glaucoma, and primary posterior capsulotomy/anterior vitrectomy performed at the time of cataract surgery ^2-10. Cataract surgery in the first year of life, and small corneal diameters have been the most consistent risk factors for glaucoma development in reported studies ^3,5-10. The effect of the placement of an intraocular lens (IOL) at the time of cataract surgery on the risk of developing glaucoma is unknown, although one retrospective review suggested a decreased incidence of glaucoma in patients who received an IOL ¹¹. However the eyes which received an IOL in that report were older at the time of surgery (mean age 5.1 years for pseudophakia versus 2.7 years for aphakia) and children with corneal diameters less than or equal to 10 mm were excluded from analysis. Other studies have noted similar rates of glaucoma in aphakic and pseudophakic children who had cataract surgery performed in the first year of life ^9,10.

The Infant Aphakia Treatment Study (IATS) is a multi-center, randomized, controlled clinical trial sponsored by the National Eye Institute. The objective of the study is to compare the use of primary IOL implantation to surgery without IOL implantation in infants with a unilateral congenital cataract removed between 1 and 6 months of age. The results of IATS during the first year after cataract surgery including visual acuity, adverse events, and additional surgery have been previously reported ¹². In this paper we report the development of glaucoma-related adverse events in IATS subjects through 1 year of follow-up.

Methods

The study design, surgical technique, follow-up schedule, patching and optical correction regimens, evaluation methods, and patient characteristics at baseline have been previously reported in detail and are therefore only briefly summarized in this report ¹³. This study was approved by the institutional review boards of all the participating institutions and was in compliance with the Health Insurance Portability and Accountability Act. The off-label research use of the Acrysof SN60AT and MA60AC IOLs (Alcon Laboratories, Fort Worth, Texas) was covered by US Food and Drug Administration investigational device exemption # G020021.

Study Design

The main inclusion criteria were a visually significant congenital cataract (≥ 3 mm central opacity) in one eye and an age of 28 days to <210 days at the time of cataract surgery. Patients with a unilateral cataract due to persistent fetal vasculature (PFV) were allowed in the study as long as the PFV was not associated with visible stretching of the ciliary processes or involvement of the retina or optic nerve as determined by the treating IATS investigator. The other main exclusion criteria were an acquired cataract, a corneal diameter <9 mm, and prematurity (<36 gestational weeks). Patients were randomized to have either an IOL placed at the time of the initial surgery (with spectacle correction) or to be left aphakic (with contact lens correction). Patients were examined at 1 day, 1 week, and 1, 3, 6, 9 and 12 months after surgery. Grating visual acuity was measured by a traveling examiner at 1year of age (±2 months) using Teller Acuity Cards (Stereo Optical, Chicago, Illinois).

Surgical Technique

Patients randomized to the contact lens (CL) group underwent a lensectomy and anterior vitrectomy. Patients randomized to the IOL group had the lens contents aspirated followed by the implantation of an AcrySof SN60AT IOL into the capsular bag. In the event that both haptics could not be implanted into the capsular bag, an AcrySof MA60AC IOL was implanted into the ciliary sulcus. Following IOL placement, a posterior capsulectomy and an anterior vitrectomy were performed through the pars plana/plicata.

Definitions for Adverse Events

Glaucoma was defined as intraocular pressure (IOP) >21 mmHg with one or more of the following anatomical changes: 1) corneal enlargement; 2) asymmetrical progressive myopic shift coupled with enlargement of the corneal diameter and/or axial length; 3) increased optic nerve cupping defined as an increase of ≥ 0.2 in the cup-to-disc ratio, or 4) the use of a surgical procedure for IOP control.

A patient was designated as a Glaucoma suspect if there was either: 1) two consecutive IOP measurements above 21 mmHg on different dates after topical corticosteroids had been discontinued without any of the anatomical changes listed above; or 2) glaucoma medication use to control IOP without any of the anatomical changes listed above.

Assessment of intraocular pressure, ocular dimensions, and optic nerve

The investigator could perform tonometry with a Tonopen, a handheld applanation tonometer, or a pneumatonometer. Protocol assessment of IOP was performed at the initial examination under anesthesia immediately after the induction of anesthesia prior to randomization and surgery, and at the one year follow-up examination under anesthesia. All other IOP measurements were performed at the discretion of the principal investigator. Corneal diameters (calipers), axial length assessment (A-scan biometry using immersion or applanation techniques), and indirect ophthalmoscopy of the optic nerve were also part of the protocol assessment during examination under anesthesia prior to randomization and at the one year follow-up.

Statistical Considerations

Statistical comparisons were made between subjects with and without a glaucoma-related adverse event using Fisher's exact test for percentages, the independent groups t-test for means and the Wilcoxon rank-sum test for medians. The nonparametric test was used for factors which were highly skewed (age at surgery and visual acuity at 1 year of age). The exact binomial method was used to compute the confidence interval for a proportion and the normal approximation was to compute the confidence interval for the difference between two proportions. Stepwise logistic regression was used to assess the relationship between the development of glaucoma and a selected set of subject characteristics: age at surgery, diagnosis of PFV, and corneal diameter. A significance level of 0.1 was set for the Wald chi-square statistic for including and retaining independent variables in the logistic regression model and 90% confidence intervals were calculated for the odds ratios. For all other analyses, a p-value < .05 was considered statistically significant and 95% confidence intervals were computed. No adjustment was made for multiple testing. Given that relatively few of the patients in the study developed glaucoma or suspicion of glaucoma, the statistical power of the study is limited.

Results

Development of Glaucoma

There were 114 patients enrolled in the study. During the first year after cataract surgery, 10 patients (9%) developed glaucoma and 4 patients (4%) became glaucoma suspects for a total of 14 patients (12%) with a glaucoma-related adverse event in the treated eye (Table 1). There were 57 patients randomized to each treatment group. Glaucoma developed in 3 patients (5%) in the CL group and 7 patients (12%) in the IOL group (p =.32, 95% CI for difference (IOL-CL) = -3% – 17%). Two patients (4%) in the CL group and 2 patients (4%) in the IOL group were glaucoma suspects. Combining glaucoma and glaucoma suspect, 5 CL patients (9%) and 9 IOL patients (16%) developed a glaucoma-related adverse event (p = .39, 95% CI for difference (IOL-CL) = -5% – 19%).

Table 1. Development of Glaucoma and Glaucoma Suspect Status During the First Year After Cataract Surgery.

	CL (n = 57)		IOL (n = 57)		Total (n = 114)
	n (%)	95% CI	n (%)	95% CI	n (%)	95% CI
Glaucoma	3 (5%)	1% - 15%	7 (12%)	5% - 24%	10 (9%)	4% - 16%
Glaucoma Suspect	2 (4%)	0.4% - 12%	2 (4%)	0.4% - 12%	4 (4%)	1% - 9%
Total	5 (9%)	3% - 19%	9 (16%)	7% - 28%	14 (12%)	7% - 20%

CL = contact lens group (eyes left aphakic after primary cataract removal)

IOL = intraocular lens group (eyes receiving primary intraocular lens implantation at the time of cataract removal)

n = number of patients

CI = confidence interval (included to show the level of uncertainty in the estimates)

Influence of Patient Characteristcs

We investigated the effect of age at surgery, corneal diameter, a diagnosis of PFV, pre-operative IOP, and additional surgery performed after cataract surgery on the development of a glaucoma-related adverse event. The median age at surgery among patients in the study was 1.8 months (quartiles = 1.2, 3.2 months). The mean corneal diameter of the treated eyes was 10.5 mm (SD = 0.7). A diagnosis of PFV was made by the treating IATS investigator in 25 patients (22%) ¹². Patients who developed a glaucoma-related adverse event tended to be younger at surgery than those who did not (median = 1.2 vs 2.2 months, p = 0.017, Table 2,). There was a trend for a smaller corneal diameter among patients developing glaucoma or glaucoma suspect compared to the other patients (mean = 10.1 vs 10.5 mm, p = .081, Table 2,). There was also a trend for a higher percentage of patients with PFV among those who developed glaucoma or glaucoma suspect compared to those without this diagnosis (43% vs 19%, p = .077, Table 2). Pre-operative IOP, intra-operative complications, and additional surgery after cataract extraction failed to demonstrate any relationship to a glaucoma-related adverse event (analyses not shown). As expected, we found some associations among these three patient characteristics. Age and corneal diameter were moderately correlated (r = 0.56, p < .001). Corneal diameter tended to be slightly smaller for patients diagnosed with PFV compared to other patients (mean = 10.5 vs. 10.3 mm, p = .17), although this difference was not statistically significant. However, age at surgery did not appear to be associated with PFV, as the median age was 2.5 months for patients with PFV compared to 2.3 months for those not having this diagnosis (p = .61).

Table 2. Patient Characteristics versus Development of Glaucoma and Glaucoma Suspect Status During the First Year After Cataract Suregery.

Patient Characteristics*	Glaucoma / Glaucoma Suspect		p-value	95% CI for Difference (No-Yes)
	No (n = 100)	Yes (n = 14)
Age (months), median (quartiles)	2.2 (1.2, 3.2)	1.2 (1.0, 1.7)	0.017	0.1 – 1.5
Corneal Diameter (mm), Mean ± sd	10.5 ± 0.7	10.1 ± 0.8	0.081	-0.06 – 0.9
Persistent Fetal Vasculature, n (%)	19 (19%)	6 (43%)	0.077	-33% – 3%

^*Refers to characteristics at initial cataract surgery

n = number of patients

CI = confidence interval

A multivariable analysis using stepwise logistic regression was done to relate age, corneal diameter and PFV to the development of glaucoma or glaucoma suspect status. An alpha-level of 0.1 was set for a patient characteristic to be included in the model. PFV was the first patient characteristic entered, followed by age. With PFV and age in the model, corneal diameter did not meet the entry criteria for inclusion in the model, which was not unexpected given the correlation between age and corneal diameter. As estimated from the model, the odds of developing a glaucoma-related adverse event was 3.1 times higher for a patient with PFV compared to a patient without this diagnosis after adjusting for age (p = 0.061, 90% CI for odds ratio = 1.2 – 8.6). Also, the odds of developing a glaucoma-related adverse event was 1.6 times higher for a patient one month younger than another patient after adjusting for PFV (p = 0.08, 90% CI = 1.03 – 2.6). The Hossmer-Lemmeshow test did not suggest a significant lack of fit for the model (p = 0.31). The relationship between age, PFV, and the development of a glaucoma-related adverse event is demonstrated in Table 3.

Table 3. Development of Glaucoma and Glaucoma Suspect Status According to Persistent Fetal Vasculature and Age.

Persistent Fetal Vasculature	Age	# of Patients	Development of Glaucoma and Glaucoma Suspect
			n (%)	95% CI
No	≤ 48 days	37	5 (14%)	5% – 29%
	≥ 49 days	52	3 (6%)	1% – 16%
Yes	≤ 48 days	13	4 (31%)	9% – 61%
	≥ 49 days	12	2 (17%)	2% – 48%

n = number of patients

CI = confidence interval

Influence of IOL Placement

Eyes which had the IOL placed in the capsular bag had a 13% rate of glaucoma or suspect status (7/52 eyes) as compared to 2/4 eyes (50%) where the IOL was placed in the ciliary sulcus. This difference was not statistically significant (p = 0.12), Both of the eyes with a sulcus IOL and a glaucoma-related adverse event had PFV, and one of these eyes was enrolled in the study despite having an exclusion criteria for PFV (stretching of the ciliary processes) ¹². Exclusion of the case with the protocol violation would leave 1/3 eyes (33%) with sulcus IOL placement and a glaucoma-related adverse event (p = 0.38).

Type of Glaucoma and Treatment

Although detailed gonioscopic information was not collected as part of the IATS study, 9/10 eyes with glaucoma were assumed to be open angle, while one eye (10%) was noted to have iris bombe and angle closure.

Glaucoma surgical procedures were required to control the glaucoma in 6/10 eyes (60%); 4/7 eyes (57.1%) in the IOL group and 2/3 eyes (67%) in the CL group. Three of the eyes with open angle glaucoma were treated with trabeculotomy (one eye with a standard trabeculotomy and two eyes with three hundred sixty degree trabeculotomy), and two eyes were treated with a Baerveldt glaucoma drainage device.; The eye with angle closure underwent removal of a pupillary membrane and peripheral iridectomy. Three of six eyes (50%) with glaucoma that required surgical intervention were on glaucoma medications at 1 year. The remaining four eyes with glaucoma were treated with glaucoma medications alone (4/10 eyes, 40%). All four patients diagnosed as glaucoma suspects were treated with glaucoma medication.

Glaucoma and Visual Acuity

Median visual acuity at 1 year of age was 0.3 logMAR units (3 Snellen lines) worse for patients who developed glaucoma or suspected glaucoma during the first year after surgery (1.1) versus those without this adverse event (0.80. This difference was not statistically significant (p = 0.15).

Discussion

Glaucoma developed in the operated eyes of 10/114 infants (9%) with unilateral cataract enrolled in the IATS study through the first year of follow-up. More eyes (7/57, 12%) developed glaucoma after primary IOL implantation than after cataract removal without IOL (3/57, 5%), but this difference was not statistically significant, although the power of this calculation is low. Multivariate regression analysis showed that the odds of developing a glaucoma-related adverse event was 3.1 times higher for a patient with PFV compared to a patient without this diagnosis after adjusting for age, and that the odds of developing a glaucoma-related adverse event was 1.6 times higher for a patient one month younger than another patient after adjusting for PFV. Corneal diameter was not statistically significant in multivariate analysis, possibly due to the correlation of corneal diameter with age and the small range of corneal diameters in IATS.

Modern lensectomy/vitrectomy surgical techniques for pediatric cataract surgery have reduced early postoperative complications, such as pupillary block, which can cause angle closure glaucoma ². However, a significant percentage of children who have had congenital cataract surgery go on to develop glaucoma, usually with predominantly open angles, and the onset of glaucoma frequently occurs years after the cataract surgery ^2,3,5,6. Numerous potential mechanisms for the development of glaucoma have been postulated, including congenital angle anomalies, post-operative inflammation leading to angle dysfunction or progressive synechial closure, corticosteroid-induced mechanisms, and some unknown effect of the aphakic state or vitreous interaction with the developing angle structures leading to reduced outflow facility ^2-11,14,15. An ultrasound biomicroscopy study of the the anterior segment after congenital cataract surgery has demonstrated a more anterior iris insertion with a smaller angle opening distance, and a flatter pars plicata, compared to normal controls ¹⁶. Since IATS was not designed as a study of the development of glaucoma following congenital cataract surgery', limited information on the mechanism of glaucoma can be ascertained from the one year outcome data. It is clear, however, that modern surgical techniques do not eliminate the early development of glaucoma, with 10/114 eyes (8.8%) of the total group developing glaucoma by the one year follow-up visit. Most cases were assumed to be open angle, with a single case (1/10 eyes, 10%) of angle closure reported.

A retrospective study of older children has suggested that the placement of an intraocular lens reduces the incidence of glaucoma following congenital cataract surgery.¹¹. Two other studies of congenital cataract surgery with and without an IOL failed to demonstrate a difference in the incidence of glaucoma. ^9,10. Although the number of eyes developing glaucoma by the one year follow-up in the IATS study suggested a higher incidence in the pseudophakic than aphakic eyes (12% vs. 5%), this difference was not statistically significant. Continuing follow-up in the IATS study for the development of glaucoma and glaucoma suspect status is critical, given that the mean interval between cataract surgery and diagnosis of glaucoma has been reported to be 4.0 – 5.2 years ^5-7.

Many previous studies of glaucoma in aphakic and pseudophakic children have lacked a consistent definition of glaucoma and a standard protocol for surveillance of at-risk eyes. Glaucoma has frequently been defined by elevated intraocular pressure alone, without structural change to the eye as part of the diagnostic criteria ^2,5-7.The definition for glaucoma in the IATS study included criteria for structural change (enlarged ocular dimensions or an increased cup-disc ratio). A standardized definition of a glaucoma suspect was also created for IATS.

PFV has been believed to be a risk factor for the development of glaucoma following congenital cataract surgery due to the associated microphthalmos and the possibility of anterior segment anomalies, but previous studies have failed to confirm this opinion ^4,6. The IATS provides evidence that PFV is likely a risk factor for the development of glaucoma.. Younger patient age at surgery was also noted to be risk factor for the development of a glaucoma related-adverse event in IATS, despite deferring cataract surgery until at least 4 weeks of age based on previous studies suggesting an increased risk of glaucoma if surgery is performed in the first 4 weeks of life ^17,18. . Cataract surgery in IATS was performed between 1-6.9 months of age, providing two nearly equal size cohorts aged </= 48 days and >/= 49 days (Table 3). Further evaluation of the visual outcomes in the IATS cohort may provide information as to the optimum timing of cataract surgery in the setting of unilateral cataract.

Central corneal thickness (CCT) is a recently recognized risk factor for the development of glaucoma in adult patients with ocular hypertension, with thinner central corneal measurements noted to be a powerful predictor for the development of open angle glaucoma ¹⁹. Various correction factors for applanation intraocular pressure measurements based on CCT measurements have been proposed ^20,21, but statistical analysis of these formulas have demonstrated less effect of CCT on IOP than predicted, potentially leading to erroneous conclusions about “corrected” IOP ²². . Aphakic and pseudophakic children have significantly thicker corneas than age-matched controls, and CCT has been noted to increase following cataract surgery ²³. Furthermore eyes which developed glaucoma (based on optic nerve changes) had a thicker CCT and higher IOP than those which did not, arguing against the concept that a thicker CCT in children leads to a lower risk of glaucoma, as in adult patients with ocular hypertension ²³. Measurement of CCT was not part of the study protocol in IATS. Children noted to have elevated IOP without structural change were placed in the glaucoma suspect category.

Treatment of children who develop glaucoma following congenital cataract surgery frequently requires surgical intervention.. Chen and co-authors noted surgical treatment was performed in 57.1% of 170 eyes with aphakic glaucoma, with medical therapy recommended in 92% of eyes ⁷. However, in another study of pediatric aphakic glaucoma surgical intervention was performed in only 15/55 eyes (27%), likely representative of less severe glaucoma ²⁴. The 60% rate of glaucoma surgery (among eyes with glaucoma) in IATS is comparable with these studies. Of note, three of the glaucoma cases in IATS which were treated with trabeculotomy surgery were controlled at one year post cataract surgery. Angle surgery in children who develop open angle glaucoma following congenital cataract surgery was noted to be successful in 57% of 14 eyes with a mean follow-up of 4.7 years(some patients required more than one angle surgery), and may decrease the need for filtering or shunt procedures ²⁵.

Visual acuity in children who develop glaucoma following congenital cataract surgery may be limited by glaucomatous optic nerve damage, amblyopia, pupillary membranes, corneal decompensation, or complications from glaucoma surgical intervention ^7,24,25. In IATS, eyes which developed a glaucoma-related adverse event had a median visual acuity that was three Snellen lines worse than those which did not . Although this difference did not reach statisical significance, likely due to the small sample size of the glaucoma group, it is reasonable to expect that a statistically significant difference in visual acuity will develop in the glaucoma group with longer follow-up.

Limitations of this study are the small sample size of the glaucoma-related adverse event group, only one year of follow-up data, and the inclusion of the glaucoma suspect group with the glaucoma group for statistical evaluation. Strengths of the study are prospective data collection and standardized definitions of glaucoma and glaucoma suspect adverse events. Planned 5 year IATS follow-up data should provide important information about risk factors for the development of glaucoma and the effect of glaucoma on visual outcomes in unilateral cataract patients.

The Infant Aphakia Treatment Study Group

Administrative Units and Participating Clinical Centers

Clinical Coordinating Center (Emory University): Scott R.Lambert, M.D. (Study Chair), Lindreth DuBois MEd, MMSc (National Coordinator)

Data Coordinating Center (Emory University): Michael Lynn MS (Director), Betsy Bridgman BS, Marianne Celano PhD, Julia Cleveland MSPH, George Cotsonis MS, Carey Drews-Botsch PhD, Nana Freret MSN, Lu Lu MS, Azhar Nizam MS, Seegar Swanson, Thandeka Tutu-Gxashe MPH

Visual Acuity Testing Center (University of Alabama, Birmingham): E. Eugenie Hartmann PhD (Director), Clara Edwards, Claudio Busettini PhD, Samuel Hayley

Steering Committee: Scott R Lambert MD, Edward G. Buckley MD, David A. Plager MD, M. Edward Wilson MD, Michael Lynn MS, Lindreth DuBois Med MMSc, Carolyn Drews-Botsch PhD, E. Eugenie Hartmann PhD, Donald F Everett MA

Contact Lens Committee: Buddy Russell COMT, Michael Ward MMSc

Participating Clinical Centers (In order by the number of patients enrolled)

Medical University of South Carolina; Charleston, South Carolina (14): M. Edward Wilson MD, Margaret Bozic CCRC, COA

Harvard University; Boston, Massachusetts (14): Deborah K. VanderVeen MD, Theresa A Mansfield RN, Kathryn Bisceglia Miller OD

University of Minnesota; Minneapolis, Minnesota (13): Stephen P. Christiansen MD, Erick D. Bothun MD, Ann Holleschau, Jason Jedlicka OD, Patricia Winters OD, Jacob Lang OD

Cleveland Clinic; Cleveland, Ohio (10): Elias I. Traboulsi MD, Susan Crowe BS, COT, Heather Hasley Cimino OD

Baylor College of Medicine; Houston, Texas (10): Kimberly G Yen MD, Maria Castanes MPH, Alma Sanchez COA, Shirley York

Oregon Health and Science University; Portland, Oregon (9): David T Wheeler MD, Ann U. Stout MD, Paula Rauch OT, CRC, Kimberly Beaudet CO, COMT, Pam Berg CO, COMT

Emory University; Atlanta, Georgia (9): Scott R. Lambert MD, Amy K. Hutchinson MD, Lindreth DuBois Med, MMSc, Rachel Robb MMSc, Marla J. Shainberg CO

Duke University; Durham, North Carolina (8): Edward G. Buckley MD, Sharon F. Freedman MD, Lois Duncan BS, B.W. Phillips, FCLSA, John T. Petrowski, OD

Vanderbilt University: Nashville, Tennessee (8): David Morrison MD, Sandy Owings COA, CCRP, Ron Biernacki CO, COMT, Christine Franklin COT

Indiana University (7): David A Plager MD, Daniel E. Neely MD, Michele Whitaker COT, Donna Bates COA, Dana Donaldson OD

Miami Children's Hospital (6): Stacey Kruger MD, Charlotte Tibi CO, Susan Vega

University of Texas Southwestern; Dallas, Texas (6): David R. Weakley MD, David R. Stager, Jr., Joost Felius PhD, Clare Dias CO, Debra L. Sager, Todd Brantley OD

Data and Safety Monitoring Committee: Robert Hardy PHD (Chair), Eileen Birch PhD, Ken Cheng MD, Richard Hertle MD, Craig Kollman PhD, Marshalyn Yeargin-Allsopp MD, (resigned), Cyd McDowell, Donald F. Everett MA

Medical Safety Monitor: Allen Beck MD

Michael Lynn and Allen Beck had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.