Efficacy, safety, and pharmacokinetics of teclistamab in Chinese patients with relapsed/refractory multiple myeloma from the China cohort of MajesTEC-1.

INTRODUCTION

Multiple myeloma (MM) is an incurable disease accounting for ∼10% of hematological malignancies and 1.8% of new cancer cases. 1 MM incidence rates in North American, Australia‐New Zealand, and European populations exceed 3.0 per 100,000, 2 although from 2006 to 2016, a rise in incidence has emerged in China 3 (1.60 per 100,000 person‐years in 2016). 3 , 4 In 2022, 22,450 new cases of, and 17,360 deaths from, MM were estimated for the Chinese population. 5

MM treatment strategies have improved, although many patients become refractory to initial therapies and relapse. 6 , 7 , 8 Current standards of care (SOC) are generally consistent between China and the rest of the world and include immunomodulatory drugs, proteasome inhibitors (PIs), and anti‐CD38 monoclonal antibodies (mAbs) 9 , 10 , 11 ; however, new effective and well‐tolerated treatments are needed for patients who develop relapsed/refractory MM (RRMM). In China, a few treatments are available for triple‐class exposed (TCE) RRMM, including selinexor 12 and two chimeric antigen receptor (CAR)‐T therapies targeting B‐cell maturation antigen (BCMA), equecabtagene autoleucel 13 and zevorcabtagene autoleucel. 14 However, with only 25% of patients responding to selinexor 15 and CAR‐T therapies having drawbacks regarding patient eligibility and convenience/feasibility, treatment options are limited. 16 Thus, with rising MM cases emerging in China, 3 , 4 the unmet clinical need increases.

Several BCMA‐directed agents, including CAR‐T cell therapies, antibody drug conjugates, and bispecific antibodies (BsAbs), have been authorized for TCE RRMM in the United States and Europe, including the BsAbs teclistamab and elranatamab, 17 , 18 , 19 making this the next class of approved therapies in this setting and representing a new SOC.

Teclistamab was the first approved BCMA‐directed BsAb in the European Union and the United States for treatment of TCE RRMM, with weight‐based dosing and the longest follow‐up of any BsAb in RRMM. 17 , 18 In the phase 1/2 MajesTEC‐1 study ( NCT03145181 / NCT04557098 ), 165 heavily pretreated patients with RRMM received the recommended phase 2 dose (RP2D) of teclistamab (1.5 mg/kg subcutaneous weekly [QW], with the option to switch to an every‐other‐week [Q2W] or less frequent dosing schedule with continued response). In this pivotal RP2D cohort, teclistamab achieved deep and durable responses, regardless of refractory status, with an overall response rate (ORR) of 63.0% (46.1% of patients achieving complete response or better [≥CR]) at 30.4 months’ follow‐up. 20 Median progression‐free survival (PFS) was 11.4 months (95% CI, 8.8–16.4) and median duration of response (DOR) was 24.0 months (95% CI, 17.0–not estimable). 21 For patients achieving ≥CR, median PFS and median DOR were not reached. The most common adverse events (AEs) were cytopenias, infections, and cytokine release syndrome (CRS). New‐onset grade ≥3 infection rates decreased over time, with the initial decline coinciding approximately with the median time to switch to Q2W dosing. 20

Serum teclistamab concentrations were sustained above a predetermined target level (6 μg/mL, based on the upper boundary of an experimentally determined range of the 90% maximal effective concentration) with a low peak‐to‐trough ratio. Of 146 patients who received the RP2D and could be evaluated for immunogenicity, none had anti‐teclistamab antibodies. 22

In the phase 2 part of MajesTEC‐1, a China cohort was added to evaluate the efficacy, safety, and pharmacokinetic (PK) profile of teclistamab at the RP2D in Chinese patients with TCE RRMM. Here, we describe patient outcomes in the China cohort which further support teclistamab as an important TCE RRMM treatment option in China.

MATERIALS AND METHODS

Study design and treatment

MajesTEC‐1 is an ongoing, multicenter, open‐label, single‐arm, phase 1/2 study in TCE patients with RRMM. 22 , 23 Following RP2D identification in phase 1 23 and results from the pivotal phase 1/2 portion of MajesTEC‐1 (165 patients enrolled March 2020–August 2021), 22 teclistamab was further evaluated in a separate, phase 2 China cohort (enrolled December 2021–September 2022). A sample size of approximately 25 Chinese patients was predefined to provide a probability of approximately 79% to observe an ORR within the 95% CI declared in the pivotal RP2D cohort. Additional details are in the Supporting Information.

Eligible patients were aged ≥18 years, had documented MM per International Myeloma Working Group (IMWG) diagnostic criteria, 24 were TCE (i.e., received prior treatment with a PI, an immunomodulatory drug, and an anti‐CD38 mAb), and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received teclistamab 1.5 mg/kg subcutaneously QW, preceded by step‐up doses (SUDs) of 0.06 and 0.3 mg/kg. Two to four days were allowed between SUD 1, SUD 2, and treatment dose 1. The phase 2 cycle duration was 28 days. Patients could change to a Q2W dosing schedule if they achieved ≥CR for ≥6 months, and subsequently switch to less frequent dosing if they continued responding on the Q2W schedule at investigator discretion. Teclistamab treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, or study end (i.e., 2 years after the last patient enrolled in the China cohort received their initial dose of teclistamab).

The study was conducted in accordance with the principles of the Declaration of Helsinki and the Good Clinical Practice guidelines of the International Council for Harmonisation. The study protocol, amendments, and relevant documents were approved by the local independent ethics committee or institutional review board at each study site. All patients provided written informed consent.

Endpoints and assessments

The primary efficacy and safety analyses were based on the all‐treated analysis set (all patients treated on or before the September 27, 2023, clinical cutoff [CCO] date). The primary efficacy endpoint was ORR. Key secondary endpoints included CR rate, very good partial response (VGPR) rate, minimal residual disease (MRD) negativity, DOR, PFS, overall survival (OS), AEs, PK, and immunogenicity. Responses were evaluated by an independent review committee per IMWG criteria. 24 MRD negativity was assessed by next generation flow cytometry (NGF) with a threshold of 10 −5 cells. AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. CRS and immune effector cell–associated neurotoxicity syndrome (ICANS) were graded according to the American Society for Transplantation and Cellular Therapy consensus grading system. 25 Serum samples were analyzed for PK and antidrug antibodies (ADA) by electrochemiluminescence immunoassay.

For binary endpoints, event rates with two‐sided 95% exact CIs are presented. For time‐to‐event endpoints, distributions were estimated using the Kaplan‐Meier method; the Kaplan‐Meier curve for DOR was also provided. For all continuous safety variables, descriptive statistics included the sample size ( N ), mean, SD, median, minimum, and maximum. Categorical variables were summarized using frequency counts and percentages.

RESULTS

Patients

The China cohort enrolled 26 patients and as of the CCO, all received teclistamab at the RP2D (Figure 1 ). Median age was 66 years, 73.1% were female, 57.7% had high‐risk cytogenetics, 34.6% had ≥1 extramedullary plasmacytoma (soft tissue plasmacytomas not associated with bone), 26.9% were International Staging System (ISS) stage III, and median prior lines of therapy (LOT) was five (range, 3–11) (Table 1 ). Twenty‐three (88.5%) patients were refractory to their last LOT and 61.5% were triple‐class refractory.

Median follow‐up was 15.0 months (range, 0.8–21.4). Median duration of therapy was 10.1 months (range, 0.7–21.3); 11 (42.3%) patients discontinued teclistamab, including six (23.1%) because of progressive disease, four (15.4%) because of death, and one (3.8%) because of patient refusal of further treatment.

Ten patients switched from QW to Q2W dosing, including six (60.0%) who met response criteria, and four who did not but changed their dosing schedule because of AEs (COVID‐19 in three patients and leukopenia/neutropenia in one). Median time to Q2W dosing was 10.0 months (range, 7.9–15.8). Four patients who switched to Q2W due to AEs were in response at the time of switching. Median duration of follow‐up after switching to Q2W dosing was 2.7 months (range, 1.0–13.5). One patient subsequently switched from Q2W dosing to Q4W dosing. In total, 15 (57.7%) patients at the time of CCO remained on teclistamab and nine (60.0%) were receiving less frequent dosing.

Efficacy

ORR was 76.9% (95% CI, 56.4–91.0). Rates of ≥VGPR and ≥CR were 76.9% (95% CI, 56.4–91.0) and 57.7% (95% CI, 36.9–76.6), respectively. In high unmet‐need populations, including patients with high‐risk cytogenetics at baseline ( n = 15) and baseline extramedullary plasmacytoma ( n = 9), ORR was 66.7% (95% CI, 38.4–88.2 and 29.9–92.5, respectively). Most responses occurred early and deepened over time. Response and follow‐up for responders ( n = 20) are shown in Figure 2 .

The median time to first response, best response, and ≥CR was 1.4 (range, 1.1–5.5), 4.8 (range, 1.2–14.2), and 6.3 months (range, 1.3–14.2), respectively. At the CCO, median DOR was not reached with 75.0% of responders censored (Figure 3A ). The probability of responders remaining in response at 6, 9, and 12 months was 95.0% (95% CI, 69.5–99.3), 85.0% (95% CI, 60.4–94.9), and 78.5% (95% CI, 51.8–91.4), respectively. Of the 20 responders, 15 maintained responses up to the CCO (including nine who switched to Q2W), three had disease progression (including one patient who switched to Q2W), and two died from AEs without documented disease progression. Nine (90.0%) of the 10 patients who switched to ≥Q2W dosing did not have progressive disease after schedule change and maintained response until the CCO; one patient had progressive disease after response and discontinued teclistamab. Among 20 patients with available MRD samples, 18 (90%) were MRD negative 10 −5 at any time point as detected by NGF. Among patients with ≥CR and have available MRD samples, MRD negativity was achieved in 14/15 (93.3%) patients. The median time to first MRD negativity was 69 days (range, 62–418).

With a 15‐month median follow‐up, median PFS was not reached with 61.5% of patients censored (Figure 3B ). The PFS rates at 6, 9, and 12 months were 76.0% (95% CI, 54.2–88.4), 72.0% (95% CI, 50.1–85.5), and 68.0% (95% CI, 46.1–82.5), respectively. Median OS was not reached with most patients censored (80.8%) (Figure 3C ). The OS rate at 6 months was 87.7% (95% CI, 66.4–95.8), and at 9 and 12 months, 83.5% (95% CI, 61.7–93.5 and 61.7–93.5, respectively).

Safety

The teclistamab safety profile in the China cohort was generally consistent with the broader MajesTEC‐1 population. All patients in the China cohort experienced ≥1 any‐grade treatment‐emergent AE (TEAE) (Table S1). Grade 3 and 4 TEAEs were reported for four (15.4%) and 19 (73.1%) patients, respectively, and three (11.5%) experienced a grade 5 TEAE (Table 2 and Supporting Information).

CRS events occurred in 96.2% of patients (grade 1: 73.1%; grade 2: 23.1%; no ≥ grade 3), lasted a median of 2 days (range, 1.0–4.0), and resolved (Table 3 ). The grade 2 CRS rate (23.1%) was comparable with the pivotal RP2D cohort (21.2%). Most patients experienced CRS following SUD (SUD 1: 61.5%; SUD 2: 50.0%) or in association with the first treatment dose (30.8%).

At least one any‐grade neurotoxic event was reported for nine (34.6%) patients, most commonly headache ( n = 5; 19.2%) (Table S2). No grade 3 or 4 neurotoxic events were reported. No patients had ICANS.

Overall, 24 (92.3%) patients had hypogammaglobulinemia by either reported TEAE or laboratory value (i.e., immunoglobulin [Ig] G level <500 mg/dL). When reported as an AE, the maximum severity grade for hypogammaglobulinemia was grade 1 for 11 (42.3%) patients and grade 2 for nine (34.6%). Of these 24 patients, 21 (80.8%) received intravenous Ig treatment at any time during the study according to institutional guidelines. No patients discontinued study treatment due to hypogammaglobulinemia.

Infections occurred in 25 (96.2%) patients (19 [73.1%) grade ≥3]), with 19 (73.1%) experiencing COVID‐19 while on teclistamab. As of the CCO, a decreased incidence of infections was observed among all treated patients, corresponding to the time of switch to less frequent dosing (10.0 months). Additional details are in the Supporting Information.

In total, 15 (57.7%) patients had prior hepatitis B virus (HBV) infections. Eleven received prophylactic antivirals for HBV and did not experience HBV reactivation. Of the four at risk for reactivation who did not receive prophylactic antivirals, three had HBV reactivation. Additional details are in the Supporting Information.

Dose holds occurred in 23 (88.5%) patients because of TEAEs; however, no patients underwent dose reduction or discontinuation because of TEAEs. Of the 19 (73.1%) patients who experienced COVID‐19 while on teclistamab, grade 3 events occurred in ten (38.5%) and grade 4 events in four (15.4%). There were no events of grade 5 COVID‐19; however, two patients died from acute myocardial infarction and pneumonia in the COVID‐19 setting. COVID‐19 was the most common TEAE leading to dose interruptions for 18 (69.2%) patients, treatment cycle delays for 14 (53.8%), dose skips for 8 (30.8%), and dose holds or dose reductions for none. Additional details are in the Supporting Information.

In total, five (19.2%) patients died, one from disease progression and four from AEs (cardiac failure, multiple organ dysfunction syndrome, acute myocardial infarction, and pneumonia for one patient each). Cardiac failure and multiple organ dysfunction syndrome occurred in the setting of infections, and the acute myocardial infarction and pneumonia occurred in the setting of COVID‐19.

Pharmacokinetics

The observed serum trough concentrations (C trough ) range in the China cohort following the teclistamab RP2D generally overlapped with the pivotal RP2D cohort, although mean C trough values were slightly lower in the China cohort (Supporting Information). Consistent with the pivotal RP2D cohort, the mean serum C trough for QW dosing in the China cohort starting from Cycle 2 Day 1 was maintained above the 90% maximal effective concentration value identified in the ex vivo cytotoxicity assay (i.e., 6.04 μg/mL). 26 , 27 Based on limited PK data, teclistamab serum C trough for 1.5 mg/kg Q2W dosing were lower than from QW dosing, as expected. The observed teclistamab PK data in Chinese patients were adequately described by a two‐compartment population PK model with first‐order absorption and parallel time‐independent and time‐dependent (decrease over time) elimination pathways established using data from patients in MajesTEC‐1. 28

Immunogenicity

Overall, a low ADA incidence was observed in Chinese patients treated with teclistamab, with one of 26 (3.8%) identified as positive to anti‐teclistamab antibodies and with low titer (i.e., 20). ADAs in that patient were transient and did not appear to impact teclistamab PK.

DISCUSSION

In this first report of the MajesTEC‐1 China cohort, teclistamab demonstrated deep and durable efficacy with a clinically manageable safety profile, consistent with the pivotal RP2D cohort. Baseline characteristics were largely consistent with some observed numerical differences between the China and pivotal RP2D cohorts. For example, there were fewer patients in the China versus pivotal RP2D cohort aged ≥75 years (China cohort: 7.7%, pivotal RP2D: 14.5%), penta‐exposed (China cohort: 53.8%, pivotal RP2D: 70.3%), and with previous transplantation (China cohort: 11.5%, pivotal RP2D: 81.8%); more patients in the China cohort had baseline features associated with worse prognosis versus the pivotal RP2D cohort (high‐risk cytogenetics, 57.7% vs 25.7%; ≥1 extramedullary plasmacytoma, 34.6% vs 17.0%; ISS stage III, 26.9% vs 12.3%). Overall, efficacy and safety outcomes were consistent with the pivotal RP2D cohort. 22 ORR in the China cohort (76.9% [95% CI, 56.4–91.0]) was above the upper limit of the pivotal RP2D cohort (63.0% [95% CI, 55.2–70.4]) at comparable time points (China cohort/pivotal RP2D: 15.0/14.1 months [median follow‐up]; 10.1/8.5 months [median duration of therapy]). 22 Furthermore, ORR in the poorer performing subgroups was numerically better in the China cohort than the pivotal RP2D cohort at similar time points (China cohort/pivotal RP2D ORR: high‐risk cytogenetics, 66.7%/60.5%; ≥1 extramedullary plasmacytoma, 66.7%/35.7%; ISS stage III, 71.4%/35.0%); however, sample sizes were small in the China cohort and in the poorer performing subgroups in both cohorts; thus, no statistically meaningful comparisons of clinical significance were derived. Among 20 patients in the China cohort with available MRD samples, 18 (90%) achieved MRD NGF negative at 10 −5 , and among the 56 MRD‐evaluable patients in the pivotal RP2D cohort, 48 (85.7%) were MRD NGS negative at 10 –5 . 20 Because of the small sample size and methodology differences, comparison of MRD results between the two cohorts should be interpreted with caution.

With a 15‐month median follow‐up, median DOR, OS, and PFS were not reached in the China cohort. These findings are encouraging for a heavily pretreated population with advanced MM based on evidence from the noninterventional LocoMMotion study that showed median DOR, PFS, and OS in TCE patients treated with SOC of 7.4, 4.6, and 12.4 months, respectively. 8 These patients achieved deep and durable responses while staying the course of therapy, with a 10.1‐month median treatment duration, without premature discontinuation, and dosing schedule adherence per protocol.

Though numerically higher CRS (China cohort: 96.2%; pivotal RP2D: 72.1%) and neurotoxicity (China cohort: 34.6%; pivotal RP2D: 14.5%) rates were observed in the China cohort, this was unlikely because of differences in clinical activity of teclistamab in different ethnicities but rather a factor of a smaller China cohort ( N = 26). All CRS events reported from the China cohort were grade 1 or 2, and grade 2 event rates (23.1%) were comparable with the pivotal RP2D cohort (21.2%). Higher CRS event rates overall were largely driven by more grade 1 CRS events, limited to pyrexia. All neurotoxicity events reported in the China cohort were grade 1 or 2 (most grade 1). Headaches were reported in five patients as neurotoxicity events; none were ICANS‐related. All CRS and neurotoxicity events were resolved, except one (grade 1 insomnia), which was not recovered as of the CCO; none resulted in treatment reduction or discontinuation.

Patients with MM have increased infection risk because of the underlying disease causing hypogammaglobulinemia and immunosuppression, and the teclistamab mechanism of action may further contribute to this risk. 29 , 30 , 31 , 32 Generally, infection TEAEs were clinically managed through dose holds and supportive care therapy. As of the CCO, a decreased infection incidence was observed among all treated patients, corresponding to the time of switching to less frequent dosing (10.0 months). These data provide promising indications that less frequent dosing may be beneficial in managing infection risk, alongside standard prophylaxis and intravenous immunoglobulin infusion. The primary contributor to higher infection rates (96.2%) in the China cohort was COVID‐19 (73.1%), with concurrent grade ≥3 infections of pneumonia. Following the initial COVID‐19 pandemic peak, infection management during teclistamab treatment was further emphasized in the China cohort based on experiences from the pivotal RP2D population 33 and aligned with recently published guidelines. 31 , 33 , 34 , 35 , 36 , 37 In addition, recent real‐world studies and peer‐reviewed guidelines underscore the positive impact of updated infection management strategies (including Ig replacement to maintain IgG levels ≥400 mg/dL) on decreasing infection rates. 38 , 39 Of note, the higher percentage of HBV reactivation observed in the China versus pivotal RP2D cohort was not unexpected because 15 (57.7%) patients had previous hepatitis B infections at screening. Three of these patients experienced HBV reactivation, which may have been prevented with prophylactic antivirals, supporting implementation of a preventive approach in patients with previous HBV. The need for preventive measures in infection mitigation was further emphasized by the pivotal RP2D cohort findings. Recommendations emerging from this study highlight the need for appropriate infection screening pre‐teclistamab, coupled with broader infection prophylaxis. 33

Teclistamab mean PK profiles following QW dosing in Chinese patients were slightly lower than the pivotal RP2D cohort, but individual serum concentration ranges overlapped. Because the China cohort PK data could be well described by the population PK model 28 established using MajesTEC‐1 data, no ethnic difference in PK was noted. Aligned with observed data presented here, the population PK model predicted 40% lower median PK exposure metrics in Chinese patients. 40 This may be explained by lower median body weight (58 vs. 73 kg) and higher proportion of ISS stage III patients (26.9 vs. 12.1%) in the China versus pivotal RP2D cohort, as body weight and ISS stage were identified as significant covariates in the population PK model. 40 However, considering that a flat exposure‐response relationship was observed in the pivotal RP2D cohort, 28 and the consistent efficacy and safety of teclistamab in the China versus pivotal RP2D cohort, the lower median predicted exposure metrics in Chinese patients is not considered clinically relevant. The incidence of teclistamab ADA‐positive patients was low in the China cohort (3.8%), ADA‐positive samples had a low titer (20), and no impact of ADA on teclistamab PK was observed.

CONCLUSIONS

MajesTEC‐1 China cohort findings constitute teclistamab as a promising advancement for treatment of Chinese patients with RRMM. The depth and durability of teclistamab response in Chinese patients, which were maintained with less frequent dosing, are noteworthy. Overall, the efficacy and safety profile in the China cohort is generally consistent with the pivotal RP2D cohort. Although incidence of new‐onset high‐grade infections was higher versus the pivotal RP2D population, these decreased over time and were clinically manageable with supportive care therapy. Teclistamab has been approved in 54 countries worldwide and recently received approval from China’s National Medical Products Administration for adults with RRMM who have received ≥3 prior LOT, with reduced dosing frequency of 1.5 mg/kg Q2W in patients maintaining a response for ≥6 months, 41 and from the U.S. Food and Drug Administration allowing a reduced dosing frequency of 1.5 mg/kg Q2W in patients with RRMM who have achieved and maintained ≥CR for ≥6 months. 42 Additionally, >14,000 patients worldwide have been treated with teclistamab since the first patient was dosed in clinical trials. These developments further strengthen teclistamab as a promising new SOC, and coupled with findings presented in this study, strongly support teclistamab as a viable treatment option for Chinese patients with TCE RRMM.

AUTHOR CONTRIBUTIONS

Zhen Cai : Investigation and resources. Zhongjun Xia : Investigation and resources. Ai‐Li He : Investigation and resources. Yu‐Jun Dong : Investigation and resources. Yafei Wang : Investigation and resources. Aijun Liao : Investigation and resources. Yang Song : Conceptualization, formal analysis, and investigation. Juanjuan Song : Conceptualization, formal analysis, and investigation. Clarissa Uhlar : Conceptualization, formal analysis, and investigation. Katherine Chastain : Conceptualization, formal analysis, and investigation. Latisha Watkins : Conceptualization, formal analysis, and investigation. Xinchao Luo : Conceptualization, formal analysis, and investigation. Lin Huang : Conceptualization, formal analysis, and investigation. Zhuolu Niu : Conceptualization, formal analysis, and investigation. Natalia A. Quijano Cardé : Conceptualization, formal analysis, and investigation. Yue Guo : Conceptualization, formal analysis, and investigation. Hongmei Xu : Conceptualization, formal analysis, and investigation. Raluca I. Verona : Conceptualization, formal analysis, and investigation. Longen Zhou : Conceptualization, formal analysis, and investigation. Jingyun Li : Conceptualization, formal analysis, and investigation. Weijun Fu : Investigation and resources. Ting Niu : Investigation and resources. Juan Du : Investigation and resources.

CONFLICT OF INTEREST STATEMENT

Zhen Cai, Yu‐Jun Dong, Juan Du, Weijun Fu, Ai‐Li He, Aijun Liao, Ting Niu, Yafei Wang, and Zhongjun Xia have no conflicts of interest to disclose.

Yang Song, Juanjuan Song, Clarissa Uhlar, Katherine Chastain, Latisha Watkins, Xinchao Luo, Lin Huang, Zhuolu Niu, Natalia A. Quijano Cardé, Yue Guo, Hongmei Xu, Longen Zhou, and Jingyun Li are employees of, and may own stock in, Janssen. Raluca I. Verona was a Janssen employee at the time of the study and is currently an employee of AbbVie Inc.

Supporting information

Supplementary Material

ACKNOWLEDGMENTS

This study was funded by Janssen Research & Development, LLC. We thank the patients who volunteered to participate in the study, their families and caregivers, the physicians and nurses who cared for the patients and supported this clinical trial, and staff members involved in data collection and analysis. Medical writing support was provided by Edwin C. Thrower, PhD, CMPP, of Eloquent Scientific Solutions, and funded by Janssen Global Services, LLC.

DATA AVAILABILITY STATEMENT

The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at https://www.janssen.com/clinicaltrials/transparency . As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at http://yoda.yale.edu .

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