Introduction: Phase 3 trial of 6-month subcutaneous leuprolide acetate (SC-LA) in children with central precocious puberty (CPP) demonstrated efficacy and safety. The aims of this secondary analysis were to evaluate unstimulated luteinizing hormone (LH) as efficacy measure, assess clinical suppression metrics, and present biochemical and clinical data for subgroups not achieving hormone suppression. Methods: Sixty-two children with treatment-naïve CPP received 2 doses of 45 mg SC-LA at 24-week intervals. Unstimulated and GnRH-stimulated LH, E2, and T concentrations were measured. Clinical measures included bone age (BA) and predicted adult height (PAH). Results: Eighty-four percentage and 86% of children achieved unstimulated LH <1 IU/L at weeks 24 and 48, respectively. Of 8 children not achieving unstimulated LH <1 IU/L at week 24 that completed the study, all showed a lack of pubertal stage progression and stable/decreased BA to chronological age ratio (BA/CA). Received operating characteristic (ROC) analyses suggested unstimulated LH is a good diagnostic predictor of GnRH-stimulated LH <4 IU/L at weeks 24 and 48 (AUC = 0.88). Across all children, mean BA/CA improved from 1.4 (screening) to 1.3 (week 48) and mean PAH increased by 3 cm. Of 7 girls not achieving stimulated LH <4 IU/L at week 24, all achieved E2 <10 pg/mL, showed a lack of pubertal stage progression, and had stable or decreased BA/CA by week 48. Additionally, 6/7 had increased PAH by week 48 and 4 had unstimulated LH <1 IU/L. Conclusion: Unstimulated LH has value as an efficacy measure and concentrations <1 IU/L may be an adequate surrogate of treatment response in children with CPP. All children who completed the study had evidence of pubertal suppression.

Changes in pubertal physical examinations, growth rate, and rate of bone age (BA) progression should be considered first when evaluating adequate pubertal suppression [1, 2]. Secondarily, luteinizing hormone (LH) concentrations following gonadotropin-releasing hormone (GnRH) stimulation tests have the potential to be used for assessing treatment efficacy as support to clinical considerations [3] but alone do not provide a complete picture of a child’s response to treatment [4, 5]. Hormonal investigations including unstimulated LH concentrations may be appropriate to monitor long-term hormone suppression during CPP treatment in children with a suboptimal clinical response [6‒8].

Direct comparisons on the magnitudes of LH suppression between different GnRH analogs (GnRHa) should be viewed with caution due to differences in trial methodologies and differences/changes in hormone assays over time. The uniqueness of each study design and the dynamic nature of hormone measurements underscore the challenge of making meaningful cross-study comparisons. Importantly, the definition of 1 International Unit (IU), the unit used to express LH concentrations, is set arbitrarily and has been updated periodically by the World Health Organization; the first International Standard (IS) was set in 1976, and the most recent (fifth IS) was established in 2012 [9, 10]. Trials have used different IU versions, potentially invalidating cross-study comparisons. For example, the fourth IS for human pituitary LH was 70 IU/ampoule and the fifth International Standard is 177 IU/ampoule. Furthermore, the timing of hormone assessments post-GnRH stimulation test has varied from 1 sample at 30 min to multiple measures over 3 h. Unstimulated LH, on the other hand, is a highly variable metric as it is produced in ultradian rhythm, minute-to-minute pulses, which can further fluctuate depending on the sex, age, time of therapy administration, and timing of sample collection. The sensitivity of the assays and instrumentation used for hormone assessments should also be considered when comparing results between trials, as there is evidence that different platforms report different LH values (e.g., LH measurements from the Cobas e601 assay were 1.3 higher than the Architect i2000sr assay). Change in hormone assays over time can affect the measurements of LH concentrations, rendering direct comparisons problematic. In addition, the degree of LH suppression that reflects adequate treatment continues to be studied, and trials undertaken for regulatory approval have used different thresholds for stimulated LH as primary efficacy endpoints [11‒13]. Therefore, comparisons should be interpreted with caution.

We had previously reported results of the pivotal trial using small-volume subcutaneous 6-month duration leuprolide acetate (LA) treatment for CPP [14] and showed 87% children achieved poststimulation LH <4 IU/L at week 24 and 88% girls and 1/2 boys maintained peak LH <4 IU/L at week 48 [14] while maintaining pubertal suppression. The principal aims of this secondary analysis of those data were to evaluate unstimulated LH as an efficacy measure while assessing clinical metrics of suppression, including changes in BA to chronological age (CA) ratio (BA/CA), difference between BA and CA (BA-CA), and predicted adult height (PAH). We also present biochemical and clinical suppression data for three subgroups who did not achieve GnRH-unstimulated LH <1 IU/L, GnRH-stimulated LH <4 IU/L, and estradiol (E2) <10 pg/mL.

FENSOLVI® is a small injection volume (0.375 mL), short needle (5/8-inch, 18-gauge), 6-month dose, 45 mg subcutaneous LA injection [14]. We derived data from the pivotal phase 3 trial of 6-month subcutaneous (SC) leuprolide acetate (SC LA) in children with CPP as previously described [14]. Sixty-two children comprised the intent-to-treat population. Three subgroups of children were further analyzed, those who did not achieve either GnRH-unstimulated LH <1 IU/L (n = 10), GnRH-stimulated LH <4 IU/L at week 24 (n = 8 girls), and girls who did not achieve E2 <10 pg/mL at week 24 (n = 6).

GnRH stimulation tests were performed by administration of 20 μg/kg or 500 μg (fixed dose) aqueous LA subcutaneously at screening and weeks 12, 24, 36, and 48. Blood samples for GnRH-stimulated LH, E2, and T were taken 30 min after the GnRHa agonist administration. Suppression of GnRH-stimulated LH levels to <5 and <2 IU/L were evaluated. Blood samples for unstimulated LH and E2 were taken at screening, baseline, and weeks 4, 12, 20, 24, 36, 44, and 48. All samples were analyzed by a central laboratory (The Doctor’s Laboratory, London, UK). Serum LH was assessed using a validated central Cobas electrochemiluminescence immunoassay (ECLIA) with a lower limit of detection (LLOD) of 0.100 IU/L. Estradiol samples were batched and analyzed by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) with LLOD of 10 pg/mL.

Received operating characteristic (ROC) curves were constructed to assess the accuracy of unstimulated LH as a diagnostic predictor of peak GnRH-stimulated LH at weeks 24 and 48, and congruence of clinical suppression (defined as decreased BA/CA, no pubertal stage progression, and peak GnRH-stimulated LH <5 IU/L) at week 48. Diagnostic accuracy was determined by the area under the curve (AUC) value rated as acceptable (AUC between 0.6 and 0.7), fair (AUC between 0.7 and 0.8), good (AUC between 0.8 and 0.9); excellent (AUC >0.9) [15].

Relationships between stimulated LH concentrations and other endpoints (unstimulated LH, change in BA/CA, change in PAH) were evaluated to determine whether stimulated LH concentrations correlated to clinically meaningful endpoints. The coefficient of determination (r2) was calculated for each correlation analysis using the Pearson correlation coefficient. Correlations were deemed statistically significant if p < 0.05, as calculated using a t test.

Radiographs of the left hand and wrist were used to determine BA using the Greulich and Pyle method, where children’s radiographs were compared to nearest standard radiograph in the atlas [16‒18]. All taken radiographs were sent to a blinded central reader from Intrinsic Imaging, LLC for bone age evaluation. Predicted adult height was calculated using Bayley-Pinneau tables [19]. Body weight (kg) and height (cm) were measured at screening, baseline, weeks 4, 12, 20, 24, 36, 44, and 48. Pubertal maturation was categorized with a modified Tanner staging system [20] using breast development as assessed by palpation (girls), external genitalia (boys), and pubic hair (both sexes). Height velocities (HV) were calculated using height measurements, with HV at week 4 substituting as a baseline value. Body mass index (BMI) was calculated using weight and height measurements. Underweight, healthy weight, overweight, and obese were defined as BMI <5th percentile, 5th to <85th percentile, 85th to <95th percentile, and ≥95th percentile, respectively [21]. The BMI z-score was calculated by assessing the number of standard deviations the BMI was above or below the average BMI for children of corresponding age and gender. Descriptive statistics were used for all analyses and were calculated for data collected at the specified timepoints. Data are presented as mean ± standard error (SE).

The standard deviation scores (SDS) for height [22, 23], body mass index [24], HV [25], PAH [26], and Tanner Staging [27] were calculated for screening (week 4 for HV), week 24, and week 48. SDS was corrected for sex only for PAH, and sex and age for height, BMI, Tanner Staging, and HV (as well as race [African vs. Non-African] for HV). Standard deviation score = (actual − average from reference group) ÷ (SD from reference group).

Statistical analysis of safety was descriptive only. Treatment-emergent adverse events (TEAEs) were defined as any adverse events (AEs) occurring or worsening on or after the first dose of the study drug. Analyses were performed using Microsoft Excel.

Demographics

Baseline demographics for the pivotal trial have been previously described [14]. In brief, 62 children (60 girls, 2 boys) with treatment-naïve CPP received 2 doses of 45 mg (0.375 mL injection volume) subcutaneous LA at 24-week intervals. Mean age was 7.5 (range: 4–9) years. The mean baseline demographics were 136.6 cm, 8.9 cm/year, and 18.6 kg/m2 and baseline SDS were 2.4, 3.4, and 0.8 for height, HV, and BMI, respectively.

Analysis of Unstimulated LH as an Efficacy Measure in the Intent-To-Treat Population

Unstimulated LH data were analyzed to assess the use of this endpoint as an additional efficacy measure. 84% and 86% of children achieved unstimulated LH <1 IU/L at weeks 24 and 48, respectively. Unstimulated LH <0.3 IU/L was achieved by 28%, 24%, 22%, and 25% of children at weeks 12, 24, 36, and 48, respectively (shown in Fig. 1).

Fig. 1.

Unstimulated LH concentrations decreased from screening. The proportion of children who achieved unstimulated LH concentrations <1.0 IU/L increased from 57% at screening to 84% and 86% at weeks 24 and 48, respectively.

Fig. 1.

Unstimulated LH concentrations decreased from screening. The proportion of children who achieved unstimulated LH concentrations <1.0 IU/L increased from 57% at screening to 84% and 86% at weeks 24 and 48, respectively.

Close modal

In the 8 children that did not achieve unstimulated LH <1 IU/L and completed the study, all 8 had effective pubertal suppression defined by lack of progression in pubertal staging (shown in Table 1). All 8 children had stable or decreased BA/CA from screening to week 48. Seven and 6 children had increased PAH from screening to week 24 and week 24–48, respectively.

Table 1.

Efficacy measures in children who did not achieve GnRH unstimulated LH <1 IU/L at week 24 (n = 10)

Table 1.

Efficacy measures in children who did not achieve GnRH unstimulated LH <1 IU/L at week 24 (n = 10)

Close modal

Exploratory analyses to evaluate an unstimulated LH threshold indicating adequate suppression were performed (shown in Table 2). At week 24, 41 of 62 total children achieved clinical suppression defined as decreased BA/CA, no pubertal stage progression, and GnRH-stimulated LH <5 IU/L. Of these 41 children, 63% had unstimulated LH levels <0.6 IU/L and 88% had <1.0 IU/L. In the same group of 41 children, children with unstimulated LH >0.6 IU/L (n = 15) and >1.0 IU/L (n = 5) had GnRH-stimulated LH concentrations of 5.7 ± 2.7 IU/L and 9.9 ± 6.4 IU/L, respectively.

Table 2.

Percentages of children who achieved unstimulated LH thresholds and other efficacy measures

Target-unstimulated LH, IU/LAll children (N = 62)Children with stimulated LH ≥5.0 IU/L at week 24 (N = 4)Children with stimulated LH <5.0 IU/L at week 24 (N = 58)Children with pubertal suppression1 and stimulated LH <5.0 IU/L at week 24 (N = 41)
<0.3 24 26 22 
<0.6 63 50 64 63 
<0.8 77 50 79 83 
<1.0 84 50 86 88 
Target-unstimulated LH, IU/LAll children (N = 62)Children with stimulated LH ≥5.0 IU/L at week 24 (N = 4)Children with stimulated LH <5.0 IU/L at week 24 (N = 58)Children with pubertal suppression1 and stimulated LH <5.0 IU/L at week 24 (N = 41)
<0.3 24 26 22 
<0.6 63 50 64 63 
<0.8 77 50 79 83 
<1.0 84 50 86 88 

1Children who had decrease in BA/CA, and no progression of pubertal stage throughout 48 weeks of treatment.

ROC analyses suggested that unstimulated LH is a good diagnostic for predicting peak GnRH-stimulated LH suppression <4 IU/L at weeks 24 and 48 (AUC = 0.88, sensitivity = 41.0%, specificity = 88.7%) (shown in online suppl. Fig. S1; for all online suppl. material, see https://doi.org/10.1159/000539110) and a fair diagnostic metric for predicting clinical suppression at week 48 (AUC = 0.75, sensitivity = 29.2%, specificity = 90.1%).

A significant positive correlation was found between GnRH-stimulated and unstimulated LH at week 24 (r2 = 0.5082) and week 48 (r2 = 0.5507) (p < 0.001 for both) (shown in Fig. 2). No correlations were found between each of the following endpoints: stimulated LH versus hormonal or clinical endpoints; stimulated LH at week 24 versus LH at 1-, 4-, or 6-h after the first study drug injection; unstimulated LH versus clinical endpoints; or unstimulated LH at week 24 versus pre-injection LH.

Fig. 2.

Correlation between GnRH-stimulated and unstimulated LH (intent-to-treat population). A positive correlation was found between GnRH-stimulated and unstimulated LH concentrations.

Fig. 2.

Correlation between GnRH-stimulated and unstimulated LH (intent-to-treat population). A positive correlation was found between GnRH-stimulated and unstimulated LH concentrations.

Close modal

Analysis of Clinical Metrics of Suppression in the Intent-To-Treat Population

In all 62 children, both BA/CA ratio and PAH improved throughout treatment. The mean ± SE BA/CA ratio decreased from 1.4 ± 0.02 cm at screening to 1.3 ± 0.02 cm by week 24 and was sustained at 1.3 ± 0.02 cm by week 48 (shown in Fig. 3). Similarly, mean ± SE PAH increased from 157.1 ± 1.0 cm at screening to 159.2 ± 1.0 cm at week 24 and 160 ± 1.0 cm at week 48, an increase of 2.8 ± 0.6 cm. PAH SDS increased from −0.3 to −0.1 from screening to week 48. Although 1 year of treatment is inadequate to fully assess changes in BA or PAH, 82% and 69% of children had increases in PAH from screening to week 24 and screening to week 48, respectively.

Fig. 3.

Biochemical and clinical endpoints throughout treatment (intent-to-treat population). All children who completed the clinical study had evidence of clinical and biochemical pubertal suppression.

Fig. 3.

Biochemical and clinical endpoints throughout treatment (intent-to-treat population). All children who completed the clinical study had evidence of clinical and biochemical pubertal suppression.

Close modal

The proportion of children with a healthy weight was similar at screening, week 24, and week 48 (56%, 49%, and 47%, respectively). Among children with healthy weight at screening, 74% remained at a healthy weight at week 48. There was a small increase in chronological age-adjusted BMI z-scores from 0.9 at screening to 1.0 at week 48.

Suppression of GnRH-stimulated LH levels to <5 and <2 IU/L was evaluated. At weeks 12, 24, 36, and 48, the proportion of children with GnRH-stimulated LH levels <5 IU/L were 92%, 94%, 93%, and 95%, respectively. At these same timepoints, 50%, 55%, 58%, and 55% of children, respectively, had GnRH-stimulated LH <2 IU/L.

Analysis of Girls Who Did Not Achieve GnRH-Stimulated LH <4 IU/L at Week 24

In the 7 girls that did not achieve stimulated LH <4 IU/L and completed the study, all 7 had effective pubertal suppression defined by lack of progression in pubertal staging (shown in Table 3) and had stable or decreased BA/CA from screening to week 48. Four and 6 girls had increased PAH from screening to week 24 and week 24–48, respectively. Four of these 7 girls had unstimulated LH <1 IU/L.

Table 3.

Efficacy measures in girls who did not achieve GnRH-stimulated LH <4 IU/L at week 24 (n = 7)

Table 3.

Efficacy measures in girls who did not achieve GnRH-stimulated LH <4 IU/L at week 24 (n = 7)

Close modal

Analysis of Girls Who Did Not Achieve E2 <10 pg/mL at Week 24

Other efficacy measures were also assessed for 6 girls who did not achieve E2 <10 pg/mL at week 24 (shown in Table 4). Mean GnRH-stimulated LH at week 24 was <4 IU/L for 4 of these girls (1.1, 1.5, 2.7, 1.9 IU/L) and 5.5 and 48.1 IU/L for the other 2. Both girls with GnRH stimulated LH >4 IU/L had unstimulated LH >1.0 IU/L and the girl with GnRH-stimulated LH >48 IU/L was discontinued from the study at week 14. All 5 remaining girls achieved GnRH-stimulated LH <4 IU/L, unstimulated LH <1.0 IU/L, and E2 <10 pg/mL at week 48. HV decreased for 1 girl, increased for 4 girls (their HV at week 24 and 48 were 4.3 and 13.0 cm/year, 6.5 and 6.9 cm/year, 4.3 and 4.8 cm/year, and 0.0 and 4.3 cm/year), and was not available for the remaining girl. For all 5 girls who did not achieve E2 <10 pg/mL at week 24 and completed the study, Tanner staging and BA/CA were stable compared to screening, and mean ± SE PAH increased by 1.7 ± 1.9 cm from screening to week 48. PAH SDS increased from −0.1 to 0.0 from screening to week 48.

Table 4.

Efficacy measures in girls who did not achieve E2 <10 pg/mL at week 24 (n = 6)

Table 4.

Efficacy measures in girls who did not achieve E2 <10 pg/mL at week 24 (n = 6)

Close modal

Safety

As described in the primary study [14], “injections of 45 mg subcutaneous leuprolide acetate administered every 24 weeks were well-tolerated. AEs did not result in withdrawal of any child from the study or discontinuation of study drug. TEAEs reported in ≥5% of the safety population included injection site pain (31%), nasopharyngitis (22%), pyrexia (17%), headache (16%), and cough (13%). All instances of injection site pain were mild (Grade 1). Other adverse reactions included emotional disorder (2%) and irritability (2%). Thirty-four percent of children experienced treatment-related AEs. No cases of sterile abscess were reported.”

Given the evidence of the utility of unstimulated LH concentrations for assessing treatment response [7], we conducted secondary analyses on our previously published data on small-volume 6-month subcutaneous leuprolide acetate treatment for CPP [14]. We observed that an unstimulated LH cutoff of 1.0 IU/L is an appropriate surrogate of pubertal suppression. Although an unstimulated LH cutoff of 1.0 IU/L is higher than what some previous publications have proposed (e.g., 0.3 [6], 0.6, or 0.83 IU/L), this threshold would still be useful and takes into account differences in assays, instruments, and other factors that impact unstimulated LH values. It should also be noted that unstimulated LH cutoffs may be higher for children over 8 years old compared to those under 8 years, as the mean age of children in this study was 7.5 years (range: 4–9) [14]. In aggregate, these data suggest that a cutoff for unstimulated LH of 1.0 IU/L is associated with adequate GnRH axis suppression in children treated with 6-month subcutaneous LA. ROC analyses also indicate that unstimulated LH is a good diagnostic tool for predicting peak GnRH-stimulated LH suppression <4 IU/L at weeks 24 and 48 (AUC = 0.88). A modest but significant degree of positive correlation between unstimulated and GnRH-stimulated LH at weeks 24 and 48 supports the use of unstimulated LH as a supplementary method to evaluate treatment response. However, the lack of significant correlation between LH concentrations and growth endpoints supports the need to use all clinical parameters when evaluating therapeutic efficacy, and not to solely rely on GnRH-stimulated LH concentrations or any other single variable. Clinical pubertal exams and decreases in the rate of bone maturation may be ultimately more important than absolute stimulated or unstimulated LH concentrations.

In the present analysis, all children who completed the clinical study had evidence of a slow down or regression of pubertal progression. Analyses of linear growth provided additional support for the effectiveness of subcutaneous LA at improving BA/CA ratios and increasing PAH. Although a 48-week treatment period is insufficient to fully determine the impact of treatment on linear growth, the high proportion of children with improved PAH (mean increase of 3 cm in height [0.2 SDS]) throughout the study suggests that taller long-term height outcomes might be seen with continued treatment. Consistent with some previous studies of other GnRHa therapies that reported increased BMI during treatment, chronological age-adjusted BMI z-scores increased here as well, albeit modestly by 0.1 from screening to week 48.

A crucial finding of this secondary analysis is that children in the three subgroups who did not achieve GnRH-unstimulated LH <1 IU/L, GnRH-stimulated LH <4 IU/L, and E2 <10 pg/mL, respectively, by week 24 were nonetheless clinically suppressed. The Cobas assay system used in the pivotal trial has been shown to overestimate LH concentrations [28], which might explain why only 87% of children achieved LH suppression <4 IU/L (94% achieved <5 IU/L) but 97% achieved E2 suppression <10 pg/mL [14]. Additionally, pubertal staging and BA/CA were stable in both subgroups of children who did not achieve unstimulated LH <1 IU/L at week 24 and girls with E2 <10 pg/mL at week 24. PAH also increased for the subgroup of 6 girls who did not achieve the exploratory efficacy endpoint of E2 <10 pg/mL at week 24.

Our study has significant strengths, including a large sample size, excellent retention of study subjects throughout the study duration, and centralized assay runs. The main limitation of the study is that it only represents a 1-year treatment period. Another noted weakness is the lack of use of a highly sensitive E2 assay that could detect concentrations as low as 2 pg/mL. Future studies should assess the use of such an E2 assay as a measure of clinical suppression in GnRHa agonist-treated children with CPP. Analysis of long-term, real-world data on endpoints such as BA, HV, and PAH should also be conducted to determine thresholds that indicate adequate clinical suppression of puberty.

Since the efficacy of GnRHa to increase PAH is clearly defined in girls with CPP younger than 6 years [2], future studies should consider stratifying the study sample according to age groups. The correlation between LH concentrations and secondary endpoints as well as the LH/FSH ratio (another useful diagnostic tool) should be considered for further studies. Future studies with larger sample size and adjusting for various confounding factors like age-related variability should confirm the promising results of the study.

These secondary analyses indicate that unstimulated LH has value as an efficacy measure and that concentrations <1 IU/L may be an adequate surrogate for GnRH-stimulated LH levels in children with CPP treated with 6-month subcutaneous LA. Additionally, after 1 year of treatment with 6-month subcutaneous LA, BA/CA decreased and PAH improved. During the 1-year study, the treatment had little to no effect on BMI. Overall, clinical and biochemical pubertal endpoints demonstrate good pubertal suppression in all children with CPP who completed the pivotal phase 3 trial using a 6-month preparation of a GnRHa agonist, including those who did not achieve GnRH-unstimulated LH <1 IU/L, GnRH-stimulated LH <4 IU/L, and E2 <10 pg/mL.

The authors would like to thank the children, families, investigators (Ximena Gaete, Jeanette Linares, Hernan Garcia, John Mitchell, Cheri Deal, Daniele Pacaud, Dardye Eugene, Elisa Lizbeth Davila Sotelo, David Jelley, Sara DiVall, Martha Taboada, Charumathi Baskaran, Mandi Cafasso, Paul Hofman, Esko Whilshire, Tony Walls) and their study coordinators and teams, and the Data and Safety Monitoring Board (Paul Kaplowitz, Philip Zeitler, Lawrence Silverman, Mitchell Geffner) for their participation in the clinical trial. Editorial support was provided by Xelay Acumen Group, Inc. All the authors have authorized the submission of their manuscript via Xelay Acumen Group, Inc. and have approved all statements and declarations, including conflicting interests and funding.

All study documents were approved by an Institutional Review Board or Independent Ethics Committee for each site prior to initiation of the study. All aspects of the study were conducted in accordance with International Council on Harmonisation Good Clinical Practice principles. Caregivers gave written informed consent and children gave assent, when applicable. The central study protocol was reviewed and approved by New England Independent Review Board, IRB #15-164. The study protocol was reviewed and approved by Ethics Committees at each of the participating sites.

All authors were principal investigators of the trial funded by Tolmar, Inc. but were not compensated for their contributions to this manuscript. Dr. Klein is a consultant for AbbVie, Arbor Pharmaceuticals, and Tolmar, Inc. Dr. Miller is a consultant for Ascendis Pharma, BioMarin, Bristol Myers Squibb, GeneScience, Novo Nordisk, Pfizer, Provention Bio, and Tolmar, Inc. and has received research support from Alexion, AbbVie, Aeterna Zentaris, Foresee Pharmaceuticals, Lumos Pharma, Novo Nordisk, Opko Health, Pfizer, Sangamo, and Tolmar, Inc. Dr. Mauras has received Institutional Research Support from AbbVie, Tolmar, Inc., and Novo Nordisk.

The study was funded by Tolmar, Inc. Study design, conduct of the study, and analysis and reporting were undertaken by Jack McLane, Ryan Tooker, Kerlin Lynch, and other employees of Tolmar, Inc. Editorial support was provided Xelay Acumen Group, Inc. (funded by Tolmar, Inc.).

Karen O. Klein, Bradley S. Miller, and Nelly Mauras: conceptualization; writing; review and editing; being principal investigators of the trial; contributing to the study analysis and reporting.

The data that support the findings of this study are available from the corresponding author upon reasonable request. Restrictions apply to the availability of data generated or analyzed during this study to preserve patient confidentiality or because they were used under license. The corresponding author K.O.K. [kklein@ucsd.edu] will on request detail the restrictions and any conditions under which access to some data may be provided.

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