Editor’s Choice: Review
Pediatric Drug Development Programs for Type 2 Diabetes: A Review
The Journal of Clinical Pharmacology 2015, 55(7) 731–738 © 2015, The American College of Clinical Pharmacology DOI: 10.1002/jcph.497
Michael L. Christensen, PharmD1, Brandi E. Franklin, PhD1, Jeremiah D. Momper, PharmD, PhD2, and Michael D. Reed, PharmD, FCCP, FCP3
Abstract Considerable progress has been made in pediatric drug development. Despite these gains there remain certain therapeutic areas where a high percentage of drugs approved for use in adults do not gain approval for use in children. Lack of sufficient US Food and Drug Administration (FDA)– approved labeling correlates with diminished therapeutic efficacy and increased risk for adverse drug reactions. Despite the increasing prevalence and important clinical challenge with pediatric type 2 diabetes mellitus (T2DM), only 1 drug (metformin) of the first 4 T2DM drugs to complete testing in children gained FDA approval. This analysis reviews 4 pediatric drug development programs for orally administered antidiabetic agents that have undergone FDA review and discusses factors influencing failure to meet specified end points for approval. Recommendations to guide future study are also provided.
Keywords type 2 diabetes mellitus, adolescents, clinical trial design
Considerable progress has been made in pediatric drug development over the past 2 decades.1 Unfortunately there are a number of therapeutic areas in which a high percentage of drugs approved for use in adults have failed to gain US Food and Drug Administration (FDA) approval for use in children. Drug development in children has been particularly difficult when the underlying pathophysiology differs between adult and pediatric patients. Type 2 diabetes mellitus (T2DM) is an example of a disease for which there are important differences in drug response. The prevalence of T2DM in youth has increased markedly in the past 2 decades, fueled in part by a parallel rise in childhood obesity.2,3 According to the most recent estimates, the prevalence of T2DM in 2009 was estimated at more than 20,000, an increase of 30% over estimates in 2001.3 The average age of onset is 13.7 years. Although the pathophysiology of T2DM has been extensively studied in adults, comparatively little research has been conducted in children. Notable differences between children and adults include: [1] children have a higher body mass index (BMI) than their adult counterparts, causing greater insulin resistance4; [2] children have a shorter latency period and lower glycated hemoglobin (HbA1C), in part because there is less time for the development of glucose dysregulation4–7; and [3] children have a higher incidence of ketoacidosis and glucose toxicity at diagnosis.4,6–9 Despite the large number of pharmacologic agents available to treat T2DM in adults, the FDA has approved only metformin
and insulin for use in children. This is reflected in the current clinical guidelines for treatment of T2DM.10 The objective of this analysis is to review oral antidiabetic agents that have completed pediatric drug development programs and undergone FDA review.
Methods We extracted and summarized data from FDA medical and clinical pharmacology reviews, product labels, and other published studies for 4 orally administered antidiabetic agents (metformin, glimepiride, metformin/glyburide, rosiglitazone) that had completed pediatric drug development programs through 2013. Drugs that received FDA
1 Department of Clinical Pharmacy and the Center for Pediatric Pharmacokinetics and Therapeutics, University of Tennessee Health Science Center, Memphis, TN, USA 2 Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA 3 The Division of Clinical Pharmacology and Toxicology and the Rebecca D. Considine Research Institute, Akron Children’s Hospital, Akron, OH, USA
Submitted for publication 13 February 2015; accepted 12 March 2015. Corresponding Author: Michael Christensen, PharmD, Professor, Department of Clinical Pharmacy, University of Tennessee Health Science Center, 881 Madison Avenue, Room 342, Memphis, TN 38163 Email: [email protected]
732 approval for pediatric use were classified as successful, and drugs that did not receive FDA approval for pediatric use were classified as failures.
Results Four orally administered drugs have been evaluated by the FDA for pediatric use in T2DM. Table 1 summarizes the completed trials, describing their study design, patient population, dosing, end points, and results. Studies enrolled an average of 180 patients (range, 82–272) aged 8–17 years. The agents studied include a biguanide (metformin), a sulfonylurea (glimepiride), a thiazolidinedione (rosiglitazone), and a combination agent (metformin/glyburide). After review of completed clinical trials, only metformin received approval for use in pediatric patients with T2DM. Each of the 4 agents also included pharmacokinetic (PK) data in their submissions; reported PK parameters for each agent are shown in Table 2. Biguanides Biguanides are pharmacologically unique from all other classes of oral antidiabetic agents. Their mechanism of action is still unclear, but they primarily reduce hepatic glucose production and intestinal absorption of glucose. These actions improve peripheral glucose uptake and utilization and increase insulin sensitivity. Unlike sulfonylureas, biguanides are not typically associated with hypoglycemia or hyperinsulinemia because they do not affect insulin output. Metformin. The pediatric metformin drug development program included a PK study and an efficacy and safety study.11 The metformin PK study included 32 subjects aged 12–16 years; PK were determined after 1 week of metformin 500 mg twice daily. Blood and urine samples were obtained over an 11-hour period. Area under the plasma concentration–time curve (AUC), peak plasma concentration (Cmax), and elimination half-life (t1/2) values for metformin were 4.49 mg h/mL, 0.73 mg/ mL, and 3.7 hours, respectively. System drug exposure (metformin AUC) in children was only 54% of that reported in adults with the same dosing; however, nonadherence was suspected in the pediatric study. A subsequent study of single-dose metformin pharmacokinetics in patients 12 to 16 years of age showed less than a 5% difference in Cmax, AUC, and half-life when compared with healthy adult subjects.12 The metformin pediatric T2DM efficacy and safety study was a 16-week randomized, multicenter, doubleblind, placebo-controlled trial comprising 82 children aged 10–16 years. The primary outcome was change in fasting plasma glucose (FPG) from baseline to the last study visit at or before week 16, with secondary measures of HbA1c, body weight, and plasma lipids. The study also
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included a subsequent open-label safety extension through 52 weeks. Pediatric subjects with T2DM and aged 8–16 years at screening were eligible, provided they had a FPG between 126 and 240 mg/dL, an HbA1c 7%, stimulated Cpeptide 1.5 ng/mL, and BMI > 50th percentile for age. Patients were excluded if they had any type 1 diabetes markers, recent treatment with another oral antidiabetic agent, known study drug hypersensitivity, renal or hepatic issues, abnormal creatinine clearance, or other serious conditions that could affect study participation. After screening, patients were randomized to metformin (n ¼ 42) or placebo (n ¼ 40). Average weight at baseline was 91.6 kg. Metformin was administered at 500 mg twice daily at initiation and then titrated at weekly intervals to 1000 mg twice daily as tolerated if FPG exceeded 126 mg/dL. Placebo was administered in a similar fashion. Rescue therapy (insulin for metformin group or metformin for placebo group) was administered if FPG exceeded predetermined thresholds in weeks 2 (230 mg/dL), 4 (180 mg/dL), or 6 and beyond (140 mg/dL). By study end, 83% of metformin patients and 78% of placebo patients were on the maximum daily dose (2000 mg). A small cohort of patients was analyzed after 8 weeks of treatment, per protocol, to determine interim FPG outcomes. Following the recommendation of the data safety and monitoring board, the FDA approved early termination of the blinded period as predetermined criteria for the primary outcome had been met (FPG reduction, P < .025). At the end of double-blind therapy, adjusted mean change in FPG from baseline was -43 and 21 mg/dL for metformin and placebo patients, respectively. The adjusted mean difference in FPG (metforminplacebo) was 64 mg/dL (P < .001). Rescue therapy was administered to 9% and 65% of metformin and placebo subjects, respectively. HbA1c levels decreased in metformin subjects but remained unchanged in placebo subjects (P < .0001). Placebo-adjusted reduction in total plasma cholesterol (10.4 mg/dL, P ¼.043) was statistically significant, as was change in total cholesterol from baseline (-9.7 mg/dL; CI, 2.7–16.6 lmg/dL) for metformin. Weight loss occurred for both groups, but metformin patients lost more (1.5 vs 0.9 kg). During the open-label period, patients initially randomized to placebo experienced FPG reductions on metformin that mirrored the double-blind period. HbA1c, weight, and BMI also fell. Conversely, FPG levels in patients initially randomized to metformin trended upward toward baseline levels. HbA1c, weight, and BMI also nearly reached baseline values by the end of the open-label period. Gastrointestinal events were reported by 43% of metformin patients and 30% of placebo patients during the blinded period. Other common adverse events
Biguanide
Sulfonylurea
Thiazolidinedione
Biguanide/ sulfonylurea
Metformin
Glimepiride
Rosiglitazone
Metformin/ glyburide
Randomized, doubleblind, activecontrolled, efficacy and safety (24 weeks) Randomized, doubleblind, 3-arm, activecontrolled, efficacy and safety (26 weeks)
9–16 years, n ¼ 167
Randomized, doubleblind, placebocontrolled, efficacy and safety (16 weeks, open-label extension through week 52) Randomized, singleblind, activecontrolled, efficacy and safety (24 weeks)
Study Design
10–17 years, n ¼ 200
8–17 years, n ¼ 272
10–16 years, n ¼ 82
Age Range, Number Enrolled
Glim: 1 mg daily (titrate up to 2, 4, 8 mg if FPG > 126 mg/dL) Met: 500 mg twice daily (titrate up to 1000 mg twice daily if FPG > 126 mg/dL)
P: D HbA1c, 24 weeks; noninferiority S: D HbA1c, 12 weeks; % HbA1c < 7%, 24 weeks; D FPG at 4, 8, 12, 18, 24 weeks; D body weight, BMI P: D HbA1c, 24 weeks; noninferiority
P: D HbA1c, 26 weeks; superiority
500 mg twice daily, titrated up to 1000 mg twice daily if FPG >126 mg/dL
P: D FPG S: D HbA1c, body weight, serum lipids
Ros: 2 mg twice daily (titrate up to 4 mg twice daily if FPG > 126 mg/dL) Met: 500 mg twice daily (titrate up to 1000 mg twice daily if FPG > 126 mg/dL) Met/Gly: 250/1.25 mg Met: 500 mg Gly: 2.5 mg (all agents titrated if FPG > 126 mg/dL)
Study Dose(s)
End Point(s)
Pediatric Trial Characteristics
FPG, fasting plasma glucose; Glim, glimepiride; Gly, glyburide; Met, metformin; P, primary; Ros, rosiglitazone; S, secondary. Study resulted in FDA approval/labeling for use in children.
Drug Class
Agent
Table 1. Study Characteristics, Agents Evaluated for Pediatric Type 2 Diabetes
Change in HbA1c, -0.8% (Met/Gly), -0.48% (Met), -0.96% (Gly) Mean differences vs Met/Gly insignificant
Mean difference in HbA1c (RosMet), -0.28%. Noninferiority test failed. Study lacked adequate power.
Mean difference in HbA1c (GlimMet), 0.44% Noninferiority test failed
Mean difference in FPG (Metplacebo), 64 mg/dL Mean difference in HbA1c, -1.2%. Results favored metformin
Results
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Table 2. Pharmacokinetic Parameters, Agents Evaluated for Pediatric Type 2 Diabetes Pharmacokinetic Parameters Agent Metformin Glimepiride Rosiglitazone Metformin/glyburide
Design
Dose (mg) 1000 1 2/4 250/1.25
Cmax (ng/mL) 730 102.4 — 473/41.3
Tmax (h) 2.0 1.0 1.5 21
AUC (ng h/mL) 4490 338.8 1520/3040 3011/167
t1/2 (h) 3.7 — — 4.17/6.82
CL/F (L/h)
V/F (L)
Similarity to Adult Data
13.7 13.5 —
No Yes Yes Yes
a
648.0 58.6 3.15 ——
a
Estimate is for renal clearance (CLR), in milliliters per minute.
reported during the study included respiratory infections and headache. On the basis of these results, the FDA approved metformin for use in pediatric patients with T2DM as an adjunct to diet and exercise to improve glycemic control. Sulfonylureas Sulfonylureas reduce blood sugar by stimulating insulin release from pancreatic beta cells. This effect is predominantly based on improved responsiveness of these cells to the physiological glucose stimulus. Sulfonylureas augment the normal action of insulin on peripheral glucose uptake and can be used alone or in combination with metformin or insulin. Glimepiride. Glimepiride is indicated in adults to treat T2DM when blood glucose concentrations cannot be controlled adequately by diet, physical exercise, and weight reduction alone. The pediatric T2DM glimepiride drug development program included a PK study and an efficacy and safety study13; the glimepiride PK study included 30 subjects. Pharmacokinetic parameters were determined following administration of a 1-mg dose after breakfast and included the glimepiride AUC and Cmax values reported as 338.8 ng h/mL and 102.4 ng/mL, respectively. Median time to reach peak plasma concentration (Tmax) was 1 hour. Negative correlations of drug clearance with age and weight were reported but were not sufficiently significant to justify dosing adjustments. Overall, pediatric PK parameters were comparable to adult data. Glimepiride’s efficacy and safety were evaluated in a 24-week randomized, multicenter, single-blind, activecontrolled (metformin) trial involving 272 children aged 8–17 years. The primary end point was change in HbA1c at 24 weeks. Noninferiority (NI) was also evaluated using a margin of 0.3% units. Other end points included change in HbA1c at 12 weeks, percentage of subjects with HbA1c < 7% at 24 weeks, and change in self-monitored blood glucose at weeks 4, 8, 12, 18, and 24. Eligibility criteria for the study included age 8–17 years, T2DM diagnosis, negative test results for glutamic acid decarboxylase (GAD) and anti-islet cell autoantibodies, and a stimulated c-peptide 1.5 ng/mL. HbA1c
levels for inclusion were 7%–12% (treatment naive) or >7.5% (on treatment with a single agent > 3 months). Initial dosing at randomization was 1 mg once daily and 500 mg twice daily for glimepiride and metformin, respectively. The glimepiride dose was titrated up (2, 4, or 8 mg) at weeks 4, 8, and 12 if FPG exceeded 126 mg/dL. Metformin was titrated up to 1000 mg twice daily at 12 weeks using the same criteria. Close to half of all study participants had previously used an antidiabetic agent prior to enrollment. The intent-to-treat analysis included 253 children: 127 received glimepiride and 126 received metformin. Average weight at baseline was 83 kg. At 24 weeks, HbA1c fell in both groups. Efficacy favored metformin, although not significantly. Glimepiride failed the noninferiority test with a difference from metformin of 0.44% units. Treatment-related serious adverse events occurred in 5% and 4% of patients on glimepiride and metformin, respectively. Glimepiride patients gained, on average, 1.3 kg. Patients receiving metformin had no change in body weight. Hypoglycemic episodes (blood glucose < 36 mg/dL) occurred in 4% of glimepiride patients and 1% of metformin patients. The FDA did not approve glimepiride for use in children, noting lack of efficacy and disadvantageous weight gain as factors in their decision. Thiazolidinediones Thiazolidinediones (TZDs) reduce insulin resistance through transactivation of peroxisome proliferator-activated receptors (PPARs), specifically PPARg. Thiazolidinediones also increase the synthesis of certain proteins involved in fat and glucose metabolism, which reduces levels of certain types of lipids and circulating free fatty acids. Rosiglitazone. Rosiglitazone was evaluated in pediatric patients with T2DM. The pediatric rosiglitazone drug development program included a PK study and an efficacy and safety study. A population PK study was conducted using a subset of randomized patients from the clinical study (n ¼ 96). Pharmacokinetics of rosiglitazone were evaluated following administration of a single dose of 2 or 4 mg. Tmax, oral clearance (CL/F), and oral volume of distribution (V/F) were 1.5 hours, 3.15 L/h, and 13.5 L,
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respectively. Predicted rosiglitazone AUC based on twice daily doses of 2 and 4 mg were 1520 and 3040 ng h/mL, respectively, reflecting linear disposition. Pediatric PK parameters were found to be consistent with adult population data. The safety and efficacy study, a 24-week randomized, multicenter, double-blind, active-controlled (metformin) trial, comprised 200 children aged 10–17 years. A 4-week placebo run-in period with diet counseling preceded randomization. The primary outcome was change in HbA1c, with a secondary noninferiority comparison of change in HbA1c from baseline. The study was inadequately powered to detect a mean difference in HbA1c effects between rosiglitazone and metformin < 0.4% (a priori determination of a clinically meaningful effect). Initial eligibility criteria at screening included aged 8– 17 years with T2DM, HbA1c 7.1%–10%, negative for type 1 diabetes (GAD, 1CA512 autoantibodies, stimulated C-peptide), and no previous pharmacologic therapy. The lower threshold for HbA1c was reduced to 6.5%, and prior treatment criteria were relaxed prior to enrollment. Patients were randomized to rosiglitazone (n ¼ 99) or metformin (n ¼ 101). Average weight at baseline was 90 kg. Initial dosing at randomization was 2 mg twice daily and 500 mg twice daily for rosiglitazone and metformin, respectively. The dose of each medication was doubled at 8 weeks based on FPG concentration > 126 mg/dL. Dose escalation occurred in nearly half the study patients for each drug. The intent-to-treat analysis included 194 patients (96 rosiglitazone, 98 metformin). At 24 weeks, the average change in HbA1c from baseline was -0.14% and -0.49% for rosiglitazone and metformin, respectively. The mean difference in effects was 0.28% (95%CI, -0.16–0.72). Because the upper bound of the confidence interval exceeded the prospectively determined threshold of 0.4% for clinical significance, rosiglitazone failed to establish noninferiority. Results of outcomes for FPG were similar, favoring metformin. An analysis of the subgroup of treatment-naive patients produced similar findings. In both the full group and treatment-naive subgroup, changes in HbA1c and FPG from baseline were small and statistically insignificant. Adverse events reported by study patients included weight gain, anemia, increased plasma lipid parameters, edema, congestive heart failure, and other cardiovascular events. Rosiglitazone was associated with more weight gain than metformin (2.7 vs 0.3 kg). Serious adverse events totaled 1 and 6 for the rosiglitazone and metformin groups, respectively. Hypoglycemia rarely occurred during the study; only 2 cases were reported (both with metformin). Owing to modest glucose lowering (relative to metformin) and weight gain, rosiglitazone was not approved for pediatric use.
735 Combination Agents Given its efficacy, low incidence of hypoglycemia, and neutral effects on weight, metformin is often formulated as a fixed-dose combination with agents of other classes including sulfonylureas, DPP-4 inhibitors, meglitinides, and TZDs. Combination agents enhance glucose lowering while reducing pill burden. A pediatric drug development program has been conducted for a combination product containing metformin and the sulfonylurea glyburide; the mechanisms of action of each component have been previously described. Metformin/Glyburide. The pediatric drug development program for the metformin/glyburide combination included a PK study and an efficacy and safety study (#NCT00035542, ClinicalTrials.gov). The PK study included 28 participants aged 10–16 years. Following administration of a single 1.25/250 mg dose of metformin/ glyburide, blood samples were collected at selected time points over a 24-hour period. Geometric mean values for AUC, Cmax, and Tmax for glyburide were 167 ng h/mL, 41.3 ng/mL, and 1 hour and for metformin were 3011 ng h/mL, 473 ng/mL, and 2 hours, respectively. When compared with similarly dosed adults, pediatric PK parameters for the metformin/glyburide combination varied by less than 6%. The efficacy and safety study was a 26-week, randomized, multicenter, 3-arm, double-blind, activecontrolled (metformin and glyburide) trial involving 167 patients aged 9–16 years. The primary efficacy end point was change in HbA1c from baseline to week 26. A superiority comparison of glyburide/metformin to each of the monotherapies was included. Eligibility criteria for pediatric patients aged 9–16 years with T2DM varied based on previous drug use. At screening, treatment-naive patients had to have an HbA1c between 6.4% and 14%, then after a 1-week lead in, a mean fasting glucose (MFG) < 350 mg/dL. Previously treated patients had to have an HbA1c between 6.4% and 9% and after a variable 2–4 week washout, a MFG between 200 and 350 mg/dL. Patients were randomized to 1 of 3 treatment arms: metformin/glyburide (250/1.25 mg), metformin (500 mg), or glyburide (2.5 mg). Average weight at baseline in each arm was 80.1, 79.7, and 78.9 kg, respectively. The protocol for dose escalation was not described, but the mean final dose for each of the arms was 623/3.1, 1500, and 6.5 mg for the metformin/glyburide, metformin, and glyburide arms respectively. The intent-to-treat analysis included 160 subjects (metformin/glyburide, n ¼ 57; metformin, n ¼ 54; glyburide, n ¼ 49). Adjusted mean change in HbA1c from baseline was -0.80%, -0.48%, and -0.96% for the metformin/glyburide, metformin, and glyburide groups, respectively. None of these changes were statistically significant. Therefore, metformin/glyburide failed to
736 demonstrate superiority over metformin or glyburide therapies. Outcomes for FPG were similar. Overall, pediatric study results varied from the adult efficacy trials. These discrepancies were attributed to a lack of patients with baseline HbA1c > 9% and enrollment of patients with previous treatment exposure. As for safety, adverse events were experienced similarly across groups. Patients on metformin gained less weight than those in the other groups. On the basis of these results, metformin/glyburide did not receive FDA approval for pediatric use.
Discussion This review summarizes results of 4 pediatric drug development programs for T2DM. Each agent achieved reductions in glycemic parameters; however, 3 of 4 failed to reach the threshold efficacy relative to their control(s) to gain FDA approval. The lack of constancy of effect from adult to pediatric trials underscores the important need for further examination. Nonetheless, these studies do provide key insights that may help to explain the high pediatric failure rate among these agents. We believe elucidating the influence of these elements on trial outcomes can strengthen future development programs. Reviewed trials varied by type of study design. The metformin trial, first among our review, was the only placebo-controlled study. With metformin’s safety and efficacy established, future pediatric trials could no longer use placebo controls (despite continued use in adult studies). Active-control NI (rosiglitazone, glimepiride) or superiority (metformin/glyburide) designs were employed in remaining pediatric studies. Superiority and NI trials differ methodologically; the former seeks to find a difference between treatment and control, whereas the latter aims to show that a new treatment is not worse than the active control by more than a predetermined margin.14 The design and interpretation of NI trials is complicated, as they rely on an assumption of assay sensitivity, selection of an NI margin that reflects the clinical value of the treatment, and high study quality.15 Assay sensitivity, the ability of a trial to distinguish treatment effects, is difficult to affirm without a placebo arm or historical data (in a similar population) to distinguish the effect of the active control from the placebo. Larger sample sizes are needed to achieve adequate power to detect small differences in effect. In the rosiglitazone trial, inadequate power was cited. Further, certain study quality factors can bias results toward the null hypothesis. In the case of the antidiabetic drug trials, poor compliance (metformin), use of concurrent antidiabetic therapies (rosiglitazone), and inadequate washout periods were noted. Finally, when an active control is very effective, establishing NI becomes more challenging.
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Unique differences in the patient populations recruited for the adult and pediatric trials invalidate assumptions of constancy of effect. In the rosiglitazone trial, pediatric study subjects had similar HbA1c values but much lower FPG levels than their adult counterparts in the historical trials. In the case of metformin/ glyburide, adult studies revealed that the drug’s effects were greatest in patients with baseline HbA1c > 9%. However, HbA1c was lower, on average, at baseline in pediatric patients (7.7%–8%). These data reflect the notable distinctions in T2DM between adolescents and adults previously cited. Accelerated onset of T2DM in children (relative to adults) could denote a more aggressive disease course that responds differently to therapeutic interventions. With the exception of metformin, the inclusion of children with previous exposure to oral agents was necessary to achieve enrollment targets but problematic. Patients receiving oral T2DM therapy were required to discontinue current diabetes medications prior to randomization to study treatments. However, to enforce a run-in period sufficient for reestablishing baseline glycemic levels in these patients would have been ethically inappropriate. As a result, the run-in period in these trials was brief or nonexistent. Not surprisingly, several studies cited differences in effect between drugnaive and previously exposed patients. We speculate that the inclusion of previously exposed patients in subsequent studies may explain, in part, the variable efficacy of metformin across studies. Elucidating the effects of new therapies in children with prior exposure to antidiabetic agents has important implications for optimizing treatment. Study results from the metformin open-label extension also warrant further comment. During the open-label extension, patients initially randomized to placebo experienced similar reductions in FPG after 16 weeks with metformin. However, FPG in the initial metformin cohort gradually returned toward baseline values. In the FDA review, it was suggested that compliance might have been a cause. This assertion was based on PK data comparisons in which pediatric subjects had reduced exposure versus adults, resulting possibly from lower absorption and higher renal clearance. Attenuation of effect for metformin has been cited in previous large-scale trials and raises serious concerns about long-term outcomes in this population.16,17 Pediatric drug development remains an important issue, both in the United States and abroad. Pharmacotherapeutic options are scant in other developed countries (eg, Canada, Europe, Japan) despite similar rising trends in the incidence of pediatric T2DM.18,19 In 2008, the FDA issued draft guidance for the development and testing of therapeutic agents to treat and prevent T2DM in the pediatric population.20 As evidenced from the reviewed
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Christensen et al Table 3. Pediatric Drug Development Among Newer T2DM Drugs, by Treatment Class Diabetes Treatment Class Oral Treatments DDP-4 inhibitors
SGLT2 antagonists
Combination oral treatments Biguanide þ DPP-4 Injectable treatments Incretins Amylin analogues
Generic Name
Date of FDA Approval
Sponsor Studies in clinicaltrials.gov
Sitagliptin Saxagliptin Linagliptin Alogliptin Canagliflozin Dapagliflozin Empagliflozin
2006 2009 2011 2013 2013 2014 2014
PK PK PK, SE PK PK PK PK
Metformin þ sitagliptin
2007
—
Exenatide Liraglutide Pramlintide
2005 2010 2007
PK, SE SE —
DPP-4, dipeptidyl-peptidase-IV; FDA, US Food and Drug Administration; PK, pharmacokinetic; SE, safety/efficacy; SGLT2, sodium-glucose co-transporter 2
trials, additional development and research are needed to fully elucidate the efficacy and safety of oral antidiabetic drugs in pediatric patients with T2DM. The dearth of approved oral agents for pediatric T2D treatment, coupled with the limited effectiveness of lifestyle management in this population, impedes efforts to enhance glycemic control.17,21 Although off-label use of other agents is likely, little is known about its impact on safety and outcomes. Future pediatric development programs should consider alternate designs to establish efficacy to enhance approval status. Given the high prevalence of previous exposure to antidiabetic agents among study subjects in the trials, add-on or dose–response designs may be more appropriate. The recently completed TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study demonstrated the effectiveness of rosiglitazone in combination with metformin to sustain glycemic control.22 The application of such evidence is limited, however, as rosiglitazone is not FDA-approved for use in pediatric T2DM. Even so, several new classes of T2DM drugs have been developed since the completion of reviewed pediatric drug development programs (Table 3); many of these newer agents have ongoing or recently completed pediatric trials listed in the National Institutes of Health clinical trials registry (clinicaltrials.gov). . These studies may yield promising new options for pediatric T2DM treatment. Finally, incentives connected to the FDA’s pediatric exclusivity program should be realigned to encourage enhancements in study quality. Acknowledgments The authors thank Drs Gilbert Burckart and Yeruk Mulugeta for their review and suggestions on the article.
Declaration of Conflicting Interests The authors have no financial conflicts of interest to disclose.
Funding There was no financial support for this article.
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738 11. Jones KL, Arslanian S, Peterokova VA, Park JS, Tomlinson MJ. Effect of metformin in pediatric patients with type 2 diabetes: a randomized controlled trial. Diabetes Care. 2002;25(1):89–94. 12. Gao X, Christensen M, Burghen GA, et al. Pharmacokinetics of Metformin in Pediatric Type 2 Diabetic and Healthy Adult Subjects. Clin Pharmacol Ther. 2003;73(2):P46–P46. 13. Gottschalk M, Danne T, Vlajnic A, Cara JF. Glimepiride versus metformin as monotherapy in pediatric patients with type 2 diabetes: a randomized, single-blind comparative study. Diabetes Care. 2007;30(4):790–794. 14. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). Guidance for Industry, Non-Inferiority Clinical Trials. Institution; March 2010. 15. D’Agostino RB, Sr., Massaro JM, Sullivan LM. Non-inferiority trials: design concepts and issues — the encounters of academic consultants in statistics. Stat Med. 2003;22(2):169–186. 16. Diabetes Control and Complications Trial Research Group. Effect of intensive diabetes treatment on the development and progression of long-term complications in adolescents with insulin-dependent diabetes mellitus: Diabetes Control and Complications Trial. J Pediatr. 1994;125(2):177–188. 17. Zeitler P, Epstein L, Grey M, et al. Treatment options for type 2 diabetes in adolescents and youth: a study of the comparative
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efficacy of metformin alone or in combination with rosiglitazone or lifestyle intervention in adolescents with type 2 diabetes. Pediatr Diabetes. 2007;8(2):74–87. Panagiotopoulos C, Riddell M, Sellers E. Canadian Diabetes Association 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada: Type 2 Diabetes in Children and Adolescents. Can J Diabetes. 2013; 37(suppl 3): S341–S342. Alberti G, Zimmet P, Shaw J, Bloomgarden Z, Kaufman F, Silink M. Type 2 diabetes in the young: the evolving epidemic. The International Diabetes Federation Consensus Workshop. Diabetes Care. 2004;27(7):1798–1811. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Division of Metabolism and Endocrinology Products. Guidance for Industry, Diabetes Mellitus: Developing Drugs and Therapeutic Biologics for Treatment and Prevention. Institution; February 2008. Kane MP, Abu-Baker A, Busch RS. The utility of oral diabetes medications in type 2 diabetes of the young. Curr Diabetes Rev. 2005;1(1):83–92. Zeitler P, Hirst K, Pyle L, et al. A clinical trial to maintain glycemic control in youth with type 2 diabetes. N Engl J Med. 2012;366(24):2247–2256.
Pediatric Drug Development Programs for Type 2 Diabetes: A Review
The Journal of Clinical Pharmacology 2015, 55(7) 731–738 © 2015, The American College of Clinical Pharmacology DOI: 10.1002/jcph.497
Michael L. Christensen, PharmD1, Brandi E. Franklin, PhD1, Jeremiah D. Momper, PharmD, PhD2, and Michael D. Reed, PharmD, FCCP, FCP3
Abstract Considerable progress has been made in pediatric drug development. Despite these gains there remain certain therapeutic areas where a high percentage of drugs approved for use in adults do not gain approval for use in children. Lack of sufficient US Food and Drug Administration (FDA)– approved labeling correlates with diminished therapeutic efficacy and increased risk for adverse drug reactions. Despite the increasing prevalence and important clinical challenge with pediatric type 2 diabetes mellitus (T2DM), only 1 drug (metformin) of the first 4 T2DM drugs to complete testing in children gained FDA approval. This analysis reviews 4 pediatric drug development programs for orally administered antidiabetic agents that have undergone FDA review and discusses factors influencing failure to meet specified end points for approval. Recommendations to guide future study are also provided.
Keywords type 2 diabetes mellitus, adolescents, clinical trial design
Considerable progress has been made in pediatric drug development over the past 2 decades.1 Unfortunately there are a number of therapeutic areas in which a high percentage of drugs approved for use in adults have failed to gain US Food and Drug Administration (FDA) approval for use in children. Drug development in children has been particularly difficult when the underlying pathophysiology differs between adult and pediatric patients. Type 2 diabetes mellitus (T2DM) is an example of a disease for which there are important differences in drug response. The prevalence of T2DM in youth has increased markedly in the past 2 decades, fueled in part by a parallel rise in childhood obesity.2,3 According to the most recent estimates, the prevalence of T2DM in 2009 was estimated at more than 20,000, an increase of 30% over estimates in 2001.3 The average age of onset is 13.7 years. Although the pathophysiology of T2DM has been extensively studied in adults, comparatively little research has been conducted in children. Notable differences between children and adults include: [1] children have a higher body mass index (BMI) than their adult counterparts, causing greater insulin resistance4; [2] children have a shorter latency period and lower glycated hemoglobin (HbA1C), in part because there is less time for the development of glucose dysregulation4–7; and [3] children have a higher incidence of ketoacidosis and glucose toxicity at diagnosis.4,6–9 Despite the large number of pharmacologic agents available to treat T2DM in adults, the FDA has approved only metformin
and insulin for use in children. This is reflected in the current clinical guidelines for treatment of T2DM.10 The objective of this analysis is to review oral antidiabetic agents that have completed pediatric drug development programs and undergone FDA review.
Methods We extracted and summarized data from FDA medical and clinical pharmacology reviews, product labels, and other published studies for 4 orally administered antidiabetic agents (metformin, glimepiride, metformin/glyburide, rosiglitazone) that had completed pediatric drug development programs through 2013. Drugs that received FDA
1 Department of Clinical Pharmacy and the Center for Pediatric Pharmacokinetics and Therapeutics, University of Tennessee Health Science Center, Memphis, TN, USA 2 Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA 3 The Division of Clinical Pharmacology and Toxicology and the Rebecca D. Considine Research Institute, Akron Children’s Hospital, Akron, OH, USA
Submitted for publication 13 February 2015; accepted 12 March 2015. Corresponding Author: Michael Christensen, PharmD, Professor, Department of Clinical Pharmacy, University of Tennessee Health Science Center, 881 Madison Avenue, Room 342, Memphis, TN 38163 Email: [email protected]
732 approval for pediatric use were classified as successful, and drugs that did not receive FDA approval for pediatric use were classified as failures.
Results Four orally administered drugs have been evaluated by the FDA for pediatric use in T2DM. Table 1 summarizes the completed trials, describing their study design, patient population, dosing, end points, and results. Studies enrolled an average of 180 patients (range, 82–272) aged 8–17 years. The agents studied include a biguanide (metformin), a sulfonylurea (glimepiride), a thiazolidinedione (rosiglitazone), and a combination agent (metformin/glyburide). After review of completed clinical trials, only metformin received approval for use in pediatric patients with T2DM. Each of the 4 agents also included pharmacokinetic (PK) data in their submissions; reported PK parameters for each agent are shown in Table 2. Biguanides Biguanides are pharmacologically unique from all other classes of oral antidiabetic agents. Their mechanism of action is still unclear, but they primarily reduce hepatic glucose production and intestinal absorption of glucose. These actions improve peripheral glucose uptake and utilization and increase insulin sensitivity. Unlike sulfonylureas, biguanides are not typically associated with hypoglycemia or hyperinsulinemia because they do not affect insulin output. Metformin. The pediatric metformin drug development program included a PK study and an efficacy and safety study.11 The metformin PK study included 32 subjects aged 12–16 years; PK were determined after 1 week of metformin 500 mg twice daily. Blood and urine samples were obtained over an 11-hour period. Area under the plasma concentration–time curve (AUC), peak plasma concentration (Cmax), and elimination half-life (t1/2) values for metformin were 4.49 mg h/mL, 0.73 mg/ mL, and 3.7 hours, respectively. System drug exposure (metformin AUC) in children was only 54% of that reported in adults with the same dosing; however, nonadherence was suspected in the pediatric study. A subsequent study of single-dose metformin pharmacokinetics in patients 12 to 16 years of age showed less than a 5% difference in Cmax, AUC, and half-life when compared with healthy adult subjects.12 The metformin pediatric T2DM efficacy and safety study was a 16-week randomized, multicenter, doubleblind, placebo-controlled trial comprising 82 children aged 10–16 years. The primary outcome was change in fasting plasma glucose (FPG) from baseline to the last study visit at or before week 16, with secondary measures of HbA1c, body weight, and plasma lipids. The study also
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included a subsequent open-label safety extension through 52 weeks. Pediatric subjects with T2DM and aged 8–16 years at screening were eligible, provided they had a FPG between 126 and 240 mg/dL, an HbA1c 7%, stimulated Cpeptide 1.5 ng/mL, and BMI > 50th percentile for age. Patients were excluded if they had any type 1 diabetes markers, recent treatment with another oral antidiabetic agent, known study drug hypersensitivity, renal or hepatic issues, abnormal creatinine clearance, or other serious conditions that could affect study participation. After screening, patients were randomized to metformin (n ¼ 42) or placebo (n ¼ 40). Average weight at baseline was 91.6 kg. Metformin was administered at 500 mg twice daily at initiation and then titrated at weekly intervals to 1000 mg twice daily as tolerated if FPG exceeded 126 mg/dL. Placebo was administered in a similar fashion. Rescue therapy (insulin for metformin group or metformin for placebo group) was administered if FPG exceeded predetermined thresholds in weeks 2 (230 mg/dL), 4 (180 mg/dL), or 6 and beyond (140 mg/dL). By study end, 83% of metformin patients and 78% of placebo patients were on the maximum daily dose (2000 mg). A small cohort of patients was analyzed after 8 weeks of treatment, per protocol, to determine interim FPG outcomes. Following the recommendation of the data safety and monitoring board, the FDA approved early termination of the blinded period as predetermined criteria for the primary outcome had been met (FPG reduction, P < .025). At the end of double-blind therapy, adjusted mean change in FPG from baseline was -43 and 21 mg/dL for metformin and placebo patients, respectively. The adjusted mean difference in FPG (metforminplacebo) was 64 mg/dL (P < .001). Rescue therapy was administered to 9% and 65% of metformin and placebo subjects, respectively. HbA1c levels decreased in metformin subjects but remained unchanged in placebo subjects (P < .0001). Placebo-adjusted reduction in total plasma cholesterol (10.4 mg/dL, P ¼.043) was statistically significant, as was change in total cholesterol from baseline (-9.7 mg/dL; CI, 2.7–16.6 lmg/dL) for metformin. Weight loss occurred for both groups, but metformin patients lost more (1.5 vs 0.9 kg). During the open-label period, patients initially randomized to placebo experienced FPG reductions on metformin that mirrored the double-blind period. HbA1c, weight, and BMI also fell. Conversely, FPG levels in patients initially randomized to metformin trended upward toward baseline levels. HbA1c, weight, and BMI also nearly reached baseline values by the end of the open-label period. Gastrointestinal events were reported by 43% of metformin patients and 30% of placebo patients during the blinded period. Other common adverse events
Biguanide
Sulfonylurea
Thiazolidinedione
Biguanide/ sulfonylurea
Metformin
Glimepiride
Rosiglitazone
Metformin/ glyburide
Randomized, doubleblind, activecontrolled, efficacy and safety (24 weeks) Randomized, doubleblind, 3-arm, activecontrolled, efficacy and safety (26 weeks)
9–16 years, n ¼ 167
Randomized, doubleblind, placebocontrolled, efficacy and safety (16 weeks, open-label extension through week 52) Randomized, singleblind, activecontrolled, efficacy and safety (24 weeks)
Study Design
10–17 years, n ¼ 200
8–17 years, n ¼ 272
10–16 years, n ¼ 82
Age Range, Number Enrolled
Glim: 1 mg daily (titrate up to 2, 4, 8 mg if FPG > 126 mg/dL) Met: 500 mg twice daily (titrate up to 1000 mg twice daily if FPG > 126 mg/dL)
P: D HbA1c, 24 weeks; noninferiority S: D HbA1c, 12 weeks; % HbA1c < 7%, 24 weeks; D FPG at 4, 8, 12, 18, 24 weeks; D body weight, BMI P: D HbA1c, 24 weeks; noninferiority
P: D HbA1c, 26 weeks; superiority
500 mg twice daily, titrated up to 1000 mg twice daily if FPG >126 mg/dL
P: D FPG S: D HbA1c, body weight, serum lipids
Ros: 2 mg twice daily (titrate up to 4 mg twice daily if FPG > 126 mg/dL) Met: 500 mg twice daily (titrate up to 1000 mg twice daily if FPG > 126 mg/dL) Met/Gly: 250/1.25 mg Met: 500 mg Gly: 2.5 mg (all agents titrated if FPG > 126 mg/dL)
Study Dose(s)
End Point(s)
Pediatric Trial Characteristics
FPG, fasting plasma glucose; Glim, glimepiride; Gly, glyburide; Met, metformin; P, primary; Ros, rosiglitazone; S, secondary. Study resulted in FDA approval/labeling for use in children.
Drug Class
Agent
Table 1. Study Characteristics, Agents Evaluated for Pediatric Type 2 Diabetes
Change in HbA1c, -0.8% (Met/Gly), -0.48% (Met), -0.96% (Gly) Mean differences vs Met/Gly insignificant
Mean difference in HbA1c (RosMet), -0.28%. Noninferiority test failed. Study lacked adequate power.
Mean difference in HbA1c (GlimMet), 0.44% Noninferiority test failed
Mean difference in FPG (Metplacebo), 64 mg/dL Mean difference in HbA1c, -1.2%. Results favored metformin
Results
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Table 2. Pharmacokinetic Parameters, Agents Evaluated for Pediatric Type 2 Diabetes Pharmacokinetic Parameters Agent Metformin Glimepiride Rosiglitazone Metformin/glyburide
Design
Dose (mg) 1000 1 2/4 250/1.25
Cmax (ng/mL) 730 102.4 — 473/41.3
Tmax (h) 2.0 1.0 1.5 21
AUC (ng h/mL) 4490 338.8 1520/3040 3011/167
t1/2 (h) 3.7 — — 4.17/6.82
CL/F (L/h)
V/F (L)
Similarity to Adult Data
13.7 13.5 —
No Yes Yes Yes
a
648.0 58.6 3.15 ——
a
Estimate is for renal clearance (CLR), in milliliters per minute.
reported during the study included respiratory infections and headache. On the basis of these results, the FDA approved metformin for use in pediatric patients with T2DM as an adjunct to diet and exercise to improve glycemic control. Sulfonylureas Sulfonylureas reduce blood sugar by stimulating insulin release from pancreatic beta cells. This effect is predominantly based on improved responsiveness of these cells to the physiological glucose stimulus. Sulfonylureas augment the normal action of insulin on peripheral glucose uptake and can be used alone or in combination with metformin or insulin. Glimepiride. Glimepiride is indicated in adults to treat T2DM when blood glucose concentrations cannot be controlled adequately by diet, physical exercise, and weight reduction alone. The pediatric T2DM glimepiride drug development program included a PK study and an efficacy and safety study13; the glimepiride PK study included 30 subjects. Pharmacokinetic parameters were determined following administration of a 1-mg dose after breakfast and included the glimepiride AUC and Cmax values reported as 338.8 ng h/mL and 102.4 ng/mL, respectively. Median time to reach peak plasma concentration (Tmax) was 1 hour. Negative correlations of drug clearance with age and weight were reported but were not sufficiently significant to justify dosing adjustments. Overall, pediatric PK parameters were comparable to adult data. Glimepiride’s efficacy and safety were evaluated in a 24-week randomized, multicenter, single-blind, activecontrolled (metformin) trial involving 272 children aged 8–17 years. The primary end point was change in HbA1c at 24 weeks. Noninferiority (NI) was also evaluated using a margin of 0.3% units. Other end points included change in HbA1c at 12 weeks, percentage of subjects with HbA1c < 7% at 24 weeks, and change in self-monitored blood glucose at weeks 4, 8, 12, 18, and 24. Eligibility criteria for the study included age 8–17 years, T2DM diagnosis, negative test results for glutamic acid decarboxylase (GAD) and anti-islet cell autoantibodies, and a stimulated c-peptide 1.5 ng/mL. HbA1c
levels for inclusion were 7%–12% (treatment naive) or >7.5% (on treatment with a single agent > 3 months). Initial dosing at randomization was 1 mg once daily and 500 mg twice daily for glimepiride and metformin, respectively. The glimepiride dose was titrated up (2, 4, or 8 mg) at weeks 4, 8, and 12 if FPG exceeded 126 mg/dL. Metformin was titrated up to 1000 mg twice daily at 12 weeks using the same criteria. Close to half of all study participants had previously used an antidiabetic agent prior to enrollment. The intent-to-treat analysis included 253 children: 127 received glimepiride and 126 received metformin. Average weight at baseline was 83 kg. At 24 weeks, HbA1c fell in both groups. Efficacy favored metformin, although not significantly. Glimepiride failed the noninferiority test with a difference from metformin of 0.44% units. Treatment-related serious adverse events occurred in 5% and 4% of patients on glimepiride and metformin, respectively. Glimepiride patients gained, on average, 1.3 kg. Patients receiving metformin had no change in body weight. Hypoglycemic episodes (blood glucose < 36 mg/dL) occurred in 4% of glimepiride patients and 1% of metformin patients. The FDA did not approve glimepiride for use in children, noting lack of efficacy and disadvantageous weight gain as factors in their decision. Thiazolidinediones Thiazolidinediones (TZDs) reduce insulin resistance through transactivation of peroxisome proliferator-activated receptors (PPARs), specifically PPARg. Thiazolidinediones also increase the synthesis of certain proteins involved in fat and glucose metabolism, which reduces levels of certain types of lipids and circulating free fatty acids. Rosiglitazone. Rosiglitazone was evaluated in pediatric patients with T2DM. The pediatric rosiglitazone drug development program included a PK study and an efficacy and safety study. A population PK study was conducted using a subset of randomized patients from the clinical study (n ¼ 96). Pharmacokinetics of rosiglitazone were evaluated following administration of a single dose of 2 or 4 mg. Tmax, oral clearance (CL/F), and oral volume of distribution (V/F) were 1.5 hours, 3.15 L/h, and 13.5 L,
Christensen et al
respectively. Predicted rosiglitazone AUC based on twice daily doses of 2 and 4 mg were 1520 and 3040 ng h/mL, respectively, reflecting linear disposition. Pediatric PK parameters were found to be consistent with adult population data. The safety and efficacy study, a 24-week randomized, multicenter, double-blind, active-controlled (metformin) trial, comprised 200 children aged 10–17 years. A 4-week placebo run-in period with diet counseling preceded randomization. The primary outcome was change in HbA1c, with a secondary noninferiority comparison of change in HbA1c from baseline. The study was inadequately powered to detect a mean difference in HbA1c effects between rosiglitazone and metformin < 0.4% (a priori determination of a clinically meaningful effect). Initial eligibility criteria at screening included aged 8– 17 years with T2DM, HbA1c 7.1%–10%, negative for type 1 diabetes (GAD, 1CA512 autoantibodies, stimulated C-peptide), and no previous pharmacologic therapy. The lower threshold for HbA1c was reduced to 6.5%, and prior treatment criteria were relaxed prior to enrollment. Patients were randomized to rosiglitazone (n ¼ 99) or metformin (n ¼ 101). Average weight at baseline was 90 kg. Initial dosing at randomization was 2 mg twice daily and 500 mg twice daily for rosiglitazone and metformin, respectively. The dose of each medication was doubled at 8 weeks based on FPG concentration > 126 mg/dL. Dose escalation occurred in nearly half the study patients for each drug. The intent-to-treat analysis included 194 patients (96 rosiglitazone, 98 metformin). At 24 weeks, the average change in HbA1c from baseline was -0.14% and -0.49% for rosiglitazone and metformin, respectively. The mean difference in effects was 0.28% (95%CI, -0.16–0.72). Because the upper bound of the confidence interval exceeded the prospectively determined threshold of 0.4% for clinical significance, rosiglitazone failed to establish noninferiority. Results of outcomes for FPG were similar, favoring metformin. An analysis of the subgroup of treatment-naive patients produced similar findings. In both the full group and treatment-naive subgroup, changes in HbA1c and FPG from baseline were small and statistically insignificant. Adverse events reported by study patients included weight gain, anemia, increased plasma lipid parameters, edema, congestive heart failure, and other cardiovascular events. Rosiglitazone was associated with more weight gain than metformin (2.7 vs 0.3 kg). Serious adverse events totaled 1 and 6 for the rosiglitazone and metformin groups, respectively. Hypoglycemia rarely occurred during the study; only 2 cases were reported (both with metformin). Owing to modest glucose lowering (relative to metformin) and weight gain, rosiglitazone was not approved for pediatric use.
735 Combination Agents Given its efficacy, low incidence of hypoglycemia, and neutral effects on weight, metformin is often formulated as a fixed-dose combination with agents of other classes including sulfonylureas, DPP-4 inhibitors, meglitinides, and TZDs. Combination agents enhance glucose lowering while reducing pill burden. A pediatric drug development program has been conducted for a combination product containing metformin and the sulfonylurea glyburide; the mechanisms of action of each component have been previously described. Metformin/Glyburide. The pediatric drug development program for the metformin/glyburide combination included a PK study and an efficacy and safety study (#NCT00035542, ClinicalTrials.gov). The PK study included 28 participants aged 10–16 years. Following administration of a single 1.25/250 mg dose of metformin/ glyburide, blood samples were collected at selected time points over a 24-hour period. Geometric mean values for AUC, Cmax, and Tmax for glyburide were 167 ng h/mL, 41.3 ng/mL, and 1 hour and for metformin were 3011 ng h/mL, 473 ng/mL, and 2 hours, respectively. When compared with similarly dosed adults, pediatric PK parameters for the metformin/glyburide combination varied by less than 6%. The efficacy and safety study was a 26-week, randomized, multicenter, 3-arm, double-blind, activecontrolled (metformin and glyburide) trial involving 167 patients aged 9–16 years. The primary efficacy end point was change in HbA1c from baseline to week 26. A superiority comparison of glyburide/metformin to each of the monotherapies was included. Eligibility criteria for pediatric patients aged 9–16 years with T2DM varied based on previous drug use. At screening, treatment-naive patients had to have an HbA1c between 6.4% and 14%, then after a 1-week lead in, a mean fasting glucose (MFG) < 350 mg/dL. Previously treated patients had to have an HbA1c between 6.4% and 9% and after a variable 2–4 week washout, a MFG between 200 and 350 mg/dL. Patients were randomized to 1 of 3 treatment arms: metformin/glyburide (250/1.25 mg), metformin (500 mg), or glyburide (2.5 mg). Average weight at baseline in each arm was 80.1, 79.7, and 78.9 kg, respectively. The protocol for dose escalation was not described, but the mean final dose for each of the arms was 623/3.1, 1500, and 6.5 mg for the metformin/glyburide, metformin, and glyburide arms respectively. The intent-to-treat analysis included 160 subjects (metformin/glyburide, n ¼ 57; metformin, n ¼ 54; glyburide, n ¼ 49). Adjusted mean change in HbA1c from baseline was -0.80%, -0.48%, and -0.96% for the metformin/glyburide, metformin, and glyburide groups, respectively. None of these changes were statistically significant. Therefore, metformin/glyburide failed to
736 demonstrate superiority over metformin or glyburide therapies. Outcomes for FPG were similar. Overall, pediatric study results varied from the adult efficacy trials. These discrepancies were attributed to a lack of patients with baseline HbA1c > 9% and enrollment of patients with previous treatment exposure. As for safety, adverse events were experienced similarly across groups. Patients on metformin gained less weight than those in the other groups. On the basis of these results, metformin/glyburide did not receive FDA approval for pediatric use.
Discussion This review summarizes results of 4 pediatric drug development programs for T2DM. Each agent achieved reductions in glycemic parameters; however, 3 of 4 failed to reach the threshold efficacy relative to their control(s) to gain FDA approval. The lack of constancy of effect from adult to pediatric trials underscores the important need for further examination. Nonetheless, these studies do provide key insights that may help to explain the high pediatric failure rate among these agents. We believe elucidating the influence of these elements on trial outcomes can strengthen future development programs. Reviewed trials varied by type of study design. The metformin trial, first among our review, was the only placebo-controlled study. With metformin’s safety and efficacy established, future pediatric trials could no longer use placebo controls (despite continued use in adult studies). Active-control NI (rosiglitazone, glimepiride) or superiority (metformin/glyburide) designs were employed in remaining pediatric studies. Superiority and NI trials differ methodologically; the former seeks to find a difference between treatment and control, whereas the latter aims to show that a new treatment is not worse than the active control by more than a predetermined margin.14 The design and interpretation of NI trials is complicated, as they rely on an assumption of assay sensitivity, selection of an NI margin that reflects the clinical value of the treatment, and high study quality.15 Assay sensitivity, the ability of a trial to distinguish treatment effects, is difficult to affirm without a placebo arm or historical data (in a similar population) to distinguish the effect of the active control from the placebo. Larger sample sizes are needed to achieve adequate power to detect small differences in effect. In the rosiglitazone trial, inadequate power was cited. Further, certain study quality factors can bias results toward the null hypothesis. In the case of the antidiabetic drug trials, poor compliance (metformin), use of concurrent antidiabetic therapies (rosiglitazone), and inadequate washout periods were noted. Finally, when an active control is very effective, establishing NI becomes more challenging.
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Unique differences in the patient populations recruited for the adult and pediatric trials invalidate assumptions of constancy of effect. In the rosiglitazone trial, pediatric study subjects had similar HbA1c values but much lower FPG levels than their adult counterparts in the historical trials. In the case of metformin/ glyburide, adult studies revealed that the drug’s effects were greatest in patients with baseline HbA1c > 9%. However, HbA1c was lower, on average, at baseline in pediatric patients (7.7%–8%). These data reflect the notable distinctions in T2DM between adolescents and adults previously cited. Accelerated onset of T2DM in children (relative to adults) could denote a more aggressive disease course that responds differently to therapeutic interventions. With the exception of metformin, the inclusion of children with previous exposure to oral agents was necessary to achieve enrollment targets but problematic. Patients receiving oral T2DM therapy were required to discontinue current diabetes medications prior to randomization to study treatments. However, to enforce a run-in period sufficient for reestablishing baseline glycemic levels in these patients would have been ethically inappropriate. As a result, the run-in period in these trials was brief or nonexistent. Not surprisingly, several studies cited differences in effect between drugnaive and previously exposed patients. We speculate that the inclusion of previously exposed patients in subsequent studies may explain, in part, the variable efficacy of metformin across studies. Elucidating the effects of new therapies in children with prior exposure to antidiabetic agents has important implications for optimizing treatment. Study results from the metformin open-label extension also warrant further comment. During the open-label extension, patients initially randomized to placebo experienced similar reductions in FPG after 16 weeks with metformin. However, FPG in the initial metformin cohort gradually returned toward baseline values. In the FDA review, it was suggested that compliance might have been a cause. This assertion was based on PK data comparisons in which pediatric subjects had reduced exposure versus adults, resulting possibly from lower absorption and higher renal clearance. Attenuation of effect for metformin has been cited in previous large-scale trials and raises serious concerns about long-term outcomes in this population.16,17 Pediatric drug development remains an important issue, both in the United States and abroad. Pharmacotherapeutic options are scant in other developed countries (eg, Canada, Europe, Japan) despite similar rising trends in the incidence of pediatric T2DM.18,19 In 2008, the FDA issued draft guidance for the development and testing of therapeutic agents to treat and prevent T2DM in the pediatric population.20 As evidenced from the reviewed
737
Christensen et al Table 3. Pediatric Drug Development Among Newer T2DM Drugs, by Treatment Class Diabetes Treatment Class Oral Treatments DDP-4 inhibitors
SGLT2 antagonists
Combination oral treatments Biguanide þ DPP-4 Injectable treatments Incretins Amylin analogues
Generic Name
Date of FDA Approval
Sponsor Studies in clinicaltrials.gov
Sitagliptin Saxagliptin Linagliptin Alogliptin Canagliflozin Dapagliflozin Empagliflozin
2006 2009 2011 2013 2013 2014 2014
PK PK PK, SE PK PK PK PK
Metformin þ sitagliptin
2007
—
Exenatide Liraglutide Pramlintide
2005 2010 2007
PK, SE SE —
DPP-4, dipeptidyl-peptidase-IV; FDA, US Food and Drug Administration; PK, pharmacokinetic; SE, safety/efficacy; SGLT2, sodium-glucose co-transporter 2
trials, additional development and research are needed to fully elucidate the efficacy and safety of oral antidiabetic drugs in pediatric patients with T2DM. The dearth of approved oral agents for pediatric T2D treatment, coupled with the limited effectiveness of lifestyle management in this population, impedes efforts to enhance glycemic control.17,21 Although off-label use of other agents is likely, little is known about its impact on safety and outcomes. Future pediatric development programs should consider alternate designs to establish efficacy to enhance approval status. Given the high prevalence of previous exposure to antidiabetic agents among study subjects in the trials, add-on or dose–response designs may be more appropriate. The recently completed TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study demonstrated the effectiveness of rosiglitazone in combination with metformin to sustain glycemic control.22 The application of such evidence is limited, however, as rosiglitazone is not FDA-approved for use in pediatric T2DM. Even so, several new classes of T2DM drugs have been developed since the completion of reviewed pediatric drug development programs (Table 3); many of these newer agents have ongoing or recently completed pediatric trials listed in the National Institutes of Health clinical trials registry (clinicaltrials.gov). . These studies may yield promising new options for pediatric T2DM treatment. Finally, incentives connected to the FDA’s pediatric exclusivity program should be realigned to encourage enhancements in study quality. Acknowledgments The authors thank Drs Gilbert Burckart and Yeruk Mulugeta for their review and suggestions on the article.
Declaration of Conflicting Interests The authors have no financial conflicts of interest to disclose.
Funding There was no financial support for this article.
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738 11. Jones KL, Arslanian S, Peterokova VA, Park JS, Tomlinson MJ. Effect of metformin in pediatric patients with type 2 diabetes: a randomized controlled trial. Diabetes Care. 2002;25(1):89–94. 12. Gao X, Christensen M, Burghen GA, et al. Pharmacokinetics of Metformin in Pediatric Type 2 Diabetic and Healthy Adult Subjects. Clin Pharmacol Ther. 2003;73(2):P46–P46. 13. Gottschalk M, Danne T, Vlajnic A, Cara JF. Glimepiride versus metformin as monotherapy in pediatric patients with type 2 diabetes: a randomized, single-blind comparative study. Diabetes Care. 2007;30(4):790–794. 14. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). Guidance for Industry, Non-Inferiority Clinical Trials. Institution; March 2010. 15. D’Agostino RB, Sr., Massaro JM, Sullivan LM. Non-inferiority trials: design concepts and issues — the encounters of academic consultants in statistics. Stat Med. 2003;22(2):169–186. 16. Diabetes Control and Complications Trial Research Group. Effect of intensive diabetes treatment on the development and progression of long-term complications in adolescents with insulin-dependent diabetes mellitus: Diabetes Control and Complications Trial. J Pediatr. 1994;125(2):177–188. 17. Zeitler P, Epstein L, Grey M, et al. Treatment options for type 2 diabetes in adolescents and youth: a study of the comparative
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