Garvey W.T.,University of Alabama at Birmingham |
Ryan D.H.,Pennington Biomedical Research Center |
Look M.,San Diego Sports Medicine |
Gadde K.M.,Duke University |
And 5 more authors.
American Journal of Clinical Nutrition | Year: 2012
Background: Obesity is a serious chronic disease. Controlled-release phentermine/topiramate (PHEN/TPM CR), as an adjunct to lifestyle modification, has previously shown significant weight loss compared with placebo in a 56-wk study in overweight and obese subjects with ≥2 weight-related comorbidities. Objective: This study evaluated the long-term efficacy and safety of PHEN/TPM CR in overweight and obese subjects with cardiometabolic disease. Design: This was a placebo-controlled, double-blind, 52-wk extension study; volunteers at selected sites continued with original randomly assigned treatment [placebo, 7.5 mg phentermine/46 mg controlledrelease topiramate (7.5/46), or 15 mg phentermine/92 mg controlledrelease topiramate (15/92)] to complete a total of 108 wk. All subjects participated in a lifestyle-modification program. Results: Of 866 eligible subjects, 676 (78%) elected to continue in the extension. Overall, 84.0% of subjects completed the study, with similar completion rates between treatment groups. At week 108, PHEN/TPM CR was associated with significant, sustained weight loss (intent-to-treat with last observation carried forward; P < 0.0001 compared with placebo); least-squares mean percentage changes from baseline in body weight were -1.8%, -9.3%, and -10.5% for placebo, 7.5/46, and 15/92, respectively. Significantly more PHEN/TPM CR-treated subjects at each dose achieved ≥5%, ≥10%, ≥15%, and ≥20% weight loss compared with placebo (P < 0.001). PHEN/TPM CR improved cardiovascular and metabolic variables and decreased rates of incident diabetes in comparison with placebo. PHEN/TPM CR was well tolerated over 108 wk, with reduced rates of adverse events occurring between weeks 56 and 108 compared with rates between weeks 0 and 56. Conclusion: PHEN/TPM CR in conjunction with lifestyle modification may provide a well-tolerated and effective option for the sustained treatment of obesity complicated by cardiometabolic disease. This trial was registered at clinicaltrials.gov as NCT00796367. © 2012 American Society for Nutrition.
Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): A randomised, placebo-controlled, phase 3 trial
Gadde K.M.,Duke University |
Allison D.B.,University of Alabama at Birmingham |
Ryan D.H.,Pennington Biomedical Research Center |
Peterson C.A.,VIVUS |
And 3 more authors.
The Lancet | Year: 2011
Obesity is associated with a reduction in life expectancy and an increase in mortality from cardiovascular diseases, cancer, and other causes. We therefore assessed the efficacy and safety of two doses of phentermine plus topiramate controlled-release combination as an adjunct to diet and lifestyle modification for weight loss and metabolic risk reduction in individuals who were overweight and obese, with two or more risk factors. In this 56-week phase 3 trial, we randomly assigned overweight or obese adults (aged 18-70 years), with a body-mass index of 27-45 kg/m2 and two or more comorbidities (hypertension, dyslipidaemia, diabetes or prediabetes, or abdominal obesity) to placebo, once-daily phentermine 7·5 mg plus topiramate 46·0 mg, or once-daily phentermine 15·0 mg plus topiramate 92·0 mg in a 2:1:2 ratio in 93 centres in the USA. Drugs were administered orally. Patients were randomly assigned by use of a computer-generated algorithm that was implemented through an interactive voice response system, and were stratified by sex and diabetic status. Investigators, patients, and study sponsors were masked to treatment. Primary endpoints were the percentage change in bodyweight and the proportion of patients achieving at least 5 weight loss. Analysis was by intention to treat. This study is registered with Clinical Trials.gov, number NCT00553787. Of 2487 patients, 994 were assigned to placebo, 498 to phentermine 7·5 mg plus topiramate 46·0 mg, and 995 to phentermine 15·0 mg plus topiramate 92·0 mg; 979, 488, and 981 patients, respectively, were analysed. At 56 weeks, change in bodyweight was -1·4 kg (least-squares mean -1·2, 95 CI -1·8 to -0·7), -8·1 kg (-7·8, -8·5 to -7·1; p<0·0001), and -10·2 kg (-9·8, -10·4 to -9·3; p<0·0001) in the patients assigned to placebo, phentermine 7·5 mg plus topiramate 46·0 mg, and phentermine 15·0 mg plus topiramate 92·0 mg, respectively. 204 (21) patients achieved at least 5 weight loss with placebo, 303 (62; odds ratio 6·3, 95 CI 4·9 to 8·0; p<0·0001) with phentermine 7·5 mg plus topiramate 46·0 mg, and 687 (70; 9·0, 7·3 to 11·1; p<0·0001) with phentermine 15·0 mg plus topiramate 92·0 mg; for ≥10 weight loss, the corresponding numbers were 72 (7), 182 (37; 7·6, 5·6 to 10·2; p<0·0001), and 467 (48; 11·7, 8·9 to 15·4; p<0·0001). The most common adverse events were dry mouth (24 , 67 , and 207  in the groups assigned to placebo, phentermine 7·5 mg plus topiramate 46·0 mg, and phentermine 15·0 mg plus topiramate 92·0 mg, respectively), paraesthesia (20 , 68 , and 204 , respectively), constipation (59 , 75 , and 173 , respectively), insomnia (47 , 29 , and 102 , respectively), dizziness (31 , 36 , 99 , respectively), and dysgeusia (11 , 37 , and 103 , respectively). 38 (4) patients assigned to placebo, 19 (4) to phentermine 7·5 mg plus topiramate 46·0 mg, and 73 (7) to phentermine 15·0 mg plus topiramate 92·0 mg had depression-related adverse events; and 28 (3), 24 (5), and 77 (8), respectively, had anxiety-related adverse events. The combination of phentermine and topiramate, with office-based lifestyle interventions, might be a valuable treatment for obesity that can be provided by family doctors. Vivus. © 2011 Elsevier Ltd.
Garvey W.T.,University of Alabama at Birmingham |
Ryan D.H.,Pennington Biomedical Research Center |
Henry R.,University of California at San Diego |
Bohannon N.J.V.,Monteagle Medical Center |
And 4 more authors.
Diabetes Care | Year: 2014
OBJECTIVE: To evaluate over 108 weeks the effect of phentermine and topiramate extended release (PHEN/TPM ER) treatment on progression to type 2 diabetes and/or cardiometabolic disease in subjects with prediabetes and/or metabolic syndrome (MetS) at baseline. RESEARCH DESIGN AND METHODS: Subanalysis of a phase 3, randomized, placebo-controlled, double-blind study of overweight/obese subjects (BMI ≥27 to ≤45 kg/m2) with two or more comorbidities. Subjects were randomized to placebo, PHEN 7.5 mg/TPM ER 46 mg (7.5/ 46), or PHEN 15 mg/TPM ER 92 mg (15/92) plus lifestyle modifications for 108 weeks. Percent weight loss in the intent-to-treat population using multiple imputation (ITT-MI), annualized incidence rate of progression to type 2 diabetes, and changes in glycemia, lipid parameters, blood pressure, and waist circumference were evaluated. RESULTS: At baseline, 475 subjects met the criteria for prediabetes and/or MetS. After 108 weeks, subjects with prediabetes and/or MetS in the placebo, 7.5/46, and 15/92 groups experienced mean percent weight loss of 2.5, 10.9, and 12.1%, respectively (ITT-MI; P < 0.0001 vs. placebo), associated with reductions of 70.5 and 78.7% in the annualized incidence rate of type 2 diabetes for those receiving 7.5/46 and 15/92, respectively (ITT, P< 0.05), versus placebo. The ability of PHEN/TPM ER to prevent diabetes was related to degree of weight lost and was accompanied by significant improvements in cardiometabolic parameters. PHEN/TPM ER was well tolerated by this subgroup over 2 years. CONCLUSIONS: PHEN/TPM ER plus lifestyle modification produced significant weight loss and markedly reduced progression to type 2 diabetes in overweight/obese patients with prediabetes and/or MetS, accompanied by improvements in multiple cardiometabolic disease risk factors. © 2014 by the American Diabetes Association.
Karl D.M.,The Endocrine Clinic |
Gill J.,Sanofi S.A. |
Zhou R.,Medpace |
Riddle M.C.,Oregon Health And Science University
Diabetes, Obesity and Metabolism | Year: 2013
Aim: Addition and titration of basal insulin is usually effective in improving glycaemic control in type 2 diabetes, but fear of hypoglycaemia remains a barrier. Ability to predict which patients might be at greatest risk of hypoglycaemia might facilitate individualization of treatment and improve safety. The aim of this study was to obtain information about clinical characteristics which might predict risk of hypoglycaemia during initiation of basal insulin. Methods: Patient-level data from 2251 participants in 11 studies in which insulin glargine was started and titrated using similar treat-to-target methods was pooled and analysed with logistic regression models. Results: Participants had mean age 58years, diabetes duration 8.9years, body mass index 31.0 and baseline A1c 8.8%. They attained mean A1c 7.1% during 6months of treatment with final mean glargine dosage 0.44units/kg. Symptomatic hypoglycaemia occurred in 52%, glucose-confirmed hypoglycaemia (blood glucose <50mg/dl) in 17%, repeated glucose-confirmed events in 7% and severe hypoglycaemia in 1.5%. Independent predictors of glucose-confirmed hypoglycaemia were younger age, lower body mass index, use of a sulphonylurea in addition to metformin, lower attained A1c and lower dosage of glargine. Conclusions: These findings confirm low rates of clinically important hypoglycaemia using this method, and suggest that higher risk of hypoglycaemia may be suspected when patients needing insulin are younger, less obese and taking metformin and a sulphonylurea, and especially when A1c levels ≤7.0% are attained with glargine dosage ≤0.4units/kg. © 2013 Blackwell Publishing Ltd.
Riddle M.,Oregon Health And Science University |
Umpierrez G.,Emory University |
Digenio A.,Sanofi S.A. |
Zhou R.,Medpace |
Rosenstock J.,Dallas Diabetes and Endocrine Center
Diabetes Care | Year: 2011
OBJECTIVE - To determine the relative contributions of basal hyperglycemia (BHG) versus postprandial hyperglycemia (PPHG) before and after treatment intensification in patients with glycated hemoglobin A1c (A1C) >7.0% while on prior oral therapy. RESEARCH DESIGN AND METHODS - Self-measured, plasma-referenced glucose profiles and A1C values were evaluated fromparticipants in six studies comparing systematically titrated insulin glargine with an alternative regimen (adding basal, premixed, or prandial insulin, or increasing oral agents). Hyperglycemic exposure (>100 mg/dL [5.6 mmol/L]) as a result of BHG versus PPHG was calculated. RESULTS - On prior oral therapy, 1,699 participants (mean age 59 years, diabetes duration 9 years) had mean fasting plasma glucose (FPG) of 194 mg/dL (10.8mmol/L), andmean A1C was 8.7%. BHG contributed an average of 76-80% to hyperglycemia over the observed range of baseline A1C levels. Adding basal insulin for 24 or 28 weeks lowered mean FPG to 117 mg/dL (6.5 mmol/L), A1C to 7.0%, and BHG contribution to 32-41%. Alternative regimens reduced FPG to 146 mg/dL (8.1 mmol/L), A1C to 7.1%, and the contribution of BHG to 64-71%. BHG contributions for patients with A1C averaging 7.6-7.7% were 76% at baseline and 34 and 68% after adding basal insulin or other therapies, respectively. CONCLUSIONS - When A1C is >7.0% despite oral therapy, BHG routinely dominates exposure. Intensified therapy reduces A1C and changes this relationship, but BHG amenable to further intervention still accounts for one-third of total hyperglycemia after basal insulin treatment and two-thirds after alternative methods. © 2011 by the American Diabetes Association.
Petri K.C.C.,Novo Nordisk AS |
Jacobsen L.V.,Novo Nordisk AS |
Clinical Pharmacokinetics | Year: 2015
Background and Objective: The safety, tolerability, and pharmacokinetics of the once-daily human glucagon-like peptide-1 (GLP-1) analog liraglutide have been evaluated in pediatric patients aged greater than 10 years with type 2 diabetes (T2D). In this study, a population pharmacokinetic analysis was compared to the pediatric pharmacokinetic data with those from two clinical pharmacology trials in adults with T2D. Methods: A one-compartment pharmacokinetic model previously found to adequately describe the pharmacokinetics of liraglutide in adults with T2D was applied to the evaluation of 13 pediatric subjects (10–17 years of age) with T2D. Steady-state estimates for apparent clearance (CL/F) for individual subjects and corresponding dose were used to derive the area under the plasma–concentration time curve from 0–24 h (AUC24) and investigate dose proportionality in the pediatric trial. A covariate analysis evaluated the effects of body weight, gender, and age category (pediatric/adult) on liraglutide exposure. Results: Dose proportionality in the dose range of 0.3–1.8 mg was indicated by the model-derived AUC24 slope: 1.05 (95 % CI 0.96–1.15). Consistent with findings from adult trials, body weight and gender were relevant covariates for liraglutide exposure in the pediatric population. The CL/F estimates, and thus exposure, for the pediatric subjects with T2D were similar to those in the adult trials. Conclusion: Based on this population pharmacokinetic analysis, the liraglutide dose regimen that was found to be clinically effective in adults is predicted to achieve the same range of exposure in the pediatric population (10–17 years of age) with a pre-trial body weight range of 57–214 kg. © 2015, The Author(s).
Fonseca V.,Tulane University Medical Center |
Gill J.,Sanofi S.A. |
Zhou R.,Medpace |
Leahy J.,University of Vermont
Diabetes, Obesity and Metabolism | Year: 2011
Aim: To evaluate the benefits of initiating insulin at an earlier versus later treatment stage, and regimens with/without sulfonylurea (SU). Methods: Pooled analysis of 11 prospective randomized clinical trials, including 2171 adults with uncontrolled type 2 diabetes initiating insulin glargine following a specific titration algorithm. Clinical outcomes were glycated haemoglobin A1c (HbA1c) reduction, per cent achieving HbA1c ≤ 7.0%, weight gain and hypoglycaemic events. Statistical analysis compared outcomes 24 weeks after basal insulin initiation in patients previously uncontrolled on 0/1 oral antidiabetic drug (OAD) versus 2 OADs, and in patients taking metformin (MET) or SU alone or in combination at baseline. A meta-analysis was also conducted. Results: For the pooled analysis, patients on 0/1 OAD and those on MET monotherapy at baseline had the largest 24-week reductions in HbA1c following the addition of insulin glargine (~0.44 U/kg). Of patients failing MET/SU monotherapy and MET + SU in combination, 68.1, 50.4 and 56.4% achieved HbA1c ≤ 7.0%, respectively (p = 0.0006). Weight gain was lowest when basal insulin was added to MET. Patients on 0/1 OAD at baseline had significantly less symptomatic hypoglycaemia when basal insulin was added than those on 2 OADs (p = 0.0007). Despite higher insulin doses, those taking MET alone had less hypoglycaemia than those taking SU or MET + SU. Results were confirmed in the meta-analysis. Conclusion: Adding insulin glargine to MET monotherapy early in treatment may provide efficacy/safety benefits over regimens including SU. This may reflect treatment earlier in the disease and supports the inclusion of insulin as a second step in the American Diabetes Association/European Association for the Study of Diabetes treatment algorithm. © 2011 Blackwell Publishing Ltd.
Current Treatment Options in Cardiovascular Medicine | Year: 2011
Opinion statement: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy among women of reproductive age, impacting 5-10% of premenopausal American women. During the reproductive years, women with PCOS seek medical attention related to infertility, hirsutism, and acne. About 60% of women with PCOS are obese and insulin resistant. Up to 40% of women with PCOS will develop diabetes by the age of 50 and many are dyslipidemic. In addition to treating the cosmetic and fertility issues associated with PCOS, health care providers must educate patients regarding the long-term cardiovascular consequences associated the this disorder. At menopause, a woman with PCOS is likely to have had multiple cardiac risk factors for several decades. Postmenopausal women with a history of PCOS, especially those with established diabetes and/or dyslipidemia, should be considered at high risk for the development of clinical cardiac disease. Exercise and a prudent calorie-restricted diet aimed at weight loss must be stressed early. Pharmacologic therapy for diabetes and hyperlipidemia should be used when appropriate. Bariatric surgery, known to positively impact all the aforementioned cardiac risk factors, may also be of benefit. © 2011 Springer Science+Business Media.
News Article | November 3, 2016
CINCINNATI--(BUSINESS WIRE)--Medpace Holdings, Inc. (Nasdaq:MEDP) (“Medpace”) today announced financial results for the third quarter ended September 30, 2016. Third Quarter 2016 Financial Results Net service revenue for the three months ended September 30, 2016, was $94.8 million, an increase of 16.1% compared to $81.6 million for the comparable prior-year period. Backlog as of September 30, 2016 grew 14.0% to $480.4 million from $421.4 million as of September 30, 2015. Net new business awards
News Article | February 27, 2017
CINCINNATI--(BUSINESS WIRE)--Medpace Holdings, Inc. (Nasdaq: MEDP) (“Medpace”) today announced financial results for the fourth quarter and full year ended December 31, 2016. Net service revenue for the three months ended December 31, 2016, was $95.4 million, an increase of 11.3% compared to $85.7 million for the comparable prior-year period. Net service revenue for the year ended December 31, 2016, was $370.6 million, an increase of 15.8% compared to $320.1 million for the year ended December 31, 2015. Backlog as of December 31, 2016 grew 12.6% to $483.9 million from $429.7 million as of December 31, 2015. Net new business awards were $99.7 million, representing a net book-to-bill ratio of 1.05x, for the fourth quarter of 2016, as compared to $95.5 million for the comparable prior-year period. The Company calculates net book-to-bill ratio by dividing net new business awards by net service revenue. For the year ended December 31, 2016, net new business awards were $427.0 million, representing a book-to-bill ratio of 1.15x, compared to $359.5 million for the year ended December 31, 2015. Net new business awards were higher in the year ended December 31, 2016 compared to the year ended December 31, 2015 primarily due to continued growth in the Company’s Oncology and Antiviral Anti-infective (AVAI) therapeutic areas. For the fourth quarter of 2016, Direct costs, excluding depreciation and amortization were $51.1 million, compared to $44.2 million in the fourth quarter of 2015. Adjusted Direct costs were $51.9 million for the fourth quarter 2016 compared to $43.9 million in the fourth quarter of 2015. For the full year 2016, Direct costs, excluding depreciation and amortization were $198.5 million, compared to $163.7 million in 2015. Adjusted Direct costs were $198.1 million for the full year 2016 compared to $165.7 million in the prior year. For the fourth quarter of 2016, Selling, general and administrative expenses were $16.8 million compared to $18.3 million in the fourth quarter of 2015. Adjusted Selling, general and administrative expenses were $16.9 million for the fourth quarter 2016 versus $14.8 million in the fourth quarter of 2015. For the full year 2016, Selling, general and administrative expenses were $61.5 million compared to $57.0 million in the full year 2015. Adjusted Selling, general and administrative expenses were $58.8 million for the full year 2016 versus $52.0 million for the full year 2015. GAAP net loss for the fourth quarter of 2016 was $0.0 million, or $(0.00) per diluted share, versus a GAAP net loss of $8.6 million, or $(0.27) per diluted share, for the fourth quarter of 2015. This resulted in a net income (loss) margin of (0.0%) and (10.0%) for the fourth quarter of 2016 and 2015, respectively. GAAP net income for the full year of 2016 was $13.4 million, or $0.37 per diluted share, versus a GAAP net loss of $8.7 million, or $(0.28) per diluted share, for the full year 2015. This resulted in a net income (loss) margin of 3.6% and (2.7%) for the full year 2016 and 2015, respectively. Adjusted EBITDA for the fourth quarter of 2016 increased 2.6% to $27.5 million, or 28.8% of net service revenue, compared to $26.8 million, or 31.3% of net service revenue, for the comparable prior-year period. Adjusted EBITDA for the full year 2016 increased 12.0% to $113.4 million, or 30.6% of net service revenue, compared to $101.2 million, or 31.6% of net service revenue, for the prior year. Adjusted Net Income for the fourth quarter of 2016 increased 75.4% to $14.3 million, compared to $8.2 million for the comparable prior-year period. Adjusted Net Income per diluted share for the fourth quarter of 2016 was $0.35, representing an increase of 34.6%, compared to Adjusted Net Income per diluted share of $0.26 for the comparable prior-year period. Adjusted Net Income for full year 2016 increased 37.8% to $55.7 million, compared to $40.4 million for the prior year. Adjusted Net Income per diluted share for the full year 2016 was $1.53, representing an increase of 18.6%, compared to Adjusted Net Income per diluted share of $1.29 for the prior year. A reconciliation of the Company’s non-GAAP financial measures, including EBITDA, Adjusted EBITDA, Adjusted EBITDA margin, Adjusted Direct costs, Adjusted Selling, general and administrative expenses, Adjusted Net Income, and Adjusted Net Income per diluted share, to the corresponding GAAP measures are provided below. On December 8, 2016, the Company entered into a credit agreement for a new Senior Secured Credit Facilities consisting of a $165 million term loan facility and a $150 million revolving credit facility. Proceeds from the term loan were used to repay and extinguish our obligations under our previous Senior Secured Credit Facilities as well as pay the fees, costs and expenses related thereto. In connection with the extinguishment of the previous Senior Secured Credit Facilities, the Company recognized a Loss on Extinguishment of Debt of approximately $10.7 million in the fourth quarter of 2016. Additionally, the Company’s Cash and cash equivalents were $37.1 million at December 31, 2016, while the Company generated $29.0 million in cash flow from operating activities during the fourth quarter of 2016. The Company forecasts 2017 net service revenue in the range of $390 million to $406 million, representing growth of 5.2% to 9.6% over 2016 net service revenue of $370.6 million. GAAP net income for full year 2017 is forecasted in the range of $43.9 million to $47.5 million. Additionally, full-year 2017 Adjusted EBITDA is expected in the range of $122 million to $126 million. Based on forecasted 2017 net service revenue of $390 to $406 million and GAAP net income of $43.9 to $47.5 million, diluted earnings per share (GAAP) is forecasted in the range of $1.06 to $1.14. Adjusted Net Income for 2017 is forecasted in the range of $66 million to $70 million, representing growth of 18.5% to 25.7% over Adjusted Net Income of $55.7 million for 2016. Furthermore, Adjusted Net Income per diluted share for 2017 is expected in the range of $1.58 to $1.68 per share. Medpace will host a conference call at 9:00 a.m. ET, Tuesday, February 28, 2017, to discuss its fourth quarter and full year 2016 results. To participate in the conference call, dial 800-219-7113 (domestic) or 574-990-1030 (international) using the passcode 67148967. To access the conference call via webcast, visit the “Investors” section of Medpace’s website at medpace.com. The webcast replay of the call will be available at the same site approximately one hour after the end of the call. A supplemental slide presentation will also be available at the “Investors” section of Medpace’s website prior to the start of the call. A recording of the call will be available at 12:00 p.m. ET on Tuesday, February 28, 2017 until 1:00 p.m. ET on Tuesday, March 14, 2017. To hear this recording, dial 855-859-2056 (domestic) or 404-537-3406 (international) using the passcode 67148967. Medpace is a scientifically-driven, global, full-service clinical contract research organization (CRO) providing Phase I-IV clinical development services to the biotechnology, pharmaceutical and medical device industries. Medpace’s mission is to accelerate the global development of safe and effective medical therapeutics through its physician-led, high-science, and disciplined operating approach that leverages regulatory and therapeutic expertise across all major areas including oncology, cardiology, metabolic disease, endocrinology, central nervous system and anti-viral and anti-infective. Headquartered in Cincinnati, Ohio, Medpace employs approximately 2,500 people across 35 countries. This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including without limitation statements regarding our anticipated financial results and business goals. These forward-looking statements are based on management’s current expectations. These statements are neither promises nor guarantees, but involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements, including, but not limited to, the following: the potential loss, delay or non-renewal of our contracts, or the non-payment by customers for services we have performed; the failure to convert backlog to revenue at our historical conversion rate; fluctuation in our results between fiscal quarters and years; decreased operating margins due to increased pricing pressure or other pressures; failure to perform our services in accordance with contractual requirements, government regulations and ethical considerations; the impact of underpricing our contracts, overrunning our cost estimates or failing to receive approval for or experiencing delays with documentation of change orders; our failure to successfully execute our growth strategies; the impact of a failure to retain key personnel or recruit experienced personnel; the risks associated with our information systems infrastructure; our failure to manage our growth effectively; adverse results from customer or therapeutic area concentration; the risks associated with doing business internationally; the risks associated with the Foreign Corrupt Practices Act and other anti-corruption laws; future net losses; the impact of income tax rate fluctuations on operations, earnings and earnings per share; the risks associated with our intercompany pricing policies; our failure to attract suitable investigators and patients to our clinical trials; the liability risks associated with our research and development services; the risks related to our Phase I clinical services; inadequate insurance coverage for our operations and indemnification obligations; fluctuations in exchange rates; the risks related to our relationships with existing or potential customers who are in competition with each other; our failure to successfully integrate potential future acquisitions; potential impairment of goodwill or other intangible assets; our limited ability to utilize our net operating loss carryforwards or other tax attributes; the risks associated with the use and disposal of hazardous substances and waste; the failure of third parties to provide us critical support services; our limited ability to protect our intellectual property rights; the risks associated with potential future investments in our customers’ business or drugs; the impact of a natural disaster or other catastrophic event; negative outsourcing trends in the biopharmaceutical industry and a reduction in aggregate expenditures and research and development budgets; our inability to compete effectively with other CROs; the impact of healthcare reform; the impact of recent consolidation in the biopharmaceutical industry; failure to comply with federal, state and foreign healthcare laws; the effect of current and proposed laws and regulations regarding the protection of personal data; our potential involvement in costly intellectual property lawsuits; actions by regulatory authorities or customers to limit the scope of or withdraw an approved drug, biologic or medical device from the market; failure to keep pace with rapid technological changes; the impact of industry-wide reputational harm to CROs; our ability to fulfill our debt obligations; the risks associated with incurring additional debt or undertaking additional debt obligations; the effect of covenant restrictions under our debt agreements on our ability to operate our business; our inability to generate sufficient cash to service all of our indebtedness; fluctuations in interest rates; and our dependence on our lenders, which may not be able to fund borrowings under the credit commitments, and our inability to borrow. These and other important factors discussed under the caption “Risk Factors” in our Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission, or SEC, on November 3, 2016, and our other reports filed with the SEC could cause actual results to differ materially from those indicated by the forward-looking statements made in this press release. Any such forward-looking statements represent management’s estimates as of the date of this press release. While we may elect to update such forward-looking statements at some point in the future, we disclaim any obligation to do so, even if subsequent events cause our views to change. These forward-looking statements should not be relied upon as representing our views as of any date subsequent to the date of this press release. Certain financial measures presented in this press release, such as EBITDA, Adjusted EBITDA, Adjusted EBITDA margin, Adjusted Direct costs, Adjusted Selling, general and administrative expenses, Adjusted Net Income, and Adjusted Net Income per diluted share, are not recognized under generally accepted accounting principles in the United States of America, or U.S. GAAP. Management uses EBITDA, Adjusted EBITDA, Adjusted EBITDA margin, Adjusted Direct costs, Adjusted Selling, general and administrative expenses, Adjusted Net Income, and Adjusted Net Income per diluted share or comparable metrics as a measurement used in evaluating our operating performance on a consistent basis, as a consideration to assess incentive compensation for our employees, for planning purposes, including the preparation of our internal annual operating budget, and to evaluate the performance and effectiveness of our operational strategies. EBITDA, Adjusted EBITDA, Adjusted EBITDA margin, Adjusted Direct costs, Adjusted Selling, general and administrative expenses, Adjusted Net Income, and Adjusted Net Income per diluted share have important limitations as analytical tools and you should not consider them in isolation, or as a substitute for, analysis of our results as reported under U.S. GAAP. See the consolidated financial statements included elsewhere in this release for our U.S. GAAP results. Additionally, for reconciliations of EBITDA, Adjusted EBITDA, Adjusted EBITDA margin, Adjusted Direct costs, Adjusted Selling, general and administrative expenses, Adjusted Net Income, Adjusted Net Income per diluted share to our closest reported U.S. GAAP measures, refer to the appendix of this press release. We believe that EBITDA, Adjusted EBITDA, and Adjusted EBITDA margin are useful to provide additional information to investors about certain material non-cash and non-recurring items. While we believe these financial measures are commonly used by investors to evaluate our performance and that of our competitors, because not all companies use identical calculations, this presentation of EBITDA, Adjusted EBITDA and Adjusted EBITDA margin may not be comparable to other similarly titled measures of other companies and should not be considered as an alternative to performance measures derived in accordance with U.S. GAAP. EBITDA is calculated as net income (loss) attributable to Medpace Holdings, Inc. before income tax expense, interest expense, net, depreciation and amortization with Adjusted EBITDA being further adjusted for unusual and other items. Adjusted EBITDA margin is calculated by dividing Adjusted EBITDA by Service revenue, net for each period. Our presentation of EBITDA, Adjusted EBITDA and Adjusted EBITDA margin should not be construed as an inference that our future results will be unaffected by unusual or non-recurring items. Adjusted Net Income measures our operating performance by adjusting net income (loss) attributable to Medpace Holdings, Inc. to include cash expenditures related to rental payments on leases classified for accounting purposes as deemed landlord liabilities, and exclude amortization expense, certain stock based compensation award non-cash expenses, certain litigation expenses, deferred financing fees and certain other non-recurring items. Adjusted Net Income per diluted share measures Adjusted Net Income on a per diluted share basis. Management uses these measures to evaluate our core operating results as it excludes certain items whose fluctuations from period-to-period do not necessarily correspond to changes in the core operations of the business, but includes certain items such as depreciation, interest expense and tax expense, which are otherwise excluded from Adjusted EBITDA. We believe the presentation of Adjusted Net Income and Adjusted Net Income per diluted share enhances our investors’ overall understanding of the financial performance. You should not consider Adjusted Net Income or Adjusted Net Income per diluted share as an alternative to Net income (loss) or Net income per diluted share attributable to Medpace Holdings Inc., determined in accordance with U.S. GAAP, as an indicator of operating performance. Adjusted Direct costs and Adjusted Selling, general and administrative expenses are useful to provide information to investors to evaluate core operating expenses as they exclude certain items whose fluctuations from period-to-period do not necessarily correspond to changes in the core operations of the business, but includes certain items such as certain lease payments which are otherwise excluded from core operating expenses. We believe that reporting these metrics enhance our investors’ overall understanding of our core recurring operating expenses. You should not consider Adjusted Direct costs and Adjusted Selling, general and administrative expenses as an alternative to Direct costs, excluding depreciation and amortization and Selling, general and administrative expenses, determined in accordance with U.S. GAAP, as an indicator of operating performance.