Focus On , Pharmacology

The Use of Capromorelin for the Clinical Problem of Inappetence

Chad M. Johannes DVM, DACVIM (SAIM, Oncology), Iowa State University College of Veterinary Medicine, Ames, Iowa

Dr. Johannes is an assistant professor of oncology at Iowa State University. His industry experience includes employment as the former medical director at Aratana Therapeutics, Inc., and coordination of the launch of Palladia®, the first FDA-approved veterinary cancer therapeutic, during his time with Pfizer Animal Health (now Zoetis). Dr. Johannes’s practice experience includes primary care, specialty care, and academic settings. His areas of research interest include oncology therapeutic development and commercialization, immunotherapeutics, and effective management of treatment-related side effects.

Margaret L. Musser DVM, DACVIM (Oncology)

Dr. Musser is an assistant professor of oncology at Iowa State University. Dr. Musser received her DVM from the University of Illinois, completed a rotating internship at VCA West Los Angeles, and completed her medical oncology residency at North Carolina State University. Before joining the faculty at Iowa State University, Dr. Musser spent 3 years in private practice specialty care in Connecticut. Her areas of research interest include immunotherapeutics and novel therapeutic approaches.

The Use of Capromorelin for the Clinical Problem of Inappetence
EAT UP Capromorelin is the first FDA-approved appetite stimulant for dogs. Its safety and effectiveness make it a promising solution for ill pets. Photo: shutterstock.com/Aleksey Boyko
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Inappetence is a common clinical sign that has an important influence on perceived quality of life and case management in dogs and cats. Prolonged inappetence can negatively affect patient nutritional status, clinical outcome, and, potentially, survival.

Capromorelin oral solution (Entyce®, Aratana Therapeutics, aratana.com) was approved by the Food and Drug Administration (FDA) in May 2016 for appetite stimulation in dogs and became available to veterinarians in the fall of 2017. Although further studies are needed to fully define the ideal use of this product in veterinary practice, capromorelin has the potential to positively affect the clinical management of inappetence and weight loss/cachexia in dogs (and, off-label, cats) with many different medical conditions. This article provides an overview of capromorelin’s mechanism of action, safety and efficacy data, and potential clinical roles.

BACKGROUND

Capromorelin oral solution is an orally active small-molecule ghrelin receptor agonist (GRA) that mimics the action of endogenous ghrelin, resulting in growth hormone secretion and appetite stimulation.1-4 Given its effect on growth hormone and, subsequently, insulin-like growth factor-1 (IGF-1) levels, capromorelin may also have a clinical role in treating cachexia.2,5

Capromorelin is the first GRA approved by the FDA for a therapeutic purpose in any species.6 Due to the limited inappetence treatment options available for cats, it may be considered for off-label use in cats that do not respond to the FDA-approved therapy mirtazapine transdermal ointment (Mirataz®, Kindred Biosciences, kindredbio.com).7 Ideal integration of capromorelin into clinical case management for both short- and long-term inappetence is still being defined.

CLINICAL CHALLENGE OF INAPPETENCE

Reduced appetite is a nonspecific clinical sign with myriad acute and chronic physiologic causes (TABLE 1). Signs are often subtle, subjective, and highly dependent on client and clinician observations. The observed decrease in appetite is often broadly described in severity along a spectrum from anorexia (complete loss of appetite) to hyporexia (decreased appetite, not consuming full caloric needs). Dysrexia—any level of altered eating pattern (e.g., eating, but not the desired diet)—can also span this clinical spectrum.8,9 Inappetence is an overarching term that is used in this article to encompass decreased and/or altered appetite/food intake.

Given the wide variety of clinical conditions that can lead to inappetence, it is no surprise that inappetence has been reported as the most common presenting problem (8.5%) for patients evaluated in the small animal primary care setting.10 This highlights the critical role that a good appetite plays when pet owners evaluate the overall quality of life for their dog or cat.11,12 Inappetence at time of admission has been associated with a higher risk of death in hospitalized dogs,13 and inappetence has been shown to be a key variable in a client’s end-of-life decision for their dog or cat.14 

BOX 1 Nonapproved Medical Treatments Considered for Inappetence in Dogs
  • Anabolic steroids (stanazol/Winstrol)
  • Hemp (Canna-Pet®)
  • Benzodiazepines (diazepam)
  • Maropitant (Cerenia®)
  • Cobalamin (vitamin B12)
  • Benzodiazepines (diazepam)
  • Medical marijuana
  • Cyproheptadine
  • Megestrol acetate (Ovaban®)
  • Fish oil
  • Mirtazapine
  • Glucocorticoids (prednisone)
  • Propofol

The importance of early and adequate enteral nutritional support in clinically ill dogs and cats has long been recognized. The challenge has been having reliably effective medical therapies to treat inappetence. BOX 1 summarizes potential appetite stimulant therapies that have been utilized historically by veterinarians. FIGURE 1 shows the results of an online survey of veterinary specialists asked about the most commonly used therapies for appetite stimulation in dogs (for chemotherapy-induced signs) before the approval of capromorelin.15 Most of these therapies have variable clinical results in dogs, likely owing to the fact that any appetite stimulation component is a secondary effect of the drug.

PHYSIOLOGY OF APPETITE REGULATION

Initiation of feeding behavior and control of appetite is complicated and continues to be investigated in hopes of identifying targets for therapeutic manipulation. A multitude of signals from peripheral tissues (gastrointestinal tract, pancreas, adipose) act on two neuronal subpopulations within the hypothalamus to influence appetite: (1) anorexigenic (suppressing) neurons and (2) orexigenic (stimulating) neurons.16 Most of these signals (peptide YY, leptin, insulin) have a suppressant effect via a positive influence on anorexigenic neurons and/or a negative influence on orexigenic neurons.8,16,17

Capromorelin oral solution has demonstrated a wide margin of safety in long-term use, being well tolerated at daily doses up to 17.5 times the label dose for 12 consecutive months in healthy dogs.21

Ghrelin, produced predominantly by the oxyntic glands of the gastric fundus, is the only known signal with a stimulatory influence on orexigenic neurons.6,17
For this reason, ghrelin is believed to play the primary role in initiation of feeding behavior, appetite stimulation, and food intake.17 Consistent with findings in other species, ghrelin levels have been demonstrated to be increased in the fasting state and suppressed with food intake in both dogs18,19 and cats.20 Exogenous administration of ghrelin to healthy beagle dogs increased daily food intake.18

MECHANISM OF ACTION IN CAPROMORELIN

As a GRA, capromorelin stimulates appetite via the hypothalamus as outlined in the above paragraph. Capromorelin also causes release of growth hormone and subsequent increase of IGF-1 (produced by the liver under growth hormone stimulation) by binding the growth hormone secretagogue receptor 1a (GHS-R1a) in the pituitary gland.1,2,6 Capromorelin administered to healthy beagle dogs for 7 days produced sustainably increased IGF-1 levels that were approximately 60% to 70% higher (4 to 8 hours post-dosing) in dogs treated with 3 mg/kg capromorelin q24h compared with dogs receiving placebo.2 These sustained IGF-1 levels may increase lean muscle mass in dogs receiving capromorelin over extended periods of time.2,5

ROLES FOR CAPROMORELIN IN PRACTICE

Clinical Use for Appetite Stimulation in Dogs

Capromorelin is dosed at 3 mg/kg PO q24h, which has been shown to increase food intake and weight gain in both inappetent client-owned dogs and healthy laboratory dogs.2-4 The pivotal field safety and effectiveness study evaluated 177 inappetent dogs (121 treated with capromorelin for 4 days, 56 with placebo). Treatment with capromorelin significantly improved appetite (68.6% versus 44.6%, respectively, P = 0.008) as well as mean body weight compared with placebo (1.8% versus 0.1%, respectively, P <0.001). The most commonly observed adverse clinical signs included diarrhea (7.0%), vomiting (6.4%), polydipsia (4.1%), and hypersalivation (2.3%).1,3

Capromorelin oral solution has demonstrated a wide margin of safety in long-term use, being well tolerated at daily doses up to 17.5 times the label dose for 12 consecutive months in healthy dogs.21 As a result of this extensive safety profile, capromorelin has no treatment duration, weight, or age restrictions on the label.1 It can be used as chronic, long-term therapy as clinically indicated in dogs.

One important consideration when incorporating capromorelin into clinical case management is setting appropriate expectations. Capromorelin has not been evaluated in clinically inappetent dogs for longer than 4 days3; therefore, the clinical considerations below are based on anecdotal experiences of the authors. In the clinical study, the response was 68.6% in capromorelin-treated dogs, so not all dogs may show a positive response.

As previously described, many peripheral signals cause appetite suppression. In the authors’ clinical experience, dogs with severe disease and/or multiple comorbidities may take time (3 to 4 days) and clinical support of the comorbidities to see a strong appetite stimulation effect. If no significant appetite stimulation response is noted after 24 to 48 hours of capromorelin therapy, consider increasing the dose to 4.5 mg/kg PO once daily. Given the demonstrated wide margin of safety, this increase to 1.5 times the label dose is a reasonable consideration. Once a response is noted, the dose can often be decreased back to the label dose. If no clinical response is noted within approximately 5 days of treatment, consider discontinuation of therapy.

Clinical Use for Appetite Stimulation in Cats

Capromorelin is not yet FDA approved for use in cats; however, data are available for healthy cats. A 91-day study demonstrated sustained increases in serum IGF-1 levels (similar to that seen in dogs) and increased food intake and body weight.22 Whether the noted increase in IGF-1 levels would be enough to cause peripheral insulin resistance leading to diabetes mellitus is not yet known. However, serum fructosamine monitoring revealed that levels did not exceed the upper end of the reference range for any cat treated with capromorelin.22

A cat-specific formulation is currently being developed, and a pivotal effectiveness study for weight management in cats with chronic kidney disease, dosing at 2 mg/kg PO q24h, is anticipated to be complete in mid-2019.23 Based on anecdotal experience of the authors, capromorelin treatment initiation in cats should be considered at a dose of 2 mg/kg PO q24h. As noted in dogs, if no significant appetite stimulation response is noted within the first 24 to 48 hours, consider increasing the dose to 3 mg/kg PO q24h. Once a response is noted, reduce the dose to 2 mg/kg q24h.

Beyond Appetite Stimulation

Given the physiologic functions of endogenous ghrelin and demonstrated activity of GRAs, therapeutic investigation of these molecules in human medicine has included treatment of gastroparesis associated with diabetes mellitus, growth hormone deficiency, frailty in the elderly, nutrition disorders, and cancer anorexia-cachexia syndrome (CACS).6,17 The last indication has garnered the most attention in human drug development based on the frequency with which CACS is seen in people with advanced cancer and the impact it has on survival and quality of life. Although not yet FDA approved, anamorelin, an orally administered GRA, has been extensively evaluated in humans with advanced non-small cell lung cancer. Anamorelin treatment has demonstrated significantly increased lean body mass and meaningful improvement of anorexia and cachexia clinical symptoms in these patients.24,25

A cat-specific formulation is currently being developed, and a pivotal effectiveness study for weight management in cats with chronic kidney disease, dosing at 2 mg/kg PO q24h, is anticipated to be complete in mid-2019.23

Numerous studies in dogs with cancer (osteosarcoma, lymphoma, solid tumors) indicate that dogs experience metabolic alterations similar to those documented in human patients with cachexia.26-29 Other common chronic medical conditions in dogs and cats documented to be associated with inappetence and related weight loss/cachexia include chronic kidney disease,30-33 congestive heart failure,34 and inflammatory bowel disease.35 One of the crucial advantages of GRAs in the treatment of cachexia lies in their unique ability to stimulate appetite and food intake as well as promote anabolism and increased muscle mass without the detrimental side effects of other anabolic drugs.25 The clinical impact that capromorelin may have in dogs and cats with acute or chronic medical conditions resulting in the metabolic changes consistent with cachexia remains to be determined, but the potential benefit and clinical role are exciting to consider.

Disclosures

Within the past 3 years, Dr. Johannes has the following disclosures relevant to this article: Aratana Therapeutics (advisory board, paid consultant, clinical trial) and Zoetis (advisory board, research grant).

Within the past 3 years, Dr. Musser has the following disclosure relevant to this article: Aratana Therapeutics (clinical trial [not related to Entyce]).

References

1. ENTYCE® (capromorelin oral solution) [package insert]. Leawood, KS: Aratana Therapeutics, Inc. March 2016.

2. Zollers B, Rhodes L, Smith RG. Capromorelin increases food consumption, body weight, growth hormone, and sustained insulin-like growth factor 1 concentrations when administered to healthy adult beagle dogs. J Vet Pharmacol Ther 2017;40(2):140-147.

3. Zollers B, Wofford JA, Heinen E, et al. A prospective, randomized, masked, placebo-controlled clinical study of capromorelin in dogs with reduced appetite. J Vet Intern Med 2016;30(6):1851-1857.

4. Zollers B, Rhodes L, Heinen E. Capromorelin oral solution (ENTYCE®) increases food consumption and body weight when administered for 4 consecutive days to healthy adult beagle dogs in a randomized, masked, placebo controlled study. BMC Vet Res 2017;13(1):10.

5. Molon-Noblot A, Laroque P, Prahalada S, et al. Effect of chronic growth hormone administration on skeletal muscle in dogs. Toxicol Pathol 1998;26(2):207-212.

6. Rhodes L, Zollers B, Wofford JA, Heinen E. Capromorelin: a ghrelin receptor agonist and novel therapy for stimulation of appetite. Vet Med Sci 2017;4(1):3-16.

7. MIRATAZ® (mirtazapine transdermal ointment) [package insert]. Burlingame, CA: Kindred Biosciences, Inc. Rev. May 2018.

8. Johnson LN, Freeman LM. Recognizing, describing, and managing reduced food intake in dogs and cats. JAVMA 2017;251:1260-1266.

9. Entyce® Inappetence overview. Available at: entyce.aratana.com. Accessed December 18, 2018.

10. Robinson NJ, Dean RS, Cobb M, et al. Investigating common clinical presentations in first opinion small animal consultations using direct observations. Vet Rec 2015;176(18):463.

11. Williams J, Phillips C, Byrd HM. Factors which influence owners when deciding to use chemotherapy in terminally ill pets. Animals 2017;7(3):E18.

12. Mallery KF, Freeman LM, Harpster NK, et al. Factors contributing to the decision for euthanasia of dogs with congestive heart failure. JAVMA 1999;214:1201-1204.

13. Molina J, Hervera M, Manzanilla EG, et al. Evaluation of the prevalence and risk factors for undernutrition in hospitalized dogs. Front Vet Sci 2018;5:205.

14. Gates MC, Hinds HJ, Dale A. Preliminary description of aging cats and dogs presented to a New Zealand first-opinion veterinary clinic at end-of-life. N Z Vet J 2017;65(6):313-317.

15. Punt NP, Johannes CM, Hackbarth LR, et al. Clinical survey of veterinary specialists evaluating management of chemotherapy induced vomiting and inappetence in dogs. In: ACVIM Forum Proceedings. 2017:45. Available at: onlinelibrary.wiley.com/doi/epdf/10.1111/jvim.14778. Accessed December 19, 2018.

16. Hormonal control [slide 17]. Available at: www.slideshare.net/MohanadAljashamy/appetite-regulation-48028311. Accessed December 29, 2018.

17. Howick K, Griffin BT, Cryan JF, et al. From belly to brain: targeting the ghrelin receptor in appetite and food intake regulation. Int J Mol Sci 2017;18(2):E273.

18. Yokoyama M, Nakahara K, Kojima M, et al. Influencing the between-feeding and endocrine responses of plasma ghrelin in healthy dogs. Eur J Endocrinol 2005;152(1):155-160.

19. Bhatti SF, Hofland LJ, van Koetsveld PM, et al. Effects of food intake and food withholding on plasma ghrelin concentrations in healthy dogs. Am J Vet Res 2006;67(9):1557-1563.

20. Ida T, Miyazato M, Naganobu K, et al. Purification and characterization of feline ghrelin and its possible role. Domest Anim Endocrinol 2007;32(2):93-105.

21. Zollers B, Huebner M, Armintrout G, et al. Evaluation of the safety in dogs of long-term, daily oral administration of capromorelin, a novel drug for stimulation of appetite. J Vet Pharmacol Ther 2017;40(3):248-255.

22. Wofford JA, Zollers B, Rhodes L, et al. Evaluation of the safety of daily administration of capromorelin in cats. J Vet Pharmacol Ther 2018;41(2):324-333.

23. Aratana Therapeutics. Aratana Therapeutics reports third quarter 2018 financial results. Available at: prnewswire.com/news-releases/aratana-therapeutics-reports-third-quarter-2018-financial-results-300742523.html. Accessed February 10, 2019.

24. Temel JS, Abernethy AP, Currow DC, et al. Anamorelin in patients with non-small-cell lung cancer and cachexia (ROMANA1 and ROMANA 2): results from two randomized, double-blind, phase 3 trials. Lancet Oncol 2016;17(4):519-531.

25. Currow DC, Maddocks M, Cella D, et al. Efficacy of anamorelin, a novel non-peptide ghrelin analogue, in patients with advanced non-small cell lung cancer (NSCLC) and cachexia – review and expert opinion. Int J Mol Sci 2018;19(11):E3471.

26. Mazzaferro EM, Hackett TB, Stein TP, et al. Metabolic alterations in dogs with osteosarcoma. Am J Vet Res 2001;62(8):1234-1239.

27. Vail DM, Ogilvie GK, Wheeler SL, et al. Alterations in carbohydrate metabolism in canine lymphoma. J Vet Intern Med 1990;4(1):8-11.

28. Ogilvie GK, Walters L, Salman MD, et al. Alterations in carbohydrate metabolism in dogs with nonhematopoietic malignancies. Am J Vet Res 1997;58(3):277-281.

29. Calvalido J, Wood GA, Mutsaers AJ, et al. Comparison of serum cytokine levels between dogs with multicentric lymphoma and healthy dogs. Vet Immunol Immunopathol 2016;182:106-114.

30. O’Neill DG, Elliott J, Church DB, et al. Chronic kidney disease in dogs in UK veterinary practices: prevalence, risk factors and survival. J Vet Intern Med 2013;27:814-821.

31. Greene JP, Lefebvre SL, Wang M, et al. Risk factors associated with the development of chronic kidney disease in cats evaluated at primary care veterinary hospitals. JAVMA 2014;244(3):320-327.

32. Markovich JE, Freeman LM, Labato MA, et al. Survey of dietary and medication practices of owners of cats with chronic kidney disease.
J Feline Med Surg 2015;17(12):979-983.

33. Freeman LM, Lachaud MP, Matthews S, et al. Evaluation of weight loss over time in cats with chronic kidney disease. J Vet Intern Med 2016;30:1661-1666.

34. Freeman LM, Rush JE, Kehayias JJ, et al. Nutritional alterations and the effect of fish oil supplementation in dogs with heart failure. J Vet Intern Med 1998;12:440-448.

35. Craven M, Simpson JW, Ridyard AE, et al. Canine inflammatory bowel disease: retrospective analysis of diagnosis and outcome in 80 cases (1995-2002). J Small Anim Pract 2004;45:336-342.

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id='input_6_10_5_label' >ZIP / Postal Code</label> </span><span class='ginput_right address_country' id='input_6_10_6_container' > <select name='input_10.6' id='input_6_10_6' aria-required="true"><option value='' selected='selected'></option><option value='Afghanistan' >Afghanistan</option><option value='Åland Islands' >Åland Islands</option><option value='Albania' >Albania</option><option value='Algeria' >Algeria</option><option value='American Samoa' >American Samoa</option><option value='Andorra' >Andorra</option><option value='Angola' >Angola</option><option value='Anguilla' >Anguilla</option><option value='Antarctica' >Antarctica</option><option value='Antigua and Barbuda' >Antigua and Barbuda</option><option value='Argentina' >Argentina</option><option value='Armenia' >Armenia</option><option value='Aruba' >Aruba</option><option value='Australia' >Australia</option><option value='Austria' >Austria</option><option value='Azerbaijan' >Azerbaijan</option><option value='Bahamas' >Bahamas</option><option value='Bahrain' >Bahrain</option><option value='Bangladesh' >Bangladesh</option><option value='Barbados' >Barbados</option><option value='Belarus' >Belarus</option><option value='Belgium' >Belgium</option><option value='Belize' >Belize</option><option value='Benin' >Benin</option><option value='Bermuda' >Bermuda</option><option value='Bhutan' >Bhutan</option><option value='Bolivia' >Bolivia</option><option value='Bonaire, Sint Eustatius and Saba' >Bonaire, Sint Eustatius and Saba</option><option value='Bosnia and Herzegovina' >Bosnia and Herzegovina</option><option value='Botswana' >Botswana</option><option value='Bouvet Island' >Bouvet Island</option><option value='Brazil' >Brazil</option><option value='British Indian Ocean Territory' >British Indian Ocean Territory</option><option value='Brunei Darussalam' >Brunei Darussalam</option><option value='Bulgaria' >Bulgaria</option><option value='Burkina Faso' >Burkina Faso</option><option value='Burundi' >Burundi</option><option value='Cambodia' >Cambodia</option><option value='Cameroon' >Cameroon</option><option value='Canada' >Canada</option><option value='Cape Verde' >Cape Verde</option><option value='Cayman Islands' >Cayman Islands</option><option value='Central African Republic' >Central African Republic</option><option value='Chad' >Chad</option><option value='Chile' >Chile</option><option value='China' >China</option><option value='Christmas Island' >Christmas Island</option><option value='Cocos Islands' >Cocos Islands</option><option value='Colombia' >Colombia</option><option value='Comoros' >Comoros</option><option value='Congo, Democratic Republic of the' >Congo, Democratic Republic of the</option><option value='Congo, Republic of the' >Congo, Republic of the</option><option value='Cook Islands' >Cook Islands</option><option value='Costa Rica' >Costa Rica</option><option value='Côte d&#039;Ivoire' >Côte d&#039;Ivoire</option><option value='Croatia' >Croatia</option><option value='Cuba' >Cuba</option><option value='Curaçao' >Curaçao</option><option value='Cyprus' >Cyprus</option><option value='Czech Republic' >Czech Republic</option><option value='Denmark' >Denmark</option><option value='Djibouti' >Djibouti</option><option value='Dominica' >Dominica</option><option value='Dominican Republic' >Dominican Republic</option><option value='Ecuador' >Ecuador</option><option value='Egypt' >Egypt</option><option value='El Salvador' >El Salvador</option><option value='Equatorial Guinea' >Equatorial Guinea</option><option value='Eritrea' >Eritrea</option><option value='Estonia' >Estonia</option><option value='Eswatini (Swaziland)' >Eswatini (Swaziland)</option><option value='Ethiopia' >Ethiopia</option><option value='Falkland Islands' >Falkland Islands</option><option value='Faroe Islands' >Faroe Islands</option><option value='Fiji' >Fiji</option><option value='Finland' >Finland</option><option value='France' >France</option><option value='French Guiana' >French Guiana</option><option value='French Polynesia' >French Polynesia</option><option value='French Southern Territories' >French Southern Territories</option><option value='Gabon' >Gabon</option><option value='Gambia' >Gambia</option><option value='Georgia' >Georgia</option><option value='Germany' >Germany</option><option value='Ghana' >Ghana</option><option value='Gibraltar' >Gibraltar</option><option value='Greece' >Greece</option><option value='Greenland' >Greenland</option><option value='Grenada' >Grenada</option><option value='Guadeloupe' >Guadeloupe</option><option value='Guam' >Guam</option><option value='Guatemala' >Guatemala</option><option value='Guernsey' >Guernsey</option><option value='Guinea' >Guinea</option><option value='Guinea-Bissau' >Guinea-Bissau</option><option value='Guyana' >Guyana</option><option value='Haiti' >Haiti</option><option value='Heard and McDonald Islands' >Heard and McDonald Islands</option><option value='Holy See' >Holy See</option><option value='Honduras' >Honduras</option><option value='Hong Kong' >Hong Kong</option><option value='Hungary' >Hungary</option><option value='Iceland' >Iceland</option><option value='India' >India</option><option value='Indonesia' >Indonesia</option><option value='Iran' >Iran</option><option value='Iraq' >Iraq</option><option value='Ireland' >Ireland</option><option value='Isle of Man' >Isle of Man</option><option value='Israel' >Israel</option><option value='Italy' >Italy</option><option value='Jamaica' >Jamaica</option><option value='Japan' >Japan</option><option value='Jersey' >Jersey</option><option value='Jordan' >Jordan</option><option value='Kazakhstan' >Kazakhstan</option><option value='Kenya' >Kenya</option><option value='Kiribati' >Kiribati</option><option value='Kuwait' >Kuwait</option><option value='Kyrgyzstan' >Kyrgyzstan</option><option value='Lao People&#039;s Democratic Republic' >Lao People&#039;s Democratic Republic</option><option value='Latvia' >Latvia</option><option value='Lebanon' >Lebanon</option><option value='Lesotho' >Lesotho</option><option value='Liberia' >Liberia</option><option value='Libya' >Libya</option><option value='Liechtenstein' >Liechtenstein</option><option value='Lithuania' >Lithuania</option><option value='Luxembourg' >Luxembourg</option><option value='Macau' >Macau</option><option value='Macedonia' >Macedonia</option><option value='Madagascar' >Madagascar</option><option value='Malawi' >Malawi</option><option value='Malaysia' >Malaysia</option><option value='Maldives' >Maldives</option><option value='Mali' >Mali</option><option value='Malta' >Malta</option><option value='Marshall Islands' >Marshall Islands</option><option value='Martinique' >Martinique</option><option value='Mauritania' >Mauritania</option><option value='Mauritius' >Mauritius</option><option value='Mayotte' >Mayotte</option><option value='Mexico' >Mexico</option><option value='Micronesia' >Micronesia</option><option value='Moldova' >Moldova</option><option value='Monaco' >Monaco</option><option value='Mongolia' >Mongolia</option><option value='Montenegro' >Montenegro</option><option value='Montserrat' >Montserrat</option><option value='Morocco' >Morocco</option><option value='Mozambique' >Mozambique</option><option value='Myanmar' >Myanmar</option><option value='Namibia' >Namibia</option><option value='Nauru' >Nauru</option><option value='Nepal' >Nepal</option><option value='Netherlands' >Netherlands</option><option value='New Caledonia' >New Caledonia</option><option value='New Zealand' >New Zealand</option><option value='Nicaragua' >Nicaragua</option><option value='Niger' >Niger</option><option value='Nigeria' >Nigeria</option><option value='Niue' >Niue</option><option value='Norfolk Island' >Norfolk Island</option><option value='North Korea' >North Korea</option><option value='Northern Mariana Islands' >Northern Mariana Islands</option><option value='Norway' >Norway</option><option value='Oman' >Oman</option><option value='Pakistan' >Pakistan</option><option value='Palau' >Palau</option><option value='Palestine, State of' >Palestine, State of</option><option value='Panama' >Panama</option><option value='Papua New Guinea' >Papua New Guinea</option><option value='Paraguay' >Paraguay</option><option value='Peru' >Peru</option><option value='Philippines' >Philippines</option><option value='Pitcairn' >Pitcairn</option><option value='Poland' >Poland</option><option value='Portugal' >Portugal</option><option value='Puerto Rico' >Puerto Rico</option><option value='Qatar' >Qatar</option><option value='Réunion' >Réunion</option><option value='Romania' >Romania</option><option value='Russia' >Russia</option><option value='Rwanda' >Rwanda</option><option value='Saint Barthélemy' >Saint Barthélemy</option><option value='Saint Helena' >Saint Helena</option><option value='Saint Kitts and Nevis' >Saint Kitts and Nevis</option><option value='Saint Lucia' >Saint Lucia</option><option value='Saint Martin' >Saint Martin</option><option value='Saint Pierre and Miquelon' >Saint Pierre and Miquelon</option><option value='Saint Vincent and the Grenadines' >Saint Vincent and the Grenadines</option><option value='Samoa' >Samoa</option><option value='San Marino' >San Marino</option><option value='Sao Tome and Principe' >Sao Tome and Principe</option><option value='Saudi Arabia' >Saudi Arabia</option><option value='Senegal' >Senegal</option><option value='Serbia' >Serbia</option><option value='Seychelles' >Seychelles</option><option value='Sierra Leone' >Sierra Leone</option><option value='Singapore' >Singapore</option><option value='Sint Maarten' >Sint Maarten</option><option value='Slovakia' >Slovakia</option><option value='Slovenia' >Slovenia</option><option value='Solomon Islands' >Solomon Islands</option><option value='Somalia' >Somalia</option><option value='South Africa' >South Africa</option><option value='South Georgia' >South Georgia</option><option value='South Korea' >South Korea</option><option value='South Sudan' >South Sudan</option><option value='Spain' >Spain</option><option value='Sri Lanka' >Sri Lanka</option><option value='Sudan' >Sudan</option><option value='Suriname' >Suriname</option><option value='Svalbard and Jan Mayen Islands' >Svalbard and Jan Mayen Islands</option><option value='Sweden' >Sweden</option><option value='Switzerland' >Switzerland</option><option value='Syria' >Syria</option><option value='Taiwan' >Taiwan</option><option value='Tajikistan' >Tajikistan</option><option value='Tanzania' >Tanzania</option><option value='Thailand' >Thailand</option><option value='Timor-Leste' >Timor-Leste</option><option value='Togo' >Togo</option><option value='Tokelau' >Tokelau</option><option value='Tonga' >Tonga</option><option value='Trinidad and Tobago' >Trinidad and Tobago</option><option value='Tunisia' >Tunisia</option><option value='Turkey' >Turkey</option><option value='Turkmenistan' >Turkmenistan</option><option value='Turks and Caicos Islands' >Turks and Caicos Islands</option><option value='Tuvalu' >Tuvalu</option><option value='Uganda' >Uganda</option><option value='Ukraine' >Ukraine</option><option value='United Arab Emirates' >United Arab Emirates</option><option value='United Kingdom' >United Kingdom</option><option value='United States' >United States</option><option value='Uruguay' >Uruguay</option><option value='US Minor Outlying Islands' >US Minor Outlying Islands</option><option value='Uzbekistan' >Uzbekistan</option><option value='Vanuatu' >Vanuatu</option><option value='Venezuela' >Venezuela</option><option value='Vietnam' >Vietnam</option><option value='Virgin Islands, British' >Virgin Islands, British</option><option value='Virgin Islands, U.S.' >Virgin Islands, U.S.</option><option value='Wallis and Futuna' >Wallis and Futuna</option><option value='Western Sahara' >Western Sahara</option><option value='Yemen' >Yemen</option><option value='Zambia' >Zambia</option><option value='Zimbabwe' >Zimbabwe</option></select> <label for='input_6_10_6' id='input_6_10_6_label' >Country</label> </span> <div class='gf_clear gf_clear_complex'></div> </div></li> </ul></div> <div class='gform_footer top_label'> <input type='submit' id='gform_submit_button_6' class='gform_button button' value='Sign Up' onclick='if(window["gf_submitting_6"]){return false;} window["gf_submitting_6"]=true; ' onkeypress='if( event.keyCode == 13 ){ if(window["gf_submitting_6"]){return false;} window["gf_submitting_6"]=true; jQuery("#gform_6").trigger("submit",[true]); }' /> <input type='hidden' class='gform_hidden' name='is_submit_6' value='1' /> <input type='hidden' class='gform_hidden' name='gform_submit' value='6' /> <input type='hidden' class='gform_hidden' name='gform_unique_id' value='' /> <input type='hidden' class='gform_hidden' name='state_6' value='WyJbXSIsIjNkNTNhNjhlOThlOGY4N2JlZWZiNTRmZDhlZDQ5OWI3Il0=' /> <input type='hidden' class='gform_hidden' name='gform_target_page_number_6' 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