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Case flow indicating how the safety (ITT) and PP populations were identified for the capromorelin and placebo treatment groups. *Some dogs were excluded for more than one reason.
Source publication
Background:
Reduced appetite is a common clinical sign in dogs. This study evaluated the effectiveness and safety of capromorelin oral solution, (ENTYCE® , Aratana Therapeutics, Leawood, KS) a new drug that is a ghrelin receptor agonist, for stimulation of appetite in dogs with reduced appetite.
Hypothesis/objectives:
Capromorelin will increase...
Context in source publication
Context 1
... seven dogs were considered unevaluable for the purpose of assessing effectiveness. Therefore, the per protocol population (PPP) included a total of 177 dogs with 121 dogs in the capromorelin treatment group and 56 in the placebo treatment group (Fig 1). In the safety popula- tion, dogs ranged in age from 4 months to 18 years of age, with the mean age of 8.0 years in the capromorelin group and 8.1 years in the placebo group. ...
Citations
... (4,48) The ghrelin receptor agonist, capromorelin has been recently approved by the US Food and Drug Administration for increasing appetite in dogs, but was not speci cally studied in dogs with cancer and is associated with side effects that may not be tolerated by this population. (49) There are a couple of limitations related to this research. Because poor eating and reduced appetite often indicate reduced quality of life, which is a primary driver in euthanasia decisions, (10) it is likely that owners would not have chosen to participate in the trial if they thought their dogs would not be able to tolerate their prescribed cancer treatment for the length of the trial. ...
Background
Cancer and its treatments can be associated with loss of appetite and poor quality of life (QoL) in dogs. The objective of this single-arm, non-controlled study was to evaluate eating enthusiasm and the nutritional effects of a new food (Hill’s Prescription Diet ON-Care Canine dry) in adult dogs undergoing treatment for malignant cancer. A total of 29 eligible (≥ 1 years old, confirmed diagnosis of malignant cancer, undergoing or recently underwent conventional anticancer therapy, not on any appetite stimulants, and maintaining current medications) dogs were fed the study food for 56 days, with a 7-day transition. Intake (grams, calories), body weight (BW), body condition score (BCS; 1 = very thin, 5 = obese), muscle condition score (MCS; 1 = normal, 4 = severe loss), body fat index (BFI; 20%=low risk, 70%=extreme risk), eating enthusiasm (1 = lowest, 7 = highest), stool quality (1 = liquid, 6 = firm), blood laboratory tests, and QoL were recorded at enrollment and at specific timepoints throughout the 56 days.
Results
Mean age, BW, BCS, MCS and BFI at Day 0 were 10.1 y, 20.9 kg, 3.2, 1.3 and 27.2%, respectively. Twenty-three of the 29 dogs completed the study. Food (g) and caloric intake measured starting on Day 8 were unchanged throughout the study. However, dogs had a significant increase in BW (1.18 kg, SE 0.30, P = 0.0006) and BFI (3.27%, SE 1.30, P = 0.0193), and improved MCS (–0.18, SE 0.08, P = 0.0375) at Day 56. BCS remained unchanged. Eating enthusiasm remained high throughout the study. QoL assessments were high and remained unchanged except for a significant increase in affection for the family on Day 14 (P = 0.0409). Mean fecal scores ranged between 4.39 and 4.78 throughout the study. Additionally, serum 25 OH-vitamin D significantly increased by 18.1 nmol/L (SE 7.6, P = 0.0257) on Day 56.
Conclusions
This study demonstrated high acceptance of the study food with significant improvement of muscle condition score and significant increase in serum 25 OH-vitamin D levels, as well as maintained eating enthusiasm and QoL in dogs with malignant cancer. Thus, this new food may provide a favorable nutritional choice for maintaining weight and QoL in dogs with malignant cancer.
... However, results have been mixed, partly because appetite stimulation is not a primary effect of these drugs and partly because there are no standards for dosing to achieve this effect [4,53]. Capromorelin, a ghrelin receptor agonist, has been shown to increase appetite in dogs and was recently approved for this indication, but was not specifically studied in dogs with cancer and is associated with side effects that may not be tolerated by this population [54]. One of the primary benefits of a food that encourages eating instead of a drug is that there should be minimal risk of adverse effects that would further compromise the fragile health status of an animal with cancer. ...
Diminished appetite and poor eating behavior accompanied by weight loss or cachexia are often reported in dogs living with cancer. This study was conducted to determine the acceptance and eating enthusiasm in dogs with cancer for a new therapeutic, nutritionally balanced, and calorically dense food designed for dogs with cancer. Adult dogs with diagnosis of cancer were recruited from general and oncology practices and were fed the study food for 28 days. Evaluations included physical examination, body weight, food intake, caloric intake, hematology and serum biochemistry, and owner assessments, namely food evaluation, quality of life, and stool scores. The dogs transitioned smoothly and tolerated the food very well. The results showed high food acceptance within the first day, with continued eating enthusiasm over the 28 days. Significant increases in food and caloric intake were observed, with the study food having a positive impact on body weight in dogs that were losing weight and helping to maintain a high quality of life. Blood laboratory parameters remained within reference ranges. Thus, the therapeutic study food was well accepted and efficacious in supporting continued eating and required caloric intake, promoting a healthy weight gain and maintaining a high quality of life in dogs with cancer.
... Given the importance of EN in the management of patients with AP and the poor reliability of appetite stimulants or simply offering enticing food to animals suffering from AP, more effective means of nutritional support are often required. Although the use of capromorelin (a ghrelin receptor agonist) has been demonstrated to increase appetite in dogs, this study only evaluated dogs that did not require hospitalization or intravenous fluids [21]. Therefore it is unknown whether capromorelin would be an effective appetite stimulant in dogs with AP who typically require hospitalization and fluid therapy among other therapies. ...
KEY POINTS
- Nutritional support is considered a key part of management of patients with acute pancreatitis.
- Feeding should be attempted in all patients if cardiovascularly stable, and parenteral nutrition should not be considered
unless enteral feeding is not tolerated.
- Placement of feeding tubes should be considered as the standard for providing nutritional support in hyporexic patients
with acute pancreatitis.
- Parenteral nutrition still has a place in the management of patients with acute pancreatitis, but it is to be reserved for
patients who fail to tolerate enteral nutrition.
Advances in Small Animal Care 3 (2022) 221–227
ADVANCES IN SMALL ANIMAL CARE
https://doi.org/10.1016/j.yasa.2022.05.006 www.advancesinsmallanimalcare.com
2666-450X/22/ © 2022 Elsevier Inc. All rights reserved. 221
... In both human and rodent studies administration of ghrelin has resulted in increased appetite and energy intake in patients with CKD (Gunta and Mak, 2013). In recent veterinary stud- ies, administration of capromorelin resulted in increased appetite, food intake and weight in normal and inappetent dogs, and increased food intake and weight in laboratory cats ( Zollers et al, 2015Zollers et al, , 2016Zollers et al, , 2017aRhodes et al, 2018). In a prospective, randomised, masked, placebo-controlled study, dogs with a reduced appetite were treated daily with capromorelin (3 mg/kg) oral solution (n = 121) or placebo oral solution (n = 56) ( Zollers et al, 2016). ...
... In recent veterinary stud- ies, administration of capromorelin resulted in increased appetite, food intake and weight in normal and inappetent dogs, and increased food intake and weight in laboratory cats ( Zollers et al, 2015Zollers et al, , 2016Zollers et al, , 2017aRhodes et al, 2018). In a prospective, randomised, masked, placebo-controlled study, dogs with a reduced appetite were treated daily with capromorelin (3 mg/kg) oral solution (n = 121) or placebo oral solution (n = 56) ( Zollers et al, 2016). Owners com- pleted an evaluation of appetite at days 0 and 3 +/-1 and success was defined as improvement in appetite at day 3. ...
Poor appetite is a common clinical complaint in patients with chronic kidney disease. Nurses can play an important role by helping to perform regular nutritional assessment to identify patients that require intervention. This article aims to discuss the importance of this clinical problem and the different mechanisms by which appetite may become abnormal in chronic kidney disease. Recent research on pharmacologic options for appetite stimulation offer new options such as mirtazapine for cats and capromorelin for dogs.
... It was shown in laboratory studies in healthy Beagles to be safe and effective at increasing food intake and body weight, as well as increasing growth hormone and IGF-1 [106][107][108][109]. In a clinical trial in dogs with reduced appetite, the drug was shown to increase appetite and body weight [110]. While it is labeled for appetite stimulation, the beneficial effects of ghrelin on LBM and other organs make it a promising drug for cachexia and sarcopenia. ...
While laboratory small animal models of cachexia and sarcopenia are well‐suited and critical for studying mechanisms and early pre‐clinical phases for potential treatments, they are not similar enough to the human conditions to always be good predictors for results in human clinical trials. As a result, translational failures can occur when large‐scale human clinical trials are conducted on drugs, even when they appear promising in pre‐clinical studies in rodent models. What is needed is a way to more efficiently and successfully translate information gained from basic science and rodent research into human clinical trials that produce effective approved drugs. Naturally‐occurring cachexia and sarcopenia in companion animals is a more representative model of human disease that can serve as a stepping stone between basic science and human clinical trials. Many of the common diseases of humans also affect companion animals, particularly pet dogs and cats. Pet dogs and cats commonly develop heart failure, cancer, and kidney disease, as well as acute trauma or illness. The population of elderly companion animals also is increasing as pets' lifespans have become longer. As a result, both cachexia and sarcopenia are very common in companion animals. Studying these conditions in dogs and cats – either in colonies or in animal clinical trials ‐ can help to identify successful treatments that can benefit both humans and companion animals.
... A prospective, placebo controlled, masked clinical study of capromorelin (ENTYCE â ) was conducted in client-owned dogs that presented to veterinary clinics with at least 2 days of reduced appetite, as reported by the owners, due to a variety of causes (Zollers et al. 2016b). ...
... The field study (Zollers et al. 2016b) was conducted in client-owned dogs (171 dogs treated with capromorelin and 73 dogs treated with placebo in the intention to treat population) treated for 4 days after being presented with a variety of underlying conditions resulting in at least 2 days of inappetence; there was no report of any cardiovascular adverse event potentially related to treatment. ...
Ghrelin is a hormone, secreted from cells in the stomach, which is important in the regulation of appetite and food intake in mammals. It exerts its action by binding to a specific G-protein-coupled receptor, the growth hormone secretagogue receptor 1a (GHS-R1a) which is found in areas of the brain associated with the regulation of food intake. Ghrelin causes a release of growth hormone (GH) through binding to GHS-R1a in the hypothalamus and pituitary gland. A class of compounds known as growth hormone secretagogues, or ghrelin receptor agonists, were developed for therapeutic use in humans for the stimulation of GH in the frail elderly, and have subsequently been studied for their effects on increasing appetite and food intake, increasing body weight, building lean muscle mass, and treating cachexia. Subsequent research has shown that ghrelin has anti-inflammatory and immunomodulatory effects. This article reviews the basic physiology of ghrelin and the ghrelin receptor agonists, including the available evidence of these effects in vitro and in vivo in rodent models, humans, dogs and cats. One of these compounds, capromorelin, has been FDA-approved for the stimulation of appetite in dogs (ENTYCE®). The data available on the safety and effectiveness of capromorelin is reviewed, along with a discussion of the potential clinical applications for ghrelin receptor agonists in both human and veterinary medicine.
... Treatment with oral capromorelin was shown to increase IGF-1 levels and total lean body mass in elderly men and women ( White et al., 2009). In addition, capromorelin has been shown to stimulate appetite, food intake, weight gain and GH and IGF-1 release in dogs ( Zollers, Huebner, Armintrout, Rausch-Derra, & Rhodes, 2017;Zollers, Rhodes, & Heinen, 2017;Zollers, Rhodes, & Smith, 2017;Zollers, Wofford, Heinen, Huebner, & Rhodes, 2016). Capromorelin is the only Food and Drug Administration (FDA)approved ghrelin receptor agonist and is currently approved for use in dogs to stimulate appetite. ...
Capromorelin is a ghrelin receptor agonist that is FDA approved for appetite stimulation in dogs. The objective of this study was to evaluate the safety of daily oral administration of capromorelin to cats over a range of doses and for an extended period. Two randomized, controlled studies were conducted: in Study 1, cats (n = 6 per group) received placebo or capromorelin at a dose of 9, 15, 30 or 60 mg/kg once daily for 14 days; and in Study 2, cats received capromorelin at 6 mg/kg (n = 8) or placebo (n = 4) once daily for 91 days. Cats were evaluated using clinical observations and clinical pathology test results for both studies, with the addition of postmortem examination in Study 1 and measurements of growth hormone and insulin-like growth factor 1 in Study 2. Abnormal clinical observations were limited to emesis, hypersalivation, lethargy/depression, head shaking and lip smacking, which occurred more frequently in the capromorelin-treated groups than in the placebo group. There were no clinically relevant differences in clinical pathology test results between the capromorelin and placebo groups in either study.
... A glance through recent issues of the Journal of Veterinary Internal Medicine identifies prospective randomized clinical trials (RCTs) involving dogs, [1][2][3][4][5][6][7][8][9] cats, 10-13 cows, 14,15 and horses 16,17 that cover the fields of neurology, 1,8 oncology, 3,5 cardiology, 4,6,12 and internal medicine. 2,[9][10][11][13][14][15][16][17] Collectively, these findings suggest that we have entered into an era of prospective veterinary RCTs. ...
... A glance through recent issues of the Journal of Veterinary Internal Medicine identifies prospective randomized clinical trials (RCTs) involving dogs, [1][2][3][4][5][6][7][8][9] cats, 10-13 cows, 14,15 and horses 16,17 that cover the fields of neurology, 1,8 oncology, 3,5 cardiology, 4,6,12 and internal medicine. 2,[9][10][11][13][14][15][16][17] Collectively, these findings suggest that we have entered into an era of prospective veterinary RCTs. Without question, this is an achievement worth celebrating, but as is often the case, with progress comes new challenges. ...
Randomized clinical trials (RCTs) are among the most rigorous ways to determine the causal relationship between an intervention and important clinical outcome. Their use in veterinary medicine has become increasingly common, and as is often the case, with progress comes new challenges. Randomized clinical trials yield important answers, but results from these studies can be unhelpful or even misleading unless the study design and reporting are carried out with care. Herein, we offer some perspective on several emerging challenges associated with RCTs, including use of composite endpoints, the reporting of different forms of risk, analysis in the presence of missing data, and issues of reporting and safety assessment. These topics are explored in the context of previously reported veterinary internal medicine studies as well as through illustrative examples with hypothetical data sets. Moreover, many insights germane to RCTs in veterinary internal medicine can be drawn from the wealth of experience with RCTs in the human medical field. A better understanding of the issues presented here can help improve the design, interpretation, and reporting of veterinary RCTs.
... In a recent clinical study in 244 dogs at over 30 veterinary clinics, dogs experiencing inappetence from a variety of conditions were treated with 3 mg/kg capromorelin for 4 days. This study demonstrated a statistically significant improvement in appetite as measured by an owner appetite assessment (P = 0.0078) and an increase in body weight (P = 0.0004) in the capromorelin treated group compared to the placebo group [10]. ...
Background
Dogs can suffer from inappetence caused by a variety of medical conditions. This may present as anorexia (complete loss of appetite), hyporexia (decreased appetite) or dysrexia (change in food preferences). A drug with a new mechanism of action, capromorelin, has potential to stimulate appetite in dogs. Capromorelin is a ghrelin receptor agonist, which mimics the action of endogenous ghrelin. It is a member of the growth hormone secretagogue (GHS) class of drugs. Capromorelin oral solution (ENTYCE®) was tested in healthy adult male and female Beagle dogs (n = 6 males and 6 females per group) for its effect on food consumption and body weight. A randomized, masked, placebo controlled study was conducted to measure the effects of a daily 3 mg/kg oral dose given over 4 days. Dogs were observed for clinical signs, physical examinations were completed prior to and at the end of treatment, and blood was drawn before and after treatment for evaluation of serum chemistry and hematology parameters.
Results
Capromorelin was well-tolerated, with no abnormalities seen on physical examination or clinical pathology. Some dogs showed increased salivation. Capromorelin treated dogs had increased mean (±SD) food consumption compared to placebo treated dogs (60.55 ± 39.87% versus -11.15 ± 14.23% respectively, P < 0.001). Treated dogs also had increased mean body weights compared to placebo treated dogs (5.96 ± 1.76% versus 0.053 ± 1.14% respectively, P < 0.001).
Conclusions
This study supports the effectiveness of capromorelin oral solution as an appetite stimulant in dogs. Treatment with the oral solution resulted in dramatic increases in appetite, as measured by food consumption, of over 60% compared to placebo. The drug was well tolerated. Capromorelin is the first ghrelin receptor agonist developed for appetite stimulation in any species, and represents a novel mechanism of action for this clinical use.
