A Study to Evaluate the Effect of Camicinal on Gastroparesis Symptoms in Type 1 and 2 Diabetic Subjects With Gastroparesis

Study Overview
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Brief Summary
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This study is a randomized, double-blind, placebo controlled trial designed to confirm the symptomatic effects of camicinal treatment vs. placebo, on gastroparesis symptoms in type 1 and 2 diabetic subjects with gastroparesis. The primary purpose of this study is to determine if a low-dose of camicinal (25 milligram[mg]) for 12 weeks of repeat administration improves gastroparesis symptoms as measured by the Gastrointestinal Cardinal Symptom Index - Daily Diary (GCSI-DD) in approximately 120 subjects with type 1 or 2 diabetes mellitus (DM) who have documented abnormally slow gastric emptying and have symptoms consistent with gastroparesis. Subjects will be randomized in a 1:1 ratio to receive either camicinal or placebo. The study will consist of a screening/baseline period of up to 35 days, a 12 week treatment period, a 2-week post-treatment assessment of symptoms and a 14 day (+/- 2 days) post treatment safety follow-up visit.

Official Title
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A Randomized, Double-blind, Placebo-controlled Phase II Study to Evaluate the Effect of 12 Weeks of Once-daily Dosing of the Oral Motilin Receptor Agonist Camicinal, on Gastroparesis Symptoms in Type 1 and 2 Diabetic Subjects With Gastroparesis

Conditions
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Gastroparesis

Intervention / Treatment
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* Drug: Placebo
* Drug: Camicinal


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 1 or 2 diabetes mellitus (acetylated hemoglobin A1 [HbA1c] <=11.0%) Male or female between 18 and 80 years of age, inclusive. Patient has gastroparesis at screening. A patient is eligible if one of the following criteria are met: Gastric half-time of emptying >upper limit of normal as determined by Carbon-13 radioisotope (C13) oral breath test; % C13-dose recovered < lower limit of normal at 90 or 120 minutes Patient must report a >=3 month history of relevant symptoms of gastroparesis (e.g., chronic post-prandial fullness, early satiety, post-prandial nausea). Patients will have a mean of the daily scores over a minimum of 7 days indicating >= mild (2) severity for the fullness/early satiety subscale as assessed using the GCSI-DD during the screening period prior to randomization. A female patient is eligible to participate if she is of non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous follicle stimulating hormone [FSH] >40 milli international units per milliliter [mIU/mL], or a value consistent with the local laboratory standard value, is confirmatory) or is of child-bearing potential and agrees to use contraception methods for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female patients must agree to use contraception for at least 5 days following the last dose of study medication. Body mass index (BMI) >18 and <=42.0 kilogram per meter square (kg/m^2) (inclusive). QTc <450 millisecond (msec) or QTc <480 msec in patients with Bundle Branch Block based on single or average QTc value of triplicate values obtained over a brief recording period. The QT correction formula (Bazett's, Fridericia's, etc) used to determine inclusion and discontinuation should be the same throughout the study. Aspartate aminotransferase and alanine aminotransferase <2x upper limit of normal (ULN); alkaline phosphatase and bilirubin <=1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. Exclusion Criteria: Patient has acute severe gastroenteritis Patient has a gastric pacemaker Patient is on chronic enteral (e.g., feeding tube) or parenteral feeding Recent (last 6 weeks) history of poor control of diabetes e.g. hypoglycaemia requiring medical intervention, diabetic ketoacidosis, admission for control of diabetes or complications of diabetes Patient has evidence of severe cardiovascular autonomic neuropathy (e.g. history of recurrent syncope in the last 6 months) Patient has a history of eating disorders (anorexia nervosa, binge eating, bulimia) Use of medications potentially influencing upper gastrointestinal motility or appetite at least 1 week prior to screening (e.g., prokinetic drugs, macrolide antibiotics [erythromycin], glucagon-like peptide-1 [GLP-1] mimetics) Patient has had intrapyloric botox injections. A patient would be eligible if the botox treatment was in the past (>6 months previously) and was not being repeated. Patient has had a gastrectomy, or major gastric surgical procedure or any evidence of bowel obstruction or strictures within the previous 12 months Dosage of any concomitant medications has not been stable for at least 3 weeks, except for routine adjustments in daily insulin treatments. Estimated (or measured) glomerular filtration rate <=30 mL/minute. Daily opiate use at screening Use of prohibited medications that potentially influence upper gastrointestinal motility or appetite, or medications that may interfere with the methods of measuring gastric emptying e.g., prokinetic drugs, macrolide antibiotics (erythromycin, azithromycin), GLP-1 mimetics, anti-cholinergics, chronic/regular use of opiates History or presence of clinically significant gastro-intestinal, hepatic or renal disease (including liver disease or known hepatic or biliary abnormalities, with the exception of Gilbert's syndrome or asymptomatic gallstones) or other condition that would in the opinion of the investigator or medical monitor make the subject unsuitable for inclusion in this clinical study. Concurrent enrollment in any other interventional study/(ies) involving a novel (i.e. unapproved or experimental) chemical or biopharmaceutical entity. History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GlaxoSmithKline Medical Monitor, contraindicates their participation. Lactating or Pregnant females as determined by positive serum or urine human chorionic gonadotropin test (from the first urine of the day) at screening or prior to dosing. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Subjects will receive camicinal matching placebo orally once daily (QD) from Day 1 to Day 84 | Drug: Placebo<br>* Camicinal matching placebo is available as tablet to be taken orally with 100mL of water in the morning<br>|
| Experimental: Camicinal 25mg<br>Subjects will receive camicinal 25 mg orally QD from Day 1 to Day 84 | Drug: Camicinal<br>* Camicinal is available as 25 mg tablet to be taken orally with 100mL of water in the morning<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Responders Based on the Fullness/Early Satiety Subscale (Responders) as Assessed by Gastrointestinal Cardinal Symptom Index-Daily Diary (GCSI-DD) at Week 12 | The GCSI-DD consists of nine symptom severity items covering the following domains: nausea/vomiting; fullness/early satiety, and bloating. In addition, the GCSI-DD contains two symptom severity items upper abdominal pain and overall rating of gastroparesis symptoms. Participants were asked to rate each symptom on a 6-point scale from 0 to 5 with lower scores representing less symptom severity and higher scores indicating more severe symptoms. Fullness/early satiety response is defined as an improvement from Baseline by at least one point in the weekly average for the subscale. A participant was defined as a responder if the participant's weekly average change from Baseline in the fullness/early satiety response score improved by at least 1 point. Percentage of participants showing response were presented. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Individual Items, Subscales and Total Score of GCSI-DD at Week 12 | Items of GCSI-DD for gastroparesis (GP) symptom assessment included: 3-nausea, 4-feeling full after meals, 5-bloating, 6-unable to finish normal meal, 7-retching, 8-vomiting, 9-stomach visibly larger, 10-stomach fullness, 11-loss of appetite, 12-upper abdominal pain, 13-upper abdominal discomfort and 14-overall severity of GP symptoms. Each symptom rated on a 6-point scale from 0 to 5 where 0 indicated absence of symptom and higher score indicated greater severity of symptom. Score of nausea/vomiting subscale was mean of items 3, 7, 8; fullness/early satiety subscale was mean of items 4, 6, 10, 11; bloating subscale was mean of items 5, 9. Total GCSI-DD score was mean of 3 subscales. For all, 0 indicated absence of symptom and higher score indicated greater severity of symptoms. Baseline was defined as weekly average of last 7 daily scores recorded during screening period. Change from Baseline was calculated by subtracting mean score for Baseline from weekly average score of Week 12. | Baseline (Screening) and Week 12 | 
| Number of Participants With Change From Baseline (Day 1) in Blood Pressure of Potential Clinical Importance (PCI) Over 100 Days | Abnormal values of systolic and diastolic blood pressure were measured. If the value for a participant at a given visit was outside the PCI, the participants were further categorized as per the increase or decrease of systolic blood pressure (SBP) and diastolic blood pressure (DBP) from Baseline by 10, 20 and 40 millimeters of mercury (mm of Hg). Number of participants with absolute (ABS) SBP (>160 mm Hg) and ABS DBP (100 mm Hg) were also analyzed. Change from Baseline (CFB) is the post-Baseline value minus the Baseline value. Participants were counted only once per parameter. Participant may have had more than 1 abnormal parameter. Only worst post-Baseline CFB values were considered. The categories mentioned for data values indicate the blood pressure ranges of clinical concern. | Up to 100 days | 
| Number of Participants With Change From Baseline (Day 1) in Heart Rate of PCI Over 100 Day | Abnormal values of heart rate over 100 days was analyzed and reported. Participants were counted only once per parameter. Participant may have had more than 1 abnormal parameter. Only worst post baseline CFB values were considered. The categories mentioned for data values indicate the heart rate ranges of clinical concern. | Up to 100 days | 
| Number of Participants With Normal and Abnormal 12-lead Electrocardiogram (ECG) Measurements Over 100 Days | The 12-lead ECG was analyzed as a measure of safety and tolerability. Number of participants with normal ECG, abnormal clinically significant, and abnormal clinically not significant ECG were reported. PR interval of < 110 and > 220 milliseconds (msec), QRS interval of <75 and > 110 msec, absolute QTc interval of > 450 to ≤ 480 or > 480 to ≤ 500 or >500 msec, and increase from Baseline in QTc of > 30 to ≤ 60 msec or >60 msec was considered as of abnormal. | Up to 100 days | 
| Number of Participants With Change From Baseline in Hematological Abnormalities of PCI by Treatment and Visit Over Period | Hematology analysis was performed at screening (fasted) and during the study at each indicated time point. Participants with abnormalities in changes from Baseline values were recorded. Total absolute neutrophil count (tANC <1.5 Giga per Liter [G/L]), hemoglobin (<25 or >25 G/L), hematocrit (<0.075 or >0.075 %), platelet count (<100 or >500 G/L), lymphocytes low (<0.8 G/L), and white blood cells (WBC <3 G/L or >20G/L) were analyzed for their low (L) or high (H) values. Change from Baseline (CFB) was the post-Baseline value minus then Baseline value. Baseline was defined as last non-missing measurement prior to dosing. One participant was randomized to Placebo arm; however, was included within the Camicinal treatment group as they reported at least one PK trough concentration >53 nano-grams per milliliter (ng/mL). | Up to 100 days | 
| Number of Participants With Change From Baseline Clinical Chemistry Abnormalities of PCI by Treatment and Visit Over Period | Clinical chemistry laboratory analysis was performed at screening (fasted) and during the study at each indicated time point. Albumin low (<30 G/L), calcium low (<2 or >2.75 millimoles per Liter [mmol/L]), creatinine (>44 micromoles per Liter change from baseline), Glucose (<3 or >18 mmol/L), potassium (<3.0 or >5.5 mmol/L), sodium (<130 or >150 mmol/L), and carbon di oxide (CO2) (<18 or >35 mmol/L) were analyzed for their low (L) or high (H) values. Participants with abnormalities in changes from Baseline values were recorded. Change from Baseline is the post-Baseline value minus the Baseline value. | Up to 100 days | 
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs), and Adverse Events Leading to Discontinuation of the Study Drug | An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Serious adverse event (SAE) is an adverse event that results in death, is life-threatening, requires inpatient hospitalization or extends a current hospital stay, results in an ongoing or significant incapacity or interferes substantially with normal life functions, or causes a congenital anomaly or birth defect. Medical events that do not result in death, are not life-threatening, or do not require hospitalization may be considered serious adverse events if they put the participant in danger or require medical or surgical intervention to prevent one of the results listed above. Any AE or SAE that led discontinuation of the study drug either by participant or by investigator was considered as an AE leading to discontinuation of the study drug. | Up to end of follow up (100 days) | 
| Trough Plasma Concentration of Camicinal on Day 28 and Day 84 | A pre-dose blood sample was collected on Days 28 and 84 for pharmacokinetic analysis. This analysis was applicable only for Camicinal arm and thus, no participants from Placebo arm were analyzed. | Day 28 and Day 84 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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repeat dose, phase II, GCSI-DD, pharmacodynamics, gastroparesis, type 1 and type 2 diabetes mellitus, camicinal, GSK962040, symptoms, gut motility