Discussion of Study Design Clause Samples

Discussion of Study Design. Including the Choice of Control Groups

Discussion of Study Design. Including the Choice of Control Groups 5 SELECTION OF STUDY POPULATION 5.1 Inclusion Criteria (1) Signed informed consent from one of the parent(s)/legal representative(s). (2) Subjects, both genders, aged 3 to 60 months. (3) Subjects with acute diarrhea (defined as the passage of three or more unformed or liquid stools within the last 24 hours and lasting for less than 3 days). 5.2 Exclusion Criteria (1) Known allergy to Racecadotril or any of its ingredients. (2) Subjects suffering from renal or hepatic impairment. (3) Subjects with fever > 39 degrees Celsius (4) Subjects with bloody and/or purulent stools. (5) Subjects suffering from antibiotic (e.g. amoxicillin)-associated diarrhea, chronic diarrhea or iatrogenic diarrhea. (6) Subjects with alternating bouts of diarrhea and constipation. (7) Diarrhea due to exacerbation of chronic gastrointestinal diseases such as irritable bowel syndrome, irritable bowel disease or pancreatic exocrine insufficiency. (8) Cystic fibrosis or coeliac disease. (9) Subjects suffering from prolonged or uncontrolled vomiting. (10) Subjects with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption syndrome or sucrase isomaltase insufficiency. (11) Subjects having received antibiotic treatment within 2 weeks prior to start of the current diarrhea episode. (12) Subjects having received antidiarrheal drugs (except pre- or probiotics see section 7.7.) 48 hours prior to Day 1. (13) Subjects with severe dehydration requiring intravenous fluid or electrolyte replacement or hospitalization treatment. (14) Subject with a history of angioedema or who had reported angioedema with angiotensin converting enzyme inhibitors (such as captopril, enalapril, lisinopril, perindopril, ramipril) (15) Subjects with combined diseases or medical situations that would prevent to be enrolled into the study, depending on the judgment of the investigator (16) Intake of experimental drug within 30 days prior to study start. (17) Subjects with contraindications to ORS or susceptible to the warnings of ORS.

Discussion of Study Design. A single-dose, parallel design is the standard design to investigate the PK of a drug in subjects with renal impairment. A parallel design is required to include subjects with renal impairment and matched-control healthy subjects with normal renal function. A single dose level of 200 mg LOXO-305 will be used because it is the dose intended for registration. The study will be open-label because the primary endpoints are objective rather than subjective. Matched-control healthy subjects with normal renal function will be enrolled in this study to serve as a reference group for interpretation of the results. Based on nonclinical and clinical data, and the known PK profile of the compound, the duration of the treatment period is considered adequate to achieve the study objectives.1 Oral doses were chosen because this is the intended clinical route of administration. Renal clearance of LOXO-305 in male and female rats was negligible. No data on renal clearance are available in other species; however, the renal excretion pathway is often conserved across species, and therefore no renal clearance would be expected in humans. In consideration of this, subjects with renal impairment assessed as severe (eGFR: < 30 mL/min/1.73 m2), along with matched-control healthy subjects, will begin enrolling into the study first. If a clinically relevant difference is observed in the PK of subject(s) with severe renal impairment compared to matched-control healthy subjects during continuous review of the safety and PK data, then subjects with renal impairment assessed as mild (60 ≤ eGFR < 90 mL/min/1.73 m2) and/or moderate (30 ≤ eGFR < 60 mL/min/1.73 m2), along with additional matched-control healthy subjects (if needed) will be enrolled, to determine the extent of the effect of varying severities of renal impairment on the PK of LOXO-305. Enrollment of subjects with mild and/or moderate renal impairment will only be initiated if deemed necessary by the Sponsor following the continuous review of safety and PK data from severe renal impairment subjects and their matched-control healthy subjects (see Section 8.2). If no clinically relevant effect on PK is observed, enrollment of mild and/or moderate subjects will not occur.

Discussion of Study Design. A single-dose, parallel design is the standard design to investigate the PK of a drug in subjects with hepatic impairment. A parallel design is required to include subjects with hepatic impairment and matched-control healthy subjects with normal hepatic function. A single dose level of LOXO-305 will be used because it is the dose intended for registration. The study will be open label because the primary endpoints are objective rather than subjective. Matched-control healthy subjects with normal hepatic function will be enrolled in this study to serve as a reference group for interpretation of the results. Patients with a range of hepatic impairment will be included to enhance the ability to detect and characterize the effects of hepatic function on the PK of LOXO-305. Based on nonclinical and clinical data, and the known PK profile of the compound, the duration of the treatment period is considered adequate to achieve the study objectives.1 Oral doses were chosen because this is the intended clinical route of administration. Preclinical and clinical data suggest that LOXO-305 is likely to be well tolerated in healthy human subjects. However, liver disease can cause alterations in drug disposition, reducing the clearance of drugs eliminated by hepatic metabolism or biliary excretion and affect plasma protein binding, which in turn could influence the processes of distribution and elimination. Therefore, in this study, a cautious approach will be adopted, where the first 2 subjects from Group 2 (mild hepatic impairment subjects) and Group 3 (moderate hepatic impairment subjects) and matched-control healthy subjects may be dosed concurrently, followed by an interim review of the safety and PK data (if available) before dosing is resumed for the remaining subjects in any (all) group(s) (see Section 8.2).