Study to Evaluate Safety/Duration in Stomach of Extended Release Capsules in Healthy Adults

Study Overview
=================
Brief Summary
-----------------
To assess how long extended release prototype capsule formulations stay in the stomach as determined by magnetic resonance imaging (MRI). To evaluate the safety of several extended release capsule formulations (LYN-PLT) and a placebo capsule.

Detailed Description
-----------------
This is a multicentre, observer blind, randomised, single dose study in healthy adult subjects. The first 5 subjects enrolled into the study will be regarded as Dosing Group 1 (sentinel group) and assigned to each of the five available study formulations. Dosing of subjects in Dosing Groups 1 and 2 will be performed at the endoscopy centre. Dosing of subjects in Dosing Groups 3 through 5 will be performed at the clinical site. Subjects remain in the inpatient unit for 7 days after dosing. During this time, subjects undergo intermittent imaging assessments for gastric retention (MRI and abdominal U/S), safety assessments and faecal collections for assessments of retrieved components and bowel movement characteristics. Subjects return to the clinic on Days 10, 15, 22 and 29 (End of Study visit). Safety assessments will be performed at all visits. MRI, abdominal U/S and outpatient faecal collections may continue based on the clinical findings from subjects dosed with modified release capsule formulations. On Day 29, the subjects will undergo final safety assessments at the clinic and thereafter, will be discharged from the study.

Official Title
-----------------
A Multicentre, Randomised, Controlled, Observer-Blind Study to Evaluate Safety and Gastric Retention Properties of Modified Release Prototype Capsules (LYN-PLT) in Healthy Adults

Conditions
-----------------
Gastric Retention, Healthy

Intervention / Treatment
-----------------
* Drug: Formulation A
* Drug: Formulation B
* Drug: Formulation C
* Drug: Formulation D
* Drug: Formulation E
* Procedure: Endoscopy
* Procedure: Magnetic Resonance Imaging


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy male and female subjects Body mass index of 18.0 to 30.0 kg/meters-squared Suitable scores for two swallowing questionnaires Demonstrate normal swallowing and gastrointestinal passage for capsule, as assessed while undergoing imaging studies Must provide written informed consent Exclusion Criteria: Participants who have previously been enrolled in this study History of any drug or alcohol abuse in the past 2 years Current smokers and those who have smoked within the past 12 months Individuals with clinically significant medical history relating to the gastrointestinal tract and potential complications, thereof Individuals with a positive test for HIV, hepatitis B or hepatitis C Serious adverse reaction or serious hypersensitivity to components of the study formulations or patency capsule Individuals who have received any experimental agent within 30 days (or 5 half-lives), whichever is longer, prior to the date of dosing Individuals with contraindication to MRI imaging Individuals with functional constipation, irritable bowel, or functional diarrhea, as evaluated by standardized questionnaire Individuals with contraindications to elective X-ray based on known or expected radiation exposure

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: A total of 40 eligible subjects participate in the Dosing and Observation period. The enrollment occurs in five Dosing Groups. Within each Dosing Group, subjects are randomized to receive either one of four LYN-PLT extended release capsules or a placebo capsule (8 per formulation).
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sentinel Group 1 LYN-PLT<br>Sentinel dosing in endoscopy center of one of each formulation (A, B, C, D, E) in a 1:1:1:1:1 ratio (centralized randomized, observer blind) and evaluation of gastric retention by MRI | Drug: Formulation A<br>* Formulation A (37/40A) of LYN-PLT containing less than 300 mg sucrose within the extended release formulation<br>* Other names: LYN-PLT Formulation A;Drug: Formulation B<br>* Formulation B (46/40A) of LYN-PLT containing less than 300 mg sucrose within the extended release formulation<br>* Other names: LYN-PLT Formulation B;Drug: Formulation C<br>* Formulation C (37/50A) of LYN-PLT containing less than 300 mg sucrose within the extended release formulation<br>* Other names: LYN-PLT Formulation C;Drug: Formulation D<br>* Formulation D (46/50A) of LYN-PLT containing less than 300 mg sucrose within the extended release formulation<br>* Other names: LYN-PLT Formulation D;Drug: Formulation E<br>* Placebo Capsule containing microcrystalline cellulose<br>* Other names: Placebo capsule;Procedure: Endoscopy<br>* Endoscopy at 2 hours post dosing<br>Procedure: Magnetic Resonance Imaging<br>* MRI will be performed on specified days according to protocol<br>* Other names: MRI;|
| Experimental: Sentinel Group 2 LYN-PLT<br>Sentinel dosing (second) in endoscopy center of one of each formulation (A, B, C, D, E) in a 1:1:1:1:1 ratio (centralized randomized, observer blind) and evaluation of gastric retention by MRI | Drug: Formulation A<br>* Formulation A (37/40A) of LYN-PLT containing less than 300 mg sucrose within the extended release formulation<br>* Other names: LYN-PLT Formulation A;Drug: Formulation B<br>* Formulation B (46/40A) of LYN-PLT containing less than 300 mg sucrose within the extended release formulation<br>* Other names: LYN-PLT Formulation B;Drug: Formulation C<br>* Formulation C (37/50A) of LYN-PLT containing less than 300 mg sucrose within the extended release formulation<br>* Other names: LYN-PLT Formulation C;Drug: Formulation D<br>* Formulation D (46/50A) of LYN-PLT containing less than 300 mg sucrose within the extended release formulation<br>* Other names: LYN-PLT Formulation D;Drug: Formulation E<br>* Placebo Capsule containing microcrystalline cellulose<br>* Other names: Placebo capsule;Procedure: Endoscopy<br>* Endoscopy at 2 hours post dosing<br>Procedure: Magnetic Resonance Imaging<br>* MRI will be performed on specified days according to protocol<br>* Other names: MRI;|
| Experimental: Group 3 LYN-PLT<br>Dosing in clinic of two of each formulation (A, B, C, D, E) in a 1:1:1:1:1 ratio (centralized, randomized, observer blind). and evaluation of gastric retention by MRI | Drug: Formulation A<br>* Formulation A (37/40A) of LYN-PLT containing less than 300 mg sucrose within the extended release formulation<br>* Other names: LYN-PLT Formulation A;Drug: Formulation B<br>* Formulation B (46/40A) of LYN-PLT containing less than 300 mg sucrose within the extended release formulation<br>* Other names: LYN-PLT Formulation B;Drug: Formulation C<br>* Formulation C (37/50A) of LYN-PLT containing less than 300 mg sucrose within the extended release formulation<br>* Other names: LYN-PLT Formulation C;Drug: Formulation D<br>* Formulation D (46/50A) of LYN-PLT containing less than 300 mg sucrose within the extended release formulation<br>* Other names: LYN-PLT Formulation D;Drug: Formulation E<br>* Placebo Capsule containing microcrystalline cellulose<br>* Other names: Placebo capsule;Procedure: Magnetic Resonance Imaging<br>* MRI will be performed on specified days according to protocol<br>* Other names: MRI;|
| Experimental: Group 4 LYN-PLT<br>Dosing in clinic of two of each formulation (A, B, C, D, E) in a 1:1:1:1:1 ratio (centralized, randomized, observer blind) and evaluation of gastric retention by MRI | Drug: Formulation A<br>* Formulation A (37/40A) of LYN-PLT containing less than 300 mg sucrose within the extended release formulation<br>* Other names: LYN-PLT Formulation A;Drug: Formulation B<br>* Formulation B (46/40A) of LYN-PLT containing less than 300 mg sucrose within the extended release formulation<br>* Other names: LYN-PLT Formulation B;Drug: Formulation C<br>* Formulation C (37/50A) of LYN-PLT containing less than 300 mg sucrose within the extended release formulation<br>* Other names: LYN-PLT Formulation C;Drug: Formulation D<br>* Formulation D (46/50A) of LYN-PLT containing less than 300 mg sucrose within the extended release formulation<br>* Other names: LYN-PLT Formulation D;Drug: Formulation E<br>* Placebo Capsule containing microcrystalline cellulose<br>* Other names: Placebo capsule;Procedure: Magnetic Resonance Imaging<br>* MRI will be performed on specified days according to protocol<br>* Other names: MRI;|
| Experimental: Group 5 LYN-PLT<br>Dosing in clinic of two of each formulation (A, B, C, D, E) in a 1:1:1:1:1 ratio (centralized, randomized, observer blind) and evaluation of gastric retention by MRI. | Drug: Formulation A<br>* Formulation A (37/40A) of LYN-PLT containing less than 300 mg sucrose within the extended release formulation<br>* Other names: LYN-PLT Formulation A;Drug: Formulation B<br>* Formulation B (46/40A) of LYN-PLT containing less than 300 mg sucrose within the extended release formulation<br>* Other names: LYN-PLT Formulation B;Drug: Formulation C<br>* Formulation C (37/50A) of LYN-PLT containing less than 300 mg sucrose within the extended release formulation<br>* Other names: LYN-PLT Formulation C;Drug: Formulation D<br>* Formulation D (46/50A) of LYN-PLT containing less than 300 mg sucrose within the extended release formulation<br>* Other names: LYN-PLT Formulation D;Drug: Formulation E<br>* Placebo Capsule containing microcrystalline cellulose<br>* Other names: Placebo capsule;Procedure: Magnetic Resonance Imaging<br>* MRI will be performed on specified days according to protocol<br>* Other names: MRI;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gastric retention assessed by Magnetic Resonance Imaging (MRI) | Visualization of formulation/formulation components in the stomach by MRI | Up to 9 Days post-dosing | 
| Safety and tolerability of four LYN-PLT modified release capsules and a placebo capsule collected from Adverse Event (AE) reporting based on spontaneous reports | The number of confirmed gastrointestinal adverse events will be reported based on spontaneous adverse event reporting | Through study completion, up to 6 months | 
| Safety and tolerability of four LYN-PLT modified release capsules and a placebo capsule collected from Adverse Event (AE) reporting based on changes in examinations pre (Day 1) and post dosing (Days 4 and 7) | Clinically significant aggregate changes in vital signs, physical examinations and safety laboratory assessments (haematology, liver function tests, clinical chemistry panel) between pre-dose (Day 1) and post-dosing (Day 4 and 7) will be reported as AE's | Through study completion, up to 6 months | 
| Safety and tolerability of four LYN-PLT modified release capsules and a placebo capsule collected from Adverse Event (AE) reporting based on post dosing evaluation of bowel movements for blood | Examination and reporting of post-dosing bowel movements for blood; clinically significant abnormal findings will be reported as AE's. | Through study completion, up to 6 months | 
| Safety and tolerability of four LYN-PLT modified release capsules and a placebo capsule collected from Adverse Event (AE) reporting | If abdominal pain occurs, a systematic algorithm to evaluate abdominal pain [modified Structured Assessment of GastroIntestinal Symptoms (SAGIS)] will be used. Clinically significantly abnormal findings will be reported as adverse events | Through study completion, up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gastric retention assessed by abdominal ultrasound (U/S) | Visualization of formulation/formulation components in the stomach by U/S | Up to 9 Days post-dosing | 
| Confirm esophageal clearance of several MR capsules and a placebo capsule | For Group 1 and Group 2 via endoscopy | 2 hours post dosing | 
| Physical Feature of Recovered Formulation Components | Record the physical features, e.g. number of polymeric arms (if separate) or if attached to the core, of formulation components recovered from collected fecal specimens | Through study completion up to Day 29 |