A Dose Ranging Study Evaluating Efficacy and Safety of NI-03

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine the safety and efficacy of NI-03.

Detailed Description
-----------------
The primary objective of the Single-Dose Phase is to assess the pharmacokinetics (PK) and safety of single doses of NI-03 when administered at doses of 100 mg, 200 mg or 300 mg to subjects with chronic pancreatitis. The primary objective of the Double-Blind Phase of the study is to determine the efficacy, PK and safety of three doses of NI-03 (100 mg, 200 mg and 300 mg) as compared to placebo when administered three times daily (TID) for 28 consecutive days in subjects with chronic pancreatitis.

Official Title
-----------------
A Phase 1, Single Dose PK and Safety Study With NI-03 Followed by a Phase 2, Randomized, Double-Blind, Parallel-Group Dose-Ranging Study to Evaluate the Safety and Efficacy of NI-03 When Compared to Placebo in Subjects With Chronic Pancreatitis

Conditions
-----------------
Chronic Pancreatitis

Intervention / Treatment
-----------------
* Drug: NI-03
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: To be eligible to participate in this study, subjects must meet all of the following criteria at Screening: Males and females aged 18 to 85 years, inclusive, at the time of consent Ability to communicate effectively with clinic site staff, ability and willingness to comply with the study schedule, restrictions, and requirements Institutional Review Board (IRB)-approved written informed consent Diagnosis of chronic pancreatitis Baseline average daily worst pain score must be a minimum of 4 using the Numeric Rating Scale (NRS) during the 7-day run-in period Patients on a non-opioid analgesic regimen that is expected to remain stable during the study period, or an opioid regimen with a morphine-equivalent dose not more than 100 mg daily. Exclusion Criteria: To be eligible to participate in this study, subjects must not meet any of the following criteria: Any other clinically significant medical condition Treatment with any investigational product within 14 days of Day 1 (or 5 drug half-lives if 5 drug half-lives are expected to exceed 14 days) of Day -7 Major abdominal surgery within 90 days of Day 1 History or presence of clinically significant cardiovascular disease History of any cancer, except non-melanoma skin cancer, within 5 years of study enrollment, History of endoscopic intervention within the previous 3 months or presence of a pancreatic duct stent History of illicit drug abuse (i.e. use of any 'illegal' drugs within 6 months) Active heavy alcohol use (defined as more than 2 alcoholic drinks per day or 14 alcoholic drinks per week) Inadequate venous access Significant blood loss, donation of ≥450 mL of blood, or blood or blood product transfusion within 7 days of Day 1 History or presence of hepatitis B (surface antigen positivity), active hepatitis C or human immunodeficiency virus (HIV) antibody Active infection within 30 days of Day 1 Pregnant, planning to become pregnant or breast feeding Positive urine or serum pregnancy test result at Screening or on Day 1 Active major psychiatric illness requiring a change in treatment within 3 months that would confound pain assessments History of seizures within the last 12 months Current use of anticonvulsants, antipsychotics, systemic steroids and, immunosuppressant therapy. *Use of gabapentin, pregabalin and benzodiazepines as treatment for chronic pancreatitis pain are allowed. Presence of generalized pain syndrome apart from chronic pancreatitis

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 85 Years

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

Accepts Healthy Volunteers
-----------------
No

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

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: placebo<br>TID Day for 28 Days | Drug: Placebo<br> <br> |
| Experimental: 100 mg NI-03<br>TID Day for 28 Days | Drug: NI-03<br> <br> |
| Experimental: 200 mg NI-03<br>TID Day for 28 Days | Drug: NI-03<br> <br> |
| Experimental: 300 mg NI-03<br>TID Day for 28 Days | Drug: NI-03<br> <br> |

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 - To determine the pharmacokinetic profile for FOY251 and GBA | Pharmacokinetic (PK) parameters such as Maximum concentration (Cmax), time to maximum concentration (Tmax), minimum concentration(Cmin), area under the curve (AUC), half-life (t1/2), apparent clearance (CL/F), and apparent volume of distribution (Vz/F) are assessed. | pre-dose and at 0.25, 0.5, 1, 2, 4 and 8 hours post-dose | 
| Phase 1 - Safety and Tolerability - Treatment Emergent Adverse Events (TEAE) via CTCAE v4.0 | Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | through 7 days post-dose | 
| Phase 1 - Safety and Tolerability - Laboratory test results | Laboratory test results will be graded and summarized based on CTCAE v4.03. and by shifts in results before and after dosing | through 7 days post-dose | 
| Phase 2 - Efficacy Analysis - average daily worst pain intensity score |  | 4 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 - To determine the pharmacokinetic profile for FOY251 and GBA -area under the curve (AUC) |  | pre-dose and at 0.25, 0.5, 1, 2, 4 and 8 hours post-dose. | 
| Phase 1 - To determine the pharmacokinetic profile for FOY251 and GBA - Maximum concentration (Cmax) |  | pre-dose and at 0.25, 0.5, 1, 2, 4 and 8 hours post-dose. | 
| Phase 1 - To determine the pharmacokinetic profile for FOY251 and GBA - time to maximum plasma concentration (tmax) |  | pre-dose and at 0.25, 0.5, 1, 2, 4 and 8 hours post-dose. | 
| Phase 1 - To determine the pharmacokinetic profile for FOY251 and GBA - apparent clearance (CL/F) |  | pre-dose and at 0.25, 0.5, 1, 2, 4 and 8 hours post-dose. | 
| Phase 1 - To determine the pharmacokinetic profile for FOY251 and GBA - plasma terminal half-life (t1/2) |  | pre-dose and at 0.25, 0.5, 1, 2, 4 and 8 hours post-dose. | 
| Phase 1 - To determine the pharmacokinetic profile for FOY251 and GBA - apparent volume of distribution (Vz/F) |  | pre-dose and at 0.25, 0.5, 1, 2, 4 and 8 hours post-dose. | 
| Phase 2 - Efficacy Analysis - Change from baseline in least pain score |  | change from baseline to Week 4 | 
| Phase 2 - Efficacy Analysis - Change from baseline in average pain score |  | 4 Weeks | 
| Phase 2 - Efficacy Analysis - Change from baseline in current pain score |  | 4 Weeks | 
| Phase 2 - Efficacy Analysis - Change from baseline in average morphine-equivalent daily opioid daily dose |  | 4 Weeks | 
| Phase 2 - Efficacy Analysis - Change from baseline in quality of life | assessed using the pain interference aspects of the Brief Pain Inventory (BPI) | change from baseline to Week 4 | 
| Phase 2 - Safety and Tolerability - Treatment Emergent Adverse Events (TEAE) via CTCAE v4.0 | Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | Through day 57 (End of Study Visit) | 
| Phase 2 - Safety and tolerability - Laboratory Test Results | Laboratory test results will be graded and summarized based on CTCAE v4.03. and by shifts in results before and after dosing | Through day 57 (End of Study Visit) | 
| Phase 2 - To determine the pharmacokinetic profile for FOY251 and GBA -area under the curve (AUC) |  | Days 1 and 29, and at 0.25, 0.5, 1, 2 and 4 hours post-dose | 
| Phase 2 - To determine the pharmacokinetic profile for FOY251 and GBA - Maximum concentration (Cmax) |  | pre-dose and at 0.25, 0.5, 1, 2, 4 and 8 hours post-dose. | 
| Phase 2 - To determine the pharmacokinetic profile for FOY251 and GBA - time to maximum plasma concentration (tmax) |  | Days 1 and 29, and at 0.25, 0.5, 1, 2 and 4 hours post-dose | 
| Phase 2 - To determine the pharmacokinetic profile for FOY251 and GBA - plasma terminal half-life (t1/2) |  | Days 1 and 29, and at 0.25, 0.5, 1, 2 and 4 hours post-dose | 
| Phase 2 - To determine the pharmacokinetic profile for FOY251 and GBA - apparent clearance (CL/F) |  | Days 1 and 29, and at 0.25, 0.5, 1, 2 and 4 hours post-dose | 
| Phase 2 - To determine the pharmacokinetic profile for FOY251 and GBA - apparent volume of distribution (Vz/F) |  | Days 1 and 29, and at 0.25, 0.5, 1, 2 and 4 hours post-dose |