A MAD Study of TT301/MW189 in Healthy Volunteers

Study Overview
=================
Brief Summary
-----------------
The purpose of this Study is to find out whether an investigational drug is safe and well tolerated. MW189 is being studied as a possible short-term treatment for people with different types of brain injury. MW189 has previously been given to healthy human volunteers as a single dose, and there were no significant problems or bad effects in people who received the Study drug. However, before it can be tested in people with brain injury, it is important to test MW189 in healthy volunteers when given multiple doses.

Detailed Description
-----------------
This is a phase 1b study. Written informed consent will be obtained from each study participant before any study-specific procedures or assessments are done. At various time points noted below, pharmacokinetic (PK) blood sampling will be performed on study participants. Throughout the study the investigator will be assessing adverse events and concomitant medication. On-Study/On-Interventions Evaluations/procedures: Participants will arrive at the Phase 1 unit after fasting a minimum of 10 hours, for admission into the unit and will undergo procedures: Medical and medication histories Infection screen Body temperature Vital signs (blood pressure and heart rate) Physical examination and weight Neurological exam Safety laboratory tests (blood and urine) Urine pregnancy test (females only) Alcohol screening (Breathalyzer) Urine drug screen Hepatitis B, C and HIV screening Randomize: Only participants who meet eligibility requirements will be randomized into the study. Day 1 - Dosing: A light breakfast will be given prior to dosing. Participants will have the following tests/procedures performed at various time points during the day following confirmation of eligibility. 8 electrocardiograms (ECG) 8 vital signs (blood pressure and heart rate) 1 body temperature 12 PK Blood draws 2 study drug administrations Day 2: A light breakfast will be given prior to dosing. 8 ECGs 8 vital signs (blood pressure and heart rate) 1 body temperature 1 PK blood draw 2 study Drug administration Day 3: Participants will fast for a minimum of 10 hours. Water is allowed. A Light breakfast will be given before dosing 1 safety laboratory tests (blood and urine) 1 ECG 2 vital signs (blood pressure and heart rate) 1 body temperature 1 PK blood draw 1 neurological examination 2 study drug administrations Day 4: A Light breakfast will be given before dosing 2 vital signs (blood Pressure and heart rate) 1 body temperature 1 PK blood draw 2 study drug administrations Day 5: A Light breakfast will be given before dosing 1 ECG 2 vital signs (Blood Pressure and heart rate) 1 body temperature 12 PK blood draw 2 study drug administration Day 6: Participants will fast for a minimum of 10 hours. Water is allowed. A Light breakfast will be given 1 safety laboratory test (blood and urine) 1 vital sign (Blood pressure and heart rate) 1 body temperature 1 neurological examination 2 PK blood draw Day 7: A light breakfast will be provided 1 vital sign 1 body temperature 1 PK blood draw Day 8 (Discharge): Participants will fast for a minimum of 10 hours. Water is allowed. A light breakfast will be offered 1 safety laboratory test (blood and urine) 1 ECG 1 vital sign (blood pressure and heart rate) 1 body temperature 1 physical examination including weight 1 neurological examination 2 Week Follow-up Visit: Participants will fast for a minimum of 10 hours. Water is allowed. during this visit participants will have the following tests and procedures performed: 1 safety laboratory test (blood and urine) 1 ECG 1 vital sign (blood pressure and heart rate) 1 body temperature 6-8 Week Follow-up Phone Call: Participants will be asked about any adverse events and any medications they may be taking.

Official Title
-----------------
A Phase 1b, Double-Blind, Randomized, Placebo-Controlled Multiple Ascending Dose Study to Evaluate the Safety, Tolerability and Pharmacokinetic Profile of TT301/MW189 Administered Intravenously to Healthy Volunteers

Conditions
-----------------
Healthy Adult Volunteers

Intervention / Treatment
-----------------
* Drug: 0.075mg/kg TT301/MW189
* Drug: 0.15mg/kg TT301MW189
* Drug: 0.25mg/kg TT301/MW189
* Drug: 0.30mg/kg TT301/MW189
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Willingness and capacity to give informed consent Is in good health Weights 50.0 - 120.0 kg Not pregnant Must agree to use birth control for 1 week after the last day of study drug administration Willingness to comply with protocol requirements, including fasting, alcohol and nicotine restrictions, during the study and is available to complete the study Adequate forearm vein access No significant dietary restrictions Must not have donated blood, platelets, or any other blood components 30 days, or plasma 60 days, prior to consenting. Must also agree not to donate blood, platelets, or any other blood components for 8 weeks after the last dose of study drug Exclusion Criteria: Lactating or is pregnant severe ischemic heart disease or congestive heart failure Heart attack within the previous 2 years; history of stroke or cardiomyopathy; significant liver or kidney disease; diabetes; history of any autoimmune disorder; or a history of chronic infections a history of cancer has received antibiotic treatment or has undergone a surgical procedure within 30 days of Day 1 has a history of Hepatitis C, Hepatitis B or tuberculosis (TB) has a history of Human Immunodeficiency Virus (HIV) a history of alcohol or drug use within the twelve months prior to study drug administration has used any immunosuppressants or chronic anti-inflammatory drugs medication including prescription medication, over-the-counter medication, health/herbal supplement or vitamin by any route of administration within 7 days of Day 1 has donated blood within 30 days of consenting or has donated plasma within 60 days of consenting has participated in a clinical trial of an immunosuppressive drug within 6 months of Day 1 has received an investigational drug, used an investigational device or received an investigational medical procedure within 60 days of Day 1, or concurrent with participation in this study has participated in any observational studies, experimental studies of non-investigational drugs, devices, or medical procedures within 30 days of Day 1, or concurrent with participation in this study has participated in a previous trial with TT301/MW189 has a history of unexplained syncope or fainting from the collection of blood; i.e., autonomic dysfunction. Lack of ability to understand verbal and/ or written English had significant trauma or surgical procedure within 1 month prior to Screening.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 50 Years

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

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

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

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 - TT301/MW189<br>TT301/MW189 0.075 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive | Drug: 0.075mg/kg TT301/MW189<br>* 0.075 mg/kg IV twice daily on Days 1 through 5<br>* Other names: TT301/MW189;|
| Experimental: Cohort 2 -TT301/MW189<br>TT301/MW189 0.15 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive | Drug: 0.15mg/kg TT301MW189<br>* 0.15 mg/kg IV twice daily on Days 1 through 5<br>* Other names: TT301/MW189;|
| Experimental: Cohort 3- TT301/MW189<br>TT301/MW189 0.25 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive | Drug: 0.25mg/kg TT301/MW189<br>* 0.25 mg/kg IV twice daily on Days 1 through 5<br>* Other names: TT301/MW189;|
| Experimental: Cohort 4- TT301/MW189<br>TT301/MW189 0.30 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive | Drug: 0.30mg/kg TT301/MW189<br>* 0.30 mg/kg IV twice daily on Days 1 through 5<br>* Other names: TT301/MW189;|
| Placebo Comparator: Placebo<br>No drug intervention. | Drug: Placebo<br>* 0.9% sodium chloride<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serious Adverse Events | The number of participants who experienced serious adverse events. | 4 weeks | 
| Treatment-Emergent Adverse Events | The number of participants who experienced treatment-emergent adverse events (TEAEs). A TEAE is defined as an adverse event that started during the treatment period. | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics - Cmax | Maximum observed concentration in plasma. | 5 days | 
| Pharmacokinetics - Tmax | Time to maximum concentration | 5 days | 
| Pharmacokinetics - AUC | Area under the concentration-time curve | 5 days | 
| Pharmacokinetics - T1/2 | Terminal half-life (T1/2) | 5 days | 
| Pharmacokinetics - Kel | Elimination rate constant | 5 days |