A Phase I- Sequential Cohort Dosing to Determine Maximum Tolerated Dose in Healthy Male Volunteers.

Phase 1

Completed

Conditions: Schizophrenia

Interventions: Drug: NW-3509a

Registration Number: NCT01955564

Lead Sponsor: Newron Pharmaceuticals SPA

Brief Summary: This is a prospective, 8-day, randomized, double-blind, placebo-controlled, sequential-cohort study designed to evaluate the safety, tolerability, and MTD of single escalating oral doses of NW-3509A in healthy male volunteers. Six independent cohorts of 12 volunteers each will participate in this study, with the first 9 volunteers in each cohort to qualify being randomized to receive study medication and the remaining 3 to be used as backups/ alternates. In each cohort, 6 subjects will be randomly assigned to receive NW-3509A and 3 subjects will receive placebo.

Detailed Description: Doses from 1 to 30 mg were tested

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 54

Inclusion Criteria

Demographics

Volunteers will meet the following demographic inclusion criteria:

Age - between 18 and 45 years of age, inclusive.
Sex - males.
The subject has a body weight of at least 45 kg and a body mass index of ≤30.

Procedural

Volunteers will meet the following procedural criteria:
They are cooperative, able to take oral medication, willing to complete all aspects of the study, and capable of doing so.
They will be able to understand the instructions and fully participate.
They will have provided written informed consent prior to participating in the study.
The subject is in good health with no history of significant medical disease as determined by the investigator.

Exclusion Criteria

The presence of any of the following will exclude a subject from study enrollment:

General Medical Status

An advanced, severe, or unstable disease of any type that may interfere with any of the study evaluations, including any medical condition that could be expected to progress, recur, or change to such an extent that it may bias the assessment of the clinical or mental status of the volunteer to a significant degree or put the volunteer at special risk (e.g., liver or kidney disease; malignancy);
A disability that may prevent the volunteer from completing all study requirements (e.g., blindness, deafness, severe language difficulty);
A current diagnosis of active, uncontrolled peptic ulceration within the last year;
A current diagnosis of acute, severe, or unstable asthmatic condition.

Cardiovascular
A current diagnosis of severe or unstable cardiovascular disease;
A current diagnosis of sick-sinus syndrome or conduction deficits (e.g., sino-atrial block (<0.22), second or third degree atrio-ventricular block);
Any history or current evidence of a cardiac illness as determined by the investigator;
Any clinically significant ECG abnormality, including a disorder of rate, rhythm, or conduction, or other morphological changes, or a QTcF interval (Fridericia's correction formula) on the ECG >450 msec. The 12-lead ECG will be used for determining the suitability of the subject for inclusion in the study (determined by the investigator);
Vital signs (supine) outside the following ranges:
- Systolic blood pressure below 100 or above 139 mmHg;
- Diastolic blood pressure below 50 or above 89 mmHg;
- Radial pulse below 50 or above 90 bpm.
CNS related
Any history or current diagnosis of any neurodegenerative illness;
History or current diagnosis of epilepsy or seizure disorder.

Psychiatric
Any past or current psychiatric illness (DSM-IV-TR Axis 1 diagnosis);
Subjects with current or past suicidal ideation.

Study-specific criteria
History of serious adverse reactions or hypersensitivity to any drug;
Presence or history of allergies requiring acute or chronic treatment (except seasonal allergic rhinitis);
Alcohol or drug abuser; currently or at any time in the last 5 years;
Abnormal physical findings of clinical significance at the screening examination or baseline that would interfere with the objectives of the study;
Need of any prescription medication within 14 days prior to the administration of the study drug, and/or non-prescription medication within 7 days prior to the administration of the drug;
Participation in other clinical trials during the last 2 months in which an investigational drug or a commercially available drug was tested;
Loss of 500 ml or more of blood during the 3-month period before the study, e.g. as a donor.
Existence of any surgical or medical condition which might interfere with the absorption, distribution, metabolism or excretion of the study drug, i.e. impaired renal or hepatic function, diabetes mellitus, cardiovascular abnormalities, inflammatory bowel disease, chronic symptoms of pronounced constipation or diarrhea, or conditions associated with total or partial obstruction of the urinary tract;
Symptoms of a significant somatic or mental illness in the four-week period preceding study drug administration;
History of hepatitis B and/or C, and/or positive serology results, which indicate the presence of hepatitis B and/or C (Hepatitis B surface antigen and/or antibody to Hepatitis C);
Positive results from the HIV serology;
Positive results of the drug and alcohol tests at screening and/or check-in at the unit;
Smoker; currently or at any time in the last 5 years;

Laboratory abnormalities
Clinically significant abnormalities in routine laboratory examinations (hematology; blood chemistry, including electrolytes and liver and kidney function tests; urinalysis), as determined by the Principal Investigator in consultation with the Sponsor, at the screening evaluation;
Clinically important laboratory abnormalities in thyroid function tests at screening:

• TSH > 8.0 mU/L and/or Free T4 < 9 pmol/L;

Concomitant therapy
A known exaggerated pharmacological sensitivity or hypersensitivity to drugs similar to NW-3509A. Possible examples are volunteers who have experienced hypersensitivity reactions to sodium channel blockers;
Ingested any of the following substances:
- An investigational drug during the past 2 months;
- A drug or treatment known to cause major organ system toxicity during the past year;
- Any prescription drug or OTC product if taken continuously (Medical Monitor from Newron should be contacted if the Investigator wants to include a volunteer who is taking an OTC product);
- Alcohol intake should be limited to 2 drinks per day during the 2 weeks prior to dosing; alcohol consumption will be prohibited from 72 hours prior to admittance on Day -1 through to the final safety evaluations on Day 8.
- Caffeine-containing products should be limited (equivalent of 2 cups of coffee per day) during the 2 weeks prior to dosing and through to the final safety evaluations on Day 8.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort 2	NW-3509a	NW-3509a 2mg or placebo
Cohort 4	NW-3509a	NW-3509a 10 mg or placebo
Cohort 3	NW-3509a	NW-3509a 5mg or placebo
Cohort 1	NW-3509a	NW-3509a - 1mg or placebo
Cohort 5	NW-3509a	NW-3509a 20 mg or placebo
Cohort 6	NW-3509a	NW-3509a 30 mg or placebo

Primary Outcome Measures

Name	Time	Method
Physical Examination Shift Table	Day -1(pre-dose) through Day 8 (Discharge)	Physical examinations were carried out on the following: Lymph nodes, mouth, neck, nervous system, nose, skin and throat.

Secondary Outcome Measures

Name	Time	Method
Maximum Plasma Concentration of NW-3509A at Doses Tested	Baseline up to 32 hours post-dose	Plasma concentration data, derived PK parameters, and urine data are summarized as maximum plasma concentration (Cmax). The plasma concentrations of NW-3509A in the samples taken from the subjects receiving placebo were below the limit of quantification (\<1.00 ng/mL) in all cases (n=18).
Total Drug Exposure Over Time (AUC0-t) of NW-3509A at Doses Tested	Baseline up to 32 hours post-dose	Plasma concentration data, derived PK parameters, and urine data were summarized as total drug exposure over time (AUC0-t). The plasma concentrations of NW-3509A in the samples taken from the subjects receiving placebo were below the limit of quantification (\<1.00 ng/mL) in all cases (n=18).