NAVX-010-Phase I Tolerability and Pharmacokinetic Study in Healthy Male Subjects

NCT03655522 | Completed Phase 1 FDA Drug

• 1 other identifier: CLN 14-030
• Study Type: interventional
• Target: 30
• Locations: 0 countries
• Sites: N/A

Brief Summary

This was a double-blind, placebo-controlled, randomized, single ascending dose, sequential group study. Each subject participated in only 1 treatment period. The primary objective was to determine the safety of single intramuscular (IM) injections of NAVX 010 in healthy subjects. The secondary objective was to determine the single dose pharmacokinetics (PK) of Gonyautoxin 2 (GTX 2) and Gonyautoxin 3 (GTX 3) following IM administration of NAVX 010 in healthy subjects. Thirty subjects were studied in 5 groups (Groups A to E); each group consisted of 6 subjects, of which 4 subjects received the Investigational Medicinal Product and 2 subjects received placebo. All subjects completed the study and data for all subjects were included in the safety analyses. A total of 20 subjects received NAVX-010 and were included in the PK population and subsequent PK analysis.

Conditions

Safety

Outcome Measures

Primary Outcomes (12)

• Adverse events related to NAVX-010

  Any signs or symptoms will be observed and elicited at least once a day by open questioning. Subjects will also be encouraged to spontaneously report AEs occurring at any other time during the study. Any AEs and remedial action required will be recorded in the subject's source data. Subjects experiencing AEs will be followed clinically until their health has returned to baseline status or until all parameters have returned to normal or have otherwise been explained.

  Monitored from dosing day until 5 days after dosed

• Oral body temperature changes

  Oral body temperature in °C (BT) will be measured. All measurements will be taken as single readings. Measurements will be repeated once if outside the relevant clinical reference ranges. If repeated, the repeat value will be used in the data analysis. Clinical research unit reference ranges will be applied.

  BT measured at screening day, check in day, -1 hour relative to dose, 24 hrs postdose and at day 5 after dosed.

• 12-lead ECG measurements changes

  At check-in, 12-lead ECG will be recorded in triplicate in the supine position for baseline measurements. The average value for each ECG parameter will be calculated as the baseline value. At all other times, a single 12-lead resting ECG with a 10-second rhythm strip will be recorded after the subject has been supine for at least 5 minutes.The 12-lead ECG will be repeated once if either of the following criteria apply:The QTcF is \>450 ms; The QTcF change from baseline (check-in) is \>60 ms. Additional 12-lead ECGs will be performed at other times if judged to be clinically appropriate or if the ongoing review of the data suggests a more detailed assessment of ECGs is required. The ECG machine will compute the PR, QT and QTc intervals, QRS duration and heart rate. The QT interval will be corrected for heart rate using Fridericia's formula.

  12-lead ECG will be measured at: screening day; check in day; 0.5, 1, 6, 12 and 24 hous postdose and day 5 after dosed.

• Changes in cardiac rhythm monitored by telemetry

  Cardiac rhythm will be monitored by telemetry. Telemetry strips will be printed out at the times indicated in the Study Plan. In addition, staff members will be instructed to print out ECGs if either of the following criteria apply: The QTcF is \>450 ms; The QTcF change from baseline (check-in) is \>60 ms. In such an event, ECGs will continue to be printed out every 20 minutes until the QTcF value has returned to normal.

  Continuous telemetry monitoring from -1 hour to 24 hour relative to dose. Telemetry strips will be printed out at 2, 3, 4 and 5 hours postdose.

• Changes in clinical laboratory evaluations

  Blood and urine samples will be collected for clinical laboratory evaluations at the times indicated in the Study Plan. Additional clinical laboratory evaluations will be performed at other times if judged to be clinically appropriate or if the ongoing review of the data suggests a more detailed assessment of clinical laboratory safety is required. The following evaluations will be performed: Serum biochemistry, hematology, coagulation, urinalysis and serology.

  Clinical laboratories evaluations will be measured at: screening day; check in day; -1 hour and 24 hour relative to dose and day 5 after dosed.

• Changes in blood glucose and phosphorous evaluations

  Blood samples will be collected for serum glucose (mg/dL) and phosphorous (mg/dL) evaluations.

  The evaluations will be measured 30 minutes and 1 hour post adminitration of the drug.

• Physical examination changes

  A full physical examination will be performed at the times indicated in the Study Plan and an abbreviated physical examination may be performed at other times.

  Physical examination will be performed at: check in day, 1 and 24 hours after dose administration and at day 5 after dosed.

• Changes in the general wellbeing of the subject

  Subjects will be asked to complete a clinical study questionnaire to assess tolerance to the study drug, with the assistance of a suitably trained CRU staff member. Subjects will be asked questions about their general wellbeing and the injection site over the period either since dosing or since the last questionnaire, as applicable. In addition, the injection site will be assessed by the CRU staff member conducting the questionnaire.

  The questionnaire will be conducted every hour for 12 hours postdose and at approximately 24 hours postdose.

• Blood pressure changes

  Systolic and Diastolic blood pressure in mmHg (BP), will be measured. At check-in, blood pressure, will be measured in triplicate within a 10-minute window. The median value for systolic and diastolic blood pressure, will be used as the baseline value in the data analysis. All other measurements will be taken as single readings. Measurements will be repeated once if outside the relevant clinical reference ranges. If repeated, the repeat value will be used in the data analysis. Clinical research unit reference ranges will be applied.

  BP: measured at screening day, check in day, continuous monitoring during dose day (until 24 hrs) and day 5 after dosed.

• Heart rate changes

  Heart rate in bpm (HR) will be measured. At check-in, heart rate will be measured in triplicate within a 10-minute window. The median value for heart rate will be used as the baseline value in the data analysis. All other measurements will be taken as single readings. Measurements will be repeated once if outside the relevant clinical reference ranges. If repeated, the repeat value will be used in the data analysis. Clinical research unit reference ranges will be applied.

  HR: measured at screening day, check in day, continuous monitoring during dose day (until 24 hrs) and day 5 after dosed.

• Respiratory rate changes

  Respiratory rate in breaths/min (RR) will be measured. At check-in, respiratory rate will be measured in triplicate within a 10-minute window. The median value for respiratory rate will be used as the baseline value in the data analysis. All other measurements will be taken as single readings. Measurements will be repeated once if outside the relevant clinical reference ranges. If repeated, the repeat value will be used in the data analysis. Clinical research unit reference ranges will be applied.

  RR: measured at screening day, check in day, continuous monitoring during dose day (until 24 hrs) and day 5 after dosed.

• Oxygen saturation changes

  Oxygen saturation in % (OS) will be measured. All measurements will be taken as single readings. Measurements will be repeated once if outside the relevant clinical reference ranges. If repeated, the repeat value will be used in the data analysis. Clinical research unit reference ranges will be applied.

  OS: measured at screening day, check in day, continuous monitoring during dose day (until 24 hrs) and day 5 after dosed.

Secondary Outcomes (14)

• Pharmacokinetic of NAVX-010: Area under the curve from time 0 up to the time of last quantifiable (AUC0-t) plasma concentration.

  Plasma samples: pre-dose and 5, 10, 20, 30, and 45 minutes plus 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24 hours postdose.

• Pharmacokinetic of NAVX-010: Area under the curve from time 0 to 24 hours postdose (AUC0-24)

  Plasma samples: pre-dose and 5, 10, 20, 30, and 45 minutes plus 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24 hours postdose.

• Pharmacokinetic of NAVX-010: Area under the curve from time 0 extrapolated to infinity (AUC0-oo)

  Plasma samples: pre-dose and 5, 10, 20, 30, and 45 minutes plus 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24 hours postdose.

• Pharmacokinetic of NAVX-010: Percentage of area under the curve that is due to extrapolation from last quantifiable concentration to infinity (%AUCextrap)

  Plasma samples: pre-dose and 5, 10, 20, 30, and 45 minutes plus 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24 hours postdose.

• Pharmacokinetic of NAVX-010: Maximum observed plasma concentration (Cmax)

  Plasma samples: pre-dose and 5, 10, 20, 30, and 45 minutes plus 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24 hours postdose.

Study Arms (2)

NAVX-010

ACTIVE COMPARATOR

Dose levels of NAVX-010 were 2, 8, 25, 50, and 75 mcg. Doses were administered as IM injections into the deltoid muscle in the fasted state. The IMP was supplied in glass vials containing 1.2 mL solution at a total GTX 2 and GTX 3 concentration of 42 mcg/mL (at a relative epimer ratio of 62% GTX 2:38% GTX 3).

Drug: NAVX-010

Placebo

PLACEBO COMPARATOR

Placebo was of identical appearance to the IMP, and was administered into the deltoid muscle in the fasted state.

Drug: Placebo

Interventions

NAVX-010 DRUG

Dose levels of NAVX-010 were 2, 8, 25, 50, and 75 mcg. Four patients per active group. Each subject participated in only 1 treatment period.

Also known as: Gonyautoxin 2/3

NAVX-010

Placebo DRUG

There were two Placebos per group.

Also known as: Placebo of NAVX-010

Placebo

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• males
• between 18 and 45 years of age
• body mass index (BMI) between 18.0 and 32.0 kg/m2 inclusive
• body weight between 50 kg and 100 kg inclusive
• Subjects must be in good health, as determined by:
• medical history
• physical examination (at check-in)
• vital sign assessment
• lead ECG
• clinical laboratory evaluations
• Subjects must be able to understand and respond to the clinical study questionnaire
• Subjects will have given their written informed consent to participate in the study and to abide by the study restrictions

You may not qualify if:

• Male subjects who are not willing, or whose partners are not willing, to use appropriate contraception (such as a condom with spermicidal oam/gel/film/cream/suppository), or to refrain from donating sperm from the time of dosing until 3 months after study drug administration.
• Male subjects whose partners are of child-bearing potential must also agree to use an additional highly effective method of contraception.
• Subjects who have donated;
• blood or platelets in the 3 months prior to screening
• plasma in the 7 days prior to screening
• Subjects who have a significant history of alcoholism or drug/chemical abuse as determined by the Investigator or consume alcohol within 48 hours prior to the screening visit and prior to check-in.
• Subjects who have smoked more than 10 cigarettes per day or the equivalent in tobacco use (e.g. chewing tobacco, eCigarettes and smoking cessation products \[nicotine patch or gum\]) during the 3 months prior to screening.
• Subjects who have used the following within 7 days prior to study drug administration, unless in the opinion of the Investigator the medication will not interfere with the study procedures or compromise safety:
• any over-the-counter systemic or topical medication
• herbal remedies
• vitamin supplements
• mineral supplements
• Subjects who have received any medications, including St John's Wort, known to chronically alter drug absorption or elimination processes within 30 days prior to study drug administration unless in the opinion of the Investigator the medication will not interfere with the study procedures or compromise safety.
• Subjects who have received:
• any prescribed systemic or topical medication within 15 days prior to study drug administration unless in the opinion of the Investigator the medication will not interfere with the study procedures or compromise safety.

Sponsors & Collaborators

• Algenis SpA: lead
• Covance: collaborator

Related Links

• Food and Drug Administration Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers.

Study Officials

• Kelly M Whitehurst, MD

  Covance Clinical Research Unit, Evansville

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: OTHER
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This was a double-blind, placebo-controlled, randomized, single ascending dose, sequential group study. Each subject participated in only 1 treatment period.

Study Record Dates

• First Submitted: August 24, 2018
• First Posted: August 31, 2018
• Study Start: May 14, 2015
• Primary Completion: September 2, 2015
• Study Completion: September 2, 2015
• Last Updated: August 31, 2018

Record last verified: 2018-08

Data Sharing

• IPD Sharing: Will not share