A Study to Assess the Safety, Tolerability and PK of NPT520-34 in Healthy Subjects

NCT03954600 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: NPT520-34-001
• Study Type: interventional
• Target: 49
• Locations: 1 country
• Sites: 1

Brief Summary

To evaluate the PK, safety and tolerability of orally administered NPT520-34 in healthy subjects at single and multiple doses that may be therapeutically relevant.

Conditions

Healthy Volunteers

Keywords

Phase 1; Safety; Tolerability; Pharmacokinetics; Parkinson's Disease; Amyotrophic Lateral Sclerosis

Outcome Measures

Primary Outcomes (28)

• Safety/Tolerability of Single Ascending Doses (125 mg, 250 mg, 500 mg and 1000 mg)

  A) Incidence of clinically significant treatment-emergent changes in the following clinical measures: 1) physical examination, 2) suicidal ideation, 3) vital signs 4) continuous telemetry for 1 hour prior to dosing and for 2 hours post-dose, 5) continuous telemetry for 1 hour prior to dosing and for 2 hours post-dose. B) Incidence in clinical significant treatment-emergent changes in the following laboratory measures: 1) hematology, 2) clinical chemistry, 3) FSH (post-menopausal women only), 4) coagulation, 5) urinalysis C) Incidence of treatment-emergent adverse events D) Incidence of treatment-emergent serious adverse events

  Baseline, Day 1, 2 3, 5 and 7

• Maximum observed plasma concentration of Single Ascending Doses (125 mg, 250 mg, 500 mg and 1000 mg)

  Noncompartmental calculation of maximum observed plasma concentration (Cmax);

  Day 1, 2, 3, 5, 7

• Time to maximum plasma concentration of Single Ascending Doses (125 mg, 250 mg, 500 mg and 1000 mg)

  Noncompartmental calculation of time to maximum plasma concentration (Tmax);

  Day 1, 2, 3, 5, 7

• Area under the plasma concentration-time curve from 0 hour to the time of the last quantifiable plasma concentration of Single Ascending Doses (125 mg, 250 mg, 500 mg and 1000 mg)

  Noncompartmental calculation of area under the plasma concentration-time curve from 0 hour to the time of the last quantifiable plasma concentration \[AUCt\];

  Day 1, 2, 3, 5, 7

• Area under the plasma concentration-time curve extrapolated to infinity of Single Ascending Doses (125 mg, 250 mg, 500 mg and 1000 mg)

  Noncompartmental calculation of area under the plasma concentration-time curve extrapolated to infinity (AUCinf) after dosing

  Day 1, 2, 3, 5, 7

• Apparent oral clearance of Single Ascending Doses (125 mg, 250 mg, 500 mg and 1000 mg)

  Noncompartmental calculation of apparent oral clearance (CL/F)

  Day 1, 2, 3, 5, 7

• Apparent oral volume of distribution during the terminal phase of Single Ascending Doses (125 mg, 250 mg, 500 mg and 1000 mg)

  Noncompartmental calculation of apparent oral volume of distribution during the terminal phase (Vz/F)

  Day 1, 2, 3, 5, 7

• Mean residence time of Single Ascending Doses (125 mg, 250 mg, 500 mg and 1000 mg)

  Noncompartmental calculation of mean residence time (MRT)

  Day 1, 2, 3, 5, 7

• Terminal elimination half-life of Single Ascending Doses (125 mg, 250 mg, 500 mg and 1000 mg)

  Noncompartmental calculation of terminal elimination half-life (T½);

  Day 1, 2, 3, 5, 7

• Safety/Tolerability as measures of hematology, clinical chemistry, FSH, coagulation and urinalysis of multiple ascending doses (250 mg and 500 mg)

  A) Incidence in clinical significant treatment-emergent changes in hematology B) Incidence in clinical significant treatment-emergent changes in clinical chemistry C) Incidence in clinical significant treatment-emergent changes in FSH (post-menopausal women only) D) Incidence in clinical significant treatment-emergent changes in coagulation E) Incidence in clinical significant treatment-emergent changes in urinalysis

  Baseline, Day 2, 4, 7, 11, 12, 13, 14, and 21

• Safety/Tolerability as measures of vital signs and physical examination of multiple ascending doses (250 mg and 500 mg)

  A) Incidence of clinically significant treatment-emergent changes in vital signs B) Incidence of clinically significant treatment-emergent changes in physical examination

  Baseline, Day 1, 2, 7, 8, 9, 10, 11, 14, 16, 18 Day 21

• Safety/Tolerability as measures of continuous telemetry of multiple ascending doses (250 mg and 500 mg)

  A) Incidence of clinically significant treatment-emergent changes in continuous telemetry

  Baseline, Day 1, 2, 7, 8, 9, 10, 11, 14, and 15

• Safety/Tolerability as measures of suicidal ideation, 12-lead ECG, adverse events and serious adverse events of multiple ascending doses (250 mg and 500 mg)

  A) Incidence in clinical significant treatment-emergent changes in suicidal ideation B) Incidence in clinical significant treatment-emergent changes in 12-lead ECG C) Incidence of treatment-emergent adverse events D) Incidence of treatment-emergent serious adverse events

  Baseline, Day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 18 Day 21

• Safety/Tolerability as measure of continuous ECG of Multiple Ascending Doses (250 mg and 500 mg)

  A) Incidence in clinical significant treatment-emergent changes in continuous ECG telemetry

  Baseline, Day 1, 7, and 14

• Maximum observed plasma concentration (Cmax) after dosing on Day 1 of Multiple Ascending Doses (250 mg, 500 mg)

  Noncompartmental calculation of maximum observed plasma concentration (Cmax) after dosing on Day 1

  Baseline, Day 1 and 2

• Maximum observed concentration at steady-state after dosing on Day 14 of Multiple Ascending Doses (250 mg, 500 mg)

  Noncompartmental calculation of maximum observed concentration at steady-state after dosing on Day 14

  Day 14

• Concentration observed at the end of the dosing interval of Multiple Ascending Doses (250 mg, 500 mg)

  Noncompartmental calculation of concentration observed at the end of the dosing interval (Ctrough)

  Day 14, 16, 18

• Time to max. plasma concentration after dosing on Day 1 of Multiple Ascending Doses (250 mg, 500 mg)

  Noncompartmental calculation of time to max. plasma concentration after dosing on Day 1

  Day 1

• Time to reach Cmax,ss of Multiple Ascending Doses (250 mg, 500 mg)

  Noncompartmental calculation of time to reach Cmax,ss

  Day 14, 16, 18 and 21

• Area under the plasma concentration-time curve from 0 hour to the time of the last quantifiable plasma concentration of Multiple Ascending Doses (250 mg, 500 mg)

  Noncompartmental calculation of area under the plasma concentration-time curve from 0 hour to the time of the last quantifiable plasma concentration (AUCt)

  Baseline, Day 1, 2, 7, 8, 9, 10, 11, 14, 16, 18 and 21

• Area under the plasma concentration-time curve extrapolated to infinity after dosing of Multiple Ascending Doses (250 mg, 500 mg)

  Noncompartmental calculation of area under the plasma concentration-time curve extrapolated to infinity after dosing (AUCinf)

  Baseline, Day 1, 2, 7, 8, 9, 10, 11, 14, 16, 18 and 21

• Area under the concentration time curve from 0-24 hours after dosing on Day 1 of Multiple Ascending Doses (250 mg, 500 mg)

  Noncompartmental calculation of the area under the concentration time curve from 0-24 hours after dosing on Day 1 (AUC0-24)

  Day 1

• The area under the concentration time curve during a dosing interval (tau) at steady state after dosing on Day 14 of Multiple Ascending Doses (250 mg, 500 mg)

  Noncompartmental calculation of the area under the concentration time curve during a dosing interval (tau) at steady state after dosing on Day 14 (AUCtau)

  Baseline, Day 1, 2, 7, 8, 9, 10, 11, 14, 16, 18 and 21

• Apparent oral clearance of Multiple Ascending Doses (250 mg, 500 mg)

  Noncompartmental calculation of apparent oral clearance (CL/F)

  Day 1

• Apparent total plasma clearance after oral administration, calculated as Dose/AUCtau after dosing on Day 14 of Multiple Ascending Doses (250 mg, 500 mg)

  Noncompartmental calculation of apparent total plasma clearance after oral (extravascular) administration (CL,ss/F), calculated as Dose/AUCtau after dosing on Day 14

  Day 14

• Apparent oral volume of distribution during the terminal phase of Multiple Ascending Doses (250 mg, 500 mg)

  Noncompartmental calculation of apparent oral volume of distribution during the terminal phase (Vz/F)

  Day 14, 16, 18 and 21

• Mean residence time of Multiple Ascending Doses (250 mg, 500 mg)

  Noncompartmental calculation of mean residence time (MRT)

  Baseline, Day 1, 2, 7, 8, 9, 10, 11, 14, 16, 18 and 21

• Terminal elimination half-life of Multiple Ascending Doses (250 mg, 500 mg)

  Terminal elimination half-life

  Day 14, 16, 18 and 21

Secondary Outcomes (2)

• Maximum Tolerated Dose of Single Ascending Doses (125 mg, 250 mg, 500 mg and 1000 mg)

  Day 1, 2, 3, 5, Day 7

• Maximum Tolerated Dose of Multiple Ascending Doses (250 mg and 500 mg)

  Baseline, Day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 18 Day 21

Other Outcomes (2)

• Exploratory Biomarkers of Single Ascending Doses (125 mg, 250 mg, 500 mg and 1000 mg)

  Baseline, Day 1, 2, Day 7

• Exploratory Biomarkers of Multiple Ascending Doses (250 mg and 500 mg)

  Baseline, Day 1, Day 7, 14, and 21

Study Arms (8)

NPT520-34 - SAD Cohort 1, Dose 1 (Unfed)

OTHER

Single ascending dose of orally administered capsule(s) NPT520-34: 125 mg OR Single dose of orally administered placebo capsule(s) to match dose. Unfed.

Drug: NPT520-34 (125 mg); Drug: Placebos (125 mg)

NPT520-34 - SAD Cohort 1, Dose 1 (Fed)

OTHER

Single ascending dose of orally administered capsule(s) NPT520-34: 125 mg OR Single dose of orally administered placebo capsule(s) to match dose. Fed.

Drug: NPT520-34 (125 mg); Drug: Placebos (125 mg)

NPT520-34 - SAD Cohort 2, Dose 2

OTHER

Single ascending dose of orally administered capsule(s) NPT520-34: 250 mg OR Single dose of orally administered placebo capsule(s) to match dose.

Drug: NPT520-34 (125 mg); Drug: Placebos (125 mg)

NPT520-34 - SAD Cohort 3, Dose 3

OTHER

Single ascending dose of orally administered capsule(s) NPT520-34: 500 mg OR Single dose of orally administered placebo capsule(s) to match dose.

Drug: NPT520-34 (125 mg); Drug: Placebos (125 mg)

NPT520-34 - SAD Cohort 4, Dose 4

OTHER

Single ascending dose of orally administered capsule(s) NPT520-34: 1000 mg OR Single dose of orally administered placebo capsule(s) to match dose.

Drug: NPT520-34 (125 mg); Drug: Placebos (125 mg)

NPT520-34 - MAD Cohort 1, Dose 1

OTHER

Multiple ascending dose of orally administered capsule(s) NPT520-34: TBD mg OR Single dose of orally administered placebo capsule(s) to match dose.

Drug: NPT520-34 (125 mg); Drug: Placebos (125 mg)

NPT520-34 - MAD Cohort 2, Dose 2

OTHER

Multiple ascending dose of orally administered capsule(s) NPT520-34: TBD mg OR Single dose of orally administered placebo capsule(s) to match dose.

Drug: NPT520-34 (125 mg); Drug: Placebos (125 mg)

NPT520-34 - MAD Cohort 3, Dose 3

OTHER

Multiple ascending dose of orally administered capsule(s) NPT520-34: TBD mg OR Single dose of orally administered placebo capsule(s) to match dose.

Drug: NPT520-34 (125 mg); Drug: Placebos (125 mg)

Interventions

NPT520-34 (125 mg) DRUG

NPT520-34, 125 mg oral capsules (size 1)

NPT520-34 - MAD Cohort 1, Dose 1; NPT520-34 - MAD Cohort 2, Dose 2; NPT520-34 - MAD Cohort 3, Dose 3; NPT520-34 - SAD Cohort 1, Dose 1 (Fed); NPT520-34 - SAD Cohort 1, Dose 1 (Unfed); NPT520-34 - SAD Cohort 2, Dose 2; NPT520-34 - SAD Cohort 3, Dose 3; NPT520-34 - SAD Cohort 4, Dose 4

Placebos (125 mg) DRUG

Placebo, 125 mg oral capsules

NPT520-34 - MAD Cohort 1, Dose 1; NPT520-34 - MAD Cohort 2, Dose 2; NPT520-34 - MAD Cohort 3, Dose 3; NPT520-34 - SAD Cohort 1, Dose 1 (Fed); NPT520-34 - SAD Cohort 1, Dose 1 (Unfed); NPT520-34 - SAD Cohort 2, Dose 2; NPT520-34 - SAD Cohort 3, Dose 3; NPT520-34 - SAD Cohort 4, Dose 4

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• informed of, and willing and able to comply with, all of the protocol requirements and the investigational nature of the study, and have signed an informed consent form in accordance with institutional and regulatory guidelines;
• male or female adults between 18 and 55 years of age, inclusive;
• female subjects must be of non-childbearing potential (i.e. post-menopausal for at least 2 years) or surgically sterile (hysterectomy, bilateral oophorectomy, tubal ligation) or nonsurgically sterile (hysteroscopic sterilization, i.e. Essure);
• male subjects must be willing to use an adequate barrier method of contraception for the duration of the study and for 90 days after dosing and no sperm donations for the duration of the study and for 90 days after dosing. Male subjects who are surgically sterile (16 weeks post-surgery, or documented proof of Post-Vasectomy Semen Analysis (PVSA) with negative sperm results) need not employ a method of contraception;
• non-smokers for at least six months;
• BMI = 18.0 - 32.0 kg/m2 inclusive;
• in good health, in the judgment of the Investigator, as determined by: 7a. medical history indicative of no serious or severe chronic conditions requiring frequent medical intervention or continual pharmacologic management, and no medical or social conditions that would potentially interfere with the subject's ability to comply with the study visit schedule or the study assessments; 7b. no clinically significant abnormalities in body temperature, heart rate, respiratory rate, blood pressure; 7c. no clinically significant abnormalities in the 12-lead electrocardiogram (ECG); 7d. no clinically significant abnormalities in clinical chemistry (ALT, AST, total bilirubin must be at or below the upper limit of normal and eGFR must be ≥ 90 mL/min), hematology (hemoglobin ≥ 11.5 g/dL for females and ≥ 13 g/dL for males), coagulation and urinalysis; lab tests may be repeated, if necessary (details are provided in the attached flow chart of study assessments).
• negative results on the following screening laboratory tests: urine drug screen, urine alcohol screen, serum pregnancy test, hepatitis B surface antigen, hepatitis C antibody, and human immunodeficiency virus antibody.

You may not qualify if:

• females of child bearing potential
• history of a significant medical condition, including cholecystectomy or clinically significant GI tract resection, that may interfere with absorption, distribution or elimination of NPT520-34, or with the clinical and laboratory safety assessments in this study;
• history of pre-existing thyroid abnormalities, such as hyper or hypothyroidism;
• history of lactose intolerance;
• history of drug hypersensitivity and disorders affecting respiratory function (e.g., COPD, asthma) and cardiac disorders predisposing to cardiac adverse events
• history of or current alcohol abuse and/or other drug addiction \< 2 years prior to screening, or a positive urine drug or alcohol screen (e.g., amphetamines, barbiturates, benzodiazepines, opiates, cannabinoids, alcohol and cocaine);
• positive for HBVsAg, HCV Ab, HIV Ab;
• lead ECG showing the following: having a corrected QTc interval \> 450 msec or \<340 msec (Fridericia's correction);
• sustained supine systolic blood pressure \> 140 or \< 90 mm Hg or supine diastolic blood pressure \> 90 or \< 50 mm Hg at Screening or Day -1. The average of the 2 assessments of BP taken at each visit will be used to exclude a subject;
• resting pulse rate at screening of \> 100 or \< 45.
• donated or lost \> 500 mL of blood \< 56 days prior to enrollment into this study;
• plasma donation within 7 days prior to enrollment into this study;
• active infection or febrile illness \< 14 days prior to the first dose of study medication;
• use of prescription (including hormone replacement therapy) or over-the-counter medications or herbal supplements ≤ 14 days prior to dosing and until completion of follow-up visit on Day 7 for the SAD subjects and Day 21 for the MAD subjects;
• excessive regular caffeine intake (\>250 mg of caffeine per day);

Sponsors & Collaborators

• Neuropore Therapies Inc.: lead
• Celerion: collaborator

Study Sites (1)

Celerion, Inc

Tempe, Arizona, 85283, United States

Location

MeSH Terms

Conditions

Parkinson Disease; Amyotrophic Lateral Sclerosis

Condition Hierarchy (Ancestors)

Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Spinal Cord Diseases; Motor Neuron Disease; TDP-43 Proteinopathies; Neuromuscular Diseases; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Officials

• Danielle Armas, M.D.

  Celerion

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 8, 2019
• First Posted: May 17, 2019
• Study Start: May 5, 2019
• Primary Completion: October 2, 2019
• Study Completion: October 9, 2019
• Last Updated: January 13, 2020

Record last verified: 2019-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)