A First-in-human Study to Assess the Safety and Tolerability of PDNO

  • STATUS
    Recruiting
  • days left to enroll
    86
  • participants needed
    48
  • sponsor
    Attgeno AB
Updated on 24 May 2021
body mass index

Summary

This is a first-in-human (FIH), single-blind, placebo-controlled, single-centre study designed to assess the safety and tolerability of PDNO in healthy male and female subjects. In addition, the exposure of 1,2 propanediol (PD) will be evaluated.

The study will be conducted in 2 parts:

Part I: single ascending dose (SAD), 7 cohorts, 30 minutes intravenous (iv) infusion of placebo followed by 1 hour iv infusion of PDNO to assess safety, tolerability and PD exposure in healthy male and female subjects.

Part II: ascending doses of PDNO in 2 cohorts, 30 minutes iv infusion of placebo followed by 3 ascending doses of PDNO in cohort 1 and 3 ascending doses of PDNO in cohort 2. The first 2 doses in each cohort will be iv infused for 30 minutes whereas the last will be iv infused for 3 hours to assess safety, tolerability and PD exposure in healthy male and female subjects.

If indicated by emerging data and recommended by the internal safety review committee (iSRC), 2 additional dose groups/cohorts (4+4 subjects) may be added to Part I and 1 dose group/cohort (4 subjects) may be added to Part II.

Description

Part I In Part I of the study, 4 subjects per cohort will first receive a 30 minutes iv infusion of placebo followed by a 1 hour iv infusion of PDNO in parallel with a continuous infusion of a sodium bicarbonate carrier buffer.

A total of 7 sequential cohorts with the following tentative dose levels are planned: 0.3, 1.0, 3.0, 10, 30, 60 and 120 nmol/kg/min. Up to 2 additional dose levels can be explored, tentatively 180 and 240 nmol/kg/min. Lower, intermediate doses (e.g. 90 nmol/kg/min) or repeated doses may also be given, based on the safety and tolerability of the drug if recommended by the iSRC. The maximum dose in the study will not exceed 240 nmol/kg/min.Subjects will come for 4 visits to the clinic. Screening (Visit 1) will take place from Day -28 to Day -1 and will include the subjects' signing of the informed consent and an eligibility check. At Visit 2, subjects will be admitted to the clinic on Day -1 for pre-dose assessments. The subjects will be carefully monitored by clinical staff during and after infusion. Vital signs (including pulse oximetry) and ECG will be checked at regular intervals. During the infusion, blood pressure will be continuously controlled via intra-arterial blood pressure monitoring.

In all cohorts, safety, tolerability and PD exposure will be assessed before, during and after the PDNO iv infusion. FeNO monitoring will be also be performed.

Part II Part II of the study will explore ascending doses of PDNO in 2 cohorts. In each cohort, 4 subjects will first receive a 30 minutes iv infusion of placebo followed by iv infusions of PDNO in 3 ascending doses in parallel with a continuous infusion of a sodium bicarbonate carrier buffer. Each of the first 2 dose levels in each cohort will be iv infused for 30 minutes whereas the highest dose level will be iv infused for 3 hours. To avoid any potential rebound effect, there will be no stabilisation period between either dose escalation.

The planned dose levels are: 1, 3 and 10 nmol/kg/min in cohort 1 and 30, 60 and 120 nmol/kg/min in cohort 2. The actual doses given in Part II will be based on emerging knowledge of safety and tolerability of PDNO observed in Part I of the study. The maximum dose in Part II will not exceed the highest dose given in Part I.

One additional cohort with additional doses or dosing schemes to establish the target dose for subsequent studies can be explored based on the safety and tolerability of the drug if recommended by the iSRC.

Details
Condition Pulmonary Hypertension
Treatment Sodium chloride, PDNO
Clinical Study IdentifierNCT04891354
SponsorAttgeno AB
Last Modified on24 May 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Willing and able to give written informed consent for participation in the study
Healthy male and female subjects aged 18 to 45 years inclusive at screening
Body Mass Index (BMI) 18.5 and 30.0 kg/m2 at screening
Clinically normal medical history, physical findings, ECG and laboratory values
Male subjects and women of non-childbearing potential may be included in the study. Male subjects must be willing to use condom or be vasectomised or practice sexual abstinence to prevent pregnancy and drug exposure of a female partner and refrain from donating sperm from the date of dosing until 3 months after dosing with the IMP. Their female partner of child-bearing potential must use contraceptive methods
Women of non-childbearing potential are defined as pre-menopausal females who are sterilised or postmenopausal

Exclusion Criteria

History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, might interfere with the drug absorption, distribution, metabolism or excretion of the drug or influence the results or the subject's ability to participate in the study
Any clinically significant illness, medical/surgical procedure or trauma within 4 weeks of the first administration of IMP
Malignancy within the past 5 years
Any planned major surgery within the duration of the study
Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody and Human Immunodeficiency Virus (HIV)
Women who are pregnant or who are breast feeding
Known patent foramen ovale or other cardiac phenomenon putting the subject at risk in the study
Presence of history of Raynaud Syndrome
After 10 minutes supine rest at the time of screening, any vital signs values outside the following ranges: Systolic blood pressure <90 or >140 mmHg, or Diastolic blood pressure <50 or >90 mmHg, or Pulse <40 or >90 bpm
Prolonged QTcF (>450 ms), cardiac arrhythmias or any clinically significant abnormalities in the resting ECG at the time of screening, as judged by the Investigator
Known history of migraine or frequent headache of other genesis (in average >1 episode of grade 2 (CTCAE v5.0, headache per week [20])
History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the Investigator, or history of hypersensitivity to drugs with a similar chemical structure or class to PDNO
History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity to the local anaesthesia planned to be used in the study
Known hypersensitivity to propanediol
Veins unsuitable for CVC and arterial cannula insertion
Failure to perform the FeNO measurement at screening
FeNO level 30 ppb
Within 1 month prior to Screening received continuous treatment with non-steroidal anti-inflammatory drugs (NSAIDs), novel oral anticoagulants (NOACs), warfarin, clopidogrel, acetylsalicylic acid
Regular use of any prescribed or non-prescribed medication including antacids, analgesics, herbal remedies, vitamins and minerals
Planned treatment or treatment with another investigational drug within 3 months prior to Day -1
Current smokers or users of nicotine products. Irregular use of nicotine
Positive screen for drugs of abuse or alcohol
Presence or history of alcohol abuse or excessive intake of alcohol
Presence or history of drug abuse, as judged by the Investigator
History of, or current use of, anabolic steroids
Excessive caffeine consumption defined by a daily intake of >5 cups of caffeine containing beverages
Intake of xanthine and/or taurine containing energy drinks at the day of screening
Plasma donation within one month of screening or blood donation
Investigator considers the subject unlikely to comply with study procedures, restrictions and requirements
Previous confirmed COVID-19 that required hospitalisation
Signs or symptoms probably consistent with COVID-19 disease within the last 7 days prior to Visit 2 or close contact with confirmed COVID-19 patient within the last 7 days prior to Visit 2, as judged by the Investigator
Positive result for ongoing SARS-CoV-2 presented at Visit 2
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