A first-in-human, randomized, double-blind, placebo-controlled, single and multiple ascending dose study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of INS-3001 in healthy subjects and patients with moderate aortic valve stenosis

Completed

Conditions: aortic valve stenosis
Cardiovascular calcification
10003216

Registration Number: NL-OMON52051

Lead Sponsor: Vifor (International) Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Completed

Sex: Not specified

Target Recruitment: 30

Inclusion Criteria

SAD part:
A1. Age : 21 to 60 years, inclusive, at screening.
A2. Body mass index (BMI) : 18.0 to 30.0 kg/m2, inclusive, at screening.
A3. Being male or female; females must be of nonchildbearing potential (ie,
surgically sterilized [ie, hysterectomy, bilateral salpingectomy, or bilateral
oophorectomy], physiologically incapable of becoming pregnant, or at least 1
year postmenopausal [amenorrhea duration of >=12 consecutive months]).
A4. Females must not be pregnant or lactating; nonpregnancy will be confirmed
for all females by a serum pregnancy test conducted at screening, at admission,
and at follow-up.
A5. Male subjects, if not surgically sterilized (ie, vasectomized), must agree
to use adequate contraception when having intercourse with a female sexual
partner of childbearing potential and to not donate sperm from admission to the
clinical site until 90 days after the follow up visit. See Section 3.4.8.2 for
the full definition of adequate contraception.
A6. In good physical and mental health on the basis of medical history,
physical examination, and routine laboratory measurements (ie, without major or
clinically relevant pathology), as judged by the Investigator.
A7. Normal arterial blood pressure (systolic blood pressure of 90 to 140 mmHg,
inclusive, and diastolic blood pressure of 45 to 90 mmHg, inclusive) and pulse
rate (40 to 100 beats per minute, inclusive). Measurement of blood pressure
and/or pulse may be repeated if in the judgment of the Investigator there is a
reason to believe the initial result is inaccurate (eg, white coat
hypertension).
A8. Computerized (12-lead) ECG recording without signs of clinically relevant
pathology, as judged by the Investigator. The ECG may be repeated if in the
judgment of the Investigator there is a reason to believe the initial result is
inaccurate.
A9. Willing and able to abstain from alcohol for 72 hours (3 days) prior to
screening and from 72 hours prior to study drug administration until the last
PK blood sampling.
A10. Willing and able to abstain from methylxanthine-containing beverages
(coffee, tea, cola, or other caffeinated beverage) from 48 hours (2 days) prior
to study drug administration until the last PK blood sampling.
A11. Willing and able to abstain from herbal medications or dietary supplements
(eg, St. John*s Wort or ginkgo biloba), vitamin preparations, grapefruit or
grapefruit juice, or Seville oranges from 14 days prior to administration of
the study drug until follow up.
A12. Willing and able to understand and comply with the protocol requirements
and instructions and likely to complete the study as planned.
A13. Willing and able to read, understand, and sign the ICF.

MAD part:
B1. Age : >55 years at screening.
B2. BMI : 18.0 to 35.0 kg/m2, inclusive, at screening.
B3. Being male or female; females must be of nonchildbearing potential (ie,
surgically sterilized [ie, hysterectomy, bilateral salpingectomy, or bilateral
oophorectomy], physiologically incapable of becoming pregnant, or at least 1
year postmenopausal [amenorrhea duration of >=12 consecutive months and
confirmed by a follicle stimulating hormone {FSH} test at screening]).
B4. Females must not be pregnant or lactating; nonpregnancy will be confirmed
for all females by a serum or urine pregnancy test conducted at screen

Exclusion Criteria

SAD part:
A1. Treatment with prescription medications within 14 days prior to study drug
administration. An exception is made for vaccines against SARS-CoV-2, which
will be allowed but must be discussed with the Investigator to mitigate against
any interruptions to trial-related procedures and assessments. Potential
subjects should only stop any prescribed medication at the direction of a
physician.
A2. Treatment with nonprescription medications within 14 days prior to study
drug administration. An exception is made for paracetamol, which is allowed up
to admission to the clinical site. Potential subjects should consult a
physician before stopping any regular treatment with nonprescription medication.
A3. Using tobacco products within 3 months prior to study drug administration.
A4. History of alcohol or drug abuse or addiction within 2 years prior to study
drug administration.
A5. Regular consumption of more than 14 units of alcohol per week for females
and more than 21 units of alcohol per week for males (1 unit equals 250 mL of
beer, 100 mL of wine, or 35 mL of spirits).
A6. Regular consumption of more than 8 cups of methylxanthine-containing
beverages (coffee, tea, cola, or other caffeinated beverage) per day (1 cup
equals 250 mL).
A7. Participation in a clinical study involving administration of an
investigational or a marketed drug within 3 months prior to screening.
Participation in more than 4 other drug studies in the 12 months prior to study
drug administration in the current study.
A8. Blood donation or a significant loss of blood (>450 mL) within 60 days
prior to study drug administration or donation of more than 1 unit of plasma
within 7 days prior to screening.
A9. Employee of PRA Health Sciences (PRA) or the Sponsor.
A10. History of any illness or condition that, in the opinion of the
Investigator, might confound the results of the study or pose an additional
risk when administering the study drug to the subject.
A11. Positive drug or alcohol screen (opiates, methadone, cocaine, amphetamines
[including ecstasy], cannabinoids, barbiturates, benzodiazepines, gamma
hydroxybutyric acid, tricyclic antidepressants, cotinine, or alcohol) at
screening or at admission to the clinical site.
A12. Previous participation in the current study.
A13. Positive result at screening for any of the following infectious disease
tests: hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibodies,
or human immunodeficiency virus (HIV) 1 and 2 antibodies.
A14. Positive PCR test for SARS CoV-2 at admission to the clinical site.
A15. Unsuitable veins for infusion or blood sampling.
A16. History of relevant drug and/or food allergies.
A17. Illness within 5 days prior to study drug administration (*illness* is
defined as an acute [serious or non-serious] condition [eg, the flu or the
common cold]).

MAD part:
B1. Rheumatic or unicuspid aortic valves.
B2. Patients with aortic sclerosis, mild or severe aortic stenosis, or absence
of aortic valve calcification (ie, parameters outside the limits defined in the
inclusion criteria).
B3. Severe mitral or aortic regurgitation.
B4. Severe mitral stenosis.
B5. History of aortic valve replacement.
B6. Aortic valve replacement or repair scheduled or anticipated during the
study period.
B7. Left ventricu

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>To assess the safety and tolerability of single and multiple ascending doses of<br /><br>INS 3001 in healthy subjects and patients with aortic valve stenosis (AVS)</p><br>

Secondary Outcome Measures

Name	Time	Method
<p>To assess the pharmacokinetic (PK) profile of INS-3001 after subcutanous (SC)<br /><br>administration of single ascending doses in healthy subjects<br /><br><br /><br>To assess the PK profile of INS-3001 after SC administration of multiple<br /><br>ascending doses in patients with AVS<br /><br><br /><br>To assess the inhibition of valvular hydroxyapatite growth by INS-3001 in<br /><br>patients with AVS by determining the change from baseline in aortic valve 18F<br /><br>NaF uptake derived from 18F NaF positron emission tomography (PET) scans</p><br>