SAD PartIn this part we will investigate how safe the new compound INS-3001 is and how well it is tolerated when it is used by healthy participants.We will also investigate how quickly and to what extent INS-3001 is absorbed, transported, and…
ID
Source
Brief title
Condition
- Arteriosclerosis, stenosis, vascular insufficiency and necrosis
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To assess the safety and tolerability of single and multiple ascending doses of
INS 3001 in healthy subjects and patients with aortic valve stenosis (AVS)
Secondary outcome
To assess the pharmacokinetic (PK) profile of INS-3001 after subcutanous (SC)
administration of single ascending doses in healthy subjects
To assess the PK profile of INS-3001 after SC administration of multiple
ascending doses in patients with AVS
To assess the inhibition of valvular hydroxyapatite growth by INS-3001 in
patients with AVS by determining the change from baseline in aortic valve 18F
NaF uptake derived from 18F NaF positron emission tomography (PET) scans
Background summary
INS-3001 is a new compound that may potentially be used for the treatment of
cardiovascular calcifications (calcium deposits in the heart and/or arteries),
that come with age. Such calcifications can result in cardiovascular diseases,
like aortic valve stenosis. Aortic valve stenosis is a narrowing of the aortic
valve that makes it harder for blood to flow from the left ventricle to the
aorta.
To date, there are no medications available that can inhibit the development of
cardiovascular calcifications. The new compound INS 3001 is able to inhibit the
formation of hydroxyapatites, the calcium crystals that cause cardiovascular
calcifications.
Study objective
SAD Part
In this part we will investigate how safe the new compound INS-3001 is and how
well it is tolerated when it is used by healthy participants.
We will also investigate how quickly and to what extent INS-3001 is absorbed,
transported, and eliminated from the body.
We will compare the effects of INS-3001 with the effects of a placebo.
INS-3001 has not been administered to humans before. It has so far only been
extensively tested in the laboratory and on animals. INS-3001 will be tested at
various dose levels.
MAD Part
In this part we will investigate how safe the new treatment INS-3001 is and how
well it is tolerated when it is used by patients. The study will investigate
how quickly and to what extent INS-3001 is absorbed, transported, and
eliminated from the body (this is called pharmacokinetics).
The study will also investigate the anti-calcification effect of the drug.
Study design
SAD Part
The study will take a maximum of 7 weeks from the screening until the follow-up
visit.
For the study it is necessary that the volunteer stays in the research center
for 1 period of 4 days (3 nights). This will be followed by 1 short visit to
the research center for a follow-up.
The volunteer will be given INS-3001 or placebo as an injection under the skin
(subcutaneous).
MAD Part
This part will take about 12 weeks in total.
For the study the patient will have 2 overnight stays at the research center (2
nights + 1 night).
The patient will be given INS-3001 or placebo as an injection under the skin
(subcutaneous).
Intervention
SAD part
From groups 1 to 7 an ascending dose of 1mg to 400mg INS-3001 or placebo.
MAD part
From groups 1 to 4 dose of 25mg to 200mg INS-3001 or placebo.
Study burden and risks
Possible side effects
The study compound may cause side effects.
As INS-3001 will be administered to humans for the first time in this study,
side effects of INS-3001 in humans are not known yet. INS-3001 has been studied
extensively in the laboratory and in animals. INS-3001 inhibits calcification
processes.
In a study with young rats, INS-3001 slowed calcium deposition in the growth
plates, but this effect was not seen in adult rats and dogs. No side effects in
the bones are therefore expected in adult humans.
INS-3001 or placebo will be given as an injection under the skin. This
subcutaneous injection may be painful or cause some bruising at the site of
injection.
The study compound may also have (serious) side effects that are still unknown.
In addition to unknown side effects, there is a (small) chance that an allergic
reaction will occur. This can be caused by the study compound or other
ingredients that are used to prepare the formulation.
Possible Discomforts
Blood draw
Drawing blood may be painful or cause some bruising. On the day of
administration of the study compound, blood will be sampled very frequently
using an indwelling cannula (a tube in a vein in the arm) to determine the
course of the concentration of INS-3001 in the blood over time. The use of an
indwelling cannula can sometimes lead to inflammation, swelling, hardening of
the vein, blood clotting, and/or bruising around the puncture site. In some
individuals, a blood draw can sometimes cause pallor, nausea, sweating, low
heart rate, and/or drop in blood pressure with dizziness or fainting.
In total, we will take about x mL of blood from the volunteer. This amount
does not cause any problems in adults. To compare: a blood donation involves
500 mL of blood being taken each time. If the investigator thinks it is
necessary for the safety of a participant, extra samples might be taken for
possible additional testing. If this happens, the total amount of blood drawn
will be more than the amount indicated above.
Heart tracing
To make a heart tracing, electrodes (small, plastic patches) will be placed on
the volunteers arms, chest, and legs. To monitor your heart rate continuously
(on the day of administration of the study drug), electrodes will be placed on
the volunteers chest and abdomen. Prolonged use of these electrodes can cause
skin irritation (rash and itching).
Fasting
If the volunteer has to fast for a prolonged time during the study, this may
lead to symptoms such as dizziness, headache, stomach upset, or fainting.
Coronavirus test
Samples for the coronavirus test will be taken from the back of the volunteers
nose and throat using swabs. Taking the samples only takes a few seconds, but
can cause discomfort and can give an unpleasant feeling. Taking a sample from
the back of the volunteers throat may cause him to gag. When the sample is
taken from the back of the volunteers nose, he may experience a stinging
sensation and his eyes may become watery.
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Age
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 screening, at
first admission, and at follow-up.
B5. 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 the first
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.
B6. Moderate AVS defined as a mean pressure gradient of 20 to 40 mmHg
(inclusive) or a peak aortic jet velocity (Vmax) of 3.0 to 4.0 m/s (inclusive),
and an aortic valve area of >1.0 cm2.
B7. Evidence of aortic valve calcification by computed tomography (CT) or
echocardiography with moderate or severe cusp calcification or with an
echocardiogram or CT calcium score above 400 Agatston units.
B8. On stable medication, defined as no change within 30 days prior to
screening. Minor changes in medication can be allowed if considered acceptable
by the Investigator.
B9. 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 the first
administration of the study drug until follow-up.
B10. Willing and able to understand and comply with the protocol requirements
and instructions and likely to complete the study as planned.
B11. Willing and able to read, understand, and sign the ICF.
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 ventricular ejection fraction <50%.
B8. ECG with QTcF >480 msec (in case of a left bundle branch block [LBBB], the
QT-interval can be corrected for LBBB by the formula QTLBBB - [0.86 * QRSLBBB -
71]; for paced rhythms, the QTc can be corrected by the formula QTc-measured -
50 ms).
B9. Patients with an estimated glomerular filtration rate <45 mL/min/1.73m2,
calculated using the modification of diet in renal disease.
B10. Patients with moderate or severe hepatic impairment.
B11. Patients with known osteopenia or osteomalacia, or with hypocalcemia
(adjusted calcium <2.20 mmol/L) or vitamin D deficiency (25-OH vitamin D <50
nmol/L) at screening.
B12. Patients with recent (within 3 months prior to screening) coronary artery
bypass grafting, percutaneous coronary intervention, acute coronary syndrome,
uncontrolled diabetes (hemoglobin A1c >9%), uncontrolled hypertension (systolic
blood pressure >180 mmHg), or scheduled for a major surgery within 3 months
after the follow-up visit.
B13. 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.
B14. Previous participation in the current study.
B15. Positive result at screening for any of the following infectious disease
tests: HBsAg, HCV antibodies, or HIV 1 and 2 antibodies.
B16. Not being vaccinated for SARS-CoV-2.
B17. Positive PCR test for SARS CoV-2 at each admission to the clinical site.
B18. Unsuitable veins for infusion or blood sampling.
B19. History of relevant drug and/or food allergies.
B20. Illness within 5 days prior to the first study drug administration
(*illness* is defined as an acute [serious or non-serious] condition [eg, the
flu or the common cold]).
B21. Recent bone fracture (ie, within 3 months prior to screening).
B22. Any contraindication to the 18F-NaF-PET scan assessment.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2021-001969-20-NL |
| CCMO | NL78901.056.21 |