Study Investigation Pharmacokinetics and Pharmacodynamics of CS1

A Single Center, Randomised Study to Investigate Pharmacokinetics of CS1, Safety and Tolerability and in Obese, Borderline Hypertensive But Otherwise Healthy and Medicine Free Subjects After Administration of Single and Multiple Doses

SAD study:

Eighteen subjects will be included in the SAD study (single dose) in 3 parallel arms, each with 6 subjects. The 3 arms will receive a single dose of one of the CS1 formulations I, II or III. The result of the pharmacokinetics analysis from the 6 first subjects is defined as SAD Pilot and will be used to evaluate the timing of PK sampling. Based on pharmacokinetic evaluations from all 18 subjects one of the formulations I (275 mg), II (276 mg) or III (276 mg) will be chosen to proceed into the MAD study. If none of the formulations show the desired PK properties the formulations may be re-dosed with a slightly different timing of the dose, i.e the IMP to be administered earlier or later during the evening.

MAD study:

Fifteen subjects will be included in a dose escalating study with 2 dose levels. The subjects will receive the lowest dose level (275 or 276 mg depending on the outcome of SAD) for the first 2 weeks before the dose is doubled (550 or 552 mg depending on the outcome of SAD) for the following 2 weeks.

Study Overview

• Status: Completed
• Conditions: Thrombosis
• Intervention / Treatment: Drug: CS1-Sodium Valproate

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 1

Contacts and Locations

Study Locations

• Sweden
  • Uppsala, Sweden, 75237
    • CTC Clinical Trial Consultants AB

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Willing and able to give written informed consent for participation in the study
2. Male and female subjects age ≥ 40 years, ≤ 75 years inclusive.
3. BMI 27- 35 kg/m2
4. PAI-1 levels minimum 15 kIE/L (applies only to the MAD study)
5. Acceptable medical history, physical findings, vital signs, ECG and laboratory values at the time of screening, as judged by the Investigator. Subjects with stable hypertension with one or more antihypertensive drugs can be accepted as acceptable medical history.
6. Male subjects who has not documented a vasectomy, must be willing to use condom from the date of dosing until three months after dosing of the IMP to prevent drug exposure of a partner and refrain from donating sperm and if they have a fertile partner, she must use contraceptive methods with a failure rate of < 1% to prevent pregnancy .
7. The females must be of non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or post-menopausal defined as 12 months of amenorrhea (simultaneous determination of follicle stimulating hormone 25-140 IU/l and estradiol < 200 pmol/l is confirmatory) -

Exclusion Criteria:

Diagnosis and main eligibility criteria

Inclusion criteria:

1. Willing and able to give written informed consent for participation in the study
2. Male and female subjects age ≥ 40 years, ≤ 75 years inclusive.
3. BMI 27- 35 kg/m2
4. PAI-1 levels minimum 15 kIE/L (applies only to the MAD study)
5. Acceptable medical history, physical findings, vital signs, ECG and laboratory values at the time of screening, as judged by the Investigator. Subjects with stable hypertension with one or more antihypertensive drugs can be accepted as acceptable medical history.
6. Male subjects who has not documented a vasectomy, must be willing to use condom from the date of dosing until three months after dosing of the IMP to prevent drug exposure of a partner and refrain from donating sperm and if they have a fertile partner, she must use contraceptive methods with a failure rate of < 1% to prevent pregnancy .
7. The females must be of non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or post-menopausal defined as 12 months of amenorrhea (simultaneous determination of follicle stimulating hormone 25-140 IU/l and estradiol < 200 pmol/l is confirmatory)

Exclusion criteria:

1. 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, or influence the results or the subject's ability to participate in the study.
2. Subjects with active or chronic liver disease or personal or familiar history of drug related severe hepatic dysfunction.
3. Subjects with phorphyria.
4. Subjects with Systemic lupus erytematosus (SLE)
5. Subjects with TPK, APTT, INR levels which are significant outside the reference intervals as judged by the investigator.
6. History of severe bleeding disease or thrombotic disease.
7. Subjects on regular treatment with anticoagulant or antiplatelets drugs
8. Subjects with significant cardiac disease.
9. Subjects with significant pancreatic disease.
10. Subjects with gastrointestinal problems/ diseases e.g. inflammatory bowel disease and irritable bowel syndrome
11. Any clinically significant illness, medical/surgical procedure or trauma within four weeks of the first administration of IMP.
12. Any planned major surgery within the duration of the study.
13. Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody and Human Immunodeficiency Virus (HIV).

14. After 10 minute supine rest at the time of screening, any vital signs values outside the following ranges:

    • Systolic blood pressure > 160 mm Hg
    • Diastolic blood pressure > 100 mm Hg
    • Heart rate < 40 or > 90 beats per minute
15. 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.
16. History of severe allergy/hypersensitivity or on-going allergy/hypersensitivity, as judged by the Investigator, or history of hypersensitivity to drugs with a similar chemical structure or class to valproate acid or any other ingredient of the investigational medicinal product.
17. Administration of another new chemical entity (defined as a compound which has not been approved for marketing) or has participated in any other clinical study that included drug treatment with less than three months between administration of last dose and first dose of IMP in this study. Subjects consented and screened but not dosed in previous phase I studies are not excluded.
18. Current smokers or users of nicotine products. Irregular use of nicotine (e.g. smoking, snuffing, chewing tobacco) less than three times per week is allowed before screening visit.
19. Positive screen for drugs of abuse or alcohol at screening or on admission to the unit prior to administration of the IMP.
20. Current or history of alcohol abuse and/or use of anabolic steroids or drugs of abuse.
21. Intake of xanthine and/or taurine containing energy drinks within two days prior to screening.
22. Plasma donation within one month of screening or blood donation (or corresponding blood loss) during the three months prior to screening.

23. Investigator considers the subject unlikely to comply with study procedures, restrictions and requirements.

    -

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: CS 1 I SAD; Single dose pharmacokinetics of CS1 I	Drug: CS1-Sodium Valproate; Single and multiple dose evaluation of CS1
ACTIVE_COMPARATOR: CS 1 II SAD; Single dose pharmacokinetics of CS1 II	Drug: CS1-Sodium Valproate; Single and multiple dose evaluation of CS1
ACTIVE_COMPARATOR: CS 1 III SAD; Single dose pharmacokinetics of CS1 III	Drug: CS1-Sodium Valproate; Single and multiple dose evaluation of CS1
ACTIVE_COMPARATOR: CS 1 II MAD; Multiple dose pharmacokinetics of CS1 II	Drug: CS1-Sodium Valproate; Single and multiple dose evaluation of CS1

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic of CS1 in plasma	Plasma concentration of Valproate in plasma	up to four weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment-Emergent Adverse Events	Adverse event recording in free text	up to four weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
change in bleeding time	Differences in bleeding time (minutes)	four weeks
Change in plasma PAI-1 levels	ng/mL	four weeks
Change in hs-CRP levels	mg/L	four weeks
Change in platelet numbers	number of platelets per microliter blood	four weeks
Change in fibrinogen levels	g/L	four weeks
Change in PAP	ng/ml	four weeks

Collaborators and Investigators

• Sponsor: Cereno Scientific AB
• Investigators: Study Chair: Niklas Bergh, PhD, Cereno Scientific AB

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 6, 2017
• Primary Completion (ACTUAL): February 28, 2018
• Study Completion (ACTUAL): March 27, 2018

Study Registration Dates

• First Submitted: March 29, 2019
• First Submitted That Met QC Criteria: April 3, 2019
• First Posted (ACTUAL): April 4, 2019

Study Record Updates

• Last Update Posted (ACTUAL): April 8, 2019
• Last Update Submitted That Met QC Criteria: April 4, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: thrombosis; fibrinolysis; tissue-plasminogen activator (t-PA); plasminogen-activator inhibitor 1 (PAI-1)
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Thrombosis; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Tranquilizing Agents; Psychotropic Drugs; GABA Agents; Anticonvulsants; Antimanic Agents; Valproic Acid
• Other Study ID Numbers: CS1-001; 2017-002140-32 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No