Safety Study of ISIS 325568 in Healthy Volunteers

A Phase I, Double-Blind, Placebo-Controlled, Dose- Escalation Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Doses of ISIS 325568 Administered to Healthy Volunteers

The primary purpose of this trial is to assess the safety of ISIS 325568 when given at increasing single doses and to assess the safety of the same doses when given multiple times.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: ISIS 325568

Detailed Description

To evaluate the safety of a single subcutaneous injection of ISIS 325568 administered at four increasing dose levels (50, 100, 200, 400 mg/week) and to evaluate the safety and tolerability of multiple doses of ISIS 325568 (three intravenous doses during Study Week 1, followed by once weekly subcutaneous administration for 5 weeks) at each of the four dose levels

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Leiden, Netherlands
    • Centre For Human Drug Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age 18 to 65 years
2. Males or females. Females must be non-pregnant and non-lactating, and either surgically sterile (hysterectomy, oophorectomy, or tubal ligation) or post-menopausal. Males must be surgically sterile, abstinent or if engaged in sexual relations of child-bearing potential, subject or partner must be using an acceptable contraceptive method during the trial and for 9 weeks after the last dose of study drug.
3. Give written informed consent to participate in study and availability for all study requirements
4. Fasting plasma glucose ≤ the upper limit of the laboratory's reference range (ULN)
5. HbA1C ≤ ULN
6. BMI < 30 kg/m2

Exclusion Criteria:

1. Clinically significant abnormalities in medical history or physical examination
2. Abnormalities on laboratory examination (ALT > ULN, AST > ULN, bilirubin > ULN, creatinine > ULN, urine protein positive by urine dipstick, platelets < lower limit of normal and any other clinically significant laboratory findings)
3. History of clinically significant abnormalities in coagulation parameters
4. Positive test result for HIV, hepatitis B virus, and/or hepatitis C virus
5. Active infection requiring antiviral or antimicrobial therapy
6. Subjects on chronic or acute prescription medication may be permitted after discussion with the Isis Medical Monitor.
7. Malignancy (with the exception of basal or squamous cell carcinoma of the skin if adequately treated and no recurrence for > 1 year)
8. Any other concurrent condition which, in the opinion of the Investigator, would preclude participation in this study or interfere with compliance
9. History of alcohol or drug abuse
10. Undergoing or have undergone treatment with another investigational drug, biologic agent or device within 90 days prior to Screening.
11. Blood donation within three months of screening

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A; 50 mg ISIS 325568 vs Placebo, s.c. injection	Drug: ISIS 325568; 4 arms of single dose s.c. injections: A 50 mg B 100 mg C 200 mg D 400 mg 4 arms of multi-dose: 3 i.v. infusions over 1 week followed by 5 weekly s.c. injections AA 50 mg BB 100 mg CC 200 mg DD 400 mg or EE 50 mg Placebo: 0.9% Sodium Chloride
Experimental: B; 100 mg ISIS 325568 vs Placebo , s.c. injection	Drug: ISIS 325568; 4 arms of single dose s.c. injections: A 50 mg B 100 mg C 200 mg D 400 mg 4 arms of multi-dose: 3 i.v. infusions over 1 week followed by 5 weekly s.c. injections AA 50 mg BB 100 mg CC 200 mg DD 400 mg or EE 50 mg Placebo: 0.9% Sodium Chloride
Experimental: C; 200 mg ISIS 325568 vs Placebo , s.c. injection	Drug: ISIS 325568; 4 arms of single dose s.c. injections: A 50 mg B 100 mg C 200 mg D 400 mg 4 arms of multi-dose: 3 i.v. infusions over 1 week followed by 5 weekly s.c. injections AA 50 mg BB 100 mg CC 200 mg DD 400 mg or EE 50 mg Placebo: 0.9% Sodium Chloride
Experimental: D; 400 mg ISIS 325568 vs Placebo, s.c. injection	Drug: ISIS 325568; 4 arms of single dose s.c. injections: A 50 mg B 100 mg C 200 mg D 400 mg 4 arms of multi-dose: 3 i.v. infusions over 1 week followed by 5 weekly s.c. injections AA 50 mg BB 100 mg CC 200 mg DD 400 mg or EE 50 mg Placebo: 0.9% Sodium Chloride
Experimental: AA; 50 mg ISIS 325568, 3x over 1 week i.v. infusion, weekly s.c. injection for 5 weeks vs Placebo	Drug: ISIS 325568; 4 arms of single dose s.c. injections: A 50 mg B 100 mg C 200 mg D 400 mg 4 arms of multi-dose: 3 i.v. infusions over 1 week followed by 5 weekly s.c. injections AA 50 mg BB 100 mg CC 200 mg DD 400 mg or EE 50 mg Placebo: 0.9% Sodium Chloride
Experimental: BB; 100 mg ISIS 325568, 3x over 1 week i.v. infusion, weekly s.c. injection for 5 weeks vs Placebo	Drug: ISIS 325568; 4 arms of single dose s.c. injections: A 50 mg B 100 mg C 200 mg D 400 mg 4 arms of multi-dose: 3 i.v. infusions over 1 week followed by 5 weekly s.c. injections AA 50 mg BB 100 mg CC 200 mg DD 400 mg or EE 50 mg Placebo: 0.9% Sodium Chloride
Experimental: CC; 200 mg ISIS 325568, 3x over 1 week i.v. infusion, weekly s.c. injection for 5 weeks vs Placebo	Drug: ISIS 325568; 4 arms of single dose s.c. injections: A 50 mg B 100 mg C 200 mg D 400 mg 4 arms of multi-dose: 3 i.v. infusions over 1 week followed by 5 weekly s.c. injections AA 50 mg BB 100 mg CC 200 mg DD 400 mg or EE 50 mg Placebo: 0.9% Sodium Chloride
Experimental: DD; 400 mg ISIS 325568, 3x over 1 week i.v. infusion, weekly s.c. injection for 5 weeks vs Placebo	Drug: ISIS 325568; 4 arms of single dose s.c. injections: A 50 mg B 100 mg C 200 mg D 400 mg 4 arms of multi-dose: 3 i.v. infusions over 1 week followed by 5 weekly s.c. injections AA 50 mg BB 100 mg CC 200 mg DD 400 mg or EE 50 mg Placebo: 0.9% Sodium Chloride

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
safety and tolerability	30 days for single dose, 16 weeks for multi-dose

Secondary Outcome Measures

Outcome Measure	Time Frame
Pharmacokinetic profile all doses and Pharmacodynamics for multi-dose groups.	4 days for single dose, 16 weeks for multi-dose

Collaborators and Investigators

• Sponsor: Ionis Pharmaceuticals, Inc.
• Investigators: Principal Investigator: J. Burggraaf, MD PhD, Centre For Human Drug Research

Publications and helpful links

General Publications

• Burel SA, Machemer T, Baker BF, Kwoh TJ, Paz S, Younis H, Henry SP. Early-Stage Identification and Avoidance of Antisense Oligonucleotides Causing Species-Specific Inflammatory Responses in Human Volunteer Peripheral Blood Mononuclear Cells. Nucleic Acid Ther. 2022 Aug 17. doi: 10.1089/nat.2022.0033. Online ahead of print.

Study record dates

Study Major Dates

• Study Start: August 1, 2007
• Primary Completion (Actual): April 1, 2008
• Study Completion (Actual): June 1, 2008

Study Registration Dates

• First Submitted: August 21, 2007
• First Submitted That Met QC Criteria: August 21, 2007
• First Posted (Estimate): August 23, 2007

Study Record Updates

• Last Update Posted (Estimate): August 19, 2008
• Last Update Submitted That Met QC Criteria: August 15, 2008
• Last Verified: August 1, 2008

More Information

Terms related to this study

• Keywords: diabetes
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2
• Other Study ID Numbers: ISIS 325568-CS1; EudraCT No: 2007-000235-25