Safety, Tolerability and Activity Study of Multiple Doses of ISIS-SGLT2Rx 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 388626 Administered to Healthy Volunteers

The primary purpose of this trial is to assess the safety and tolerability of ISIS-SGLT2Rx when given at increasing single doses and to assess the safety and tolerability of the same doses when given multiple times.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: ISIS 388626

Detailed Description

To evaluate the safety and tolerability of a single subcutaneous injection of ISIS-SGLT2Rx administered at four increasing dose levels (50, 100, 200, 400 mg) and to evaluate the safety and tolerability of multiple doses of ISIS 388626 administered subcutaneously of either 6 or 13 weeks.

• Study Type: Interventional
• Enrollment (Actual): 103
• Phase: Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Leiden, Netherlands
    • Center 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:

• Age 18 to 65 years
• Male or female gender although females must be post-menopausal or surgically sterile (hysterectomy, oophorectomy or tubal ligation)
• Give written informed consent to participate in the study and availability for all study requirements
• Fasting plasma glucose </= the upper limit of the laboratory's reference range (ULN)
• HbA1c </= ULN
• BMI < 30 kg/m²
• Agree to maintain steady hydration throughout study participation and agree not to fluid restrict

Exclusion Criteria:

• Pregnant women, nursing mothers or women of childbearing potential
• Clinically significant abnormalities in medical history or physical examination
• Clinically significant abnormalities in laboratory examination (including 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)
• Estimated GFR < 60 mL/min per 1.73m²
• History of clinically significant abnormalities in coagulation parameters
• Positive test result for HIV, hepatitis B virus, and/or hepatitis C virus
• Active infection requiring antiviral or antimicrobial therapy
• Subjects on chronic or acute prescription medication may be permitted after discussion with the Isis Medical Monitor
• Malignancy (with the exception of basal or squamous cell carcinoma of the skin if adequately treated and no recurrence for > 1 year)
• Any other concurrent condition which, in the opinion of the Investigator, would preclude participation in this study or interfere with compliance
• Past and present history of alcohol or drug abuse (defined as > 3 units daily)
• Undergoing or have undergone treatment with another investigational drug, biologic agent or device within 90 days prior to Screening
• 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

10

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A; 50 mg ISIS 388626 vs Placebo, s.c. injection	Drug: ISIS 388626; 4 arms of single dose s.c. injections: A 50 mg, B 100 mg, C 200 mg, D 400 mg, 2 arms of multi-dose: 3 s.c. injections over 1 week followed by 5 weekly s.c. injections: AA 50 mg, BB 100 mg 3 arms of multi-dose 13 weekly s.c. injections: AAA 50 mg, BBB 100 mg, CCC 200 mg, FFF 50 mg Placebo: 0.9% sterile saline
Experimental: B; 100 mg ISIS 388626 vs Placebo, s.c. injection	Drug: ISIS 388626; 4 arms of single dose s.c. injections: A 50 mg, B 100 mg, C 200 mg, D 400 mg, 2 arms of multi-dose: 3 s.c. injections over 1 week followed by 5 weekly s.c. injections: AA 50 mg, BB 100 mg 3 arms of multi-dose 13 weekly s.c. injections: AAA 50 mg, BBB 100 mg, CCC 200 mg, FFF 50 mg Placebo: 0.9% sterile saline
Experimental: C; 200 mg ISIS 388626 vs Placebo, s.c. injection	Drug: ISIS 388626; 4 arms of single dose s.c. injections: A 50 mg, B 100 mg, C 200 mg, D 400 mg, 2 arms of multi-dose: 3 s.c. injections over 1 week followed by 5 weekly s.c. injections: AA 50 mg, BB 100 mg 3 arms of multi-dose 13 weekly s.c. injections: AAA 50 mg, BBB 100 mg, CCC 200 mg, FFF 50 mg Placebo: 0.9% sterile saline
Experimental: D; 400 mg ISIS 388626 vs Placebo, s.c. injection	Drug: ISIS 388626; 4 arms of single dose s.c. injections: A 50 mg, B 100 mg, C 200 mg, D 400 mg, 2 arms of multi-dose: 3 s.c. injections over 1 week followed by 5 weekly s.c. injections: AA 50 mg, BB 100 mg 3 arms of multi-dose 13 weekly s.c. injections: AAA 50 mg, BBB 100 mg, CCC 200 mg, FFF 50 mg Placebo: 0.9% sterile saline
Experimental: AA; 50 mg ISIS 388626, 3x over 1 week s.c. injection, weekly s.c. injection for 5 weeks vs Placebo	Drug: ISIS 388626; 4 arms of single dose s.c. injections: A 50 mg, B 100 mg, C 200 mg, D 400 mg, 2 arms of multi-dose: 3 s.c. injections over 1 week followed by 5 weekly s.c. injections: AA 50 mg, BB 100 mg 3 arms of multi-dose 13 weekly s.c. injections: AAA 50 mg, BBB 100 mg, CCC 200 mg, FFF 50 mg Placebo: 0.9% sterile saline
Experimental: BB; 100 mg ISIS 388626, 3x over 1 week s.c. injection, weekly s.c. injection for 5 weeks vs Placebo	Drug: ISIS 388626; 4 arms of single dose s.c. injections: A 50 mg, B 100 mg, C 200 mg, D 400 mg, 2 arms of multi-dose: 3 s.c. injections over 1 week followed by 5 weekly s.c. injections: AA 50 mg, BB 100 mg 3 arms of multi-dose 13 weekly s.c. injections: AAA 50 mg, BBB 100 mg, CCC 200 mg, FFF 50 mg Placebo: 0.9% sterile saline
Experimental: AAA; 50 mg ISIS 388626, weekly s.c. injection for 13 weeks vs Placebo	Drug: ISIS 388626; 4 arms of single dose s.c. injections: A 50 mg, B 100 mg, C 200 mg, D 400 mg, 2 arms of multi-dose: 3 s.c. injections over 1 week followed by 5 weekly s.c. injections: AA 50 mg, BB 100 mg 3 arms of multi-dose 13 weekly s.c. injections: AAA 50 mg, BBB 100 mg, CCC 200 mg, FFF 50 mg Placebo: 0.9% sterile saline
Experimental: BBB; 100 mg ISIS 388626, weekly s.c. injection for 13 weeks vs Placebo	Drug: ISIS 388626; 4 arms of single dose s.c. injections: A 50 mg, B 100 mg, C 200 mg, D 400 mg, 2 arms of multi-dose: 3 s.c. injections over 1 week followed by 5 weekly s.c. injections: AA 50 mg, BB 100 mg 3 arms of multi-dose 13 weekly s.c. injections: AAA 50 mg, BBB 100 mg, CCC 200 mg, FFF 50 mg Placebo: 0.9% sterile saline
Experimental: CCC; 200 mg ISIS 388626, weekly s.c. injection for 13 weeks vs Placebo	Drug: ISIS 388626; 4 arms of single dose s.c. injections: A 50 mg, B 100 mg, C 200 mg, D 400 mg, 2 arms of multi-dose: 3 s.c. injections over 1 week followed by 5 weekly s.c. injections: AA 50 mg, BB 100 mg 3 arms of multi-dose 13 weekly s.c. injections: AAA 50 mg, BBB 100 mg, CCC 200 mg, FFF 50 mg Placebo: 0.9% sterile saline
Experimental: FFF; 50 mg ISIS 388626, weekly s.c. injection for 13 weeks vs Placebo	Drug: ISIS 388626; 4 arms of single dose s.c. injections: A 50 mg, B 100 mg, C 200 mg, D 400 mg, 2 arms of multi-dose: 3 s.c. injections over 1 week followed by 5 weekly s.c. injections: AA 50 mg, BB 100 mg 3 arms of multi-dose 13 weekly s.c. injections: AAA 50 mg, BBB 100 mg, CCC 200 mg, FFF 50 mg Placebo: 0.9% sterile saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
To evaluate the safety and tolerability of single and multiple doses of ISIS-SGLT2Rx administered subcutaneously	30 days for single dose, 11 weeks for 6-week dosing, 18 weeks for 13-week dosing

Secondary Outcome Measures

Outcome Measure	Time Frame
Pharmacokinetic profile all doses and Pharmacodynamics for multi-dose groups	3 days for single dose, 11 weeks for 6-week dosing, 18 weeks for 13-week dosing

Collaborators and Investigators

• Sponsor: Ionis Pharmaceuticals, Inc.
• Investigators: Principal Investigator: Adam Cohen, MD, PhD, Center for Human Drug Research

Study record dates

Study Major Dates

• Study Start: January 1, 2009
• Primary Completion (Actual): October 1, 2011
• Study Completion (Actual): January 1, 2012

Study Registration Dates

• First Submitted: February 2, 2009
• First Submitted That Met QC Criteria: February 2, 2009
• First Posted (Estimate): February 4, 2009

Study Record Updates

• Last Update Posted (Estimate): February 3, 2012
• Last Update Submitted That Met QC Criteria: February 2, 2012
• Last Verified: February 1, 2012

More Information

Terms related to this study

• Keywords: diabetes; SGLT2 inhibitor
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2
• Other Study ID Numbers: ISIS 388626-CS1