Safety, Tolerability and Activity Study of Multiple Doses of ISIS-SGLT2Rx in Healthy Volunteers

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: ISIS 388626


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>50 mg ISIS 388626 vs Placebo, s.c. injection | Drug: ISIS 388626<br>* 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<br>|
| Experimental: B<br>100 mg ISIS 388626 vs Placebo, s.c. injection | Drug: ISIS 388626<br>* 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<br>|
| Experimental: C<br>200 mg ISIS 388626 vs Placebo, s.c. injection | Drug: ISIS 388626<br>* 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<br>|
| Experimental: D<br>400 mg ISIS 388626 vs Placebo, s.c. injection | Drug: ISIS 388626<br>* 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<br>|
| Experimental: AA<br>50 mg ISIS 388626, 3x over 1 week s.c. injection, weekly s.c. injection for 5 weeks vs Placebo | Drug: ISIS 388626<br>* 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<br>|
| Experimental: BB<br>100 mg ISIS 388626, 3x over 1 week s.c. injection, weekly s.c. injection for 5 weeks vs Placebo | Drug: ISIS 388626<br>* 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<br>|
| Experimental: AAA<br>50 mg ISIS 388626, weekly s.c. injection for 13 weeks vs Placebo | Drug: ISIS 388626<br>* 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<br>|
| Experimental: BBB<br>100 mg ISIS 388626, weekly s.c. injection for 13 weeks vs Placebo | Drug: ISIS 388626<br>* 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<br>|
| Experimental: CCC<br>200 mg ISIS 388626, weekly s.c. injection for 13 weeks vs Placebo | Drug: ISIS 388626<br>* 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<br>|
| Experimental: FFF<br>50 mg ISIS 388626, weekly s.c. injection for 13 weeks vs Placebo | Drug: ISIS 388626<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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diabetes, SGLT2 inhibitor