Primary: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…
ID
Source
Brief title
Condition
- Glucose metabolism disorders (incl diabetes mellitus)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Tolerability of ISIS 325568
PK of ISIS 325568
Effects of ISIS 325568 (hepatic glucose production)
Secondary outcome
NA
Background summary
Pharmacological antagonism of glucagon action has been investigated
non-clinically as a potential therapeutic approach for type 2 diabetes. Both
peptide antagonists as well as monoclonal antibodies against glucagon receptor
have been shown to attenuate hyperglycemia in animal models.
Development of small molecules against the glucagon receptor has been slow due
to issues with pharmacokinetics, selectivity, cross species differences and
lack of sustained effects after non-competitive blockade (McCormack et.al.
2001). Only a single Phase 1 study has been published that describes the acute
effects of a small molecule glucagon receptor inhibitor in man (Petersen et.al.
2001).
Antisense compounds such as ISIS 325568 is a very potent antisense inhibitor of
the human glucagon receptor. After systemic administration, the primary
mechanism of ISIS 325568 is to reduce hepatic and adipose tissue glucagon
receptor abundance. Preclinical data indicate that the antidiabetic effects of
ISIS 325568 will likely be due to a dual mechanism (i) Reduction of hepatic
glucose output that is due to attenuation of glucagon action in the liver, and
(ii) A secondary increase in active GLP-1, which occurs due to increased
processing of preproglucagon in the pancreas.
Study objective
Primary:
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.
Secondary:
To evaluate the pharmacokinetic profile of ISIS 325568 given subcutaneously and
intravenously at each of the dose levels.
To evaluate the pharmacodynamics of ISIS 325568 given for six weeks.
Study design
Double-Blind, Placebo-Controlled, Dose-Escalation Study
Intervention
ISIS 325568 or placebo
Study burden and risks
As with each first in human study there are risks associated with this study.
The risk however are considered small and manageable because there is a
carefull dose escaltion, regular monitoring and experience with antisense
compounds of the same generation.
The burden for the volunteers depends on the phase of the study in which they
participate. It ranges from participating in a part of the study in which a
single dose is adminsitered and a relatively short observation period is
scheduled until a demanding phase with multiple administrations, long study
days (with 2 glucagon challenges and fat biopsies and a long observation
period.
These experiments have been performed earlier at CHDR and are generally well
tolerated by the volunteers.
1896 Rutherford Road
Carlsbad, CA 92008
USA
1896 Rutherford Road
Carlsbad, CA 92008
USA
Listed location countries
Age
Inclusion criteria
1. healthy subjects of either gender aged between 18-65 years
2. Females must be non-pregnant and non-lactating, and either
surgically sterile (hysterectomy, oophrectomy, or tubal ligation) or postmenopausal.
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
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
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 | EUCTR2007-000235-25-NL |
| CCMO | NL17359.000.07 |