To evaluate the safety and tolerability of a single subcutaneous (s.c.) injection of ISIS 388626 administered at four increasing dose levels (50, 100, 200, 400 mg) and to evaluate the safety and tolerability of multiple doses of ISIS 388626…
ID
Source
Brief title
Condition
- Glucose metabolism disorders (incl diabetes mellitus)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety Endpoints
The safety and tolerability of ISIS 388626 will be assessed by determining the
incidence, severity and dose-relationship of adverse effects and changes in
laboratory evaluations within each dose cohort. Safety results in subjects
dosed with ISIS 388626 will be compared with those from subjects dosed with
placebo.
Pharmacokinetic Endpoints
The pharmacokinetics of ISIS 388626 will be assessed following single and
multiple dose administration. Plasma concentration of ISIS 388626 and percent
of administered dose in urine at the selected 0-24 and 24-48 hour intervals
will be determined.
Pharmacodynamic Endpoints
Pharmacodynamic assessments will be made in all the multiple dosing cohorts by
measuring the change in urinary glucose excretion from Baseline following six
or thirteen-weeks of ISIS 388626 dosing and at other time-points. Additional
pharmacodynamic assessments will compare plasma glucose concentration in
response to an oral glucose tolerance test and inhibition of urinary glucose
reabsorption conducted prior to and following thirteen-weeks of ISIS 388626
dosing, and at other time-points.
Secondary outcome
NA
Background summary
A therapeutic approach that has been under considerable investigation in recent
years involves inhibition of glucose reabsorption by the kidney by reducing the
renal sodium glucose cotransporter 2 (SGLT2). While proof of concept for this
approach was obtained many years ago by using phlorizinit is only in the past
couple of years that clinical proof of concept has been demonstrated. While
several small molecule SGLT2 inhibitors are currently under investigation in
the clinic, they only inhibit renal fractional glucose reabsorption by about
50%. In contrast, ISIS 388626 is a very potent and selective inhibitor of SGLT2
that inhibits renal SGLT2 expression by >= 80%. Furthermore, the specificity and
selective renal distribution of ISIS 388626 has resulted in potent
anti-hyperglycemic effects in many preclinical models of diabetes without the
side effects that can result due to inhibition of other transporters such as
SGLT1 (for example, gastro-intestinal side effects have been reported due to
SGLT1 inhibition with some small molecules).
Study objective
To evaluate the safety and tolerability of a single subcutaneous (s.c.)
injection of ISIS 388626 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 s.c. for either 6 or 13 weeks. The 6-week
multiple-dose cohorts will receive three s.c. doses during Week 1, followed by
once weekly s.c. administration for 5 weeks, at each of the four dose levels
(50, 100, 200, 400 mg/week). Cohort CC, DD and EE were cancelled and will be
replaced by the 13-week multiple-dose cohorts receiving once weekly s.c.
administration for 13 weeks (dose levels 50, 100, or 200 mg/wk).
To evaluate the pharmacokinetic profile of single and multiple doses of ISIS
388626 at all dose levels.
To evaluate the pharmacodynamics of multiple doses of ISIS 388626 at all dose
levels.
To conduct renal clearance studies using PAH/Sinistrin (cohort FFF) at regular
intervals to explore the mechanism that may underlie the renal changes observed
in the clinic for cohort AA, BB and AAA.
Study design
Double-Blind, Placebo-Controlled, Dose-Escalation Study
Intervention
ISIS 388626 or placebo (0.9% sterile saline)
Study burden and risks
As with each first in human study there are risks associated with this study.
However, the risk are considered small and manageable because in animal
experiments and investigations with similar drugs have shown these drugs are
safe to administer to humans. There is a chance that for developing
hypoglycemia and/or an urinary tract infection, but in animal experiments this
has never occurred,
Addition: After multiple doses of study drug in the ongoing cohort AAA (50 mg),
serum creatinine and urine beta 2 microglobulin increases have been observed.
These changes are transient and do not progress in subjects with continued
dosing, which is similar in nature to the changes observed in subjects treated
with 50 mg of ISIS 388626 in Cohort AA. The renal changes in cohort AAA
occurred despite the removal of the loading dose, which was not anticipated at
this dose level based on previous results from the preclinical studies
indicating that the serum creatinine increases were largely avoided when the
loading dose was omitted. Further, the preclinical studies indicated that in
animals in which serum creatinine increases did occur, no changes in renal
histology were seen at a time when serum creatinine had peaked, an observation
that was consistent with lack of any significant histological changes in the
3-month toxicology studies in mice and monkeys. (Investigator Brochure,
Revision 1 dated 23 December 2009).
At the time of this amendment, all 16 subjects in Cohort AAA have been
enrolled. There have been no serious adverse events and adverse events
reported are mostly mild in severity.
For Cohort FFF 50 mg dose level will be repeated and additional tests to
explore the mechanism (GFR, renal blood flow) that may underlie the renal
changes observed in the clinic will be included. Renal clearance tests will be
performed 7 times during 18-week study duration; prehydration, 2- hour iv
infusion of PAH/Sinistrin, 2 cannula's, during the test every 30 minutes plasma
& urine sampling, subjects have to stay in bed during this test.
1896 Rutherford Road
Carlsbad, CA 92008
US
1896 Rutherford Road
Carlsbad, CA 92008
US
Listed location countries
Age
Inclusion criteria
1. Healthy volunteers aged between 18 to 65 years
2. Male or female gender although females must be post-menopausal or surgically sterile (hysterectomy, oophrectomy or tubal ligation).
3. Give written informed consent to participate in the 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. Pregnant women, nursing mothers or women of childbearing potential
2. Presence of any of the following conditions:
a. Clinically significant abnormalities in medical history or physical examination
b. Clinically significant abnormalities in laboratory examination. (ALT > ULN, AST > ULN, bilirubin > ULN, creatinine > ULN, urine protein positive by dipstick, platelets < lower limit of normal and any other clinical significant laboratory findings)
c. Clinically significant abnormalities in coagulation parameters
d. Positive test result for HIV, hepatitis B virus, and/or hepatitis C virus
e. Active infection requiring antiviral or antimicrobial therapy
f. Subjects on chronic or acute prescription medication may be permitted after discussion with the Isis Medical Monitor.
g. Malignancy (with the exception of basal or squamous cell carcinoma of the skin if adequately treated and no recurrence for > 1 year)
h. Any other concurrent condition which, in the opinion of the Investigator, would preclude participation in this study or interfere with compliance
3. History of alcohol or drug abuse
4. Undergoing or have undergone treatment with another investigational drug, biologic agent or device within 90 days prior to Screening.
5. 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 | EUCTR2008-005629-13-NL |
| CCMO | NL24864.000.08 |