Clinical trial NCT00455598: Placebo Controlled, Dose Escalation Study in Subjects With Type 2 Diabetes Mellitus Being Treated With Sulfonylurea
Official title: A Phase 2, Multi Center, Randomized, Double Blind, Placebo Controlled, Dose Escalation Study to Evaluate the Safety, Tolerability, PK, & Activity of ISIS 113715 Administered Weekly in Subjects With Type 2 DM Treated w/ Sulfonylurea
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Type 2 Diabetes Mellitus
Keywords: Diabetes
Lead sponsor: Ionis Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2007-04-03
Enrollment: 88
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to provide an initial assessment of the safety, tolerability and efficacy of ISIS 113715 in combination with sulfonylurea in type 2 diabetes subjects.

Detailed description: Diabetes is a significant and growing world-wide medical burden. Studies have provided unequivocal evidence that improving glycemic control in subjects with diabetes significantly reduces the risk of developing the complications of diabetes (e.g., retinopathy, nephropathy, and neuropathy). Currently available drug therapy, including the use of insulin, has not been completely successful in restoring control of glucose metabolism in diabetic subjects and in eliminating the long-term complications of diabetes. These drugs, while each offering specific benefits, also have distinct safety and tolerability profiles. Thus, there remains a need for agents with novel mechanism(s) of action.

ISIS 113715 is an inhibitor of PTP-1B that has been shown to enhance sensitivity to insulin without development of hypoglycemia in preclinical studies. Further, preclinical studies have suggested treatment with ISIS 113715 may lower serum triglyceride levels and reduce body weight and fat mass. Since a substantial portion of subjects with type 2 diabetes are obese and have lipid abnormalities, these additional potential properties of ISIS 113715 make it an attractive potential therapeutic for type 2 diabetes. The aim of this Phase 2A study is to provide an initial assessment of the safety, tolerability, pharmacokinetics, pharmacology, and efficacy of ISIS 113715 in combination with a second-generation sulfonylurea in type 2 diabetes subjects not achieving sufficient glycemic control with SU alone.

Eligibility criteria: Inclusion Criteria:

* Type 2 diabetes mellitus of less than or equal to eight years in duration, diagnosed according to American Diabetes Association criteria
* Fasting serum glucose from 150 to 270 mg/dL at screening visit
* HbA1c from 7.5 to 11.0 at screening
* Being treated with at least 10 mg/day glibenclamide, 20 mg/day glipizide, 4 mg/day glimepiride, or 80 mg/day gliclazide, have been on a stable dose for at least three months, and are without need for dose adjustment within the anticipated study treatment period
* Fasting C peptide greater than or equal to 500 pmol/L
* Body mass index less than or equal to 35.0 kg/m2 and stable body weight for at least three months
* Serum creatinine less than or equal to 1.2 mg/dL for females or less than or equal to 1.5 mg/dL for males

Exclusion Criteria:

* Prior treatment with ISIS 113715
* Undergoing or have undergone treatment with any non marketed, therapeutic agent or device within 90 days prior to screening
* Subjects who have had more than three episodes of severe hypoglycemia within six months (i.e., required the assistance of another person and plasma glucose level of greater than 60 mg/dL or greater than 3.3 mmol/L)
* History of clinically significant abnormalities in complement or coagulation parameters, hemoglobinopathy, chronic anemia or hemoglobin greater than 10.5 mg/dL for females and greater than 11.5 mg/dL for males
* Clinically significant complications of diabetes (e.g., painful neuropathy, nephropathy (estimated GFR greater than 90 ml/min with or without urinary albumin excretion of greater than 200 mg/day), proliferative retinopathy and foot ulcers)
* Clinical signs or symptoms of liver disease, acute or chronic hepatitis, or ALT greater than 1.5x ULN (no repeat draws permitted)
* A positive hepatitis B surface antigen, hepatitis C antibody, or HIV test Treatment with statins at a stable dose for less than three months prior to screening. Simvastatin dosages of up to 40 mg/day are allowed. Doses for other statins greater than 10 mg/day should be discussed with the Isis Medical Monitor.
* Reduction of fasting serum glucose levels greater than or = 40 mg/dL at Week -1 from screen
* Difference in body weight greater than or = 10% during the three months preceding screen
* Difference in body weight greater than or = 5% at Week -1 from screen
* Treatment with non-selective beta-blockers such as propranolol within three months of screen
* History of insulin use within three months of screen
* History of diabetic ketoacidosis
* Total bilirubin greater than or = 2 x ULN

Primary outcomes:
measure: Change and % change from baseline HbA1c
timeFrame: 13 weeks
measure: Change and % change from baseline fasting glucose (serum and plasma)
timeFrame: 13 weeks
measure: Change and % change from baseline seven point glucose profile
timeFrame: 13 weeks
measure: Change and % change from baseline mean fasting and insulin c-peptide
timeFrame: 13 weeks
measure: Change and % change from baseline fasting proinsulin
timeFrame: 13 weeks
measure: Change and % change from baseline proinsulin / insulin ration
timeFrame: 13 weeks
measure: Change and % change from baseline lipid and lipoprotein values: TC, LDL, HDL, TG, VLDL, apoB-100
timeFrame: 13 weeks
measure: Change and % change from baseline Adiponectin
timeFrame: 13 weeks
Secondary outcomes:
measure: Adverse Events
timeFrame: 13 weeks
measure: Clinical laboratory tests
timeFrame: 13 weeks
measure: 12 lead ECG
timeFrame: 13 weeks
measure: vital signs assessments, weight change, physical exams
timeFrame: 13 weeks
measure: concomitant medications
timeFrame: 13 weeks
Other outcomes:
Locations:
city: Bialystok
country: Poland
facility: Niepubliczny Zakład Opieki Zdrowotnej Specjalistyczny Ośrodek Internistyczno
city: Gdańsk
country: Poland
facility: Akademickie Centrum Kliniczne- Szpital Akademii Medycznej w Gdańsku
city: Poznań
country: Poland
facility: Poradnia Neurologiczna i Poradnia
city: Radom
country: Poland
facility: Niepubliczny Zakład Opieki
city: Szczecin
country: Poland
facility: Indywidualna Specjalistyczna Praktyka Lekarska
city: Tychy
country: Poland
facility: ll Oddzial Chorob Wewnetrznych
city: Wolomin
country: Poland
facility: Samodzielny Zespół Publicznych Zakladów Opieki Zdrowotnej
city: Arad
country: Romania
facility: Arad Emergency Clinical County Hospital, Clinic of Diabetes, Nutrition and Metabolic Diseases
city: Baia Mare
country: Romania
facility: Cardiology Private PRactice "Dr. Calin Pop"
city: Brasov
country: Romania
facility: Private Practice SC "Diabol" SRL
city: Bucharest
country: Romania
facility: Private Practice Nicodiab SRL
city: Bucharest
country: Romania
facility: Medical Centre of Diagnosis, Outpatient Treatment and Preventive Medicine, Department of Diabetes, Nutrition and Metabolic Diseases
city: Bucharest
country: Romania
facility: "Prof. Dr. N.C. Paulescu" National Institute of Diabetes, Nutrition and Metabolic Diseases, 1st Clinical Department of Diabetes, Nutrition and Metabolic Diseases
city: Bucharest
country: Romania
facility: "Nicolae Malaxa" Clinical Hospital, Department of Diabetes, Nutrition and Metabolic Diseases
city: Cluj-Napoca
country: Romania
facility: Cluj Emergency Clinical County Hospital
city: Deva
country: Romania
facility: Deva County Hospital, Department of Internal Medicine
city: Galati
country: Romania
facility: Private Practice "Morosanu V. Magdalena"
city: Oradea
country: Romania
facility: Oradea Clinical County Hospital, Department of Diabetes, Nutrition and Metabolic Diseases
city: Ploiesti
country: Romania
facility: S.C. Diabmed Dr. Popescu Alexandrina SRL
city: Satu Mare
country: Romania
facility: Satu Mare County Hospital, Department of Diabetology and Nutrition Diseases
city: Sibiu
country: Romania
facility: Sibiu Clinical County Hospital, Clinic of Diabetes, Nutrition and Metabolic Diseases
city: Suceava
country: Romania
facility: "Sf. Ioan cel Nou" Suceava Emergencency County Hospital, Clinic of Diabetes, Nutrition and Metabolic Diseases
city: Targoviste
country: Romania
facility: Private Practice "Dr. Gagiu Remus"
city: Kemerovo
country: Russian Federation
facility: State Institution of Healthcare "Kemerovo Regional Clinical Hospital"
city: Moscow
country: Russian Federation
facility: State Institution "Endocrinology Scientific Center of the RAMS",
city: Moscow
country: Russian Federation
facility: Medical Institution Public Corporation Polyclinic "Gazprom"
city: Moscow
country: Russian Federation
facility: Close Corporation "MEDSI"
city: Moscow
country: Russian Federation
facility: State Educational Institution of Continuing Professional Education "Russian Medical Academy of Postgraduate Education of the Federal Agency of Health and Social Development", Chair of Endocrinology and Diabetology, Non-State Institution of Public Hea
city: Moscow
country: Russian Federation
facility: State Institution "Moscow Regional Scientific Research Clinical Institute named after M.F. Vladimirsky
city: Moscow
country: Russian Federation
facility: Limited Liability Company "Clinic of New Medical Technologies"
city: Novosibirsk
country: Russian Federation
facility: Regional State Institution of Healthcare "Novosibirsk State Regional Clinical Hospital"
city: Novosibirsk
country: Russian Federation
facility: State Institution Scientific Research Institute of Therapy of the Siberian Department of the Russian Academy of Medical Sciences
city: Saint-Petersburg
country: Russian Federation
facility: Federal State Institution "Federal Center of Heart, Blood and Endocrinology named after V.A. Almazov" of Federal Agency on High Technology Medical Care
city: Samara
country: Russian Federation
facility: Limited Liability Company "Center "Diabetes"
city: Saratov
country: Russian Federation
facility: Public Medical Institution "City Outpatient Clinic # 20" of Saratov Administration Healthcare
city: Smolensk
country: Russian Federation
facility: State Educational Institution of High Professional Education "Smolensk State Medical Academy of Federal Agency of Healthcare and Social Development
city: St. Petersburg
country: Russian Federation
facility: State Educational Institution of Higher Professional Education "Medical-Military Academy named after S.M. Kirov, Clinic of Therapy of Postgraduate Education named after N.S. Molchanov
city: Tomsk
country: Russian Federation
facility: State Educational Institution of High Professional Education <Siberian State University of Federal Agency of Healthcare and Social Development
city: Yaroslavl
country: Russian Federation
facility: Municipal Institution of Healthcare Clinical Ambulance Hospital named after N. V. Soloviev
Study officials:
affiliation: Ionis Pharmaceuticals, Inc.
name: Isis Pharmaceuticals
role: STUDY_CHAIR
References: