<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01706211</url>
  </required_header>
  <id_info>
    <org_study_id>49653/128</org_study_id>
    <nct_id>NCT01706211</nct_id>
  </id_info>
  <brief_title>A Study to Evaluate the Efficacy and Safety of BRL 49653C in Non-insulin Dependent Diabetes</brief_title>
  <official_title>A Double-blind, Placebo Controlled, Parallel Group Comparative Study to Evaluate the Efficacy and Safety of BRL 49653C With Concurrent Sulphonylurea Therapy, When Administered to Patients With Non-insulin Dependent Diabetes Mellitus.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Taiwan University Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Taiwan University Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      At least 30% of patients initially treated with sulphonylureas for NIDOM will have a poor&#xD;
      response, and in the remaining 70% the subsequent failure rate is approximately 4% to 5% per&#xD;
      year. BRL 49653C has a different mechanism of action to the sulphonylureas, and therefore the&#xD;
      effects on fasting plasma glucose and Hb A1c are expected to be additive. Since circulatory&#xD;
      insulin levels should decrease, and plasma glucose should be regulated, these combinations&#xD;
      are also anticipated to slow both the progression of diabetic complications and delay the&#xD;
      need for exogenous insulin.&#xD;
&#xD;
      The proposed study is intended primarily to determine the effectiveness of BRL 49653C by&#xD;
      measure of glucose homeostasis as determined by Hb A1c and fasting plasma glucose, when added&#xD;
      to sulphonylurea therapy (sulphonylureas are limited to: glibenclamide, glipazide and&#xD;
      gliclazide). In addition, the clinical safety of BRL 49653C will be assessed in this patient&#xD;
      population. The starting doses have been selected based on dose response studies examining&#xD;
      safety, tolerability and efficacy in the U.S.A.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Non-insulin dependent diabetes mellitus (NIDDM) is the most common form of the hyperglycaemic&#xD;
      state. Although NIDDM exists in all populations, its prevalence varies greatly, depending&#xD;
      upon age and race, and appears to be increasing. It is estimated that NIDOM occurs in 5% of&#xD;
      50-year-old-adults and 20% of the 80-year-old population with a linear progression between&#xD;
      these age groups. Aberrant insulin secretion from pancreatic p-cells, and insulin resistance&#xD;
      in peripheral tissues with reduced glucose uptake (particularly in muscle and liver) are the&#xD;
      primary pathogenic mechanisms believed to be responsible for the metabolic abnormalities&#xD;
      associated with NIDDM. Insulin resistance progresses to overt diabetes at the rate of&#xD;
      approximately 5% of patients per year.&#xD;
&#xD;
      Patients with insulin resistance, but no overt diabetes mellitus, are generally overweight,&#xD;
      usually have a sedentary lifestyle, and frequently have a family history of diabetes&#xD;
      mellitus. Insulin-resistant phenotype is commonly associated with cardiovascular risk factors&#xD;
      such as hypertension and dyslipidemia (decreased HDL and increased VLDL, LDL and&#xD;
      triglycerides). Current available therapies for NIDOM include insulin and oral hypoglycemic&#xD;
      agents (e.g. sulphonylurea compounds and biguanides). Sulphonylureas achieve blood glucose&#xD;
      control by enhancing pancreatic insulin secretion. However, a significant failure rate does&#xD;
      exist for this mode of treatment, and many patients who have received long term treatment&#xD;
      with sulphonylureas do require exogenous insulin therapy when there is no longer adequate&#xD;
      pancreatic insulin secretion (even in response to sulphonylureas). Single therapy with the&#xD;
      biguanide, metformin, or combination therapy with an additional sulphonylurea may also be&#xD;
      administered to NIDDM patients. However, the overall effect of metformin on glycemic control&#xD;
      seems to be smaller than that of sulphonylureas, and in many cases, combination therapy does&#xD;
      not stop the need for insulin after a period of time.&#xD;
&#xD;
      BRL 49653C is a highly potent and orally active anti-diabetic thiazolidinedione compound. The&#xD;
      thiazolidinediones such as BRL 49653C represent a novel class of compounds that act as&#xD;
      &quot;insulin sensitizers&quot; in target tissues. Unlike sulphonylureas, BRL 49653C improves the&#xD;
      sensitivity of muscle and liver to insulin. An agent that enhances insulin sensitivity may be&#xD;
      effective in regulating elevated blood glucose in patients with NIDDM and theoretically may&#xD;
      be beneficial in reducing the frequency and severity of morbid complications of this disease.&#xD;
      BRL 49653C does not increase pancreatic insulin secretion; therefore, treatment with BRL&#xD;
      49653C should not have the potential to exhaust pancreatic function, or produce the untoward&#xD;
      effect of hypoglycemia (a potential complication of treatment with sulphonylureas).&#xD;
&#xD;
      In animal testing, repeat oral administration of BRL 49653C has been effective in reducing&#xD;
      hyperglycemia, hyperinsulinemia, hypertriglyceridemia, and free fatty acids associated with&#xD;
      insulin-resistant models of NIDDM2. In the genetically obese mouse, the potency of BRL49653C&#xD;
      as an anti-hyperglycemic agent, was compared with competitor insulin sensitizers, and BRL&#xD;
      49653C was proven to be at least 100 times more potent than CS-045 (troglitazone) and at&#xD;
      least 30 times more potent than pioglitazone.&#xD;
&#xD;
      Six month toxicological findings were similar to those observed in one month studies. Please&#xD;
      refer to the Investigator Brochure for more detailed information about pre-clinical studies&#xD;
      and the pharmacology, metabolism, and toxicology of BRL 49653C.&#xD;
&#xD;
      To date, seven completed Phase I studies have shown BRL 49653C to be safe and well tolerated.&#xD;
      The levels of exposure to BRL 49653C have been shown to be similar in both the fed and fasted&#xD;
      state, and pharmacokinetic analysis has shown no evidence of accumulation after 10 days once&#xD;
      daily dosing of 1 to 5 mg in obese volunteers. A total of 140 volunteers received BRL 49653C&#xD;
      ranging in doses of 0.2 to 20 mg (20 mg dose is approximately 4 to 5-fold higher than doses&#xD;
      expected to be administered to NIDDM patients). Of these, 140 subjects, 91 received one or&#xD;
      more single doses of BRL 49653C up to 20 mg. This includes 10 healthy elderly males (&gt;= 65&#xD;
      years of age). Additionally, 49 obese subjects have received dosages of up to 5 mg/day for 10&#xD;
      consecutive days.&#xD;
&#xD;
      SmithKline Beecham Phase I clinical studies have shown BRL 49653C to be safe and well&#xD;
      tolerated. The most frequently observed adverse experience was headache. Serious adverse&#xD;
      experiences of transient asymptomatic accelerated unifocal ventricular rhythm of less than 10&#xD;
      seconds duration were observed in two volunteers. The arrhythmias were noted at 27 minutes&#xD;
      and 2 hours and 20 minutes after administration of a single dose of BRL 49653C 2mg. Hotter&#xD;
      monitoring was performed in two studies in order to evaluate the arrythmogenicity of BRL&#xD;
      49653C. Study 002, was a placebo controlled, 10 day repeat dose, two-period, period balanced,&#xD;
      cross-over study, within each of three dose groups (1, 2 or 5 mg) of BRL 49653C. Study 016&#xD;
      was a single dose, double-blind, randomized (with respect to order of placebo), placebo&#xD;
      controlled, five period cross-over, oral dose rising study in which each subject received a&#xD;
      randomly allocated placebo and four doses of BRL 49653C (5, 10, 15, 20 mg). In both of these&#xD;
      studies, there was no evidence of protocol- defined incidence of ventricular tachycardia,&#xD;
      ventricular premature beats, or supraventricular tachycardia.&#xD;
&#xD;
      A recent study with another thiazolidinedione compound, troglitazone, has shown that there is&#xD;
      no increase in cardiac mass or cardiac function impairment in patients with NIDDM . To the&#xD;
      contrary, these patients were observed to have decreases in systemic vascular resistance,&#xD;
      with enhanced cardiac output and stroke volume. Other studies examining thiazolidinediones&#xD;
      have shown beneficial effects on Hemoglobin A1c with statistically significant decreases&#xD;
      indicating beneficial effects on glucose homeostasis over periods of time.&#xD;
&#xD;
      BRL 49653C has also been examined in combination with glyburide (glibenclamide). BRL 49653C&#xD;
      was administered 2mg bd to NIDDM patients receiving stable doses of glyburide for seven days.&#xD;
      No changes were observed in either the 24 hour glucose or insulin profiles, suggesting that&#xD;
      the combined treatment is not associated with any acute pharmacokinetic interaction that&#xD;
      would likely result in an acute untoward pharmacodynamics effect.&#xD;
&#xD;
      The safety, tolerability and efficacy of BRL 49653C in patients with NIDDM has been examined&#xD;
      in a phase II, double-blind, placebo controlled dose response study. A total of 380 patients&#xD;
      received either placebo, 005mg bid, 0.25mg bid, 1mg bid or 2mg bid for 12 weeks. Analysis of&#xD;
      variance showed highly significant (p&lt;0.001) treatment effects on fasting blood glucose from&#xD;
      week 2 onwards, although it was clear that a plateau in response had not been achieved at the&#xD;
      highest dose tested. At the higher dose of 2mg bid, there were statistically significant&#xD;
      differences compared to placebo, at week 12 for fasting plasma glucose (-40.1 mg/dL),&#xD;
      fructosamine (-27.1 mmol/L) and insulin (-16%), and a significant reduction in hemoglobin Alc&#xD;
      (0.4%). The lowering of fasting glucose in the 2mg bid group with a concomitant 16% decrease&#xD;
      in insulin levels supports the hypothesis of insulin sensitization as a mechanism of action&#xD;
      for BRL 49653.&#xD;
&#xD;
      The drug was found to be safe with no adverse effects on vital signs, ECG or clinical&#xD;
      chemistry. 2D M-Mode echocardiography revealed no on left ventricular mass effects, and the&#xD;
      small reductions in hemoglobin 14.5 to 14.3 g/100ml in the highest dose group) and hematocrit&#xD;
      (from 42.6% to 41.8%) are not regarded as being clinically significant. Furthermore, BRL&#xD;
      49653C was found to be well tolerated over the dose range 0.05-2.0mg bid with an adverse&#xD;
      event profile that was similar to placebo both qualitatively and quantitatively.&#xD;
&#xD;
      During the study a total of 18 serious adverse events (sAE) were reported, 9 during the&#xD;
      screening/run-in phase and 9 during the 12 week randomization period. There were 3 sAE in&#xD;
      each of the placebo and 2.0mg BRL 49653 groups and I in each of the 0.05, 0.25 and 1.0mg&#xD;
      groups. There were 2 deaths during the study, one case of myocardial infarction (2.0mg group)&#xD;
      in a 52 year old male was designated as possibly related, and the other case (0.25mg group),&#xD;
      a 71 year old male with cardiopulmonary arrest, was unrelated. All other sAE were specified&#xD;
      by the investigators as being unrelated to trial medication, apart from 1 case of exercise&#xD;
      induced non-sustained ventricular tachycardia in a 56 year old male receiving placebo. Causal&#xD;
      relationship was given as possibly related in this case.&#xD;
&#xD;
      At least 30% of patients initially treated with sulphonylureas for NIDDM will have a poor&#xD;
      response, and in the remaining 70% the subsequent failure rate is approximately 4% to 5% per&#xD;
      year. BRL 49653C has a different mechanism of action to the sulphonylureas, and therefore the&#xD;
      effects on fasting plasma glucose and Hb A1c are expected to be additive. Since circulatory&#xD;
      insulin levels should decrease, and plasma glucose should be regulated, these combinations&#xD;
      are also anticipated to slow both the progression of diabetic complications and delay the&#xD;
      need for exogenous insulin.&#xD;
&#xD;
      The proposed study is intended primarily to determine the effectiveness of BRL 49653C by&#xD;
      measure of glucose homeostasis as determined by Hb A1c and fasting plasma glucose, when added&#xD;
      to sulphonylurea therapy (sulphonylureas are limited to: glibenclamide. glipazide and&#xD;
      gliclazide). In addition, the clinical safety of BRL 49653C will be assessed in this patient&#xD;
      population. The starting doses have been selected based on dose response studies examining&#xD;
      safety, tolerability and efficacy in the USA.&#xD;
&#xD;
      Please refer to the Investigator Brochure for a review of the pre-clinical and clinical&#xD;
      studies of BRL 49653C.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>October 1998</start_date>
  <completion_date type="Actual">April 2000</completion_date>
  <primary_completion_date type="Actual">April 2000</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>To determine the effectiveness of BRL 49653C (2 mg bd) compared to placebo when added to sulphonylurea therapy, for 24 weeks in out-patients with NIDDM.</measure>
    <time_frame>7 months</time_frame>
    <description>Primary: Change from baseline for Hb A1c at week 24.&#xD;
Secondary: Mean change from baseline for:&#xD;
fasting plasma glucose,insulin levels, immune reactive,lipid levels (ie.total cholesterol, HDL-cholesterol, LDL cholesterol, triglycerides), body weight (WHR), vital signs (systolic, diastolic blood pressure and heart rate)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>To assess the clinical safety of BRL 49653C (2 mg bd) compared to placebo when added to sulphonylurea therapy, for 24 weeks in out-patients with NIDOM.</measure>
    <time_frame>7 months</time_frame>
    <description>Physical examination, adverse experiences, laboratory safety data, ECG parameters</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">77</enrollment>
  <condition>Diabetes Mellitus Non Insulin Dependent Oral Agent Therapy</condition>
  <arm_group>
    <arm_group_label>BRL 49653C</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Eligible patients may enter the study at visit 1 according to the inclusion/exclusion criteria. At the screening visit, patients will enter a single blind placebo run-in period to establish baseline characteristics. Patients must have been stable on sulphonylurea therapy for at least 2 months prior to the screening visit to be included. For the duration of the run-in period, patients will receive BRL 49653C placebo in addition to their constant dose of sulphonylurea. Patients eligible to enter the double-blind phase of the study will be randomized in equal numbers at visit 2, to one of two treatment groups (BRL 49653C 2 mg bid. or placebo bid). Patients will then continue to take their study medication arid the constant dose of sulphonylurea through visits 3 to 8 (weeks 4 to 24).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Eligible patients may enter the study at visit 1 according to the inclusion/exclusion criteria. At the screening visit, patients will enter a single blind placebo run-in period to establish baseline characteristics. Patients must have been stable on sulphonylurea therapy for at least 2 months prior to the screening visit to be included. For the duration of the run-in period, patients will receive BRL 49653C placebo in addition to their constant dose of sulphonylurea. Patients eligible to enter the double-blind phase of the study will be randomized in equal numbers at visit 2, to one of two treatment groups (BRL 49653C 2 mg bid. or placebo bid). Patients will then continue to take their study medication arid the constant dose of sulphonylurea through visits 3 to 8 (weeks 4 to 24).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>BRL 49653C</intervention_name>
    <description>BRL 49653C 2 mg bid or placebo bid through weeks 1 to 24.</description>
    <arm_group_label>BRL 49653C</arm_group_label>
    <other_name>Avandia, rosiglitazone</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <arm_group_label>placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Men or women between 30-80 years of age inclusive at time of enrolment.&#xD;
&#xD;
          -  Patients who had non-independent diabetes mellitus (NIDDM) defined by the criteria of&#xD;
             the National Diabetes Data Group.&#xD;
&#xD;
          -  Patients who had sulphonylurea therapy for at least 6 months and a constant dose for&#xD;
             at least 2 months prior to visit 1.&#xD;
&#xD;
          -  Patients who had fasting plasma glucose &lt;= 15.0 mmol/L at screening. Hemoglobin A1c &gt;=&#xD;
             7.5%.&#xD;
&#xD;
          -  Female patients must be (1) post-menopausal, i.e. &gt; 6 months without menstrual period,&#xD;
             surgically sterile, or (2) using hormonal contraceptives or intrauterine contraceptive&#xD;
             devices. Female patients who were taking hormonal contraceptives must also use an&#xD;
             additional barrier form or intrauterine form of birth control.&#xD;
&#xD;
          -  Patients who had given their written informed consent to participate.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Female patients who were pregnant, breast feeding or planning a pregnancy during the&#xD;
             course of the study.&#xD;
&#xD;
          -  Patients who had a fasting plasma glucose &gt; 15.0 mmol/L at screening, or severity of&#xD;
             diabetes mellitus requiring administration of insulin, or patients with ketonuria.&#xD;
&#xD;
          -  Patients who had clinically significant renal or hepatic disease (i.e., patients with&#xD;
             serum creatinine &gt; 160 micromol/L (1.8 mg/dL); ALT, AST, total bilirubin, gamma GT, or&#xD;
             alkaline phosphatase more than 2.5 times the upper limit of the normal laboratory&#xD;
             range).&#xD;
&#xD;
          -  Any clinically significant abnormality identified on the screening physical&#xD;
             examination, laboratory tests, electrocardiogram which in the judgment of the&#xD;
             investigator would preclude safe completion of the study.&#xD;
&#xD;
          -  Patients who had leukocyte count &lt; 3000/mm3 or platelet count &lt;120,000/mm3.&#xD;
&#xD;
          -  Systolic blood pressure &gt;180mmHg or diastolic blood pressure &gt;114mmHg while on&#xD;
             appropriate hypertensive therapy.&#xD;
&#xD;
          -  Significant anemia (hemoglobin &lt; 11 g/dL for males or &lt; 10g/dL for females) or&#xD;
             diagnosis of porphyria.&#xD;
&#xD;
          -  Symptomatic diabetic neuropathy of sufficient severity to require treatment for&#xD;
             control of symptoms (eg, painful peripheral neuropathy, symptomatic orthostatic&#xD;
             hypotension, urinary retention, gastric stasis, pedal ulcers).&#xD;
&#xD;
        Diabetic retinopathy imminently requiring treatment for preserving or restoring vision.&#xD;
&#xD;
          -  Body mass index(BMI) &lt; 22 and &gt;38 kg/m2 (Formula: BMI= weight, kg ÷height, m2)and&#xD;
             variation in body weight of &gt;=5% between screening and visit2.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>30 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Lee-Ming Chuang, PHD</last_name>
    <role>Study Chair</role>
    <affiliation>National Taiwan University Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>National Taiwan University Hospital</name>
      <address>
        <city>Taipei</city>
        <zip>10002</zip>
        <country>Taiwan</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Taiwan</country>
  </location_countries>
  <results_reference>
    <citation>Yang WS, Jeng CY, Wu TJ, Tanaka S, Funahashi T, Matsuzawa Y, Wang JP, Chen CL, Tai TY, Chuang LM. Synthetic peroxisome proliferator-activated receptor-gamma agonist, rosiglitazone, increases plasma levels of adiponectin in type 2 diabetic patients. Diabetes Care. 2002 Feb;25(2):376-80. doi: 10.2337/diacare.25.2.376.</citation>
    <PMID>11815513</PMID>
  </results_reference>
  <verification_date>September 2012</verification_date>
  <study_first_submitted>October 10, 2012</study_first_submitted>
  <study_first_submitted_qc>October 12, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 15, 2012</study_first_posted>
  <last_update_submitted>October 12, 2012</last_update_submitted>
  <last_update_submitted_qc>October 12, 2012</last_update_submitted_qc>
  <last_update_posted type="Estimate">October 15, 2012</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>non insulin dependent diabetes mellitus, rosiglitazone</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Diabetes Mellitus</mesh_term>
    <mesh_term>Diabetes Mellitus, Type 2</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Rosiglitazone</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01706211
org study id: 49653/128
nct id: NCT01706211
lead sponsor: 
has dmc: Yes
At least 30% of patients initially treated with sulphonylureas for NIDOM will have a poor
      response, and in the remaining 70% the subsequent failure rate is approximately 4% to 5% per
      year. BRL 49653C has a different mechanism of action to the sulphonylureas, and therefore the
      effects on fasting plasma glucose and Hb A1c are expected to be additive. Since circulatory
      insulin levels should decrease, and plasma glucose should be regulated, these combinations
      are also anticipated to slow both the progression of diabetic complications and delay the
      need for exogenous insulin.

      The proposed study is intended primarily to determine the effectiveness of BRL 49653C by
      measure of glucose homeostasis as determined by Hb A1c and fasting plasma glucose, when added
      to sulphonylurea therapy (sulphonylureas are limited to: glibenclamide, glipazide and
      gliclazide). In addition, the clinical safety of BRL 49653C will be assessed in this patient
      population. The starting doses have been selected based on dose response studies examining
      safety, tolerability and efficacy in the U.S.A.
Non-insulin dependent diabetes mellitus (NIDDM) is the most common form of the hyperglycaemic
      state. Although NIDDM exists in all populations, its prevalence varies greatly, depending
      upon age and race, and appears to be increasing. It is estimated that NIDOM occurs in 5% of
      50-year-old-adults and 20% of the 80-year-old population with a linear progression between
      these age groups. Aberrant insulin secretion from pancreatic p-cells, and insulin resistance
      in peripheral tissues with reduced glucose uptake (particularly in muscle and liver) are the
      primary pathogenic mechanisms believed to be responsible for the metabolic abnormalities
      associated with NIDDM. Insulin resistance progresses to overt diabetes at the rate of
      approximately 5% of patients per year.

      Patients with insulin resistance, but no overt diabetes mellitus, are generally overweight,
      usually have a sedentary lifestyle, and frequently have a family history of diabetes
      mellitus. Insulin-resistant phenotype is commonly associated with cardiovascular risk factors
      such as hypertension and dyslipidemia (decreased HDL and increased VLDL, LDL and
      triglycerides). Current available therapies for NIDOM include insulin and oral hypoglycemic
      agents (e.g. sulphonylurea compounds and biguanides). Sulphonylureas achieve blood glucose
      control by enhancing pancreatic insulin secretion. However, a significant failure rate does
      exist for this mode of treatment, and many patients who have received long term treatment
      with sulphonylureas do require exogenous insulin therapy when there is no longer adequate
      pancreatic insulin secretion (even in response to sulphonylureas). Single therapy with the
      biguanide, metformin, or combination therapy with an additional sulphonylurea may also be
      administered to NIDDM patients. However, the overall effect of metformin on glycemic control
      seems to be smaller than that of sulphonylureas, and in many cases, combination therapy does
      not stop the need for insulin after a period of time.

      BRL 49653C is a highly potent and orally active anti-diabetic thiazolidinedione compound. The
      thiazolidinediones such as BRL 49653C represent a novel class of compounds that act as
      "insulin sensitizers" in target tissues. Unlike sulphonylureas, BRL 49653C improves the
      sensitivity of muscle and liver to insulin. An agent that enhances insulin sensitivity may be
      effective in regulating elevated blood glucose in patients with NIDDM and theoretically may
      be beneficial in reducing the frequency and severity of morbid complications of this disease.
      BRL 49653C does not increase pancreatic insulin secretion; therefore, treatment with BRL
      49653C should not have the potential to exhaust pancreatic function, or produce the untoward
      effect of hypoglycemia (a potential complication of treatment with sulphonylureas).

      In animal testing, repeat oral administration of BRL 49653C has been effective in reducing
      hyperglycemia, hyperinsulinemia, hypertriglyceridemia, and free fatty acids associated with
      insulin-resistant models of NIDDM2. In the genetically obese mouse, the potency of BRL49653C
      as an anti-hyperglycemic agent, was compared with competitor insulin sensitizers, and BRL
      49653C was proven to be at least 100 times more potent than CS-045 (troglitazone) and at
      least 30 times more potent than pioglitazone.

      Six month toxicological findings were similar to those observed in one month studies. Please
      refer to the Investigator Brochure for more detailed information about pre-clinical studies
      and the pharmacology, metabolism, and toxicology of BRL 49653C.

      To date, seven completed Phase I studies have shown BRL 49653C to be safe and well tolerated.
      The levels of exposure to BRL 49653C have been shown to be similar in both the fed and fasted
      state, and pharmacokinetic analysis has shown no evidence of accumulation after 10 days once
      daily dosing of 1 to 5 mg in obese volunteers. A total of 140 volunteers received BRL 49653C
      ranging in doses of 0.2 to 20 mg (20 mg dose is approximately 4 to 5-fold higher than doses
      expected to be administered to NIDDM patients). Of these, 140 subjects, 91 received one or
      more single doses of BRL 49653C up to 20 mg. This includes 10 healthy elderly males (>= 65
      years of age). Additionally, 49 obese subjects have received dosages of up to 5 mg/day for 10
      consecutive days.

      SmithKline Beecham Phase I clinical studies have shown BRL 49653C to be safe and well
      tolerated. The most frequently observed adverse experience was headache. Serious adverse
      experiences of transient asymptomatic accelerated unifocal ventricular rhythm of less than 10
      seconds duration were observed in two volunteers. The arrhythmias were noted at 27 minutes
      and 2 hours and 20 minutes after administration of a single dose of BRL 49653C 2mg. Hotter
      monitoring was performed in two studies in order to evaluate the arrythmogenicity of BRL
      49653C. Study 002, was a placebo controlled, 10 day repeat dose, two-period, period balanced,
      cross-over study, within each of three dose groups (1, 2 or 5 mg) of BRL 49653C. Study 016
      was a single dose, double-blind, randomized (with respect to order of placebo), placebo
      controlled, five period cross-over, oral dose rising study in which each subject received a
      randomly allocated placebo and four doses of BRL 49653C (5, 10, 15, 20 mg). In both of these
      studies, there was no evidence of protocol- defined incidence of ventricular tachycardia,
      ventricular premature beats, or supraventricular tachycardia.

      A recent study with another thiazolidinedione compound, troglitazone, has shown that there is
      no increase in cardiac mass or cardiac function impairment in patients with NIDDM . To the
      contrary, these patients were observed to have decreases in systemic vascular resistance,
      with enhanced cardiac output and stroke volume. Other studies examining thiazolidinediones
      have shown beneficial effects on Hemoglobin A1c with statistically significant decreases
      indicating beneficial effects on glucose homeostasis over periods of time.

      BRL 49653C has also been examined in combination with glyburide (glibenclamide). BRL 49653C
      was administered 2mg bd to NIDDM patients receiving stable doses of glyburide for seven days.
      No changes were observed in either the 24 hour glucose or insulin profiles, suggesting that
      the combined treatment is not associated with any acute pharmacokinetic interaction that
      would likely result in an acute untoward pharmacodynamics effect.

      The safety, tolerability and efficacy of BRL 49653C in patients with NIDDM has been examined
      in a phase II, double-blind, placebo controlled dose response study. A total of 380 patients
      received either placebo, 005mg bid, 0.25mg bid, 1mg bid or 2mg bid for 12 weeks. Analysis of
      variance showed highly significant (p<0.001) treatment effects on fasting blood glucose from
      week 2 onwards, although it was clear that a plateau in response had not been achieved at the
      highest dose tested. At the higher dose of 2mg bid, there were statistically significant
      differences compared to placebo, at week 12 for fasting plasma glucose (-40.1 mg/dL),
      fructosamine (-27.1 mmol/L) and insulin (-16%), and a significant reduction in hemoglobin Alc
      (0.4%). The lowering of fasting glucose in the 2mg bid group with a concomitant 16% decrease
      in insulin levels supports the hypothesis of insulin sensitization as a mechanism of action
      for BRL 49653.

      The drug was found to be safe with no adverse effects on vital signs, ECG or clinical
      chemistry. 2D M-Mode echocardiography revealed no on left ventricular mass effects, and the
      small reductions in hemoglobin 14.5 to 14.3 g/100ml in the highest dose group) and hematocrit
      (from 42.6% to 41.8%) are not regarded as being clinically significant. Furthermore, BRL
      49653C was found to be well tolerated over the dose range 0.05-2.0mg bid with an adverse
      event profile that was similar to placebo both qualitatively and quantitatively.

      During the study a total of 18 serious adverse events (sAE) were reported, 9 during the
      screening/run-in phase and 9 during the 12 week randomization period. There were 3 sAE in
      each of the placebo and 2.0mg BRL 49653 groups and I in each of the 0.05, 0.25 and 1.0mg
      groups. There were 2 deaths during the study, one case of myocardial infarction (2.0mg group)
      in a 52 year old male was designated as possibly related, and the other case (0.25mg group),
      a 71 year old male with cardiopulmonary arrest, was unrelated. All other sAE were specified
      by the investigators as being unrelated to trial medication, apart from 1 case of exercise
      induced non-sustained ventricular tachycardia in a 56 year old male receiving placebo. Causal
      relationship was given as possibly related in this case.

      At least 30% of patients initially treated with sulphonylureas for NIDDM will have a poor
      response, and in the remaining 70% the subsequent failure rate is approximately 4% to 5% per
      year. BRL 49653C has a different mechanism of action to the sulphonylureas, and therefore the
      effects on fasting plasma glucose and Hb A1c are expected to be additive. Since circulatory
      insulin levels should decrease, and plasma glucose should be regulated, these combinations
      are also anticipated to slow both the progression of diabetic complications and delay the
      need for exogenous insulin.

      The proposed study is intended primarily to determine the effectiveness of BRL 49653C by
      measure of glucose homeostasis as determined by Hb A1c and fasting plasma glucose, when added
      to sulphonylurea therapy (sulphonylureas are limited to: glibenclamide. glipazide and
      gliclazide). In addition, the clinical safety of BRL 49653C will be assessed in this patient
      population. The starting doses have been selected based on dose response studies examining
      safety, tolerability and efficacy in the USA.

      Please refer to the Investigator Brochure for a review of the pre-clinical and clinical
      studies of BRL 49653C.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: To determine the effectiveness of BRL 49653C (2 mg bd) compared to placebo when added to sulphonylurea therapy, for 24 weeks in out-patients with NIDDM.
time frame: 7 months
description: Primary: Change from baseline for Hb A1c at week 24.
Secondary: Mean change from baseline for:
fasting plasma glucose,insulin levels, immune reactive,lipid levels (ie.total cholesterol, HDL-cholesterol, LDL cholesterol, triglycerides), body weight (WHR), vital signs (systolic, diastolic blood pressure and heart rate)
measure: To assess the clinical safety of BRL 49653C (2 mg bd) compared to placebo when added to sulphonylurea therapy, for 24 weeks in out-patients with NIDOM.
time frame: 7 months
description: Physical examination, adverse experiences, laboratory safety data, ECG parameters
arm group label: BRL 49653C
arm group type: Experimental
description: Eligible patients may enter the study at visit 1 according to the inclusion/exclusion criteria. At the screening visit, patients will enter a single blind placebo run-in period to establish baseline characteristics. Patients must have been stable on sulphonylurea therapy for at least 2 months prior to the screening visit to be included. For the duration of the run-in period, patients will receive BRL 49653C placebo in addition to their constant dose of sulphonylurea. Patients eligible to enter the double-blind phase of the study will be randomized in equal numbers at visit 2, to one of two treatment groups (BRL 49653C 2 mg bid. or placebo bid). Patients will then continue to take their study medication arid the constant dose of sulphonylurea through visits 3 to 8 (weeks 4 to 24).
arm group label: placebo
arm group type: Placebo Comparator
description: Eligible patients may enter the study at visit 1 according to the inclusion/exclusion criteria. At the screening visit, patients will enter a single blind placebo run-in period to establish baseline characteristics. Patients must have been stable on sulphonylurea therapy for at least 2 months prior to the screening visit to be included. For the duration of the run-in period, patients will receive BRL 49653C placebo in addition to their constant dose of sulphonylurea. Patients eligible to enter the double-blind phase of the study will be randomized in equal numbers at visit 2, to one of two treatment groups (BRL 49653C 2 mg bid. or placebo bid). Patients will then continue to take their study medication arid the constant dose of sulphonylurea through visits 3 to 8 (weeks 4 to 24).
intervention type: Drug
intervention name: BRL 49653C
description: BRL 49653C 2 mg bid or placebo bid through weeks 1 to 24.
arm group label: BRL 49653C
other name: Avandia, rosiglitazone
intervention type: Drug
intervention name: Placebo
arm group label: placebo
criteria: 
gender: All
minimum age: 30 Years
maximum age: 80 Years
healthy volunteers: No
last name: Lee-Ming Chuang, PHD
role: Study Chair
affiliation: National Taiwan University Hospital
facility: 
country: Taiwan
citation: Yang WS, Jeng CY, Wu TJ, Tanaka S, Funahashi T, Matsuzawa Y, Wang JP, Chen CL, Tai TY, Chuang LM. Synthetic peroxisome proliferator-activated receptor-gamma agonist, rosiglitazone, increases plasma levels of adiponectin in type 2 diabetic patients. Diabetes Care. 2002 Feb;25(2):376-80. doi: 10.2337/diacare.25.2.376.
PMID: 11815513
responsible party type: Sponsor
mesh term: Diabetes Mellitus
mesh term: Diabetes Mellitus, Type 2
mesh term: Rosiglitazone