clinical trials for diabetes
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Clinical Trials for Diabetes
Yeong-Liang Lin, MD, MS
Center for Drug Evaluation
Background
Metabolic disorder characterized by hyperglycemia, relative or absolute insulin deficiency and development of vascular diseases
Two major types with several less common forms
Diagnosed by random plasma glucose greater than 200 mg/dL, fasting plasma glucose greater than 126 mg/dL or 2-hour glucose greater than 200 mg/dL in 75-g oral glucose tolerance study
Type 1 Diabetes
Insulin deficiency Result from a cellular autoimmune destruction
of β cells of the pancreas Islet autoantibodies
Type 2 Diabetes
Insulin resistance and relative deficiency Most patients have obesity-related insulin
resistance Others have increased visceral adiposity Genetic predisposition Risk factors include age, obesity and
gestational diabetes
Present treatment
Insulin Sulfonylureas α-glucosidase inhibitors Thiozolidinediones Biguanides
Clinical Trials
Studies concerning blood sugar Long term outcome studies
Consideration
Efficacy endpoint Patient population Inclusion/exclusion Duration Control Withdrawal criteria Safety monitoring
Efficacy Endpoint
Hemoglobin A1c Fasting plasma glucose Responder rate Reduction in insulin dose Lipid profile Body weight change Insulin antibody
HbA1c
Most widely accepted measure of long-term control of blood glucose
Average glucose levels in previous 2 to 3 months
Strongly associated with vascular complications
Effect size Margin
Plasma Glucose
Real time measurement 8-point plasma glucose profile Detection of hypoglycemia and adjustment of
treatment dose Secondary endpoint
Responder Rate
Proportion of subjects achieving a pre-defined HbA1c value
7% frequently used If other values are used, pre-define by the
applicant Secondary endpoint
Responder
Reduction of 0.7% units in HbA1c Decrease of fasting glucose of 30 mg/dL from
baseline
Reduction in Insulin Dose
Rate of elimination of insulin use Reduction in insulin dose accompanied by
improvement in symptoms Secondary endpoint
Insulin Antibody
Proportion of subjects developing insulin antibody
Related to efficacy
Population
Clinical trial population representative of the target population
Body mass index defined Range of HbA1c specified, determined by the
efficacy evidence Range of fasting plasma glucose Severity of disease defined Pre-study treatment
Inclusion
Types Body mass index, HbA1c, usually ≥ 6.5% and ≤ 11% Duration of diabetes, must be examined at
the analysis stage Fasting C-peptide Pre-study treatment
Exclusion
Pregnant or nursing women Daily insulin doses too high, e.g. 100U Treatment with steroids Impaired liver function, e.g. ALT 2.5 times
ULN
Duration
Run in period, usually 4 weeks
- to ensure subject eligibility Titration period
- titrate according to plasma glucose to
achieve normoglycemia Maintenance period, 12 weeks or longer
- to evaluate efficacy and risk of
hypoglycemia
Long Term Effectiveness
Improvement of HbA1c durable for 12 months
Control
Use of placebo - duration not jeopardizing patient safety - low starting HbA1c - clear withdrawal criteria Use of active control - longer duration allowed - more severe patients allowed - clear withdrawal criteria - selection of control
Withdrawal Criteria
Withdrawal due to inadequate efficacy - Plasma glucose higher than a pre- defined value, e.g. higher than 400 mg/dL Withdrawal due to safety concern - Frequent hypoglycemia episode - Development of LVH by ECG - Decline of pulmonary function
Concomitant Medication
Antihypertensive drugs Lipid lowering drugs
Confirmatory Clinical Trials
Randomized Double blind Placebo controlled Demonstration of superiority of the study drug
over a placebo in a study of no less than 3 months duration, using HbA1c as the primary endpoint
Safety
Safety monitoring according to individual safety profile
Hypoglycemic episode – severity and frequency
Cardiovascular function – QT interval Laboratory findings – liver function Other adverse events
Insulin
Hypoglycemia Insulin antibody Hypersensitivity Tumor formation, unlikely to be monitored by
clinical trials Lung function
OHA
Hypoglycemia Liver dysfunction Hypersensitivity Heart failure Lactic acidosis
Hypoglycemia
Symptomatic hypoglycemia Severe symptomatic hypoglycemia Nocturnal hypoglycemia
Demonstration of Efficacy
Efficacy will be demonstrated by Noninferiority of study drug to approved drugs,
based on change in HbA1c Equivalent glycemic control to the comparator
with long term administration Efficacy maintained irrespective of BMI, age,
sex and race
Demonstration of Safety
Safety will be demonstrated by Incidence of TEAE, especially SAE, compara
ble in pooled study drug and pooled comparator groups
Incidence of hypoglycemic event, sequelae of hypoglycemic event including seizure, diabetic ketoacidosis, injection site reaction, systemic hypersensitivity
Conclusion
Efficacy including long term efficacy Safety Other supportive evidence
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