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