6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure of 3,017 patients to AFREZZA and include 1,026 patients with type 1 diabetes and 1,991 patients with type 2 diabetes.
The mean exposure duration was 8.2 months for patients with type 1 diabetes and those with type 2 diabetes. In the overall population: 1,874 patients were exposed to AFREZZA for 6 months and 724 patients for greater than one year. 620 and 1,254 patients with type 1 and type 2 diabetes, respectively, were exposed to AFREZZA for up to 6 months. 238 and 486 patients with type 1 and type 2 diabetes, respectively, were exposed to AFREZZA for greater than one year (median exposure was 1.8 years).
AFREZZA was studied in placebo and active-controlled trials (n = 3 and n = 10, respectively). The mean age of the population was 50 years and 20 patients were older than 75 years of age; 51% of the population were males; 83% were White, 5% were Black or African American, and 2% were Asian; 10% were Hispanic. At baseline, the type 1 diabetes population had diabetes for an average of 17 years and had a mean HbA1c of 8.3%, and the type 2 diabetes population had diabetes for an average of 11 years and had a mean HbA1c of 8.8%.
At baseline, 33% of the population reported peripheral neuropathy, 32% reported retinopathy and 20% had a history of cardiovascular disease. Table 2 shows the frequency of common adverse reactions, excluding hypoglycemia, associated with the use of AFREZZA in the pool of controlled trials in type 2 diabetes patients that occurred more commonly on AFREZZA than on placebo and/or comparator and occurred in at least 2% of patients treated with AFREZZA.
Table 2. Common Adverse Reactions That Occurred in ≥ 2% in Patients with Type 2 Diabetes Mellitus (excluding Hypoglycemia) Treated with AFREZZA *Carrier particle without insulin was used as placebo [see Description ( 11.1 )] . AFREZZA (n = 1,991) % Placebo* (n = 290) % Non-placebo comparators (n=1,363) % Cough 26 4 3 3 2 2 2 20 4 3 1 1 1 0.3 5 1 2 2 1 1 1 Throat pain or irritation Headache Diarrhea Productive cough Fatigue Nausea Table 3 shows the frequency of common adverse reactions, excluding hypoglycemia, associated with the use of AFREZZA in the pool of active-controlled trials in type 1 diabetes patients.
These adverse reactions were not present at baseline, occurred more commonly on AFREZZA than on comparator, and occurred in at least 2% of patients treated with AFREZZA. Table 3. Common Adverse Reactions That Occurred in ≥ 2% in Patients with Type 1 Diabetes Mellitus (excluding Hypoglycemia) Treated with AFREZZA AFREZZA (n=1,026) Subcutaneous Insulin (n = 835) Cough 29 5 Throat pain or irritation 6 2 Headache 5 3 Pulmonary function test decreased 3 1 Bronchitis 3 2 Urinary tract infection 2 2 Hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including AFREZZA [see Warnings and Precautions ( 5.3 )] .
The incidence of severe and non-severe hypoglycemia in AFREZZA-treated patients versus placebo-treated patients with type 2 diabetes is shown in Table 4 . A hypoglycemic episode was recorded if a patient reported symptoms of hypoglycemia with or without a blood glucose value consistent with hypoglycemia. Severe hypoglycemia was defined as an event with symptoms consistent with hypoglycemia requiring the assistance of another person and associated with either a blood glucose value consistent with hypoglycemia or prompt recovery after treatment for hypoglycemia.
Table 4. Incidence of Severe and Non-Severe Hypoglycemia in a Placebo-Controlled Study of Patients with Type 2 Diabetes AFREZZA (N=177) Placebo (N=176) Severe Hypoglycemia 5% 2% Non-Severe Hypoglycemia 67% 30% Cough Approximately 27% of patients treated with AFREZZA reported cough, compared to approximately 5% of patients treated with comparator. In clinical trials, cough was the most common reason for discontinuation of AFREZZA therapy (3% of AFREZZA-treated patients).
Pulmonary Function Decline In clinical trials lasting up to 2 years, excluding patients with chronic lung disease, patients treated with AFREZZA had a 40 mL (95% CI: -80, -1) greater decline from baseline in forced expiratory volume in one second (FEV 1 ) compared to patients treated with comparator anti-diabetes treatments. The decline occurred during the first 3 months of therapy and persisted over 2 years ( Figure 1 ).
A decline in FEV 1 of ≥ 15% occurred in 6% of AFREZZA-treated patients compared to 3% of comparator-treated patients [see Warnings and Precautions ( 5.4 )]. Figure 1. Mean (+/-SE) Change in FEV 1 (Liters) from Baseline for Type 1 and Type 2 Diabetes Patients Figure 1 Weight Gain Weight gain has occurred with some insulin therapies, including AFREZZA. Weight gain has been attributed to the anabolic effects of insulin and the decrease in glycosuria.
In a clinical trial of patients with type 2 diabetes [see Clinical Studies ( 14.3 )] , there was a mean 0.49 kg weight gain among AFREZZA-treated patients compared with a mean 1.13 kg weight loss among placebo-treated patients.
