Reference/Study

Study Design

Results

de la Peña A, et al1.

Randomized, double-blind, single-site, crossover, euglycemic clamp study including 24 healthy subjects who were

• obese: BMI=34.4±2.6 kg/m²,a and
• aged: 21-65 years old.

Evaluated PK/PD of U‑500R and U‑100R administered as single SC injection of

• 50-unit dose, and
• 100-unit dose.

Primary objective was relative exposure (AUC_0-t’) for U‑500R and U‑100R.

Secondary objectives included

• Comparison of PK/PD parameters between the 2 formulations and doses
• safety, and
• tolerability.

Similar between U‑100R and U‑500R at both doses were

• relative exposure, and
• overall effect: total glucose infused during a clamp.

Significantly (p<.05) lower for U‑500R at both doses were

• peak insulin concentration, and
• peak effect.

Significantly (p<.05) longer for U‑500R vs U‑100R at both doses was

• duration of action.

Significantly (p<.05) longer for U‑500R at only the 100‑unit dose were

• time to peak concentration, and
• time to peak effect.

Authors concluded that

• dosing 30 minutes before the meal is likely appropriate for U‑500R as recommended for U‑100R
• U‑500R as insulin monotherapy may be a reasonable treatment option for obese patients with T2DM due to the longer duration of effect, and
• precautions should be taken to monitor for and avoid hypoglycemia, particularly at night with the use of U‑500R.

No severe TEAE was reported.

No discontinuation due to AE.

AEs reported included

• headache (12), and
• nausea (2).

de la Peña A, et al2.

Simulation modeling PK/PD study with U‑500R derived from 3

• single-dose
• crossover
• euglycemic clamp studies.

Evaluated PK/PD of single-dose U‑500R in

• 46 healthy obese subjects
• 18 healthy normal BW subjects, and
• 30 T1DM normal BW patients.

Insulin doses:

• healthy obese:
  • 0.4-0.6 units/kg (50 units), or
  • 0.8-1.3 units/kg (100 units).
• healthy normal BW:
  • 0.05-0.4 units/kg.
• T1DM normal BW:
  • 0.1-0.2 units/kg (12 units).

Simulation profiles:

• once-daily, single doses of 165, 250, 500, and 750 units and at steady-state ~500 unit dose at 7 AM
• twice-daily, steady-state doses of 300 and 200 units at 7 AM and 6 PM, and
• thrice-daily, steady-state doses of 200, 150, and 150 units at 7 AM, noon, and 6 PM.

All 3 dosing regimens achieved steady-state PK by 24 hours post dose.

• Once-daily regimen showed
  • greatest fluctuation in the PK/PD parameters
  • peak insulin concentration
  • effect 5 and 7 hours after dosing, and
  • substantial decrease in insulin effects in the evening hours.
• Twice-daily regimen showed
  • gradual increase in insulin concentration, and
  • effects with each dose and a stable basal effect.
    
•  Thrice-daily regimen showed
  • sustained effects between doses
  • less pronounced postdose PD effects, and
  • marginally better PD effects throughout the entire day.b

Hood RC, et al3.

Randomized, prospective, open-label, multicenter, 24-week study, including 325 patients with T2DM taking >200 units of insulin/day.

Compared the efficacy and safety of U‑500R dosed

• thrice daily, and
• twice daily.

Mean baseline demographics were

• age: 55.4±9.8 years
• BMI: 41.9±7.5 kg/m²
• HbA1c: 8.7%±1%
• T2DM duration: 15.2±7.4 years
• TDI: 287.5±80.5 units/day or 2.4±0.8 units/kg/day
• number of daily injections: 4.8±1.3 of U-100R.

Primary objective was HbA1c change.c

Secondary objective was 7-point SMPG profiles.

Hypoglycemia definitions were

• documented symptomatic: PG ≤70 mg/dL and ≥1 sign/symptom indicative of hypoglycemia
• nocturnal: documented symptomatic between bedtime and waking, and
• severe: documented symptomatic requiring third-party assistance.

HbA1c change: LSM=0.10% (95% CI, -0.33 to 0.12%), supporting clinical equivalence between the 2 dosing regimens.d

HbA1c reductions significant (p<.001) for both groups were

• 1.22% for twice-daily dosing regimen, and
• 1.12% for thrice-daily dosing regimen. 

7-point SMPG profiles difference between groups were

• not significant at randomization, and
• not significant at week 24.

Thrice-daily dosing resulted in a significantly lower incidence (p=.003) and rate of documented symptomatic hypoglycemia than twice-daily dosing (p=.02).

There was no difference in the incidence or rate of severe hypoglycemia groups.

The prandial/basal time-concentration/action characteristics of U‑500R provide explanation for the differences between the groups in

• nonsevere hypoglycemia rates
• timing of hypoglycemic events
• timing of nonsevere hypoglycemia, and
• differing rates of nonsevere hypoglycemia.

Higher rate of hypoglycemia in

• the twice-daily group at noon correlated with
  • 60% TDI at breakfast.
    
• the thrice-daily group at dinner correlated with
  • 40% TDI at breakfast, and
  • 30% TDI at lunch.