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Drug Trials Snapshot: RYZODEG


HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the clinical trials that supported the FDA approval of this drug, and whether there were differences among sex, race and age groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.

LIMITATIONS OF THIS SNAPSHOT:
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your health provider about the risks and benefits of a drug. Refer to the RYZODEG Prescribing Information for complete information.

RYZODEG (insulin degludec and insulin aspart injection)
RY-zoh-deg
Novo Nordisk
Approval date: September 26, 2015


DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

RYZODEG is a mixture of a long-acting insulin and fast-acting insulin that improves blood sugar control in adults with diabetes mellitus (DM). It can be used in patients with type 1 or type 2 DM.

How is this drug used?

RYZODEG is available as a liquid that comes in a prefilled pen. It is injected once daily under the skin (subcutaneously).

What are the benefits of this drug?

In patients with type 1 and type 2 who need better blood sugar control, treatment with RYZODEG can lower HbA1c (hemoglobin A1c, which is a measure of blood sugar control). RYZODEG’s ability to lower HbA1c is in line with other, previously approved long-acting or pre-mixed (combination of long-acting and fast-acting) insulin products on the market.

What are the benefits of this drug (results of trials used to assess efficacy)?

The efficacy of RYZODEG in patients with type 1 DM was evaluated in one trial (referred to here as Trial A).  The efficacy of RYZODEG in patients with type 2 DM was evaluated in four trials (Trials B through E).  All of the studies were a non-inferiority design which is a design to demonstrate that RYZODEG works no worse than the comparator (i.e., provides an average change in HbA1c no smaller than 0.4% less than the comparator insulin product).  Table 3 below summarizes the results for the primary efficacy endpoint, the change from the start of the trials (baseline) in HbA1c to week 26 for RYZODEG minus the comparator for each trial.

Table 3. Change from baseline in HbA1c (%) by trial


Study
Primary
Hypothesis
Treatment Groups Treatment Difference
(Ryzodeg - Control)
LS Mean 95% CI
Type 1 Diabetes Mellitus (T1DM)
Study A
NN5401-3594
Non-inferiority Ryzodeg (IDegAsp)
IDet
-0.05 (-0.18, 0.08)
Type 2 Diabetes Mellitus (T2DM)
Study B
NN5401-3590
Non-inferiority Ryzodeg (IDegAsp)
IGlar
0.03 (-0.14 ,0.20)
Study C
NN5401-3590
Non-inferiority Ryzodeg (IDegAsp)
IGlar
-0.03 (-0.20, 0.14)
Study D
NN5401-3592
Non-inferiority Ryzodeg (IDegAsp)
BIAsp 30
-0.03 (-0.18, 0.13)
Study E
NN5401-3597
Non-inferiority Ryzodeg (IDegAsp)
BIAsp
0.05 (-0.10, 0.20)

IDegAsp 100 – insulin degludec 100 U/mL; IDet - LEVEMIR (insulin detemir 100 U/mL); IGlar – LANTUS (insulin glargine 100 U/mL); BIAsp: Novo Log Mix 70/30 (biphasic insulin aspart) 
FDA Statistical Review
 

Were there any differences in how well the drug worked in clinical trials among sex, race and age?

Subgroup analyses were conducted for sex, race and age.

  • Sex:  RYZODEG worked similarly in men and women.
  • Race:  In patients with type 1 DM, RYZODEG worked similarly in Whites and Black or African Americans.  There were too few Asian patients with type 1 DM to determine whether they responded differently to RYZODEG. In patients with type 2 DM, RYZODEG worked similarly among all racial groups studied.
  • Age: RYZODEG worked similarly in patients below and above 65 years of age.

Figures 7 (for type 1 DM) and 8 (for type 2 DM) below summarize the results for the primary efficacy endpoint, the change in HbA1c from the start of each trial to week 26 for RYZODEG minus the comparator by sex, age, race, and ethnicity. Trials with the same comparator are combined to allow for the largest possible sample sizes in each subgroup, and since comparisons of the treatment effect across subgroups were consistent across trials.

Figure 7. Difference (95% Confidence Interval) in Average Change in HbA1c (%) from the Start of the Trial in T1DM

Table summarizes the results for the primary efficacy endpoint, the change in HbA1c from the start of each trial to week 26 for RYZODEG minus the comparator by sex, age, race, and ethnicity.

IDet - LEVEMIR (insulin detemir 100 U/mL); IGlar – LANTUS (insulin glargine 100 U/mL); T1DM – Type 1 diabetes mellitus; T2DM – Type 2 diabetes mellitus; P-value for statistical test measuring whether the treatment effect differs across subgroups (i.e., p-value for test of treatment-by-subgroup interaction) for studies A, B, and C, respectively:  Sex: 0.19, 0.38, and 0.13; Age, 0.07, 0.32, and 0.91; Race: 0.18, 0.93, and 0.51; Ethnicity: 0.06, 0.14, and 0.53
FDA Statisical Review

Figure 8. Difference (95% Confidence Interval) in Average Change in HbA1c (%) from the Start of Each Trial in T2DM

Table summarizes the results for the primary efficacy endpoint, the change in HbA1c from the start of each trial to week 26 for RYZODEG minus the comparator by sex, age, race, and ethnicity.

IGlar – LANTUS (insulin glargine 100 U/mL); BIAsp: Novo Log Mix 70/30 (biphasic insulin aspart); T2DM – Type 2 diabetes mellitus P-value for statistical test measuring whether the treatment effect differs across subgroups (i.e., p-value for test of treatment-by-subgroup interaction) for combined analysis of studies B and C and combined analysis of studies D and E, respectively: Sex: 0.10, and 0.90; Age: 0.42, and 0.55; Race: 0.65, and 0.051; Ethnicity: 0.10, and NA
FDA Statistical Review

What are the possible side effects?

The most common side effects were low blood sugar (hypoglycemia), allergic reactions, injection site reactions, pitting at the injection site (lipodystrophy), itching, rash, swelling, and weight gain.

The tables below summarize common adverse reactions for the two trial populations. These reflect the Safety population, which includes any patient who received at least one dose of study drug.

Table 4. Adverse Reactions Occurring in ≥5% of RYZODEG 70/30-Treated Patients with Type 1 DM

Adverse Reaction RYZODEG 70/30
(N=362)
Nasopharyngitis 24.6 %
Headache 9.7 %
Upper respiratory tract infection 9.1 %
Influenza 6.9 %

RYZODEG Prescribing Information, Table 1

Table 5. Adverse Reactions Occurring in 5% of RYZODEG 70/30-Treated Patients with Type 2 DM

Adverse Reaction RYZODEG 70/30
(N=998)
Nasopharyngitis 11.1 %
Upper respiratory tract infection 5.7 %
Headache 5.6 %

RYZODEG Prescribing Information, Table 2

Were there any differences in side effects among sex, race and age?

Subgroup analyses were conducted for sex, race and age.

  • Sex:  The risk of side effects was similar in men and women.
  • Race:  In patients with type 1 DM, the majority of patients were white. Differences in side effects among races could not be determined. In patients with type 2 DM, the majority of patients were white and Asian. The risk of side effects was similar in Whites and Asians. Differences in side effects among other races could not be determined.
  • Age: The risk of side effects was similar in patients below and above 65 years of age.

The tables below summarize overall adverse events during the clinical trials, by subgroup. Table 6 is for the type 1 population and Table 7 is for the type 2 population.

Table 6. Overall TEAEs by Subgroup—Clinical Trial in the Type 1 DM Population


Demographic Parameters
Ryzodeg
n/N (%)
Control
n/N (%)
Overall TEAES
Sex
Men 135/189 (71.4) 61/82 (74.4)
Women 132/173 (76.3) 66/98 (67.3)
Age Group
Below 65 years 260/353 (73.7) 116/166 (69.9)
65 years and above 7/9 (77.8) 11/14 (78.6)
Race
White 245/331 (74.0) 113/160 (70.6)
Black or African American 5/10 (50.0) 4/6 (66.7)
Asian 3/4 (75.0) 3/3 (100.0)
Other 14/17 (82.4) 7/11 (63.6)
Ethnicity
Hispanic or Latino 7/10 (70.0) 3/5 (60.0)
Not Hispanic or Latino 247/337 (73.3) 118/167 (70.7)
Not applicable 13/15 (86.7) 6/8 (75.0)

Percentages are calculated based on the number of subjects in the subgroup per arm.
Clinical Trial Data

Table 7. Overall TEAEs by Subgroup—4 Pooled Clinical Trials for the Type 2 Population

Demographic Parameters Ryzodeg
n/N (%)
Control
n/N (%)
Overall TEAES
Sex
Men 319/539 ( 59.2) 280/460 (60.9)
Women 300/459 ( 65.4) 235/397 (59.2)
Age Group
Below 65 years 466/742 ( 62.8) 381/629 (60.6)
65 years and above 153/256 ( 59.8) 134/228 (58.8)
Race
White 250/436 ( 57.3) 260/439 (59.2)
Black or African American 26/43 ( 60.5) 13/29 (44.8)
Asian 338/514 ( 65.8) 240/384 (62.5)
Other 5/5 (100.0) 2/5 (40.0)
Ethnicity
Hispanic or Latino 30/62 ( 48.4) 37/73 (50.7)
Not Hispanic or Latino 572/905 ( 63.2) 472/762 (61.9)
Not applicable 17/31 (54.8) 6/22 (27.3)

Percentages are calculated based on the number of subjects in the subgroup per arm.
Clinical Trial Data

WHO WAS IN THE CLINICAL TRIALS?

Who participated in the clinical trials?

The FDA approved RYZODEG based on evidence from 1 clinical trial of 548 patients with type 1 DM and 4 clinical trials in 1860 patients (total) with type 2 DM.

Figure 1 summarizes how many men and women were enrolled in the clinical trials used to evaluate efficacy. Figure 1 includes the trials of patients with type 1 DM, and Figure 2 includes the trials of patients with type 2 DM.

Figure 1. Patients with Type 1 DM by Sex (Total Patients=548)

Pie chart summarizing how many men and women were enrolled in the clinical trial used to evaluate efficacy of the drug RYZODEG for patients with Type 1 DM.  In total, 272 men (50%) and 276 women (50%) participated in the clinical trial used to evaluate efficacy of the drug RYZODEG for patients with Type 1 DM.  Clinical Trial Data

Figure 2. Patients with Type 2 DM by Sex (Total Patients=1860)

Pie chart summarizing how many men and women were enrolled in the clinical trial used to evaluate efficacy of the drug RYZODEG for patients with Type 2 DM.  In total, 1001 men (54%) and 859 women (46%) participated in the clinical trial used to evaluate efficacy of the drug RYZODEG for patients with Type 2 DM.

Clinical Trial Data

The figures below summarize how many patients by racial group participated in the clinical trials used to evaluate efficacy. Figure 3 includes the trials of patients with type 1 DM, and Figure 4 includes the trials of patients with type 2 DM.

Figure 3. Patients with Type 1 DM by Racial Group

 Pie chart summarizing the percentage of patients by race enrolled in the RYZODEG clinical trial for patients with Type 1 DM. In total, 495 Whites (90%), 7 Asians (1%), 16 Black or African American (3%), and 30 Other (5%) participated in the clinical trial for patients with Type 1 DM.

Clinical Trial Data

Table 1. Demographics of Efficacy Trials by Race-Patients with Type 1 DM

Race Number of Patients Percentage
White 495 90%
Black or African American 16 3%
Asian 7 1%
Other 30 5%

Figure 4. Patients with Type 2 DM by Racial Group

Pie chart summarizing the percentage of patients by race enrolled in the RYZODEG clinical trial for patients with Type 2 DM. In total, 878 Whites (47%), 900 Asians (48%), 72 Black or African American (4%), and 10 Other (1%) participated in the clinical trial for patients with Type 2 DM.

Clinical Trial Data

Table 2. Demographics of Efficacy Trials by Race—Patients with Type 2 DM

Race Number of Patients Percentage
White 878 47%
Black or African American 72 4%
Asian 900 48%
Other 10 1%

Clinical Trial Data

The figures below summarize how many patients by age group (at the start of the trials) participated in the clinical trials for type 1 patients (Figure 5) and type 2 patients (Figure 6).

Figure 5. Trials of Patients with Type 1 DM by Age Group

Pie chart summarizing the percentage of patients by race enrolled in the RYZODEG clinical trial for patients with Type 1 DM.  In total, 523 participants were below 65 years old (95%) and 25 participants were 65 and older (5%).

Clinical Trial Data

Figure 6. Trials of Patients with Type 2 DM by Age Group

Ryzodeg Figure 6

Clinical Trial Data

The table below summarizes who participated in the clinical trial of patients with Type 1 DM.

Table 8. Baseline Demographics for Type 1 Patients in the Clinical Trial


Demographic Parameters
Ryzodeg
n/N (%)
Control
n/N (%)
Total
n/N (%)
Sex
Men 190/366 (51.9) 82/182 (45.1) 272/548 (49.6)
Women 176/366 (48.1) 100/182 (54.9) 276/548 (50.4)
Age Group
Below 65 years 355/366 (97.0) 168/182 (92.3) 523/548 (95.4)
65 years and above 11/366 (3.0) 14/182 (7.7) 25/548 (4.6)
Race
White 333/366 (91.0) 162/182 (89.0) 495/548 (90.3)
Black or African American 10/366 (2.7) 6/182 (3.3) 16/548 (2.9)
Asian 4/366 (1.1) 3/182 (1.6) 7/548 (1.3)
Other 19/366 (5.2) 11/182 (6.0) 30/548 (5.5)
Ethnicity
Hispanic or Latino 10/366 (2.7) 7/182 (3.8) 17/548 ( 3.1)
Not Hispanic or Latino 339/366 (92.6) 167/182 (91.8) 506/548 (92.3)
Not applicable 17/366 (4.6) 8/182 (4.4) 25/548 (4.6)

Clinical Trial Data

Table 9. Baseline Demographics for Pooled Clinical Trials in Patients with Type 2 DM


Demographic Parameters
Ryzodeg
n/N (%)
Control
n/N (%)
Total
n/N (%)
Sex
Men 540/1000 (54.0) 461/860 (53.6) 1001/1860 (53.8)
Women 460/1000 (46.0) 399/860 (46.4) 859/1860 (46.2)
Age Group
Below 65 years 744/1000 (74.4)  630/860 (73.3) 1374/1860 (73.9)
65 years and above 256/1000 (25.6) 230/860 (26.7) 486/1860 (26.1)
Race
White 437/1000 (43.7) 441/860 (51.3) 878/1860 (47.2)
Black or African American 43/1000 (4.3) 29/860 (3.4) 72/1860 (3.9)
Asian 515/1000 (51.5) 385/860 (44.8) 900/1860 (48.4)
Other 5/1000 (0.5) 5/860 (0.6) 10/1860 (0.5)
Ethnicity
Hispanic or Latino 63/1000 (6.3) 74/860 (8.6) 137/1860 (7.4)
Not Hispanic or Latino 906/1000 (90.6) 764/860 (88.8) 1670/1860 (89.8)
Not applicable 31/1000 (3.1) 22/860 (2.6) 53/1860 (2.8)

How were the trials designed?

The benefits and side effects of RYZODEG 70/30 administered once-daily with the main meal of the day in patients with type 1 diabetes was evaluated in one randomized, open-label, treat-to-target, active-controlled trial. In this trial, patients were randomly assigned to either receive RYZODEG 70/30 once-daily administered at the main meal of the day and a mealtime insulin at remaining meals or another long-acting insulin once or twice daily combined with rapid-acting insulin at meals.

RYZODEG 70/30 administered once or twice daily with the main meal(s) in patients with type 2 diabetes when used with common oral anti-diabetic drugs was evaluated in four randomized, open-label, treat-to-target, active-controlled trials. In these trials, patients were randomized to RYZODEG 70/30 once-daily at breakfast or another long-acting or pre-mixed insulin once-daily according to approved labeling. Metformin, an oral medication, was given in both arms.

In each trial, the change in HbA1c from the start to finish of the trial was measured.

(No further info).

GLOSSARY

CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo used in clinical trials that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.

PRESCRIBING INFORMATION

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