Baqsimi ® (glukagon näspulver)

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Baqsimi® (glukagon näspulver): Pivotala studier på vuxna

Hos vuxna med diabetes har glukagon näspulver påvisat icke-inferioritet jämfört med IM-glukagon med avseende på att vända insulininducerad hypoglykemi. Huvudvärk och nässymtom inträffade oftare med glukagon näspulver, men de flesta var övergående.

Adult Pivotal Studies: Efficacy and Safety in Adults With Diabetes

Two similarly designed comparator-controlled studies, Study 1 and Study 2, evaluated the efficacy and safety of a single dose of Nasal Glucagon compared to a 1 mg dose of IM glucagon in adults with DM.1,2

Study 1

Study Design

Study Description

Study 1 was a randomized, multicenter, open-label, crossover study that evaluated Nasal Glucagon  3 mg compared with injectable glucagon 1 mg administered IM as treatment for insulin-induced hypoglycemia in adults with T1DM.2

Study 1 used the final Nasal Glucagon drug product manufactured at commercial scale.2

Hypoglycemia was induced in participants using an IV insulin infusion to a BG of less than 3.3 mmol/L (60 mg/dL).2 Study glucagon, either Nasal Glucagon or IM glucagon, was administered 5 minutes after stopping the insulin infusion, and multiple BG measurements were obtained up to 90 minutes.2 

Outcome Measures

The primary outcome was the proportion of participants achieving treatment success within 30 minutes after receiving study glucagon without receiving additional interventions to increase the BG concentration.3

Treatment success was defined as an

  • increase in BG to greater than or equal to 3.9 mmol/L (70 mg/dL), or

  • increase in BG of greater than or equal to 1.1 mmol/L (20 mg/dL) above the BG nadir concentration.3

The BG nadir concentration was defined as the minimum BG concentration at the time of, or within 10 minutes after, glucagon administration.3

Spontaneously reported adverse reactions were evaluated and a Nasal and Non-Nasal Symptom Questionnaire solicited local tolerability of Nasal Glucagon.2  

Patient Characteristics

Study 1 included 70 adults with T1DM with

  • a mean age of 41.7 years

  • a mean DM duration of 19.8 years, and 

  • 27 (39%) being female.4

Mean Blood Glucose Nadir Concentrations

The mean BG nadir was 3.1 mmol/L (55.2 mg/dL) for Nasal Glucagon and 3.1 mmol/L (56.0 mg/dL) for IM glucagon.4

Efficacy

Treatment Success and Blood Glucose Criterion Met

Nasal Glucagon demonstrated non-inferiority to IM glucagon in reversing insulin-induced hypoglycemia with 100% of Nasal Glucagon -treated patients and 100% of IM glucagon-treated patients achieving treatment success within 30 minutes (Table 1).2

Table 1. Adults With T1DM Meeting Treatment Success and Other Blood Glucose Criteria in Study 13


 

T1DM
(N=66)
a

NG 3 mg

IM Glucagon 1 mg

Treatment Success, n (%)

66 (100)

66 (100)

Treatment Difference, % (2-sided 95% CI)bc

0 (-2.9, 2.9)

BG criterion met, n (%)

(i) ≥3.9 mmol/L (≥70 mg/dL)

66 (100)

66 (100)

(ii) increase by ≥1.1 mmol/L (≥20 mg/dL) from BG nadir

66 (100)

66 (100)

Both (i) and (ii)

66 (100)

66 (100)

Abbreviations: BG = blood glucose; IM = intramuscular; NG = nasal glucagon (glucagon nasal powder); T1DM = type 1 diabetes mellitus.

a The Efficacy Analysis Population consisted of all adults with T1DM who received both doses of the Study Drug with evaluable primary outcome.

b Difference calculated as (percentage with success in Baqsimi) - (percentage with success in IM glucagon).

c 2-sided 95% CI of paired differences using a Wald-Min correction; non-inferiority margin = -10%.

Time to Treatment Success

The mean time to treatment success was 11.6 minutes in the Nasal Glucagon treatment group and 9.9 minutes in the IM glucagon treatment group.2

Both Nasal Glucagon and IM Glucagon elicited a similar BG-raising effect ( ).2

Figure 1. Nasal Glucagon Mean Blood Glucose Concentrations After Administration of Nasal Glucagon and IM Glucagon2

Abbreviations: IM = intramuscular; IMG = intramuscular glucagon; NG = nasal glucagon (glucagon nasal powder).

Study 2

Study Design

Study Description

Study 2 was a randomized, multicenter, open-label, crossover study that evaluated NG 3 mg compared with injectable glucagon 1 mg administered IM as treatment for insulin-induced hypoglycemia in adults with T1DM or T2DM.1

Hypoglycemia was induced in participants using an IV insulin infusion to a BG of less than 3.3 mmol/L (60 mg/dL).1 Study glucagon, either Nasal Glucagon or IM glucagon, was administered 5 minutes after stopping the insulin infusion, and multiple BG measurements were obtained up to 90 minutes.1

Outcome Measures

The primary outcome was the proportion of participants achieving treatment success within 30 minutes after receiving study glucagon without receiving additional interventions to increase the BG concentration.1

Treatment success was defined as an

  • increase in BG to greater than or equal to 3.9 mmol/L (70 mg/dL), or

  • increase in BG of greater than or equal to 1.1 mmol/L (20 mg/dL) above the BG nadir glucose concentration.1

The BG nadir concentration was defined as the minimum BG concentration at the time of, or within 10 minutes after glucagon administration.1

Spontaneously reported adverse reactions were evaluated and a Nasal and Non-Nasal Symptom Questionnaire solicited local tolerability of Nasal Glucagon.1

Patient Characteristics

Study 2 enrolled 83 adults between 18 and <65 years of age1 

Seventy-seven adults had T1DM with 

  • a mean age of 32.9 years

  • a mean DM duration of 18.1 years, and 

  • 45 (58%) being female.1

Six adults had T2DM with

  • a mean age of 47.8 years

  • a mean DM duration of 18.8 years, and

  • 4 (67%) being female.4

Mean Blood Glucose Nadir Concentrations

The mean BG nadir was 2.4 mmol/L (44.1 mg/dL) for Nasal Glucagon and 2.6 mmol/L (47.2 mg/dL) for IM glucagon.4

Efficacy

Treatment Success and Blood Glucose Criterion Met

Nasal Glucagon demonstrated non-inferiority to IM glucagon in reversing insulin-induced hypoglycemia with 98.8% of Nasal Glucagon -treated patients and 100% of IM glucagon-treated patients achieving treatment success within 30 minutes (Table 2).4

Table 2. Adults With T1DM and T2DM Meeting Treatment Success and Other Blood Glucose Criteria in Study 24


T1DM and T2DM
(N=80)
a

NG 3 mg

IM Glucagon 1 mg

Treatment Success, n (%)b

79 (98.8)

80 (100)

Success criterion met, n (%)c

(i) ≥3.9 mmol/L (≥70 mg/dL)

77 (97)

79 (99)

(ii) increase by ≥1.1 mmol/L (≥20 mg/dL) from BG nadir

79 (100)

80 (100)

Both (i) and (ii)

77 (97)

79 (99)

Difference in proportion with successd

Unadjusted difference (1-sided upper 97.5% CI)e

0.013 (0.037)

Adjusted difference (1-sided upper 97.5% CI)f

0.013 (0.039)

Abbreviations: BG = blood glucose; IM = intramuscular; NG = nasal glucagon (glucagon nasal powder); T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus.

a The Efficacy Analysis Population consisted of all adults who received both doses of the Study Drug with evaluable primary outcome.

b Success defined as an increase in central lab BG to ≥70 mg/dL or an increase of ≥20 mg/dL from BG nadir within 30 minutes after glucagon was administered.

c Proportion based on total number meeting success (N=79 for NG and N=80 for IM glucagon).

d Difference in proportion with success defined as (proportion with success with IM glucagon treatment) - (proportion with success with NG treatment).

e 1-sided CI from 1-sample mean of the paired differences in occurrence of outcome; non-inferiority margin = 0.1.

f Difference and 1-sided CI from a Poisson regression model adjusted for treatment period and BG value immediately before administration of glucagon.

Time to Treatment Success

The mean time to treatment success was 16.2 minutes in the Nasal Glucagon treatment group and 12.2 minutes in the IM glucagon treatment group.4

Adults With T1DM in Study 2

Both Nasal Glucagon and IM glucagon elicited a similar BG-raising effect in adults with T1DM ( ).1

Figure 2. Mean Blood Glucose Concentrations After Administration of Nasal Glucagon and IM Glucagon in Adults with T1DM1

Abbreviations: IM = intramuscular; NG = nasal glucagon (glucagon nasal powder); T1DM = type 1 diabetes mellitus.

Data are mean ± SD.

The one T1DM participant in Study 2 treated with Nasal Glucagon  that did not meet the primary outcome criteria had a BG nadir concentration of 2.6 mmol/L (47 mg/dL) with an increase to 3.6 mmol/L (65 mg/dL) by 30 minutes and an increase to 4 mmol/L (72 mg/dL) by 40 minutes without any other intervention.1

Pharmacologic concentrations of glucagon were present within 5 minutes after Nasal Glucagon and IM glucagon administration. Median time to peak plasma glucagon concentration was 20 minutes for Nasal Glucagon and 15 minutes for IM glucagon (p<.001), but the glucagon concentrations were not different after 20 minutes in the participants with T1DM in the primary analysis cohort.1

The difference in time to glycemic response of Nasal Glucagon is likely not clinically relevant, and in many circumstances when using injectable recombinant glucagon, the overall time required to prepare and administer the medication, including errors in preparation or administration, and failures to deliver the full dose of medication may offset the difference in time to primary outcome.1

Pooled Adverse Reactions for Study 1 and Study 2

Nausea and vomiting are well-known adverse reactions of glucagon administration. Headache and nasal symptoms occurred more frequently with Nasal Glucagon, but were transient, resolving on the same day as onset(Table 3).4

Table 3. Pooled Spontaneously Reported Adverse Reactions (≥2%) in Adults With T1DM and T2DM in Study 1 and Study 24

Adverse Reactions

NG 3 mg
(N=153)
%

IM Glucagon 1 mg
(N=151)
%

Nausea

26.1

33.8

Headache

18.3

9.3

Vomiting

15.0

13.9

Upper respiratory tract irritationa

12.4

1.3

Abbreviations: IM = intramuscular; NG = nasal glucagon (glucagon nasal powder); T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus.

a Upper respiratory tract irritation: rhinorrhea, nasal discomfort, nasal congestion, cough, and epistaxis.

No serious adverse reactions were reported in Study 1 or Study 2 for either treatment group.1,3

Nasal and ocular symptoms were solicited through a patient questionnaire in Study 1 and Study 2 and these adverse reactions were more commonly reported with Nasal Glucagon (Table 4).4

Table 4. Solicited Nasal and Non-Nasal Adverse Reactions in Adults With T1DM and T2DM Pooled From Study 1 and Study 24

Adverse Reactionsa

NG 3 mg
(N=153)
%

IM Glucagon 1 mg
(N=151)
%

Any increase in symptom severitya

Watery eyes

58.8

2.0

Nasal congestion

42.5

6.0

Nasal itching

39.2

4.6

Runny nose

34.6

0.0

Redness of eyes

24.8

2.6

Itchy eyes

21.6 

1.3

Sneezing

19.6

0.0

Itching of throat

12.4

1.3

Itching of ears

3.3

0.7

Abbreviations: Baqsimi = Baqsimi™ (glucagon) nasal powder; IM = intramuscular; T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus.

a Subjects were asked to report whether they have the symptom, as well as severity (mild, moderate, severe) at baseline, and after glucagon administration up to 90 minutes post dose.

References

1. Rickels MR, Ruedy KJ, Foster NC, et al; T1D Exchange Intranasal Glucagon Investigators. Intranasal glucagon for treatment of insulin-induced hypoglycemia in adults with type 1 diabetes: a randomized crossover noninferiority study. Diabetes Care. 2016;39(2):264-270. https://doi.org/10.2337/dc15-1498

2. Suico JG, Hövelmann U, Zhang S, et al. Glucagon administration by nasal and intramuscular routes in adults with type 1 diabetes during insulin-induced hypoglycaemia: a randomised, open-label, crossover study. Diabetes Ther. 2020;11(7):1591-1603. https://doi.org/10.1007/s13300-020-00845-7

3. Suico J, Hovelmann U, Zhang S, et al. Nasal glucagon: a viable alternative to treat insulin-induced hypoglycemia in adults with type 1 diabetes. Talk presented at: Proceedings from the European Association for the Study of Diabetes; October 1-5, 2018; Berlin.

4. Data on file, Eli Lilly and Company and/or one of its subsidiaries.

Glossary

BG = blood glucose

DM = diabetes mellitus

IM = intramuscular

IV = intravenous

NG = nasal glucagon (glucagon nasal powder)

T1DM = type 1 diabetes mellitus

T2DM = type 2 diabetes mellitus

Datum fӧr senaste ӧversyn 2019 M07 24


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