Diabetes Mellitus, Drug-specific Antibodies
Conditions
Keywords
Diabetes Mellitus, Hypoglycemia, Glucagon, Anti-glucagon Antibody, Immunogenicity
Brief summary
This study provides information on immunogenicity of Nasal Glucagon (AMG504-1) with regards to the potential development of treatment-emergent anti-glucagon antibodies.
Detailed description
This study is a single center, randomized, laboratory-blinded, three periods, parallel design study. The main objective of this study is to evaluate the immunogenicity of repeated single doses of glucagon following nasal and intramuscular (IM) administration in adults with Type 1 or Type 2 diabetes (T1D or T2D). The secondary objective is to evaluate the safety and tolerability of glucagon following NG and IM administration in adults with T1D or T2D. A single dose of glucagon was administered in the morning after a 10-hour overnight fast, either by intranasal or intramuscular route, on 3 occasions. Each drug administration was separated by at least seven calendar days. Patients were randomized in a 2:1 ratio (NG:IMG) to receive NG or IMG at each of the 3 periods. Blood samples were collected for measurement of anti-glucagon antibodies at screening visit, prior to dosing at Period 3, and at the post-study visit (approximately 4 weeks after the last glucagon administration).
Interventions
DRUGNasal Glucagon (NG)
DRUGGlucagon IM
Sponsors
Locemia Solutions ULC
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Availability for the entire study period 2. Motivated volunteer and absence of intellectual problems likely to limit the validity of consent to participate in the study or the compliance with protocol requirements; ability to cooperate adequately; ability to understand and observe the instructions of the physician or designee 3. Male or female patient with a history of Type 1 or Type 2 diabetes of at least 2 years duration 4. A female volunteer must meet one of the following criteria: 1. Participant is of childbearing potential and agrees to use one of the accepted contraceptive regimens throughout the entire duration of the study (from the screening visit until study completion). Additionally, if the participant is using systemic contraceptives, she must use an additional form of acceptable contraception. An acceptable method of contraception includes one of the following: * Abstinence from heterosexual intercourse * Systemic contraceptives (birth control pills, injectable/implant /insertable hormonal birth control products, transdermal patch) * Intrauterine device (with and without hormones) * Condom with spermicide or 2. Participant is of non-childbearing potential, defined as surgically sterile (i.e. has undergone complete hysterectomy, bilateral oophorectomy, or tubal ligation) or in a menopausal state (at least 1 year without menses) 5. Volunteer aged of at least 18 years but not older than 70 years 6. Volunteer with a BMI greater than or equal to 18.50 and below 35.00 kg/m2 7. Light-, non- or ex-smokers. A light smoker is defined as someone smoking 10 cigarettes or less per day for at least 3 months before day 1 of this study. An ex- smoker is defined as someone who completely stopped smoking for at least 6 months before day 1 of this study 8. In good general health with no conditions that could influence the outcome of the trial, and in the judgment of the Investigator is a good candidate for the study based on review of available medical history, physical examination and clinical laboratory evaluations 9. Willingness to adhere to the protocol requirements as evidenced by the informed consent form (ICF) duly read, signed and dated by the volunteer The informed consent form must be signed by all volunteers, prior to their participation in the study.
Exclusion criteria
1. Females who are pregnant, actively attempting to get pregnant, or are lactating 2. History of significant hypersensitivity to glucagon or any related products as well as severe hypersensitivity reactions (such as angioedema) to any drugs 3. Presence of significant gastrointestinal, liver or kidney disease, or any other conditions which in the judgment of the Investigator could interfere with the absorption, distribution, metabolism or excretion of drugs, or could potentiate or predispose to undesired effects 4. Suicidal tendency, history of or disposition to seizures, state of confusion, clinically relevant psychiatric diseases 5. Known presence of rare hereditary problems of galactose and /or lactose intolerance 6. Known presence or history of pheochromocytoma (i.e. adrenal gland tumor) or insulinoma (i.e. insulin secreting pancreas tumor) 7. Presence of clinically significant findings on nasal examination or bilateral anterior rhinoscopy, such as structural abnormalities, nasal polyps, marked septal deviation, nasal tumors 8. Nasal surgery in the previous 28 days before Day 1 of this study 9. Use of a systemic beta-blocker drug, indomethacin, warfarin or anticholinergic drugs in the previous 28 days before Day 1 of this study 10. Use of an immunomodulator medication (including steroids, glucocorticoids, tacrolimus, etc.) in the 28 days before day 1 of this study 11. Any other concomitant maintenance therapy that would influence the outcome of the trial or compromise the safety of the patient, at the discretion of the Investigator and the Sponsor, in the previous 28 days before day 1 of this study 12. Significant history of drug dependency or alcohol abuse (\> 3 units of alcohol per day, intake of excessive alcohol, acute or chronic) 13. Any clinically significant illness in the previous 28 days before day 1 of this study 14. Any history of tuberculosis and/or prophylaxis for tuberculosis 15. Positive urine screening of alcohol and/or drugs of abuse 16. Females who are pregnant according to a positive pregnancy test 17. Concurrent participation or intention of participating in another clinical trial during this study 18. Volunteers who took an Investigational Product (in another clinical trial) or donated 50 mL or more of blood in the previous 28 days before day 1 of this study 19. Donation of 500 mL or more of blood (Canadian Blood Services, Hema-Quebec, clinical studies, etc.) in the previous 56 days before day 1 of this study No participants will be allowed to enroll in this study more than once (i.e. if the study is conducted with more than 1 group).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Treatment-emergent Anti-Drug Antibody (ADA) | Baseline through study completion (up to 10 weeks) | Glucagon anti-drug antibodies (ADA) were assessed at baseline through study completion. Percentage of participants (Pts) with ADA=(number of Pts with treatment-emergent ADA/number of Pts assessed)\*100. Treatment-Emergent ADA includes treatment-induced ADA and treatment boosted ADA. Treatment-induced is defined as participants with 'Not Detected' ADA at baseline (drug-naive) and at least one post-baseline ADA 'Detected' sample with a corresponding titer that is one 2-fold dilution higher than the MRD (minimal required dilution) of the assay. For the nasal glucagon Tier 1-3 ADA screening assay, the MRD is 1:20. Treatment-boosted is defined as Patient with ADA 'Detected' at baseline (drug-naive) and at least one post-baseline ADA 'Detected' sample with a corresponding titer that is at least (\>or=) 4-fold higher than the baseline titer. |
| Percentage of Participants With Neutralizing Antibodies | Baseline through study completion (up to 10 weeks) | — |
| Number of Participants With At Least One Adverse Event | First dose of study drug through the post-study completion (up to 10 weeks) | Safety parameters assessed included the occurrence of adverse events, the measurement of clinical laboratory parameters; vital signs, ECGs, physical examination, blood glucose, and examination of the injection site (following the IM administration). An AE was defined as any untoward medical occurrence in a clinical investigation subject administered the investigational product and which did not necessarily have a causal relationship with this treatment A summary of other nonserious AEs, and all SAE's, regardless of causality, is located in the Reported Adverse Events section. |
Countries
Canada
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Glucagon IM Glucagon dose of 1 mg administered intramuscularly as 3 doses separated by at least 7 days. | 26 |
| Nasal Glucagon (NG) NG administered at 3 mg as 3 doses, separated by at least 7 days. | 49 |
| Total | 75 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Second Dose | Adverse Event | 1 | 0 |
| Third Dose | Adverse Event | 0 | 1 |
Baseline characteristics
| Characteristic | Glucagon IM | Nasal Glucagon (NG) | Total |
|---|---|---|---|
| Age, Continuous | 42 years STANDARD_DEVIATION 12 | 43 years STANDARD_DEVIATION 15 | 43 years STANDARD_DEVIATION 14 |
| BMI (Body Mass Index) | 27.08 kilogram per square metre (kg/m2) STANDARD_DEVIATION 4.28 | 27.18 kilogram per square metre (kg/m2) STANDARD_DEVIATION 3.93 | 27.15 kilogram per square metre (kg/m2) STANDARD_DEVIATION 4.03 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 24 Participants | 44 Participants | 68 Participants |
| Region of Enrollment Canada | 26 Participants | 49 Participants | 75 Participants |
| Sex: Female, Male Female | 6 Participants | 13 Participants | 19 Participants |
| Sex: Female, Male Male | 20 Participants | 36 Participants | 56 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 21 / 26 | 49 / 49 |
| serious Total, serious adverse events | 0 / 26 | 0 / 49 |
Outcome results
Primary
Number of Participants With At Least One Adverse Event
Safety parameters assessed included the occurrence of adverse events, the measurement of clinical laboratory parameters; vital signs, ECGs, physical examination, blood glucose, and examination of the injection site (following the IM administration). An AE was defined as any untoward medical occurrence in a clinical investigation subject administered the investigational product and which did not necessarily have a causal relationship with this treatment A summary of other nonserious AEs, and all SAE's, regardless of causality, is located in the Reported Adverse Events section.
Time frame: First dose of study drug through the post-study completion (up to 10 weeks)
Population: Participants who received at least one dose of glucagon (IM or NG).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Glucagon IM | Number of Participants With At Least One Adverse Event | 21 Participants |
| Nasal Glucagon (NG) | Number of Participants With At Least One Adverse Event | 49 Participants |
Primary
Percentage of Participants With Neutralizing Antibodies
Time frame: Baseline through study completion (up to 10 weeks)
Population: All enrolled participants who received at least 1 dose of study drug and either had baseline and at least 1 post-baseline evaluable samples or had no evaluable baseline and all negative post-baseline anti-drug antibody negative samples.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Glucagon IM | Percentage of Participants With Neutralizing Antibodies | 0 percentage of participants |
| Nasal Glucagon (NG) | Percentage of Participants With Neutralizing Antibodies | 0 percentage of participants |
Primary
Percentage of Participants With Treatment-emergent Anti-Drug Antibody (ADA)
Glucagon anti-drug antibodies (ADA) were assessed at baseline through study completion. Percentage of participants (Pts) with ADA=(number of Pts with treatment-emergent ADA/number of Pts assessed)\*100. Treatment-Emergent ADA includes treatment-induced ADA and treatment boosted ADA. Treatment-induced is defined as participants with 'Not Detected' ADA at baseline (drug-naive) and at least one post-baseline ADA 'Detected' sample with a corresponding titer that is one 2-fold dilution higher than the MRD (minimal required dilution) of the assay. For the nasal glucagon Tier 1-3 ADA screening assay, the MRD is 1:20. Treatment-boosted is defined as Patient with ADA 'Detected' at baseline (drug-naive) and at least one post-baseline ADA 'Detected' sample with a corresponding titer that is at least (\>or=) 4-fold higher than the baseline titer.
Time frame: Baseline through study completion (up to 10 weeks)
Population: All enrolled participants who received at least 1 dose of study drug with an evaluable baseline ADA result and a post-baseline ADA result.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Glucagon IM | Percentage of Participants With Treatment-emergent Anti-Drug Antibody (ADA) | 0 percentage of participants |
| Nasal Glucagon (NG) | Percentage of Participants With Treatment-emergent Anti-Drug Antibody (ADA) | 2.0 percentage of participants |