This study has been transitioned to CTIS with ID 2024-515417-17-00 check the CTIS register for the current data. The main objective of this trial is to investigate glucagon receptor occupancy of BI 456906 in the liver with PET imaging using the…
ID
Source
Brief title
Condition
- Other condition
- Appetite and general nutritional disorders
Synonym
Health condition
obesity
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint:
· Percentage of glucagon receptors occupancy in the liver using PET imaging at
End of Treatment visit (EOT).
Secondary outcome
Secundary endpoints:
· Percentage of glucagon-like Peptide 1 receptor occupancy in the pancreas
using PET imaging at EOT visit.
Background summary
BI 456906 is a dual agonist of Glucagon-like-Peptide 1 (GLP-1) and Glucagon
(GCG) receptors. GLP-1 receptor agonists lower body weight by the inhibition of
food intake and by delaying gastric emptying and intestinal transit. GCG
receptor agonist is expected to reduce body weight by increasing energy
expenditure and might directly increase the fatty acid oxidation in the liver,
potentially reducing the lipotoxicity. Simultaneous dual activation of GLP-1
receptor and GCG receptor by BI 456906 is anticipated to improve glycemic
control, body weight loss as well as NASH and fibrosis. Clinical Phase I data
indicate that BI 456906 is more efficacious on body weight reduction compared
to a GLP-1 agonist alone suggesting that activation of the GCG receptor
contributes to the efficacy of BI 456906. However, it is not known to what
extent BI 456906 activates the GLP-1 receptor and in particular the GCG
receptor in man.
The trial was developed to investigate occupancy of BI 456906 on the GCG and
GLP-1 receptors to prove the dual receptor agonism and to compare against the
GLP-1 agonist semaglutide available on the market.
Study objective
This study has been transitioned to CTIS with ID 2024-515417-17-00 check the CTIS register for the current data.
The main objective of this trial is to investigate glucagon receptor occupancy
of BI 456906 in the liver with PET imaging using the radiolabeled tracer
[68Ga]Ga-DO3A-VS-Cys40-Tuna-2.
The secondary objectives is to investigate the GLP-1 receptor occupancy by BI
456906 in the pancreas with PET imaging using the radiolabelled tracer
[68Ga]Ga-NODAGA-Exendin-4. The comparator for both GCG and GLP-1 receptor
occupancy arms will be the GLP-1 receptor agonist, semaglutide
Study design
This trial is designed as open-label, randomised, parallel-groups, phase I
clinical study of BI 456906 versus semaglutide.
It is planned to include a total of 30 subjects in the trial with BMI of >=30
and <=40 kg/m2 and body weight >=70kg and <=150 kg. The subjects will be assigned
to 4 groups. Groups 1 (n=12) and 3 (n=6) will receive BI 456906, and Groups 2
(n=6) and 4 (n=6) will receive semaglutide.
The four groups will be combined into two tracer arms according to which PET
tracer they will receive. The first tracer arm consists of Groups 1 and 2,
receiving the GCG tracer ([68Ga]Ga-DO3A-VS-Cys40-Tuna-2) and PET/CT imaging for
analysis of the liver. The second tracer arm will consist of Groups 3 and 4,
which will receive the GLP-1 tracer (68Ga]Ga-NODAGA-Exendin-4) and PET/CT
imaging for analysis of the pancreas and brain.
Intervention
See the study design
Study burden and risks
Participation in this clinical trial is without any (therapeutic) benefit for
subjects. However, it is anticipated, that volunteers participating in this
trial might have benefit in their weight management. Their participation,
however, is of major importance to investigate the effect of the trial
medication on GCG and GLP-1 receptors. Subjects are exposed to risks of study
procedures and risks related to the exposure to the trial medication.
Procedure-related risks
PET/CT examinations: In connection with the PET/CT imaging examinations, the
subjects will get a low dose injection of one of two different radioactive
tracers. There is a connection between ionizing radiation and risk for cell
damage and cancer. Exposure to a 1 millisievert (mSv) dose of radiation results
in a 1 in 17,000 chance of developing cancer. The total radiation dose per
subject in this trial will be under 10 mSv. This corresponds approximately to
the radiation dose from naturally occurring radiation sources during a 3 to 4
year period for a person living in a country where the clinical trial will be
conducted. Previous studies in rat, Cynomolgus monkey, and human have shown
that both [68Ga]Ga-DO3A-VS-Cys40-Tuna-2 and [68Ga]Ga-NODAGA-Exendin-4
demonstrate a safe profile in regards to dosimetry and adverse events, when
given intravenously at microdoses [R21-1576, R21-1575, R21-1574, R21-1573]. The
toxicological profile of unlabelled DO3A-VS-Cys40-Tuna-2 has previously been
investigated in a single dose study in rat with intravenous bolus
administration of 2, 20, or 200 µg/kg in rats. Ga-DO3A-VS-Cys40-Tuna-2 was well
tolerated, with no adverse findings or evidence of delayed onset toxicity.
Under the conditions of this study, the NOAEL is 200 µg/kg. The toxicological
profile of unlabelled NODAGA-Exendin-4 was previously investigated in a single
dose study in rat with intravenous bolus administration of maximum 20 µg/kg in
rats. NODAGA-Exendin-4 was well tolerated, with no adverse findings or evidence
of delayed onset toxicity noted. Under the conditions of this study, the NOAEL
is 20 µg/kg. Both tracers will be infused at very low, sub-pharmacological
doses and will therefore fall under the legislation of a microdosing approach
according to the *Approach 1* as laid down in the *Guidance on nonclinical
safety studies for the conduct of human clinical trials and marketing
authorization for pharmaceuticals M3(R2) (2009)*. The tracers will be
administered by i.v. injection at a target dose of <0.2 µg/kg for
[68Ga]Ga-DO3A-VS-Cys40-Tuna-2 and at a target dose of <0.2 µg/kg for
[68Ga]Ga-NODAGA-Exendin-4. The absolute total dose of each tracer will be <100
µg and <1/100th of the NOAEL. The target activity dose will be approximately
0.5 MBq/kg [68Ga]Ga-DO3A-VS-Cys40-Tuna-2 and maximum 0.8 MBq/kg for
[68Ga]Ga-NODAGA-Exendin-4. For a subject with a body weight of 100 kg, the
target dose will be therefore be approximately 50 MBq for [68Ga]
Ga-DO3A-VS-Cys40-Tuna-2 and 80 MBq for [68Ga]Ga-NODAGA-Exendin-4. Based on
published dosimetry data the expected radiation dose of one injection of 50 MBq
[68Ga]Ga-DO3A-VS-Cys40-Tuna-2 is 1.05 mSv [R21-1576] and of one injection of 80
MBq [68Ga]Ga-NODAGA-Exendin-4 1.28 mSv [R21-1574].
The maximum expected radiation dose from the low dose CT scan, which will
include both upper abdomen and brain, is 2 mSv.
The subjects in Groups 1 and 2 will undergo two [68Ga]Ga-DO3A-VS-Cys40-Tuna-2
PET/CT examinations.
The subjects in Groups 3 and 4 will undergo two [68Ga]Ga-NODAGA-Exendin-4
PET/CT examinations.
Therefore, the subjects in Groups 1 and 2 will receive a total dose of 6.1 mSv
(3.05 + 3.05) for a 100kg person; subjects in Groups 3 and 4 will receive a
total effective dose of 6.56 mSv (3.28 + 3.28) for a 100 kg person.
MRI examination:
The MRI examination combines strong magnetic field and radiofrequency waves. No
evidence for any risks has been identified in extensive research to evaluate
whether the magnetic fields and radio waves used during an MRI scan pose a risk
to the human body. MRI is thus considered one of the safest medical procedures
currently available. The examination can be uncomfortable if the subject
suffers from claustrophobia. Subjects will be screened for any
contraindications to MRI prior to being included in the study. Besides factors
that risk harming a subject, also factors that may make image data unevaluable
will be considered, to avoid that a subject is exposed to radiation from other
parts of the protocol in vain.
Blood collection: The use of an indwelling venous catheter or venepuncture for
e.g. blood sampling may result in mild bruising and, in rare cases, in
transient inflammation of the wall of the vein, or nerve injury, potentially
resulting in paraesthesia, reduced sensibility, and/or pain for an indefinite
period. The total volume of blood withdrawn per subject during the entire study
will not exceed the volume of a normal blood donation (500 mL). No
health-related risk to healthy subjects is expected from withdrawal of this
volume of blood.
Drug-related risks and safety measures: There are no important identified risks
specified for BI 456906, based on the toxicology program or any clinical trials
conducted for this product to date.
There are 4 important potential risks based on other GLP 1R agonists currently
approved (class effect), and data from the completed Phase II trials of BI
456906. The 4 important potential risks include MTC (C-cell carcinogenicity),
acute pancreatitis, pancreatic cancer, and pre-renal acute kidney injury due to
dehydration.
The risks for subjects caused by participation in the trial, including the
trial procedures and exposure to the IMP, are reasonably low and do not
outweigh the potential benefits. The expected side effects are known to be
temporary, dose dependent, easy to monitor, and manageable in clinical trials.
An overview of trial related risks is presented in Table 1.4: 2.
Basisweg 10
Amsterdam 1043 AP
NL
Basisweg 10
Amsterdam 1043 AP
NL
Listed location countries
Age
Inclusion criteria
1. Healthy male or female subjects according to the assessment of the
investigator, as based on a complete medical history including a physical
examination, vital signs (BP, PR), 12-lead ECG, and clinical laboratory tests
2. Age of 18 to 65 years (inclusive)
3. BMI of >=30 and <=40 kg/m2 and body weight >=70 kg and <=150 kg.
4. Signed and dated written informed consent prior to admission to the study,
in accordance with GCP and local legislation
5. Women of childbearing potential (WOCBP) 1 must be willing and able to use
two forms of effective contraception where at least one form is a highly
effective method of birth control per ICH M3 (R2) that result in a low failure
rate of less than 1% per year when used consistently and correctly. A list of
contraception methods meeting these criteria is provided in the subject
information (Section 4.2.2.3).
Exclusion criteria
Subjects will not be allowed to participate if any of the following general
criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG) deviating
from normal and assessed as clinically relevant by the investigator
2. Resting heart rate >100 beats per minute (bpm) and/or systolic blood
pressure >=160 mmHg and/or diastolic blood pressure >=95 mmHg at screening
3. Any laboratory value outside the reference range that the investigator
considers to be of clinical relevance. Subjects with the following abnormal
values are not eligible for the trial participation:
- LDL >160 mg/dL (4.15 mmol/L)
- total cholesterol >240 mg/dL (6.22 mmol/L)
- triglyceride >200 mg/dL (2.26 mmol/L)
- blood glucose >126 mg/dl (7 mmol/L) fasting and/or HbA1c >6.5%
4. Any evidence of a concomitant disease assessed as clinically relevant by the
investigator. Subjects with type 1 and type 2 diabetes mellitus are not
eligible for the trial
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic,
immunological or hormonal disorders assessed as clinically relevant by the
investigator
6. Diseases of the central nervous system (including but not limited to any
kind of seizures), and other relevant neurological or psychiatric disorders
7. History of relevant orthostatic hypotension, fainting spells, or blackouts
8. Personal or family history of medullary thyroid carcinoma or multiple
endocrine neoplasia syndrome type 2, manifest hypo- or hyperthyroidism at Visit
1
9. Calcitonin >=100 pg/mL (29.26 pmol/L) at screening
10. Any suicidal behaviour or history of major depressive disorder requiring
inpatient treatment or escalation of care in the past 2 years before
randomization, any suicidal ideation of type 4 or 5 in the C-SSRS in the past 3
months prior to Visit 1
11. Chronic or relevant acute infections
12. History of chronic or acute pancreatitis or elevation of serum
lipase/amylase >2x ULN
13. History of relevant allergy or hypersensitivity (including allergy to the
trial medication or its excipients) according to investigator's assessment
14. Use of prescription or over-the counter drugs within 30 days of planned
administration of trial medication that might reasonably influence the results
of the trial including drugs known to significantly prolong the QT/QTcF
interval; please refer to Section 4.2.2
15. Intake of an investigational drug in another clinical trial within 60 d of
planned administration of investigational drug in the current trial, or
concurrent participation in another clinical trial in which investigational
drug is administered
16. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day) and
inability to refrain from smoking on specified trial days
17. Ongoing chronic alcohol use or drug abuse other than the ones described in
Table 5.2.3: 2, that in the investigator*s opinion, makes the subject an
unreliable trial subject or unlikely to complete the trial
18. Blood donation of more than 500 mL within 30 d of planned administration of
trial medication or intended blood donation during the trial
19. Intention to perform excessive physical activities within one week prior to
the administration of trial medication or during the trial
20. Inability to comply with the dietary regimen of the trial site
21. A marked baseline prolongation of QT/QTc interval (such as QTcF intervals
greater than 450 ms at screening) or any other abnormal or clinically
significant ECG finding at screening (e.g. type 2 second-degree AV block [Type
Mobitz II] or third-degree AV block)
22. History of ventricular tachycardia, type 2 second-degree AV block (Type
Mobitz II) or third-degree AV block
23. A history of additional risk factors for Torsade de Pointes (such as heart
failure, hypokalaemia, Lyme disease, or family history of Long QT Syndrome)
24. Heart rhythm disturbances (e.g. bradycardia with baseline heart rate <50
bpm, in the absence of heart rate lowering medications), tachycardia or
tachyarrhythmia (e.g. atrial fibrillation, atrial flutter or ventricular
tachycardia), considered by the Investigator indicative of relevant cardiac
disease or with abnormalities that may interfere with the interpretation of
changes in ECG intervals at Visit 1
25. Any of the following conditions or procedures within the last six months
prior to Visit 1: myocardial infarction, unstable angina (e.g. Canadian
Cardiovascular Society [CCS] grading of Angina pectoris grade III and IV),
artery bypass (e.g. coronary artery bypass graft, carotid bypass, peripheral
artery bypass), percutaneous coronary intervention (diagnostic angiograms are
permitted), transient ischaemic attack, cerebrovascular accident (stroke)
26. History of or currently diagnosed with congestive heart failure, New York
Health Association (NYHA) class III-IV at screening
27. Treatment with medications known to cause heart block or bradycardia, such
as beta-blockers, verapamil, and diltiazem, unless these drugs are indicated
for hypertension treatment
28. Subject is assessed as unsuitable for inclusion by the investigator, for
instance, because the subject is not considered able to understand and comply
with study requirements, or has a condition that would not allow safe
participation in the study
29. History of a major surgery including surgery of liver and pancreas (except
appendectomy) within 5 years prior to screening, or history of splenectomy
30. Confirmed diagnosis of malignancy within 5 years prior to screening, except
for basal- or squamous-cell carcinoma of the skin that has been treated
successfully. Trial participants under evaluation for malignant disease
currently are not eligible for study participation
31. Women who are pregnant, nursing, or who plan to become pregnant while in
the trial
In addition, the following trial-specific exclusion criteria apply:
32. Contraindication to magnetic resonance imaging including, but not limited
to: severe claustrophobia, extensive tattoos, inner ear implant, pacemakers or
other implanted cardiac rhythm management devices, intracranial aneurysm clips
incompatible with MRI, any other metallic, non-MR compatible implanted devices
(e.g. insulin pump, hip joint replacement), a history of intra-orbital metal
fragments that have not been removed, and weight or girth that exceeds scanner
capabilities
33. Previous medical PET, SPECT, abdominal or thoracic CT examination within 12
months
34. Having worked as a metal worker or welder
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-515417-17-00 |
| EudraCT | EUCTR2021-000363-76-NL |
| CCMO | NL82814.018.22 |