Overview
The purpose of this study is to measure the changes in small bowel uptake of radioligand [11C]AZ14132516 after IV administration of a single dose of AZD7798 in healthy participants and participants with Crohn's disease.
Study details include:
- The study duration will be variable (adaptive design).
- There will be 5 in-person study visits: 1 screening visit, 1 visit for the baseline PET examination, 1 residential (24h) visit for AZD7798 administration and 2 visits for repeated PET examinations. There will be a final follow-up virtual visit (telephone call).
Eligibility
Inclusion Criteria:
HEALTHY PARTICIPANTS:
- Capable of giving signed informed consent as described in Appendix A which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
- Able and willing to participate in all scheduled evaluations, abide by all study restrictions, and complete all required tests and procedures.
- Participant must be ≥ 20 to 65 years of age inclusive, at the time of signing the
informed consent.
Type of Participant and Disease Characteristics
- Participants who are overtly healthy as determined by medical evaluation including
medical history, physical examination, laboratory parameters, and cardiac monitoring
before first administration of investigational product.
Weight
- Body weight within 50.0 to 100.0 kg and body mass index within the range 18.0 to 30.0 kg/m2 (inclusive).
- Contraceptive use by males or females should be consistent with local regulations
regarding the methods of contraception for those participating in clinical studies.
(b) Male participants:
- Non-sterilised male participants who are sexually active with a female partner of childbearing potential must use a condom with spermicide during the study period and for at least 7 days following last radioligand administration and 4 months following last dose of AZD7798, whichever is longer.
- It is strongly recommended that female partners of male participants also use at least one highly effective method of contraception throughout this period.
- Male participants must refrain from fathering a child or donating sperm during the study period and for at least 7 days following last radioligand administration and 4 months following last dose of AZD7798, whichever is longer.
(c) Female participants: (i) Women of non-child bearing potential are defined as
meeting one of the following criteria at screening:
- Postmenopausal defined as amenorrhoea for at least 12 months following cessation of
all exogenous hormonal treatments and FSH levels in the postmenopausal range.
- Documentation of irreversible surgical sterilisation by hysterectomy, bilateral
oophorectomy, or bilateral salpingectomy but not tubal ligation.
(ii) WOCBP (ie, not meeting criteria above) must have a negative pregnancy test at
screening and before PET examination.
(iii) If sexually active with a non-sterilised male partner, WOCBP must use at least
one highly effective method of birth control during the study period and for at least
7 days following last radioligand administration and 4 months following last dose of
AZD7798, whichever is longer.
(iv) It is strongly recommended that non-sterilised male partners of WOCBP
participants use a male condom plus spermicide during the study period.
(v) WOCBP participants must not breastfeed and must not donate or retrieve ova for
their own use during the study period and for at least 7 days following last
radioligand administration and 4 months following last dose of AZD7798, whichever is
longer (d) Highly effective methods of birth control (i) Methods that can achieve a
failure rate of less than 1% per year when used consistently and correctly are
considered as highly effective birth control methods. Such methods include:
- Combined (oestrogen and progesterone containing) hormonal contraception
associated with inhibition of ovulation (oral, intravaginal or transdermal)
- Progesterone-only contraception associated with inhibition of ovulation (oral,
injectable or implantable)
- Intrauterine device or hormone-releasing system
- Bilateral tubal occlusion
- Vasectomised partner (only acceptable if the partner is the sole sexual partner
of the participant and the vasectomised partner has received medical assessment
of surgical success)
- Sexual abstinence as defined by refraining from heterosexual intercourse during
the entire period of risk associated with the study intervention. It is only
acceptable if the preferred and usual lifestyle of the participant.
PARTICIPANTS WITH CROHN'S DISEASE
1. As for Healthy Participants (IC#1) procedures.
2. Participant must be ≥ 20 to 65 years of age inclusive, at the time of signing the
informed consent.
3. Participants with confirmed Crohn's disease with small bowel involvement per study
gastroenterologist (diagnosed via combination of clinical findings and at least one of
endoscopy and/or histology and/or imaging) with diagnosis made at least 3 months prior
to screening.
4. Body weight within 50.0 to 100.0 kg and body mass index within the range 18.0 to 30.0
kg/m2 (inclusive).
5. As for Healthy Participants (IC#6).
Exclusion Criteria:
HEALTHY PARTICIPANTS:
1. Current significant major or unstable respiratory disease, heart disease,
cerebrovascular disease, haematological disease, hepatic disease, renal disease,
gastrointestinal disease, or other major disease.
2. History of cancer with the following exceptions
(a) Solid malignancy with curative therapy completed at least 5 years prior to
screening (b) Basal cell carcinoma or localised squamous cell carcinoma of the skin or
in-situ carcinoma of the cervix, provided that curative therapy was completed at least
12 months prior to screening
3. History of severe allergy/hypersensitivity or ongoing clinically important
allergy/hypersensitivity, as judged by the Investigator, or history of
hypersensitivity to biologic therapies.
4. Participants with unstable hypertension (as judged by the Investigator) or symptomatic
hypotension, history of pre-syncope or syncope due to orthostatic hypotension and/or
induced by change of posture (orthostatic hypotension defined as 25 mmHg decrease in
systolic and/or 15 mmHg).
5. Significant abnormalities on clinical examination, including neurological and physical
examination, vital signs and ECG.
6. Chemistry, haematology, or urine analysis results that may interfere with the study or
present a safety risk to the participant.
7. Leukocyte, lymphocyte or neutrophil counts below the LLN. A re-test is allowed during
screening in cases of mild leukopenia clinically suspected to be transient.
8. Abnormal vital signs, after 10 minutes of supine rest as judged by the investigator.
As a guide, any readings outside the following should be considered in the evaluation:
1. systolic BP ≥ 150 mmHg
2. diastolic BP ≥ 90 mmHg
3. heart rate ≤ 35 bpm or ≥ 100 bpm The inclusion of participants meeting the above
criteria may be decided on a case-by case basis by the Principal Investigator.
9. Any clinically important abnormalities in rhythm, conduction or morphology of resting
ECG that may interfere with the interpretation of QTc interval changes. This may
include participants with any of the following:
(a) PR (PQ) interval prolongation of clinical significance as judged by the
Investigator (b) Intermittent second or third-degree AV block (AV block II Mobitz type
1, Wenchebach, while asleep or in deep rest is not disqualifying) (c) Incomplete,
full, or intermittent bundle branch block (QRS ≤ 110 ms with normal QRS and T wave
morphology is acceptable if there is no evidence of left ventricular hypertrophy) (d)
Abnormal T wave morphology (e) Prolonged QTcF ≥ 470 ms or shortened QTcF ≤ 340 ms or a
family history of long QT syndrome The inclusion of participants meeting the above
criteria may be decided on a case-by case basis by the Principal Investigator.
10. Positive hepatitis B, hepatitis C or HIV serology as defined by:
(a) HBsAg or anti-HBc Ab positivity (b) Anti-HCV Ab positivity (c) Anti-HIV Ab
positivity Prior/Concomitant Therapy
11. Participants must abstain from taking prescription or non-prescription drugs
(including vitamins, recreational drugs, and dietary or herbal supplements) within 7
days or 5 halflives (whichever is longer) before the start of study intervention until
completion of the follow-up visit, unless, in the opinion of the investigator and
sponsor, the medication will not interfere with the study.
12. Current drug abuse or dependence or positive screen for drugs of abuse at screening
visit.
13. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
staff and/or staff at the study site).
14. Suffers from claustrophobia that limits the ability to undergo the scanning procedure.
15. Positive SARS-CoV-2 rapid antigen test at screening.
16. Any other reason that, in the study PI opinion, prohibits the inclusion of the
participants into the study.
17. Judgement by the investigator that the participant should not participate in the study
if the participant is unlikely to comply with study procedures, restrictions, and
requirements.
18. Live or attenuated vaccine within 4 weeks of Screening and until the end of the
follow-up period and until 12 weeks after the end of the follow-up period (1 year for
BCG vaccination).
19. An active infection, or history of serious infection within the preceding 28 days.
20. Use of antibiotics within 28 days prior to the first administration of IMP, unless, in
the opinion of the investigator, the medication will not interfere with the study.
21. History of symptomatic herpes simplex (excluding cold sores) or herpes zoster
infection within 3 months prior to screening.
22. Positive or indeterminate tuberculosis (TB) QuantiFERON test.
23. Has received another new chemical entity (defined as a compound which has not been
approved for marketing) within 30 days/5 half-lives, whichever is longer, of the first
administration of IMP in this study. The period of exclusion begins 30 days/5
half-lives, whichever is longer, after the final dose.
24. Participation in a PET imaging research study within last year.
PARTICIPANTS WITH CROHN'S DISEASE
1. Current diagnosis of ulcerative colitis, indeterminate colitis, inflammatory bowel
disease unclassified, infectious colitis, or ischaemic colitis.
2. History of CMV colitis within 12 months prior to screening.
3. Complications of Crohn's Disease including short bowel syndrome, strictures/stenoses
with symptomatic obstruction or pre-stenotic dilation, or other conditions where
surgery may be anticipated during the study period.
4. Planned bowel or perianal surgery for Crohn's disease prior to end of study follow up
visit.
5. Recent bowel resection surgery within 6 months of screening.
6. Participants with undrained fistula or abscess, including active perianal disease.
7. Positive C. difficile toxin test during screening.
8. Current significant major or unstable respiratory disease, heart disease,
cerebrovascular disease, haematological disease, hepatic disease, renal disease,
gastrointestinal disease, or other major diseases other than active Crohn's disease.
9. History of cancer with the following exceptions (a) Solid malignancy with curative
therapy completed at least 5 years prior to screening (b) Basal cell carcinoma or
localised squamous cell carcinoma of the skin or in-situ carcinoma of the cervix,
provided that curative therapy was completed at least 12 months prior to screening
10. History of severe allergy/hypersensitivity or ongoing clinically important
allergy/hypersensitivity, as judged by the Investigator, or history of
hypersensitivity to biologic therapies.
11. Participants with unstable hypertension (as judged by the Investigator) or symptomatic
hypotension, history of pre-syncope or syncope due to orthostatic hypotension and/or
induced by change of posture (orthostatic hypotension defined as 25 mmHg decrease in
systolic and/or 15 mmHg).
12. Significant abnormalities on clinical examination, including neurological and physical
examination, vital signs and ECG other than signs of Crohn's disease.
13. Chemistry, haematology, or urine analysis results that may interfere with the study or
present a safety risk to the participant.
14. Abnormal vital signs, after 10 minutes of supine rest as judged by the investigator.
As a guide, any readings outside the following should be considered in the evaluation:
(a) systolic blood pressure (BP) ≥ 150 mmHg (b) diastolic BP ≥ 90 mmHg (c) heart rate
≤ 35 bpm or ≥100 bpm The inclusion of participants meeting the above criteria may be
decided on a case-by case basis by the Principal Investigator.
15. Any clinically important abnormalities in rhythm, conduction or morphology of resting
ECG that may interfere with the interpretation of QTc interval changes. This may
include participants with any of the following:
1. PR (PQ) interval prolongation of clinical significance as judged by the
Investigator
2. Intermittent second or third-degree AV block (AV block II Mobitz type 1,
Wenchebach, while asleep or in deep rest is not disqualifying)
3. Incomplete, full, or intermittent bundle branch block (QRS ≤ 110 ms with normal
QRS and T wave morphology is acceptable if there is no evidence of left
ventricular hypertrophy)
4. Abnormal T wave morphology
5. Prolonged QTcF ≥ 470 ms or shortened QTcF ≤ 340 ms or a family history of long QT
syndrome.
The inclusion of participants meeting the above criteria may be decided on a case-by
case basis by the Principal Investigator.
16. Positive hepatitis B, hepatitis C or HIV serology as defined by:
1. HBsAg or anti-HBc Ab positivity
2. Anti-HCV Ab positivity and HCV RNA positivity
3. Anti-HIV Ab positivity Prior/Concomitant Therapy
17. Treatment with an anti-TNF biologic within 8 weeks of first dose and throughout the
study period, unless therapeutic drug monitoring is performed and drug concentrations
are undetectable.
18. Treatment with any biologic, other than an anti-TNF (including vedolizumab and
ustekinumab) within 12 weeks prior to first dose and throughout the study period,
unless therapeutic drug monitoring is performed and drug concentrations are
undetectable.
19. Treatment with rituximab within 12 months prior to first dose and throughout the study
period.
20. Treatment with Sphingosine-1-phosphate receptor modulators within 12 weeks prior to
first dose and throughout the study period.
21. Treatment with Janus Kinase inhibitors within 2 weeks prior to first dose and
throughout the study period
22. Treatment with apheresis (eg, Adacolumn, Cellsorba) within 2 weeks prior to first dose
and throughout the study period.
23. Treatment with corticosteroids at a total daily dose of greater than 20 mg prednisone
or equivalent.
24. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
staff and/or staff at the study site).
25. Suffers from claustrophobia that limits the ability to undergo the scanning procedure.
26. Positive SARS-CoV-2 rapid antigen test at screening.
27. Any other reason that, in the study PI opinion, prohibits the inclusion of the
participants into the study.
28. Judgement by the investigator that the participant should not participate in the study
if the participant is unlikely to comply with study procedures, restrictions, and
requirements.
29. Live or attenuated vaccine within 4 weeks of Screening and until 12 weeks after the
end of the follow-up period (1 year for Bacillus Calmette-Guerin vaccination).
30. An active infection, or history of serious infection within the preceding 28 days.
31. History of symptomatic herpes simplex (excluding cold sores) or herpes zoster
infection within 3 months prior to screening.
32. Positive or indeterminate TB QuantiFERON test performed within 1 year of screening
(without known interval exposure to TB) or during screening period unless evidence of
completion of full treatment course for latent TB with no clinical symptoms or signs
indicative of re-activation.
33. Chest x-ray with signs of malignancy or latent or active TB infection performed within
1 year of screening (without known interval exposure to TB) or during screening
period.
34. Has received another new chemical entity (defined as a compound which has not been
approved for marketing) within 30 days/5 half-lives, whichever is longer, of the first
administration of IMP in this study. The period of exclusion begins 30 days/5
half-lives, whichever is longer, after the final dose.