Clinical trial NCT06053424: Positron Emission Tomography Study of Changes in [11C]AZ14132516 Uptake Following Administration of AZD7798 to Healthy Participants and Patients With Crohn's Disease
Official title: A Phase 1b Open Label Positron Emission Tomography Study to Assess Changes in Abdominal [11C]AZ14132516 Uptake Following Administration of Single Doses of AZD7798 to Healthy Participants and Patients With Crohn's Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Crohn's Disease
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2023-09-25
Enrollment: 12
Sex: ALL
Minimum age (years): 20
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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 criteria: Inclusion Criteria:

HEALTHY PARTICIPANTS:

1. 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.
2. Able and willing to participate in all scheduled evaluations, abide by all study restrictions, and complete all required tests and procedures.
3. Participant must be ≥ 20 to 65 years of age inclusive, at the time of signing the informed consent.

   Type of Participant and Disease Characteristics
4. 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
5. Body weight within 50.0 to 100.0 kg and body mass index within the range 18.0 to 30.0 kg/m2 (inclusive).
6. 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

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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.

Primary outcomes:
measure: Change from baseline in small bowel SUV/SUVR
timeFrame: Day 14 and 42 (may vary between panels)
Secondary outcomes:
measure: Change from baseline in number and percent of circulating CCR9+ T cells and CCR9 receptor occupancy
timeFrame: Day 14 and 42 (may vary between panels)
measure: Serum AZD7798 concentration
timeFrame: Day 14 and 42 (may vary between panels)
measure: where data permit PK parameter Cmax
timeFrame: Day 14 and 42 (may vary between panels)
measure: where data permit PK parameter AUC
timeFrame: Day 14 and 42 (may vary between panels)
Other outcomes:
measure: Number of participants with safety findings, AEs
timeFrame: Until final follow-up (Day 85 - may vary between panels)
Locations:
city: Stockholm
country: Sweden
facility: Research Site
Study officials:
affiliation: Karolinska University Hospital
name: Maria Creignou, MD
role: PRINCIPAL_INVESTIGATOR
References: