PET Study to Determine Muscarinic Receptor Occupancy in Lungs After Inhalation of AZD2115 and Tiotropium

An Open-label Positron Emission Tomography Phase I Study to Determine Muscarinic Receptor Occupancy in the Lungs in Healthy Volunteers After Inhalation of Single Dose of Tiotropium or AZD2115.

An open-label study using positionemissiontomography (PET) to explore the binding of AZD2115 and Tiotropium to muscarinic receptors in the lungs in healthy volunteers after inhalation.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: AZD2115; Radiation: [11C]AZ13754366; Drug: SPIRIVA

Detailed Description

A phase I open-label exploratory study in healthy male volunteers using positionemissiontomography (PET). The study will test the hypothesis that Tiotropium and AZD2115 binds to the mAchRs in a saturable manner and aims to examine the relationship between receptor occupancy and drug exposure.

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 1

Contacts and Locations

Study Locations

• Sweden
  • Stockholm, Sweden, 171 76
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 50 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Provision of signed and dated written informed consent prior to any study specific procedures
• Healthy male subjects, aged 20 to 50 years (inclusive)
• Male subjects must be surgically sterile or use an acceptable method of contraception (defined as barrier methods in conjunction with spermicides) for the duration of the study (from the first dose) and for 3 months after the last dose of study drug to prevent pregnancy in a partner
• Body mass index (BMI) between 18.0 and 30.0 kg/m2 inclusive and weigh at least 50.0 kg and no more than 100.0 kg, inclusive
• Able and willing to participate in all scheduled evaluations and abide by all study restrictions
• Ability to inhale from the study drug training devices at visit 1
• Subjects who are blood donors should not donate blood during the study and for 3 months following their last dose of study drug.

Exclusion Criteria:

• History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the study results or the subject's ability to participate in the study.
• Any clinical significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of investigational medicinal product (IMP)
• Any clinically significant abnormalities in clinical chemistry, haematology, or urinalysis results, as judged by the investigator.
• Any positive results on screening for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody and human immunodeficiency virus (HIV)

• Abnormal vital signs, after 10 minutes of supine rest, defined as any of the following:

  • Systolic blood pressure (BP) <90 mmHg or >140 mmHg
  • Diastolic BP <50 mmHg or >90 mmHg
  • Heart rate <45 bpm or > 100 bpm

• Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG that may interfere with the interpretation of QTc interval changes, as determined by the investigator. This may include subjects with any of the following:

  • PR (PQ) interval prolongation of clinical significance as judged by the Investigator
  • Intermittent second or third degree AV block (AV block II Mobitz type 1 Wenchebach, while asleep or in deep rest is not disqualifying)
  • Incomplete, full, or intermittent bundle branch block (QRS less than 110 ms with normal QRS and T wave morphology is acceptable if there is no evidence of left ventricular hypertrophy)
  • Abnormal T wave morphology, particularly in the protocol-defined primary lead
  • Prolonged QT interval corrected for heart rate using Fridericia's formula (QTcF) greater than 450 ms or shortened QTcF less than 340 ms or a family history of long QT syndrome.
• History of alcohol abuse or excessive intake of alcohol, as judged by the investigator.
• Positive screen for drugs of abuse at visit 1.
• History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, other than seasonal allergies, as judged by the Investigator, or history of hypersensitivity to drugs with similar chemical structure or class as AZD2115.
• Use of any prescribed or non-prescribed medication, during the 4 weeks (or longer depending on the medication's half-life) prior to the administration of IMP.
• Use of drugs with enzyme inducing properties such as St John's Wort within 4 weeks prior to the investigational product administration.
• Current smokers or subjects who have smoked or used nicotine products within 6 months prior to visit 1
• Plasma donation within 1 month of screening or any blood donation/blood loss equal to or greater than 500 mL during the 3 months prior to screening.
• Previous enrolment in the present study
• Involvement in the planning and/or conduct of the study
• Participation in another clinical study with an investigational product during the last 3 months
• Negative Allen test in both hands
• Claustrophobia that would contraindicate PET measurement.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: AZD2115	Drug: AZD2115; AZD2115; Radiation: [11C]AZ13754366; Radioligand
ACTIVE_COMPARATOR: Spiriva (Tiotropium)	Radiation: [11C]AZ13754366; Radioligand; Drug: SPIRIVA; Tiotropium
EXPERIMENTAL: [11C]AZ13754366	Radiation: [11C]AZ13754366; Radioligand

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction in distribution volume (VT)%	To describe the AZD2115 dose-muscarinic receptor occupancy relationship in the lungs in healthy volunteers	up to 9 h post dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Receptor occupancy (RO) %	To describe the muscarinic receptor occupancy after inhalation of AZD2115 and Tiotropium in the lungs in healthy volunteers	up to 9 h post dose

Collaborators and Investigators

• Sponsor: AstraZeneca

Publications and helpful links

General Publications

• Cselenyi Z, Jucaite A, Kristensson C, Stenkrona P, Ewing P, Varrone A, Johnstrom P, Schou M, Vazquez-Romero A, Moein MM, Bolin M, Siikanen J, Gryback P, Larsson B, Halldin C, Grime K, Eriksson UG, Farde L. Quantification and reliability of [11C]VC - 002 binding to muscarinic acetylcholine receptors in the human lung - a test-retest PET study in control subjects. EJNMMI Res. 2020 Jun 3;10(1):59. doi: 10.1186/s13550-020-00634-0.

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 26, 2017
• Primary Completion (ACTUAL): December 30, 2017
• Study Completion (ACTUAL): December 30, 2017

Study Registration Dates

• First Submitted: March 6, 2017
• First Submitted That Met QC Criteria: March 27, 2017
• First Posted (ACTUAL): March 31, 2017

Study Record Updates

• Last Update Posted (ACTUAL): August 30, 2021
• Last Update Submitted That Met QC Criteria: August 27, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: Healthy volunteer study
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Respiration Disorders; Respiratory Aspiration; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Antagonists; Cholinergic Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Tiotropium Bromide
• Other Study ID Numbers: D3060C00014

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No