A study in healthy post-menopausal female volunteers to assess how the test medicine [14C]AZD9833 is taken up, broken down and removed from the body

ISRCTN ISRCTN46127225
DOI https://doi.org/10.1186/ISRCTN46127225
EudraCT/CTIS number 2022-000834-40
IRAS number 1005259
ClinicalTrials.gov number NCT05364255
Secondary identifying numbers D8532C00005, IRAS 1005259
Submission date
31/03/2022
Registration date
05/05/2022
Last edited
22/06/2023
Recruitment status
No longer recruiting
Overall study status
Completed
Condition category
Cancer
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data
Record updated in last year

Plain English summary of protocol

Background and study aims
The Sponsor is developing the test medicine AZD9833 for the potential treatment of oestrogen receptor (ER)-positive breast cancer. Breast cancer is the second most common type of cancer in the UK and worldwide. Most women diagnosed with breast cancer are over the age of 50 years, but younger women and men can also get breast cancer. Estrogen receptor (ER)-positive breast cancer means the cancer cells grow in response to the hormone oestrogen. AZD9833 has the potential to prevent ER activity and increase overall survival in advanced breast cancer patients. This single-part, healthy volunteer study will try to identify how the test medicine is taken up, broken down and removed from the body. To help investigate this, the test medicine is radiolabelled, which means that the test medicine has a radioactive component (carbon-14) which can be used to track where the test medicine is in the body. The safety and tolerability of the test medicine will also be studied.

Who can participate?
Post-menopausal female volunteers aged between 50 to 70 years

What does the study involve?
On Day 1, volunteers will receive a 75 mg dose of [14C]AZD9833 oral solution in the fasted state (on an empty stomach). Volunteers’ blood, urine and faeces will be taken throughout the study for analysis of the test medicine and its breakdown products (metabolites) and for volunteer safety. Volunteers will remain in the clinical unit until Day 8, however, if the relevant radioactivity criteria have not been met, volunteers may be required to remain at the clinic until Day 10. If relevant criteria have not been met at this point, home collections of urine and/or faeces may be required. Volunteers are expected to be involved in this study for about 6 weeks from screening to discharge.

What are the possible benefits and risks of participating?
Participants will get no medical benefit from the test medicine, however, the development of a treatment for breast cancer may benefit the population as a whole. As this is a Phase I study, the most relevant population is healthy volunteers. It is considered that the risk/benefit evaluation in this study supports the use of healthy volunteers. There is always a risk that the stipend in healthy volunteer studies could represent coercion. The time spent in the clinic, travel, inconvenience and other expenses factor in calculating the stipend. Perception of risk is not considered in this calculation. Volunteers may experience side effects from the test medicine. Full information on possible side effects is provided to volunteers in the participant information sheet (PIS)/informed consent form (ICF). When investigating new medicines there is also a risk of unexpected side effects and occasionally allergic reactions. All volunteers will be closely monitored during the study and safety assessments will be performed at regular intervals. Risks are further mitigated by ensuring that only volunteers who meet all inclusion/exclusion criteria are included and that if the safety of any volunteer represents a concern they will be withdrawn. There will be an extended period of fasting for the volunteers taking part in this study. Volunteers will be allowed water up to 1 hour before the scheduled dosing time and will be provided with 240 ml of water at 1-hour post-dose. Water will be allowed after 1-hour post-dose. Decaffeinated fluids will be allowed from lunchtime on the day of dosing. Blood samples will be collected during the study. Collection of these samples can cause soreness and bruising of the arms but these problems usually clear up within a few days to a few weeks. ECG stickers on volunteers' chests and limbs may cause some local irritation and may be uncomfortable to remove but volunteers will be closely monitored to ensure any local irritation does not persist. By taking part in the study the volunteers will be exposed to a small amount of radiation.

Where is the study run from?
AstraZeneca (Sweden)

When is the study starting and how long is it expected to run for?
March 2022 to June 2022

Who is funding the study?
AstraZeneca (Sweden)

Who is the main contact?
Dr Manuel Selvi Miralles
manuel.selvimiralles@astrazeneca.com

Contact information

Dr Manuel Selvi Miralles
Scientific

AstraZeneca UK, Central Cambridge
310 Milton Rd
Milton
Cambridge
CB4 0WG
United Kingdom

Phone +44 (0)738 5026328
Email manuel.selvimiralles@astrazeneca.com
Dr Caroline Langham
Public

AstraZeneca - Charter Way
Macclesfield
SK10 2NA
United Kingdom

Phone +44 (0)778 8354613
Email caroline.langham@astrazeneca.com
Dr Somasekhara Menakuru
Principal Investigator

Mere Way
Ruddington Fields
Ruddington
NG11 6JS
United Kingdom

Phone +44 (0)330 303 1000
Email recruitment@weneedyou.co.uk

Study information

Study designNon-randomized study
Primary study designInterventional
Secondary study designNon randomised study
Study setting(s)Other
Study typeTreatment
Participant information sheet Not available in web format, please use the contact details to request a participant information sheet
Scientific titleA Phase I, open-label, single-dose, single-period study to assess the mass balance recovery, metabolite profile and metabolite identification of [14C]AZD9833 after oral administration in healthy post-menopausal female subjects
Study acronymQSC205863
Study objectives1. To determine the mass balance recovery after a single oral dose of [14C]AZD9833
2. To perform metabolite profiling and structural identification from plasma, urine and faecal samples
3. To determine the routes and rates of elimination of [14C]AZD9833
4. To determine the oral pharmacokinetics (PK) of AZD9833 in plasma and total radioactivity in plasma and whole blood
5. To evaluate the extent of distribution of total radioactivity into blood cells
6. To provide additional safety and tolerability information for AZD9833
Ethics approval(s)Approved 25/04/2022, Fast Track REC (Health Research Authority, 2 Redman Place, Stratford, London, E20 1JQ, UK; +44 (0)207 104 8012; fasttrack.rec@hra.nhs.uk), ref: 22/FT/0050
Health condition(s) or problem(s) studiedER-positive, HER2-negative breast cancer
InterventionThis is a single-part, healthy volunteer study to identify how the test medicine is taken up, broken down and removed from the body. To help investigate this, the test medicine is radiolabelled, which means that the test medicine has a radioactive component (carbon-14) which helps track where the test medicine is in the body. The safety and tolerability of the test medicine will also be studied. This study will take place at one non-NHS site, and will consist of a single study period involving up to 6 post-menopausal female volunteers, aged between 50 to 70 years. On Day 1, volunteers will receive a 75 mg dose of [14C]AZD9833 oral solution in the fasted state. Volunteers’ blood, urine and faeces will be taken throughout the study for analysis of the test medicine and its breakdown products (metabolites) and for volunteer safety. Volunteers will remain in the clinical unit until Day 8, however, if the relevant radioactivity criteria have not been met, volunteers may be required to remain at the clinic until Day 10. If relevant criteria have not been met at this point, home collections of urine and/or faeces may be required. Volunteers are expected to be involved in this study for approximately 6 weeks from screening to discharge.
Intervention typeDrug
Pharmaceutical study type(s)
PhasePhase I
Drug / device / biological / vaccine name(s)[14C]AZD9833
Primary outcome measure1. Mass balance recovery of total radioactivity in all excreta (urine and faeces): CumAe and Cum%Ae measured by accelerator mass spectrometry from samples taken at timepoints between Day 1 up to Day 10
2. Levels and structures of drug and metabolites in plasma, urine and faeces measured by ultra-performance liquid chromatography coupled to high-resolution mass spectrometry (hrMS)/mass spectrometry (MS) from samples taken at timepoints between Day 1 up to Day 10 (plus any additional samples taken beyond this period if warranted)
Secondary outcome measures1. Mass balance recovery of total radioactivity in urine and faeces separately: Ae, %Ae, CumAe and Cum%Ae by interval measured by accelerator mass spectrometry from samples taken at timepoints between Day 1 up to Day 10
2. Assessment of the PK of AZD9833 and total radioactivity by calculation of tmax, Cmax, AUC0-t, AUC0-inf, AUC%extr, t1/2, λz, CL/F and Vz/F measured by LC-UV-MS from samples taken at timepoints between Day 1 up to Day 10
3. Whole blood:plasma concentration ratios for total radioactivity evaluated using samples taken at timepoints between Day 1 up to Day 10
4. Safety and tolerability information via measures including physical examinations, vital signs, ECGs and laboratory safety tests will be assessed by standard phase 1 unit monitoring at screening, from Day -1 to discharge from the ward on (up to) Day 10
Overall study start date29/03/2022
Completion date20/06/2022

Eligibility

Participant type(s)Healthy volunteer
Age groupAdult
SexFemale
Target number of participants6
Total final enrolment6
Key inclusion criteria1. Provision of signed and dated, written informed consent prior to any study-specific procedures
2. Aged between 50 to 70 years inclusive at the time of signing informed consent
3. Healthy post-menopausal females, defined as post-menopausal by fulfilling the following criterion:
3.1. Amenorrhoea for at least 12 months following cessation of all exogenous hormonal treatments and without an alternative medical or surgical cause and confirmed by an FSH result of ≥30 IU/l
4. Must be willing and able to communicate and participate in the whole study
5. Have a body mass index (BMI) between 19.0 to 35.0 kg/m², weigh at least 50 kg and no more than 100 kg inclusive as measured at screening.
6. Must have regular bowel movements (i.e. average stool production of ≥1 and ≤3 stools per day)
Key exclusion criteria1. History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the volunteer at risk because of participation in the study, or influence the results or the volunteer’s ability to participate in the study
2. History or presence of GI, hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs
3. Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of IMP
4. History of or ongoing clinically significant visual disturbances including but not limited to visual hallucinations, migraine with visual symptoms, blurred vision, frequent floaters/flashes associated with other symptoms such as dizziness
5. Any clinically significant abnormalities in clinical chemistry, haematology, or urinalysis results, at screening as judged by the Investigator.
6. Any clinically significant abnormal findings in vital signs at screening as judged by the Investigator, including systolic BP <100 mmHg, diastolic BP <50 mmHg or heart rate <50 bpm. Vital signs outside these limits can be repeated once for confirmation
7. Any clinically significant abnormalities on 12-lead ECG at screening, as judged by the Investigator, including non-sinus rhythms, PR interval <120 msec or >220 msec, ventricular rate <50 bpm or >100 bpm, QRS interval >120 msec, or QTcF >470 msec as a mean of triplicate. ECGs can be repeated once in triplicate if parameters are outside these limits for confirmation
8. Evidence of renal impairment at screening, as indicated by an estimated creatinine clearance (CLcr) of <60 ml/min/1.73m² using the Cockcroft-Gault equation
9. Any positive result on screening for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV Ab), and human immunodeficiency virus (HIV) 1 and 2 antibodies
10. Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 4 weeks prior to Day 1, or less than 5 elimination half-lives + 6 days prior to Day 1, whichever is longer. Note: subjects consented and screened, but not administered IMP in this study or a previous Phase I study, are not excluded
11. Plasma donation within 1 month of screening or any blood donation/loss more than 500 ml during the 3 months prior to screening
12. History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the Investigator or history of hypersensitivity to drugs with a similar chemical structure or class to AZD9833. Hay fever is allowed unless it is active
13. Any known or suspected hypersensitivity or contraindication to the components of the study drug, AZD9833, judged to be clinically relevant by the investigator
14. Current smokers or those who have smoked or used nicotine products (including e-cigarettes) within the 3 months prior to screening
15. A confirmed breath carbon monoxide reading of greater than 10 ppm at screening or admission
16. Positive screen for drugs of abuse at screening or on each admission to the study centre
17. Regular alcohol consumption >14 units per week (1 unit = ½ pint beer, or a 25 mL shot of 40% spirit, 1.5 to 2 units = 125 mL glass of wine, depending on type)
18. A confirmed positive alcohol breath test at screening or admission
19. Subjects who are taking, or have taken:
19.1. Any prescribed or over-the-counter drug (other than up to 4 g of paracetamol per day) or herbal remedies in the 14 days before IMP administration or longer if the medication has a long half-life. COVID-19 vaccines are accepted concomitant medications. Exceptions may apply, as determined by the Investigator, if each of the following criteria are met: medication with a short half-life if the washout is such that no PD activity is expected by the time of dosing with IMP; and if the use of medication does not jeopardise the safety of the trial subject; and if the use of medication is not considered to interfere with the objectives of the study
19.2. Atropine or atropine containing drugs, in the 14 days before IMP administration
19.3. Systemic oestrogen-containing hormone replacement therapy in the 6 months prior to IMP administration
20. Use of drugs with enzyme-inducing properties such as St John’s Wort within 3 weeks or 5 half-lives (whichever is longer) or any drugs with a known risk, potential risk or conditional risk for QTca prolongation as defined and outlined in the Credible Meds website within 4 weeks prior to Day 1
21. Subjects who do not agree to avoid the use of warfarin or phenytoin (and other coumarin-derived vitamin K antagonist anticoagulants) for 2 weeks after administration of IMP
22. Excessive intake of caffeine-containing drinks or food (e.g., coffee, tea, chocolate) as judged by the Investigator. Excessive intake of caffeine defined as the regular consumption of more than 600 mg of caffeine per day (e.g., >5 cups of coffee) or would likely be unable to refrain from the use of caffeine-containing beverages during confinement at the clinical unit
23. Involvement of any AstraZeneca, Quotient or study site employee or their close relatives
24. Subjects who report having previously received AZD9833 in the last 12 months
25. Judgment by the Investigator that the volunteer should not participate in the study if they have any ongoing or recent (i.e., during the screening period) minor medical complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions, and requirements
26. Evidence of current SARS-CoV-2 infection
27. Radiation exposure, including that from the present study, excluding background radiation but including diagnostic x-rays and other medical exposures, exceeding 5 mSv in the last 12 months or 10 mSv in the last 5 years. No occupationally exposed worker, as defined in the Ionising Radiation Regulations 2017, shall participate in the study
28. Vulnerable subjects, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order
29. Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed by the Investigator or delegate at screening
30. Subjects with an anticipated need for major surgery and/or any surgery requiring general anaesthesia during the participation in the study (which may entail administration of atropine in an anaesthetic context)
31. Failure to satisfy the Investigator of fitness to participate for any other reason
Date of first enrolment10/05/2022
Date of final enrolment20/06/2022

Locations

Countries of recruitment

  • England
  • United Kingdom

Study participating centre

Quotient Sciences Limited
Mere Way
Ruddington Fields
Nottingham
NG11 6JS
United Kingdom

Sponsor information

AstraZeneca (Sweden)
Industry

Pepparedsleden 1
431 83
Mölndal
Södertälje
151 85
Sweden

Phone +1 (0)877 2409479
Email Information.Center@astrazeneca.com
Website http://www.astrazeneca-us.com/home/
ROR logo "ROR" https://ror.org/04wwrrg31

Funders

Funder type

Industry

AstraZeneca
Government organisation / For-profit companies (industry)
Alternative name(s)
AstraZeneca PLC, Pearl Therapeutics
Location
United Kingdom

Results and Publications

Intention to publish date20/06/2024
Individual participant data (IPD) Intention to shareYes
IPD sharing plan summaryAvailable on request
Publication and dissemination plan1. Internal report
2. Publication on website
3. Submission to regulatory authorities

The findings of this Phase I study will be shared with the Sponsor, AstraZeneca AB. Information about this research study will be posted on http://astrazenecaclinicaltrials.com and https://www.clinicaltrialsregister.eu/. Trial Result Summaries are a short and easy to understand summary of the results of a study. These will be added to https://www.trialsummaries.com
IPD sharing planThe SAS datasets are available after CSR submission and are retained for 1 year before disposal. Requests for data should be directed to the Data Protection Officer in the Data Privacy Office via email at Privacy@astrazeneca.com. Subjects consent to future use of data during the Screening and Enrolment process and are provided with the privacy notice as requested. All data will be anonymized and transferred via a secure, encrypted method.

Editorial Notes

22/06/2023: The intention to publish date has been changed from 20/06/2023 to 20/06/2024.
08/07/2022: The following changes have been made:
1. The recruitment end date has been changed from 10/06/2022 to 20/06/2022.
2. The overall trial end date has been changed from 10/06/2022 to 20/06/2022.
3. The intention to publish date has been changed from 10/06/2023 to 20/06/2023.
4. The final enrolment number has been added.
5. The NCT number has been added.
26/04/2022: ISRCTN received notification of combined HRA/MHRA approval for this trial on 26/04/2022.
31/03/2022: Trial's existence confirmed by the HRA.