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A Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Ascending Doses of AZD9567.

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ClinicalTrials.gov Identifier: NCT02760316
Recruitment Status : Completed
First Posted : May 3, 2016
Last Update Posted : October 17, 2017
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Brief Summary:
A study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of multiple ascending doses of AZD9567.

Condition or disease Intervention/treatment Phase
Rheumatoid Arthritis Drug: AZD9567 10 mg Drug: AZD9567 20 mg Drug: AZD9567 40 mg Drug: AZD9567 80 mg Drug: Prednisolone 20 mg Drug: AZD9567 125 mg Drug: AZD9567 155 mg Drug: Prednisolone 5 mg Drug: Prednisolone 40 mg Phase 1

Detailed Description:

This is a phase 1, randomised, single-blind, multiple ascending dose, double-dummy sequential group study in healthy subjects .

The study is planned to have 6 cohorts with the option to include up to two additional cohorts if deemed necessary. Nine subjects participated in the first cohort (7 subjects randomised to receive AZD9567 and 2 subjects randomised to receive prednisolone 20 mg)and eleven subjects will participate in subsequent 3 cohorts (7 subjects will be randomised to receive AZD9567 and 4 subjects randomised to receive prednisolone 20 mg). A cohort 5 was included in the study in version 4.0 of the CSP. In this cohort two doses of prednisolone was tested, 5 mg and 20 mg. Up to six dose levels of AZD9567 are planned to be tested in the study and an additional cohort will be used in case any previous dose needs to be repeated or a new lower dose explored (ref CSP 5.0).

Therefore a maximum of 95 individuals could be included in the study (as stated in version 5.0 of this protocol). Subjects will be dosed for 5 consecutive days and a follow-up visit will occur 10-14 days after the last dose.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 64 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Official Title: A Phase I, Randomised, Single-blind Study to Asses the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Ascending Doses of AZD9567 in Healthy Volunteers Using Prednisolone as Positive Control
Actual Study Start Date : May 2, 2016
Actual Primary Completion Date : September 11, 2017
Actual Study Completion Date : September 11, 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: AZD9567 oral suspension of 10 mg
Participants will receive oral supension of 10 mg dose strength
Drug: AZD9567 10 mg
Oral suspension Multiple doses 5 days of treatment Once daily

Experimental: AZD9567 oral suspension of 20 mg
Participants will receive oral suspension of 20 mg dose strength
Drug: AZD9567 20 mg
Oral suspension Multiple doses 5 days of treatment Once daily

Experimental: AZD9567 oral suspension of 40 mg
Participants will receive oral suspension of 40 mg dose strength
Drug: AZD9567 40 mg
Oral suspension Multiple doses 5 days of treatment Once daily

Experimental: AZD9567 oral suspension of 80 mg
Participants will receive oral suspension of 80mg dose strength
Drug: AZD9567 80 mg
Oral suspension Multiple doses 5 days of treatment Once daily

Active Comparator: Prednisolone oral capsules of 20 mg
Participants will receive oral capsules of 5 mg dose strength
Drug: Prednisolone 20 mg
Oral Multiple doses 5 days of treatment Once daily

Experimental: AZD9567 oral suspension of 125 mg
Participants will receive oral suspension of 125 mg dose strength
Drug: AZD9567 125 mg
Oral Multiple doses 5 days of treatment Once daily

Experimental: AZD9567 oral suspension of 155 mg
Participants will receive oral suspension of 155 mg dose strength
Drug: AZD9567 155 mg
Oral Multiple doses 5 days of treatment Once daily

Active Comparator: Prednisolone oral capsules of 5 mg
Participants will receive oral capsules of 5 mg dose strength
Drug: Prednisolone 5 mg
Oral Multiple doses 5 days of treatment Once daily

Active Comparator: Prednisolone oral capsules of 40 mg
Participants will receive oral capsules of 5 mg dose strength
Drug: Prednisolone 40 mg
Oral Multiple doses 5 days of treatment Once daily




Primary Outcome Measures :
  1. Safety and tolerability: Adverse events (AEs) [ Time Frame: Up to 5 days ]
    Adverse events will be summarized by each dose of AZD9567, pooled prednisolone 20 mg and pooled AZD9567 doses. Tabulations will include causality and severity (mild, moderate and severe), where applicable, and be presented by System Organ Class (SOC) and Preferred Term (PT) where applicable.

  2. Safety and tolerability: Vital signs (blood pressure [BP], pulse rate, weight and oral body temperature) [ Time Frame: Up to 5 days ]
    Descriptive statistics will be presented by treatment and time point for both observed values and changes from baseline, based on the safety analysis sets. The incidence of clinically notable vital sign abnormalities (vital signs outside the predefined criteria) will be summarized.

  3. Safety and tolerability: Clinical laboratory safety evaluations (hematology, serum biochemistry [including S-cortisol and basal S-DHEAS], coagulation and urinalysis) [ Time Frame: Up to 5 days ]

    Summary tabulations will be presented by treatment including observed values and changes from baseline.

    Shift tables will be presented to show the shifts from baseline to the minimum and maximum post-baseline measurements, respectively, by treatment, based on the safety analysis set.


  4. Safety and tolerability: Electrocardiograms (12-lead dECGs, safety ECG's, and telemetry) [ Time Frame: Up to 5 days ]
    Results of the safety ECGs, including normal/abnormal and specific findings will be listed for each subject.

  5. Safety and tolerability: Physical examinations [ Time Frame: Up to 5 days ]
    The results of the physical examination will be listed by body system for each subject.


Secondary Outcome Measures :
  1. Pharmacokinetic parameter: Observed maximum concentration (Cmax) [ Time Frame: Up to 5 days ]
    Plasma concentrations, and plasma PK parameters will be summarized by dose level of AZD9567 using descriptive statistics (n, geometric mean, geometric coefficient of variation [CV%], arithmetic mean, arithmetic Standard Deviation (SD), minimum, median and maximum) based on the respective PK analysis sets.

  2. Pharmacokinetic parameter: Area Under the curve from 0 to last quantifiable (AUC (0-last)) [ Time Frame: Up to 5 days ]
    Plasma concentrations, and plasma PK parameters will be summarized by dose level of AZD9567 using descriptive statistics (n, geometric mean, geometric coefficient of variation [CV%], arithmetic mean, arithmetic Standard Deviation (SD), minimum, median and maximum) based on the respective PK analysis sets.

  3. Pharmacokinetic parameter: Area Under the curve from 0 to 24h (AUC (0-24)) [ Time Frame: Up to 5 days ]
    Plasma concentrations, and plasma PK parameters will be summarized by dose level of AZD9567 using descriptive statistics (n, geometric mean, geometric coefficient of variation [CV%], arithmetic mean, arithmetic Standard Deviation (SD), minimum, median and maximum) based on the respective PK analysis sets.

  4. Pharmacokinetic parameter: Area Under the curve from 0 to infinity (AUC(0-inf)) [ Time Frame: Up to 5 days ]
    Plasma concentrations, and plasma PK parameters will be summarized by dose level of AZD9567 using descriptive statistics (n, geometric mean, geometric coefficient of variation [CV%], arithmetic mean, arithmetic Standard Deviation (SD), minimum, median and maximum) based on the respective PK analysis sets.

  5. Pharmacokinetic parameter: Area Under the curve from 0 to last quantifiable divided by the dose (AUC(0-last)/D) [ Time Frame: Up to 5 days ]
    Plasma concentrations, and plasma PK parameters will be summarized by dose level of AZD9567 using descriptive statistics (n, geometric mean, geometric coefficient of variation [CV%], arithmetic mean, arithmetic Standard Deviation (SD), minimum, median and maximum) based on the respective PK analysis sets.

  6. Pharmacokinetic parameter: Area Under the curve from 0 to 24h divided by the dose (AUC(0-24)/D) [ Time Frame: Up to 5 days ]
    Plasma concentrations, and plasma PK parameters will be summarized by dose level of AZD9567 using descriptive statistics (n, geometric mean, geometric coefficient of variation [CV%], arithmetic mean, arithmetic Standard Deviation (SD), minimum, median and maximum) based on the respective PK analysis sets.

  7. Pharmacokinetic parameter: Area Under the curve from 0 to infinity divided by the dose (AUC/D) [ Time Frame: Up to 5 days ]
    Plasma concentrations, and plasma PK parameters will be summarized by dose level of AZD9567 using descriptive statistics (n, geometric mean, geometric coefficient of variation [CV%], arithmetic mean, arithmetic Standard Deviation (SD), minimum, median and maximum) based on the respective PK analysis sets.

  8. Pharmacokinetic parameter: Observed maximum concentration divided by the dose (Cmax/D) [ Time Frame: Up to 5 days ]
    Plasma concentrations, and plasma PK parameters will be summarized by dose level of AZD9567 using descriptive statistics (n, geometric mean, geometric coefficient of variation [CV%], arithmetic mean, arithmetic Standard Deviation (SD), minimum, median and maximum) based on the respective PK analysis sets.

  9. Pharmacokinetic parameter: Time to reach maximum concentration (tmax) [ Time Frame: Up to 5 days ]
    Plasma concentrations, and plasma PK parameters will be summarized by dose level of AZD9567 using descriptive statistics (n, geometric mean, geometric coefficient of variation [CV%], arithmetic mean, arithmetic Standard Deviation (SD), minimum, median and maximum) based on the respective PK analysis sets.

  10. Pharmacokinetic parameter: Terminal rate constant (λz) [ Time Frame: Up to 5 days ]
    Plasma concentrations, and plasma PK parameters will be summarized by dose level of AZD9567 using descriptive statistics (n, geometric mean, geometric coefficient of variation [CV%], arithmetic mean, arithmetic Standard Deviation (SD), minimum, median and maximum) based on the respective PK analysis sets.

  11. Pharmacokinetic parameter: Terminal half-life (t1/2) [ Time Frame: Up to 5 days ]
    Plasma concentrations, and plasma PK parameters will be summarized by dose level of AZD9567 using descriptive statistics (n, geometric mean, geometric coefficient of variation [CV%], arithmetic mean, arithmetic Standard Deviation (SD), minimum, median and maximum) based on the respective PK analysis sets.

  12. Pharmacokinetic parameter: Apparent clearance divided by AUC (CL/F) [ Time Frame: Up to 5 days ]
    Plasma concentrations, and plasma PK parameters will be summarized by dose level of AZD9567 using descriptive statistics (n, geometric mean, geometric coefficient of variation [CV%], arithmetic mean, arithmetic Standard Deviation (SD), minimum, median and maximum) based on the respective PK analysis sets.

  13. Pharmacokinetic parameter: Aparent volume of distribution estimated by dividing de apparent clearance (Vz/F) [ Time Frame: Up to 5 days ]
    Plasma concentrations, and plasma PK parameters will be summarized by dose level of AZD9567 using descriptive statistics (n, geometric mean, geometric coefficient of variation [CV%], arithmetic mean, arithmetic Standard Deviation (SD), minimum, median and maximum) based on the respective PK analysis sets.

  14. Pharmacokinetic parameter: Average plasma concentration (Cav) [ Time Frame: Up to 5 days ]
    Plasma concentrations, and plasma PK parameters will be summarized by dose level of AZD9567 using descriptive statistics (n, geometric mean, geometric coefficient of variation [CV%], arithmetic mean, arithmetic Standard Deviation (SD), minimum, median and maximum) based on the respective PK analysis sets.

  15. Pharmacokinetic parameter: fluctuation index [ Time Frame: Up to 5 days ]
    Plasma concentrations, and plasma PK parameters will be summarized by dose level of AZD9567 using descriptive statistics (n, geometric mean, geometric coefficient of variation [CV%], arithmetic mean, arithmetic Standard Deviation (SD), minimum, median and maximum) based on the respective PK analysis sets.

  16. Pharmacodynamic parameter: Plasma glucose measured by Oral Glucose Tolerance Test (OGTT) [ Time Frame: Up to 5 days ]
    Concentration data for the OGTT (plasma glucose) will be listed and summarized by treatment, visit and time point. Each of the plasma glucose AUC (total net and incremental) parameters (0 to 2 hours and 0 to 4 hours) will be listed and summarized (including changes from baseline for the AUC values, where the baseline is the AUC values measured on Day -1) by visit and treatment for the final clinical study report. In addition, the glucose ratio values by time point and their corresponding AUCs will also be summarized.

  17. Pharmacodynamic parameter: Serum insulin measured by Oral Glucose Tolerance Test (OGTT) [ Time Frame: Up to 5 days ]
    Concentration data for the OGTT (serum insulin) will be listed and summarized by treatment, visit and time point. Each of the serum insulin AUC (total net and incremental) parameters (0 to 2 hours and 0 to 4 hours) will be listed and summarized (including changes from baseline for the AUC values, where the baseline is the AUC values measured on Day -1) by visit and treatment for the final clinical study report. In addition, the serum insulin ratio values by time point and their corresponding AUCs will also be summarized.

  18. Pharmacodynamic parameter: Serum C-peptide measured by Oral Glucose Tolerance Test (OGTT) [ Time Frame: Up to 5 days ]
    Concentration data for the OGTT (serum C-peptide) will be listed and summarized by treatment, visit and time point. Each of the serum C-peptide AUC (total net and incremental) parameters (0 to 2 hours and 0 to 4 hours) will be listed and summarized (including changes from baseline for the AUC values, where the baseline is the AUC values measured on Day -1) by visit and treatment for the final clinical study report.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Male or non-childbearing potential female subject, aged 18 to 55 years (both inclusive) with suitable veins for cannulation or repeated venipuncture. Explanatory note: Female subjects must be of non-childbearing potential, confirmed at screening by fulfilling study predefined criteria
  2. Body mass index (BMI) between 18 and 29.9 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive.
  3. Serum cortisol levels within normal limits at Screening (collected as part of the clinical chemistry panel) at the discretion of the Investigator.
  4. Able to understand, read and speak the language of the ICD approved by the EC/IRB
  5. Provision of signed and dated, written informed consent prior to any study specific procedures.

Exclusion Criteria:

  1. History of any clinically important disorder which, in opinion of the Investigator, may either put the subject at risk or influence the results or the subject's ability to participate in the study.
  2. History or presence of gastrointestinal (GI), hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
  3. History or presence of dyspepsia or oral intolerance to steroids.
  4. History of or active or latent tuberculosis (TB), or at risk for having acquired TB (social workers or prison staff in countries with endemic rates of TB, having lived with patients with known TB).
  5. History suggesting abnormal immune function, as judged by the Investigator.
  6. History of severe affective disorder including depressive or maniac-depressive illness.
  7. History of previous steroid psychosis
  8. Any clinically important illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of IMP.
  9. Any latent or chronic infections or at risk of infection, or history of skin abscesses within 90 days prior to the first administration of IMP at the discretion of the Investigator.
  10. Any clinically important laboratory abnormalities (serum biochemistry, hematology, coagulation or urinalysis results) at Screening or prior to randomisation, as judged by the Investigator. Explanatory note: In particular a subject with an abnormal value (2x upper level of normal) for alkaline phosphatase (ALP), alanine aminotransferase (ALT) or aspartate aminotransferase (AST), serum creatinine (1.2x upper level of normal), and/or above the upper level of normal in serum bilirubin, or with an abnormal value for haemoglobin (Hb), white blood cell (WBC) and/or absolute neutrophil count below the normal limit will be excluded.
  11. Any positive result at Screening for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody and/or human immunodeficiency virus (HIV).
  12. Abnormal vital signs after 10 minutes supine rest.

    Explanatory note: Deviations from normal vital signs within the following ranges will not be allowed as any of the following:

    • Systolic BP (SBP) < 90mmHg or > 140 mmHg
    • Diastolic BP (DBP) < 50mmHg or > 90 mmHg
    • Heart rate < 50 or > 90 beats per minute (bpm)
  13. Any clinically important abnormalities in rhythm, conduction or morphology of the resting ECG and 12-lead ECG that may interfere with the interpretation of QTc changes Explanatory note: this also includes abnormal ST-T-wave morphology, particularly in the protocol defined primary lead or left ventricular hypertrophy.
  14. Prolonged QTcF > 450 ms or family history of long QT syndrome.
  15. PR(PQ) interval shortening < 120 ms (PR > 110 ms but < 120 ms is acceptable if there is no evidence of ventricular pre-excitation).
  16. PR (PQ) interval prolongation (> 240 ms) intermittent second (Wenckebach block while asleep is not exclusive) or third degree AV block, or AV dissociation.
  17. Persistent or intermittent complete bundle branch block (BBB), incomplete bundle branch block (IBBB), or intraventricular conduction delay (IVCD) with QRS > 110 ms.

    Explanatory note: Subjects with QRS > 110 ms but < 115 ms are acceptable if there is no evidence of, for example, ventricular hypertrophy or pre-excitation.

  18. Known or suspected history of drug abuse in the last 6 months, as judged by the Investigator.
  19. Smokers that smoke ≥ 5 cigarettes/pipes per day, or use tobacco in any other form. Smoking will not be allowed during the study treatment period (Day -2 to Day 6) (1 e-cigarette = 1 cigarette).
  20. History of alcohol abuse or excessive intake of alcohol, as judged by the Investigator.
  21. Positive screen for drugs of abuse or alcohol at Screening or on admission to the clinical unit.
  22. History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity to drugs with a similar chemical structure or class to study drugs.
  23. Excessive intake of caffeine containing drinks or food (e.g., coffee, tea, chocolate), as judged by the Investigator.
  24. Receipt of live or live attenuated vaccine within 4 weeks prior to the first administration of IMP.
  25. Use of drugs with enzyme inducing properties such as St John's Wort within 3 weeks prior to the first administration of IMP.
  26. Use of any prescribed or non-prescribed medication during the two weeks prior to the first administration of IMP or longer if the medication has a long half-life. Explanatory note: the prohibited medication includes antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, megadose vitamins (intake of 20 to 600 times the recommended daily dose) and minerals
  27. Plasma donation within one month of screening or any blood donation/blood loss > 500 mL during the 3 months prior to screening.
  28. Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 3 months or 5 half-lifes, whatever is the longest of the first administration of IMP.

    Explanatory note: the period of exclusion begins three months after the final dose or one month after the last visit whichever is the longest. Subjects consented and screened, but not randomised in this study or a previous phase I study, are not excluded.

  29. Vulnerable subject, e.g., kept in detention, protected adult under guardianship, trusteeship, or committed to an institution by governmental or juridical order.
  30. Involvement of any Astra Zeneca or PAREXEL or study site employee or their close relatives.
  31. Judgment by the Investigator that the subject should not participate in the study Explanatory note: for example, if the subject has any ongoing or recent (i.e., during the screening period) minor medical complaints that may interfere with the interpretation of study data, or is considered unlikely to comply with study procedures, restrictions and requirements, the subject should not be randomised.
  32. Subject who is a vegan or has medical dietary restrictions.
  33. Subject who cannot communicate reliably with the Investigator/site staff.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02760316


Locations
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Germany
Research Site
Berlin, Germany, 14050
United Kingdom
Research Site
Harrow, United Kingdom, HA1 3UJ
Sponsors and Collaborators
AstraZeneca
Investigators
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Principal Investigator: Rainard Fuhr, Dr. med. PAREXEL Early Phase Clinical Unit, Berlin
Principal Investigator: Pablo ForteSoto, Dr. PAREXEL Early Phase Clinical Unit, London
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT02760316    
Other Study ID Numbers: D6470C00002
First Posted: May 3, 2016    Key Record Dates
Last Update Posted: October 17, 2017
Last Verified: October 2017

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AstraZeneca:
Healthy Volunteers
Obese
Insulin Resistant Subjects
Rheumatoid Arthritis
Additional relevant MeSH terms:
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Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Prednisolone
Methylprednisolone Acetate
Methylprednisolone
Methylprednisolone Hemisuccinate
Prednisolone acetate
Prednisolone hemisuccinate
Prednisolone phosphate
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Gastrointestinal Agents
Neuroprotective Agents
Protective Agents