Dose Escalating Study of CCI15106 Inhalation Capsules in Healthy Subjects and Moderate Chronic Obstructive Pulmonary Disease (COPD) Patients

Pulmonary Disease, Chronic Obstructive Clinical Trial

Official title:

A Double-blind (Sponsor Unblind), Randomized, Placebo-controlled, Single and Repeat Escalating Dose Study to Investigate the Safety, Tolerability, and Pharmacokinetics of CCI15106 Capsules for Inhalation in Healthy Subjects and Patients With Moderate Chronic Obstructive Pulmonary Disease (COPD)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03243760
• Other study ID #: 202031
• Secondary ID: 2015-003960-35
• Status: Terminated
• Phase: Phase 1
• Start date: February 10, 2016
• Est. completion date: August 20, 2016

Study information

• Verified date: June 2020
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will be the first administration of CCI15106 capsules for inhalation to humans. The primary objective of the study is to investigate the safety and tolerability of single and repeat escalating doses of CCI15106 in healthy subjects and patients with moderate chronic obstructive pulmonary disease (COPD). The intention of this study is to provide sufficient confidence in the safety of the molecule delivered by inhalation to inform progression to further repeat dose and proof of concept studies.

This will be a three-part study. Part 1 will investigate single ascending doses and Part 2 repeat ascending doses in healthy subjects. In Part 3, a single dose will be administered to patients with moderate COPD.

There will be screening period of up to 30 days. The treatment period will be 3 days for Parts 1 and 3 and 16 days for Part 2. Follow-up will be performed within 30 days after the last dose.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 60
• Est. completion date: August 20, 2016
• Est. primary completion date: July 20, 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

For Healthy Subjects

• Between 18 and 65 years of age inclusive, at the time of signing the informed consent.

• Healthy as determined by the investigator.

• Body weight >= 50 kilogram (kg) for males and 45 kg for females and body mass index (BMI) within the range 19 - 31 kg/meter square (m^2) (inclusive)

• Male or Female: Male subjects with female partners of child bearing potential must comply with the contraception requirements as specified in protocol. A female subject is eligible to participate if she is of non-reproductive potential.

• Capable of giving signed informed consent.

For COPD Patients

• Between 40 and 75 years of age inclusive, at the time of signing the informed consent.

• Diagnosed with moderate COPD (GOLD class II) by a qualified physician as defined by the GOLD guidelines (http://www.goldcopd.org/).

• The subject has spirometry at screening, showing: a) post-bronchodilator forced expiratory volume in 1 second (FEV1)>=50% and <80% predicted normal; b) post-bronchodilator FEV1/ forced vital capacity (FVC)<0.7.

• Subject is a smoker or an ex-smoker.

• Body weight >= 45 kg and BMI within the range 17 - 32 kg/m^2 (inclusive).

• Male or Female: Male subjects with female partners of child bearing potential must comply with the contraception requirements as specified in protocol. A female subject is eligible to participate if she is of non-reproductive potential.

• Capable of giving signed informed consent.

Exclusion Criteria:

For Healthy Subjects

• Male partners of women who are pregnant or lactating

• Alanine transaminase (ALT) and/or bilirubin >1.5xupper limit of normal (ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).

• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).

• QT interval corrected for heart rate (QTc )> 450 millisecond (msec).

• Heart rate: <40 and >100 beats per minute (bpm) for males and <50 and >100 bpm for females, PR Interval: <120 and >220 msec, QRS duration: <70 and >120 msec, QTcF interval: >450 msec

• Any clinically significant central nervous system (e.g., seizures), cardiac, pulmonary, metabolic, renal, hepatic or gastrointestinal conditions or history of such conditions.

• Unable to refrain from prescription or non-prescription drugs

• History of regular alcohol consumption within 3 months of the study

• Breath test indicative of smoking at day -1

• History of sensitivity to any of the study medications

• For cohorts that will undergo BAL, contraindications to bronchoalveolar lavage

• Documented lactose allergy/intolerance for cohorts with lactose placebo if they are used in the study.

• Hemoglobin (Hgb) below the lower level of the normal range with one repeat testing allowed, or known hemoglobinopathies.

• Known severe hypersensitivity reactions such as Stevens-Johnson Syndrome, toxic epidermal necrolysis, and erythema multiforme.

• Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment.

• A positive pre-study drug/alcohol screen.

• A positive test for human immunodeficiency virus (HIV) antibody.

• Where participation in the study would result in donation of blood or blood products in excess of 500 mL within 3 month period.

• The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 3 months, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).

• Exposure to more than four new chemical entities within 12 months prior to the first dosing day.

For COPD Patients

• Male partners of women who are pregnant or lactating.

• ALT and/or bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).

• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).

• QTc > 450 msec or QTc > 480 msec in subjects with Bundle Branch Block.

• Heart rate: <40 and >100 bpm for males and <50 and >100 bpm for females, PR Interval:

<120 and >220 msec, QRS duration: <70 and >120 msec, QTcF interval: >450 msec

• Subject has poorly controlled COPD as defined in protocol

• History of an upper or lower respiratory tract infection requiring antibiotics in the 4 weeks prior to screening.

• Subject has a diagnosis of active tuberculosis, lung cancer, clinically overt bronchiectasis, pulmonary fibrosis, asthma or any other respiratory condition that might, in the opinion of the Investigator, compromise the safety of the subject or affect the interpretation of the results.

• Subjects who have past or current medical conditions or diseases that are not well controlled.

• Subjects are not allowed to take oral corticosteroids from 4 weeks prior to screening and for the duration of the study.

• Patients taking medications for any chronic conditions have to be on stable doses for 4 weeks prior to screening and until after completion of the treatment period. This includes COPD maintenance therapies (e.g. inhaled corticosteroids, long-acting beta-agonists, long-acting muscarinic agonists).

• Didanosine and azathioprine are not allowed.

• Use of short-acting inhaled bronchodilators is allowed, but patients must be able to discontinue their medications twice during the study.

• Use of long-acting bronchodilators is allowed, but patients must be able to modify the schedule of their medications twice during the study.

• Unable to refrain from smoking for 2 hour (h) prior to dosing and until all assessments are complete for 4 h after dosing and also for 1 h prior to any vital signs and ECG assessments.

• History of regular alcohol consumption within 3 months of the study

• History of sensitivity to any of the study medications.

• Documented lactose allergy/intolerance

• Impaired renal function (creatinine clearance < 50 mL/ minute).

• Known severe hypersensitivity reactions such as Stevens-Johnson Syndrome, toxic epidermal necrolysis, and erythema multiforme.

• Hgb below the lower level of the normal range with one repeat testing allowed or known hemoglobinopathies.

• Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment.

• A positive pre-study drug/alcohol screen.

• A positive test for HIV antibody.

• Where participation in the study would result in donation of blood or blood products in excess of 500 mL within 3 months.

• The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 3 months, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).

• Exposure to more than four new chemical entities within 12 months prior to the first dosing day.

Related Conditions & MeSH terms

• Lung Diseases
• Lung Diseases, Obstructive
• Pulmonary Disease, Chronic Obstructive

Intervention

Drug:
• CCI15106 7.5 mg capsule
Orange capsule containing a white to off-white powder, 21.4 mg of CCI15106: Trehalose:Trileucine 35/55/10 weight by weight (w/w)
• Placebo
Orange capsule containing a white to off-white powder, 21.4 mg of Trehalose:Trileucine 85/15 w/w
• Placebo-2
Orange capsule containing a white to off-white powder, 21.4 mg of lactose. Placebo-2 to be used if unexpected safety signals are observed with the use of matching placebo.

Locations

Country	Name	City	State
United Kingdom	GSK Investigational Site	London

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part 1: Number of participants with adverse events (AE)	An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AE will be collected from the start of study treatment until the final follow-up visit.	Up to 33 days
Primary	Part 2: Number of participants with AE	An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AE will be collected from the start of study treatment until the final follow-up visit.	Up to 46 days
Primary	Part 3: Number of participants with AE	An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AE will be collected from the start of study treatment until the final follow-up visit.	Up to 33 days
Primary	Part 1: Number of subjects with abnormal clinical hematology test findings	Hematology tests will be performed as a measure of safety	Up to 33 days
Primary	Part 2: Number of subjects with abnormal clinical hematology test findings	Hematology tests will be performed as a measure of safety	Up to 46 days
Primary	Part 3: Number of subjects with abnormal clinical hematology test findings	Hematology tests will be performed as a measure of safety	Up to 33 days
Primary	Part 1: Number of subjects with abnormal clinical chemistry test findings	Clinical chemistry laboratory tests will be performed as a measure of safety	Up to 33 days
Primary	Part 2: Number of subjects with abnormal clinical chemistry test findings	Clinical chemistry laboratory tests will be performed as a measure of safety	Up to 46 days
Primary	Part 3: Number of subjects with abnormal clinical chemistry test findings	Clinical chemistry laboratory tests will be performed as a measure of safety	Up to 33 days
Primary	Part 1: Number of subjects with abnormal urine analysis test findings	Urine analysis tests will be performed as a measure of safety	Up to 33 days
Primary	Part 2: Number of subjects with abnormal urine analysis test findings	Urine analysis tests will be performed as a measure of safety	Up to 46 days
Primary	Part 3: Number of subjects with abnormal urine analysis test findings	Urine analysis tests will be performed as a measure of safety	Up to 33 days
Primary	Part 1: Number of subjects with abnormal findings of body temperature	Body temperature will be measured in a semi-supine position after 5 minutes of rest	Up to 33 days
Primary	Part 2: Number of subjects with abnormal findings of body temperature	Body temperature will be measured in a semi-supine position after 5 minutes of rest	Up to 46 days
Primary	Part 3: Number of subjects with abnormal findings of body temperature	Body temperature will be measured in a semi-supine position after 5 minutes of rest	Up to 33 days
Primary	Part 1: Number of subjects with abnormal blood pressure values	Systolic and diastolic blood pressure values will be measured in a semi-supine position after 5 minutes of rest	Up to 33 days
Primary	Part 2: Number of subjects with abnormal blood pressure values	Systolic and diastolic blood pressure values will be measured in a semi-supine position after 5 minutes of rest	Up to 46 days
Primary	Part 3: Number of subjects with abnormal blood pressure values	Systolic and diastolic blood pressure values will be measured in a semi-supine position after 5 minutes of rest	Up to 33 days
Primary	Part 1: Number of subjects with abnormal pulse rate values	Pulse rate will be measured in a semi-supine position after 5 minutes of rest	Up to 33 days
Primary	Part 2: Number of subjects with abnormal pulse rate values	Pulse rate will be measured in a semi-supine position after 5 minutes of rest	Up to 46 days
Primary	Part 3: Number of subjects with abnormal pulse rate values	Pulse rate will be measured in a semi-supine position after 5 minutes of rest	Up to 33 days
Primary	Part 1: Number of subjects with abnormal respiratory rate values	Respiratory rate will be measured in a semi-supine position after 5 minutes of rest	Up to 33 days
Primary	Part 2: Number of subjects with abnormal respiratory rate values	Respiratory rate will be measured in a semi-supine position after 5 minutes of rest	Up to 46 days
Primary	Part 3: Number of subjects with abnormal respiratory rate values	Respiratory rate will be measured in a semi-supine position after 5 minutes of rest	Up to 33 days
Primary	Part 1: Number of subjects with abnormal electrocardiogram (ECG) findings	12-lead ECG will be obtained during the study in semi-supine position after 5 minutes rest.	Up to 33 days
Primary	Part 2: Number of subjects with abnormal ECG findings	12-lead ECG will be obtained during the study in semi-supine position after 5 minutes rest.	Up to 46 days
Primary	Part 3: Number of subjects with abnormal ECG findings	12-lead ECG will be obtained during the study in semi-supine position after 5 minutes rest.	Up to 33 days
Primary	Part 1: Number of subjects with abnormal Telemetry findings	Cardiac telemetry will be performed continuously till 4hour post morning dose.	Up to 33 days
Primary	Part 2: Number of subjects with abnormal telemetry findings	Cardiac telemetry will be performed continuously till 4hour post morning dose.	Up to 46 days
Primary	Part 3: Number of subjects with abnormal telemetry findings	Cardiac telemetry will be performed continuously till 4hour post morning dose.	Up to 33 days
Primary	Part 1: Number of subjects with abnormal spirometry findings	Spirometry is a test to diagnose lung conditions. Spirometry will be performed at selected time points during the study.	Up to 4 hour post-dose
Primary	Part 2: Number of subjects with abnormal spirometry findings	Spirometry is a test to diagnose lung conditions. Spirometry will be performed at selected time points during the study.	Up to 14 days
Primary	Part 3: Number of subjects with abnormal spirometry findings	Spirometry is a test to diagnose lung conditions. Spirometry will be performed at selected time points during the study.	Up to 4 hour post dose
Primary	Part 1: Area under the curve (AUC) from time zero to infinity (AUC[0-inf] following single dose administration of CCI15106	Blood samples will be collected at specific time points to evaluate AUC(0-inf) of drug	Pre dose, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 24 hour post-dose and on follow-up
Primary	Part 3: AUC[0-inf] following single dose administration of CCI15106	Blood samples will be collected at specific time points to evaluate AUC(0-inf) of drug	Pre dose, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 24 hour post-dose and on follow-up
Primary	Part 1: AUC from time zero to the time of last quantifiable concentration (AUC[0-last]) following single dose administration of CCI15106	Blood samples will be collected at specific time points to evaluate AUC(0-last) of drug	Pre dose, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 24 hour post-dose and on follow-up
Primary	Part 3: AUC[0-last] following single dose administration of CCI15106	Blood samples will be collected at specific time points to evaluate AUC(0-last) of drug	Pre dose, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 24 hour post-dose and on follow-up
Primary	Part 1: Maximum plasma concentration (Cmax) following single dose administration of CCI15106	Blood samples will be collected at specific time points to evaluate Cmax of drug	Pre dose, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 24 hour post-dose and on follow-up
Primary	Part 2: Cmax following repeat dose administration of CCI15106	Blood samples will be collected at specific time points to evaluate Cmax of drug	Pre-dose, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12 hours post dose on Day 1 and 14; Pre-dose on Day 2-12 and on follow-up
Primary	Part 3: Cmax following single dose administration of CCI15106	Blood samples will be collected at specific time points to evaluate Cmax of drug	Pre dose, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 24 hour post-dose and on follow-up
Primary	Part 1: time of maximum concentration (Tmax) following single dose administration of CCI15106	Blood samples will be collected at specific time points to evaluate Tmax of drug	Pre dose, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 24 hour post-dose and on follow-up
Primary	Part 2: Tmax following repeat dose administration of CCI15106	Blood samples will be collected at specific time points to evaluate Tmax of drug	Pre-dose, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12 hours post dose on Day 1 and 14; Pre-dose on Day 2-12 and on follow-up
Primary	Part 3: Tmax following single dose administration of CCI15106	Blood samples will be collected at specific time points to evaluate Tmax of drug	Pre dose, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 24 hour post-dose and on follow-up
Primary	Part 1: Elimination half life (T1/2) following single dose administration of CCI15106	Blood samples will be collected at specific time points to evaluate T1/2 of drug	Pre dose, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 24 hour post-dose and on follow-up
Primary	Part 3: T1/2 following single dose administration of CCI15106	Blood samples will be collected at specific time points to evaluate T1/2 of drug	Pre dose, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 24 hour post-dose and on follow-up
Primary	Part 1: Clearance (CL/F) following single dose administration of CCI15106	Clearance will be calculated from concentration-time curve based on each individual subject's profile.	Pre dose, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 24 hour post-dose and on follow-up
Primary	part 3: CL/F following single dose administration of CCI15106	Clearance will be calculated from concentration-time curve based on each individual subject's profile.	Pre dose, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 24 hour post-dose and on follow-up
Primary	Part 2: AUC from time zero to end of dosing interval (AUC[0-tau]) following repeat dose administration of CCI15106	Blood samples will be collected at specific time points to evaluate AUC(0-tau) of drug	Pre-dose, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12 hours post dose on Day 1 and 14; Pre-dose on Day 2-12 and on follow-up
Secondary	Part 1 Concentrations of CCI15106 in ELF and BAL cell pellet	BAL samples will be collected for assessing concentrations of CCI15106 in lung epithelial lining fluid (ELF) and bronchoalveolar lavage (BAL) cell pellet in cohort D.	Up to 2 hour post-dose
Secondary	Part 2: Concentrations of CCI15106 in ELF and BAL cell pellet	BAL samples will be collected for assessing concentrations of CCI15106 in lung ELF and BAL cell pellet in cohort I.	Up to 13 days
Secondary	Part 1: Number of medical device incidents	Device incident is malfunction or deterioration in performance of a device, as well as any inadequacy in the labeling or the instructions for use which, directly or indirectly, might lead to or might have led to the death of a patient/user/other person or to a serious deterioration in their state of health. Device incident assessment will be done at the time of each dosing to investigate the performance of the Modified Air Inlet Rotahaler™ device.	Day 1
Secondary	Part 2: Number of medical device incidents	Device incident is malfunction or deterioration in performance of a device, as well as any inadequacy in the labeling or the instructions for use which, directly or indirectly, might lead to or might have led to the death of a patient/user/other person or to a serious deterioration in their state of health. Device incident assessment will be done at the time of each dosing to investigate the performance of the Modified Air Inlet Rotahaler™ device.	Up to 14 days
Secondary	Part 3: Number of medical device incidents	Device incident is malfunction or deterioration in performance of a device, as well as any inadequacy in the labeling or the instructions for use which, directly or indirectly, might lead to or might have led to the death of a patient/user/other person or to a serious deterioration in their state of health. Device incident assessment will be done at the time of each dosing to investigate the performance of the Modified Air Inlet Rotahaler™ device.	Day 1