Clinical trial NCT03243760: Dose Escalating Study of CCI15106 Inhalation Capsules in Healthy Subjects and Moderate Chronic Obstructive Pulmonary Disease (COPD) Patients
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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: CCI15106
pharmacokinetics
BAL
COPD
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2017-08-09
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Part 1: Number of participants with adverse events (AE)
timeFrame: Up to 33 days
measure: Part 2: Number of participants with AE
timeFrame: Up to 46 days
measure: Part 3: Number of participants with AE
timeFrame: Up to 33 days
measure: Part 1: Number of subjects with abnormal clinical hematology test findings
timeFrame: Up to 33 days
measure: Part 2: Number of subjects with abnormal clinical hematology test findings
timeFrame: Up to 46 days
measure: Part 3: Number of subjects with abnormal clinical hematology test findings
timeFrame: Up to 33 days
measure: Part 1: Number of subjects with abnormal clinical chemistry test findings
timeFrame: Up to 33 days
measure: Part 2: Number of subjects with abnormal clinical chemistry test findings
timeFrame: Up to 46 days
measure: Part 3: Number of subjects with abnormal clinical chemistry test findings
timeFrame: Up to 33 days
measure: Part 1: Number of subjects with abnormal urine analysis test findings
timeFrame: Up to 33 days
measure: Part 2: Number of subjects with abnormal urine analysis test findings
timeFrame: Up to 46 days
measure: Part 3: Number of subjects with abnormal urine analysis test findings
timeFrame: Up to 33 days
measure: Part 1: Number of subjects with abnormal findings of body temperature
timeFrame: Up to 33 days
measure: Part 2: Number of subjects with abnormal findings of body temperature
timeFrame: Up to 46 days
measure: Part 3: Number of subjects with abnormal findings of body temperature
timeFrame: Up to 33 days
measure: Part 1: Number of subjects with abnormal blood pressure values
timeFrame: Up to 33 days
measure: Part 2: Number of subjects with abnormal blood pressure values
timeFrame: Up to 46 days
measure: Part 3: Number of subjects with abnormal blood pressure values
timeFrame: Up to 33 days
measure: Part 1: Number of subjects with abnormal pulse rate values
timeFrame: Up to 33 days
measure: Part 2: Number of subjects with abnormal pulse rate values
timeFrame: Up to 46 days
measure: Part 3: Number of subjects with abnormal pulse rate values
timeFrame: Up to 33 days
measure: Part 1: Number of subjects with abnormal respiratory rate values
timeFrame: Up to 33 days
measure: Part 2: Number of subjects with abnormal respiratory rate values
timeFrame: Up to 46 days
measure: Part 3: Number of subjects with abnormal respiratory rate values
timeFrame: Up to 33 days
measure: Part 1: Number of subjects with abnormal electrocardiogram (ECG) findings
timeFrame: Up to 33 days
measure: Part 2: Number of subjects with abnormal ECG findings
timeFrame: Up to 46 days
measure: Part 3: Number of subjects with abnormal ECG findings
timeFrame: Up to 33 days
measure: Part 1: Number of subjects with abnormal Telemetry findings
timeFrame: Up to 33 days
measure: Part 2: Number of subjects with abnormal telemetry findings
timeFrame: Up to 46 days
measure: Part 3: Number of subjects with abnormal telemetry findings
timeFrame: Up to 33 days
measure: Part 1: Number of subjects with abnormal spirometry findings
timeFrame: Up to 4 hour post-dose
measure: Part 2: Number of subjects with abnormal spirometry findings
timeFrame: Up to 14 days
measure: Part 3: Number of subjects with abnormal spirometry findings
timeFrame: Up to 4 hour post dose
measure: Part 1: Area under the curve (AUC) from time zero to infinity (AUC[0-inf] following single dose administration of CCI15106
timeFrame: Pre dose, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 24 hour post-dose and on follow-up
measure: Part 3: AUC[0-inf] following single dose administration of CCI15106
timeFrame: Pre dose, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 24 hour post-dose and on follow-up
measure: Part 1: AUC from time zero to the time of last quantifiable concentration (AUC[0-last]) following single dose administration of CCI15106
timeFrame: Pre dose, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 24 hour post-dose and on follow-up
measure: Part 3: AUC[0-last] following single dose administration of CCI15106
timeFrame: Pre dose, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 24 hour post-dose and on follow-up
measure: Part 1: Maximum plasma concentration (Cmax) following single dose administration of CCI15106
timeFrame: Pre dose, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 24 hour post-dose and on follow-up
measure: Part 2: Cmax following repeat dose administration of CCI15106
timeFrame: 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
measure: Part 3: Cmax following single dose administration of CCI15106
timeFrame: Pre dose, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 24 hour post-dose and on follow-up
measure: Part 1: time of maximum concentration (Tmax) following single dose administration of CCI15106
timeFrame: Pre dose, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 24 hour post-dose and on follow-up
measure: Part 2: Tmax following repeat dose administration of CCI15106
timeFrame: 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
measure: Part 3: Tmax following single dose administration of CCI15106
timeFrame: Pre dose, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 24 hour post-dose and on follow-up
measure: Part 1: Elimination half life (T1/2) following single dose administration of CCI15106
timeFrame: Pre dose, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 24 hour post-dose and on follow-up
measure: Part 3: T1/2 following single dose administration of CCI15106
timeFrame: Pre dose, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 24 hour post-dose and on follow-up
measure: Part 1: Clearance (CL/F) following single dose administration of CCI15106
timeFrame: Pre dose, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 24 hour post-dose and on follow-up
measure: part 3: CL/F following single dose administration of CCI15106
timeFrame: Pre dose, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 24 hour post-dose and on follow-up
measure: Part 2: AUC from time zero to end of dosing interval (AUC[0-tau]) following repeat dose administration of CCI15106
timeFrame: 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 outcomes:
measure: Part 1 Concentrations of CCI15106 in ELF and BAL cell pellet
timeFrame: Up to 2 hour post-dose
measure: Part 2: Concentrations of CCI15106 in ELF and BAL cell pellet
timeFrame: Up to 13 days
measure: Part 1: Number of medical device incidents
timeFrame: Day 1
measure: Part 2: Number of medical device incidents
timeFrame: Up to 14 days
measure: Part 3: Number of medical device incidents
timeFrame: Day 1
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Dumont EF, Oliver AJ, Ioannou C, Billiard J, Dennison J, van den Berg F, Yang S, Chandrasekaran V, Young GC, Lahiry A, Starbuck DC, Harrell AW, Georgiou A, Hopchet N, Gillies A, Baker SJ. A Novel Inhaled Dry-Powder Formulation of Ribavirin Allows for Efficient Lung Delivery in Healthy Participants and Those with Chronic Obstructive Pulmonary Disease in a Phase 1 Study. Antimicrob Agents Chemother. 2020 Apr 21;64(5):e02267-19. doi: 10.1128/AAC.02267-19. Print 2020 Apr 21.