Clinical Trials Register

Summary
EudraCT Number:	2019-002915-24
Sponsor's Protocol Code Number:	0178
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2019-08-20
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2019-002915-24

A.3

Full title of the trial

A Randomized, Double-blind, Placebo-controlled, 3-period Crossover Study to Evaluate the Effects of Repeated Doses of Inhaled TD-8236 and Impact on Airway Responses Following Allergen Challenge in Patients with Asthma

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A phase 2 study to assess the effects of repeated doses of inhaled TD-8236 following allergen challenge in patients with asthma

A.3.2

Name or abbreviated title of the trial where available

Effect of inhaled TD-8236 on allergen-induced asthmatic response

A.4.1

Sponsor's protocol code number

0178

A.5.4

Other Identifiers

Name:

MEU number

Number:

MEU 19/387

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Theravance Biopharma Ireland Limited
B.1.3.4	Country	Ireland
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Theravance Biopharma Ireland Limited
B.4.2	Country	Ireland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Theravance Biopharma Ireland Limited
B.5.2	Functional name of contact point	Nathan Pfeifer
B.5.3	Address:
B.5.3.1	Street Address	901 Gateway Blvd
B.5.3.2	Town/ city	South San Francisco, CA
B.5.3.3	Post code	94080
B.5.3.4	Country	United States
B.5.4	Telephone number	001(650) 808-3711
B.5.6	E-mail	npfeifer@theravance.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	TD-8236 150μg
D.3.2	Product code	TD-8236
D.3.4	Pharmaceutical form	Inhalation powder, hard capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Inhalation use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	TD-8236
D.3.9.2	Current sponsor code	TD-8236
D.3.9.3	Other descriptive name	TD-8236
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	150
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	TD-8236 500μg
D.3.2	Product code	TD-8236
D.3.4	Pharmaceutical form	Inhalation powder, hard capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Inhalation use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	TD-8236
D.3.9.2	Current sponsor code	TD-8236
D.3.9.3	Other descriptive name	TD-8236
D.3.9.4	EV Substance Code	AS2
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	500
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Inhalation powder, hard capsule
D.8.4	Route of administration of the placebo	Inhalation use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Treatment of airway inflammation, initially in asthma

E.1.1.1

Medical condition in easily understood language

Asthma

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10003553
E.1.2	Term	Asthma
E.1.2	System Organ Class	10038738 - Respiratory, thoracic and mediastinal disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Characterize the late asthmatic response (LAR) in terms of area under the FEV1 (Forced expiratory volume in one second) curve after inhaled allergen challenge (breathing in a fine mist of the allergen that the participant is sensitive to) in mild asthmatic subjects receiving 14 days of TD-8236 or placebo (dummy drug containing no active ingredient)

E.2.2

Secondary objectives of the trial

Secondary:
•Characterize the late asthmatic response (LAR) in terms of maximum decline in FEV1 (Forced expiratory volume in one second) and area under the percent change FEV1 curve after inhaled allergen challenge (breathing in a fine mist of the allergen that the participant is sensitive to) in mild asthmatic subjects receiving 14 days of TD-8236 or placebo (dummy drug containing no active ingredient)
•Assess the pharmacokinetics (PK - the levels of study medication in the body and the time it takes the body to break it down) of TD-8236 in subjects with asthma
•Evaluate the safety and tolerability of inhaled TD-8236 administered for 14 days in subjects with mild asthma

Exploratory:
•Characterize the early asthmatic response (EAR) after inhaled allergen challenge in mild asthmatic subjects receiving 14 days of TD-8236 or placebo
•Characterize the overall asthmatic response from 0-8 hours after inhaled allergen challenge in mild asthmatic subjects receiving 14 days of TD-8236 or placeb

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Male or female, 18 to 65 years of age, inclusive, at Screening.
2.BMI ≥ 18.0 and ≤ 35.0 kg/m2 at Screening and weighs ≥ 50 kg at Screening.
3.Documented physician-diagnosed asthma for ≥ 4 months prior to Screening.
4.Pre-bronchodilator FEV1 ≥ 70% predicted at Screening and prior to Day 1 dosing in Treatment Period 1.
5.Documented allergy to at least one common allergen as confirmed by the skin prick test, with wheal diameter ≥3mm greater than the negative control. Historical data up to one year can be used.
6.Subject should be a dual responder to inhaled bronchial allergen challenges as manifested by positive allergen-induced early (LAR) and late airway bronchoconstriction (LAR) at screening, defined as follows:
•EAR is defined as a fall in FEV1 of at least 20% from pre-challenge post diluent baseline values during the 30 minutes after inhaled bronchial allergen challenge.
•LAR is defined by a fall from post diluent value of FEV1 of at least 15% on at least 3 occasions, 2 of which must be consecutive, between 3 to 8 hours after inhaled allergen challenge.
7.Able to correctly use the DPI inhaler and to generate sufficient peak inspiratory flow rate (PIFR) (at least 40 L/min) using the In-Check DIAL device at Screening and prior to dosing on Day 1 of Treatment Period 1.
8.Subject has no clinically significant abnormalities as determined by the PI in the results of laboratory evaluations at Screening, including:
•Liver function tests (i.e., ALT, AST, ALP, GGT, and bilirubin) ≤ upper limit of normal or deemed medically acceptable at the discretion of the PI and Sponsor’s Medical Monitor
•Absolute lymphocyte counts within normal range or should be deemed medically acceptable at the discretion of the PI and Sponsor’s Medical Monitor
9.Subject must have a negative QuantiFeron® Test result at Screening.
10.Pregnancy concerns:
•Female subjects must be either of non-childbearing potential or if of childbearing potential use a highly effective birth control method (see Section 6.3.10) during the study and through 30 days after the last dose of TD-8236.
•Male subjects (with partners of child-bearing potential) must use acceptable contraception (see Section 6.3.10) during the study and through 30 days after the last dose of study medication
•Male subjects must agree not to donate semen during the study and for 30 days after the last dose of study medication
11.Understands the study procedures in the ICF, and is willing and able to comply with the protocol-defined study procedures and expectations.

E.4

Principal exclusion criteria

1.Is mentally or legally incapacitated at the time of Screening or Day 1 TP1, or expected during the conduct of the study that in the opinion of the PI/designee indicates the subject is inappropriate for the study
2.Have abnormal ECG measurements at Screening or pre-dose Day 1 TP1 indicating:
•2nd or 3rd-degree AV block
•QRS>120 msec
•QTcF>450 msec(male) or >460msec(female)
•PR interval >220msec
3.Subject has a known personal or family history of congenital long QT syndrome or known family history of sudden death
4.Subject has a resting bradycardia (pulse <40 bpm) or a resting tachycardia (pulse >100 bpm) at Screening or Day 1 TP1
5.Lung disease other than stable, mild asthma; worsening of asthma that requires a change in asthma therapy or is deemed clinically significant by the PI or Medical Monitor
6.History of clinically significant hypotensive episodes or symptoms of fainting, dizziness, or light-headedness
7.History of lymphoma, leukemia, or other types of malignancy (except for completely resected squamous or basal cell cancer)
8.Any signs of RTI within 6 weeks of screening or prior to Day 1 TP1 that are deemed clinically significant by the PI or Medical Monitor.
9.Subject who has a current bacterial, parasitic, fungal, or viral infection; any infection requiring hospitalization or IV antibiotics within 6 months prior to Screening; any infection requiring oral or topical antimicrobial treatment within 2 weeks prior to Screening or prior to Day 1 TP1; a history of > 1 episode of herpes zoster infection
10.Any evidence of current or previous clinically significant disease (with the exception of stable, mild asthma)
11.History of life-threatening asthma, defined as an asthma episode that required intubation and/or was associated with hypercapnoea, respiratory arrest and/or hypoxic seizures or hospitalisation (including emergency room visits) for the treatment of asthma within 3 months of Screening, or have been hospitalized or have attended emergency room visits for asthma > twice in last 12 months
12.Subject has any condition of the oro-laryngeal or respiratory tract (incl. but not limited to, prior surgery) that could possibly affect drug administration, deposition, or absorption, or ability to perform lung function, allergen challenge, sputum induction as determined by the PI or Sponsor Medical Monitor
13.Positive alcohol results at Screening or Day 1 TP1, or history or presence of alcoholism within the past 2 years prior to dosing on Day 1 TP1
14.Alcohol consumption >21 units per week (males) or >14 units per week (females)
15.Positive drugs of abuse test result (unless in the opinion of the investigator this can be explained by the patient’s current medications) at Screening or Day 1 TP1
16.Positive urine cotinine test result at Screening or Day 1 TP1
17.Uses or has used tobacco or nicotine-containing products within 6 months prior to Screening, or has history of >5 pack-years
18.History of hypersensitivity to drugs, latex allergy, band aids, adhesive dressing, or medical tape, with a clinically significant reaction as determined by the PI or designee
19.History of serious adverse reaction, severe hypersensitivity or allergy to any drug or in any other circumstance
20.Female subjects with a positive pregnancy test at Screening or Day 1 TP1, or who are breastfeeding or lactating
21.Subjects who have had a live viral vaccine within 8 weeks prior to Screening and/or are unwilling to avoid live viral vaccines for until at-least 8 weeks following completion of the final study visit
22.Positive results at screening for HIV, HAV antibodies (anti-HAV: both IgG and IgM positive, IgG positive in the absence of IgM positive is acceptable), HBsAg, or HCV
23.Subject who has a history of latent or active TB
24.Unable to refrain from or anticipates the use of any drug including prescription and nonprescription medications, herbal remedies, or vitamin supplements beginning 14 days prior to Screening and throughout the study
•Paracetamol (up to 1g per 24 hrs) will be allowed from Screening and throughout the study
•HRT will be allowed
•Acceptable contraception will be allowed
•Oral and inhaled ICS (or ICS/LABA) are prohibited for 6 weeks prior to Screening and throughout the study
•A SABA may be used as required, with the exception of 8 hours before lung function
•Stable treatment of medications for at least 3 months prior to randomization may be permitted on a case-by-case basis
25.Subject has dietary restrictions incompatible with the diet that can be provided by the study site
26.Donation of blood (≥400 mL) or plasma, or significant blood loss within 56 days prior to Day 1 TP1
27.Donation of bone marrow within the last 6 months prior to dosing on Day 1 TP1
28.Subject has previously received TD-8236
29.Participation in another clinical study within 60 days, or <5.5 half-lives
30.Exposure to biologic therapies within the last 6 months prior to dosing Day 1 TP1

E.5 End points

E.5.1

Primary end point(s)

•Area under the curve (AUC) of change from baseline FEV1 from 3 to 8 hours after inhaled allergen challenge at Day 14

E.5.1.1

Timepoint(s) of evaluation of this end point

FEV1 measured at Day 14 of each treatment period from pre-allergen challenge and the period beginning 3 hours and ending 8 hours after the allergen challenge.

E.5.2

Secondary end point(s)

Secondary
1. AUC of percentage change from baseline in FEV1 from 3 to 8 hours after inhaled allergen challenge at Day 14
2. Maximum decline in FEV1 from 3 to 8 hours after inhaled allergen challenge at Day 14
3. Maximum percentage decline in FEV1 from 3 to 8 hours after inhaled allergen challenge at Day 14
4. Day 14 plasma PK parameters of TD-8236 in subjects with mild asthma
5. Safety and tolerability of TD-8236 over 14 days of dosing, including frequency and severity of adverse events, vital signs, clinical laboratory evaluations, and 12-lead ECG changes from baseline

Exploratory
1. AUC of change from baseline FEV1 from 0 to 2 hours after inhaled allergen challenge at Day 14
2. AUC of percentage change from baseline in FEV1 from 0 to 2 hours after inhaled allergen challenge at Day 14
3. Maximum decline in FEV1 from 0 to 2 hours after inhaled allergen challenge at Day 14
4. Maximum percentage decline in FEV1 from 0 to 2 hours after inhaled allergen challenge at Day 14
5. AUC of change from baseline FEV1 from 0 to 8 hours after inhaled allergen challenge
6. AUC of percentage change from baseline FEV1 from 0 to 8 hours after inhaled allergen challenge
7. Change in pre-dose FEV1 from Day 1 to Day 14 for each treatment period
8. Change over time (change and percent change; pre-dose over 14 days, and pre-/post allergen challenge) in fraction exhaled nitric oxide (FeNO)
9. Total and differential cell counts in induced sputum and blood PD biomarker samples
10. Known or potential asthma-related biomarkers in induced sputum samples, including but not limited to: eosinophilic cationic protein (ECP), periostin, and various cytokines
11. Change from baseline in Total ACQ-5 score

E.5.2.1

Timepoint(s) of evaluation of this end point

Secondary
1,2,3. Pre-BAC & between 3 & 8 hrs post-BAC (Day 14 of each TP)
4. Days 1,7 pre-dose. Day 14 pre-dose,0.5,1,2,4,6,8 & 24 hrs post-dose (each TP)
5.
AEs: From signing of consent to follow-up.
Vital signs & ECG: SV1,pre-dose Days 1,7,14 & follow-up
Labs: SV1,pre-dose on Days 1,7,14,Day 15 & follow-up

Exploratory
1,2. Pre-BAC & between 0 & 2 hrs post-BAC (Day 14 of each TP)
3,4. Between 0 & 2 hrs post-BAC (Day 14 of each TP)
5,6. Pre-BAC & between 0 & 8 hrs post-BAC (Day 14 of each TP)
7. Pre-dose Day 1,7,14 (each TP)
8. Pre-dose Day 1,7,14, pre-BAC,8,24 hrs post-BAC (screen & all TPs)
9,10.
Sputum: 8,24 hrs post-BAC (screen & all TPs)
Blood: Pre-BAC & 24 hrs post-BAC (screen & all TPs)
11. SV1, Day 1,7,14 (all TPs), follow-up

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

Yes

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Placebo controlled

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

The end of this trial is defined as the date that the last protocol defined study visit occurs for the last subject enrolled in the study.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1