The Effects of RPL554 in Addition to Tiotropium in COPD Patients

• Sponsor: Verona Pharma plc (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03028142
• Collaborator: (none)
• Enrollment: 30
• Arms: 3
• Duration (Months): 7

Study Details

Study Description

Brief Summary

This is a phase II, randomised, double blind, placebo controlled, complete block, three way crossover study to investigate treatment with nebulised RPL554 and tiotropium together in patients with moderate to severe chronic obstructive pulmonary disease (COPD). The purpose of this study is to assess the bronchodilator effect (opening of the airways) of RPL554 when used in combination with a long acting anti-muscarinic receptor antagonist (tiotropium) whilst dosing the RPL554 to steady state blood levels. It is planned to randomise up to 30 patients to have 24 evaluable patients at one study centre. In each treatment period, patients will receive an open label dose of tiotropium from a dry power inhaler (DPI) followed immediately by a double blind dose of either RPL554 6mg, 1.5mg or placebo (depending on treatment sequence) from a nebuliser in the morning on Day 1, Day 2 and Day 3. The dose of RPL554 or placebo will be repeated in the evening on Day 1 and Day 2; there will not be an evening dose on Day 3.

Condition or Disease	Intervention/Treatment	Phase
Chronic Obstructive Pulmonary Disease Moderate	Drug: 1.5 mg RPL554 plus tiotropium; Drug: 6 mg RPL554 plus tiotropium; Drug: Placebo plus tiotropium	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Study Start Date: Jan 1, 2017
• Actual Primary Completion Date: Aug 1, 2017
• Actual Study Completion Date: Aug 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Lower Dose Nebulised Treatment 1.5 mg nebulised RPL554 twice daily plus 10 mcg tiotropium DPI once daily for 3 days	Drug: 1.5 mg RPL554 plus tiotropium
Experimental: Higher Dose Nebulised Treatment 6 mg nebulised RPL554 twice daily plus 10 mcg tiotropium DPI once daily for 3 days	Drug: 6 mg RPL554 plus tiotropium
Placebo Comparator: Placebo Nebulised RPL554 matched placebo twice daily plus 10 mcg tiotropium DPI once daily for 3 days	Drug: Placebo plus tiotropium

Outcome Measures

Primary Outcome Measures

1. Peak Forced Expired Volume in 1 Second (FEV1) on the Third Day of Dosing [Day 3]

   Peak forced expired volume in 1 second (FEV1) over 4 hours on the third day of dosing

2. Average FEV1 Over 12 Hours on the Third Day of Dosing [Day 3]

   Average FEV1 area under the curve (AUC) over 12 hours on the third day of dosing

Secondary Outcome Measures

1. Peak FEV1 on Day 1 [Day 1]

   Peak FEV1 over 4 hours on Day 1

2. Average FEV1 Over 12 Hours on Day 1 [Day 1]

   Average FEV1 AUC over 12 hours on Day 1

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Sign an informed consent document indicating they understand the purpose of and procedures required for the study and are willing to participate in the study.

2. Male or female aged between 40 and 75 years inclusive, at the time of informed consent.

3. If male: must agree to meet the following from the first dose up to 1 month after the last dose of study treatment:

• Not donate sperm

• Either: be sexually abstinent in accordance with a patient's usual and preferred lifestyle (but agree to abide by the contraception requirements below should their circumstances change) Or: use a condom with all sexual partners. If the partner is of childbearing potential the condom must be used with spermicide and a second highly effective form of contraception must also be used

1. If female: either be:

2. Of non-childbearing potential defined as being:

• Either: post-menopausal (being spontaneously amenorrhoeic for at least 1 year with an appropriate clinical profile [e.g. age appropriate, history of vasomotor symptoms]

• Or: permanently sterilised e.g. tubal occlusion, hysterectomy, bilateral oophorectomy, bilateral salpingectomy

1. Of childbearing potential and agreeing to use a highly effective method of contraception until completion of the end of study visit.

2. Have a 12-lead ECG recording at screening and randomisation (pre-dose in Treatment

Period 1) showing the following:

• Heart rate between 45 and 90 beats per minute (bpm)

• QT interval corrected for heart rate using Fridericia's formula (QTcF) ≤450 msec for males and ≤470 ms for females

• QRS interval ≤120 msec

• No clinically significant abnormalities (as judged by the Investigator) including morphology (e.g. left bundle branch block, atrio-ventricular nodal dysfunction, ST segment abnormalities)

1. Have a screening Holter report with a minimum of 18 hours recording that is able to be evaluated for rhythm analysis which shows no abnormality which indicates a significant impairment of patient safety or which may significantly impairs interpretation in the opinion of the Investigator including:

• Significant arrhythmias including atrial flutter, atrial fibrillation, ventricular tachycardia

• Any symptomatic arrhythmia (except isolated extra systoles)

• Any sustained second or third degree heart block

1. Capable of complying with all study restrictions and procedures including ability to use the study nebuliser and HandiHaler® DPI correctly.

2. Body mass index (BMI) between 18 and 33 kg/m2 (inclusive) with a minimum weight of 45 kg.

3. COPD diagnosis: Patients with a diagnosis of COPD as defined by the American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines (Celli and MacNee, 2004) with symptoms compatible with COPD for at least 1 year prior to screening.

4. Post-bronchodilator (four puffs of salbutamol) spirometry at screening:

• Post-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio of ≤0.70

• Post-bronchodilator FEV1 ≥40 % and ≤80% of predicted normal

• Demonstrates ≥150 mL increase from pre-bronchodilator FEV1

1. Clinically stable COPD in the 4 weeks prior to screening and randomisation (pre-dose in Treatment Period 1).

2. A chest X-ray (post-anterior) at screening, or in the 12 months prior to screening showing no abnormalities, which are both clinically significant and unrelated to COPD.

3. Meet the concomitant medication restrictions and be expected to do so for the rest of the study.

4. Smoking history of ≥10 pack years.

5. Capable of withdrawing from long acting bronchodilators for the duration of the study, and short acting bronchodilators for 8 hours prior to spirometry.

Exclusion Criteria:

1. A history of life-threatening COPD exacerbation including Intensive Care Unit admission and/or requiring intubation.

2. COPD exacerbation requiring oral steroids, or lower respiratory tract infection requiring antibiotics, in the 3 months prior to screening or randomisation (pre-dose in Treatment Period 1).

3. A history of one or more hospitalisations for COPD in the 12 months prior to screening or randomisation (pre-dose in Treatment Period 1).

4. Lactation (female patients only).

5. Positive urine or serum pregnancy test at screening, or a positive urine pregnancy test prior to randomisation (female patients of childbearing potential only).

6. Prior exposure to RPL554 or known hypersensitivity to RPL554 or its components.

7. Intolerance or hypersensitivity to tiotropium.

8. Evidence of cor pulmonale.

9. Other respiratory disorders: Patients with a current diagnosis of asthma, active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, interstitial lung diseases, sleep apnoea, known alpha-1 antitrypsin deficiency or other active pulmonary diseases.

10. Previous lung resection or lung reduction surgery.

11. Use of oral COPD medications (e.g. oral steroids, theophylline and romifulast) in the 3 months prior to screening or randomisation (pre-dose in Treatment Period 1).

12. History of, or reason to believe, a patient has drug or alcohol abuse within the past 3 years.

13. Inability to perform technically acceptable spirometry or whole body plethysmography (at screening or randomisation [pre dose in Treatment Period 1])

14. Received an experimental drug within 30 days or five half lives, whichever is longer.

15. Patients with a history of chronic uncontrolled disease including, but not limited to, endocrine, active hyperthyroidism, neurological, hepatic, gastrointestinal, renal, haematological, urological, immunological, or ophthalmic diseases that the Investigator believes are clinically significant.

16. Documented cardiovascular disease: arrhythmias, angina, recent or suspected myocardial infarction, congestive heart failure, a history of unstable, or uncontrolled hypertension, or has been diagnosed with hypertension in the 3 months prior to screening or randomisation.

17. Concurrent use of non-cardioselective oral beta-blockers.

18. Has had major surgery, (requiring general anaesthesia) in the 6 weeks prior to screening or randomisation (pre-dose in Treatment Period 1), or will not have fully recovered from surgery, or planned surgery through the end of the study.

19. A disclosed history or one known to the Investigator, of significant non compliance in previous investigational studies or with prescribed medications.

20. Requires oxygen therapy, even on an occasional basis.

21. Clinically significant prostatic hyperplasia (judged by the Investigator) or bladder-neck obstruction or with narrow-angle glaucoma.

22. Any other reason that the Investigator considers makes the patient unsuitable to participate.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Verona Pharma plc

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Apr 26, 2017
• Statistical Analysis Plan - Sep 19, 2017

More Information

Publications

None provided.

• Responsible Party: Verona Pharma plc
• ClinicalTrials.gov Identifier: NCT03028142
• Other Study ID Numbers: RPL554-CO-202
• First Posted: Jan 23, 2017
• Last Update Posted: Feb 27, 2019
• Last Verified: Jan 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide

Study Results

Participant Flow

Pre-assignment Detail	74 were screened.Main reasons for screen failure were reversibility criteria not met (21), withdrew consent (5) and unsuitable chronic obstructive pulmonary disorder (COPD) history (4). Patients had to discontinue long acting bronchodilators on the day before screening and short acting bronchodilators for 8 hours before all spirometry assessments

Arm/Group Title	Placebo Then Low Dose RPL554 Then High Dose RPL554	Low Dose Dose RPL554 Then High Dose RPL554 Then Placebo	High Dose RPL554 Then Placebo Then Low Dose RPL554	High Dose RPL554 Then Low Dose RPL554 Then Placebo	Low Dose RPL554 Then Placebo Then High Dose RPL554	Placebo Then High Dose RPL554 Then Low Dose RPL554
Arm/Group Description	Placebo twice daily plus 10 mcg tiotropium once daily for 3 days then 1.5 mg RPL554 twice daily plus 10 mcg tiotropium once daily for 3 days then 6 mg RPL554 twice daily plus 10 mcg tiotropium for 3 days, with a 7-21 day washout period between treatments	1.5 mg RPL554 twice daily plus 10 mcg tiotropium once daily for 3 days then 6 mg RPL554 twice daily plus 10 mcg tiotropium once daily for 3 days then placebo twice daily plus 10 mcg tiotropium for 3 days, with a 7-21 day washout period between treatments	High dose RPL554 twice daily plus 10 mcg tiotropium once daily for 3 days then placebo twice daily plus 10 mcg tiotropium once daily for 3 days then 1.5 mg RPL554 twice daily plus 10 mcg tiotropium for 3 days, with a 7-21 day washout period between treatments	High dose RPL554 twice daily plus 10 mcg tiotropium once daily for 3 days then 1.5 mg RPL554 twice daily plus 10 mcg tiotropium once daily for 3 days then placebo twice daily plus 10 mcg tiotropium for 3 days, with a 7-21 day washout period between treatments	Low dose RPL554 twice daily plus 10 mcg tiotropium once daily for 3 days then placebo twice daily plus 10 mcg tiotropium once daily for 3 days then 6 mg RPL554 twice daily plus 10 mcg tiotropium for 3 days, with a 7-21 day washout period between treatments	Placebo twice daily plus 10 mcg tiotropium once daily for 3 days then 6 mg RPL554 twice daily plus 10 mcg tiotropium once daily for 3 days then 1.5 mg RPL554 twice daily plus 10 mcg tiotropium for 3 days, with a 7-21 day washout period between treatments
Period Title: Overall Study
STARTED	5	5	6	4	6	4
COMPLETED	4	4	6	4	5	3
NOT COMPLETED	1	1	0	0	1	1

Baseline Characteristics

Arm/Group Title	Overall
Arm/Group Description	All patients before the start of the study treatment sequence
Overall Participants	30
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	64.5
Sex: Female, Male (Count of Participants)
Female	13 43.3%
Male	17 56.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	30 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Percentage of predicted FEV1 post-bronchodilator (%) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [%]	60.1 (9.73)

Outcome Measures

1. Primary Outcome

Title	Peak Forced Expired Volume in 1 Second (FEV1) on the Third Day of Dosing
Description	Peak forced expired volume in 1 second (FEV1) over 4 hours on the third day of dosing
Time Frame	Day 3

Outcome Measure Data

Analysis Population Description

All randomized patients with sufficient data collected after intake of study treatment to compute the pharmacodynamics parameters on at least two treatment periods.

Arm/Group Title	Lower Dose Nebulised Treatment	Higher Dose Nebulised Treatment	Placebo
Arm/Group Description	1.5 mg nebulised RPL554 twice daily plus 10 mcg tiotropium dry powder inhaler (DPI) once daily for 3 days 1.5 mg RPL554 plus tiotropium	6 mg nebulised RPL554 twice daily plus 10 mcg tiotropium DPI once daily for 3 days 6 mg RPL554 plus tiotropium	Nebulised RPL554 matched placebo twice daily plus 10 mcg tiotropium DPI once daily for 3 days Placebo plus tiotropium
Measure Participants	28	27	27
Mean (Standard Deviation) [Liters]	0.477 (0.1673)	0.500 (0.2157)	0.373 (0.1970)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lower Dose Nebulised Treatment, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0022
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Means ratio
	Estimated Value	1.05
	Confidence Interval	(2-Sided) 95%; 1.02 to 1.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Higher Dose Nebulised Treatment, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Means ratio
	Estimated Value	1.09
	Confidence Interval	(2-Sided) 95%; 1.05 to 1.12
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Average FEV1 Over 12 Hours on the Third Day of Dosing
Description	Average FEV1 area under the curve (AUC) over 12 hours on the third day of dosing
Time Frame	Day 3

Outcome Measure Data

Analysis Population Description

All randomized patients with sufficient data collected after intake of study treatment to compute the pharmacodynamics parameters on at least two treatment periods.

Arm/Group Title	Lower Dose Nebulised Treatment	Higher Dose Nebulised Treatment	Placebo
Arm/Group Description	1.5 mg nebulised RPL554 twice daily plus 10 mcg tiotropium DPI once daily for 3 days 1.5 mg RPL554 plus tiotropium	6 mg nebulised RPL554 twice daily plus 10 mcg tiotropium DPI once daily for 3 days 6 mg RPL554 plus tiotropium	Nebulised RPL554 matched placebo twice daily plus 10 mcg tiotropium DPI once daily for 3 days Placebo plus tiotropium
Measure Participants	28	27	27
Mean (Standard Deviation) [Liters*hour]	3.804 (1.8512)	3.967 (2.2134)	3.197 (2.2826)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lower Dose Nebulised Treatment, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0988
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Means ratio
	Estimated Value	1.03
	Confidence Interval	(2-Sided) 95%; 0.99 to 1.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Higher Dose Nebulised Treatment, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0009
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Means ratio
	Estimated Value	1.06
	Confidence Interval	(2-Sided) 95%; 1.02 to 1.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Peak FEV1 on Day 1
Description	Peak FEV1 over 4 hours on Day 1
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

All randomized patients with sufficient data collected after intake of study treatment to compute the pharmacodynamics parameters on at least two treatment periods.

Arm/Group Title	Lower Dose Nebulised Treatment	Higher Dose Nebulised Treatment	Placebo
Arm/Group Description	1.5 mg nebulised RPL554 twice daily plus 10 mcg tiotropium DPI once daily for 3 days 1.5 mg RPL554 plus tiotropium	6 mg nebulised RPL554 twice daily plus 10 mcg tiotropium DPI once daily for 3 days 6 mg RPL554 plus tiotropium	Nebulised RPL554 matched placebo twice daily plus 10 mcg tiotropium DPI once daily for 3 days Placebo plus tiotropium
Measure Participants	28	27	27
Mean (Standard Deviation) [Liters]	0.383 (0.1448)	0.432 (0.1720)	0.337 (0.1854)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lower Dose Nebulised Treatment, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2496
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Means ratio
	Estimated Value	1.02
	Confidence Interval	(2-Sided) 95%; 0.98 to 1.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Higher Dose Nebulised Treatment, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0039
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Means ratio
	Estimated Value	1.06
	Confidence Interval	(2-Sided) 95%; 1.02 to 1.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Average FEV1 Over 12 Hours on Day 1
Description	Average FEV1 AUC over 12 hours on Day 1
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lower Dose Nebulised Treatment	Higher Dose Nebulised Treatment	Placebo
Arm/Group Description	1.5 mg nebulised RPL554 twice daily plus 10 mcg tiotropium DPI once daily for 3 days 1.5 mg RPL554 plus tiotropium	6 mg nebulised RPL554 twice daily plus 10 mcg tiotropium DPI once daily for 3 days 6 mg RPL554 plus tiotropium	Nebulised RPL554 matched placebo twice daily plus 10 mcg tiotropium DPI once daily for 3 days Placebo plus tiotropium
Measure Participants	28	27	27
Mean (Standard Deviation) [Liters*hour]	3.058 (1.4851)	3.094 (1.9624)	2.510 (1.9381)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lower Dose Nebulised Treatment, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1404
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Means ratio
	Estimated Value	1.03
	Confidence Interval	(2-Sided) 95%; 0.99 to 1.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Higher Dose Nebulised Treatment, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0228
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Means ratio
	Estimated Value	1.04
	Confidence Interval	(2-Sided) 95%; 1.01 to 1.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	From informed consent until the end of the study.
Arm/Group Title	Lower Dose Nebulised Treatment		Higher Dose Nebulised Treatment		Placebo
Arm/Group Description	1.5 mg nebulised RPL554 twice daily plus 10 mcg tiotropium DPI once daily for 3 days 1.5 mg RPL554 plus tiotropium		6 mg nebulised RPL554 twice daily plus 10 mcg tiotropium DPI once daily for 3 days 6 mg RPL554 plus tiotropium		Nebulised RPL554 matched placebo twice daily plus 10 mcg tiotropium DPI once daily for 3 days Placebo plus tiotropium
All Cause Mortality
	Lower Dose Nebulised Treatment		Higher Dose Nebulised Treatment		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/29 (0%)		0/27 (0%)		0/28 (0%)
Serious Adverse Events
	Lower Dose Nebulised Treatment		Higher Dose Nebulised Treatment		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/29 (3.4%)		0/27 (0%)		0/28 (0%)
Infections and infestations
Pneumonia	1/29 (3.4%)	1	0/27 (0%)	0	0/28 (0%)	0
Other (Not Including Serious) Adverse Events
	Lower Dose Nebulised Treatment		Higher Dose Nebulised Treatment		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/29 (41.4%)		12/27 (44.4%)		12/28 (42.9%)
Gastrointestinal disorders
Frequent bowel movements	1/29 (3.4%)	1	0/27 (0%)	0	0/28 (0%)	0
Nausea	1/29 (3.4%)	1	0/27 (0%)	0	0/28 (0%)	0
General disorders
Medical device site reaction	4/29 (13.8%)	4	1/27 (3.7%)	1	4/28 (14.3%)	4
Chest discomfort	1/29 (3.4%)	1	1/27 (3.7%)	1	2/28 (7.1%)	3
Catheter site bruise	0/29 (0%)	0	1/27 (3.7%)	1	0/28 (0%)	0
Chills	0/29 (0%)	0	1/27 (3.7%)	1	0/28 (0%)	0
Fatigue	0/29 (0%)	0	0/27 (0%)	0	1/28 (3.6%)	1
Infections and infestations
Herpes simplex	0/29 (0%)	0	0/27 (0%)	0	1/28 (3.6%)	1
Lower respiratory tract infection	0/29 (0%)	0	0/27 (0%)	0	1/28 (3.6%)	1
Pneumonia	1/29 (3.4%)	1	0/27 (0%)	0	0/28 (0%)	0
Rhinitis	0/29 (0%)	0	0/27 (0%)	0	1/28 (3.6%)	1
Skin infection	0/29 (0%)	0	1/27 (3.7%)	1	0/28 (0%)	0
Injury, poisoning and procedural complications
Arthropod bite	0/29 (0%)	0	0/27 (0%)	0	1/28 (3.6%)	1
Contusion	0/29 (0%)	0	1/27 (3.7%)	1	0/28 (0%)	0
Skin wound	0/29 (0%)	0	1/27 (3.7%)	1	0/28 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	0/29 (0%)	0	1/27 (3.7%)	1	0/28 (0%)	0
Muscle spasms	1/29 (3.4%)	1	0/27 (0%)	0	0/28 (0%)	0
Musculoskeletal chest pain	0/29 (0%)	0	1/27 (3.7%)	1	0/28 (0%)	0
Myalgia	1/29 (3.4%)	1	0/27 (0%)	0	0/28 (0%)	0
Nervous system disorders
Headache	2/29 (6.9%)	2	5/27 (18.5%)	8	3/28 (10.7%)	3
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/29 (3.4%)	1	1/27 (3.7%)	1	2/28 (7.1%)	3
Chronic obstructive pulmonary disease	0/29 (0%)	0	1/27 (3.7%)	1	0/28 (0%)	0
Cough	1/29 (3.4%)	1	0/27 (0%)	0	0/28 (0%)	0
Larngeal discomfort	1/29 (3.4%)	1	0/27 (0%)	0	0/28 (0%)	0
Sputum increased	0/29 (0%)	0	1/27 (3.7%)	1	0/28 (0%)	0
Skin and subcutaneous tissue disorders
Rash	1/29 (3.4%)	1	0/27 (0%)	0	0/28 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The employees of the Medicines Evaluation shall not be permitted to present at symposia, national or regional professional meetings, and to publish in journals, theses or dissertations, or otherwise of their own choosing, methods and results of the Clinical Trial subject to the publication policy described in the Protocol without prior written approval of the Sponsor.