Investigation Of a New Oral Anti-Histamine in Healthy Male Subjects

A Double-blind, Placebo-controlled, Randomized Cross-over Single Dose Escalation Study and a Double-blind, Placebo-controlled, Randomised Parallel Group 7-days Once Daily Repeat Dose Study to Investigate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Oral H1/H3 Dual Antagonist Compound in Healthy Male Subjects

This study is designed to assess the safety and tolerability of single, escalating oral doses and repeat oral doses (7 days, once daily) of GSK835726 in healthy male subjects

Study Overview

• Status: Completed
• Conditions: Rhinitis, Allergic, Seasonal
• Intervention / Treatment: Drug: GSK835726; Drug: Placebo

Detailed Description

A double-blind, placebo controlled, randomized cross-over single dose escalation study and a double-blind, placebo controlled, randomised parallel group 7-days once daily repeat dose study to investigate safety, tolerability, pharmacokinetics and pharmacodynamics of oral H1/H3 dual antagonist compound in healthy male subjects

• Study Type: Interventional
• Enrollment (Actual): 29
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, NW10 7EW
    • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion criteria:

• Male aged between 18 and 50 years inclusive.
• Body mass index within the range 19-29kg/m2 (inclusive), with weight range of 55kg-100kg (inclusive).
• Healthy (defined as individuals who are free from significant nasal, cardiac, pulmonary, gastrointestinal, hepatic, renal, haematological, malignancy, endocrine, neurological and psychiatric disease as determined by history, physical examination and screening investigations).
• Non-smoking status as verified by urinary cotinine levels below 300 ng/mL cotinine at the screening visit. This can include ex-smokers who have given up smoking for >1 year.
• Subjects to be entered in cohorts I and III only: Skin prick test reactivity to histamine of 3mm wheal > than saline control and some associated surrounding erythema.
• Subjects to be entered in cohorts I and III only: Negative skin prick test reactivity to saline control.
• The subject is able and willing to give written informed consent to take part in the study and is available to complete all study measurements.
• If sexually active, male subjects must agree to use a condom with spermicide during sexual intercourse, from the first dose of the study drug until 84 days after the last dose. In addition, female partners of male subjects, who are of childbearing potential, must use a reliable contraceptive method or they must refrain from sexual intercourse from the first dose of study medication until 84 days after the last dose. Reliable forms of contraception include an IUD, condom or diaphragm with spermicide, oral contraceptives, injectable progesterone, subdermal implants, contraceptive patches or a tubal ligation."

Exclusion criteria:

• As a result of the medical interview, physical examination or screening investigations, the Investigator or appropriately qualified designee considers the subject unfit for the study.
• The subject has a history of drug or any other allergy, which, in the opinion of the Investigator or appropriately qualified designee, contraindicates their participation, including known or suspected personal history or family history of adverse reactions or hypersensitivity to anti histamines.
• The subject has participated in a study with a new molecular entity during the previous 3 months or any other study during the previous 2 months.
• The subject regularly, or on average, drinks more than 21 units of alcohol a week or more than an average intake of 3 units per day (One unit = 125ml wine or 25ml spirits or 250ml normal strength lager).
• The subject is currently taking regular (or a course of) medication, prescribed (including all anti-allergy medication) or not (including over the counter medication or herbal remedies such as St Johns Wort). Paracetamol is an exception and will be permitted at daily doses of up to 4g following all doses of investigational product.
• The subject has tested positive for hepatitis C antibody or hepatitis B surface antigen.
• The subject has tested positive for HIV.
• The subject has a positive drugs of abuse and alcohol test.
• Donation of blood (450 mL or more) within 2 months of screening.
• Donation during the study would result in >500mL of blood being donated over a 56 day period

• Significant cardiac conduction abnormalities on two or more ECG tracings separated by at least 5 minutes at screening, including:

  • QTc interval > 450 msec
  • PR interval > 240 msec
  • Evidence of second- or third- degree atrioventricular (AV) block
  • Ventricular rate < 45 beats per minute (bpm) or > 100 bpm
  • Pathological Q-waves (defined as Q-wave > 40 msec or depth greater than 0.4-0.5 mV)
  • Evidence of ventricular pre-excitation
  • Evidence of left axis deviation, non-specific intraventricular conduction delay (QRS duration > 120 msec), or complete left bundle branch block
• Subjects with Perennial Allergic Rhinitis (PAR) and Seasonal Allergic Rhinitis (SAR), unless subjects with SAR are asymptomatic and it is outside of the pollen season
• Subjects with dermatographism and other skin conditions that might interfere with the wheal and flare test.
• Subjects who are unable to comply with study procedures.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Subjects receiving treatment in cohort I; Eligible subjects will receive three single doses of GSK835726 and one single dose of placebo in cohort I.	Drug: GSK835726; GSK835726 will be available in single dose and repeat dose formulations.; Drug: Placebo; Placebo will be given to subjects.
Experimental: Subjects receiving GSK835726 in cohort II; Eligible subjects will receive repeat doses of GSK835726 once daily for 7 days.	Drug: GSK835726; GSK835726 will be available in single dose and repeat dose formulations.
Placebo Comparator: Subjects receiving placebo in cohort II; Eligible subjects will receive repeat doses of placebo once daily for 7 days.	Drug: Placebo; Placebo will be given to subjects.
Experimental: Subjects receiving treatment in cohort III; Eligible subjects will receive two single doses of GSK835726 and one single dose of placebo in cohort III.	Drug: GSK835726; GSK835726 will be available in single dose and repeat dose formulations.; Drug: Placebo; Placebo will be given to subjects.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
ECG monitoring during 24 hours after each dose in the single dose cohorts and on days 1 and 7 in the repeat dose cohorts.	during 24 hours after each dose in the single dose cohorts and on days 1 and 7 in the repeat dose cohorts.
Heart rate and blood pressure changes over 24 hours after dosing in single and repeat dose cohorts	over 24 hours after dosing in single and repeat dose cohorts

Secondary Outcome Measures

Outcome Measure	Time Frame
Change in plasma drug concentration (AUC, Cmax, t1/2, tmax)	over 24 hours after dosing
Changes in histamine-induced wheal and flare measurements	over 24 hours after dosing
Derived pharmacokinetic parameters for GSK835726 including area under the plasma drug concentration versus time curve (AUC(0-t), AUC(0-¥)), maximum observed plasma drug concentration (Cmax),	over 24 hours after dosing
time to maximum observed plasma drug concentration (tmax), apparent clearance (CL/F) and terminal half life (t1/2) following single and repeat oral dosing.	over 24 hours after dosing

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

General Publications

• Daley-Yates P, Ambery C, Sweeney L, Watson J, Oliver A, McQuade B. The efficacy and tolerability of two novel H(1)/H(3) receptor antagonists in seasonal allergic rhinitis. Int Arch Allergy Immunol. 2012;158(1):84-98. doi: 10.1159/000329738. Epub 2011 Dec 29.

Helpful Links

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Study record dates

Study Major Dates

• Study Start (Actual): October 29, 2007
• Primary Completion (Actual): May 3, 2008
• Study Completion (Actual): May 3, 2008

Study Registration Dates

• First Submitted: January 18, 2008
• First Submitted That Met QC Criteria: January 18, 2008
• First Posted (Estimate): January 31, 2008

Study Record Updates

• Last Update Posted (Actual): August 21, 2017
• Last Update Submitted That Met QC Criteria: August 16, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: first time in human; Allergic rhinitis
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Immune System Diseases; Hypersensitivity, Immediate; Otorhinolaryngologic Diseases; Respiratory Hypersensitivity; Hypersensitivity; Nose Diseases; Rhinitis; Rhinitis, Allergic; Rhinitis, Allergic, Seasonal
• Other Study ID Numbers: HH3110161

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

Study Data/Documents

1. Annotated Case Report Form
   Information identifier: HH3110161
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
2. Clinical Study Report
   Information identifier: HH3110161
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
3. Informed Consent Form
   Information identifier: HH3110161
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
4. Individual Participant Data Set
   Information identifier: HH3110161
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
5. Statistical Analysis Plan
   Information identifier: HH3110161
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
6. Study Protocol
   Information identifier: HH3110161
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
7. Dataset Specification
   Information identifier: HH3110161
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register