Clinical trial NCT01424514: SB705498 Proof of Concept Chamber Challenge in Subjects With Non Allergic Rhinitis
Official title: A Randomised, Double Blind Placebo Controlled, 2 Way Cross Over Study in Adults With Non-allergic Rhinits to Evaluate the Effect of Once Daily Administration of Intranasal SB-705498 12mg for Two Weeks and the Response to a Chamber Challenge of Cold Dry Air
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Rhinitis
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2011-08-29
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to assess the pharmacodynamic (PD) effects (Total Symptom Score (TSS) and its individual components: rhinorrhoea, nasal congestion, post-nasal drip) of intranasal, repeat dose SB-705498 in non-allergic rhinitis (NAR) patients elicited by a cold dry air challenge in an environmental exposure chamber (EEC). SB-705498 is a selective antagonist of the transient receptor potential vanilloid-1 (TRPV1) ligand gated ion channel. TRPV1 is a cation permeable ion channel that can be activated by several physiological factors, such as heat, protons (pH), osmotic stress, eicosanoid derivatives, anandamide, and by products of inflammation, such as histamine, prostaglandins and bradykinin. In the nose, the local TRPV1 expressing sensory C-fibres are thought to play a key role in the development of nasal hyper-responsiveness to environmental provocateurs. It has been proposed that blocking the nasal sensory nerve stimulation may control nasal hyper-responsiveness and therefore prevent the induction of rhinitis symptoms. In this context, preclinical evidence supports that targeting TRPV1 by SB-705498 may be an attractive option.

In this study NAR patients will be randomised, in a double blind, placebo controlled cross over design to receive 14 day repeat doses of 12mg intra-nasal SB-705498 once daily. Whilst dosing at home, subjects will record symptom scores to document their symptoms. In addition, during visits to the clinical unit, acoustic rhinometry, quality of life questionnaires and safety assessments will be monitored.


Eligibility criteria: Inclusion Criteria:

Deviations from inclusion criteria are not allowed because they can potentially jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.

A subject will be eligible for inclusion in this study only if all of the following criteria apply:

1. Diagnosis of NAR, as determined by the presence of perennial rhinitis symptoms that last for several months per year, for more than 1 year and are not attributed to allergy, infections or nasal abnormalities. Positive history of rhinitis symptoms triggered by environmental provocateurs (e.g. weather changes, irritants, air pollution etc), but not allergens.
2. Normal levels of total plasma IgE and negative allergy skin or Rast tests to common aeroallergens.
3. Male or female between 18 and 65 years of age inclusive.
4. A female subject is eligible to participate if she is of:

   * Non-childbearing potential defined as pre-menopausal females with a \\documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \> 40 MlU/ml and estradiol \< 40 pg/ml (\<147 pmol/L) is confirmatory\]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods in Section 8.1 if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.
   * Child-bearing potential and agrees to use one of the contraception methods listed in Section 8.1 for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until 84 days post-last treatment administration.
5. Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods listed in Section 8.1. This criterion must be followed from the time of the first dose of study medication until 84 days post-last treatment administration.
6. Body weight ≥ 50 kg (males) and ≥45kg (females) and BMI within the range 19 - 29.9 kg/m2 (inclusive).
7. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
8. Available to complete all the required study measurements.
9. Single QTc, \< 450 msec; or QTc \< 480 msec in subjects with Bundle Branch Block.
10. The subject must demonstrate at screening TSS ≥ 4 (on a 9 point scale) at screening visits 1 and 2.
11. AST and ALT \< 2xULN; alkaline phosphatase and bilirubin less than or equal to 1.5xULN (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).

Exclusion Criteria:

Deviations from exclusion criteria are not allowed because they can potentially jeopardise the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.

A subject will not be eligible for inclusion in this study if any of the following criteria apply:

1. Nasal abnormalities likely to affect the outcome of the study, i.e. nasal septal perforation, nasal polyps, other nasal malformations.
2. History of frequent nosebleeds.
3. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening
4. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
5. Positive pre-study drug/alcohol/smoking screen. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates, cannabinoids, benzodiazepines and methadone
6. A positive test for HIV antibody.
7. History of regular alcohol consumption within 6 months of the study defined as:

   • An average weekly intake of \>14 drinks for males or \>7 drinks for females. One drink is equivalent to 12 g of alcohol: 12 ounces (360 ml) of beer, 5 ounces (150 ml) of wine or 1.5 ounces (45 ml) of 80 proof distilled spirits.
8. 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: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
9. Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
10. Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days prior to the first dose of study medication, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.

    Subjects who are using some of the medications below on an as needed basis, may participate in the study if they remain free of medication for the following periods of time prior to each visit:
    * Nasal antihistamines: 48 hours
    * Oral antihistamines A (cetirizine, fexofenadine, loratadine, desloratadine): 7 days
    * Oral antihistamines B (all others): 7 days
    * Nasal decongestants: 24 hours
    * Oral decongestants: 24 hours
    * Nasal glucocorticosteroids: 4 weeks
    * Inhaled glucocorticoids: 4 weeks
    * Oral glucocorticosteroids: 12 weeks
    * Oral leukotriene receptor antagonists: 7 days
    * Oral 5-lipoxygenase inhibitors: 7 days
    * Oral methylxanthines: 7 days Subjects with recent upper respiratory tract infections (URTIs) will be allowed in the study only if their nasal symptoms have been completely resolved for more than 3 weeks prior to screening.
11. History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
12. Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
13. Pregnant females as determined by positive serum or urine hCG test at screening or prior to dosing.
14. Lactating females.
15. Unwillingness or inability to follow the procedures outlined in the protocol.
16. Subject is mentally or legally incapacitated.

Primary outcomes:
measure: Mean Total Symptom Score (TSS) Elicited by a 1 Hour (h) Cold Dry Air (CDA) Challenge, 1 h and 24 h on Day 14 to Compare the Effect of 14 Day Repeat Dosing of Intranasal SB-705498 12 mg With Placebo
timeFrame: Day 14 to Day 15 of each period (Day 14, 24 h post- dose was done on Day 15)
measure: Mean Individual Component of TSS of Rhinorrhoea (Runny Nose), Nasal Congestion and Post-nasal Drip Elicited by a 1 h CDA Challenge, 1 h and 24 h on Day 14 to Compare the Effect of 14 Day Repeat Dosing of Intranasal SB-705498 12 mg With Placebo
timeFrame: Day 14 to Day 15 of each period (Day 14, 24 h post- dose was done on Day 15)
Secondary outcomes:
measure: Mean Total Symptom Score (TSS) Elicited by a 1 Hour (h) CDA Challenge, 1 h Post-dose on Day 1 to Compare the Effect of a Single Dose of 12 mg Intranasal SB-705498 With Placebo
timeFrame: Day 1 of each period
measure: Mean Individual Component of TSS of Rhinorrhoea (Runny Nose), Nasal Congestion and Post-nasal Drip Elicited by a 1 h CDA Challenge, 1 h Post-dose on Day 1 to Compare the Effect of a Single Dose of 12 mg Intranasal SB-705498 With Placebo
timeFrame: Day 1 of each period
measure: Mean TSS From Day 7 to Day 14 (Post-dose Prior to Challenge) Following Repeat Doses of SB-705498
timeFrame: Day 7 to Day 14 of each period
measure: Mean Individual Component of TSS of Rhinorrhoea (Runny Nose), Nasal Congestion and Post-nasal Drip From Day 7 to Day 14 Following Repeat Doses of SB-705498
timeFrame: Day 7 to Day 14 of each period
measure: Mean Sneezing Elicited by a 1 h CDA Challenge at 1 h Post-dose on Day 1, 1 and 24 h Post-dose on Day 14 to Compare the Effect of Intranasal SB-705498 12 mg With Placebo
timeFrame: Day 1, Day 14 and Day 15 of each period (Day 14, 24 h post- dose was done on Day 15)
measure: Mean Change From Baseline to Day 14 of Acoustic Rhinometry (AR) Following Repeat Dosing of SB-705498 at 2 h and 25 h Post-dose
timeFrame: Baseline (Day 1 pre-dose), Day 14 and Day 15 of each period (Day 14, 25 h post dose on Day 14 was evaluated on Day 15)
measure: Mean Change From Baseline in Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) Following Repeat Doses of SB-705498 on Day 14
timeFrame: Baseline (Day 1 pre-dose) and Day 14 of each period
measure: Mean Total Ocular Symptom Score (TOSS; Red, Itchy and Tearing Eyes) Elicited by a 1 h CDA Challenge at 1 h Post-dose on Day 1, 1 and 24 h Post-dose on Day 14 to Compare the Effect of Intranasal SB-705498 12 mg Compared With Placebo
timeFrame: Day 1 and 15 of each period (Day 14, 24 h post- dose was assessed on Day 15)
measure: Pharmacokinetic Parameter of Area Under the Plasma Concentration-time Curves From Time Zero (Pre- Dose) to 3 h and 24 h (t) on Day 1 and Day 14 (AUC [0-3], AUC [0-t])
timeFrame: Pre-dose (0 h), 1, 2, 3 and 24 h post-dose on Day 1 and Day 14 of each period.
measure: Pharmacokinetic Parameter of Maximum Observed Plasma Concentration (Cmax) on Day 1 and 14
timeFrame: Pre-dose (0 h), 1, 2, 3 and 24 h post-dose on Day 1 and Day 14 of each period.
measure: Pharmacokinetic Parameter of Time to Maximum Observed Plasma Concentration (Tmax) on Day 1 and 14
timeFrame: Pre-dose (0 h), 1, 2, 3 and 24 h post-dose on Day 1 and Day 14 of each period.
measure: Number of Participants With Any Adverse Event (AE), Serious Adverse Event or Drug-related AE
timeFrame: Start of study treatment (Day 1 of first period) up to follow up, for up to 28 days.
measure: Number of Participants With Abnormal (Both Not Clinically Significant and Clinically Significant) Electrocardiogram (ECG) Findings
timeFrame: Day 1 (pre-dose) and Day 14 (pre-dose)
measure: Number of Participants With Haematology Abnormalities of Potential Clinical Importance (PCI) at Any Time During Treatment
timeFrame: Day 14 of each period
measure: Number of Participants With Clinical Chemistry PCI Abnormalities of Albumin, Calcium, Glucose, Potassium, Sodium and Total Carbon Dioxide (CO2) at Any Time During Treatment
timeFrame: Day 14 of each period
measure: Number of Participants With Clinical Chemistry PCI Abnormalities of Creatinine, Blood Urea Nitrogen (BUN), Uric Acid, Cholesterol, Triglycerides, Lactate Dehydrogenase (LDH) and Liver Function Test at Any Time During Treatment
timeFrame: Day 14 of each period
measure: Number of Participants With Vital Sign of Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), HR and Body Temperature of PCI Abnormalities at Any Time During Treatment
timeFrame: Day 1 and Day 14 of each period
Other outcomes:
Locations:
city: Mississauga
country: Canada
facility: GSK Investigational Site
state: Ontario
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: