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A 12-week, multicenter, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of QAW039 when added to standard-of-care asthma therapy in patients with uncontrolled asthma

PHRR180320-001820

CQAW039A2316

2017-CT0434

A 12-week, multicenter, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of QAW039 when added to standard-of-care asthma therapy in patients with uncontrolled asthma

This study uses a randomized, multicenter, double-blind, placebo-controlled parallel-group study design in which QAW039 or placebo is added to incoming SoC asthma therapy (Figure 3-1).  Asthma patients who are already receiving ICS or ICS with one asthma controller medication (see inclusion criterion 4 for allowed ICS doses and combinations) are the target population for this study.  Patients will continue to receive the SoC asthma medication they were receiving at Visit 1 throughout the remainder of the study.  No change in SoC asthma medication and no dosage adjustments will be permitted throughout the study.

Regime Classification Priority
2017 - 2022 Global competitiveness and innovation in health Drug discovery and development
Start Date Duration in Months Target Completion Date Actual Completion Date
2018-07-04 17 2019-12-04 2020-01-24

Completed

Institution Classification Region LTO #
Novartis Healthcare Philippines, Inc. Private Business NCR CDRR-NCR-S-1
Institution Classification Region LTO #
PAREXEL Clinical Research (Philippines) Ltd. Corp. Private Business NCR
Institution Region
Novartis Healthcare Philippines, Inc. NCR
Name E-Mail Institution and Institution Address
Anna Liza Calingasin anna_liza.calingasin@novartis.com 5F Ayala North Exchange Building Tower One, Ayala Avenue corner Salcedo and Amorsolo Streets, San Lorenzo, Makati City 1229
Name E-Mail Institution and Institution Address
Ivy Emily Peneyro-Vergara ivy_emily.peneyro-vergara@novartis.com 5F Ayala North Exchange Building Tower One, Ayala Avenue corner Salcedo and Amorsolo Streets, San Lorenzo, Makati City 1229
Name Expertise Affiliation
Camilo C. Roa Jr., MD Pulmonology Manila Doctors Hospital
Jose Felipe Hernandez, MD Pulmonology Mary Mediatrix Medical Center
Marie Grace Dawn T. Isidro, MD Pulmonology West Visayas State University Medical Center
Teresita S. de Guia, MD Pulmonology Philippine Heart Center
Project Location Institutional Ethics Review Board
Manila Doctors Hospital Manila Doctors Hospital Institutional Review Board
Mary Mediatrix Medical Center Mary Mediatrix Medical Center Research Ethics Review Committee
West Visayas State University Medical Center N/A
Philippine Heart Center Philippine Heart Center Ethics Review Committee

Asthma

Change from baseline in pre-dose FEV1 (L) at Week 12.

1.     Change from baseline in daytime asthma symptom score over 12 weeks of treatment.

2.     Change from baseline in number of puffs of SABA taken per day over 12 weeks of treatment.

3.     Change from baseline in AQLQ+12 score at Week 12.

4. Summaries of treatment-emergent adverse events, systolic and diastolic blood pressure, pulse rate, body weight, ventricular rate, RR interval, PR interval, QRS duration, heart rate, and Fridericia’s QTc, laboratory values and change from baseline for continuous laboratory values.

Completed

  • Argentina
  • Philippines
  • Romania
  • South Africa
  • Tunisia
  • Vietnam

Clinical Trial

CQAW039A2316

20171129113153

2018-02-08

0000-00-00

50

57

The sites randomized 57 patients in the study and was able to over recruit.

2018-07-04

Patients eligible for inclusion in this study must fulfill all of the following criteria:

1.      Written informed consent and assent (if applicable) must be obtained within 14 days prior to or at Visit 1 before any assessment is performed including any adjustment to asthma medication.

2.      Male and female patients at a minimum age of 12 years (or higher minimum age limit as allowed by health authority and/or independent ethics committee/institutional review board (IEC/IRB) approvals).

3.      Patients must have a diagnosis of asthma (according to GINA 2016) for a period of at least 6 months prior to Visit 1.

4.      Patients who have been treated with:

·         Medium dose ICS, or

·         High dose ICS, or

·         Low  dose ICS plus long-acting beta agonist (LABA), or

·         Low  dose ICS plus leukotriene receptor antagonist (LTRA), or

·         Medium dose ICS plus LABA.

for at least 3 months prior to Visit 1 and the doses have been stable for at least 4 weeks prior to Visit 1. 

5.      For patients aged ≥18 years, FEV1 of ≤85% of the predicted normal value for the patient, after withholding bronchodilators at Visit 1 and Visit 101. For patients aged 12 to

NOTE: Withholding of bronchodilators prior to spirometry:

·         Short-acting β2-agonists (SABAs) ≥ 6 hours;

·         Long-acting β2-agonists (LABAs) given twice daily ≥ 12 hours;

·         LABAs given once daily ≥ 24 hours;

·         Fixed dose combinations (FDC) of LABA and ICS given twice daily ≥ 12 hours; and

·         Fixed dose combinations of LABA and ICS given once daily ≥ 24 hours.

6.      Patients must have a daytime asthma symptom score (0 to 6 scale) of ≥1 per day during 4 of the last 7 days of the placebo run-in period.

7.      Patients must have a total daily SABA use ≥1 puff per day during 4 of the last 7 days of the placebo run-in period.

8.      Demonstrated reversible airway obstruction as determined by the central reader from the spirometry vendor at Visit 1 or Visit 101.  Reversibility is defined as an increase of ≥12% and ≥200 ml in FEV1 approximately 10 to 15 minutes after administration of 400 mcg of salbutamol/albuterol (or equivalent).  Spacer devices are permitted for administration of salbutamol/albuterol (or equivalent) during reversibility testing only. The Investigator or delegate may decide whether or not to use a spacer for the reversibility testing.  

·         If reversibility is not demonstrated at Visit 1, reversibility will be attempted at Visit 101. If not achieved at Visit 101, then one additional attempt to demonstrate reversibility is permitted within 4 days following Visit 101 in an ad-hoc visit to meet this eligibility criterion. 

Review Visit 1 or Visit 101 or the one additional attempt reversibility result from overread by the spirometry vendor central reader prior to randomization.

9.      An ACQ score ≥ 1.5 at Visit 199.


Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No additional exclusions may be applied by the investigator, in order to ensure that the study population will be representative of all eligible patients.

1.      Use of other investigational drugs within 5 half-lives of enrollment, or within 30 days, whichever is longer.

2.      History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar chemical classes to QAW039.

3.      History of lactose or milk sensitivity.

4.      Patients with a history or current diagnosis of ECG abnormalities indicating significant risk of safety for patients participating in the study such as:

·         Concomitant clinically significant cardiac arrhythmias, e.g., sustained ventricular tachycardia, and clinically significant second or third degree atrioventricular (AV) block without a pacemaker.

·         History of familial long QT syndrome or known family history of Torsades de Pointes.

5.      Patients with a resting QTcF (Fridericia) ≥450 msec (male) or ≥460 msec (female) at Visit 1.

6.      Use of agents known to prolong the QT interval unless it can be permanently discontinued for the duration of the study.

7.      Patients with a history of malignancy of any organ system (other than localized basal cell carcinoma of the skin or in situ cervical cancer), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.

8.      Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test.

9.      Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using basic methods of contraception during dosing of study drug. Basic contraception methods include:

·         Total abstinence (when this is in line with the preferred and usual lifestyle of the subject) if allowed as an effective method of contraception by local regulations. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception

·         Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment.  In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment

·         Male sterilization (at least 6 months prior to screening). For female patients on the study, the vasectomized male partner must be the sole partner for that subject

·         Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) if allowed as an effective method of contraception by local regulations.  For United Kingdom: with spermicidal foam/gel/film/cream/ vaginal suppository

·         Use of oral, injected* or implanted* hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception

·         Placement of an intrauterine device (IUD) or intrauterine system (IUS)

*Not approved in Japan

In case of use of oral contraception women must have been stable on the same pill for a minimum of 3 months before taking study drug.

In case local regulations deviate from the contraception methods listed above, local regulations apply and will be described in the informed consent form (ICF).

Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.

10.  Patients who have smoked or inhaled any substance other than asthma medications within the 6 month period prior to Visit 1, or who have a cigarette smoking history of greater than 10 pack years (Note: 10 pack years = 1 pack /day x 10 yrs., or ½ pack/day x 20 yrs.).

11.  Patients who have had an asthma exacerbation requiring systemic corticosteroids, hospitalization, or emergency room visit within 6 weeks prior to Visit 1. 

12.  Patients who have an asthma exacerbation requiring systemic corticosteroids, hospitalization or emergency room visit during the screening or placebo run-in periods. Patients who experience an asthma exacerbation during screening may be re-screened 4 weeks after complete recovery from the exacerbation.

13.  Patients who have had a respiratory tract infection or asthma worsening within 4 weeks of Visit 1.  Patients who experience a respiratory tract infection or asthma worsening during screening may be re-screened after 4 weeks after recovery.

14.  Patients with any chronic condition of the respiratory tract which in the opinion of the investigator may interfere with study evaluation or optimal participation in the study.

15.  Patients with a history of chronic lung disease other than asthma, including (but not limited to) chronic obstructive pulmonary disease (as defined by Global Initiative For Chronic Obstructive Lung Disease (GOLD) standards), bronchiectasis, (non-clinically significant bronchiectasis may be allowed provided recent (within 3 months prior to Visit 101) computed tomography (CT) scan proof is available), sarcoidosis interstitial lung disease, cystic fibrosis, and tuberculosis.

16.  Patients with a history of conditions other than asthma or allergic rhinitis that could result in elevated eosinophils (e.g., hypereosinophilic syndromes, Churg-Strauss Syndrome, eosinophilic esophagitis).  Patients with known parasitic infestation within 6 months prior to Visit 1 are also excluded.

17.  Patients with uncontrolled diabetes having an hemoglobin A1c (HbA1c) test result ≥8% at the Visit 1 laboratory test.

18.  Patients who have a clinically significant laboratory abnormality at  the Visit 1 laboratory test including (but not limited to):

·         Total white blood cell count

·         Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.0 X ULN or total bilirubin >1.3 X ULN;

·         Estimated Glomerular Filtration Rate (eGFR) by the modification of diet in renal disease study (MDRD) equation or Bedside Schwartz equation  

19.  Patients who in the judgment of the investigator have a clinically significant condition such as (but not limited to) unstable ischemic heart disease, New York Heart Association (NYHA) Class III/IV left ventricular failure, arrhythmia, uncontrolled hypertension, cerebrovascular disease, neurodegenerative diseases, or other neurological disease, uncontrolled hypo- and hyperthyroidism and other autoimmune diseases, hypokalemia, hyperadrenergic state, or ophthalmologic disorder or patients with a medical condition that might compromise patient safety or compliance, interfere with evaluation, or preclude completion of the study.

20.  Patients with a history of myocardial infarction within 12 months of Visit 1.

21.  Patients with serious co-morbidities including, but not limited to, neurodegenerative diseases, rheumatoid arthritis and other autoimmune diseases.

22.  Patients with a history of alcohol or drug abuse within 12 months prior to Visit 1.

23.  Patients with a weight

24.  Patients aged 12 to Center for Disease Control and Prevention, 2000) if local growth charts are not available).

25.  Patients receiving any other asthma treatment that is not stipulated in Inclusion Criterion #4.

26.  Patients receiving any medications in the classes listed in Table 5-3 must be excluded unless they meet the criteria as specified in Table 5-3.

27.  Patients receiving medications in the classes listed in Table 5-1must be excluded unless the medication has been stabilized for the specified period and the stated conditions have been met.

28.  Patients who started immunotherapy or desensitization for allergies, within 3 months prior to Visit 1, or where the maintenance dose is expected to change during the study.

29.  Patients with a known history of non-compliance to medication or who are unable or unwilling to complete an electronic patient diary or who are unable or unwilling to use the Electronic Peak Expiratory Flow (PEF) with eDiary device or who are unable to demonstrate good eDiary compliance (defined as >70% compliance) during the placebo run-in period.

30.  Inability to comply with all study requirements and demonstrate good study drug compliance (≥ 80% compliance) during the placebo run-in period.

31.  Patients with any medical or psychological condition that, in the investigator’s opinion, renders the patient unable to understand the nature, scope, and possible consequences of the study.

32.  Patients with a history of being unable to swallow tablets.

33.  Patients who have received methotrexate, oral gold, troleandomycin, cyclosporine azathioprine or any experimental anti-inflammatory therapies within 6 months of Visit 101.

34.  Patients with regular use of oral or systemic corticosteroids within 12 months or any intra-articular or short-acting, intramuscular corticosteroid within 1 month or intramuscular, long acting depot corticosteroids within 3 months of Visit 101.

35.  Patients who have a history of or current treatment for hepatic disease including but not limited to acute or chronic hepatitis, cirrhosis or hepatic failure.

36.  Patients with a history of immunodeficiency disease or hepatitis B or hepatitis C.

37.  Patients on >20 mg of simvastatin, > 40 mg of atorvastatin, > 40 mg of pravastatin, or >2 mg of pitavastatin.  Statin doses less than or equal to these doses as well as other statins will be permitted during the study.

38.  Patients on any statin therapy with a CK level >2 x ULN at Visit 1.

39.  Patients on rifampin, probenecid, ritonavir and valproic acid (i.e. medications blocking several pathways important for the elimination of QAW039 (broad range uridine-diphosphate glucuronosyltransferase (UGT) inhibition and/or inhibition of organic anion transporter 3 (OAT3), organic anion transporter P1B3 (OATP1B3), multi-xenobiotic resistance protein (MXR) and p-glycoprotein (P-gp)).

40.  No person directly associated with the administration of the study is allowed to participate as a study subject.

 

41.  No family member of the investigational study staff is allowed to participate in this study.

Interventional

QAW039/Fevipiprant

Fevipiprant (QAW039) is a DP2 antagonist expected to provide benefit in asthma by binding to prostaglandin D2 receptor 2 (DP2)on eosinophils, basophils, and T lymphocytes in the blood and tissues; thus, inhibiting migration and activation of these cells into the airway tissues and blocking the PGD2-driven release of T helper 2 (Th2) cytokines

Date Amendment Classification Reason
2018-11-16 Amendments related to the protocol Informed consent

Randomized

Double Blind

During the placebo run-in period, all patients will receive placebo to QAW039 once daily (one tablet blinded placebo to QAW039 150 mg). Patients will be assigned to one of two treatment arms as follows in a 1:1 ratio in the treatment period: ·         QAW039 150 mg once daily ·         Matching placebo to QAW039 150 mg, once daily

Parallel

The purpose of this study is to determine the efficacy and safety of QAW039 (150 mg once daily), compared with placebo, when added to standard-of-care (SoC) asthma therapy in adult and adolescent (≥12 years) patients with uncontrolled asthma with respect to change from baseline in FEV1 at the end of 12 weeks of treatment.

Phase III

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