Safety, Tolerability, Pharmacokinetics, and Preliminary Pharmacodynamics of QBW251 in Healthy Subjects and Cystic Fibrosis Patients

Novartis

Status and phase: Terminated; Phase 2; Phase 1

Conditions: Cystic Fibrosis

Treatments: Drug: QBW251; Drug: Placebo

Study type: Interventional

Funder types: Industry

Identifiers

NCT02190604

CQBW251X2101

2011-005085-37 (EudraCT Number)

Details and patient eligibility

About

This study is designed to assess the safety, tolerability, pharmacokinetics and preliminary pharmacodynamics (proof of concept) of QBW251 in healthy subjects and cystic fibrosis patients following single and multiple doses. This first-in-human and proof of concept study will consist of 4 parts, with Parts 1 and 2 in healthy volunteers and Parts 3 and 4 in cystic fibrosis patients.

Enrollment: 153 patients

Sex: All

Ages: 18 to 65 years old

Volunteers: Accepts Healthy Volunteers

Inclusion and exclusion criteria

Key inclusion criteria (Parts 1 and 2)

• Healthy female (of non-childbearing potential) and male subjects of 18 to 55 years of age (inclusive)
• Body mass index (BMI) must be within the range of 15 to 30 kg/m2
• Oxygen saturation (O2) at screening must be ≥ 96% on room air.

Key exclusion criteria (Parts 1 and 2)

• Use of any prescription drugs or herbal supplements within four (4) weeks prior to dosing or within 5 half-lives of the drug, whichever is longer
• Over-the-counter (OTC) medication (including vitamins, dietary supplements) within two (2) weeks prior to dosing
• Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer
• Unwilling to avoid direct sun exposure by covering exposed skin, using topical sun block and wearing sunglasses from the first dose of study drug to the end of participation in the study
• Pregnant or nursing (lactating) women.

Key inclusion criteria (Parts 3 and 4):

• Male and female patients of 18 to 65 years of age (inclusive) with a confirmed diagnosis of cystic fibrosis as per the Cystic Fibrosis Foundation (CFF) consensus guidelines
• Heterozygous with one allele represented as any CFTR mutation and the other allele must represent a class III, IV, V, VI CFTR mutation (Note: since the CFTR mutation, F508del, can be considered either a class II or III mutation, heterozygous CF patients that have one allele that contains F508del, must have the other allele contain a class III (i.e., not F508del), IV, V, or VI mutation). Patients with F508del/F508del mutation should only be included in Part 3 Cohort 3.
• Body mass index (BMI) must be within the range of 15-35 kg/m2
• FEV1 at Screening must be 40 to 100% predicted (inclusive) by NHANES/Hankinson standards
• Oxygen saturation (O2) at screening must be > 90% on room air.

Key exclusion criteria (Parts 3 and 4)

• Use of herbal supplements within four (4) weeks prior to dosing or within 5 half-lives of the supplement, whichever is longer
• Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer
• Unwilling to avoid direct sun exposure by covering exposed skin, using topical sun block and wearing sunglasses from the first dose of study drug to the end of participation in the study
• Pregnant or nursing (lactating) women
• Women of child-bearing potential, UNLESS they are using highly effective contraception
• Any changes in concomitant medications for 14 days prior to screening
• History or clinical evidence of pancreatic injury or pancreatitis; clinical evidence of liver disease or liver injury as indicated by clinically significant abnormal liver function tests as judged by the investigator such as SGOT, SGPT, GGT, alkaline phosphatase, or serum bilirubin
• History or presence of impaired renal function as indicated by abnormal creatinine or BUN values or abnormal urinary constituents (e.g., albuminuria)
• History of Burkholderia cepacia respiratory tract infection (must have at least two negative cultures and no positive cultures in the past 18 months prior to screening to be eligible for enrollment)
• Sexually active males unless they use a condom during intercourse while taking drug and for condom is required to be used also by vasectomized men in order to prevent delivery of drug via seminal fluid.
• Patient is currently receiving (or has received within 4 weeks of baseline visit) VX-770/Ivacaftor.
• History of lung transplant

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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153 participants in 20 patient groups, including a placebo group

Part 1 Cohort 1: QBW251

Experimental group

Description:

Single dose of QBW251 10 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).

Treatment:

Drug: QBW251

Part 1 Cohort 2: QBW251

Experimental group

Description:

Single dose of QBW251 25 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).

Treatment:

Drug: QBW251

Part 1 Cohort 3: QBW251

Experimental group

Description:

Single dose of QBW251 75 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).

Treatment:

Drug: QBW251

Part 1 Cohort 4: QBW251

Experimental group

Description:

Single dose of QBW251 150 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).

Treatment:

Drug: QBW251

Part 1 Cohort 5: QBW251

Experimental group

Description:

Single dose of QBW251 300 mg in healthy volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).

Treatment:

Drug: QBW251

Part 1 Cohort 6: QBW251

Experimental group

Description:

Single dose of QBW251 500 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).

Treatment:

Drug: QBW251

Part 1 Cohort 6: QBW251(fed)

Experimental group

Description:

Single dose of QBW251 500 mg (fed). single dose with food for a preliminary assessment of the effect of food on the absorption of QBW251 in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).

Treatment:

Drug: QBW251

Part 1 Cohort 7: QBW251

Experimental group

Description:

Single dose of QBW251 750 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).

Treatment:

Drug: QBW251

Part 1 Cohort 8: QBW251

Experimental group

Description:

Single dose of QBW251 1000 mg in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).

Treatment:

Drug: QBW251

Part 1 Placebo

Placebo Comparator group

Description:

Placebo to QBW251 in all cohorts of part 1 in Healthy Volunteers. Each treatment period was comprised of a baseline period (Day -1), an inpatient dosing period (Days 1 to 3), three follow-up visits (Days 4, 5, and 8), and one end-of-treatment-period evaluation performed 14 days after the dose of study drug (Day 15).

Treatment:

Drug: Placebo

Part 2 Cohort 1: QBW251

Experimental group

Description:

Multiple doses of QBW25 150 mg qd in Healthy Volunteers. 14-day treatment period, follow-up study visits (Days 18, 22 and 29) and one End-of-Study evaluation (Day 36).

Treatment:

Drug: QBW251

Part 2 Cohort 2: QBW251

Experimental group

Description:

Multiple doses of QBW251 400 mg qd in Healthy Volunteers. 14-day treatment period, follow-up study visits (Days 18, 22 and 29) and one End-of-Study evaluation (Day 36).

Treatment:

Drug: QBW251

Part 2 Cohort 3: QBW251

Experimental group

Description:

Multiple doses of QBW251 750 mg qd in Healthy Volunteers. 14-day treatment period, follow-up study visits (Days 18, 22 and 29) and one End-of-Study evaluation (Day 36).

Treatment:

Drug: QBW251

Part 2 Cohort 4: QBW251

Experimental group

Description:

Multiple doses of QBW251 450 mg bid in Healthy Volunteers. 14-day treatment period, follow-up study visits (Days 18, 22 and 29) and one End-of-Study evaluation (Day 36).

Treatment:

Drug: QBW251

Part 2 Cohort 5: QBW251

Experimental group

Description:

Multiple doses of QBW251 750 mg bid in Healthy Volunteers. 14-day treatment period, follow-up study visits (Days 18, 22 and 29) and one End-of-Study evaluation (Day 36).

Treatment:

Drug: QBW251

Part 2 Placebo

Placebo Comparator group

Description:

Placebo to QBW251 in all cohorts of part 2 in Healthy Volunteers. 14-day treatment period, follow-up study visits (Days 18, 22 and 29) and one End-of-Study evaluation (Day 36).

Treatment:

Drug: Placebo

Part 3 Cohort 1: QBW251

Experimental group

Description:

150 mg b.i.d. Multiple doses. Patients having a class III, IV, V, or VI mutation on one allele and any other CFTR mutation on the other allele in patients. treatment period (Day 1 to Day 14) with study visits on Days 1, 4, 7 and 14 with follow-up visits on Days 15, 28 and 42.

Treatment:

Drug: QBW251

Part 3 Cohort 2: QBW251

Experimental group

Description:

450 mg b.i.d. Multiple doses. Patients having a class III, IV, V, or VI mutation on one allele and any other CFTR mutation on the other allele in patients. treatment period (Day 1 to Day 14) with study visits on Days 1, 4, 7 and 14 with follow-up visits on Days 15, 28 and 42.

Treatment:

Drug: QBW251

Part 3 Cohort 3: QBW251

Experimental group

Description:

450 mg b.i.d. Multiple doses. Patients who are homozygous for the F508del mutation in patients. treatment period (Day 1 to Day 14) with study visits on Days 1, 4, 7 and 14 with follow-up visits on Days 15, 28 and 42.

Treatment:

Drug: QBW251

Part 3 Placebo

Placebo Comparator group

Description:

Placebo to QBW251 in all cohorts of part 3 in patients. treatment period (Day 1 to Day 14) with study visits on Days 1, 4, 7 and 14 with follow-up visits on Days 15, 28 and 42.

Treatment:

Drug: Placebo