Evaluation of (R)-Roscovitine Safety and Effects in Subjects With Cystic Fibrosis, Homozygous for the F508del-CFTR Mutation

Cystic Fibrosis Clinical Trial

— ROSCO-CF  

Official title:

A Phase II, Dose Ranging, Multicenter, Double-blind, Placebo Controlled Study to Evaluate Safety and Effects of (R)-Roscovitine in Adults Subjects With Cystic Fibrosis, Carrying 2 Cystic Fibrosis Causing Mutations With at Least One F508del-CFTR Mutation and Chronically Infected With Pseudomonas Aeruginosa, a Study Involving 36 CF Patients (24 Treated, 12 Controls). ROSCO-CF.

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02649751
• Other study ID #: RB 15.098 (ROSCO CF)
• Status: Terminated
• Phase: Phase 2
• Start date: February 22, 2016
• Est. completion date: July 26, 2018

Study information

• Verified date: July 2018
• Source: University Hospital, Brest
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a phase II, dose ranging, multicenter, randomized, double-blind, placebo-controlled study.

The aim of this study is to assess the safety of increasing doses of roscovitine administered orally for 4 cycles of 4 consecutive days (treatment "on") separated by a 3 days treatment free period (treatment "off") in adult CF subjects with Cystic Fibrosis carrying 2 Cystic Fibrosis causing mutations with at least one F508del-CFTR mutation and chronically infected with Pseudomonas aeruginosa.

This study involved 36 Cystic Fibrosis patients: 24 treated and 12 controls.

Description:

ROSCO-CF is a phase II, dose ranging, multicenter, double-blind, placebo controlled study to evaluate safety and effects of (R)-roscovitine in subjects with Cystic Fibrosis carrying 2 Cystic Fibrosis causing mutations with at least one F508del-CFTR mutation and chronically infected with Pseudomonas aeruginosa.

The aim of this study is to assess the safety of increasing doses of roscovitine administered orally for 4 cycles of 4 consecutive days (treatment "on") separated by a 3 days treatment free period (treatment "off") in 36 adult cystic fibrosis subjects.

These 36 patients will be allocated to 3 groups of 12 subjects who will be randomized in a 2:1 ratio (active drug to matching placebo). In each group, 8 patients will receive roscovitine (200 mg, 400 mg, 2 X 400 mg in group 1, 2 and 3, respectively) and 4 will receive a matching placebo. Treatment will be provided by oral administration of capsules. Each patient will receive the same treatment throughout the 28 day study.

This phase II trial will give some preliminary information about safety and hints of effects of a new experimental treatment. If the data suggest that a short term treatment with roscovitine provides a safe, effective and convenient approach for CF patients chronically infected with Pseudomonas aeruginosa, patients participating in this proof of concept trial will be offered to participate in further longer term studies.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 49
• Est. completion date: July 26, 2018
• Est. primary completion date: July 26, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Male or female aged over 18 years of age on the date of informed consent;

• Diagnosed CF patients. Confirmed diagnosis of CF (Rosenstein and Cutting, 1998);

• Patients carrying 2 Cystic Fibrosis causing mutations with at least one F508del-CFTR mutation, genotype to be confirmed at screening;

• Forced expiratory volume at 1 second (FEV1) 40%

• Chronic lung Pseudomonas aeruginosa infection according to the definition from the French Consensus Conference;

• Able to understand and comply with all protocol requirements, restrictions and instructions and likely to complete the study as planned (as judged by the investigator);

• Provide written informed consent prior to the performance of any study-related procedure;

Exclusion Criteria:

• Acute upper or lower respiratory infection, pulmonary exacerbation or changes in therapy (including antibiotics) for pulmonary disease within 4 weeks before V2;

• Recent patient reported history of:

• non recovered viral upper respiratory tract infection

• solid organ or hematological transplantation

• Burkholderia cepacia complex or Non Tuberculous Mycobacteria (NTM) respiratory tract infection;

• Undergone major surgery within 1 month prior to screening;

• Currently treated allergic broncho-pulmonary aspergillosis (ABPA);

• Diabetic patients whose blood glucose is poorly controlled as evidenced by HbA1C >8%;

• Hemoptysis more than 60 mL at any time within 4 weeks prior to first study drug administration (V2);

• History of any other comorbidity that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug to the subject;

• Any other clinically significant conditions (not associated with the study indication) at Screening (V1) which might interfere with the assessment of this study;

• Any of the following abnormal laboratory values at screening:

• Hemoglobin <10 g/dL

• Abnormal liver function

• Serum K+ <3,5 mmol/L

• Abnormal renal function

• Any clinically significant laboratory abnormalities;

• Patients who have clinically significant impairment in cardiovascular function;

• Concomitant disease(s) that could prolong the QT interval;

• Patients with a history of alcohol or drug abuse in the past year;

• Patients with a history of noncompliance to medical regimens and patients or caregivers who are considered potentially unreliable;

• Use of one (or several) prohibited medications and/or food;

• Administration of any investigational drug within 30 days prior to Screening (V1) or 5 half-lives, whichever is longer;

• Use of systemic anti-pseudomonal antibiotics within 28 days prior to first study drug administration (V2). However use of inhaled anti-pseudomonal antibiotic treatment is allowed if initiated for more than 28 days;

• Use of loop diuretics within 7 days prior to first study drug administration (V2);

• Pregnant or nursing females.

Related Conditions & MeSH terms

• Cystic Fibrosis
• Fibrosis

Intervention

Drug:
• Roscovitine
Roscovitine is an experimental drug candidate in the family of pharmacological cyclin-dependent kinase (CDK) inhibitors that preferentially inhibit multiple enzyme targets including CDK2, CDK7 and CDK9. Seliciclib is a 2,6,9-substituted purine analog.
• Placebo
The placebo treatment is lactose capsule.

Locations

Country	Name	City	State
France	CHR - Hôpital Calmette	Lille
France	CH Lyon Sud	Lyon
France	Hôpital Arnaud de Villeneuve	Montpellier
France	CHU Nantes	Nantes
France	CHU de Nice - Hôpital Pasteur	Nice
France	Hôpital Cochin	Paris
France	CHU de Bordeaux - Hôpital Haut-Lévêque	Pessac
France	Centre de Ressources et de Compétences de la mucoviscidose	Reims
France	Centre de Perharidy	Roscoff
France	Hôpital Larrey	Toulouse
France	Centre Hospitalier Bretagne Atlantique	Vannes

Sponsors (3)

Lead Sponsor	Collaborator
University Hospital, Brest	Cyclacel Pharmaceuticals, Inc., ManRos Therapeutics

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety of increasing doses of Roscovitine	The primary objective of this study is to assess the safety of increasing doses of roscovitine administered orally for 4 cycles of 4 consecutive days (treatment "on") separated by a 3 days treatment free period (treatment "off") in adult CF subjects who carrying 2 Cystic Fibrosis causing mutations with at least F508del mutation	3 months
Secondary	Change in the concentration of Pseudomonas Aeruginosa	Change in the concentration (CFU/mL) of Pseudomonas aeruginosa in the sputum at each visit from V1 (Screening) up to V7 (Completion Visit).	3 months
Secondary	PK parameters	PK parameters: Maximum Concentration (Cmax), Time to reach Cmax (Tmax), Area Under Curve (AUCt and AUCInf), Half-life (t1/2) for roscovitine and its M3 metabolite.	3 months
Secondary	Pro- and anti-inflammatory cytokines	Monitoring the levels of pro- and anti-inflammatory cytokines, in particular: interleukin (IL)-17A, IL-5, IFN-?, IL-1 receptor antagonist, IL-4, IL-6, IL-10, tumor necrosis factor-alpha, and IL-18 on V2, V3 and V7 (Completion Visit)	3 months
Secondary	C-reactive protein	Change in C-reactive protein (CRP) at each visit from V1 (Screening) up to V7 (Completion)	3 months
Secondary	Cystic Fibrosis Questionnaire-Revised	Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) at each visit from V1 up to V8 (Safety Follow-up)	3 months
Secondary	Body Mass Index	Change in body mass index (BMI) at each visit from V1 (Screening) up to V7 (Completion Visit)	3 months
Secondary	Forced expiratory volume in 1 second	Change in forced expiratory volume in 1 second (FEV1) at each visit from V1 (Screening) up to V7 (Completion Visit)	3 months
Secondary	Sweat Chloride Concentration	Change in Sweat Chloride Concentration at V2, V3, V5 and V7 (Completion)	3 months
Secondary	Nasal Potential Difference	Change in Nasal Potential Difference (NPD) at V1 (Screening) and V6 (for patients included in Paris Cochin CF Center)	3 months
Secondary	Pain questionnaire	Evaluate of the pain and of the impact of the pain in patients with cystic fibrosis	3 months