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

Sponsor

University Hospital, Brest (Other)

Overall Status

Terminated

CT.gov ID

NCT02649751

Collaborator

ManRos Therapeutics (Other), Cyclacel Pharmaceuticals, Inc. (Industry)

Enrollment

Locations

Arms

29.1

Actual Duration (Months)

4.5

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Cystic Fibrosis	Drug: Roscovitine Drug: Placebo	Phase 2

Detailed 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.

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

49 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

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.

Actual Study Start Date :

Feb 22, 2016

Actual Primary Completion Date :

Jul 26, 2018

Actual Study Completion Date :

Jul 26, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group 1 200 mg roscovitine (8) or placebo (4) once daily for 4 cycles of 7 days (4 days "on" and 3 days "off")	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. Other Names: Seliciclib CYC202 Drug: Placebo The placebo treatment is lactose capsule.
Experimental: Group 2 400 mg roscovitine (8) or placebo (4) once daily for 4 cycles of 7 days (4 days "on" and 3 days "off")	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. Other Names: Seliciclib CYC202 Drug: Placebo The placebo treatment is lactose capsule.
Experimental: Group 3 400 mg roscovitine (8) or (4) placebo twice daily for cycles of 7 days (4 days "on" and 3 days "off")	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. Other Names: Seliciclib CYC202 Drug: Placebo The placebo treatment is lactose capsule.

Arm

Intervention/Treatment

Experimental: Group 1

200 mg roscovitine (8) or placebo (4) once daily for 4 cycles of 7 days (4 days "on" and 3 days "off")

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.

Other Names:

Seliciclib

CYC202

Drug: Placebo

The placebo treatment is lactose capsule.

Experimental: Group 2

400 mg roscovitine (8) or placebo (4) once daily for 4 cycles of 7 days (4 days "on" and 3 days "off")

Drug: Roscovitine

Other Names:

Seliciclib

CYC202

Drug: Placebo

The placebo treatment is lactose capsule.

Experimental: Group 3

400 mg roscovitine (8) or (4) placebo twice daily for cycles of 7 days (4 days "on" and 3 days "off")

Drug: Roscovitine

Other Names:

Seliciclib

CYC202

Drug: Placebo

The placebo treatment is lactose capsule.

Outcome Measures

Primary Outcome Measures

Safety of increasing doses of Roscovitine [3 months]
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

Secondary Outcome Measures

Change in the concentration of Pseudomonas Aeruginosa [3 months]
Change in the concentration (CFU/mL) of Pseudomonas aeruginosa in the sputum at each visit from V1 (Screening) up to V7 (Completion Visit).
PK parameters [3 months]
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.
Pro- and anti-inflammatory cytokines [3 months]
Monitoring the levels of pro- and anti-inflammatory cytokines, in particular: interleukin (IL)-17A, IL-5, IFN-γ, IL-1 receptor antagonist, IL-4, IL-6, IL-10, tumor necrosis factor-alpha, and IL-18 on V2, V3 and V7 (Completion Visit)
C-reactive protein [3 months]
Change in C-reactive protein (CRP) at each visit from V1 (Screening) up to V7 (Completion)
Cystic Fibrosis Questionnaire-Revised [3 months]
Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) at each visit from V1 up to V8 (Safety Follow-up)
Body Mass Index [3 months]
Change in body mass index (BMI) at each visit from V1 (Screening) up to V7 (Completion Visit)
Forced expiratory volume in 1 second [3 months]
Change in forced expiratory volume in 1 second (FEV1) at each visit from V1 (Screening) up to V7 (Completion Visit)
Sweat Chloride Concentration [3 months]
Change in Sweat Chloride Concentration at V2, V3, V5 and V7 (Completion)
Nasal Potential Difference [3 months]
Change in Nasal Potential Difference (NPD) at V1 (Screening) and V6 (for patients included in Paris Cochin CF Center)
Pain questionnaire [3 months]
Evaluate of the pain and of the impact of the pain in patients with cystic fibrosis

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	CHR - Hôpital Calmette	Lille	France	59037
2	CH Lyon Sud	Lyon	France	69495
3	Hôpital Arnaud de Villeneuve	Montpellier	France	34295
4	CHU Nantes	Nantes	France	44093
5	CHU de Nice - Hôpital Pasteur	Nice	France	06001
6	Hôpital Cochin	Paris	France	75014
7	CHU de Bordeaux - Hôpital Haut-Lévêque	Pessac	France	33604
8	Centre de Ressources et de Compétences de la mucoviscidose	Reims	France	51100
9	Centre de Perharidy	Roscoff	France	29684
10	Hôpital Larrey	Toulouse	France	30030
11	Centre Hospitalier Bretagne Atlantique	Vannes	France	56017