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

• ClinicalTrials.gov Identifier: NCT02649751
• Recruitment Status: Terminated
• First Posted: January 7, 2016
• Last Update Posted: December 13, 2018
• Sponsor: University Hospital, Brest
• Collaborators: ManRos Therapeutics; Cyclacel Pharmaceuticals, Inc.
• Information provided by (Responsible Party): University Hospital, Brest

Tracking Information

• First Submitted Date: January 6, 2016
• First Posted Date: January 7, 2016
• Last Update Posted Date: December 13, 2018
• Actual Study Start Date: February 22, 2016
• Actual Primary Completion Date: July 26, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 6, 2016)

Safety of increasing doses of Roscovitine [ Time Frame: 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

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: January 6, 2016)

• Change in the concentration of Pseudomonas Aeruginosa [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 3 months ]
  Change in C-reactive protein (CRP) at each visit from V1 (Screening) up to V7 (Completion)
• Cystic Fibrosis Questionnaire-Revised [ Time Frame: 3 months ]
  Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) at each visit from V1 up to V8 (Safety Follow-up)
• Body Mass Index [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 3 months ]
  Change in Sweat Chloride Concentration at V2, V3, V5 and V7 (Completion)
• Nasal Potential Difference [ Time Frame: 3 months ]
  Change in Nasal Potential Difference (NPD) at V1 (Screening) and V6 (for patients included in Paris Cochin CF Center)
• Pain questionnaire [ Time Frame: 3 months ]
  Evaluate of the pain and of the impact of the pain in patients with cystic fibrosis

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

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.

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.

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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Cystic 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.
  Other Names:

  • Seliciclib
  • CYC202
• Drug: Placebo
  The placebo treatment is lactose capsule.

Study Arms

• 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")
  Interventions:

  • Drug: Roscovitine
  • Drug: Placebo
• 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")
  Interventions:

  • Drug: Roscovitine
  • Drug: Placebo
• Experimental: Group 3
  400 mg roscovitine (8) or (4) placebo twice daily for cycles of 7 days (4 days "on" and 3 days "off")
  Interventions:

  • Drug: Roscovitine
  • Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: August 1, 2018): 49
• Original Estimated Enrollment (submitted: January 6, 2016): 36
• Actual Study Completion Date: July 26, 2018
• Actual Primary Completion Date: July 26, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France

Administrative Information

• NCT Number: NCT02649751
• Other Study ID Numbers: RB 15.098 (ROSCO CF)
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: University Hospital, Brest
• Original Responsible Party: Same as current
• Current Study Sponsor: University Hospital, Brest
• Original Study Sponsor: Same as current

Collaborators

• ManRos Therapeutics
• Cyclacel Pharmaceuticals, Inc.

Investigators

• Principal Investigator: Gilles RAULT, MD; Centre de Pérharidy - Roscoff

• PRS Account: University Hospital, Brest
• Verification Date: July 2018