Sent: 18 April 2014 16:02 To: Patel, Sanjay [md0u92cd] Cc: Southern, Kevin
Subject: RE: Cochrane Systematic Review of CFTR correctors - request for information
thank you for the note, Sanjay. I'll need to ask vertex for the data/information that you request. I do not have the data personally
best, jpc
From: Patel, Sanjay [md0u92cd] [[email protected]] Sent: Wednesday, April 16, 2014 5:26 AM
To: Clancy, John Cc: Southern, Kevin
Subject: Cochrane Systematic Review of CFTR correctors - request for information Dear Professor Clancy,
I am a postgraduate researcher at the University of Liverpool, UK. My research topic is on the novel cystic fibrosis mutation specific therapies that target the underlying CFTR defect. As part of my research, I am working with the Cochrane Cystic Fibrosis & Genetic Disorders Group to conduct a Cochrane systematic review on CFTR correctors. I have attached a copy of the protocol for this systematic review for your information.
We would like to include the study “Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation” (Clinical trial number NCT00865904). I am contacting you to request for:
1) additional data for the outcomes measured during the trial; 2) data for other outcomes important to our review;
3) information on missing data; 4) the trial protocol;
5) information on any additional clinical trials of CFTR corrects that you may be aware of.
1. For the following continuous data outcomes we would appreciate it if you were able to send us values for the mean and standard deviation for each group (all treatment groups and control).
a) Relative change from baseline in FEV1 b) Change from baseline in FVC and FEF25-75
c) Change from baseline in sweat chloride concentration
In addition we would like to know what respiratory adverse events caused study drug termination in the 4 discontinued participants and how many subjects required study interruption and the reason for this.
154 Some of this information has been provided in the publications. However the table below shows exactly what information is required.
2. There are outcomes in our review, that do not correspond to outcomes measured in your trial however we feel it is important to request this information, in case the information available. The additional outcomes we would like data for are
a. Survival
b. Hospital admissions c. School/work days missed d. Extra antibiotics
e. Radiological outcomes
f. Nutritional outcomes (weight, height, BMI)
g. Acquisition and eradication of respiratory pathogens 3. Issues on missing data that require clarification:
a. In Table 2 (Frequency of occurrence of adverse events occurring in more than one subject in any VX-809 treatment group), the total number of subjects in the trial is shown to be 45, yet the total number of randomised participants is 89.
b. In Figure 1b (Sweat chloride change from baseline to day 28) the total number of participants in the treatment arms adds up to 63 (16+16+15+16). However, a total of 72 participants were randomised to the intervention arms.
Outcome measure Data required
Relative change from baseline in FEV1 through day 28
1. Standard deviation values for the mean change from baseline results in all treatment arms
Change from baseline in FVC and FEF25 75 through day 28
1. Mean change from baseline in each arm. 2. Standard deviation for the change from
baseline results in all treatment arms Change from baseline in sweat chloride
concentration through day 28
1. Mean change from baseline in each arm. 2. Standard deviation for the change from
baseline results in all treatment arms. NB: We understand that data has been plotted on a graph, but we cannot estimate the values from the graph with accuracy.
Safety 1. Number of participants who required
study drug interruption and why 2. What respiratory adverse events caused
study drug termination in the 4 discontinued participants?
155 c. In Supplementary appendix, the CFQ-R domain scores have been reported. The number of
participants analysed (n = 85) excludes 4 recruited participants.
4. We would also like to request the trial protocol.
5. So far we have retrieved the following additional studies through our electronic and manual literature searches.
1. Boyle 2011: “Study of VX-809 Alone and in Combination With VX-770 in Cystic Fibrosis (CF) Patients Homozygous or Heterozygous for the F508del-CFTR Mutation” (Clinical trial number NCT01225211)
2. Donaldson 2013: “VX-661, an investigational CFTR corrector, in combination with ivacaftor, a CFTR potentiator, in patients with CF and homozygous for the F508Del-CFTR mutation”
(Clinical trial number NCT01531673)
3. McCarty 2002: “A Phase 1 Randomized, Multicenter Trial of CPX in Adult Subjects With Mild Cystic Fibrosis” (Clinical trial number NCT00004428)
4. Rubenstein 1998 “A Pilot Clinical Trial of Oral Sodium 4-Phenylbutyrate (Buphenyl) in DF508- Homozygous Cystic Fibrosis Patients”
5. Zeitlin 2002 “Evidence of CFTR Function in Cystic Fibrosis after Systemic Administration of 4- Phenylbutyrate”
As a leader in the field of cystic fibrosis, I would also like to ask if you know about any additional clinical trials on CFTR correctors (with published or unpublished results) that we may have missed out.
Thank you for taking the time out to read this e-mail. Any additional information would go towards shaping the results of the review and would be highly appreciated. We will, of course, acknowledge your assistance in the published version of the review.
156 Evidence of contact with primary author of the Lumacaftor-Ivacaftor study
E-mail 16: Interaction with primary author of the Lumacaftor-Ivacaftor study before publication of