Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05519020 |
| Other study ID # |
STH22060 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
July 27, 2022 |
| Est. completion date |
December 31, 2026 |
Study information
| Verified date |
August 2022 |
| Source |
Sheffield Teaching Hospitals NHS Foundation Trust |
| Contact |
Tracey E Daniels, MSc |
| Phone |
07866 206204 |
| Email |
traceydaniels1[@]nhs.net |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Cystic fibrosis (CF) is a life-limiting and life-long genetic condition which requires
intensive preventative treatment to manage the symptoms and progression of disease. While
preventative treatments target the effects of cystic fibrosis, precision medicines target the
underlying dysfunction of the cystic fibrosis transmembrane regulator (CFTR) protein at a
cell level.
The first of these expensive precision medicines also known as modulator therapies,
Ivacaftor, was shown to be highly effective in clinical trials with an increase of over 10%
in lung function. Real-world studies showed an increase of only 6% and a return to baseline
lung function by year five of treatment. Preventative therapies were continued during the
Ivacaftor clinical trials whereas there is real world evidence of declining inhaled
preventative therapy use following Ivacaftor initiation. This is a potential explanation for
the efficacy-effectiveness gap. The first study in the National Efficacy Effectiveness
Modulator Optimisation (NEEMO) programme is exploring this (REC ref: 21/HRA/4940, IRAS
301975).
Ivacaftor/Tezacaftor/Elexacaftor is the most recent modulator available, commissioned in the
UK (United Kingdom) in 2020, and suitable for around 90% of people with cystic fibrosis. It
is not yet known if the efficacy effectiveness gap seen with Ivacaftor also exists for
Ivacaftor/Tezacaftor/Elexacaftor. There is also uncertainty about the continued need for
preventative inhaled therapy alongside the prescription of Ivacaftor/Tezacaftor/Elexacaftor.
This second study in the NEEMO programme is a cohort, observational study and will explore
adherence to inhaled preventative therapies in adults with cystic fibrosis before and after
commencing Ivacaftor/Tezacaftor/Elexacaftor, and in those not prescribed
Ivacaftor/Tezacaftor/Elexacaftor. It will also look at the relationship between adherence to
preventative inhaled therapy and outcome for adults with CF taking
Ivacaftor/Tezacaftor/Elexacaftor. The analysis will use routinely collected pseudo anonymised
data from the CFHealthHub learning health system (CFHealthHub), alongside anonymised data
from the CF registry and routinely collected clinical data.
Description:
Aim of the study:
To understand the impact of adherence to preventative inhaled therapies on outcomes in people
with CF (pwCF) treated with Ivacaftor/Tezacaftor/Elexacaftor.
Background:
Cystic Fibrosis (CF) is a multi-system, life-long genetic condition affecting around 10,500
people in the UK with a median predicted survival of 49 years. The gene mutations responsible
for CF result in dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR),
which acts as a chloride channel. Impaired chloride secretion in CF leads to sticky and thick
secretions for a range of epithelial tissues such as the airways and pancreatic duct. This
results in malabsorption, suboptimal nutritional status, recurrent respiratory infections,
progressive lung damage and respiratory failure.
Standard treatment for CF, until recently, has focused on managing the symptoms and
consequences of CF. Inhaled therapies, specifically inhaled antibiotics, mucolytics and
osmotics, are particularly important to reduce exacerbations and maintain lung health in
people with CF.
Precision medicines, in the form of highly effective CFTR modulators, first became available
around a decade ago for those with CF caused by a gating mutation, comprising around 5% of
the CF population. Further developments now see highly effective modulators suitable for
around 90% of people with CF (pwCF). This is changing the landscape for many pwCF with rapid
and transformative improvements in health. This rapid change creates some uncertainty about
the ongoing need for established treatment regimens.
The landmark randomised controlled trial evaluating the efficacy of Ivacaftor among pwCF and
the G551D gene mutation found a 10.6% between-group difference in forced expiratory volume in
one second (FEV1) over twelve months in favour of Ivacaftor. The between-group FEV1
difference was 9.9% even among adults ≥18 years in the RCT (Randomised Controlled Trial).
Real world data from the UK CF registry found a between-group FEV1 difference of only 6% over
twelve months. This efficacy-effectiveness gap is unlikely to be fully explained by
differences in people's characteristics compared to the RCT because Ivacaftor was licensed in
the UK only for people with at least one G551D gene mutation during the period of evaluation
(from 2012 to 2013).
Preventative inhaled therapies were continued during the randomised controlled trial whereas
there is real world evidence of declining inhaled therapies prescription and use following
Ivacaftor initiation. This provides a potential explanation as to why the real-world
effectiveness of Ivacaftor was only around 60% of the efficacy observed in the randomised
controlled trial where participants are likely to have maintained high level of adherence to
inhaled therapies.
Ivacaftor/Tezacaftor/Elexacaftor is a combination modulator commissioned in the UK in the
summer of 2020 and is suitable for around 90% of the CF population. The first key randomised
controlled trial involved 403 people with a F508del mutation and a minimal function mutation.
After 24 weeks of treatment, people who took Ivacaftor/Tezacaftor/Elexacaftor had an average
increase in percentage point of forced expiratory volume in the first second (ppFEV1) of 13.9
percentage points compared with a reduction of 0.4 percentage points in people who took
placebo. In another study involving 107 people with two F508del mutations, people who took
Ivacaftor/Tezacaftor/Elexacaftor had an average increase in ppFEV1 of 10.4 percentage points
compared with an increase of 0.4 percentage points in people who took a combination of
Ivacaftor and Tezacaftor alone.
Data is not yet available to identify whether the efficacy effectiveness gap seen for
Ivacaftor also exists for Ivacaftor/Tezacaftor/Elexacaftor. There is a unique opportunity
within the CFHealthHub learning health system to answer this important research question
owing to the unique dataset of objective inhaled therapy adherence data available only within
CFHealthHub.
Plan of the investigation This will be an observational study designed to emulate a target
trial; the target trial being a comparison of Ivacaftor/Tezacaftor/Elexacaftor with usual
care.
Methodology Adults with cystic fibrosis, who attend one of the CF centres within, or
previously participating in, the CFHealthHub learning health system (REC ref: 17/LO/0032,
IRAS 216782) and who are, or have ever been, prescribed Ivacaftor/Tezacaftor/Elexacaftor will
be identified by their local centre. Data will also be analysed for people with CF from these
centres who do not participate in CFHealthHub but who consent to share their data with the CF
Registry (REC ref: 07/Q0104/01, IRAS 35220).
The CFHealthHub digital Learning Health System (ISRCTN14464661) consists of seventeen adult
CF centres in the UK (with around 1,500 adults involved) where the metric for improvement is
medication adherence. Electronic data capture of preventative inhaled therapy is undertaken
using a bluetooth enabled nebuliser device (eTrack® or Ineb®) which connects to a platform
accessible by people with CF and by their care team to view the inhaled preventative therapy
adherence data. CFHealthHub is conducted as a trials within cohorts study and, therefore, at
the point of entry, people have the option to consent to pseudo-anonymised data within
CFHealthHub to be used for future research and also to be included for selection in future
research studies which have been ethically approved.
The UK Cystic Fibrosis Registry (Doi: 10.1093/ije/dyx196) is a UK based, secure centralised
database, sponsored and managed by the Cystic Fibrosis Trust. Over 99% of people with CF
across every UK specialist centre and clinic have consented to their data being submitted to
the CF registry by their CF care teams. When consenting to the CF registry people have the
option to consent to anonymised data being shared with researchers both in the UK and in
other countries.
For people consented to both CFHealthHub and the CF registry, data from CFHealthHub, the CF
registry and routine clinical data will be collected by the local centre on a standardised
spreadsheet. Data will include: month and year of birth; sex; ethnicity; height; pancreatic
and diabetic status; FEV1; body mass index; date of starting and stopping (if applicable)
Ivacaftor/Tezacaftor/Elexacaftor; Pseudomonas status; medications; comorbidities; healthcare
utilisation (oral and intravenous antibiotic days); adherence to
Ivacaftor/Tezacaftor/Elexacaftor (measured by medication possession ratio); and effective
adherence to preventative inhaled therapies.
Data will be collected and analysed from twelve months before
Ivacaftor/Tezacaftor/Elexacaftor initiation and, annually, for five years after initiation.
For those consented only to the CF registry, data will be collected as above but without
inhaled therapy adherence data.
Design This is a cohort observational study utilising data collected as part of routine
clinical practice and/or ongoing approved research projects. This design is being used to
explore the effect of starting precision medicines on adherence to preventative inhaled
therapy adherence and the place of preventative inhaled therapy adherence as a potential
target to optimise outcomes for people with CF taking Ivacaftor/Tezacaftor/Elexacaftor.
Sample size A corresponding trial powered for an effect size of 8% FEV1 difference between
control and treatment arm (based on a similar efficacy-effectiveness gap to that observed for
ivacaftor) would require n=50 participants in each arm to achieve 90% power at 5%
significance. Given an estimated pool of 150 control participants, and 1300 treated
participants this should easily be reached.
For consideration of different effect sizes among different adherence, we note that a
corresponding trial powered for an effect size of 3% FEV1 difference between high and low
adherers would require n=400 participants in each arm to achieve 90% power at 5%
significance.
In addition, these numbers demonstrate that a loss of availability of 20% of participants
(i.e., reduction to 120 control patients and 1040 treated patients) would be tolerable.
Analysis FEV1, body mass index, age at starting ivacaftor, CFTR genotype, sex, Pseudomonas
status, medications, comorbidities, healthcare utilisation, adherence to
Ivacaftor/Tezacaftor/Elexacaftor (measured by medication possession ratio) and effective
adherence to preventative inhaled therapies (where the person is consented to CFHealthHub)
will be analysed from 12 months before Ivacaftor/Tezacaftor/Elexacaftor initiation and at six
months after Kaftrio initiation, then 12-monthly intervals following that.
For the people consented to and with data within CFHealthHub, the inhaled therapy adherence
data will be explored, including determinants of adherence, and comparisons will be performed
among those with different levels of adherence. FEV1 and BMI data will be presented as change
from baseline to determine the difference between real-world effectiveness and the efficacy
observed in clinical trials. The highest value recorded in the six months prior to starting
Ivacaftor/Tezacaftor/Elexacaftor will be used as the baseline. This is an approach taken in
previous literature assessing the longitudinal effects of Ivacaftor. Regression analysis will
be used to look at the association between MPR (Medication Possession Ratio) and clinical
outcomes and the association between adherence to preventative inhaled therapies and clinical
outcomes.
The approach will follow the target trial emulation approach. Time zero will be the date of
Ivacaftor/Tezacaftor/Elexacaftor initiation among those eligible for
Ivacaftor/Tezacaftor/Elexacaftor (treated group). Time zero for eligible controls (i.e.,
those ineligible for any CFTR modulators) will have their time zero drawn at random from the
list of start dates for treated group. This approach of selecting time zero for controls is
similar to the Salford Lung Study. As a sensitivity analysis, time zero will be set as 21st
Aug 2020 for all participants since that is the date of Ivacaftor/Tezacaftor/Elexacaftor
announcement by the UK CF Trust.
The outcome is best FEV1 in the defined study period, with mean FEV1 over that period as a
sensitivity analysis. A previous analysis by the epidemiologic study of cystic fibrosis group
has identified average FEV1 over a six-month period as potentially a more relevant marker of
lung health compared to best FEV1.
Inverse probability weighting will be conducted to achieve exchangeability between treated
and control groups at baseline. Identified confounders are: age; gender; baseline FEV1; and
prior year IV days. Baseline FEV1 is the best FEV1 in a six-month period prior to time zero,
with mean FEV1 in that period as a sensitivity analysis.
Analysis 1: this is a comparison of the best FEV1 over the six month period a month following
time zero (then in 12-monthly intervals until Year 5) in a linear model of the weighted
population.
Analysis 2: the efficacy-effectiveness gap is evaluated as the difference in the FEV1 effect
size identified in analysis one, and the FEV1 effect size identified in the trial9 (which was
14.3% for those with a single copy of F508del mutation in comparison to placebo).
Analysis 3: this is a descriptive analysis in which adherence to preventative inhaled therapy
is described in both treatment and control groups. It will be identified whether adherence
decreases more in the treatment groups, and if there are specific individuals in the
treatment group whose adherence drops substantially.
Analysis 4: a per-protocol trial will be emulated, in which individuals are only considered
for the treatment group when their adherence remains sufficient on all medications, including
Ivacaftor/Tezacaftor/Elexacaftor. Exploratory analyses of the health outcomes among people
with differing levels of adherence will also be performed.
