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Alton EWFW, Armstrong DK, Ashby D, et al.; on behalf of the UK Cystic Fibrosis Gene Therapy Consortium. A randomised, double-blind, placebo-controlled trial of repeated nebulisation of non-viral cystic fibrosis transmembrane conductance regulator (CFTR) gene therapy in patients with cystic fibrosis. Southampton (UK): NIHR Journals Library; 2016 Jul. (Efficacy and Mechanism Evaluation, No. 3.5.)

Cover of A randomised, double-blind, placebo-controlled trial of repeated nebulisation of non-viral cystic fibrosis transmembrane conductance regulator (CFTR) gene therapy in patients with cystic fibrosis

A randomised, double-blind, placebo-controlled trial of repeated nebulisation of non-viral cystic fibrosis transmembrane conductance regulator (CFTR) gene therapy in patients with cystic fibrosis.

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Chapter 5Safety and adverse events

The trial was monitored at intervals by the independent DMEC, who scrutinised the unblinded group data and provided written confirmation to the TSC that the trial could continue with no modifications. Overall, the drug was well tolerated and AEs were of the nature expected in CF trials. In this section we describe the findings from the early safety cohort, AEs including a detailed description of serious AEs (SAEs) and present results of safety assays throughout the study.

Early safety cohort

The early safety cohort was designed to include 20 patients receiving three doses under intensified monitoring conditions ahead of enrolment of the complete cohort. Two patients who had been successfully screened became unwell before their planned first dose and could not be included without delaying timelines, so were excluded from this subgroup. The data presented to the DMEC came from 18 patients (eight of whom received placebo), 17 of whom had received three doses and one two doses. In addition to the procedures outlined in the general protocol, they had been seen for symptom review, lung function and blood tests (inflammatory markers, liver and renal function) at day 2 following each dose. The data from this cohort were reviewed by the Data Monitoring Safety Board at a meeting in September 2012.

Relevant data have been extracted from the closed report, to which the investigators have been unblinded only since database lock; any amendments to the original text have been made only for typographic or language errors, otherwise text and tables were as presented.

Throughout this section, the placebo group is referred to as group A and the active-treatment group as group B.

Adverse events

The AEs are presented as an aggregate number of events and also are listed by site and treatment group. The total numbers of AEs are presented in Tables 3 and 4.

TABLE 3

TABLE 3

Early safety cohort: number of AEs

TABLE 4

TABLE 4

Adverse events: 2 days after dosing – number of AEs

Table 3 presents the total number of AEs that were observed initially in the trial, we observed that that there was only one severe AE.

Table 4 presents the number of AEs that were observed 2 days after dosing the subjects. No SAEs were observed 2 days after dosing the subjects. Table 5 presents changes in spirometric indices.

We observe that, overall, there were no SAEs occurring during the trial.

Spirometry data

TABLE 5

Changes in spirometric values [mean (range)] from screening to dosing periods in the early safety cohort. A negative change indicates a decrease in the spirometry parameters

Dosing period 1Dosing period 2Dosing period 3
AllGroup AGroup BAllGroup AGroup BAllGroup AGroup B
FEV1 (l)0.05 (–0.20 to 0.29) n = 170.00 (–0.12 to 0.17) n = 80.14 (–0.20 to 0.29) n = 90.00 (–0.28 to 0.55) n = 18–0.07 (–0.22 to 0.06) n = 80.22 (–0.28 to 0.55) n = 10–0.04 (–0.49 to 0.43) n = 18–0.10 (–0.31 to 0.04) n = 80.27 (–0.49 to 0.43) n = 10
Percentage predicted FEV11.15 (–7.01 to 7.57) n = 18–0.03 (–3.87 to 6.24) n = 83.91 (–7.01 to 7.57) n = 10–0.12 (–8.79 to 15.06) n = 18–2.26 (–4.99 to 1.62) n = 86.46 (–8.79 to 15.06) n = 10–0.92 (–11.28 to 12.47) n = 18–2.92 (–6.65 to 0.42) n = 87.42 (–11.28 to 12.47) n = 10
FVC (l)0.03 (–0.23 to 0.42) n = 18–0.04 (–0.23 to 0.25) n = 80.18 (–0.17 to 0.42) n = 100.05 (–0.28 to 0.89) n = 180.02 (–0.28 to 0.57) n = 80.32 (–0.25 to 0.89) n = 10–0.01 (–0.44 to 0.37) n = 17–0.11 (–0.44 to 0.10) n = 70.21 (–0.32 to 0.37) n = 10
MEF25 (l)0.07 (–0.13 to 0.45) n = 180.06 (–0.13 to 0.42) n = 80.16 (–0.10 to 0.45) n = 100.03 (–0.18 to 0.42) n = 18–0.03 (–0.13 to 0.03) n = 80.18 (–0.18 to 0.42) n = 10–0.04 (–0.42 to 0.21) n = 18–0.04 (–0.17 to 0.10) n = 80.20 (–0.42 to 0.21) n = 10
MEF50 (l)0.15 (–0.26 to 0.52) n = 180.14 (–0.14 to 0.47) n = 80.25 (–0.26 to 0.52) n = 10–0.12 (–0.98 to 0.75) n = 18–0.33 (–0.98 to 0.10) n = 80.39 (–0.61 to 0.75) n = 10–0.05 (–0.87 to 1.14) n = 18–0.14 (–0.37 to 0.17) n = 80.64 (–0.87 to 1.14) n = 10
MEF75 (l)0.07 (–0.62 to 0.63) n = 170.05 (–0.62 to 0.60) n = 80.26 (–0.19 to 0.63) n = 90.17 (–1.29 to 1.84) n = 17–0.10 (–1.29 to 0.69) n = 80.88 (–0.86 to 1.84) n = 9–0.33 (–2.16 to 1.00) n = 17–0.32 (–0.95 to 0.08) n = 81.01 (–2.16 to 1.00) n = 9

Clinical examination

Table 6 presents the change in clinical examination parameters from screening day to dosing day. The changes in the clinical examination are presented as a number of cases that change from a positive result to a negative result; change from a negative result to a positive result; and do not change.

TABLE 6

TABLE 6

Clinical examination findings: n (%)

Current symptoms

Table 7 presents the symptoms expressed as change from the dosing day to 2 days after dosing.

TABLE 7

TABLE 7

Reported symptoms: n (%)

Vital signs

Table 8 presents the change from screening day to dosing day. A negative change indicates a decrease in vital sign parameters.

TABLE 8

TABLE 8

Vital signs: mean (range)

Biochemistry parameters

Table 9 presents the change from screening day to dosing day. A negative change indicates a decrease in the biochemistry parameters.

TABLE 9

TABLE 9

Biochemical tests: mean (range)

Haematology parameters

Table 10 presents the change from screening day to dosing day. A negative change indicates a decrease in the haematology parameters.

TABLE 10

TABLE 10

Haematology: mean (range)

Gas transfer

Table 11 presents the change from the screening day to 2 days after dosing. A negative change indicates a decrease in the gas transfer.

TABLE 11

TABLE 11

Gas transfer: mean (range)

In summary, the DMEC did not consider there was a safety signal on reviewing these results and wrote approving continuation of full recruitment into the trial at the 5-ml dose.

Adverse events and serious adverse events

General adverse events

All recorded AEs were categorised as in Table 12, and the frequency of their occurrence expressed proportional to the number of patients in each group. All patients in both groups reported AEs, as would be expected in a population of CF patients monitored for 12 months. However, the majority of AEs were of a nature expected in this clinical context and frequencies were similar between groups; there were no statistically significant differences in number overall or once they were broken down into the categories as tabulated.

TABLE 12. Adverse event frequency in the ITT and PP populations expressed separately for active-treatment and placebo groups.

TABLE 12

Adverse event frequency in the ITT and PP populations expressed separately for active-treatment and placebo groups. Numbers represent the total number of AEs in each category proportional to the numbers of patients in the group. There were no differences seen (more...)

One patient in the placebo group (fatigue and increased respiratory symptoms) and one in the active-treatment group (flu-like symptoms) discontinued study treatment because of AEs.

Serious adverse events

There were no deaths during the study. Six SAEs were documented, all in the active-treatment group (Table 13). Neither the DMEC nor the TSC considered any SAE was related to the trial medication, but that one (case 2) was probably related to a trial procedure (bronchoscopy).

TABLE 13

TABLE 13

Description of SAEs

Other safety assays

There were no clinically relevant changes in haematology (Figure 33), biochemistry (Figures 34 and 35), urinary markers (Table 14), histology (Figure 36), or lipid staining in sputum (Table 15) or biopsy cells (Table 16) during the trial. There was no immunological evidence to suggest the development of anti-DNA antibodies (Table 17) or anti-CFTR T cells (Table 18). There were no treatment-related differences in change in weight or BMI (Figure 37). Figures 33–37 present longitudinal values as mean (standard error of the mean; SEM), although in many cases error bars are small and not visible outside the mean point.

FIGURE 33. Haematological parameters.

FIGURE 33

Haematological parameters.

FIGURE 34. Blood biochemistry and renal markers.

FIGURE 34

Blood biochemistry and renal markers.

FIGURE 35. Liver and pancreatic function.

FIGURE 35

Liver and pancreatic function.

TABLE 14

TABLE 14

Urinalysis assessed by dipstick for protein, blood and glucose

FIGURE 36. Histological assessment of bronchial biopsies.

FIGURE 36

Histological assessment of bronchial biopsies. Bronchial biopsies were collected before the first dose (pre) and 28 ± 5 days after the last dose (post). Sections were stained with H&E. Out of the 50 possible biopsies, 39 (more...)

TABLE 15

TABLE 15

Differential counts of lipid-staining cells present in sputum samples from placebo and active-treatment subjects

TABLE 16

TABLE 16

Quantification of lipid-laden macrophages in bronchial biopsies

TABLE 17

TABLE 17

Quantification of anti-dsDNA antibodies

TABLE 18

TABLE 18

Quantification of CFTR-specific T cells in the PP population

FIGURE 37. Change from baseline: (a) weight; and (b) BMI.

FIGURE 37

Change from baseline: (a) weight; and (b) BMI.

Copyright © Queen’s Printer and Controller of HMSO 2016. This work was produced by Alton et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

Included under terms of UK Non-commercial Government License.

Bookshelf ID: NBK373645
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