Patients: Baseline characteristics
The patient disposition consort figure was published previously (17) but in brief, of the 316 patients who were screened for entry into the trial, 261 did not meet the criteria for randomization, declined to participate or were not eligible. One patient consented but did not enter the study. A total of 54 patients were randomly assigned to the main study group 1 (26 patients to FDI and 28 patients to the placebo) and constituted the intention-to-treat population. Follow-up was complete for all patients except 2 who missed their final follow-up visit, but all patients did not carry out all tests.
The characteristics of the 2 arms of Group 1 (the study group) were similar at baseline, although there was a 4 years age difference with the FDI group (n = 26; mean (SD) age 61.6 (10.1) years) vs the placebo group (n = 28; mean (SD) age 57.8 (12.9) years). Mean (SD) serum creatinine was 167.0 (40.2) vs. 204.9 (67.3) micromol/L and eGFR 33.2 (9.6) vs. 29.1 (9.6) ml/min/1.73 m2 at baseline in FDI and placebo treated patients, respectively. There was a difference in the mean (SD) baseline distance covered during the 6MWT (386.6 (135.8) meters in FDI vs 414.7 (104.5) meters in placebo treated patients; Table 1).
Table 1
Baseline Demographic Data; Mean (Standard deviation) n, or number (%) for the total for group 1 and unblinded data; the 2 control groups (2 and 3). uACR/uPCR = urinary albumin/protein:creatinine ratio. eGFR = Estimated glomerular filtration rate; CRP = C-Reactive Protein. 6MWT = Six-minute walk test. MLHF = Minnesota Living and Heart Failure Questionnaire. RLSS = Restless leg syndrome scale. ECG: N = Within normal limits; NCS = Abnormal and not clinically significant; ACS = Abnormal and clinically significant. FDI = Ferric Derisomaltose
Group and number of participants
|
FDI or Placebo
N = 54
CKD, no anemia but iron deficiency
|
FDI
N = 26
|
Placebo
N = 28
|
Control
Group 2
N = 10
CKD no anemia & no Iron deficiency
|
Control
Group 3
N = 10
|
Age (years)
|
59.6 (11.7)
n = 53
|
61.6 (10.1)
37–78
|
57.8 (12.9)
32–78
|
60.0 (11.1)
|
50.7 (11.8)
|
Sex
Male
Female
Unknown
|
26 (49%)
27 (51%)
1
|
11 (42.3%)
14 (53.8%)
1
|
15 (53.6%)
13 (46.4%)
0
|
5 (50%)
5 (50%)
0
|
5 (50%)
5 (50%)
0
|
Ethnicity
White
Asian
Black
Mixed Race
Unknown/other
|
42 (78%)
3 (5%)
7 (13%)
1 (2%)
1 (2%)
|
19 (73.1%)
1 (3.8%)
4 (15.4%)
1 (3.8%)
1 (3.8%)
|
23 (82.1%)
2 (7.1%)
3 (10.7%)
0 (0%)
0 (0%)
|
9 (90%)
0
1 (10%)
0
0
|
10 (100%)
0
0
0
0
|
Smoker
Yes current
Yes previous
No
|
5 (9%)
17 (32%)
32 (59%)
|
1 (3.8%)
8 (30.8%)
17 (65.4%)
|
4 (14.3%)
9 (32.1%)
15 (53.6%)
|
2 (20%)
3 (30%)
5 (50%)
|
0 (0%)
4 (40%)
6 (60%)
|
Body Mass Index (BMI)
|
30.3 (6.5), 53
|
30.7 (6.8)
|
30.01 (6.4)
|
29.4 (5.4)
|
26.8 (2.94)
|
Serum Ferritin (SF) (microg/L)
|
66.3
(44.1)
53
|
64.2
(29.1)
26
|
68.4
(55.3)
27
|
221.2
(110.9)
|
76.1
(63.8)
|
Transferrin Saturation % (TSAT)
|
20.1 (7.4)
53
|
22.3 (8.8)
26
|
19.7 (5.6)
27
|
27.4 (8.5)
|
27 (11.3)
|
Hemoglobin (Hb) (g/L)
|
128.7
(10.1), 54
|
131
(7.4), 26
|
126.6
(11.8), 28
|
121.5
(12.3)
|
138.2
(14.08)
|
Serum Creatinine (micromol/L)
|
186.7
(58.6), 54
|
167
(40.2), 26
|
204.9
(67.3), 28
|
189
(50.01)
|
72.8
(14.9)
|
eGFR (ml/min/1.73 m2)
|
31.1
(9.6), 54
|
33.2
(9.3), 26
|
29.1
(9.6), 28
|
31.5
(9.2)
|
87.5
(6.1)
|
Cystatin C
|
2.2
(0.6), 52
|
2.1
(0.5), 26
|
2.4
(0.6), 26
|
2.52
(0.33)
|
0.95
(0.11)
|
uACR (mg/mmol)
|
60.9
(133.3), 26
|
26.9
(40), 13
|
94.8
(181.4), 13
|
26.6
(37.3)
|
1.26
(1.93)
|
uPCR (mg/mmol)
|
83.8
(128.4), 40
|
51.9
(59.3), 19
|
112.7
(164.8), 21
|
51.7
(39.0)
|
11.4
(5.8)
|
CRP
(mg/L)
|
5.0
(4.4), 53
|
6.3
(5.5), 26
|
3.8
(2.4), 27
|
4.9
(5.2)
|
3.65
(4.8)
|
Serum Albumin (g/L)
|
39.8
(5.6)
|
40.8
(4.2)
|
38.8
(6.9)
|
37.8
(1.55)
|
39.5
(2.68)
|
Platelet count
(X105)
|
235
(58.9)
|
226
(52.4)
|
243
(64.1)
|
244.3
(79.9)
|
261.4
(60.75)
|
Phosphate
(mmol/L)
|
1.2
(0.2)
|
1.1
(0.2)
|
1.2
(0.2)
|
1.05
(0.24)
|
1.12
(0.11)
|
NT pro BNP
(ng/L)
|
485.2
(1268.4), 51
|
422.5 (881.9), 25
|
545.4 (1569.5), 26
|
1041.0 (993.6)
|
98.0
(99.4)
|
PWV measurement
|
8.3
(3.2), 54
|
8.3
(2.8), 26
|
8.3
(3.6), 28
|
7.24
(2.62)
|
6.6
(1.53)
|
AiX measurement
|
24.2 (10.7)
54
|
25.4 (10.7)
26
|
24.1 (10.8)
28
|
23.7 (16.1)
|
17 (10.78)
|
6MWT
Metres (m)
|
401.2
(120.2), 52
|
386.6
(135.8), 25
|
414.7
(104.5), 27
|
392.6
(158.5)
|
528.4
(87.3)
|
KD-KQoL SF36
(normalised data)
|
40.2
(10.4), 48
|
40.2
(10.4), 21
|
40.4
(9.55), 27
|
46.9
(8.7), 10
|
56.3
(6.2), 10
|
MLHF
|
23.97
(26.3)
|
22.7 (25.7)
18
|
25.0 (27.3)
24
|
29.6
(23.7)
|
1.88
(5.3)
|
RLSS
|
9.670
(10.3)
|
9.5 (10.4)
20
|
9.8 (10.4)
23
|
6.8
(12.4)
|
1.8
(5.69)
|
Systolic Blood Pressure
(mmHG)
|
133.6
(19.5), 54
|
138.2 (19.9), 26
|
129.4
(18.4), 28
|
143.8
(13.6)
|
126.8
(17.2)
|
Diastolic Blood Pressure
(mmHG)
|
77.3
(11.3), 54
|
78.5
(10.7), 26
|
76.2
(11.8), 28
|
81.1
(6.4), 26
|
79.6
(13.9), 28
|
Baseline ECG
N
NCS
ACL
Not Recorded
|
38
13
1
2
|
17
8
1
0
|
21
5
0
2
|
4
6
0
0
|
10
0
0
0
|
Etiology of renal disease in whole cohort of patients in all groups
|
Diabetes
|
17
|
8
|
9
|
2
|
0
|
Hypertension
|
4
|
2
|
2
|
1
|
0
|
Polycystic Kidney Disease
|
5
|
2
|
3
|
2
|
0
|
Pyelonephritis/Reflux
|
3
|
1
|
2
|
1
|
0
|
Glomerulonephritis / IgA/vasculitis/interstitial nephritis
|
14
|
8
|
6
|
2
|
0
|
Other/unknown
|
11
|
5
|
6
|
1
|
0
|
In the additional control groups, the mean (SD) age of Group 2 (patients with CKD, no iron deficiency and no anemia) was similar to Group 1 at 60 (11.1) years, but this was a decade older than Group 3 (healthy controls) in whom the mean (SD) age was 50.7 (11.8) years. The CKD patients in Group 2 walked approximately 130 meters less on average during the 6MWT (mean (SD) 392.6 (158.5) meters compared to the healthy control subjects (528.4 (87.3) meters); (Table 1).
Primary endpoint: 6MWT
Adjusting for baseline 6MWT, the 6MWT in the main study participants (Group 1) at 1 month and 3 months showed no statistically significant difference between FDI and placebo arms (p = 0.736 and 0.741 respectively). Using a repeated measure ANOVA, with baseline, 1-month and 3-month data (18 FDI patients and 24 placebo patients), there was no significant difference between the arms of Group 1 (p = 0.124). (Fig. 1). Analysis of change in 6MWT showed that the mean (SD) change for FDI patients from baseline to 3 months was 6.0 (89.1) meters compared to 1.9 (111.2) meters for the placebo arm patients; this was not significantly different (Suppl Table 1). During follow up there was a greater than 25 meter increase in 6MWT observed in 8/22 (36.4%) of patients at 1 month and 10/20 (50%) at 3 months in the FDI group vs 8/25 (32% − 1 month) and 10/24 (41.7% − 3 months) patients in the placebo arm, respectively (p = 0.753, p = 0.580).
Secondary efficacy outcomes
There was no statistically significant difference in Hb at 1 month (p = 0.195) and 3 months (p = 0.152) (Fig. 2 and Table 2). There was an upwards trend in Hb with an absolute mean increase of 1.7 g/L and 3.7 g/L with FDI compared to a fall of 1.0 g/L and 0.3 g/L in the placebo arm, thus, there was a difference of 2.7 g/L and 4.0 g/L in Hb in favor of FDI at 1 and 3 months, respectively.
Table 2
Summary of mean (SD) for hemoglobin (Hb) and hematinics; serum ferritin and transferrin saturation (TSAT) at baseline, 1 and 3 months.
|
|
FDI
|
Placebo
|
|
|
Mean
|
SD
|
n
|
Mean
|
SD
|
n
|
P value
|
Hb
|
Baseline
|
131.0
|
7.4
|
26
|
126.5
|
11.8
|
28
|
|
1 month
|
132.7
|
7.2
|
24
|
125.5
|
12.8
|
26
|
0.195
|
3 months
|
134.7
|
8.9
|
20
|
126.2
|
12.4
|
25
|
0.152
|
Ferritin
|
Baseline
|
64.2
|
29.1
|
26
|
68.4
|
55.3
|
27
|
|
1 month
|
266.0
|
105.8
|
23
|
70.5
|
55.8
|
26
|
< 0.001
|
3 months
|
234.4
|
105.3
|
21
|
69.4
|
59.8
|
24
|
< 0.001
|
TSAT
|
Baseline
|
22.3
|
8.8
|
26
|
19.7
|
5.6
|
27
|
|
1 month
|
29.6
|
9.5
|
22
|
19.1
|
7.1
|
26
|
< 0.001
|
3 months
|
26.4
|
10.5
|
21
|
18.0
|
6.8
|
23
|
< 0.001
|
There was a statistically significant difference for SF and TSAT at both 1-month (p < 0.001, p < 0.001) and 3 (p < 0.001 and p = 0.001) months, respectively, with greater increases in the FDI group (Figs. 3 and 4, Table 2).
Overall, 96% and 95% of participants achieved a SF > 100microgram/L at 1 and 3 months in the FDI group in comparison to 19% and 21% in the placebo group, respectively (p < 0.001, p < 0.001). 77% and 67% of participants achieved a TSAT > 20% at 1 and 3 months in the FDI group in comparison to 23% and 30% in the placebo group, respectively (p < 0.001, p = 0.016).
Questionnaires
The RLSS showed that patients with CKD and iron deficiency had a 5-fold higher score in comparison to healthy controls (Table 1). Those receiving IV iron had similar baseline scores to placebo in Group 1 (Table 1), and FDI led to a non-statistically significant improvement of the RLSS score compared to placebo.
The MLHF questionnaire showed that patients with CKD and iron deficiency had a 12-fold higher score in comparison to healthy controls and were therefore more symptomatic (Table 1). Those receiving IV iron had similar baseline scores to placebo in Group 1, and IV iron did not impact this score significantly (Table 1 and Suppl Table 2).
The numerical improvements at 1 and 3 months in the normalized KD-QoL-SF-36 questionnaires in FDI patients were modest but not statistically significant. At baseline, the overall component summary Measure (Physical and Mental Health) KD-QoL-SF36 scores in Group 1 were on average 15% lower than those in Group 2, and 29% lower than healthy controls in Group 3 (Table 1), thus indicating an impact of both iron deficiency and CKD, independently, on quality of life scores. At 1-month, despite the numerical increases in normalized scores (difference of 1.5), there was no significant difference between the intervention arms in Group 1 (p = 0.981) (Fig. 5 and Suppl Table 3a). At three months, there was a larger difference (2.3) which was not significant between the two arms of Group 1 (p = 0.451) (Fig. 5 and Suppl Table 3a). Repeated measures analysis across the three time points included 14 FDI and 23 placebo patients with complete baseline, 1-month and 3-month data and there was no statistically significant difference between the two arms (p = 0.515) (Suppl Table 3b).
Safety Analysis
Renal Function
Renal Function as assessed by serum creatinine, eGFR and cystatin C were similar in both arms of Group 1 with no statistically significant difference between FDI and placebo at 1 or 3 months. Proteinuria did not change with time or with IV iron treatment (Suppl Table 4).
Phosphate, albumin, platelets and CRP
Serum phosphate levels and platelet count remained stable with no significant changes throughout the study period in both FDI and placebo arms of Group 1. Serum albumin was similar in both arms of Group1 and did not change throughout the study. Mean (SD) CRP was unchanged throughout the study period; it was 4.2 (2.7) vs 6.9 (18.3) mg/L at 1-month (p = 0.6), and 7.5 (6.8) vs 10.3 (23.0) mg/L at 3 months (p = 0.46) in the FDI and placebo patients, respectively.
Blood pressure and endothelial function
Blood pressure remained stable over follow-up and was similar in both arms of Group 1 (Suppl Table 5). Endothelial function measured clinically using PWV and AiX did not change at 1 or 3 months post FDI infusion or in the placebo arm (Suppl Table 5).
Adverse events
A total of 19 adverse events were documented in 13 participants during the duration of the study (Table 3). This equated to 19 events in 162 patient months in the whole cohort of Group 1. There were no treatment-related serious adverse events adjudicated by the primary investigators at each site, and no deaths, strokes or hospitalizations during the study period. There were also no hypersensitivity reactions or infusion reactions with FDI.
Table 3
Summary of adverse events
Adverse Events
|
Total
|
FDI
|
Placebo
|
Infections
|
5 Infections consisting of one urinary tract infection (UTI); 1 lower respiratory tract infection (LRTI), 1 flu and one exacerbation of chronic obstructive pulmonary disease (eCOPD) and one shingles flare
|
1 flu
1 UTI,
1 infective
1 eCOPD
|
1 LRTI
1 shingles
|
Cardiovascular events
|
Angina x 2
|
0
|
2
|
Shortness of breath
|
2
|
0
|
2
|
Other
|
Hypoglycaemia
Had intravenous fluid for elective CTscan
? lung Cancer
Gout
Depression
Per Rectal bleeding
Acute Kidney Injury episode
Cough
Poor Blood Pressure control
|
0
0
0
1
1
0
0
1
1
2
|
1
0
1
0
0
1
1
0
0
0
|
|
19
in 13 patients
|
9
in 6 patients
|
10 in 7 patients
|
Cardiac Assessments
Patients were classified into NYHA categories I to IV, and the average was similar in both placebo and FDI arms of group1. In total 3/18 (16%) and 3/22 (14%) patients had an improvement in NYHA category in the FDI arm compared to the placebo arm, respectively after 3 months. There was only one ECG which was deemed clinically significantly abnormal at baseline during the study, and this remained unchanged throughout the study in the placebo arm. No patient manifested a change in the status of the ECG. The standard 2-D echocardiogram results were also similar over time in the 2 randomized arms of Group 1. One echocardiogram was reported as abnormal and clinically significant at baseline in one patient and a further one in a second patient during the 3-month study period in the placebo arm of the study.
NT-Pro BNP levels were approximately 5-fold higher in patients with CKD and iron deficiency compared to healthy controls, but there was also a 2-fold difference between Group 1 and 2 and the level of NT-Pro BNP was higher in CKD patients without iron deficiency (Group 2) but this was not significant. (Table 1). The mean (SD) NT-Pro BNP levels appeared to fall post FDI infusion (422.5 (881.9) pg/ml at baseline to 242.5 (209.1) pg/ml at 1 month) in comparison to placebo (545.4 (1569.5) pg/ml at baseline to 608.8 (1891)pg/ml at 1 month), but this did not reach significance (p = 0.371) (Suppl Table 6).