An international multicenter efficacy and safety study of IqYmune in initial and maintenance treatment of patients with chronic inflammatory demyelinating polyradiculoneuropathy: PRISM study

Abstract This prospective, multicenter, single‐arm, open‐label phase 3 study aimed to evaluate the efficacy and safety of IqYmune in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Patients received one induction dose of 2 g/kg and then seven maintenance doses of 1 g/kg at 3‐week intervals. The primary endpoint was the responder rate at the end of study (EOS), defined as an improvement of ≥1 point on the adjusted inflammatory neuropathy cause and treatment (INCAT) disability scale. The responder rate was compared with the responder rate of a historical placebo group (33.3%). Secondary endpoints included changes from baseline to EOS of adjusted INCAT disability score, grip strength, Medical Research Council (MRC) sum score, Rasch‐modified MRC sum score, Rasch‐built overall disability scale score and the clinical global impression. Forty‐two patients, including 23 Ig‐naïve and 19 Ig‐pre‐treated, were included in the efficacy set. The overall response rate at EOS was 76.2% (95% confidence interval [60.5%‐87.9%]). The superiority of IqYmune compared to the historical placebo control was demonstrated (P < .0001). The responder rate was numerically higher in Ig‐pre‐treated than in Ig‐naïve patients but confidence intervals were overlapping (84.2% [60.4%‐96.6%] vs 69.6% [47.1%‐86.8%]). All secondary endpoints confirmed this conclusion. The median time to response was 15 weeks [8.9‐19.1 weeks]. A total of 156 adverse events including five serious were considered related to IqYmune, 87.2% were mild. Neither hemolysis nor signs of renal or hepatic impairment were observed. These results demonstrate that IqYmune is an effective and well‐tolerated treatment in patients with CIDP.


| INTRODUCTION
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired rare heterogeneous disorder affecting sensory and motor peripheral nerves caused by a patchy demyelinating process than can produce sensory loss and positive sensory symptoms as well as motor weakness. 1 The worldwide prevalence is estimated to be 2 to 7 individuals per 100 000. 2 Published in 2008, the ICE study is considered the reference study for the treatment of CIDP with intravenous immunoglobulin (IVIg), given the high number of evaluated patients (n = 117). This study showed short-term and long-term efficacy and safety of a 10% IVIg in this indication. 3 The favorable benefit-risk ratio of IVIg in CIDP was confirmed by an additional study. 4 IqYmune (I10E for code product) is a highly purified, ready-touse, 10% liquid preparation of normal human immunoglobulin (100 mg/mL) for intravenous administration. This formulation is obtained from thousands of healthy donors and has been shown to be effective and well tolerated in patients with primary immunodeficiency 5 (PID), multifocal motor neuropathy 6 (MMN), and primary immune thrombocytopenia (ITP). 7 IqYmune was designed in a novel purification process based on the quality by design (QbD) approach 8  This study aimed to demonstrate the improvement of disability by IqYmune in adult patients with CIDP previously treated with IVIg or not. The assessment of safety was a secondary objective. IqYmune was administered at an initial dose of 2 g/kg over 2 to 5 days during the first course, then maintenance doses of 1 g/kg over 1 to 2 days repeated every 3 weeks (± 7 days) during the 7 subsequent courses. Allowed infusion rates ranged from 0.5 to 6 mL/kg/h. For patients older than 65 years, the maximum infusion flow rate was not to exceed 2 mL/kg/h. The duration of the treatment was approximately 21 weeks and the entire follow-up period was 24 weeks as end of the study (EOS) visit occurred 3 weeks after the last treatment course.

| Participant selection
used for historical reference. The disability of the arms is scored from 0 to 4 and of the legs from 0 to 5. The total score can vary from 0 (normal) to 9 (maximal disability). The adjusted INCAT score was measured at baseline and every 3 weeks thereafter, until the end of the study (Week 24). Response was defined a decrease of ≥1 point in the adjusted INCAT disability score between baseline and EOS visit or the last study visit in case of premature discontinuation.
Secondary efficacy endpoints either assessing a different approach of the primary endpoint or exploring different aspects of the disability were performed to reinforce the robustness of measurements and to substantiate the efficacy of IqYmune in CIDP patients.
These included responder rate at week 12, time to response, changes from baseline to week 12 (not reported in this article) and to EOS visit for adjusted INCAT disability score, and grip strength in both hands with a Martin Vigorimeter, 10 and other neurological scores for CIDP. Throughout the study, safety was evaluated by assessing the occurrence of AEs and their relationship to IqYmune. AEs were assessed in terms of percentages of patients affected. A physical examination was performed and vital signs, biochemical, and hematological parameters were also monitored.

| Data analyses
The study was designed to demonstrate superiority of IqYmune compared to the historical placebo control estimated from the ICE study. 3 Thirty-eight evaluable patients were needed in order to obtain 90% power using an exact binomial test with a 1-sided at the nominal level of significance of α = 2.5%. This sample size was based on the predefined success criterion of 60% of responders with IqYmune and of 33% with the historical placebo control in the ICE study which was estimated based on upper boundary of the 95% Clopper-Pearson confidence interval (CI) of the observed rate (12/58 = 20.7%, 95% CI [11.2%-33.3%]). To note: the responder rate in ICE study for the group treated with IVIg was 54% (32/59 patients including 39 Ig-naïve and 20 Ig-pre-treated) based on the same definition for response. Patients included could be either Ig-naïve or relapsing Igpre-treated patients; each subgroup was described but no statistical test has been performed. Analyses for efficacy were performed based on the full analysis set (FAS) which included all patients who received the drug at least once (ie, total treated set [TTS]) and had available assessment of the primary efficacy endpoint. Analyses for safety were performed based on the TTS. Per-protocol analyses based on the FAS patients without any major protocol deviation (deviations as having a potential impact on the primary efficacy endpoint) were performed.
Missing data was handled using the last observation carried forward method. Patients withdrew due to lack of efficacy of IqYmune were classified as non-responders and INCAT measurements after the intake of prohibited treatment were censored.
For the secondary efficacy endpoints, the change from baseline to week 12 (not presented in this article) and to EOS was analyzed by producing non-parametric Hodges-Lehmann point estimates and their corresponding 95% CIs. The time to adjusted INCAT response was analyzed using the Kaplan-Meier method. Descriptive statistics (mean, SD, median, minimum, maximum, and 25%-75% quantile) were calculated for all safety variables.  Table 1 shows patient demographics and baseline characteristics. Forty patients (93%) had definite and 3 (7%) had probable CIDP; 37 patients (86%) had typical form of CIDP and six patients (14%) had atypical form. The mean time since first symptoms was comparable between Ig-naïve and Ig-pre-treated patients. Although no statistical tests were performed to compare both subgroups, the mean age, time since diagnosis, and total adjusted INCAT disability score seemed numerically higher in Ig-pre-treated patients than Ig-naïve patients.

| Study treatment administration
The 43 patients of the TTS received total of 319 courses administered as 581 infusions.
Overall, patient exposure was similar between Ig-naïve and Igpre-treated patients (supplementary information Table S1).
Theoretically, a patient who fully completed the study should have IqYmune exposure of 6 months, a total number of courses of eight, a total number of infusions from 9 to 19 and a maximal flow rate of 6 mL/kg/h. Both actual mean duration of exposure (5.3 ± 1.4 months) and total number of courses (7.4 ± 1.8) are close to the theoretical values confirming the good compliance. The flow rate did not exceed 6 mL/kg/h during the study.

| Primary efficacy endpoint
At the end of the study visit, 32 (76.2%) of 42 patients in the FAS were responders, with the two-sided 95% Exact Clopper-Pearson CI of [60.5%-87.9%] ( Table 2). The P-value of the one-sided exact binomial Clopper-Pearson test (P < .0001) indicates that the response rate is statistically higher than the higher bound of the 95% CI (33.3%) of the historical placebo control group in the ICE study.
Although no statistical tests were performed to compare both subgroups, the rate of response would appear higher in the Ig-pretreated subgroup than in the Ig-naïve subgroup but CIs of these In addition, the responder rate at week 12 was 47.6%. Compared to the 76.6% responder rate at the end of the study, it is important to note that 29% of the patient had achieved a response after the fifth course. In other words, 12 responders (three Ig-pre-treated patients and nine Ig-naïve patients) out of 32 showed a late response. Three patients had achieved a response at week 15, three at week 21, four at week 18, and two at EOS visit as shown in Table 3.

| Secondary efficacy endpoints
Time to response Time to response was estimated using a subset of patients with response at EOS visit. Non-responder patients were considered censored at their last assessment of the adjusted INCAT disability score.
Patients who took a prohibited treatment before a response were considered censored at the date of the first intake of prohibited treatment.
The median time to response of responders was 15  Kaplan-Meier curve is reported in Figure 2. Note that since the first post-baseline assessment of INCAT disability score was performed 3 weeks after the first course of IqYmune, the first opportunity to identify a response could not arise before 3 weeks (even in patients who improved sooner).

Changes in neurological scores and grip strength from baseline to EOS visit
Results for all other neurological scores and for grip strength are presented in Table 3.
The median change from baseline to EOS visit of the adjusted INCAT score was −1.0 point with a 95% CI of [−1.5 to −1.0 points] which is highly statistically significant (P < .0001).
All other scores and grip strength measurements showed a statistically significant improvement at EOS visit compared to baseline, supporting the result from the primary efficacy analysis. (Table 4)

| Serious AEs
Nine serious AEs (SAEs) occurred in seven patients from which five were related to IqYmune in three patients (ie, a transient ischemic attack in one patient leading to a premature withdrawal; a severe headache leading to hospitalization, an increase in fibrin D-dimer and an anaphylactic reaction in one other patient; and a asymptomatic neutropenia in the third patient). All SAEs resolved without sequelae, except a femur fracture, which was recovering at EOS visit.

| Biology and vital signs
Results from hematological and biochemistry testing before and after treatment showed: • No case of renal or hepatic function impairment.
The mean changes in the vital signs (blood pressure, heart rate, and body temperature) from before the course to the end of infusions were unremarkable.

| DISCUSSION
The PRISM study was a prospective, open-label investigation to assess the efficacy and safety of IqYmune in the initial and maintenance treatment during 6 months in patients with CIDP and to evaluate the role of different scales in the assessment of clinical response.
The data showed that, whichever the scale was used for response evaluation, IqYmune can be considered as effective treatment with a favorable benefit-risk profile in this indication.
Initially this study was planned to complete the European regis-  This may also explain the earlier response in Ig-pre-treated patients than in Ig-naïve patients as also observed in a previous study. 4 The decrease in the mean adjusted INCAT score change between baseline and EOS visit was also higher in the Ig-pre-treated patients than in the Ig-naïve patients (−1.6 ± 1.21 points vs −0.9 ± 1.28 points). This may reflect the fact the Ig-pre-treated patients started from a mean higher score value (3.4 ± 1.77 points vs 2.7 ± 1.26 points), possibly due to their inclusion in the trial at the time of relapse, but ended up with a comparable score at EOS (1.7 ± 1.19 points vs 1.8 ± 1.65 points).
In this study, we also found a good correlation between the investigator and the patient assessment of response to treatment. Among the 78 assessments performed in 40 patients by both patient and investigator at week 12 or EOS visit, 58 (74%) were similar between the patients and the investigators, in 9 (12%), the patients were less satisfied than the investigators and in 11 (14%), the patients were more satisfied than the investigators.
We did not find any correlation between the clinical response and the IgG level variations between before and 14 days after the maintenance dose. 16 It was previously reported that the increase in serum IgG level after a standard dose of IVIg during a stable maintenance treatment of CIDP is relatively constant within individual patients, but differs between patients treated with the same IVIg dose and treatment schedule 17 without a clear-cut correlation with clinical response.
A better understanding of the reasons for this heterogeneity between patients might help however to better individualize therapy with IVIg. 18 The safety is in line with the use of IVIg in CIDP. Regarding headaches, they were also the most frequent drug-related AEs reported in previous clinical studies. 3,4 They are well known adverse reactions to IVIg and may be related to the rate of infusion. 14 It is interesting to note that, in the patient experiencing three SAEs, the headache appeared on the fourth day of the first treatment course, 20 minutes after the flow rate had been increased to 4 mL/kg/h and was initially moderate. However, the infusion flow rate was nevertheless increased to 6 mL/kg/h until the course completion and 30 minutes after the end of infusion, the headache became severe leading to hospitalization (first SAE). In the context of recurrent headache in this patient, further investigations were performed. An increase in fibrin D-Dimer up to 6000 μg/L was reported (second SAE in this patient).
Based on these results, a CT scan and angio-MRI were performed and ruled out a cerebral venous thrombosis. It can be hypothesized that avoiding a dose increase in front of this headache would have prevent its worsening. Same, at the time of the fifth treatment course, the course had been prescribed over a single day (when previous were over 2 days), and started at an infusion flow rate of 6 mL/kg/h (instead of 0.5 mL/kg/h as recommended in the protocol) which could explain the poor tolerance with a blood pressure fall, fever and tachycardia diagnosed as an anaphylactic reaction by the investigator (third SAE in this patient). The small number of thromboembolic events in our study probably reflects the exclusion of patients with risk factors for these events possibly limiting the external validity of this finding considering their relatively high frequency in the adult population.
In conclusion, the PRISM study demonstrated that IqYmune administered as a regimen of a 2 g/kg induction dose and 1 g/kg maintenance doses every 3 weeks is an effective treatment in patients with CIDP with a superiority of IqYmune compared to the historical placebo control after 24 weeks of treatment in CIDP. In addition, no new safety finding or trend arised from this study confirming the known safety profile of this group of therapies. 15