A randomised, multi‐centre phase III study of 3 different doses of intravenous immunoglobulin 10% in patients with chronic inflammatory demyelinating polyradiculoneuropathy (ProCID trial): Study design and protocol

Patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) show varying degrees of response to intravenous immunoglobulin (IVIg) therapy. This randomised phase III study in patients with CIDP (ProCID trial) will compare the efficacy and safety of 3 different doses (0.5, 1.0, and 2.0 g/kg) of IVIg 10% (panzyga) administered every 3 weeks for 24 weeks. The primary efficacy endpoint is the rate of treatment response, defined as a decrease in adjusted inflammatory neuropathy cause and treatment disability score of ≥1 point, in the IVIg 1.0 g/kg arm at week 24. Patients with definite or probable CIDP according to European Federation of Neurological Sciences/Peripheral Nerve Society criteria with IVIg or corticosteroid dependency and active disease are eligible. All potentially eligible patients will undergo IVIg or corticosteroid dose reduction (washout phase) over ≤12 weeks or until deterioration of CIDP (active disease). Patients with deterioration during the washout phase will be randomised to receive study treatment during a dose‐evaluation phase starting with a loading dose of IVIg 2.0 g/kg followed by maintenance treatment with IVIg 0.5, 1.0, or 2.0 g/kg every 3 weeks. Rescue medication (2 doses of IVIg 2.0 g/kg given 3 weeks apart) will be administered to patients in the IVIg 0.5 and 1.0 g/kg groups who deteriorate after week 3 and before week 18 or who do not improve at week 6. Safety, tolerability and quality of life will be assessed. The ProCID study will provide new information on the best maintenance dose of IVIg for patients with CIDP.

Patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) show varying degrees of response to intravenous immunoglobulin (IVIg) therapy. This randomised phase III study in patients with CIDP (ProCID trial) will compare the efficacy and safety of 3 different doses (0.5, 1.0, and 2.0 g/kg) of IVIg 10% (panzyga) administered every 3 weeks for 24 weeks.
The primary efficacy endpoint is the rate of treatment response, defined as a decrease in adjusted inflammatory neuropathy cause and treatment disability score of ≥1 point, in the IVIg 1.0 g/kg arm at week 24. Patients with definite or probable CIDP according to European Federation of Neurological Sciences/Peripheral Nerve Society criteria with IVIg or corticosteroid dependency and active disease are eligible. All potentially eligible patients will undergo IVIg or corticosteroid dose reduction (washout phase) over ≤12 weeks or until deterioration of CIDP (active disease). Patients with deterioration during the washout phase will be randomised to receive study treatment during a dose-evaluation phase starting with a loading dose of IVIg 2.0 g/kg followed by maintenance treatment with IVIg 0.5, 1.0, or 2.0 g/kg every 3 weeks. Rescue medication (2 doses of IVIg 2.0 g/kg given 3 weeks apart) will be administered to patients in the IVIg 0.5 and 1.0 g/kg groups who deteriorate after week 3 and before week 18 or who do not improve at week 6. Safety, tolerability and quality of life will be assessed. The ProCID study will provide new information on the best maintenance dose of IVIg for patients with CIDP. In almost all of the previous clinical studies of IVIg in patients with CIDP, only one dose of IVIg was assessed. [3][4][5][6][7][8][9][10][11] The efficacy and safety of different induction doses of IVIg (0.05, 0.2, or 0.4 g/kg/d for 5 days) has been evaluated head-to-head in only one non-placebo-controlled study of Japanese patients with CIDP (n = 40) or multi-focal motor neuropathy (n = 20), in which dose-dependent improvements in electrophysiology and clinical disease at 5 weeks were observed in all patients. 12 The Polyneuropathy and Treatment with Hizentra (PATH) study, which investigated 2 different maintenance doses of weekly subcutaneous immunoglobulin (SCIg) 0.2 or 0.4 g/kg in 172 patients with CIDP, showed that both doses of SCIg had significantly superior efficacy to placebo. 13,14 The ProCID study is a randomised, multi-centre, phase III trial of IVIg in patients with CIDP that will compare the efficacy and safety of 3 different maintenance doses (0.5, 1.0, and 2.0 g/kg) of IVIg (panzyga) administered every 3 weeks over 24 weeks, following an induction dose of 2 g/ kg. Data from the ProCID study will provide important new information on the best maintenance dose of IVIg to use when treating patients with CIDP. Here, we report the design and protocol of the ProCID study.

| Study design
The ProCID study is a prospective, randomised, double-blind, parallelgroup, multi-centre, phase III trial. An overview of the study design is shown in Figure 1

| Patient population
The study will enrol a minimum of 140 adult patients with definite or probable CIDP according to EFNS/PNS criteria 1 from approximately 45 study sites worldwide. The enrolment period is expected to last for about 20 months. Eligible patients will be those who have active disease (defined below) and are dependent on IVIg or corticosteroids.
Full study inclusion and exclusion criteria are shown in Table 1. After screening, eligible patients will undergo a predefined reduction of immunoglobulin or corticosteroids over a maximum of 12 weeks or until deterioration (washout phase). Immunoglobulin doses will be reduced by 25% at each sequential infusion, and corticosteroids will be reduced as per investigator discretion.
Patients with deterioration of CIDP during the washout phase (ie, those with active disease) will be randomised to receive study treatment.
Deterioration is defined as a decrease in the patients' global impression of change (PGIC) scale plus one of the following: (1) an increase of ≥1 point on the adjusted inflammatory neuropathy cause and treatment (INCAT) disability score, 6 (2) a decrease of ≥8 kPa in grip strength in one hand, 15 or (3) an Inflammatory Rasch-built Overall Disability Scale (I-RODS) minimum clinically important difference SE (MCID-SE) cut-off of −1.96 or less. 16,17 Patients who do not experience deterioration of CIDP during the 12-week washout phase (ie, those with inactive disease during the 12 weeks) will not continue in the study. During the study, the investigator may decide to withdraw patients in cases of adverse events (AEs), poor compliance, withdrawal of patient consent, pregnancy, risk of severe harm due to continued study treatment or protocol procedures, disease development that interferes with study treatment or meets an exclusion criterion, or administration of an immunoglobulin product other than panzyga. Additional patients will be enrolled when the proportion of patients who withdraw exceeds 10% (unless the planned number of patients in the dose group has already been achieved). Replacement patients will be assigned to the same dose group as the withdrawn patients; however, patients who withdraw from the study because of safety issues will not be replaced.

| Study treatment
All patients who worsen in the washout phase will receive an initial loading dose of IVIg 2.0 g/kg. Patients will then be centrally randomised to maintenance treatment using an interactive web response system and stratified by previous immunoglobulin or corticosteroid treatment using a stratified block design. Patients will be assigned in a 1:2:1 ratio to receive double-blind maintenance IVIg (panzyga) doses of 0.5, 1.0, or 2.0 g/kg, respectively, administered every 3 weeks (AE4 days) for 24 weeks (dose-evaluation phase).
To maintain blinding during the dose-evaluation phase, all patients will receive the same infusion volume as in the 2.0 g/kg treatment arm, using saline solution to match the volume in the 0.5 and 1.0 g/kg treatment arms. Each infusion will be administered over 2 consecutive days, and the content of each infusion bag will be concealed with an overpouch (normally used for light protection) and new identical labels on both IVIg and saline bags. The IVIg and saline solutions will not be mixed prior to administration (ie, no dilution of IVIg will occur).
Rescue medication with 2 doses of IVIg 2.0 g/kg given 3 weeks apart may be administered to the patients in the IVIg 0.5 and 1.0 g/kg groups if they have: (1) deterioration of CIDP (defined as an increase in adjusted INCAT disability score of ≥1 point) after week 3 and before week 18; or (2) no improvement in CIDP (defined as an unchanged adjusted INCAT disability score) at week 6. After administration of rescue medication, these patients discontinue study treatment and attend an end-of-study assessment visit at 3 weeks after the second rescue dose. Patients in the IVIg 2.0 g/kg group with deterioration of CIDP after week 3 and before week 18 or no improvement at week 6 will also discontinue study treatment.
A summary of permitted and prohibited concomitant medications during the study is shown in Table 2.

| Study endpoints
The primary efficacy endpoint is the proportion of patients in the IVIg 1.0 g/kg group with response to treatment at week 24 (defined as a decrease in adjusted INCAT disability score of ≥1 point). The adjusted INCAT disability score differs from the standard score by exclusion of changes in upper limb function from 0 (normal) to 1 (minor symptoms) or from 1 to 0, as these changes are not considered to be clinically relevant in all patients. 3 The following secondary efficacy endpoints will also be assessed: pro-

| Statistical analysis
The statistical analysis will be delegated under an agreement of transfer of responsibilities to an external contract research organisation.   Table 3). The primary endpoint analysis will be conducted for the FAS and PPS, the secondary endpoints will be evaluated in the FAS and in the PPS (in case the 2 populations differ by >5%), and the safety analysis will be conducted in the SAF. All efficacy and safety analyses will be summarised using descriptive statistics.
In general, data derivations will be based on observed values only, and missing data will not be imputed. If missing values occur in the confirmatory analysis of the FAS primary endpoint, they will be imputed as worst observed values (ie, observed patients will be analysed as a non-responder).

| DISCUSSION
The ProCID study is a randomised, double-blind, multi-centre, phase III trial that has been designed to compare 3 different IVIg maintenance doses for the treatment of patients with CIDP: 0.5, 1.0, and 2.0 g/kg once every 3 weeks for 24 weeks. The use of 3 maintenance  dose groups in the dose-evaluation phase will allow for confirmation of the clinical efficacy of IVIg observed in previous clinical trials. [3][4][5][6][7][8][9][10][11][12] In a post hoc analysis of the ICE study, almost half of IVIg responders showed improvement in adjusted INCAT disability scores within the first 3 weeks of treatment (ie, after the initial 2.0 g/kg loading dose). 18 To be comparable with data from the ICE study, 3 the primary endpoint of the ProCID study will be the proportion of patients in the IVIg 1.0 g/kg group with response to treatment, as defined by an improvement from baseline of ≥1 point on the adjusted INCAT disability score. Consistent with the ICE 3 and Privigen Impact on Mobility and Autonomy (PRIMA) 7 studies, the primary endpoint of this study will be assessed at week 24.
The only other randomised-controlled study to have prospectively evaluated the efficacy of different IVIg doses observed a dose-response relationship following a single dose of IVIg 0.25, 1.0 or 2.0 g/kg over 5 days. 12 Among 60 patients with CIDP or multi-focal motor neuropathy who received treatment, high-dose IVIg therapy (2.0 g/kg) was associated with a higher initial response rate compared with the 0.25 and 1.0 g/kg doses (response rates of 60% vs 15% and 21%, respectively) at 5 weeks; 24-week data were not presented in this study. 12 However, this study was not randomised and did not include a placebo group. 19 In the PATH study of 172 patients with definite or probable CIDP who received weekly SCIg 0.2 or 0.4 g/kg or placebo, the proportion of patients who had a relapse was 19% with SCIg 0.4 g/kg and 33% with SCIg 0.2 g/kg. 14 Although the difference in relapse rates between SCIg doses was not significant, relapse rates with both SCIg doses were significantly lower than with placebo (56%; P < .001). 14 The ProCID study will also evaluate whether different maintenance doses of IVIg may result in changes in treatment response in patients with definite or probable CIDP, and whether this efficacy will differ compared with that observed in the ICE 3 and PRIMA 7 studies.
While maintenance doses of IVIg vary considerably, most patients start with a standard maintenance dose of 1 g/kg every 3 weeks (or equivalent), with subsequent dose adjustments being made as needed.

FAS
According to the intent-to-treat principle, and includes all patients from the SAF population for whom data were collected post-infusion of study treatment PPS A subset of the FAS, which excludes patients with significant protocol deviations that could potentially significantly affect evaluation of the primary outcome a FAS, full analysis set; PPS, per-protocol set; SAF, safety set. a The classification of protocol violations will be conducted and documented before the database is locked, the data is unblinded and the statistical analyses are performed. This study will evaluate whether a higher or lower starting dose to the maintenance phase is better than the widely used standard dose of 1 g/kg every 3 weeks and will assess the safety and tolerability of these additional doses to provide clinicians further data in choosing IVIg maintenance doses for patients with CIDP.