Publication date: November 2020
Source: Clinical Neurology and Neurosurgery, Volume 198
Author(s): Dario Cocito, Erdita Peci, Simona Rigaldo, Carlotta Canavese, Giuseppe Migliaretti, Federico M. Cossa
Keywords
Neuropathology
Randomized clinical trial
Demyelinating diseases
Polyradiculitis
Polyneuropathy
Chronic inflammatory demyelinating polyradiculoneuropathy
1. Introduction
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired chronic peripheral sensory-motor neuropathy presenting with a progressive weakness in the limbs [1] with a prevalence ranging from 0.8 to 8.9/100,000. Over half (54 %) of CIDP patients have disabilities with a modified Rankin scale grade 4 or 5 [2]. CIDP is variably characterized by a progressive, relapsing-remitting or monophasic course involving everyday life activity and quality of life (QoL) of affected patients [1]. There is a general consensus that CIDP is an immune-mediated disorder. It is treated with immune therapies including steroids, plasma exchange, and high-dose intravenous immunoglobulin (IVIg) that are effective in 50–80 % of patients [[3], [4], [5], [6], [7]]. IVIg treatment needs to be continued for a long period of time to avoid patient relapse after therapy suspension.
Multicenter studies have demonstrated that CIDP treatment through subcutaneous immunoglobulin (SCIg) could be an effective alternative to IVIg [[8], [9], [10]].
SCIg may be administered using two techniques:
- •
- Pump administering 50−100 ml per infusion: depending on the selected dose per kg, patients have to undergo 1–3 weekly administrations if the preparation has a 20 % concentration; or
- •
- Manual push technique (MPT), involving self-administration (day or multi-day) of small doses of immunoglobulin.
To date, no studies on the use of MPT in CIDP patients have been published. Conversely, its use for primary immunodeficiency diseases (PIDD) has been documented.
As shown by Shapiro [11] in his retrospective medical record review of data from 173 PIDD patients on IgG replacement therapy, MPT is a feasible, effective, convenient, and safe alternative to infusion pump. MPT decreases the duration of administration but requires more frequent infusions. Patients self-administering SCIg through this technique reported fewer adverse events than their counterparts on infusion pump (15.6 % vs. 20.7 %). This previous study suggested that a standard monthly IgG dose, administered more frequently at a lower volume per infusion, could reduce plasma IgG catabolism, and thus result in a higher serum IgG level [11].
This proof-of-concept study aims to evaluate the feasibility and (both clinical and laboratory) efficacy of a novel regimen of immunoglobulin administration involving daily administration of lower SCIg volumes using MPT in CIDP patients. We postulated that daily manual administration of SCIG through a syringe (maintaining the same cumulative monthly dose) might have comparable effectiveness to that of mono-tri-weekly administration performed using a pump.
Since immunoglobulins have linear pharmacokinetics (the greater the quantity injected, the greater the rate of its catabolism) [12], we assessed whether MPT could increase plasma IgG levels more than infusion pumps. We also evaluated whether it improved the QoL.
2. Methods
2.1. Patients
We performed polyneuropathy inflammatory manual push assessment (the “PIMPA” study), a randomized, controlled, two-arm, crossover interventional clinical trial.
Patients referring to Divisione di Riabilitazione Neuromotoria, Istituti Clinici Scientifici Maugeri (Torino) and Dipartimento di Neuroscienze, A.O.U. Città della Salute e della Scienza di Torino were recruited. Follow-ups occurred in the period 30/7/2018−1/6/2019.
Inclusion criteria included: definite or probable CIDP as defined by the EFNS/PNS criteria [13], availability of results for nerve conduction studies (NCS) performed within 12 months prior to the screening, previous sustained response to IVIg therapy with evidence of “wear-off” effect, administration of SCIg through infusion pump for 3 months prior to enrollment at the same monthly dose as the last IVIg infusion.
Exclusion criteria included any serious medical condition that could interfere with the clinical assessment or MPT feasibility and anticipated poor compliance of the patient or caregiver with study procedures. Ten patients were randomly assigned 1:1 to receive SCIg either by MPT (given as 2 g, i.e., 10 mL per daily infusion) or pumps for 4 consecutive months with crossover to the other. All patients received 60 g /month of SCIg (IgG 20 %).
All subjects gave written informed consent and we obtained ethical committee approval (CS2/833 Prot. n° 0078380, 27 July 2018) from Comitato Etico Interaziendale Città della Salute e della Scienza di Torino. The work described has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans.
2.2. Objectives and outcome measures
The primary objective and secondary objectives of the study were to assess whether MPT had the same effectiveness as pump administration and whether MPT resulted in greater plasma IgG levels and improved the QoL compared to pump administration, respectively.
The primary outcomes were the following clinical efficacy parameters, which were assessed monthly:
- ●
- Inflammatory neuropathy cause and treatment (INCAT) disability scale;
- ●
- Medical Research Council (MRC) scale, evaluating eight muscle groups bilaterally (shoulder abduction, elbow flexion, wrist extension, first dorsal interosseous, hip flexion, knee extension, and ankle flexion/extension) with a maximum score of 80 points;
- ●
- Rasch-built Overall Disability Scale (R-ODS);
- ●
- Grip strength (GS), as measured using the Martin vigorimeter.
The secondary outcomes were:
- ●
- Plasma IgG levels, assessed monthly just before the subsequent SCIg infusion;
- ●
- Life Quality Index (LQI), measured at the end of each treatment period. This is a validated scale assessing “treatment interference”, “therapy-related problems,” “therapy setting,” and “treatment costs.”
Finally, we also evaluated the number and type of SCIg-related adverse events during each study period.
2.3. Sample size
Based on the non-inferiority design of the study and considering a clinically relevant variation of 15 % with a non-inferiority of 10 % of the INCAT scale (one of the principal outcomes of the study), a sample size of 10 subjects observed for 10 time points were required to reach a power of 80 % and a two-tailed significance level of 0.05.
2.4. Statistical analysis
To describe the parameter in study, measures at each time point are presented in terms of mean and relative 95 % confidence intervals. Comparisons at corresponding time points were performed using the non-parametric paired Wilcoxon test. The differences in variation over time separately for the two treatment regimens of the parameters in the study were evaluated performing Anova for repeated measure models or the non-parametric Friedman test for the non-gaussian distributed parameters INCAT and MRC.
In order not to overestimate the beta error, the alpha levels were not adjusted for multiple comparisons.
The Statistical Package for Social Sciences 24.0 (SPSS, SPSS Inc., Chicago, IL) was
used for all analyses.
3. Results
Ten patients fulfilled the inclusion/exclusion criteria and were enrolled in the study. Data were collected from each patient during an 8-month follow up period.
Table 1 summarizes the patients’ main clinical and demographic characteristics at baseline.
Table 1. Clinical and demographic data. All the values, except gender, are reported at entry as mean ± standard deviation (range).
| Patients (n = 10) | |
|---|---|
| Gender (men/women) | 4/6 |
| Age (years) | 48.3 ± 15.44 (25–71) |
| Disease duration (years) | 9.6 ± 4.99 (4–19) |
| Age at onset (years) | 38.7 ± 14.61 (14–54) |
| Weight (kg) | 60.3 ± 4.32 (55–65) |
| Dose g/kg/month (SCIg = MPT) | 1 ± 0.07 (0.92–1.09) |
| INCAT | 2.4 ± 1.35 (0–4) |
| MRC | 76.4 ± 4.59 (68–80) |
The patients’ age ranged from 25 to 71 years and the disease durations from 4 to 19 years.
The efficacy scales INCAT, MRC, ROD-S, and GS show a nonsignificant variation between the groups, both when considering all the period from T0 to T4 (repeated measures ANOVA/Friedman test), and just T0 versus T4 (INCAT p = 0.15; MRC p = 0.49; R-ODS = 0.43; GS = 0.61)
Regarding IgG plasma concentration, a mean variation of 5.4 % in the group treated with MPT (p = 0.15) versus a negative variation of 4.3 % in the group who used pump administration was observed (Fig. 1).
Fig. 1. Mean serum IgG levels during MPT (manual push technique) therapy and infusion pump period, from T0 (beginning of therapy with that technique) to T4 (four months from beginning of therapy with that technique).
LQI sub-scale I (treatment interference) significantly improved in the MPT period (p = 0.02). Conversely, the other dimensions of LQI sub scale (i.e., “therapy-related problems”, “therapy setting”, and “treatment costs”) showed no statistically significant differences. All patients using MPT were able to prepare and infuse at home their subcutaneous immunoglobulin doses in 10 min or less, whereas the mean duration of pump infusion and preparation was 75 min (range: 70–85 min). All patients were able to self-injected the therapy after a mean of two session of nurse’s training.
There were no cases of drop-out or dose adjustment during follow-up and none of them had any adverse events.
4. Discussion
This is a proof-of-concept study of CIDP patients who were IgG therapy responders self-administering SCIg via MPT or infusion pump. This is, to our knowledge, the first study on SCIg administered via MPT in CIDP patients.
All enrolled patients were IgG therapy responders and had received SCIg for 3 months prior to enrollment at a similar monthly dose as the last IVIG infusion. Our study shows that, at least in the short term, infusion pump and MPT are equally effective in CIDP patients, as demonstrated with the clinical evaluation performed using the INCAT, MRC, R-ODS, and GS scales.
In addition, MPT improves the QoL, as demonstrated by improvement in the LQI sub-scale I (treatment interference), which could be due to the shorter time required for preparation and administration.
We also found an increase of 5.4 % (p = 0.15) in plasma IgG levels in the MPT period compared to the infusion pump period (Fig. 1). Our data suggest that frequent administration of small doses delays IgG clearance, and thus increases plasma levels.
The use of MPT in PIDD patients has been well reported. A retrospective medical record review [11] analyzed data on 173 PIDD patients who self-administered SCIg via infusion pump or MPT. In this study, the mean serum IgG levels were higher among MPT users than pump users, which is similar to our findings.
It is well documented that the IgG catabolism rate is proportional to its serum level, which is a unique phenomenon restricted to this immunoglobulin class [14]. Therefore, the initial high peak level after IVIg infusion induces a greater IgG catabolic clearance rate. Since SCIg is generally administered weekly or more frequently, the IgG dose is absorbed and redistributed much more slowly, which results in less fluctuation of serum IgG levels [15].
Therefore, we suggest that MPT may grant stable plasma IgG levels, avoiding the wear-off effect due to lengthy administration (Fig. 1).
However, it is still uncertain whether high trough or peak levels are more effective in IgG therapy for CIDP, even if the recent study of Markvardsen et al. found that in patients with CIDP receiving SCIg or IVIg, changes in plasma IgG levels during treatment did not correlate with changes in muscle strength or other motor performance skills [16].
Our study shows that MPT slightly increases plasma IgG levels with respect to infusion pump and maintains clinical effectiveness.
This proof-of-concept study has some limitations, mainly involving the study design (in particular the absence of blindness), the small sample size (a hurdle difficult to overcome, given the rarity of CIDP), and the short treatment period.
Further studies with larger samples sizes and longer follow-up periods are needed to confirm these findings.
5. Conclusions
CIDP patients included in this study had documented clinical response to IVIg with evidence of wear-off effect. Before entering this study, patients were administered SCIg therapy for at least three months, as replacement for the previous IVIg treatment.
MPT technique, which is widely used in PIDD patients, in our group proved as effective as the traditional subcutaneous administration with pump, with improved QoL.
In addition, we detected a slight increase in plasma IgG levels during MPT therapy period in comparison with pump infusion period.
Our proof-of-concept study highlights the feasibility of MPT in stabilizing symptoms in CIDP patients. The slight increase in plasma IgG levels obtained with this technique, if confirmed by further study with greater sample sizes, may allow the reduction in individual doses, with obvious repercussions on the cost of therapy.
Funding
Publishing support and journal styling services were provided by SEEd Medical Publishers and funded by CSL Behring, Italy. The sponsor had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. Associazione Neuropatie Croniche Piemonte, Italy financially supported the study investigators (partly).
Data statement
The data that support the findings of this study are available in the supplementary material of this article.
CRediT authorship contribution statement
Dario Cocito: Conceptualization, Methodology, Writing - original draft, Supervision, Funding acquisition. Erdita Peci: Data curation, Supervision. Simona Rigaldo: Project administration. Carlotta Canavese: Project administration. Giuseppe Migliaretti: Formal analysis. Federico M. Cossa: Supervision.
Declaration of Competing Interest
DC received honoraria for lecturing from Baxter, CSL Behring, and Kedrion; he received personal compensation for serving on the Advisory Board of CSL Behring, Kedrion and travel grants to attend scientific meetings from Baxter, Kedrion, and CSL Behring.
EP reports travel grants to attend scientific meetings from CSL Behring and Kedrion. SR reports travel grants to attend scientific meetings from CSL Behring and Shire Italia S.p.A.CC, GM and FMC report no disclosures.
Appendix A. Supplementary data
The following is Supplementary data to this article:
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© 2020 The Authors. Published by Elsevier B.V.
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