Dose response of IVIg in CIDP.

Hand grip strength (Vigorimeter) will be used as the primary outcome
measure. A difference in the (mean of the 4) Vigorimeter changes from
baseline between the two groups of > 8 kPa (mean of both hands) is
considered clinically relevant. A difference of > 8 kPa in Vigorimeter
change from baseline in favour of the group treated with half the dosage
and interval as compared with the other treatment group will be
considered a clinical relevant improvement.

The Rasch-built overall disability scale (R-ODS) measuring activity status, Rasch fatigue severity scale (R-FSS) measuring fatigue, and quality of life (SF-36) will be used as secondary
outcome measures. The secondary objective will be to record the
occurrence of side-effects.

STATISTICAL ANALYSIS PLAN

Dose response trial of IV immunoglobulin in

chronic inflammatory demyelinating polyradiculoneuropathy

DRIP study
NTR number: 3705

Erasmus MC, Rotterdam, The Netherlands

Version 2
February 14th 2019
Protocol version 1.04


Prepared by:
Krista Kuitwaard
Dept. of Neurology, Erasmus MC

Trial statistician:
Hester F. Lingsma
Dept. of Public Health, Erasmus MC

Coordinating investigator:
Pieter A. van Doorn
Dept. of Neurology, Erasmus MC


Introduction
The purpose of the dose response double-blind randomised placebo-controlled trial (DRIP trial) of intravenous immunoglobulin (IVIg) in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is to assess whether high frequency low dosage IVIg treatment is more effective and results in less side effects than low frequency high dosage maintenance treatment for CIDP. The protocol was published earlier. 1
Here we will summarize the statistical analysis of the data. We will describe how missing data will be handled and how (subgroup) analyses will be performed. We do not imply that all analysis will be described in the main paper, because of space restrictions.

Status of the trial
The first patient was included in the DRIP trial in April 2015. In the following years a total of 25 patients were included in 3 centres in the Netherlands. From these 25 patients, 22 patients completed both treatments of this double-blind crossover trial. Three patients did not receive the second treatment because of clinical worsening due to either a treatment failure or a normal fluctuation of their CIDP. The last follow-up took place in July 2018.

Research questions
Primary research question
The primary objective of this study is to assess whether more frequent low dosage IVIg treatment is more effective than less frequent high dosage IVIg treatment as maintenance treatment for CIDP.
Secondary research questions
The secondary objectives are to assess whether more frequent low dosage of IVIg results in less adverse events compared to less frequent high IVIg dosage and to prove that more frequent low dosage of IVIg results in higher IgG trough levels than less frequent high dosage.

Trial design
This is a multi-centre randomised placebo controlled double-blind cross-over intervention trial. In this trial every patient will be treated at baseline (one infusion) according to their own individual established IVIg dosage and interval prior to start of the trial. During the double-blind phase (4 infusions) one group (intervention group) will be treated with half of their normal dosage of IVIg (with placebo added to maintain the total volume) at half of the interval. The other group (contrast treatment) will be treated with their normal dosage and interval of IVIg, followed by a placebo infusion between their regular infusions, so that they receive an infusion of either IVIg or placebo at half of the interval. After a wash-out phase (2 infusions) patients will cross-over to the other treatment group. The total amount of IVIg given during the whole double-blind phase will remain the same in both treatment groups.

Inclusion and exclusion criteria
For a complete list of in- and exclusion criteria we refer to paragraph 4.2 and 4.3 of the protocol version 1.4 on page 16-17, as well as to the publication of the protocol. 1 In short, patients with CIDP of 18 years and older, who are IVIg dependent and who received a stable maintenance dose and interval of IVIg are in principle eligible for inclusion in the trial. To indicate that each single patient is still IVIg dependent and has active CIDP, patients must have shown either an objective deterioration (decrease in muscle strength as measured by the Vigorimeter or the MRC sumscore) following a reduction of IVIg dose or lengthening of the IVIg interval, or an objective improvement following an increase in IVIg dose or shortening of the IVIg interval at some time during the 9 months before randomisation. To be able to measure an improvement in the primary outcome measurement, patients are only eligible when their hand grip strength as measured on the Martin Vigorimeter is less than the median value for an age and sex matched healthy control. 2

Primary and secondary outcomes
The primary outcome is the score on the Martin Vigorimeter (hand grip strength).3, 4 Prior to every infusion, hand grip strength will be measured (mean of the three measurements of both hands will be used) by the nurse administrating the IVIg. To avoid any difference between Vigorimeters, the same Vigorimeter will be used throughout the whole study. The mean of the two Vigorimeter measurements before the first infusion of each double-blind phase will be taken as baseline measurement. In order to assess the effect of the second treatment period, each patient will also be examined (Vigorimeter) at the first infusion after finishing the second part of the study. A difference of > 8 kPa in the mean of the four Vigorimeter changes from baseline in favor of the group treated with half the dosage and interval as compared with the other treatment group will be considered a relevant clinical improvement. The value of 8 kPa is based on the minimum clinically important difference cut-off value of 8 kPa for grip strength (Vigorimeter) using the ½ SD technique. 5
Secondary outcomes concern clinical parameters (regarding disability, fatigue and quality of life), laboratory parameters and safety parameters. Blood samples will be drawn before and after every infusion and questionnaires will be completed after every infusion (except for the Sf-36 which will be taken less often).
Clinical parameters:
- Changes in the score on the Rasch-built Overall Disability Scale (R-ODS). 6, 7
- Changes in the score on the modified Rasch-built Fatigue Severity Scale (R-FSS).8, 9
- Changes in the score on the Short Form (36) Health Survey, Dutch language acute version 2 (SF-36). 10

Laboratory parameters:
- Changes in the serum IgG level as determined by turbidimetry.

The percentage of patients with at least one serious adverse event (SAE) will be compared. Furthermore, the most common reported side effects will be described and the number of patients reporting these will be compared between both groups.

Randomisation and blinding
A computer-generated list of random assignments was prepared by the study statistician. A block randomisation was made for each centre. The pharmacist holds treatment codes for all participants in the trial. Allocation concealment was ensured via sequentially numbered, opaque, sealed envelopes. A trial pharmacist prepared and blinded the trial medication during both blind phases of the trial. Albumin 0.5% was chosen as the placebo because of its identical appearance to IVIg during visual inspection in EVA bags and has been used in other IVIg trials.11 Blinded study medication was always divided over two EVA bags during the whole study so that IVIg as well as placebo did not have to be diluted and in order to maintain the blind. When half the dosage of IVIg was given, placebo was added to maintain the blind by using the same volume in total. Allocation will be revealed after all patients have completed the trial and data entry has been declared complete.

Statistical analysis
Primary effect analysis
The main analysis of this trial consists of a comparison of the change from baseline in Vigorimeter measurements between the two treatments. A cross-over design was chosen because of its statistical efficiency where each patient acts as his/her own control, enabling a more precise estimate of the treatment effect. The analysis is based on the intention-to-treat principle. Patients who did not complete both treatments in this cross-over trial are described in detail, but will be excluded from the analysis. The mean Vigorimeter change from baseline, as well as the changes in secondary outcomes such as in serum IgG level, will be compared between both treatments using mixed models adjusting for possible carry-over effect. The percentage of patients with at least one SAE (for which a doctor was consulted) will be compared using McNemar’s test. The most common reported side-effects will be described using descriptive statistics and the number of patients reporting these in both groups will be compared using chi-square test of Fisher’s exact test.
Missing data
Missing data (if any) for secondary outcome variables will be analysed for randomness and imputed with standard methods. Missing items responses on the SF-36 are handled according to the user’s manual for the SF-36 version 2 Health survey. 12

1. Kuitwaard K, Fokkink WR, Brusse E, et al. Protocol of a dose response trial of IV immunoglobulin in chronic inflammatory demyelinating polyradiculoneuropathy (DRIP study). Journal of the peripheral nervous system : JPNS 2018; 23(1): 5-10.
2. Merkies IS, Schmitz PI, Samijn JP, Meche FG, Toyka KV, van Doorn PA. Assessing grip strength in healthy individuals and patients with immune-mediated polyneuropathies. Muscle Nerve 2000; 23(9): 1393-401.
3. Latov N, Deng C, Dalakas MC, et al. Timing and course of clinical response to intravenous immunoglobulin in chronic inflammatory demyelinating polyradiculoneuropathy. Arch Neurol 2010; 67(7): 802-7.
4. Merkies IS, Schmitz PI, van der Meche FG, Samijn JP, van Doorn PA. Connecting impairment, disability, and handicap in immune mediated polyneuropathies. Journal of neurology, neurosurgery, and psychiatry 2003; 74(1): 99-104.
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6. van Nes SI, Vanhoutte EK, van Doorn PA, et al. Rasch-built Overall Disability Scale (R-ODS) for immune-mediated peripheral neuropathies. Neurology 2011; 76(4): 337-45.
7. Merkies IS, Schmitz PI, van der Meche FG, Samijn JP, van Doorn PA. Clinimetric evaluation of a new overall disability scale in immune mediated polyneuropathies. Journal of neurology, neurosurgery, and psychiatry 2002; 72(5): 596-601.
8. van Nes SI, Vanhoutte EK, Faber CG, Garssen M, van Doorn PA, Merkies IS. Improving fatigue assessment in immune-mediated neuropathies: the modified Rasch-built fatigue severity scale. Journal of the peripheral nervous system : JPNS 2009; 14(4): 268-78.
9. Merkies IS, Schmitz PI, Samijn JP, van der Meche FG, van Doorn PA. Fatigue in immune-mediated polyneuropathies. European Inflammatory Neuropathy Cause and Treatment (INCAT) Group. Neurology 1999; 53(8): 1648-54.
10. Merkies IS, Schmitz PI, van der Meche FG, Samijn JP, van Doorn PA. Quality of life complements traditional outcome measures in immune-mediated polyneuropathies. Neurology 2002; 59(1): 84-91.
11. Hughes RA, Donofrio P, Bril V, et al. Intravenous immune globulin (10% caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomised placebo-controlled trial. Lancet Neurol 2008; 7(2): 136-44.
12. Ware JE Jr KM, Bjorner JB, Turner-Bowker DM, Gandek B, Maruish ME. User's manual for the SF-36v2 Health Survey. . Quality Metric Inc Lincoln 2007; 6(5): 53-64.