Confirming the efficacy of intravenous immunoglobulin in ...



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Confirming the efficacy of intravenous immunoglobulin in CIDP through minimum clinically important differences: shifting from statistical significance to clinical relevance

ISJ Merkies,1,2 SI van Nes,2 K Hanna,3 RAC Hughes,4 C Deng3

1Department of Neurology, Spaarne Hospital, Hoofddorp, The Netherlands; 2Department of Neurology, Erasmus Medical Centre, Rotterdam, The Netherlands; 3Department of Clinical Development, Talecris Biotherapeutics, Inc, Research Triangle Park, North Carolina, USA; 4Department of Clinical Neuroscience, King’s College London, United Kingdom

METHODS

This study was a randomized, double-blind, placebo-controlled, response-conditional (rescue) trial and included a first period, a crossover (rescue) period, and an extension phase (fig 1).[1] Eligible patients were randomized to receive either immune globulin intravenous, 10% caprylate/chromatography purified (IGIV-C; Gamunex®, Talecris Biotherapeutics, Inc, Research Triangle Park, North Carolina, USA) or placebo (0.1% albumin). Patients received a baseline loading dose of 2 g/kg (commencement of first or crossover periods) and then a maintenance infusion of 1 g/kg every 3 weeks for up to 24 weeks. An adjusted inflammatory neuropathy cause and treatment (INCAT) disability score was applied to assess functional disability at prespecified intervals. Any patient with an adjusted INCAT disability score that worsened from baseline by ≥1 point at any time from day 16 until week 24 during the first period was required to switch to rescue therapy during a crossover period of 24 weeks. Patients who were stable during the first period (no change from baseline in adjusted INCAT disability score) at week 6 or afterward were also required to switch to rescue therapy during a crossover period. This included patients who may have improved from baseline at week 6 but whose adjusted INCAT disability scores returned to baseline levels or lower after week 6. Patients who entered the crossover (rescue) period received the alternate treatment according to the same treatment schedule as the first period. During the crossover period, any patient who did not improve by ≥1 point from baseline on the adjusted INCAT disability score after the first rescue treatment infusion was withdrawn from the study. Patients who improved but subsequently deteriorated to the point where a ≥1-point improvement in adjusted INCAT disability score was no longer maintained were also withdrawn from the study. The study was approved by the institutional review boards or ethics committees of all participating centers, and all patients provided written informed consent.

Assessment scales

Electromyography: In order for patients to enter the study, the INCAT electrophysiologic criteria had to have been met, with bilateral testing of tibial, peroneal, median, and ulnar motor nerves.[2] The procedures used have been previously described.[3] The following parameters were selected for the purposes of the current paper: (1) compound muscle action potential amplitude (CMAP; mV) of the most severely affected motor nerve was investigated as measured from the proximal site that produced the greatest proportional reduction in amplitude. Assessment of the most severely affected motor nerve at baseline was relative to the normal ranges of the central neurophysiology laboratory for that nerve; (2) averaged CMAP (mV) from all motor nerves assessed; (3) averaged conduction velocity (m/s) from all motor nerves assessed; and (4) percent conduction block. Conduction block was calculated as the reduction of amplitude from the most distal measurement site to the most proximal measurement site divided by the amplitude in the most distal measurement site multiplied by 100.

The Medical Research Council (MRC) sum score is a summation of the MRC scores (range, 0-5) in integers of the following muscles on each side, upper arm abductors, elbow flexors, wrist extensors, hip flexors, knee extensors, and foot dorsal flexors. It ranges from 0 (total paralysis) to 60 (normal strength).[4]

The Vigorimeter (Martin, Tuttlingen, Germany) is an instrument that has been used to measure grip strength.[5, 6] The pressure in the bulb is registered on a manometer via a rubber junction tube and is expressed in kPa. Grip strength was assessed for both dominant and nondominant hands.

The INCAT sensory sum score comprises pinprick and vibration sense plus a 2-point discrimination value in the arms and legs and ranges from 0 (normal sensation) to 20 (most severe sensory deficit).[7]

The INCAT disability scale and the Rotterdam handicap scale (RHS) were used to capture daily and social activities in the patients. The INCAT scale comprises a functional description of the arms and legs in a checklist form suitable for interviewing and observing patients’ capabilities.[2] Daily arm activities such as dressing the upper part of the body, doing and undoing buttons and zips, washing and brushing hair, and handling coins are scored as being “not affected,” “affected but not prevented,” or “prevented”. The leg scale measures problems regarding walking, taking into account the use of aids. The INCAT scale ranges from 0 (no signs of disability) to 10 (most severe disability score). The RHS measures handicap or extended disability activities (mobility indoors and outdoors; domestic tasks indoors and outdoors; kitchen tasks; leisure activities indoors and outdoors; ability to drive a car, ride a bicycle, or go by bus; and ability to work or study) and ranges from 9 (“unable to fulfill any applicable task or activity”) to 36 (“able to fulfill all applicable tasks or activities”).[8]

The Short Form 36® (Medical Outcomes Trust, Boston, MA; SF-36) health survey is designed to be completed by patients and is composed of 36 items grouped into 8 domains.[9] For the current paper, only the corresponding physical component summary scores and mental component summary scores were used. Question number 2 of the SF-36, which assesses global health change compared with a period of “1 year ago,” was chosen as an minimum clinically important difference anchor in the current study due to its established clinical relevance to patients. This question does not contribute to the calculation of domain scores or component summary scores.

REFERENCES

1. Hughes RAC, Donofrio P, Bril V, et al, on behalf of the ICE Study Group. 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;7:136-44.

2. Hughes R, Bensa S, Willison H, et al, and the Inflammatory Neuropathy Cause and Treatment (INCAT) Group. Randomized controlled trial of intravenous immunoglobulin versus oral prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy. Ann Neurol 2001;50:195-201.

3. Bril V, Katzberg H, Donofrio P, et al, on behalf of the ICE Study Group. Electrophysiology in chronic inflammatory demyelinating polyneuropathy with IGIV. Muscle Nerve 2009;39:448-55.

4. Kleyweg RP, van der Meché FGA, Schmitz PIM. Interobserver agreement in the assessment of muscle strength and functional abilities in Guillain-Barré syndrome. Muscle Nerve 1991;14:1103-9.

5. Merkies ISJ, Schmitz PIM, Samijn JPA, et al, for the Inflammatory Neuropathy Cause and Treatment (INCAT) Group. Assessing grip strength in healthy individuals and patients with immune-mediated polyneuropathies. Muscle Nerve 2000;23:1393-401.

6. Fünfgeld EW. [The vigorimeter: for measurement of the strength of the hand and simulation testing]. Dtsch Med Wochenschr 1966;91:2214-6.

7. Merkies ISJ, Schmitz PIM, van der Meché FGA, et al, for the Inflammatory Neuropathy Cause and Treatment (INCAT) Group. Psychometric evaluation of a new sensory scale in immune-mediated polyneuropathies. Neurology 2000;54:943-9.

8. Merkies ISJ, Schmitz PIM, van der Meché FGA, et al. Psychometric evaluation of a new handicap scale in immune-mediated polyneuropathies. Muscle Nerve 2002;25:370-7.

9. Ware JE Jr, Kosinski M, Gandek B. SF-36® health survey. Manual and interpretation guide. Lincoln, RI: QualityMetric Incorporated 2000.

FIGURE LEGEND

Figure 1 Eligible patients were randomized to receive either immune globulin IV, 10% caprylate/chromatography purified (IGIV-C), or placebo for up to 24 weeks. If the adjusted inflammatory neuropathy cause and treatment (INCAT) disability score worsened by ≥1 point relative to baseline at any time between day 16 and week 24 or if the adjusted INCAT disability score was stable starting at week 6, the patient crossed over to receive the alternate (rescue) treatment for up to 24 weeks. Patients who responded (≥1-point improvement from baseline) during the first period at week 24 or responded to treatment during the crossover (rescue) period at week 24 were eligible to be re-randomized in a double-blind extension phase for an additional 24 weeks of treatment with IGIV-C or placebo.

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