A dose-response trial of IV immunoglobulin in Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)/DRIP study

K. Kuitwaard^1,2, E Brusse¹, A.F.J.E. Vrancken⁴, F. Eftimov⁵, N.C. Notermans⁴, A.J. van der Kooi⁵, I.S.J. Merkies^6,7, B.C. Jacobs^1,3, P.A. van Doorn¹

¹Department of Neurology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

²Department of Neurology, Albert Schweitzer Hospital, Dordrecht, The Netherlands

³Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

⁴Department of Neurology, Brain Center Rudolf Magnus University Medical Center Utrecht, Utrecht, The Netherlands

⁵Department of Neurology, Academic Medical Center, Amsterdam, The Netherlands

⁶Department of Neurology, School of Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands

⁷Department of Neurology, St. Elisabeth Hospital, Willemstad, Curaçao

In clinical practice CIDP patients are treated with several dosages of intravenous immunoglobulin (IVIg) as well as with different intervals. It has never been investigated what the optimum dosage and frequency of IVIg in CIDP is. The effective component of IVIg is IgG. More frequent dosing will lead to more stable IgG levels in the blood as well as higher trough levels (the level directly before the next dose) which may lead to an improvement in muscle strength. Furthermore, more frequent dosing will lead to lower peak levels (the highest level in the blood) which may lead to less side-effects. It has never been investigated whether high frequency low dosage IVIg treatment is more effective than low frequency high dosage. In the DRIP study we investigate if:

1. A more frequent infusion at a lower dosage is more effective in CIDP.
2. A more frequent infusion at a lower dosage leads to less side-effects.
3. A more frequent infusion at a lower dosage leads to more stable blood levels.

It has been shown that a lot of CIDP patients are still receiving immunoglobulins even though they do not need treatment any longer. Therefore we will check before the start of the study whether patients still need IVIg treatment. CIDP patients ≥ 18 years old who are receiving a stable maintenance dose and interval of IVIg (10% liquid; Kiovig) can be included. To get an equal distribution of the treatment schedules, the distribution will be selected by lottery (randomization). The chance that a patient will receive the new treatment schedule in the first or in the second part of the study is both 50%. Neither the patient, nor the treating physician will know when which treatment schedule will be given. This is called a double-blind study. By comparing both groups we can discover if this new treatment schedule is more effective and leads to less side-effects than the schedule that the patients are used to right now. In the first part of the study patients will be given, depending on the results of the lottery, two times an infusion according to their normal dosage and frequency as they receive right now, alternated by two times a “fake infusion” (placebo or sham infusion) or four times an infusion with half the dosage, which means half the dosage twice as often (supplemented with placebo so that the volume remains the same). This means that over the full period patients will receive in total the same amount of IVIg as they are used to right now. After twice a normal infusion according to the normal treatment frequency patients will crossover to the other group/other treatment schedule (cross-over study). In order to be able to compare which treatment schedules works best, all patients will receive both treatment schedules. An example of what the study will look like for a patient who is treated with 30 grams of IVIg once every 4 weeks is given in Table 1. Handgrip strength will be measured before every infusion by using the Martin Vigorimeter. Patients are requested to fill in questionnaires after every infusion regarding disability, fatigue and quality of life and side-effects. Blood samples will be drawn (from the infusion needle) before and after every infusion. It is expected that giving an infusion more often with a lower dosage will lead to more stable blood levels. An advantage of participation can be that these more stable blood levels will lead to fewer complaints and an improvement in muscle strength and less side-effects. The information that we will get from this study might help us to improve the treatment of CIDP in the future. Because patients will be treated with the same medicine during the study as now and they receive the same dosage overall there are no risks to be expected from participation of this study. This study is set-up by the Erasmus MC and currently running in three hospitals in the Netherlands. Twenty patients are included in the study so far, of whom 17 have finished. We expect to include the last patient by the end of this year; results are expected mid-2018. The DRIP trial is registered in the Dutch trial register (Nederlands trial register = NTR) as NTR3705. This study is supported by an unconditional research grant from Baxalta.

Figure 1: Study outline

Example of the study outline for a patient treated with 30 grams of IVIg every 4 weeks.

* Placebo is added to maintain the total volume.