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CIDP: Treatment

Jon Katz, MD, Neurology, discusses CIDP treatment options as well as the ICE study.

Transcript

CIDP: Treatment

Jon Katz, MD, Neurology, discusses CIDP treatment options as well as the ICE study.

Hi, I'm Jon Katz from San Francisco, California and this afternoon I'm going to be talking about the treatment of CIDP. When we talk about the treatment of CIDP we should look at what the guidelines specifically say and what the recommendations are. So let's first mention IVIG which you all know is a common treatment for CIDP. That has level A recommendation. Corticosteroids which haven't had a ton of clinical trials have a level C recommendation and should be considered in sensory and motor types of CIDP. And if IVIG and corticosteroids are ineffective, we move over to plasma exchange which should also be considered and actually has a level A recommendation as well.

So let's talk about plasma exchange in CIDP. There was a study by Hahn et al, which was a double-blind study of 18 CIDP patients, 9 patients with progressive neuropathy and 9 with a relapse and remitting course. They were given plasma exchange over 4 weeks. The patients received either 10 sham treatments or plasmapheresis itself with a washout period and then a crossover. Fifteen patients completed the trial and 12 of these 15 patients turned out to improve with plasma exchange. Once plasma exchange was stopped, 8 of the 12 patients relapsed within 1 to 2 weeks. All the patients subsequently improved in an open-label part of the study, so it was concluded the plasma exchange was effective.

Prednisone is another treatment we often use for CIDP, and prednisone's evidence is really, as I said before, not based on clinical trials but on a load of open-label experience. One study we like to point to when we talk about the efficacy of prednisone is a study by Baron that was done in 1989 that looked at prednisone in 60 patients treated with IVIG. The response rate of these patients, which were very specifically selected—not just by nerve conduction studies but by physical exam—was that 90% of the patients responded to a course of prednisone and the mean time to improvement was about 2 months. And the mean time to maximum improvement was about 6 months in this study.

Corticosteroids has been first-line therapy of CIDP for a long time and, what we said earlier, it's not strictly level-one evidence, there's a vast clinical experience that's been important in the classification of the evidence in this case. Many studies exist showing that prednisone and other steroids are effective, they induce clinical improvement in various scenarios, including unrandomized, retrospective, and non-controlled studies. The consensus of experts therefore is that glucocorticoid therapy produces a significant improvement and the delivery is deemed effective using either oral or intravenous delivery protocols.

Now let's talk about IVIG in CIDP. We're going to talk about the ICE trial. This is an international, multicenter, randomized, double-blind, placebo-controlled, crossover design trial that was performed in 117 patients. The patients who were selected for the study met specific neurophysiological, inflammatory, neuropathy, cause and treatment also known as INCAT criteria for CIDP. They were treated with IVIG versus placebo every 3 weeks for up to 24 weeks in an initial treatment period.

The primary outcome for this study was the percentage of patients who maintained an improvement from baseline in adjusted INCAT disability score of 1 point or more through the 24th week of treatment. There were secondary outcomes that were measured as well, including grip strength, MRC score, quality of life measures, and the time to relapse. We're going to look at time to relapse as well as some of the other measures going forward.

In clinical studies the most common adverse reactions with GAMUNEX-C were headache, pyrexia, hypertension, chills, rash, nausea, arthralgia, and asthenia (in CIDP). The most serious adverse reactions in clinical studies were pulmonary embolism (PE) in 1 subject with a history of PE (in CIDP).

This is the design of the ICE study. This is a complicated slide but I'll basically explain it to you as simplistically as I can. To the left side of this slide what you see is the patients were initially treated with either IVIG or placebo. The patients who were treated with IVIG or placebo, if they responded would remain in this arm of the study for 24 weeks. If they didn't respond or if they responded and then relapsed they'd be crossed over to the other treatment and treatment would be continued.

At the end of the initial phase of the study, the responders were kept in the study and then they were randomized—so now you're looking at the right side of the study. They were randomized to either receive placebo or receive IVIG and then they were followed to see if they relapsed—so there were 2 measurements here. To the left of the slide what we would consider is, did the patients respond to therapy in the IVIG versus placebo group? To the right side of the study we're going to take the responders and we're going to see if we either continue IVIG or put them back on placebo whether they relapse over time. Let's see how everything pans out.

Here's what the dosing was in the study. The loading dose was 2 grams per kilogram over 2 to 4 days. Then, maintenance was 1 gram per kilogram every 3 weeks over 1 to 2 days. This was the dose used throughout the ICE trial. They allowed 3 cycles to assess for a response so if a patient received either 3 cycles of placebo or 3 cycles of IVIG, if they responded they were kept in that first arm of the study. If they hadn't responded through the first 3 cycles they were switched over into the other arm of the study and continued on therapy. Then obviously, patients were followed for objective parameters throughout the study to measure relapses and outcomes.

So how long did it take to see a response to IVIG? Among the IVIG responders, 14 of 32 were improved by the third week of therapy, 16 of the 32 improved by the sixth week of therapy, 1 of the 32 improved by the twelfth week of therapy, and another last patient improved by the eighteenth week of therapy. If we summarize this slide, it suggested that the majority of patients who respond are going to respond by that sixth week of therapy. So now let's look at the primary outcome of this study. So now we're looking at that left side of the diagram that I just showed you, and this is the primary outcome of the patients who were treated over that first period of time.

54% of the treated patients showed improvement in their INCAT scores versus only 21% of the placebo group. This had a P-value of 0.002 which argues strongly that IVIG was effective compared to placebo. And now among the responders to IVIG, 14 of the 32 improved by the third week of therapy, 16 of 32 improved by the sixth week of therapy, initial 1 of 32 improved by the twelfth week of therapy, and 1 more patient improved by the eighteenth week of therapy. So if we combine this, 30 of the 32 patients improved by the sixth week of therapy, which suggests to us that the majority of patients who are treated with IVIG who are going to respond are going to do so by 6 weeks.

Looked at another way, we can ask, what's the time for maximal improvement with IVIG therapy? Among the responder group, 4 of the 32 patients reached their maximal improvement by the third week of therapy, 18 of the 32, which is more than half of the patients, reached the maximal improvement by the sixth week of therapy, and all 32 reached their maximal improvement by the twenty-fourth week of therapy. Now we're going to move over to the right side of that original study diagram and we're going to look at the probability of relapse after tapering therapy.

So if you remember, we have the group of patients that originally responded to therapy. And what's happening here is we're taking half of those patients and putting them on placebo again and we're taking half of those patients and continuing them on IVIG. And what you find out here is that over time the group that continues on placebo, which is the blue line at the top of this graph, are much more likely to relapse than the group that are continued on IVIG. And this also shows that IVIG remains effective in the tapering group compared to placebo.

So now let's look at a summary of the ICE Study. During the treatment study 59 patients were randomized to IVIG and 58 were randomized to placebo. The initial dosing was 2 grams per kilogram as the loading dose, which was followed by 1 gram per kilogram every 3 weeks. In the IVIG arm, 36 patients improved and 23 showed progression. On the placebo arm, 12 patients improved and 45 patients relapsed. So now let's look at the primary outcome: 54% of treated patients showed improved INCAT scores versus 21% of placebo patients.

This sets a P-value of 0.002, suggesting that IVIG was superior to placebo. During the 24-week extension phase, 57 patients were re-randomized. Patients who received IVIG for the 48 weeks had a significantly lower relapse rate. Thus, IVIG is effective for treatment of CIDP. The maintenance dose of 1 gram per kilogram every 3 weeks is effective in preventing relapse versus placebo.

Thank you and I hope this information will be useful to you in your practice.

Transcript

CIDP: Treatment

Jon Katz, MD, Neurology, discusses CIDP treatment options as well as the ICE study.

Hi, I'm Jon Katz from San Francisco, California and this afternoon I'm going to be talking about the treatment of CIDP. When we talk about the treatment of CIDP we should look at what the guidelines specifically say and what the recommendations are. So let's first mention IVIG which you all know is a common treatment for CIDP. That has level A recommendation. Corticosteroids which haven't had a ton of clinical trials have a level C recommendation and should be considered in sensory and motor types of CIDP. And if IVIG and corticosteroids are ineffective, we move over to plasma exchange which should also be considered and actually has a level A recommendation as well.

So let's talk about plasma exchange in CIDP. There was a study by Hahn et al, which was a double-blind study of 18 CIDP patients, 9 patients with progressive neuropathy and 9 with a relapse and remitting course. They were given plasma exchange over 4 weeks. The patients received either 10 sham treatments or plasmapheresis itself with a washout period and then a crossover. Fifteen patients completed the trial and 12 of these 15 patients turned out to improve with plasma exchange. Once plasma exchange was stopped, 8 of the 12 patients relapsed within 1 to 2 weeks. All the patients subsequently improved in an open-label part of the study, so it was concluded the plasma exchange was effective.

Prednisone is another treatment we often use for CIDP, and prednisone's evidence is really, as I said before, not based on clinical trials but on a load of open-label experience. One study we like to point to when we talk about the efficacy of prednisone is a study by Baron that was done in 1989 that looked at prednisone in 60 patients treated with IVIG. The response rate of these patients, which were very specifically selected—not just by nerve conduction studies but by physical exam—was that 90% of the patients responded to a course of prednisone and the mean time to improvement was about 2 months. And the mean time to maximum improvement was about 6 months in this study.

Corticosteroids has been first-line therapy of CIDP for a long time and, what we said earlier, it's not strictly level-one evidence, there's a vast clinical experience that's been important in the classification of the evidence in this case. Many studies exist showing that prednisone and other steroids are effective, they induce clinical improvement in various scenarios, including unrandomized, retrospective, and non-controlled studies. The consensus of experts therefore is that glucocorticoid therapy produces a significant improvement and the delivery is deemed effective using either oral or intravenous delivery protocols.

Now let's talk about IVIG in CIDP. We're going to talk about the ICE trial. This is an international, multicenter, randomized, double-blind, placebo-controlled, crossover design trial that was performed in 117 patients. The patients who were selected for the study met specific neurophysiological, inflammatory, neuropathy, cause and treatment also known as INCAT criteria for CIDP. They were treated with IVIG versus placebo every 3 weeks for up to 24 weeks in an initial treatment period.

The primary outcome for this study was the percentage of patients who maintained an improvement from baseline in adjusted INCAT disability score of 1 point or more through the 24th week of treatment. There were secondary outcomes that were measured as well, including grip strength, MRC score, quality of life measures, and the time to relapse. We're going to look at time to relapse as well as some of the other measures going forward.

In clinical studies the most common adverse reactions with GAMUNEX-C were headache, pyrexia, hypertension, chills, rash, nausea, arthralgia, and asthenia (in CIDP). The most serious adverse reactions in clinical studies were pulmonary embolism (PE) in 1 subject with a history of PE (in CIDP).

This is the design of the ICE study. This is a complicated slide but I'll basically explain it to you as simplistically as I can. To the left side of this slide what you see is the patients were initially treated with either IVIG or placebo. The patients who were treated with IVIG or placebo, if they responded would remain in this arm of the study for 24 weeks. If they didn't respond or if they responded and then relapsed they'd be crossed over to the other treatment and treatment would be continued.

At the end of the initial phase of the study, the responders were kept in the study and then they were randomized—so now you're looking at the right side of the study. They were randomized to either receive placebo or receive IVIG and then they were followed to see if they relapsed—so there were 2 measurements here. To the left of the slide what we would consider is, did the patients respond to therapy in the IVIG versus placebo group? To the right side of the study we're going to take the responders and we're going to see if we either continue IVIG or put them back on placebo whether they relapse over time. Let's see how everything pans out.

Here's what the dosing was in the study. The loading dose was 2 grams per kilogram over 2 to 4 days. Then, maintenance was 1 gram per kilogram every 3 weeks over 1 to 2 days. This was the dose used throughout the ICE trial. They allowed 3 cycles to assess for a response so if a patient received either 3 cycles of placebo or 3 cycles of IVIG, if they responded they were kept in that first arm of the study. If they hadn't responded through the first 3 cycles they were switched over into the other arm of the study and continued on therapy. Then obviously, patients were followed for objective parameters throughout the study to measure relapses and outcomes.

So how long did it take to see a response to IVIG? Among the IVIG responders, 14 of 32 were improved by the third week of therapy, 16 of the 32 improved by the sixth week of therapy, 1 of the 32 improved by the twelfth week of therapy, and another last patient improved by the eighteenth week of therapy. If we summarize this slide, it suggested that the majority of patients who respond are going to respond by that sixth week of therapy. So now let's look at the primary outcome of this study. So now we're looking at that left side of the diagram that I just showed you, and this is the primary outcome of the patients who were treated over that first period of time.

54% of the treated patients showed improvement in their INCAT scores versus only 21% of the placebo group. This had a P-value of 0.002 which argues strongly that IVIG was effective compared to placebo. And now among the responders to IVIG, 14 of the 32 improved by the third week of therapy, 16 of 32 improved by the sixth week of therapy, initial 1 of 32 improved by the twelfth week of therapy, and 1 more patient improved by the eighteenth week of therapy. So if we combine this, 30 of the 32 patients improved by the sixth week of therapy, which suggests to us that the majority of patients who are treated with IVIG who are going to respond are going to do so by 6 weeks.

Looked at another way, we can ask, what's the time for maximal improvement with IVIG therapy? Among the responder group, 4 of the 32 patients reached their maximal improvement by the third week of therapy, 18 of the 32, which is more than half of the patients, reached the maximal improvement by the sixth week of therapy, and all 32 reached their maximal improvement by the twenty-fourth week of therapy. Now we're going to move over to the right side of that original study diagram and we're going to look at the probability of relapse after tapering therapy.

So if you remember, we have the group of patients that originally responded to therapy. And what's happening here is we're taking half of those patients and putting them on placebo again and we're taking half of those patients and continuing them on IVIG. And what you find out here is that over time the group that continues on placebo, which is the blue line at the top of this graph, are much more likely to relapse than the group that are continued on IVIG. And this also shows that IVIG remains effective in the tapering group compared to placebo.

So now let's look at a summary of the ICE Study. During the treatment study 59 patients were randomized to IVIG and 58 were randomized to placebo. The initial dosing was 2 grams per kilogram as the loading dose, which was followed by 1 gram per kilogram every 3 weeks. In the IVIG arm, 36 patients improved and 23 showed progression. On the placebo arm, 12 patients improved and 45 patients relapsed. So now let's look at the primary outcome: 54% of treated patients showed improved INCAT scores versus 21% of placebo patients.

This sets a P-value of 0.002, suggesting that IVIG was superior to placebo. During the 24-week extension phase, 57 patients were re-randomized. Patients who received IVIG for the 48 weeks had a significantly lower relapse rate. Thus, IVIG is effective for treatment of CIDP. The maintenance dose of 1 gram per kilogram every 3 weeks is effective in preventing relapse versus placebo.

Thank you and I hope this information will be useful to you in your practice.


Gamunex Connexions Support 1-888-MYGAMUNEX (1-888-694-2686)

GAMUNEX®-C (immune globulin injection [human], 10% caprylate/chromatography purified) is indicated for the treatment of primary humoral immunodeficiency disease (PIDD) in patients 2 years of age and older, idiopathic thrombocytopenic purpura (ITP) in adults and children, and chronic inflammatory demyelinating polyneuropathy (CIDP) in adults.

Thrombosis may occur with immune globulin products, including GAMUNEX-C. Risk factors may include: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factors. For patients at risk of thrombosis, administer GAMUNEX-C at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity.

Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur with immune globulin intravenous (IVIG) products in predisposed patients. Patients predisposed to renal dysfunction include those with any degree of preexisting renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. Renal dysfunction and acute renal failure occur more commonly in patients receiving IVIG products containing sucrose. GAMUNEX-C does not contain sucrose. For patients at risk of renal dysfunction or failure, administer GAMUNEX-C at the minimum concentration available and the minimum infusion rate practicable.

GAMUNEX-C is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin. It is contraindicated in IgA-deficient patients with antibodies against IgA and history of hypersensitivity.

Severe hypersensitivity reactions may occur with IVIG products, including GAMUNEX-C. In case of hypersensitivity, discontinue GAMUNEX-C infusion immediately and institute appropriate treatment.

Monitor renal function, including blood urea nitrogen (BUN), serum creatinine, and urine output in patients at risk of developing acute renal failure.

Hyperproteinemia, increased serum viscosity, and hyponatremia may occur in patients receiving IVIG treatment, including GAMUNEX-C.

There have been reports of aseptic meningitis, hemolytic anemia, and noncardiogenic pulmonary edema (transfusion-related acute lung injury [TRALI]) in patients administered with IVIG, including GAMUNEX-C.

The high-dose regimen (1g/kg x 1-2 days) is not recommended for individuals with expanded fluid volumes or where fluid volume may be a concern.

Because GAMUNEX-C is made from human blood, it may carry a risk of transmitting infectious agents, eg, viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent.

Do not administer GAMUNEX-C subcutaneously in patients with ITP because of the risk of hematoma formation.

Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk of developing acute renal failure. Assess renal function, including measurement of BUN and serum creatinine, before the initial infusion of GAMUNEX-C and at appropriate intervals thereafter.

Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies, because of the potentially increased risk of thrombosis.

If signs and/or symptoms of hemolysis are present after an infusion of GAMUNEX-C, perform appropriate laboratory testing for confirmation.

If TRALI is suspected, perform appropriate tests for the presence of antineutrophil antibodies and anti-HLA antibodies in both the product and patient's serum.

After infusion of IgG, the transitory rise of the various passively transferred antibodies in the patient's blood may yield positive serological testing results, with the potential for misleading interpretation.

In clinical studies, the most common adverse reactions with GAMUNEX-C were headache, pyrexia, hypertension, chills, rash, nausea, arthralgia, and asthenia (in CIDP); cough, rhinitis, pharyngitis, headache, asthma, nausea, fever, diarrhea, and sinusitis with intravenous use (in PIDD) and local infusion-site reactions, fatigue, headache, upper respiratory tract infection, arthralgia, diarrhea, nausea, sinusitis, bronchitis, depression, allergic dermatitis, migraine, myalgia, viral infection, and pyrexia with subcutaneous use (in PIDD); and headache, ecchymosis, vomiting, fever, nausea, rash, abdominal pain, back pain, and dyspepsia (in ITP).

The most serious adverse reactions in clinical studies were pulmonary embolism (PE) in 1 subject with a history of PE (in CIDP), an exacerbation of autoimmune pure red cell aplasia in 1 subject (in PIDD), and myocarditis in 1 subject that occurred 50 days post-study drug infusion and was not considered drug related (in ITP).

Please see accompanying full Prescribing Information for GAMUNEX-C.

Terms to know

IG=immune globulin, CIDP=chronic inflammatory demyelinating polyneuropathy, PIDD=primary immunodeficiency disease, ITP=idiopathic thrombocytopenic purpura, Sub Q=subcutaneous, IV=intravenous, ICE=10% caprylate-chromatography purified immune globulin intravenous (IGIV-C) CIDP efficacy.

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