Comparison of Clinical Effects of Azathioprine and Rituximab NMO-SD Patients

• Sponsor: Isfahan University of Medical Sciences (Other)
• Overall Status: Completed
• CT.gov ID: NCT03002038
• Collaborator: (none)
• Enrollment: 86
• Location: 1
• Arms: 2
• Duration (Months): 15
• Patients Per Site Per Month: 5.7

Study Details

Study Description

Brief Summary

The purpose of this study is to compare annual relapse rate, expanded disability status scale, and side effects of azathioprine and rituximab in patients with neuromyelitis optica spectrum disorder during a one year follow up through a randomized clinical trial.

Condition or Disease	Intervention/Treatment	Phase
Neuromyelitis Optica Spectrum Disorder	Drug: Azathioprine; Drug: Rituximab	Phase 2/Phase 3

Detailed Description

Neuromyelitis Optica Spectrum Disorder (NMO-SD) is a recurrent inflammatory demyelinating disease affecting the central nervous system. The disease is clinically recognized by optic neuritis and transverse myelitis and is associated with high risk of mortality. Each attack worsens patients' disability. This means that after 5 years of the disease onset, half of patients need to use wheelchair and approximately 50% of them become blind.

Considering that the disease can be disabling for patients, the maintenance treatment should be applied in addition to treatment of acute attacks, in order to prevent future recurrences. Acute attacks are usually treated with high doses of intravenous corticosteroids. Plasmapheresis is also used when patients fail to response to corticosteroids. B lymphocyte inhibitors are used as the maintenance therapy in these patients. First line therapeutic medications include azathioprine and rituximab which are being recommended for long term therapy and second line medications include methotrexate and mycophenolate mofetil.

Azathioprine is an immune-modulatory agent which is available in the oral form and don't require hospitalization to be administered, however, because of side effects such as bone marrow suppression and hepatotoxicity, periodic check of blood cells and liver enzymes are needed. Rituximab is a cluster of differentiation antigen 20 inhibitor which leads to decreased B lymphocytes and antibody in patients. This medication is only available in the injectable form and needs hospitalization to be administered. Close monitory is needed during the administration considering severe side effects such as allergic reactions and respiratory distress. However, laboratory tests are not needed in patients taking rituximab although it is more expensive than azathioprine. No clinical trial has been performed previously to compare clinical efficacy of these two drugs in NMO-SD patients. Therefore, we aimed to compare their efficacy through a randomized clinical trial.

Study Design

• Study Type: Interventional
• Actual Enrollment: 86 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Comparison of Annual Relapse Rate, Expanded Disability Status Scale, and Side Effects Between Azathioprine and Rituximab in Patients With Neuromyelitis Optica Spectrum Disorders
• Study Start Date: Sep 1, 2015
• Actual Primary Completion Date: Nov 1, 2016
• Actual Study Completion Date: Dec 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Azathioprine Patients in this group will receive 50 mg of azathioprine, two times each day and gradually increased to maximum dose of 3 g daily with the aim of lymphocytes count less than 1500.	Drug: Azathioprine; Patients are started with Azathioprine 50 mg tablets, taken orally twice a day. The medication dose is increased gradually with the aim of lymphocytes count bellow 1500 and to the maximum dose of 3 g Azathioprine per day. Cell blood count is checked once a week in the first month of treatment, once every two weeks in the second month of treatment, and monthly in the third month of treatment to make decision about medication dose.; Other Names: Azathioprine Mehrdaru®
Experimental: Rituximab Patients in this group will receive 1g of Rituximab in 500 cc normal saline serum through intravenous infusion with two weeks intervals (as one course) and each course of treatment is repeated every 6 months.	Drug: Rituximab; Patients will receive 1 g of Rituximab (two vials of RediTux 500 mg/50 ml) in 500 cc normal saline serum through intravenous infusion and this will be repeated two weeks later. This cycle will be repeated every 6 months.; Other Names: RediTux®

Outcome Measures

Primary Outcome Measures

1. Annual Relapse Rate [one year]

   annual relapse rate will be measured in the baseline (according to patients' history in the last year) and after 12 months of intervention.

Secondary Outcome Measures

1. Expanded Disability Status Scale [one year]

   expanded disability status scale will be measured in the baseline and after 12 months of intervention. Expanded disability status scale (EDSS) is a measure of disability for patients. The score ranges from 0-10, with 0 showing normal neurological exam and 10 showing death due to the disabling disease. Thus, higher scores represent more profound levels of disability.

Other Outcome Measures

1. Number of Participants With Adverse Drug Reactions [one year]

   adverse drug reactions will be observed closely and reported during the intervention. We will compare the number of adverse drug reactions in two groups. Also, adverse drug reactions will be described by details in each group.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of neuromyelitis optica spectrum disorder based on the recent guidelines in 2015

• Expanded disability status scale between 0 and 7

• Age between 18 and 50 years old

Exclusion Criteria:

• Pregnancy or lactation during the study

• Deciding to leave the study by patient

• Lack of consent to enter the study

• Lack of cooperation for follow up

• Severe side effect of the medication

• Treatment with other immunosuppressant medications (including but not limited to cyclophosphamide, mycophenolate mofetil, methotrexate, others) within two months before intervention

• Taking any other immunosuppressant or other type of medication (including herbal drugs) without permission of the physician during the study.

• Presence of other autoimmune disease (including but not limited to Behcet disease, systemic lupus erythematosus, rheumatoid arthritis, and others)

• Presence of liver disorders

• Presence of hematologic disorders

• Presence of heart failure

• Receipt of a live vaccine within 4 weeks prior to intervention

• Previous treatment with Azathioporine or Rituximab

• History of HIV, hepatitis B, or hepatitis C

• Ongoing daily steroid use

• History of severe allergic or anaphylactic reaction to monoclonal antibodies

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Kashani Hospital	Isfahan		Iran, Islamic Republic of	8174673461

Sponsors and Collaborators

• Isfahan University of Medical Sciences

Investigators

• Study Chair: Vahid Shaygannejad, M.D., Department of Neurology, School of Medicine, Isfahan University of Medical Sciences

Study Documents (Full-Text)

None provided.

More Information

Publications

• Costanzi C, Matiello M, Lucchinetti CF, Weinshenker BG, Pittock SJ, Mandrekar J, Thapa P, McKeon A. Azathioprine: tolerability, efficacy, and predictors of benefit in neuromyelitis optica. Neurology. 2011 Aug 16;77(7):659-66. doi: 10.1212/WNL.0b013e31822a2780. Epub 2011 Aug 3.
• Katz Sand I. Neuromyelitis Optica Spectrum Disorders. Continuum (Minneap Minn). 2016 Jun;22(3):864-96. doi: 10.1212/CON.0000000000000337. Review.
• Kim SH, Huh SY, Lee SJ, Joung A, Kim HJ. A 5-year follow-up of rituximab treatment in patients with neuromyelitis optica spectrum disorder. JAMA Neurol. 2013 Sep 1;70(9):1110-7.
• Morrow MJ, Wingerchuk D. Neuromyelitis optica. J Neuroophthalmol. 2012 Jun;32(2):154-66. doi: 10.1097/WNO.0b013e31825662f1. Review.
• Sato DK, Lana-Peixoto MA, Fujihara K, de Seze J. Clinical spectrum and treatment of neuromyelitis optica spectrum disorders: evolution and current status. Brain Pathol. 2013 Nov;23(6):647-60. doi: 10.1111/bpa.12087. Review.
• Trebst C, Jarius S, Berthele A, Paul F, Schippling S, Wildemann B, Borisow N, Kleiter I, Aktas O, Kümpfel T; Neuromyelitis Optica Study Group (NEMOS). Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the Neuromyelitis Optica Study Group (NEMOS). J Neurol. 2014 Jan;261(1):1-16. doi: 10.1007/s00415-013-7169-7. Epub 2013 Nov 23. Review.

• Responsible Party: Vahid Shaygannejad, Associate Professor of Neurology, Isfahan University of Medical Sciences
• ClinicalTrials.gov Identifier: NCT03002038
• Other Study ID Numbers: 395275
• First Posted: Dec 23, 2016
• Last Update Posted: Sep 30, 2020
• Last Verified: Sep 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Keywords provided by Vahid Shaygannejad, Associate Professor of Neurology, Isfahan University of Medical Sciences: neuromyelitis optica spectrum disorder; azathioprine; rituximab; clinical trial; annual relapse rate; expanded disability status scale
• Additional relevant MeSH terms: Neuromyelitis Optica; Rituximab; Azathioprine

Study Results

Participant Flow

Arm/Group Title	Azathioprine	Rituximab
Arm/Group Description	Patients in this group will receive 50 mg of azathioprine, two times each day and gradually increased to maximum dose of 3 g daily with the aim of lymphocytes count less than 1500. Azathioprine: Patients are started with Azathioprine 50 mg tablets, taken orally twice a day. The medication dose is increased gradually with the aim of lymphocytes count bellow 1500 and to the maximum dose of 3 g Azathioprine per day. Cell blood count is checked once a week in the first month of treatment, once every two weeks in the second month of treatment, and monthly in the third month of treatment to make decision about medication dose.	Patients in this group will receive 1g of Rituximab in 500 cc normal saline serum through intravenous infusion with two weeks intervals (as one course) and each course of treatment is repeated every 6 months. Rituximab: Patients will receive 1 g of Rituximab (two vials of RediTux 500 mg/50 ml) in 500 cc normal saline serum through intravenous infusion and this will be repeated two weeks later. This cycle will be repeated every 6 months.
Period Title: Overall Study
STARTED	46	40
COMPLETED	35	33
NOT COMPLETED	11	7

Baseline Characteristics

Arm/Group Title	Azathioprine	Rituximab	Total
Arm/Group Description	Patients in this group will receive 50 mg of azathioprine, two times each day and gradually increased to maximum dose of 3 g daily with the aim of lymphocytes count less than 1500. Azathioprine: Patients are started with Azathioprine 50 mg tablets, taken orally twice a day. The medication dose is increased gradually with the aim of lymphocytes count bellow 1500 and to the maximum dose of 3 g Azathioprine per day. Cell blood count is checked once a week in the first month of treatment, once every two weeks in the second month of treatment, and monthly in the third month of treatment to make decision about medication dose.	Patients in this group will receive 1g of Rituximab in 500 cc normal saline serum through intravenous infusion with two weeks intervals (as one course) and each course of treatment is repeated every 6 months. Rituximab: Patients will receive 1 g of Rituximab (two vials of RediTux 500 mg/50 ml) in 500 cc normal saline serum through intravenous infusion and this will be repeated two weeks later. This cycle will be repeated every 6 months.	Total of all reporting groups
Overall Participants	46	40	86
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	32.11 (9.36)	34.33 (5.86)	33.14 (7.32)
Sex: Female, Male (Count of Participants)
Female	38 82.6%	34 85%	72 83.7%
Male	8 17.4%	6 15%	14 16.3%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
Iran	46 100%	40 100%	86 100%
Expanded disability status scale (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	2.40 (1.24)	3.55 (1.95)	2.96 (1.52)
Annualized relapse rate (numbers of relapses) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [numbers of relapses]	1.02 (0.39)	1.30 (0.65)	1.15 (0.51)
Positive AQP4-IgG (Count of Participants)
Count of Participants [Participants]	25 54.3%	17 42.5%	42 48.8%

Outcome Measures

1. Primary Outcome

Title	Annual Relapse Rate
Description	annual relapse rate will be measured in the baseline (according to patients' history in the last year) and after 12 months of intervention.
Time Frame	one year

Outcome Measure Data

Analysis Population Description

Per protocol analysis

Arm/Group Title	Azathioprine	Rituximab
Arm/Group Description	Patients in this group will receive 50 mg of azathioprine, two times each day and gradually increased to maximum dose of 3 g daily with the aim of lymphocytes count less than 1500. Azathioprine: Patients are started with Azathioprine 50 mg tablets, taken orally twice a day. The medication dose is increased gradually with the aim of lymphocytes count bellow 1500 and to the maximum dose of 3 g Azathioprine per day. Cell blood count is checked once a week in the first month of treatment, once every two weeks in the second month of treatment, and monthly in the third month of treatment to make decision about medication dose.	Patients in this group will receive 1g of Rituximab in 500 cc normal saline serum through intravenous infusion with two weeks intervals (as one course) and each course of treatment is repeated every 6 months. Rituximab: Patients will receive 1 g of Rituximab (two vials of RediTux 500 mg/50 ml) in 500 cc normal saline serum through intravenous infusion and this will be repeated two weeks later. This cycle will be repeated every 6 months.
Measure Participants	35	33
Baseline	1 (0.38)	1.30 (0.68)
Outcome	0.51 (0.55)	0.21 (0.42)

2. Secondary Outcome

Title	Expanded Disability Status Scale
Description	expanded disability status scale will be measured in the baseline and after 12 months of intervention. Expanded disability status scale (EDSS) is a measure of disability for patients. The score ranges from 0-10, with 0 showing normal neurological exam and 10 showing death due to the disabling disease. Thus, higher scores represent more profound levels of disability.
Time Frame	one year

Outcome Measure Data

Analysis Population Description

Per protocol analysis

Arm/Group Title	Azathioprine	Rituximab
Arm/Group Description	Patients in this group will receive 50 mg of azathioprine, two times each day and gradually increased to maximum dose of 3 g daily with the aim of lymphocytes count less than 1500. Azathioprine: Patients are started with Azathioprine 50 mg tablets, taken orally twice a day. The medication dose is increased gradually with the aim of lymphocytes count bellow 1500 and to the maximum dose of 3 g Azathioprine per day. Cell blood count is checked once a week in the first month of treatment, once every two weeks in the second month of treatment, and monthly in the third month of treatment to make decision about medication dose.	Patients in this group will receive 1g of Rituximab in 500 cc normal saline serum through intravenous infusion with two weeks intervals (as one course) and each course of treatment is repeated every 6 months. Rituximab: Patients will receive 1 g of Rituximab (two vials of RediTux 500 mg/50 ml) in 500 cc normal saline serum through intravenous infusion and this will be repeated two weeks later. This cycle will be repeated every 6 months.
Measure Participants	35	33
Baseline	2.40 (1.24)	3.55 (1.95)
Outcome	1.95 (1.13)	2.56 (1.99)

3. Other Pre-specified Outcome

Title	Number of Participants With Adverse Drug Reactions
Description	adverse drug reactions will be observed closely and reported during the intervention. We will compare the number of adverse drug reactions in two groups. Also, adverse drug reactions will be described by details in each group.
Time Frame	one year

Outcome Measure Data

Analysis Population Description

intention to treat analysis

Arm/Group Title	Azathioprine	Rituximab
Arm/Group Description	Patients in this group will receive 50 mg of azathioprine, two times each day and gradually increased to maximum dose of 3 g daily with the aim of lymphocytes count less than 1500. Azathioprine: Patients are started with Azathioprine 50 mg tablets, taken orally twice a day. The medication dose is increased gradually with the aim of lymphocytes count bellow 1500 and to the maximum dose of 3 g Azathioprine per day. Cell blood count is checked once a week in the first month of treatment, once every two weeks in the second month of treatment, and monthly in the third month of treatment to make decision about medication dose.	Patients in this group will receive 1g of Rituximab in 500 cc normal saline serum through intravenous infusion with two weeks intervals (as one course) and each course of treatment is repeated every 6 months. Rituximab: Patients will receive 1 g of Rituximab (two vials of RediTux 500 mg/50 ml) in 500 cc normal saline serum through intravenous infusion and this will be repeated two weeks later. This cycle will be repeated every 6 months.
Measure Participants	46	40
Count of Participants [Participants]	3 6.5%	4 10%

Adverse Events

Time Frame	1 year
Arm/Group Title	Azathioprine		Rituximab
Arm/Group Description	Patients in this group will receive 50 mg of azathioprine, two times each day and gradually increased to maximum dose of 3 g daily with the aim of lymphocytes count less than 1500. Azathioprine: Patients are started with Azathioprine 50 mg tablets, taken orally twice a day. The medication dose is increased gradually with the aim of lymphocytes count bellow 1500 and to the maximum dose of 3 g Azathioprine per day. Cell blood count is checked once a week in the first month of treatment, once every two weeks in the second month of treatment, and monthly in the third month of treatment to make decision about medication dose.		Patients in this group will receive 1g of Rituximab in 500 cc normal saline serum through intravenous infusion with two weeks intervals (as one course) and each course of treatment is repeated every 6 months. Rituximab: Patients will receive 1 g of Rituximab (two vials of RediTux 500 mg/50 ml) in 500 cc normal saline serum through intravenous infusion and this will be repeated two weeks later. This cycle will be repeated every 6 months.
All Cause Mortality
	Azathioprine		Rituximab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/46 (0%)		0/40 (0%)
Serious Adverse Events
	Azathioprine		Rituximab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/46 (2.2%)		1/40 (2.5%)
Hepatobiliary disorders
Impaired liver function test	1/46 (2.2%)	1	0/40 (0%)	0
Immune system disorders
Severe allergic reaction	0/46 (0%)	0	1/40 (2.5%)	1
Other (Not Including Serious) Adverse Events
	Azathioprine		Rituximab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/46 (4.3%)		3/40 (7.5%)
Gastrointestinal disorders
Gastrointestinal intolerance	2/46 (4.3%)	2	0/40 (0%)	0
Immune system disorders
Mild/moderate allergic reactions	0/46 (0%)	0	3/40 (7.5%)	3

Limitations/Caveats

lack of blinding, uneven assignment of patients to treatment groups, lack of compliance measures, and short follow-up duration

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.