New Onset of Type 1 Diabetes Mycophenolate Mofetil-Daclizumab Clinical Trial

• ClinicalTrials.gov Identifier: NCT00100178
• Recruitment Status: Completed
• First Posted: December 24, 2004
• Results First Posted: August 16, 2016
• Last Update Posted: August 16, 2016
• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID); Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Juvenile Diabetes Research Foundation; National Center for Research Resources (NCRR)
• Information provided by (Responsible Party): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator)
• Condition: Diabetes Mellitus, Type 1
• Interventions: Drug: Mycophenolate mofeteil (MMF); Drug: Daclizumab (DZB); Drug: Placebo control for Mycophenolate mofeteil (MMF); Drug: Placebo control for Daclizumab (DZB)
• Enrollment: 126

Participant Flow

Recruitment Details	Thirteen Clinical Centers at academic institutions recruited and enrolled 126 subjects ages 8 to 45 years with autoimmune T1D for less than 3 months.
Pre-assignment Details	Subjects were screened for evidence of autoantibodies and c-peptide >0.2 pmol on a stimulated 2 hr Mixed Meal Tolerance Test to determine eligibility for the study.The MMTT must be conducted at least 21 days from the diagnosis of diabetes and no more than one month (37 days) prior to the date of randomization.

Arm/Group Title	MMF and DZB	MMF Alone	MMF-DZB Placebo Control
Arm/Group Description	DZB given by intravenous infusion (1 mg/kg)at baseline and 2 weeks later, and 600 mg/m2 (2000 mg/day maximum) in 2-3 divided doses for 2 years.	600 mg/m2 (2000 mg/day maximum) in 2-3 divided doses for 2 years and saline intravenous infusions given at baseline and two weeks later.	Placebo pills given daily for two years and saline intravenous infusions given at baseline and two weeks later.
Period Title: Overall Study
Started	41	31 [1]	42
Completed	32	21	32
Not Completed	9	10	10
Reason Not Completed
Lost to Follow-up	0	6	5
Adverse Event	2	2	1
Withdrawal by Subject	1	1	1
Physician Decision	6	1	3
[1] 12 subjects randomized to the MMF alone group were excluded from analysis due to randomization error

Baseline Characteristics

Arm/Group Title		MMF and DZB	MMF Alone	MMF-DZB Placebo Control	Total
Arm/Group Description		600 mg/m2 (2000 mg/day maximum) in 2-3 divided doses for 2 years AND DZB given by intravenous infusion (1 mg/kg)at baseline and 2 weeks later.	600 mg/m2 (2000 mg/day maximum) in 2-3 divided doses for 2 years AND saline intravenous infusions given at baseline and two weeks later	Placebo pills given daily for two years AND saline intravenous infusions given at baseline and two weeks later.	Total of all reporting groups
Overall Number of Baseline Participants		41	31	42	114
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	41 participants	31 participants	42 participants	114 participants
		18.4 (9.09)	17.1 (6.71)	18.8 (10.44)	18.2 (9.01)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	41 participants	31 participants	42 participants	114 participants
	Female	18 43.9%	11 35.5%	17 40.5%	46 40.4%
	Male	23 56.1%	20 64.5%	25 59.5%	68 59.6%

Outcome Measures

1. Primary Outcome

Title	Mean Stimulated C-peptide Area Under the Curve
Description	The primary outcome is the area under the stimulated C-peptide curve (AUC) based on data collected at time 0 to 2 hours of a 4-hour mixed meal glucose tolerance test (MMTT) conducted at the primary endpoint visit. The timed measurements are done at: 0, 15, 30 60, 90, and 120 minutes.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

Participants who completed a 4-hour mixed meal glucose tolerance test at the two-year visit were included in the analysis

Arm/Group Title	MMF and DZB	Placebo Control	MMF Alone
Arm/Group Description:	DZB given by intravenous infusion (1 mg/kg)at baseline and 2 weeks later, and 600 mg/m2 (2000 mg/day maximum) in 2-3 divided doses for 2 years.	Placebo pills given daily for two years and saline intravenous infusions given at baseline and two weeks later.	600 mg/m2 (2000 mg/day maximum) in 2-3 divided doses for 2 years and saline intravenous infusions given at baseline and two weeks later.
Overall Number of Participants Analyzed	22	20	18
Geometric Mean (95% Confidence Interval); Unit of Measure: pmol/ml
	0.28; (0.19 to 0.37)	0.27; (0.18 to 0.37)	0.25; (0.14 to 0.37)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MMF and DZB, Placebo Control
	Comments	The calculation for the concentration of c-peptide is a weighted average of the 6 timed measurements of c-peptide in nano-moles/Liter. We try to distinguish this calculation from the AUC by referring to it as the “AUC mean” and may be expressed algebraically as the AUC/(120 min.); thus, the units are the same as the y-axis.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.47
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	MMF and DZB		MMF Alone		MMF-DZB Placebo Control
Arm/Group Description	600 mg/m2 (2000 mg/day maximum) in 2-3 divided doses for 2 years and DZB given by intravenous infusion (1 mg/kg)at baseline and 2 weeks later .		600 mg/m2 (2000 mg/day maximum) in 2-3 divided doses for 2 years and saline intravenous infusions given at baseline and two weeks later.		Placebo pills given daily for two years AND saline intravenous infusions given at baseline and two weeks later.
All-Cause Mortality
	MMF and DZB		MMF Alone		MMF-DZB Placebo Control
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--		--/--
Serious Adverse Events
	MMF and DZB		MMF Alone		MMF-DZB Placebo Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/41 (36.59%)		5/31 (16.13%)		5/42 (11.90%)
Blood and lymphatic system disorders
Lymphopenia † 1	0/41 (0.00%)	0	1/31 (3.23%)	1	0/42 (0.00%)	0
Blood/Bone Marrow Unspecified † 1	3/41 (7.32%)	3	1/31 (3.23%)	1	1/42 (2.38%)	1
Cardiac disorders
Cardiac General - Other † 1	1/41 (2.44%)	1	0/31 (0.00%)	0	0/42 (0.00%)	0
Eye disorders
Cataract † 1	1/41 (2.44%)	2	0/31 (0.00%)	0	0/42 (0.00%)	0
Ocular/Visual - Other † 1	1/41 (2.44%)	1	0/31 (0.00%)	0	0/42 (0.00%)	0
Gastrointestinal disorders
Diarrhea † 1	1/41 (2.44%)	1	1/31 (3.23%)	1	0/42 (0.00%)	0
Vomiting † 1	0/41 (0.00%)	0	0/31 (0.00%)	0	1/42 (2.38%)	1
Gastrointestinal- Other † 1	0/41 (0.00%)	0	0/31 (0.00%)	0	1/42 (2.38%)	1
General disorders
Secondary Malignancy Unspecified † 1	0/41 (0.00%)	0	1/31 (3.23%)	1	0/42 (0.00%)	0
Hepatobiliary disorders
Hepatobiliary/Pancreas - Other † 1	0/41 (0.00%)	0	1/31 (3.23%)	1	0/42 (0.00%)	0
Infections and infestations
Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils (ANC <1.0 x 10e † 1	1/41 (2.44%)	1	0/31 (0.00%)	0	0/42 (0.00%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils † 1	1/41 (2.44%)	1	0/31 (0.00%)	0	0/42 (0.00%)	0
Metabolism and nutrition disorders
Amylase † 1	0/41 (0.00%)	0	1/31 (3.23%)	1	0/42 (0.00%)	0
Glucose, serum-high (hyperglycemia) † 1	1/41 (2.44%)	1	1/31 (3.23%)	1	2/42 (4.76%)	2
Glucose, serum-low (hypoglycemia) † 1	1/41 (2.44%)	1	0/31 (0.00%)	0	1/42 (2.38%)	1
Metabolic/Laboratory - Other † 1	1/41 (2.44%)	1	0/31 (0.00%)	0	0/42 (0.00%)	0
Metabolic/Laboratory Unspecified † 1	2/41 (4.88%)	2	0/31 (0.00%)	0	0/42 (0.00%)	0
Musculoskeletal and connective tissue disorders
Fracture † 1	1/41 (2.44%)	1	0/31 (0.00%)	0	0/42 (0.00%)	0
Nervous system disorders
Seizure † 1	1/41 (2.44%)	1	0/31 (0.00%)	0	0/42 (0.00%)	0
Psychiatric disorders
Mood alteration † 1	1/41 (2.44%)	2	1/31 (3.23%)	2	0/42 (0.00%)	0
Reproductive system and breast disorders
Sexual/Reproductive Function - Other † 1	1/41 (2.44%)	1	0/31 (0.00%)	0	0/42 (0.00%)	0
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, CTCAE (3.0)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	MMF and DZB		MMF Alone		MMF-DZB Placebo Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	41/41 (100.00%)		31/31 (100.00%)		41/42 (97.62%)
Blood and lymphatic system disorders
Blood/Bone Marrow - Other † 1	4/41 (9.76%)	5	5/31 (16.13%)	10	0/42 (0.00%)	0
Leukocytes (total WBC) † 1	5/41 (12.20%)	7	4/31 (12.90%)	10	0/42 (0.00%)	0
Blood/Bone Marrow Unspecified † 1	6/41 (14.63%)	9	7/31 (22.58%)	14	7/42 (16.67%)	13
Lymphatics - Other † 1	4/41 (9.76%)	5	0/31 (0.00%)	0	0/42 (0.00%)	0
Lymphopenia † 1	0/41 (0.00%)	0	2/31 (6.45%)	3	0/42 (0.00%)	0
Cardiac disorders
Vasovagal episode † 1	0/41 (0.00%)	0	2/31 (6.45%)	2	0/42 (0.00%)	0
Endocrine disorders
Thyroid function, high (hyperthyroidism, thyrotoxicosis) † 1	0/41 (0.00%)	0	2/31 (6.45%)	2	0/42 (0.00%)	0
Gastrointestinal disorders
Dental: periodontal disease † 1	0/41 (0.00%)	0	2/31 (6.45%)	2	0/42 (0.00%)	0
Dental: teeth † 1	3/41 (7.32%)	3	4/31 (12.90%)	4	0/42 (0.00%)	0
Diarrhea † 1	12/41 (29.27%)	14	5/31 (16.13%)	8	12/42 (28.57%)	13
Gastrointestinal - Other † 1	0/41 (0.00%)	0	3/31 (9.68%)	3	5/42 (11.90%)	6
Nausea † 1	7/41 (17.07%)	11	5/31 (16.13%)	5	6/42 (14.29%)	7
Vomiting † 1	8/41 (19.51%)	11	7/31 (22.58%)	8	6/42 (14.29%)	6
General disorders
Fatigue (asthenia, lethargy, malaise) † 1	0/41 (0.00%)	0	2/31 (6.45%)	2	0/42 (0.00%)	0
Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L) † 1	4/41 (9.76%)	4	3/31 (9.68%)	4	0/42 (0.00%)	0
Other AE Unspecified † 1	5/41 (12.20%)	6	5/31 (16.13%)	11	5/42 (11.90%)	8
Pain † 1	10/41 (24.39%)	11	6/31 (19.35%)	18	8/42 (19.05%)	11
Flu-like syndrome † 1	0/41 (0.00%)	0	0/31 (0.00%)	0	4/42 (9.52%)	5
Immune system disorders
Allergic reaction/hypersensitivity (including drug fever) † 1	0/41 (0.00%)	0	2/31 (6.45%)	3	0/42 (0.00%)	0
Allergic rhinitis (including sneezing, nasal stuffiness, postnasal drip) † 1	6/41 (14.63%)	7	0/31 (0.00%)	0	3/42 (7.14%)	3
Infections and infestations
Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils (ANC <1.0 x 10e † 1	5/41 (12.20%)	6	4/31 (12.90%)	4	5/42 (11.90%)	6
Infection - Other † 1	5/41 (12.20%)	5	0/31 (0.00%)	0	0/42 (0.00%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils † 1	10/41 (24.39%)	18	6/31 (19.35%)	15	7/42 (16.67%)	8
Infection with unknown ANC † 1	36/41 (87.80%)	106	27/31 (87.10%)	61	34/42 (80.95%)	94
Infection Unspecified † 1	10/41 (24.39%)	23	2/31 (6.45%)	11	6/42 (14.29%)	8
Metabolism and nutrition disorders
Glucose, serum-high (hyperglycemia) † 1	0/41 (0.00%)	0	3/31 (9.68%)	5	0/42 (0.00%)	0
Glucose, serum-low (hypoglycemia) † 1	13/41 (31.71%)	24	9/31 (29.03%)	21	10/42 (23.81%)	26
Metabolic/Laboratory Unspecified † 1	8/41 (19.51%)	10	0/31 (0.00%)	0	0/42 (0.00%)	0
Musculoskeletal and connective tissue disorders
Fracture † 1	3/41 (7.32%)	3	0/31 (0.00%)	0	7/42 (16.67%)	8
Musculoskeletal/Soft Tissue - Other † 1	8/41 (19.51%)	13	3/31 (9.68%)	5	9/42 (21.43%)	10
Nervous system disorders
Dizziness † 1	0/41 (0.00%)	0	2/31 (6.45%)	2	0/42 (0.00%)	0
Psychiatric disorders
Mood alteration † 1	0/41 (0.00%)	0	2/31 (6.45%)	2	3/42 (7.14%)	3
Reproductive system and breast disorders
Irregular menses (change from baseline) † 1	3/41 (7.32%)	4	0/31 (0.00%)	0	0/42 (0.00%)	0
Sexual/Reproductive Function - Other † 1	0/41 (0.00%)	0	0/31 (0.00%)	0	3/42 (7.14%)	3
Respiratory, thoracic and mediastinal disorders
Cough † 1	11/41 (26.83%)	14	2/31 (6.45%)	2	4/42 (9.52%)	5
Skin and subcutaneous tissue disorders
Dermatology/Skin - Other † 1	4/41 (9.76%)	5	6/31 (19.35%)	7	0/42 (0.00%)	0
Rash/desquamation † 1	11/41 (26.83%)	14	3/31 (9.68%)	5	5/42 (11.90%)	6
Rash: acne/acneiform † 1	3/41 (7.32%)	4	4/31 (12.90%)	4	0/42 (0.00%)	0
Vascular disorders
Hemorrhage, pulmonary/upper respiratory † 1	0/41 (0.00%)	0	3/31 (9.68%)	5	0/42 (0.00%)	0
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, CTCAE (3.0)

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.

Results Point of Contact

• Name/Title: Peter Gottleib, MD
• Organization: Barbara Davis Center for Childhood Diabetes, Health Sciences Center, University of Colorado
• Phone: 303-724-6714
• EMail: Peter.Gottleib@uchsc.edu

Publications:

Palmer JP, Fleming GA, Greenbaum CJ, Herold KC, Jansa LD, Kolb H, Lachin JM, Polonsky KS, Pozzilli P, Skyler JS, Steffes MW. C-peptide is the appropriate outcome measure for type 1 diabetes clinical trials to preserve beta-cell function: report of an ADA workshop, 21-22 October 2001. Diabetes. 2004 Jan;53(1):250-64. Erratum in: Diabetes. 2004 Jul;53(7):1934.

Kaufman DB, Leventhal JR, Stuart J, Abecassis MM, Fryer JP, Stuart FP. Mycophenolate mofetil and tacrolimus as primary maintenance immunosuppression in simultaneous pancreas-kidney transplantation: initial experience in 50 consecutive cases. Transplantation. 1999 Feb 27;67(4):586-93.

Feutren G, Papoz L, Assan R, Vialettes B, Karsenty G, Vexiau P, Du Rostu H, Rodier M, Sirmai J, Lallemand A, et al. Cyclosporin increases the rate and length of remissions in insulin-dependent diabetes of recent onset. Results of a multicentre double-blind trial. Lancet. 1986 Jul 19;2(8499):119-24.

Placebo-controlled study of mycophenolate mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection. European Mycophenolate Mofetil Cooperative Study Group. Lancet. 1995 May 27;345(8961):1321-5.

Brazelton TR, Morris RE. Molecular mechanisms of action of new xenobiotic immunosuppressive drugs: tacrolimus (FK506), sirolimus (rapamycin), mycophenolate mofetil and leflunomide. Curr Opin Immunol. 1996 Oct;8(5):710-20. Review.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Loechelt BJ, Boulware D, Green M, Baden LR, Gottlieb P, Krause-Steinrauf H, Weinberg A; Type 1 Diabetes TrialNet Daclizumab/Mycophenolic Acid Study Group. Epstein-Barr and other herpesvirus infections in patients with early onset type 1 diabetes treated with daclizumab and mycophenolate mofetil. Clin Infect Dis. 2013 Jan;56(2):248-54. doi: 10.1093/cid/cis848. Epub 2012 Oct 5.

• Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• ClinicalTrials.gov Identifier: NCT00100178 History of Changes
• Other Study ID Numbers: MMFDZB (IND) (completed)
• First Submitted: December 23, 2004
• First Posted: December 24, 2004
• Results First Submitted: May 13, 2016
• Results First Posted: August 16, 2016
• Last Update Posted: August 16, 2016