A Multicenter Clinical Trial of Allopurinol to Prevent Kidney Function Loss in Type 1 Diabetes

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ClinicalTrials.gov Identifier: NCT02017171

Recruitment Status : Completed

First Posted : December 20, 2013

Results First Posted : November 20, 2020

Last Update Posted : December 4, 2020

Sponsor:

Collaborators:

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Juvenile Diabetes Research Foundation

Joslin Diabetes Center

University of Minnesota

University of Colorado, Denver

University of Michigan

University of Toronto

Feinberg School of Medicine, Northwestern University

Albert Einstein College of Medicine

Steno Diabetes Center Copenhagen

Washington University School of Medicine

University of Washington

Emory University

University of Calgary

University of Alberta

University of Texas Southwestern Medical Center

BCDiabetes.Ca

Information provided by (Responsible Party):

Alessandro Doria, Joslin Diabetes Center

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Prevention
Conditions	Diabetic Nephropathies Coronary Artery Disease
Interventions	Drug: Allopurinol Drug: Placebo
Enrollment	530

Participant Flow

Recruitment Details
Pre-assignment Details


Arm/Group Title	Allopurinol	Placebo
Arm/Group Description	Oral allopurinol at a dose of 100 m...	Oral placebo tablets (Inactive oral...
Arm/Group Description	Oral allopurinol at a dose of 100 mg per day for 4 weeks and then at a dose ranging from 200 to 400 mg per day depending on kidney function	Oral placebo tablets (Inactive oral tablets identical in appearance to allopurinol tablets)
Period Title: Overall Study
Started	267	263
Completed	205	217
Not Completed	62	46
Reason Not Completed
Death	10	4
Withdrawal by Subject	23	17
Lost to Follow-up	21	20
ESKD	6	2
Miscellaneous	2	3

Baseline Characteristics

Arm/Group Title		Allopurinol	Placebo	Total
Arm/Group Description		Oral allopurinol at a dose of 100 m...	Oral placebo tablets (Inactive oral...	Total of all reporting groups
Arm/Group Description		Oral allopurinol at a dose of 100 mg per day for 4 weeks and then at a dose ranging from 200 to 400 mg per day depending on kidney function	Oral placebo tablets (Inactive oral tablets identical in appearance to allopurinol tablets)	Total of all reporting groups
Overall Number of Baseline Participants		267	263	530
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	267 participants	263 participants	530 participants
		50.4 (11.2)	51.8 (10.6)	51.1 (10.9)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	267 participants	263 participants	530 participants
	Female	84 31.5%	95 36.1%	179 33.8%
	Male	183 68.5%	168 63.9%	351 66.2%
Ethnicity (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	267 participants	263 participants	530 participants
	Hispanic or Latino	16 6.0%	7 2.7%	23 4.3%
	Not Hispanic or Latino	250 93.6%	254 96.6%	504 95.1%
	Unknown or Not Reported	1 0.4%	2 0.8%	3 0.6%
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	267 participants	263 participants	530 participants
	American Indian or Alaska Native	1 0.4%	1 0.4%	2 0.4%
	Asian	1 0.4%	5 1.9%	6 1.1%
	Native Hawaiian or Other Pacific Islander	0 0.0%	1 0.4%	1 0.2%
	Black or African American	28 10.5%	30 11.4%	58 10.9%
	White	230 86.1%	216 82.1%	446 84.2%
	More than one race	5 1.9%	6 2.3%	11 2.1%
	Unknown or Not Reported	2 0.7%	4 1.5%	6 1.1%
Body Mass Index ^[1] Mean (Standard Deviation) Unit of measure: Kg/m^2
	Number Analyzed	265 participants	260 participants	525 participants
		29.5 (6.1)	29.5 (5.9)	29.5 (6.0)
		[1] Measure Analysis Population Description: BMI values were missing for two participants in the allopurinol group and three participants in the placebo group.
Glycated hemoglobin (HbA1c) ^[1] Mean (Standard Deviation) Unit of measure: Percent
	Number Analyzed	265 participants	263 participants	528 participants
		8.2 (1.3)	8.2 (1.3)	8.2 (1.3)
		[1] Measure Analysis Population Description: HbA1c values were missing for two participants in the Allopurinol group
Serum uric acid Mean (Standard Deviation) Unit of measure: Mg/dl
	Number Analyzed	267 participants	263 participants	530 participants
		6.1 (1.5)	6.1 (1.5)	6.1 (1.5)
Estimated glomerular filtration rate (eGFR) ^[1] Mean (Standard Deviation) Unit of measure: Ml/min/1.73 m^2
	Number Analyzed	267 participants	263 participants	530 participants
		75.4 (18.7)	74.0 (19.4)	74.7 (19.1)
		[1] Measure Description: Glomerular filtration rate estimated from serum creatinine with the CKD-EPI equation
Measured (iohexol-based) glomerular filtration rate (iGFR) ^[1] [2] Mean (Standard Deviation) Unit of measure: Ml/min/1.73 m^2
	Number Analyzed	267 participants	262 participants	529 participants
		68.7 (17.1)	67.3 (16.7)	68 (16.9)
		[1] Measure Description: Glomerular filtration rate measured by the plasma disappearance of an i.v. bolus of the contrast medium iohexol [2] Measure Analysis Population Description: Measured GFR value was missing for one participant in the placebo group
Diabetes duration Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	267 participants	263 participants	530 participants
		33.8 (12.2)	35.3 (12.5)	34.6 (12.3)
Systolic blood pressure (mmHg) Mean (Standard Deviation) Unit of measure: mmHg
	Number Analyzed	267 participants	263 participants	530 participants
		125.6 (14.7)	126.3 (13.6)	126.0 (14.2)
Diastolic blood pressure (mmHg) Mean (Standard Deviation) Unit of measure: mmHg
	Number Analyzed	267 participants	263 participants	530 participants
		71.2 (10.4)	71.3 (10.0)	71.2 (10.2)
Urinary albumin excretion rate (AER) ^[1] Median (Inter-Quartile Range) Unit of measure: Ug/min
	Number Analyzed	267 participants	261 participants	528 participants
		41.1 (7.7 to 216.0)	43.0 (9.0 to 198.0)	41.6 (8.5 to 207.5)
		[1] Measure Analysis Population Description: Urinary AER values were missing for two participants in the placebo group.
Albuminuria ^[1] [2] Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	267 participants	261 participants	528 participants
	Normoalbuminuria	97 36.3%	92 35.2%	189 35.8%
	Microalabuminuria	97 36.3%	106 40.6%	203 38.4%
	Macroalbuminuria	73 27.3%	63 24.1%	136 25.8%
		[1] Measure Description: Based on overnight urinary albumin excretion rate (AER): normoalbuminuria: AER<20 ug/min, microalbuminuria: AER 20-199 ug/min, macroalbuminuria: AER => 200 ug/min [2] Measure Analysis Population Description: Urinary AER values were missing for two participants in the placebo group.
Use of renin-angiotensin inhibitors Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	267 participants	263 participants	530 participants
		247 92.5%	230 87.5%	477 90.0%
Smoking Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	267 participants	263 participants	530 participants
	Current	27 10.1%	31 11.8%	58 10.9%
	Past	70 26.2%	80 30.4%	150 28.3%
	Never	170 63.7%	152 57.8%	322 60.8%

Outcome Measures

1.Primary Outcome


Title	iGFR at the End of the Wash-out Period
Description	Glomerular filtration rate (GFR) at the end of the 2-month wash-out pe...
Description	Glomerular filtration rate (GFR) at the end of the 2-month wash-out period following the 3-year treatment period, measured by the plasma disappearance of non-radioactive iohexol (iGFR) and adjusted for the iGFR at baseline.
Time Frame	End of the 2-month wash-out period following the 3-year treatment period (week 164)

Outcome Measure Data

Analysis Population Description

Intention-to-treat population with missing values being imputed


Arm/Group Title	Allopurinol	Placebo
Arm/Group Description:	Oral allopurinol at a dose of 100 m...	Oral placebo tablets (inactive oral...
Arm/Group Description:	Oral allopurinol at a dose of 100 mg per day for 4 weeks and then at a dose ranging from 200 to 400 mg per day depending on kidney function	Oral placebo tablets (inactive oral tablets identical in appearance to allopurinol tablets).
Overall Number of Participants Analyzed	267	263
Least Squares Mean (95% Confidence Interval) Unit of Measure: ml/min/1.73 m^2
	61.2 (58.1 to 64.2)	61.2 (58.1 to 64.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Allopurinol, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.999
	Comments	p value is not adjusted for multiple comparisons, a priori threshold for statistical significance: p<0.05
	Method	linear model for correlated errors
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.001
	Confidence Interval	(2-Sided) 95% -1.9 to 1.9
	Estimation Comments	Treatment difference = Allopurinol-Placebo

2.Secondary Outcome


Title	eGFR at 4 Months of Treatment
Description	Glomerular filtration rate (GFR) at 4 months after randomization, esti...
Description	Glomerular filtration rate (GFR) at 4 months after randomization, estimated from serum creatinine and cystatin C and adjusted for the eGFR at baseline.
Time Frame	4 months after randomization (week 16)

Outcome Measure Data

Analysis Population Description

Intention-to-treat population, with missing values being imputed


Arm/Group Title	Allopurinol	Placebo
Arm/Group Description:	Oral allopurinol at a dose of 100 m...	Oral placebo tablets (Inactive oral...
Arm/Group Description:	Oral allopurinol at a dose of 100 mg per day for 4 weeks and then at a dose ranging from 200 to 400 mg per day depending on kidney function	Oral placebo tablets (Inactive oral tablets identical in appearance to allopurinol tablets)
Overall Number of Participants Analyzed	267	263
Least Squares Mean (95% Confidence Interval) Unit of Measure: ml/min/1.73 m2
	70.3 (67.3 to 73.3)	70.0 (67.1 to 72.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Allopurinol, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 95% -1.6 to 2.2
	Estimation Comments	Treatment difference = Allopurinol - Placebo

3.Secondary Outcome


Title	iGFR the End of Treatment Period
Description	Glomerular filtration rate (GFR) at the end of the 3-year treatment pe...
Description	Glomerular filtration rate (GFR) at the end of the 3-year treatment period, measured by the plasma disappearance of non-radioactive iohexol (iGFR) and adjusted for the iGFR at baseline.
Time Frame	End of the 3-yr treatment period (week 156)

Outcome Measure Data

Analysis Population Description

Intention-to-treat population, with missing values being imputed


Arm/Group Title	Allopurinol	Placebo
Arm/Group Description:	Oral allopurinol at a dose of 100 m...	Oral placebo tablets (Inactive oral...
Arm/Group Description:	Oral allopurinol at a dose of 100 mg per day for 4 weeks and then at a dose ranging from 200 to 400 mg per day depending on kidney function	Oral placebo tablets (Inactive oral tablets identical in appearance to allopurinol tablets)
Overall Number of Participants Analyzed	267	263
Least Squares Mean (95% Confidence Interval) Unit of Measure: ml/min/1.73 m2
	61.3 (58.3 to 64.3)	61.0 (57.9 to 64.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Allopurinol, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 95% -1.7 to 2.3
	Estimation Comments	Treatment difference = Allopurinol - Placebo

4.Secondary Outcome


Title	iGFR Time Trajectory
Description	Glomerular filtration rate time trajectory estimated from iohexol disa...
Description	Glomerular filtration rate time trajectory estimated from iohexol disappearance GFR (iGFR) measurements at weeks 0, 80, 156, and 164. iGFR slopes were estimated by a linear mixed-effects model for longitudinal iGFR measures using a multiple imputation technique for missing values. Positive values denote increasing GFR over time, negative values denote declining iGFR over time.
Time Frame	Weeks 0, 80, 156, and 164 (from baseline to the end of washout period)

Outcome Measure Data

Analysis Population Description

Intention-to-treat population, with missing values being imputed


Arm/Group Title	Allopurinol	Placebo
Arm/Group Description:	Oral allopurinol at a dose of 100 m...	Oral placebo tablets (Inactive oral...
Arm/Group Description:	Oral allopurinol at a dose of 100 mg per day for 4 weeks and then at a dose ranging from 200 to 400 mg per day depending on kidney function	Oral placebo tablets (Inactive oral tablets identical in appearance to allopurinol tablets)
Overall Number of Participants Analyzed	267	263
Least Squares Mean (95% Confidence Interval) Unit of Measure: ml/min/1.73 m2/year
	-3.0 (-3.7 to -2.3)	-2.5 (-3.1 to -1.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Allopurinol, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.6
	Confidence Interval	(2-Sided) 95% -1.5 to 0.4
	Estimation Comments	Treatment difference = Allopurinol - Placebo. Confidence intervals are not adjusted for multiplicity and should not be used to infer treatment effects.

5.Secondary Outcome


Title	eGFR Time Trajectory
Description	Glomerular filtration rate time trajectory from baseline to end of the...
Description	Glomerular filtration rate time trajectory from baseline to end of the 2-month wash-out period (week 164) estimated from quarterly serum creatinine measurements (eGFR). eGFR slopes were estimated by a linear mixed-effects model for longitudinal eGFR measures using a multiple imputation technique for missing values. Positive values denote increasing eGFR over time, negative values denote declining eGFR over time.
Time Frame	Weeks 0, 4, 16, 32, 48, 64, 80, 96, 112, 128, 156, and 164 (from baseline to the end of washout period)

Outcome Measure Data

Analysis Population Description

Intention-to-treat population, with missing values being imputed


Arm/Group Title	Allopurinol	Placebo
Arm/Group Description:	Oral allopurinol at a dose of 100 m...	Oral placebo tablets (Inactive oral...
Arm/Group Description:	Oral allopurinol at a dose of 100 mg per day for 4 weeks and then at a dose ranging from 200 to 400 mg per day depending on kidney function	Oral placebo tablets (Inactive oral tablets identical in appearance to allopurinol tablets)
Overall Number of Participants Analyzed	267	263
Least Squares Mean (95% Confidence Interval) Unit of Measure: ml/min/1.73 m2/year
	-2.4 (-2.9 to -1.8)	-2.1 (-2.6 to -1.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Allopurinol, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95% -1.0 to 0.5
	Estimation Comments	Treatment difference = Allopurinol - Placebo. Confidence intervals are not adjusted for multiplicity and should not be used to infer treatment effects.

6.Secondary Outcome


Title	Serum Creatinine Doubling or End Stage Renal Disease (ESRD)
Description	Risk of serum creatinine doubling or end stage renal disease (ESRD) in...
Description	Risk of serum creatinine doubling or end stage renal disease (ESRD) in the allopurinol arm as compared to placebo. Results are expressed as the number of participants who experienced an event in each treatment group. The risk of an event in the allopurinol group as compared to the risk in the placebo group is expressed as hazard ratio (estimated by means of proportional hazard regression).
Time Frame	Up to the end of the 2-month wash-out period following the 3-year treatment period (Week 0 to Week 164)

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	Allopurinol	Placebo
Arm/Group Description:	Oral allopurinol at a dose of 100 m...	Oral placebo tablets (Inactive oral...
Arm/Group Description:	Oral allopurinol at a dose of 100 mg per day for 4 weeks and then at a dose ranging from 200 to 400 mg per day depending on kidney function	Oral placebo tablets (Inactive oral tablets identical in appearance to allopurinol tablets)
Overall Number of Participants Analyzed	267	263
Measure Type: Count of Participants Unit of Measure: Participants
	13 4.9%	11 4.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Allopurinol, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.2
	Confidence Interval	(2-Sided) 95% 0.5 to 2.9
	Estimation Comments	Hazard ratio = Allopurinol / Placebo. Confidence intervals are not adjusted for multiplicity and should not be used to infer treatment effects.

7.Secondary Outcome


Title	AER at the End of the Wash-out Period
Description	Geometric mean of two urinary albumin excretion (AER) measurements at ...
Description	Geometric mean of two urinary albumin excretion (AER) measurements at the end of the 2-month wash-out period following the 3-year treatment period, adjusted for the mean urinary AER at baseline. Results are expressed as least square means of the geometric means in each subject in each group.
Time Frame	End of the 2-month wash-out period following the 3-year treatment period (week 164)

Outcome Measure Data

Analysis Population Description

Intention-to-treat population, with missing values being imputed


Arm/Group Title	Allopurinol	Placebo
Arm/Group Description:	Oral allopurinol at a dose of 100 m...	Oral placebo tablets (Inactive oral...
Arm/Group Description:	Oral allopurinol at a dose of 100 mg per day for 4 weeks and then at a dose ranging from 200 to 400 mg per day depending on kidney function	Oral placebo tablets (Inactive oral tablets identical in appearance to allopurinol tablets)
Overall Number of Participants Analyzed	267	263
Least Squares Mean (95% Confidence Interval) Unit of Measure: ug/min
	42.9 (24.7 to 74.4)	31.7 (19.5 to 51.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Allopurinol, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Ratio (Final Values)
	Estimated Value	1.4
	Confidence Interval	(2-Sided) 95% 1.0 to 1.8
	Estimation Comments	Ratio = Allopurinol / Placebo. Confidence intervals are not adjusted for multiplicity and should not be used to infer treatment effects.

8.Secondary Outcome


Title	AER at the End of the Treatment Period
Description	Geometric mean of urinary albumin excretion rate (AER) during the last...
Description	Geometric mean of urinary albumin excretion rate (AER) during the last three months of the treatment period (Visits 15 and 16), adjusted for the mean urinary AER at baseline. Results are expressed as least square means of the geometric means in each subject in each group.
Time Frame	Last three months of treatment period (Weeks 142 and 156)

Outcome Measure Data

Analysis Population Description

Intention-to-treat population, with missing values being imputed


Arm/Group Title	Allopurinol	Placebo
Arm/Group Description:	Oral allopurinol at a dose of 100 m...	Oral placebo tablets (Inactive oral...
Arm/Group Description:	Oral allopurinol at a dose of 100 mg per day for 4 weeks and then at a dose ranging from 200 to 400 mg per day depending on kidney function	Oral placebo tablets (Inactive oral tablets identical in appearance to allopurinol tablets)
Overall Number of Participants Analyzed	267	263
Least Squares Mean (95% Confidence Interval) Unit of Measure: ug/min
	47.9 (32.5 to 70.6)	37.4 (25.3 to 55.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Allopurinol, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Ratio (Final Values)
	Estimated Value	1.3
	Confidence Interval	(2-Sided) 95% 1.0 to 1.6
	Estimation Comments	[Not Specified]

Other Statistical Analysis		Ratio = Allopurinol / Placebo. Confidence intervals are not adjusted for multiplicity and should not be used to infer treatment effects.

9.Secondary Outcome


Title	Fatal or Non-fatal Cardiovascular Events
Description	Risk of cardiovascular events defined as the composite of CVD death (I...
Description	Risk of cardiovascular events defined as the composite of CVD death (ICD-10 code I10 to I74.9), myocardial infarction, stroke (ischemic or hemorrhagic), coronary artery bypass grafting, or percutaneous coronary intervention in the allopurinol arm as compared to placebo.Results are expressed as the number of participants who experienced an event in each treatment group. The risk of an event in the allopurinol group as compared to the risk in the placebo group is expressed as hazard ratio (estimated by means of proportional hazard regression).
Time Frame	Up to the end of the 2-month wash-out period following the 3-year treatment period (week 0 to 164)

Outcome Measure Data

Analysis Population Description

Intention-to-treat population


Arm/Group Title	Allopurinol	Placebo
Arm/Group Description:	Oral allopurinol at a dose of 100 m...	Oral placebo tablets (Inactive oral...
Arm/Group Description:	Oral allopurinol at a dose of 100 mg per day for 4 weeks and then at a dose ranging from 200 to 400 mg per day depending on kidney function	Oral placebo tablets (Inactive oral tablets identical in appearance to allopurinol tablets)
Overall Number of Participants Analyzed	267	263
Measure Type: Count of Participants Unit of Measure: Participants
	15 5.6%	9 3.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Allopurinol, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.9
	Confidence Interval	(2-Sided) 95% 0.8 to 4.5
	Estimation Comments	Hazard Ratio = Allopurinol / Placebo. Confidence intervals are not adjusted for multiplicity and should not be used to infer treatment effects.

Adverse Events

Time Frame	In each participants, adverse event data were collected from randomization to two months after the end of pharmacological treatment, or until study discontinuation for participants who did not complete the study. This corresponds to up to 164 weeks for participants who completed the study.
Adverse Event Reporting Description	The definition of Adverse Events and/or Serious Adverse Events correspond to that from the clinicaltrials.gov definitions

Arm/Group Title	Allopurinol		Placebo
Arm/Group Description	Oral allopurinol at a dose of 100 m...		Oral placebo tablets (Inactive oral...
Arm/Group Description	Oral allopurinol at a dose of 100 mg per day for 4 weeks and then at a dose ranging from 200 to 400 mg per day depending on kidney function		Oral placebo tablets (Inactive oral tablets identical in appearance to allopurinol tablets)
All-Cause Mortality
	Allopurinol		Placebo
	Affected / at Risk (%)		Affected / at Risk (%)
Total	10/267 (3.75%)		4/263 (1.52%)
Serious Adverse Events Serious Adverse Events
	Allopurinol		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	93/267 (34.83%)		82/263 (31.18%)
Blood and lymphatic system disorders
Anaemia ^† 1	1/267 (0.37%)	1	1/263 (0.38%)	1
Cardiac disorders
Acute coronary syndrome ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Acute myocardial infarction ^† 1	7/267 (2.62%)	7	5/263 (1.90%)	6
Angina unstable ^† 1	2/267 (0.75%)	2	1/263 (0.38%)	1
Aortic valve stenosis ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Atrial fibrillation ^† 1	1/267 (0.37%)	1	1/263 (0.38%)	1
Atrial flutter ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Atrioventricular block complete ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Brugada syndrome ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Cardiac arrest ^† 1	2/267 (0.75%)	2	1/263 (0.38%)	1
Cardiac failure ^† 1	1/267 (0.37%)	1	2/263 (0.76%)	2
Cardiac failure congestive ^† 1	3/267 (1.12%)	3	3/263 (1.14%)	4
Coronary artery disease ^† 1	4/267 (1.50%)	4	4/263 (1.52%)	4
Coronary artery stenosis ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Myocardial infarction ^† 1	3/267 (1.12%)	3	2/263 (0.76%)	2
Myocardial ischaemia ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Myocarditis ^† 1	1/267 (0.37%)	2	0/263 (0.00%)	0
Pericarditis ^† 1	1/267 (0.37%)	2	0/263 (0.00%)	0
Endocrine disorders
Hypercalcaemia of malignancy ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Gastrointestinal disorders
Abdominal pain ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Colonic pseudo-obstruction ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Constipation ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Diabetic gastroparesis ^† 1	2/267 (0.75%)	2	1/263 (0.38%)	2
Diabetic gastropathy ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Diarrhoea ^† 1	2/267 (0.75%)	2	0/263 (0.00%)	0
Gastritis ^† 1	0/267 (0.00%)	0	2/263 (0.76%)	2
Gastrointestinal haemorrhage ^† 1	3/267 (1.12%)	3	0/263 (0.00%)	0
Gastrooesophageal reflux disease ^† 1	1/267 (0.37%)	1	1/263 (0.38%)	1
Impaired gastric emptying ^† 1	2/267 (0.75%)	2	3/263 (1.14%)	5
Oesophageal perforation ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Pancreatitis acute ^† 1	3/267 (1.12%)	3	0/263 (0.00%)	0
Small intestinal obstruction ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Vomiting ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	2
General disorders
Chest discomfort ^† 1	1/267 (0.37%)	2	1/263 (0.38%)	1
Chest pain ^† 1	4/267 (1.50%)	5	2/263 (0.76%)	2
Death ^† 1	2/267 (0.75%)	2	1/263 (0.38%)	1
Oedema due to renal disease ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Pain ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Sudden cardiac death ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Ulcer ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Hepatobiliary disorders
Bile duct obstruction ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Infections and infestations
Appendicitis ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Bursitis infective ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Cellulitis ^† 1	3/267 (1.12%)	3	5/263 (1.90%)	5
Clostridium difficile colitis ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Cystitis escherichia ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Diabetic foot infection ^† 1	0/267 (0.00%)	0	3/263 (1.14%)	3
Extradural abscess ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Gastroenteritis ^† 1	1/267 (0.37%)	1	3/263 (1.14%)	3
Gastroenteritis viral ^† 1	1/267 (0.37%)	1	1/263 (0.38%)	1
Herpes simplex meningitis ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Infected skin ulcer ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Infection ^† 1	0/267 (0.00%)	0	4/263 (1.52%)	4
Lobar pneumonia ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Localised infection ^† 1	1/267 (0.37%)	1	1/263 (0.38%)	1
Osteomyelitis ^† 1	6/267 (2.25%)	8	4/263 (1.52%)	6
Osteomyelitis acute ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Pneumonia ^† 1	4/267 (1.50%)	4	5/263 (1.90%)	5
Pneumonia viral ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Renal abscess ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Sepsis ^† 1	1/267 (0.37%)	1	1/263 (0.38%)	1
Staphylococcal infection ^† 1	2/267 (0.75%)	2	0/263 (0.00%)	0
Upper respiratory tract infection ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Urosepsis ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Injury, poisoning and procedural complications
Concussion ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Extradural haematoma ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Fall ^† 1	1/267 (0.37%)	1	1/263 (0.38%)	1
Femur fracture ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Fracture ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Fractured sacrum ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Hip fracture ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Humerus fracture ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Multiple injuries ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Patella fracture ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Pelvic fracture ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Road traffic accident ^† 1	2/267 (0.75%)	2	0/263 (0.00%)	0
Spinal compression fracture ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Spinal fracture ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Subdural haematoma ^† 1	0/267 (0.00%)	0	2/263 (0.76%)	2
Transplant dysfunction ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Investigations
Blood glucose fluctuation ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Laboratory test abnormal ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Metabolism and nutrition disorders
Dehydration ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Diabetic ketoacidosis ^† 1	15/267 (5.62%)	18	13/263 (4.94%)	17
Fluid overload ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Gout ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Hyperglycaemia ^† 1	3/267 (1.12%)	3	5/263 (1.90%)	5
Hyperglycaemic hyperosmolar nonketotic syndrome ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Hypoglycaemia ^† 1	2/267 (0.75%)	2	9/263 (3.42%)	10
Ketoacidosis ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Intervertebral disc protrusion ^† 1	1/267 (0.37%)	1	1/263 (0.38%)	1
Musculoskeletal pain ^† 1	0/267 (0.00%)	0	2/263 (0.76%)	2
Osteoarthritis ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Rotator cuff syndrome ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Spinal column stenosis ^† 1	0/267 (0.00%)	0	2/263 (0.76%)	2
Arthritis ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Diffuse large B-cell lymphoma ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Hepatic neoplasm ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Non-Hodgkin's lymphoma ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Small cell carcinoma ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Ureteral neoplasm ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Nervous system disorders
Cerebrovascular accident ^† 1	3/267 (1.12%)	3	1/263 (0.38%)	1
Convulsion ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Dizziness ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Dystonia ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Encephalopathy ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Hypoaesthesia ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Hypoglycaemic seizure ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Metabolic encephalopathy ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Presyncope ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	2
Syncope ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Tension headache ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Transient ischaemic attack ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous ^† 1	2/84 (2.38%)	4	1/95 (1.05%)	1
Hyperemesis gravidarum ^† 1	1/84 (1.19%)	1	0/95 (0.00%)	0
Pregnancy ^† 1	1/84 (1.19%)	1	0/95 (0.00%)	0
Psychiatric disorders
Agitation ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Bipolar disorder ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Major depression ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Renal and urinary disorders
Hydronephrosis ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Nephrolithiasis ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Polyuria ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Renal failure acute ^† 1	3/267 (1.12%)	6	8/263 (3.04%)	9
Renal failure chronic ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Tubulointerstitial nephritis ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Reproductive system and breast disorders
Ovarian cyst ruptured ^† 1	0/84 (0.00%)	0	1/95 (1.05%)	1
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Asthma ^† 1	2/267 (0.75%)	2	1/263 (0.38%)	1
Cough ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Dyspnoea ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Pulmonary embolism ^† 1	1/267 (0.37%)	1	1/263 (0.38%)	1
Pulmonary mass ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Skin and subcutaneous tissue disorders
Diabetic ulcer ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Hypersensitivity vasculitis ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Skin ulcer ^† 1	2/267 (0.75%)	2	1/263 (0.38%)	1
Surgical and medical procedures
Amputation ^† 1	2/267 (0.75%)	2	0/263 (0.00%)	0
Arthrodesis ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Debridement ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Gastric bypass ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Insertion of ambulatory peritoneal catheter ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Knee arthroplasty ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Nephrectomy ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Penile prosthesis insertion ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Shoulder operation ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Spinal laminectomy ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Stent placement ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Surgery ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Toe amputation ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Vascular graft ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Vascular disorders
Accelerated hypertension ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Aneurysm ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Aortic stenosis ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Hypertension ^† 1	1/267 (0.37%)	1	1/263 (0.38%)	1
Leriche syndrome ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Orthostatic hypotension ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Peripheral arterial occlusive disease ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Peripheral vascular disorder ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
Shock ^† 1	1/267 (0.37%)	1	0/263 (0.00%)	0
Thrombophlebitis superficial ^† 1	0/267 (0.00%)	0	1/263 (0.38%)	1
1 Term from vocabulary, MedDRA 18.1 to 22.0 † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Allopurinol		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	121/267 (45.32%)		119/263 (45.25%)
General disorders
Influenza like illness ^† 1	17/267 (6.37%)	20	14/263 (5.32%)	14
Infections and infestations
Bronchitis ^† 1	10/267 (3.75%)	10	22/263 (8.37%)	27
Sinusitis ^† 1	16/267 (5.99%)	18	13/263 (4.94%)	16
Upper respiratory tract infection ^† 1	31/267 (11.61%)	47	30/263 (11.41%)	37
Urinary tract infection ^† 1	17/267 (6.37%)	33	21/263 (7.98%)	36
Nasopharyngitis ^† 1	18/267 (6.74%)	21	20/263 (7.60%)	22
Metabolism and nutrition disorders
Hypoglycaemia ^† 1	26/267 (9.74%)	33	29/263 (11.03%)	47
Musculoskeletal and connective tissue disorders
Pain in extremity ^† 1	14/267 (5.24%)	17	16/263 (6.08%)	16
Skin and subcutaneous tissue disorders
Rash ^† 1	43/267 (16.10%)	58	39/263 (14.83%)	45
1 Term from vocabulary, MedDRA 18.1 to 22.0 † Indicates events were collected by systematic assessment

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

Layout table for Results Point of Contact information

Name/Title:	Dr. Alessandro Doria (Sponsor and PI of the study)
Organization:	Joslin Diabetes Center
Phone:	617-319-0970
EMail:	alessandro.doria@joslin.harvard.edu

Publications:

Ficociello LH, Rosolowsky ET, Niewczas MA, Maselli NJ, Weinberg JM, Aschengrau A, Eckfeldt JH, Stanton RC, Galecki AT, Doria A, Warram JH, Krolewski AS. High-normal serum uric acid increases risk of early progressive renal function loss in type 1 diabetes: results of a 6-year follow-up. Diabetes Care. 2010 Jun;33(6):1337-43. doi: 10.2337/dc10-0227. Epub 2010 Mar 23.

Hovind P, Rossing P, Tarnow L, Johnson RJ, Parving HH. Serum uric acid as a predictor for development of diabetic nephropathy in type 1 diabetes: an inception cohort study. Diabetes. 2009 Jul;58(7):1668-71. doi: 10.2337/db09-0014. Epub 2009 May 1. Erratum in: Diabetes. 2010 Oct;59(10):2695.

Jalal DI, Rivard CJ, Johnson RJ, Maahs DM, McFann K, Rewers M, Snell-Bergeon JK. Serum uric acid levels predict the development of albuminuria over 6 years in patients with type 1 diabetes: findings from the Coronary Artery Calcification in Type 1 Diabetes study. Nephrol Dial Transplant. 2010 Jun;25(6):1865-9. doi: 10.1093/ndt/gfp740. Epub 2010 Jan 11.

Maahs DM, Caramori L, Cherney DZ, Galecki AT, Gao C, Jalal D, Perkins BA, Pop-Busui R, Rossing P, Mauer M, Doria A; PERL Consortium. Uric acid lowering to prevent kidney function loss in diabetes: the preventing early renal function loss (PERL) allopurinol study. Curr Diab Rep. 2013 Aug;13(4):550-9. doi: 10.1007/s11892-013-0381-0. Review.

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

Doria A, Galecki AT, Spino C, Pop-Busui R, Cherney DZ, Lingvay I, Parsa A, Rossing P, Sigal RJ, Afkarian M, Aronson R, Caramori ML, Crandall JP, de Boer IH, Elliott TG, Goldfine AB, Haw JS, Hirsch IB, Karger AB, Maahs DM, McGill JB, Molitch ME, Perkins BA, Polsky S, Pragnell M, Robiner WN, Rosas SE, Senior P, Tuttle KR, Umpierrez GE, Wallia A, Weinstock RS, Wu C, Mauer M; PERL Study Group. Serum Urate Lowering with Allopurinol and Kidney Function in Type 1 Diabetes. N Engl J Med. 2020 Jun 25;382(26):2493-2503. doi: 10.1056/NEJMoa1916624.

Layout table for additonal information

Responsible Party:	Alessandro Doria, Joslin Diabetes Center
ClinicalTrials.gov Identifier:	NCT02017171
Obsolete Identifiers:	NCT01575379
Other Study ID Numbers:	DK101108 UC4DK101108-01 ( U.S. NIH Grant/Contract )
First Submitted:	December 16, 2013
First Posted:	December 20, 2013
Results First Submitted:	October 7, 2020
Results First Posted:	November 20, 2020
Last Update Posted:	December 4, 2020

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