Trial Outcomes & Findings for A Multicenter Clinical Trial of Allopurinol to Prevent Kidney Function Loss in Type 1 Diabetes (NCT NCT02017171)

NCT ID: NCT02017171

Last Updated: 2020-12-04

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

530 participants

Primary outcome timeframe

End of the 2-month wash-out period following the 3-year treatment period (week 164)

Results posted on

2020-12-04

Participant Flow

Participant milestones

Participant milestones
Measure	Allopurinol 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	Placebo Oral placebo tablets (Inactive oral tablets identical in appearance to allopurinol tablets)
Overall Study STARTED	267	263
Overall Study COMPLETED	205	217
Overall Study NOT COMPLETED	62	46

Reasons for withdrawal

Reasons for withdrawal
Measure	Allopurinol 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	Placebo Oral placebo tablets (Inactive oral tablets identical in appearance to allopurinol tablets)
Overall Study Death	10	4
Overall Study Withdrawal by Subject	23	17
Overall Study Lost to Follow-up	21	20
Overall Study ESKD	6	2
Overall Study Miscellaneous	2	3

Baseline Characteristics

BMI values were missing for two participants in the allopurinol group and three participants in the placebo group.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Allopurinol n=267 Participants 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	Placebo n=263 Participants Oral placebo tablets (Inactive oral tablets identical in appearance to allopurinol tablets)	Total n=530 Participants Total of all reporting groups
Age, Continuous	50.4 years STANDARD_DEVIATION 11.2 • n=267 Participants	51.8 years STANDARD_DEVIATION 10.6 • n=263 Participants	51.1 years STANDARD_DEVIATION 10.9 • n=530 Participants
Sex: Female, Male Female	84 Participants n=267 Participants	95 Participants n=263 Participants	179 Participants n=530 Participants
Sex: Female, Male Male	183 Participants n=267 Participants	168 Participants n=263 Participants	351 Participants n=530 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	16 Participants n=267 Participants	7 Participants n=263 Participants	23 Participants n=530 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	250 Participants n=267 Participants	254 Participants n=263 Participants	504 Participants n=530 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=267 Participants	2 Participants n=263 Participants	3 Participants n=530 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=267 Participants	1 Participants n=263 Participants	2 Participants n=530 Participants
Race (NIH/OMB) Asian	1 Participants n=267 Participants	5 Participants n=263 Participants	6 Participants n=530 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=267 Participants	1 Participants n=263 Participants	1 Participants n=530 Participants
Race (NIH/OMB) Black or African American	28 Participants n=267 Participants	30 Participants n=263 Participants	58 Participants n=530 Participants
Race (NIH/OMB) White	230 Participants n=267 Participants	216 Participants n=263 Participants	446 Participants n=530 Participants
Race (NIH/OMB) More than one race	5 Participants n=267 Participants	6 Participants n=263 Participants	11 Participants n=530 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants n=267 Participants	4 Participants n=263 Participants	6 Participants n=530 Participants
Body Mass Index	29.5 kg/m^2 STANDARD_DEVIATION 6.1 • n=265 Participants • BMI values were missing for two participants in the allopurinol group and three participants in the placebo group.	29.5 kg/m^2 STANDARD_DEVIATION 5.9 • n=260 Participants • BMI values were missing for two participants in the allopurinol group and three participants in the placebo group.	29.5 kg/m^2 STANDARD_DEVIATION 6.0 • n=525 Participants • BMI values were missing for two participants in the allopurinol group and three participants in the placebo group.
Glycated hemoglobin (HbA1c)	8.2 Percent STANDARD_DEVIATION 1.3 • n=265 Participants • HbA1c values were missing for two participants in the Allopurinol group	8.2 Percent STANDARD_DEVIATION 1.3 • n=263 Participants • HbA1c values were missing for two participants in the Allopurinol group	8.2 Percent STANDARD_DEVIATION 1.3 • n=528 Participants • HbA1c values were missing for two participants in the Allopurinol group
Serum uric acid	6.1 mg/dl STANDARD_DEVIATION 1.5 • n=267 Participants	6.1 mg/dl STANDARD_DEVIATION 1.5 • n=263 Participants	6.1 mg/dl STANDARD_DEVIATION 1.5 • n=530 Participants
Estimated glomerular filtration rate (eGFR)	75.4 ml/min/1.73 m^2 STANDARD_DEVIATION 18.7 • n=267 Participants	74.0 ml/min/1.73 m^2 STANDARD_DEVIATION 19.4 • n=263 Participants	74.7 ml/min/1.73 m^2 STANDARD_DEVIATION 19.1 • n=530 Participants
Measured (iohexol-based) glomerular filtration rate (iGFR)	68.7 ml/min/1.73 m^2 STANDARD_DEVIATION 17.1 • n=267 Participants • Measured GFR value was missing for one participant in the placebo group	67.3 ml/min/1.73 m^2 STANDARD_DEVIATION 16.7 • n=262 Participants • Measured GFR value was missing for one participant in the placebo group	68 ml/min/1.73 m^2 STANDARD_DEVIATION 16.9 • n=529 Participants • Measured GFR value was missing for one participant in the placebo group
Diabetes duration	33.8 years STANDARD_DEVIATION 12.2 • n=267 Participants	35.3 years STANDARD_DEVIATION 12.5 • n=263 Participants	34.6 years STANDARD_DEVIATION 12.3 • n=530 Participants
Systolic blood pressure (mmHg)	125.6 mmHg STANDARD_DEVIATION 14.7 • n=267 Participants	126.3 mmHg STANDARD_DEVIATION 13.6 • n=263 Participants	126.0 mmHg STANDARD_DEVIATION 14.2 • n=530 Participants
Diastolic blood pressure (mmHg)	71.2 mmHg STANDARD_DEVIATION 10.4 • n=267 Participants	71.3 mmHg STANDARD_DEVIATION 10.0 • n=263 Participants	71.2 mmHg STANDARD_DEVIATION 10.2 • n=530 Participants
Urinary albumin excretion rate (AER)	41.1 ug/min n=267 Participants • Urinary AER values were missing for two participants in the placebo group.	43.0 ug/min n=261 Participants • Urinary AER values were missing for two participants in the placebo group.	41.6 ug/min n=528 Participants • Urinary AER values were missing for two participants in the placebo group.
Albuminuria Normoalbuminuria	97 Participants n=267 Participants • Urinary AER values were missing for two participants in the placebo group.	92 Participants n=261 Participants • Urinary AER values were missing for two participants in the placebo group.	189 Participants n=528 Participants • Urinary AER values were missing for two participants in the placebo group.
Albuminuria Microalabuminuria	97 Participants n=267 Participants • Urinary AER values were missing for two participants in the placebo group.	106 Participants n=261 Participants • Urinary AER values were missing for two participants in the placebo group.	203 Participants n=528 Participants • Urinary AER values were missing for two participants in the placebo group.
Albuminuria Macroalbuminuria	73 Participants n=267 Participants • Urinary AER values were missing for two participants in the placebo group.	63 Participants n=261 Participants • Urinary AER values were missing for two participants in the placebo group.	136 Participants n=528 Participants • Urinary AER values were missing for two participants in the placebo group.
Use of renin-angiotensin inhibitors	247 Participants n=267 Participants	230 Participants n=263 Participants	477 Participants n=530 Participants
Smoking Current	27 Participants n=267 Participants	31 Participants n=263 Participants	58 Participants n=530 Participants
Smoking Past	70 Participants n=267 Participants	80 Participants n=263 Participants	150 Participants n=530 Participants
Smoking Never	170 Participants n=267 Participants	152 Participants n=263 Participants	322 Participants n=530 Participants

PRIMARY outcome

Timeframe: End of the 2-month wash-out period following the 3-year treatment period (week 164)

Population: Intention-to-treat population with missing values being imputed

Outcome measures

Outcome measures
Measure	Allopurinol n=267 Participants 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	Placebo n=263 Participants Oral placebo tablets (inactive oral tablets identical in appearance to allopurinol tablets).
iGFR at the End of the Wash-out Period	61.2 ml/min/1.73 m^2 Interval 58.1 to 64.2	61.2 ml/min/1.73 m^2 Interval 58.1 to 64.2

SECONDARY outcome

Timeframe: 4 months after randomization (week 16)

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

Glomerular filtration rate (GFR) at 4 months after randomization, estimated from serum creatinine and cystatin C and adjusted for the eGFR at baseline.

Outcome measures

Outcome measures
Measure	Allopurinol n=267 Participants 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	Placebo n=263 Participants Oral placebo tablets (inactive oral tablets identical in appearance to allopurinol tablets).
eGFR at 4 Months of Treatment	70.3 ml/min/1.73 m2 Interval 67.3 to 73.3	70.0 ml/min/1.73 m2 Interval 67.1 to 72.9

SECONDARY outcome

Timeframe: End of the 3-yr treatment period (week 156)

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

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.

Outcome measures

Outcome measures
Measure	Allopurinol n=267 Participants 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	Placebo n=263 Participants Oral placebo tablets (inactive oral tablets identical in appearance to allopurinol tablets).
iGFR the End of Treatment Period	61.3 ml/min/1.73 m2 Interval 58.3 to 64.3	61.0 ml/min/1.73 m2 Interval 57.9 to 64.0

SECONDARY outcome

Timeframe: Weeks 0, 80, 156, and 164 (from baseline to the end of washout period)

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

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.

Outcome measures

Outcome measures
Measure	Allopurinol n=267 Participants 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	Placebo n=263 Participants Oral placebo tablets (inactive oral tablets identical in appearance to allopurinol tablets).
iGFR Time Trajectory	-3.0 ml/min/1.73 m2/year Interval -3.7 to -2.3	-2.5 ml/min/1.73 m2/year Interval -3.1 to -1.8

SECONDARY outcome

Timeframe: Weeks 0, 4, 16, 32, 48, 64, 80, 96, 112, 128, 156, and 164 (from baseline to the end of washout period)

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

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.

Outcome measures

Outcome measures
Measure	Allopurinol n=267 Participants 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	Placebo n=263 Participants Oral placebo tablets (inactive oral tablets identical in appearance to allopurinol tablets).
eGFR Time Trajectory	-2.4 ml/min/1.73 m2/year Interval -2.9 to -1.8	-2.1 ml/min/1.73 m2/year Interval -2.6 to -1.6

SECONDARY outcome

Timeframe: Up to the end of the 2-month wash-out period following the 3-year treatment period (Week 0 to Week 164)

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).

Outcome measures

Outcome measures
Measure	Allopurinol n=267 Participants 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	Placebo n=263 Participants Oral placebo tablets (inactive oral tablets identical in appearance to allopurinol tablets).
Serum Creatinine Doubling or End Stage Renal Disease (ESRD)	13 Participants	11 Participants

SECONDARY outcome

Timeframe: End of the 2-month wash-out period following the 3-year treatment period (week 164)

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

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.

Outcome measures

Outcome measures
Measure	Allopurinol n=267 Participants 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	Placebo n=263 Participants Oral placebo tablets (inactive oral tablets identical in appearance to allopurinol tablets).
AER at the End of the Wash-out Period	42.9 ug/min Interval 24.7 to 74.4	31.7 ug/min Interval 19.5 to 51.6

SECONDARY outcome

Timeframe: Last three months of treatment period (Weeks 142 and 156)

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

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.

Outcome measures

Outcome measures
Measure	Allopurinol n=267 Participants 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	Placebo n=263 Participants Oral placebo tablets (inactive oral tablets identical in appearance to allopurinol tablets).
AER at the End of the Treatment Period	47.9 ug/min Interval 32.5 to 70.6	37.4 ug/min Interval 25.3 to 55.5

SECONDARY outcome

Timeframe: Up to the end of the 2-month wash-out period following the 3-year treatment period (week 0 to 164)

Population: Intention-to-treat population

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).

Outcome measures

Outcome measures
Measure	Allopurinol n=267 Participants 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	Placebo n=263 Participants Oral placebo tablets (inactive oral tablets identical in appearance to allopurinol tablets).
Fatal or Non-fatal Cardiovascular Events	15 Participants	9 Participants

Adverse Events

Allopurinol

Serious events: 93 serious events

Other events: 121 other events

Deaths: 10 deaths

Placebo

Serious events: 82 serious events

Other events: 119 other events

Deaths: 4 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Allopurinol n=267 participants at risk 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	Placebo n=263 participants at risk Oral placebo tablets (Inactive oral tablets identical in appearance to allopurinol tablets)
General disorders Influenza like illness	6.4% 17/267 • Number of events 20 • 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. The definition of Adverse Events and/or Serious Adverse Events correspond to that from the clinicaltrials.gov definitions	5.3% 14/263 • Number of events 14 • 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. The definition of Adverse Events and/or Serious Adverse Events correspond to that from the clinicaltrials.gov definitions
Infections and infestations Bronchitis	3.7% 10/267 • Number of events 10 • 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. The definition of Adverse Events and/or Serious Adverse Events correspond to that from the clinicaltrials.gov definitions	8.4% 22/263 • Number of events 27 • 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. The definition of Adverse Events and/or Serious Adverse Events correspond to that from the clinicaltrials.gov definitions
Infections and infestations Sinusitis	6.0% 16/267 • Number of events 18 • 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. The definition of Adverse Events and/or Serious Adverse Events correspond to that from the clinicaltrials.gov definitions	4.9% 13/263 • Number of events 16 • 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. The definition of Adverse Events and/or Serious Adverse Events correspond to that from the clinicaltrials.gov definitions
Infections and infestations Upper respiratory tract infection	11.6% 31/267 • Number of events 47 • 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. The definition of Adverse Events and/or Serious Adverse Events correspond to that from the clinicaltrials.gov definitions	11.4% 30/263 • Number of events 37 • 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. The definition of Adverse Events and/or Serious Adverse Events correspond to that from the clinicaltrials.gov definitions
Infections and infestations Urinary tract infection	6.4% 17/267 • Number of events 33 • 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. The definition of Adverse Events and/or Serious Adverse Events correspond to that from the clinicaltrials.gov definitions	8.0% 21/263 • Number of events 36 • 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. The definition of Adverse Events and/or Serious Adverse Events correspond to that from the clinicaltrials.gov definitions
Metabolism and nutrition disorders Hypoglycaemia	9.7% 26/267 • Number of events 33 • 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. The definition of Adverse Events and/or Serious Adverse Events correspond to that from the clinicaltrials.gov definitions	11.0% 29/263 • Number of events 47 • 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. The definition of Adverse Events and/or Serious Adverse Events correspond to that from the clinicaltrials.gov definitions
Musculoskeletal and connective tissue disorders Pain in extremity	5.2% 14/267 • Number of events 17 • 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. The definition of Adverse Events and/or Serious Adverse Events correspond to that from the clinicaltrials.gov definitions	6.1% 16/263 • Number of events 16 • 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. The definition of Adverse Events and/or Serious Adverse Events correspond to that from the clinicaltrials.gov definitions
Skin and subcutaneous tissue disorders Rash	16.1% 43/267 • Number of events 58 • 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. The definition of Adverse Events and/or Serious Adverse Events correspond to that from the clinicaltrials.gov definitions	14.8% 39/263 • Number of events 45 • 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. The definition of Adverse Events and/or Serious Adverse Events correspond to that from the clinicaltrials.gov definitions
Infections and infestations Nasopharyngitis	6.7% 18/267 • Number of events 21 • 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. The definition of Adverse Events and/or Serious Adverse Events correspond to that from the clinicaltrials.gov definitions	7.6% 20/263 • Number of events 22 • 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. The definition of Adverse Events and/or Serious Adverse Events correspond to that from the clinicaltrials.gov definitions

Additional Information

Dr. Alessandro Doria (Sponsor and PI of the study)

Joslin Diabetes Center

Phone: 617-319-0970

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place