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Tolvaptan Phase 3 Efficacy and Safety Study in Autosomal Dominant Polycystic Kidney Disease (ADPKD) (TEMPO3:4)

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ClinicalTrials.gov Identifier: NCT00428948
Recruitment Status : Completed
First Posted : January 30, 2007
Results First Posted : July 2, 2017
Last Update Posted : July 2, 2017
Sponsor:
Collaborator:
Otsuka Pharmaceutical Co., Ltd.
Information provided by (Responsible Party):
Otsuka Pharmaceutical Development & Commercialization, Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Polycystic Kidney Disease, Autosomal Dominant
Interventions Drug: Tolvaptan
Drug: Placebo
Enrollment 1445
Recruitment Details  
Pre-assignment Details Intent-to-treat population: All randomized participants.
Arm/Group Title Tolvaptan Placebo
Hide Arm/Group Description Participants received the highest tolerated split-dose regimen (upon awakening and 9 hours later) of tolvaptan 45/15 mg, 60/30 mg, or 90/30 mg orally for 36 months. Participants received placebo (upon awakening and 9 hours later) orally for 36 months.
Period Title: Overall Study
Started 961 484
Received Treatment 961 483
Completed 740 417
Not Completed 221 67
Reason Not Completed
Lost to Follow-up             15             8
Adverse Event             148             24
Subject Met Withdrawal Criteria             4             0
Investigator Withdrew Subject             3             4
Subject Withdrew Consent             50             30
Protocol Deviation             1             1
Arm/Group Title Tolvaptan Placebo Total
Hide Arm/Group Description Participants received the highest tolerated split-dose regimen (upon awakening and 9 hours later) of tolvaptan 45/15 mg, 60/30 mg, or 90/30 mg orally for 36 months. Participants received placebo (upon awakening and 9 hours later) orally for 36 months. Total of all reporting groups
Overall Number of Baseline Participants 961 484 1445
Hide Baseline Analysis Population Description
Intent-to-treat population: All randomized participants.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 961 participants 484 participants 1445 participants
38.6  (7.1) 38.8  (7.1) 38.7  (7.1)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 961 participants 484 participants 1445 participants
Female
466
  48.5%
233
  48.1%
699
  48.4%
Male
495
  51.5%
251
  51.9%
746
  51.6%
1.Primary Outcome
Title Percentage Change Per Year in Total Kidney Volume From Baseline to Month 36
Hide Description Kidney volume was assessed in T1-weighted magnetic resonance images collected at each study site and sent to a central reviewing facility. At the central reviewing facility, blinded radiologists used proprietary software to measure the volume of both kidneys.
Time Frame Baseline to Month 36
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: All randomized participants who had Baseline and post-baseline observations of total kidney volume. Only participants with available data were included in the analysis.
Arm/Group Title Tolvaptan Placebo
Hide Arm/Group Description:
Participants received the highest tolerated split-dose regimen (upon awakening and 9 hours later) of tolvaptan 45/15 mg, 60/30 mg, or 90/30 mg orally for 36 months.
Participants received placebo (upon awakening and 9 hours later) orally for 36 months.
Overall Number of Participants Analyzed 819 458
Mean (Standard Deviation)
Unit of Measure: Percentage change per year
2.777  (5.659) 5.608  (5.330)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tolvaptan, Placebo
Comments The null hypothesis was that there was no difference in the percentage change per year in total kidney volume between the tolvaptan group and the placebo group.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Linear mixed model
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -2.708
Confidence Interval (2-Sided) 95%
-3.269 to -2.147
Estimation Comments The variance of the random effect intercept was zero and resulted in a non-positive, definite variance-covariance matrix for the random effects.
2.Secondary Outcome
Title Number of ADPKD Clinical Progression Events Per 100 Follow-up Years From Baseline to Month 36
Hide Description These ADPKD events in the key secondary Outcome Measure were selected on the basis of their potential relationship to progressing cystogenesis. Reducing the rate of cyst development and expansion would likely slow the progression of ADPKD. The 4 events were: (1) Onset or progression of hypertension (someone is hypertensive if they have > 139 mmHg systolic blood pressure [BP], > 89 mmHg diastolic BP, or if they are taking antihypertensive medication at any BP level); (2) severe renal pain requiring medical intervention; (3) worsening albuminuria (by category, see below); and (4) worsening renal function, defined as a 25% decrease in 1/serum creatinine from Baseline. Albuminuria was assessed using spot urine albumin/creatinine ratio measurements (all measurements in mg/mmol). Categories included normal (< 2.8 female or < 2.0 male), microalbuminuria (2.8-28 female or 2.0-20 male), and overt proteinuria (> 28 female or > 20 male.
Time Frame Baseline to Month 36
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: All randomized participants. Only participants with available data were included in the analysis.
Arm/Group Title Tolvaptan Placebo
Hide Arm/Group Description:
Participants received the highest tolerated split-dose regimen (upon awakening and 9 hours later) of tolvaptan 45/15 mg, 60/30 mg, or 90/30 mg orally for 36 months.
Participants received placebo (upon awakening and 9 hours later) orally for 36 months.
Overall Number of Participants Analyzed 961 483
Measure Type: Number
Unit of Measure: Events/100 follow-up years
43.94 50.04
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tolvaptan, Placebo
Comments The null hypothesis was that there was no difference in the ADPKD clinical progression events/100 follow-up years between the tolvaptan group and the placebo group.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0095
Comments [Not Specified]
Method Recurrent event analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.865
Confidence Interval (2-Sided) 95%
0.775 to 0.965
Estimation Comments Tolvaptan divided by placebo.
3.Secondary Outcome
Title Change in Renal Function Per Year From Week 3 to Month 36
Hide Description Renal function was assessed using serum creatinine measurements and was estimated using 1/serum creatinine. The formula for 1/serum creatinine is: 1/Pcr, where Pcr = serum creatinine concentration (mg/dL). The change in renal function per year was based on the slope of change, obtained by regressing renal function data against time by subject.
Time Frame Week 3 to Month 36
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: All randomized participants with at least 4 months of follow-up. Only participants with available data were included in the analysis.
Arm/Group Title Tolvaptan Placebo
Hide Arm/Group Description:
Participants received the highest tolerated split-dose regimen (upon awakening and 9 hours later) of tolvaptan 45/15 mg, 60/30 mg, or 90/30 mg orally for 36 months.
Participants received placebo (upon awakening and 9 hours later) orally for 36 months.
Overall Number of Participants Analyzed 842 464
Mean (Standard Deviation)
Unit of Measure: (mg/mL)^-1 per year
-2.555  (9.767) -3.682  (6.361)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tolvaptan, Placebo
Comments The null hypothesis was that there was no difference in the change in renal function per year between the tolvaptan group and the placebo group.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments Derived from testing the time treatment interaction using linear mixed model in which both intercept and slope are fixed and random effects.
Method of Estimation Estimation Parameter Difference in slope
Estimated Value 0.977
Confidence Interval (2-Sided) 95%
0.597 to 1.357
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Change in Mean Arterial Blood Pressure Per Year in Non-hypertensive Participants From Baseline to Month 36
Hide Description For participants who were non-hypertensive (systolic BP ≤ 139 mmHg and diastolic BP ≤ 89 mmHg without taking antihypertensive medications) at baseline, mean arterial blood pressure was measured at scheduled clinic visits up to the point of exposure to antihypertensive therapy for any reason. The change in mean arterial blood pressure per year was based on the slope of blood pressure, obtained by regressing blood pressure against time by subject.
Time Frame Baseline to Month 36
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: All randomized participants with at least 4 months of follow-up. Only non-hypertensive participants with available data were included in the analysis.
Arm/Group Title Tolvaptan Placebo
Hide Arm/Group Description:
Participants received the highest tolerated split-dose regimen (upon awakening and 9 hours later) of tolvaptan 45/15 mg, 60/30 mg, or 90/30 mg orally for 36 months.
Participants received placebo (upon awakening and 9 hours later) orally for 36 months.
Overall Number of Participants Analyzed 129 74
Mean (Standard Deviation)
Unit of Measure: mmHg
2.561  (9.798) 2.592  (7.095)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tolvaptan, Placebo
Comments The null hypothesis was that there was no difference in mean arterial blood pressure in non-hypertensive participants between the tolvaptan group and the placebo group.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5520
Comments [Not Specified]
Method Mixed Models Analysis
Comments Derived from testing the time treatment interaction using linear mixed model in which both intercept and slope are fixed and random effects.
Method of Estimation Estimation Parameter Difference in slope
Estimated Value -0.246
Confidence Interval (2-Sided) 95%
-1.059 to 0.566
Estimation Comments Placebo minus tolvaptan.
5.Secondary Outcome
Title Area Under the Concentration-time Curve of Change in Renal Pain From Baseline to Month 36
Hide Description Change from baseline in renal pain was assessed by a 0 to 10 pain scale as average area under the concentration-time curve (AUC) between baseline and the last trial visit or the last visit prior to initiating medical (eg, narcotic or anti-nociceptives [eg, tricyclic antidepressants]) or surgical therapy for pain. In the pain scale, score 0 represented no pain at all and score 10 represented the worst pain. A negative change score indicates less pain. AUC of renal pain was derived from renal pain scores within treatment period and was calculated using the trapezoidal rule, by dividing the number of days between the first and last assessment.
Time Frame At screening, Baseline, Day 1, every 4 months up to month 36/early tremination (ET), follow-up visit 1 and 2
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: All randomized participants with at least 4 months of follow-up. Only participants with available data were included in the analysis.
Arm/Group Title Tolvaptan Placebo
Hide Arm/Group Description:
Participants received the highest tolerated split-dose regimen (upon awakening and 9 hours later) of tolvaptan 45/15 mg, 60/30 mg, or 90/30 mg orally for 36 months.
Participants received placebo (upon awakening and 9 hours later) orally for 36 months.
Overall Number of Participants Analyzed 926 467
Mean (Standard Deviation)
Unit of Measure: units on a scale
-0.00  (1.29) 0.08  (1.43)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tolvaptan, Placebo
Comments The null hypothesis was that there was no difference in the change in renal pain between the tolvaptan group and the placebo group.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1604
Comments [Not Specified]
Method ANCOVA
Comments The analysis included baseline renal pain as a covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.08
Confidence Interval (2-Sided) 95%
-0.20 to 0.03
Estimation Comments Derived from ANCOVA with factors of treatment and baseline stratification factor interaction and covariate renal pain baseline.
6.Secondary Outcome
Title Number of Hypertensive Events Per 100 Follow-up Years in Non-hypertensive Participants From Baseline to Month 36
Hide Description A hypertensive event was defined as a change from non-hypertensive (systolic BP ≤ 139 mmHg and diastolic BP ≤ 89 mmHg without taking antihypertensive medications) status to 1 of 3 conditions: (1) High pre-hypertensive (systolic BP [sBP] > 129 mmHg and/or diastolic BP [dBP] > 84 mmHg), (2) hypertensive (sBP > 139 mmHg and/or dBP > 89 mmHg), or (3) requiring antihypertensive therapy.
Time Frame Baseline to Month 36
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: All randomized participants with at least 4 months of follow-up. Only non-hypertensive participants with available data were included in the analysis.
Arm/Group Title Tolvaptan Placebo
Hide Arm/Group Description:
Participants received the highest tolerated split-dose regimen (upon awakening and 9 hours later) of tolvaptan 45/15 mg, 60/30 mg, or 90/30 mg orally for 36 months.
Participants received placebo (upon awakening and 9 hours later) orally for 36 months.
Overall Number of Participants Analyzed 174 79
Measure Type: Number
Unit of Measure: Events/100 follow-up years
31.80 29.60
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tolvaptan, Placebo
Comments The null hypothesis was that there was no difference in the hypertensive events per 100 follow-up years in non-hypertensive participants between the tolvaptan group and the placebo group.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9704
Comments [Not Specified]
Method Recurrent event analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.996
Confidence Interval (2-Sided) 95%
0.805 to 1.233
Estimation Comments Derived from rate and mean model of time to recurrent event analysis with factor treatment.
7.Secondary Outcome
Title Percentage of Participants With a Clinically Sustained Decrease of Blood Pressure Leading to a Sustained Reduction in Antihypertensive Therapy From Baseline to Month 36
Hide Description [Not Specified]
Time Frame Baseline to Month 36
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: All randomized participants with at least 4 months of follow-up. Only participants taking antihypertensive medication at Baseline with available data were included in the analysis.
Arm/Group Title Tolvaptan Placebo
Hide Arm/Group Description:
Participants received the highest tolerated split-dose regimen (upon awakening and 9 hours later) of tolvaptan 45/15 mg, 60/30 mg, or 90/30 mg orally for 36 months.
Participants received placebo (upon awakening and 9 hours later) orally for 36 months.
Overall Number of Participants Analyzed 481 267
Measure Type: Number
Unit of Measure: Percentage of participants
6.24 5.62
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tolvaptan, Placebo
Comments The null hypothesis was that there was no difference in the percentage of participants with a clinically sustained decrease of blood pressure leading to a sustained reduction in antihypertensive therapy between the tolvaptan group and the placebo group.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7532
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 1.100
Confidence Interval (2-Sided) 95%
0.602 to 2.017
Estimation Comments Tolvaptan divided by placebo.
Time Frame Adverse events were collected from the time of signing the informed consent, throughout the 3 year treatment period and up to 42 days after the last dose of study medication
Adverse Event Reporting Description Safety population: All randomized participants who received study treatment. One participant in the placebo group did not receive study treatment and was not included in the safety population.
 
Arm/Group Title Tolvaptan Placebo
Hide Arm/Group Description Participants received the highest tolerated split-dose regimen (upon awakening and 9 hours later) of tolvaptan 45/15 mg, 60/30 mg, or 90/30 mg orally for 36 months. Participants received placebo (upon awakening and 9 hours later) orally for 36 months.
All-Cause Mortality
Tolvaptan Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Hide Serious Adverse Events
Tolvaptan Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   177/961 (18.42%)   95/483 (19.67%) 
Blood and lymphatic system disorders     
Iron deficiency anaemia * 1  0/961 (0.00%)  1/483 (0.21%) 
Cardiac disorders     
Acute myocardial infarction * 1  0/961 (0.00%)  2/483 (0.41%) 
Angina pectoris * 1  2/961 (0.21%)  0/483 (0.00%) 
Atrial fibrillation * 1  3/961 (0.31%)  1/483 (0.21%) 
Bradycardia * 1  0/961 (0.00%)  1/483 (0.21%) 
Coronary artery disease * 1  1/961 (0.10%)  0/483 (0.00%) 
Mitral valve incompetence * 1  0/961 (0.00%)  1/483 (0.21%) 
Mitral valve prolapse * 1  1/961 (0.10%)  0/483 (0.00%) 
Myocardial infarction * 1  1/961 (0.10%)  0/483 (0.00%) 
Myocardial ischaemia * 1  1/961 (0.10%)  0/483 (0.00%) 
Palpitations * 1  2/961 (0.21%)  0/483 (0.00%) 
Pericardial effusion * 1  1/961 (0.10%)  0/483 (0.00%) 
Pericarditis * 1  1/961 (0.10%)  0/483 (0.00%) 
Sick sinus syndrome * 1  1/961 (0.10%)  0/483 (0.00%) 
Ventricular extrasystoles * 1  1/961 (0.10%)  0/483 (0.00%) 
Congenital, familial and genetic disorders     
Multiple endocrine adenomatosis * 1  0/961 (0.00%)  1/483 (0.21%) 
Deafness * 1  1/961 (0.10%)  0/483 (0.00%) 
Ear and labyrinth disorders     
Vertigo * 1  2/961 (0.21%)  0/483 (0.00%) 
Eye disorders     
Glaucoma * 1  1/961 (0.10%)  0/483 (0.00%) 
Retinal detachment * 1  2/961 (0.21%)  0/483 (0.00%) 
Uveitis * 1  0/961 (0.00%)  1/483 (0.21%) 
Gastrointestinal disorders     
Abdominal adhesions * 1  0/961 (0.00%)  1/483 (0.21%) 
Abdominal distension * 1  1/961 (0.10%)  0/483 (0.00%) 
Abdominal hernia obstructive * 1  0/961 (0.00%)  1/483 (0.21%) 
Abdominal pain * 1  3/961 (0.31%)  2/483 (0.41%) 
Abdominal pain upper * 1  1/961 (0.10%)  1/483 (0.21%) 
Anal fissure * 1  1/961 (0.10%)  0/483 (0.00%) 
Anal fistula * 1  1/961 (0.10%)  0/483 (0.00%) 
Colonic polyp * 1  1/961 (0.10%)  0/483 (0.00%) 
Diverticulum intestinal * 1  1/961 (0.10%)  0/483 (0.00%) 
Dysphagia * 1  0/961 (0.00%)  1/483 (0.21%) 
Gastritis * 1  1/961 (0.10%)  1/483 (0.21%) 
Gastrooesophageal reflux disease * 1  1/961 (0.10%)  0/483 (0.00%) 
Hiatus hernia * 1  1/961 (0.10%)  0/483 (0.00%) 
Ileus * 1  1/961 (0.10%)  0/483 (0.00%) 
Inguinal hernia * 1  2/961 (0.21%)  1/483 (0.21%) 
Intestinal haemorrhage * 1  0/961 (0.00%)  1/483 (0.21%) 
Nausea * 1  1/961 (0.10%)  1/483 (0.21%) 
Pancreatitis acute * 1  0/961 (0.00%)  1/483 (0.21%) 
Pancreatitis relapsing * 1  0/961 (0.00%)  1/483 (0.21%) 
Periodontitis * 1  1/961 (0.10%)  0/483 (0.00%) 
Peritoneal haemorrhage * 1  0/961 (0.00%)  1/483 (0.21%) 
Rectal haemorrhage * 1  1/961 (0.10%)  0/483 (0.00%) 
Sigmoiditis * 1  0/961 (0.00%)  1/483 (0.21%) 
Umbilical hernia * 1  2/961 (0.21%)  1/483 (0.21%) 
Umbilical hernia, obstructive * 1  0/961 (0.00%)  1/483 (0.21%) 
Vomiting * 1  1/961 (0.10%)  1/483 (0.21%) 
General disorders     
Chest pain * 1  8/961 (0.83%)  2/483 (0.41%) 
Exercise tolerance decreased * 1  1/961 (0.10%)  0/483 (0.00%) 
Fatigue * 1  3/961 (0.31%)  0/483 (0.00%) 
Pyrexia * 1  0/961 (0.00%)  2/483 (0.41%) 
Thirst * 1  1/961 (0.10%)  0/483 (0.00%) 
Hepatobiliary disorders     
Cholangitis * 1  1/961 (0.10%)  0/483 (0.00%) 
Hepatic cyst * 1  1/961 (0.10%)  2/483 (0.41%) 
Hepatic function abnormal * 1  3/961 (0.31%)  0/483 (0.00%) 
Hepatic pain * 1  2/961 (0.21%)  0/483 (0.00%) 
Hepatitis * 1  1/961 (0.10%)  0/483 (0.00%) 
Hepatomegaly * 1  0/961 (0.00%)  2/483 (0.41%) 
Liver disorder * 1  1/961 (0.10%)  0/483 (0.00%) 
Immune system disorders     
Anaphylactic shock * 1  1/961 (0.10%)  0/483 (0.00%) 
Infections and infestations     
Abscess limb * 1  1/961 (0.10%)  0/483 (0.00%) 
Acute tonsillitis * 1  0/961 (0.00%)  1/483 (0.21%) 
Appendicitis * 1  1/961 (0.10%)  4/483 (0.83%) 
Arthritis bacterial * 1  1/961 (0.10%)  1/483 (0.21%) 
Bartholin's abscess * 1  1/961 (0.10%)  0/483 (0.00%) 
Cellulitis * 1  1/961 (0.10%)  0/483 (0.00%) 
Diverticulitis * 1  2/961 (0.21%)  0/483 (0.00%) 
Febrile infection * 1  0/961 (0.00%)  1/483 (0.21%) 
Gastroenteritis * 1  1/961 (0.10%)  0/483 (0.00%) 
Hepatic cyst infection * 1  0/961 (0.00%)  2/483 (0.41%) 
Hepatitis B * 1  1/961 (0.10%)  0/483 (0.00%) 
Kidney infection * 1  2/961 (0.21%)  0/483 (0.00%) 
Liver abscess * 1  1/961 (0.10%)  0/483 (0.00%) 
Malaria * 1  1/961 (0.10%)  0/483 (0.00%) 
Meningitis viral * 1  0/961 (0.00%)  1/483 (0.21%) 
Mycoplasma infection * 1  1/961 (0.10%)  0/483 (0.00%) 
Perineal abscess * 1  1/961 (0.10%)  0/483 (0.00%) 
Pneumonia * 1  3/961 (0.31%)  0/483 (0.00%) 
Pyelonephritis * 1  5/961 (0.52%)  5/483 (1.04%) 
Renal cyst infection * 1  6/961 (0.62%)  4/483 (0.83%) 
Respiratory tract infection viral * 1  1/961 (0.10%)  0/483 (0.00%) 
Sepsis * 1  0/961 (0.00%)  2/483 (0.41%) 
Syphilis * 1  1/961 (0.10%)  0/483 (0.00%) 
Urinary tract infection * 1  1/961 (0.10%)  3/483 (0.62%) 
Urogenital infection bacterial * 1  1/961 (0.10%)  0/483 (0.00%) 
Varicella * 1  0/961 (0.00%)  1/483 (0.21%) 
Viral infection * 1  1/961 (0.10%)  1/483 (0.21%) 
Injury, poisoning and procedural complications     
Ankle fracture * 1  1/961 (0.10%)  1/483 (0.21%) 
Cartilage injury * 1  2/961 (0.21%)  0/483 (0.00%) 
Clavicle fracture * 1  1/961 (0.10%)  0/483 (0.00%) 
Fall * 1  1/961 (0.10%)  0/483 (0.00%) 
Fracture * 1  0/961 (0.00%)  1/483 (0.21%) 
Hand fracture * 1  1/961 (0.10%)  0/483 (0.00%) 
Head injury * 1  0/961 (0.00%)  1/483 (0.21%) 
Induced abortion haemorrhage * 1  1/961 (0.10%)  0/483 (0.00%) 
Joint dislocation * 1  0/961 (0.00%)  1/483 (0.21%) 
Joint injury * 1  0/961 (0.00%)  1/483 (0.21%) 
Limb injury * 1  0/961 (0.00%)  1/483 (0.21%) 
Lumbar vertebral fracture * 1  1/961 (0.10%)  0/483 (0.00%) 
Meniscus lesion * 1  0/961 (0.00%)  1/483 (0.21%) 
Multiple fractures * 1  1/961 (0.10%)  0/483 (0.00%) 
Post procedural haemorrhage * 1  1/961 (0.10%)  0/483 (0.00%) 
Spinal compression fracture * 1  1/961 (0.10%)  0/483 (0.00%) 
Spinal fracture * 1  1/961 (0.10%)  0/483 (0.00%) 
Tibia fracture * 1  0/961 (0.00%)  1/483 (0.21%) 
Ulna fracture * 1  1/961 (0.10%)  0/483 (0.00%) 
Wrist fracture * 1  1/961 (0.10%)  0/483 (0.00%) 
Investigations     
Alanine aminotransferase increased * 1  9/961 (0.94%)  2/483 (0.41%) 
Aspartate aminotransferase increased * 1  9/961 (0.94%)  2/483 (0.41%) 
Blood bilirubin increased * 1  1/961 (0.10%)  0/483 (0.00%) 
Gamma-glutamyltransferase increased * 1  1/961 (0.10%)  1/483 (0.21%) 
Lipase increased * 1  0/961 (0.00%)  1/483 (0.21%) 
Liver function test abnormal * 1  2/961 (0.21%)  1/483 (0.21%) 
Transaminases increased * 1  4/961 (0.42%)  0/483 (0.00%) 
Metabolism and nutrition disorders     
Dehydration * 1  3/961 (0.31%)  2/483 (0.41%) 
Hyperamylasaemia * 1  0/961 (0.00%)  1/483 (0.21%) 
Hypercreatininaemia * 1  0/961 (0.00%)  1/483 (0.21%) 
Hyperglycaemia * 1  1/961 (0.10%)  0/483 (0.00%) 
Hyponatraemia * 1  1/961 (0.10%)  1/483 (0.21%) 
Hypovolaemia * 1  1/961 (0.10%)  0/483 (0.00%) 
Musculoskeletal and connective tissue disorders     
Arthralgia * 1  0/961 (0.00%)  1/483 (0.21%) 
Back pain * 1  1/961 (0.10%)  2/483 (0.41%) 
Bursitis * 1  0/961 (0.00%)  1/483 (0.21%) 
Cervical spinal stenosis * 1  1/961 (0.10%)  0/483 (0.00%) 
Chondromalacia * 1  0/961 (0.00%)  1/483 (0.21%) 
Fistula * 1  1/961 (0.10%)  0/483 (0.00%) 
Foot deformity * 1  1/961 (0.10%)  0/483 (0.00%) 
Intervertebral disc protrusion * 1  2/961 (0.21%)  1/483 (0.21%) 
Ligament pain * 1  1/961 (0.10%)  0/483 (0.00%) 
Musculoskeletal pain * 1  1/961 (0.10%)  0/483 (0.00%) 
Osteoarthritis * 1  1/961 (0.10%)  2/483 (0.41%) 
Osteoarthropathy * 1  1/961 (0.10%)  0/483 (0.00%) 
Rotator cuff syndrome * 1  1/961 (0.10%)  0/483 (0.00%) 
Spondylolisthesis * 1  0/961 (0.00%)  1/483 (0.21%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Breast cancer * 1  3/961 (0.31%)  1/483 (0.21%) 
Cervix carcinoma stage 0 * 1  1/961 (0.10%)  0/483 (0.00%) 
Cholesteatoma * 1  0/961 (0.00%)  1/483 (0.21%) 
Chronic myeloid leukaemia * 1  1/961 (0.10%)  0/483 (0.00%) 
Lipoma * 1  0/961 (0.00%)  1/483 (0.21%) 
Malignant melanoma * 1  2/961 (0.21%)  0/483 (0.00%) 
Malignant melanoma in situ * 1  1/961 (0.10%)  0/483 (0.00%) 
Pituitary tumour benign * 1  1/961 (0.10%)  0/483 (0.00%) 
Uterine leiomyoma * 1  2/961 (0.21%)  2/483 (0.41%) 
Nervous system disorders     
Cerebral haemorrhage * 1  1/961 (0.10%)  0/483 (0.00%) 
Dizziness * 1  1/961 (0.10%)  0/483 (0.00%) 
Headache * 1  5/961 (0.52%)  0/483 (0.00%) 
Intracranial aneurysm * 1  3/961 (0.31%)  1/483 (0.21%) 
Ischaemic stroke * 1  0/961 (0.00%)  1/483 (0.21%) 
Loss of consciousness * 1  2/961 (0.21%)  0/483 (0.00%) 
Migraine with aura * 1  1/961 (0.10%)  0/483 (0.00%) 
Nerve root compression * 1  1/961 (0.10%)  0/483 (0.00%) 
Paraesthesia * 1  2/961 (0.21%)  0/483 (0.00%) 
Parkinsonism * 1  1/961 (0.10%)  0/483 (0.00%) 
Presyncope * 1  1/961 (0.10%)  0/483 (0.00%) 
Sciatica * 1  1/961 (0.10%)  0/483 (0.00%) 
Subarachnoid haemorrhage * 1  1/961 (0.10%)  2/483 (0.41%) 
Syncope * 1  1/961 (0.10%)  0/483 (0.00%) 
Transient ischaemic attack * 1  0/961 (0.00%)  2/483 (0.41%) 
Vertebral artery dissection * 1  1/961 (0.10%)  0/483 (0.00%) 
VIIth nerve paralysis * 1  1/961 (0.10%)  0/483 (0.00%) 
Psychiatric disorders     
Depression * 1  1/961 (0.10%)  1/483 (0.21%) 
Major depression * 1  1/961 (0.10%)  0/483 (0.00%) 
Schizoaffective disorder * 1  0/961 (0.00%)  1/483 (0.21%) 
Suicide attempt * 1  1/961 (0.10%)  1/483 (0.21%) 
Renal and urinary disorders     
Bladder prolapse * 1  1/961 (0.10%)  0/483 (0.00%) 
Calculus urinary * 1  0/961 (0.00%)  1/483 (0.21%) 
Haematuria * 1  4/961 (0.42%)  1/483 (0.21%) 
Nephrolithiasis * 1  2/961 (0.21%)  3/483 (0.62%) 
Pollakiuria * 1  2/961 (0.21%)  0/483 (0.00%) 
Polyuria * 1  1/961 (0.10%)  0/483 (0.00%) 
Renal colic * 1  0/961 (0.00%)  2/483 (0.41%) 
Renal cyst * 1  1/961 (0.10%)  0/483 (0.00%) 
Renal cyst haemorrhage * 1  3/961 (0.31%)  4/483 (0.83%) 
Renal cyst ruptured * 1  1/961 (0.10%)  1/483 (0.21%) 
Renal failure acute * 1  0/961 (0.00%)  1/483 (0.21%) 
Renal failure chronic * 1  1/961 (0.10%)  0/483 (0.00%) 
Renal impairment * 1  1/961 (0.10%)  0/483 (0.00%) 
Renal pain * 1  1/961 (0.10%)  4/483 (0.83%) 
Stress urinary incontinence * 1  0/961 (0.00%)  1/483 (0.21%) 
Urge incontinence * 1  0/961 (0.00%)  1/483 (0.21%) 
Urinary incontinence * 1  1/961 (0.10%)  0/483 (0.00%) 
Urinary retention * 1  0/961 (0.00%)  2/483 (0.41%) 
Reproductive system and breast disorders     
Asthenospermia * 1  0/961 (0.00%)  1/483 (0.21%) 
Cervical dysplasia * 1  1/961 (0.10%)  0/483 (0.00%) 
Hysterocele * 1  0/961 (0.00%)  1/483 (0.21%) 
Menorrhagia * 1  3/961 (0.31%)  0/483 (0.00%) 
Metrorrhagia * 1  0/961 (0.00%)  1/483 (0.21%) 
Ovarian cyst * 1  2/961 (0.21%)  0/483 (0.00%) 
Ovarian torsion * 1  1/961 (0.10%)  0/483 (0.00%) 
Pelvic prolapse * 1  1/961 (0.10%)  0/483 (0.00%) 
Uterine polyp * 1  0/961 (0.00%)  1/483 (0.21%) 
Uterine prolapse * 1  3/961 (0.31%)  0/483 (0.00%) 
Uterovaginal prolapse * 1  1/961 (0.10%)  0/483 (0.00%) 
Varicocele * 1  0/961 (0.00%)  1/483 (0.21%) 
Respiratory, thoracic and mediastinal disorders     
Dyspnoea * 1  2/961 (0.21%)  0/483 (0.00%) 
Laryngeal oedema * 1  1/961 (0.10%)  0/483 (0.00%) 
Nasal septum deviation * 1  1/961 (0.10%)  0/483 (0.00%) 
Pharyngeal oedema * 1  0/961 (0.00%)  1/483 (0.21%) 
Productive cough * 1  1/961 (0.10%)  0/483 (0.00%) 
Pulmonary embolism * 1  1/961 (0.10%)  0/483 (0.00%) 
Respiratory failure * 1  1/961 (0.10%)  0/483 (0.00%) 
Skin and subcutaneous tissue disorders     
Angioedema * 1  1/961 (0.10%)  0/483 (0.00%) 
Hidradenitis * 1  1/961 (0.10%)  0/483 (0.00%) 
Urticaria * 1  1/961 (0.10%)  0/483 (0.00%) 
Vascular disorders     
Deep vein thrombosis * 1  0/961 (0.00%)  1/483 (0.21%) 
Haematoma * 1  1/961 (0.10%)  0/483 (0.00%) 
Hypertension * 1  1/961 (0.10%)  3/483 (0.62%) 
Hypotension * 1  3/961 (0.31%)  1/483 (0.21%) 
Orthostatic hypotension * 1  1/961 (0.10%)  0/483 (0.00%) 
Thrombophlebitis superficial * 1  1/961 (0.10%)  0/483 (0.00%) 
Varicose vein * 1  1/961 (0.10%)  0/483 (0.00%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (14.1)
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Tolvaptan Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   793/961 (82.52%)   372/483 (77.02%) 
Blood and lymphatic system disorders     
Anaemia * 1  30/961 (3.12%)  26/483 (5.38%) 
Gastrointestinal disorders     
Abdominal distension * 1  49/961 (5.10%)  17/483 (3.52%) 
Abdominal pain * 1  63/961 (6.56%)  32/483 (6.63%) 
Abdominal pain upper * 1  63/961 (6.56%)  43/483 (8.90%) 
Constipation * 1  81/961 (8.43%)  12/483 (2.48%) 
Diarrhoea * 1  133/961 (13.84%)  54/483 (11.18%) 
Dry mouth * 1  154/961 (16.02%)  60/483 (12.42%) 
Dyspepsia * 1  78/961 (8.12%)  16/483 (3.31%) 
Nausea * 1  101/961 (10.51%)  59/483 (12.22%) 
Vomiting * 1  81/961 (8.43%)  40/483 (8.28%) 
General disorders     
Asthenia * 1  58/961 (6.04%)  27/483 (5.59%) 
Fatigue * 1  132/961 (13.74%)  47/483 (9.73%) 
Oedema peripheral * 1  88/961 (9.16%)  46/483 (9.52%) 
Pyrexia * 1  45/961 (4.68%)  41/483 (8.49%) 
Thirst * 1  532/961 (55.36%)  99/483 (20.50%) 
Infections and infestations     
Bronchitis * 1  59/961 (6.14%)  36/483 (7.45%) 
Gastroenteritis * 1  55/961 (5.72%)  22/483 (4.55%) 
Influenza * 1  78/961 (8.12%)  38/483 (7.87%) 
Nasopharyngitis * 1  221/961 (23.00%)  111/483 (22.98%) 
Sinusitis * 1  56/961 (5.83%)  23/483 (4.76%) 
Upper respiratory tract infection * 1  87/961 (9.05%)  42/483 (8.70%) 
Urinary tract infection * 1  87/961 (9.05%)  65/483 (13.46%) 
Investigations     
Blood creatinine increased * 1  140/961 (14.57%)  71/483 (14.70%) 
Metabolism and nutrition disorders     
Decreased appetite * 1  69/961 (7.18%)  5/483 (1.04%) 
Polydipsia * 1  100/961 (10.41%)  17/483 (3.52%) 
Musculoskeletal and connective tissue disorders     
Arthralgia * 1  70/961 (7.28%)  29/483 (6.00%) 
Back pain * 1  138/961 (14.36%)  90/483 (18.63%) 
Myalgia * 1  52/961 (5.41%)  17/483 (3.52%) 
Pain in extremity * 1  42/961 (4.37%)  27/483 (5.59%) 
Nervous system disorders     
Dizziness * 1  108/961 (11.24%)  42/483 (8.70%) 
Headache * 1  243/961 (25.29%)  123/483 (25.47%) 
Psychiatric disorders     
Insomnia * 1  55/961 (5.72%)  23/483 (4.76%) 
Renal and urinary disorders     
Haematuria * 1  71/961 (7.39%)  68/483 (14.08%) 
Nocturia * 1  281/961 (29.24%)  63/483 (13.04%) 
Pollakiuria * 1  222/961 (23.10%)  26/483 (5.38%) 
Renal pain * 1  266/961 (27.68%)  172/483 (35.61%) 
Polyuria * 1  369/961 (38.40%)  83/483 (17.18%) 
Respiratory, thoracic and mediastinal disorders     
Cough * 1  78/961 (8.12%)  38/483 (7.87%) 
Oropharyngeal pain * 1  50/961 (5.20%)  18/483 (3.73%) 
Skin and subcutaneous tissue disorders     
Dry skin * 1  49/961 (5.10%)  9/483 (1.86%) 
Vascular disorders     
Hypertension * 1  324/961 (33.71%)  178/483 (36.85%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (14.1)
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: Global Medical Affairs
Organization: Otsuka Pharmaceutical Development and Commercialization
Phone: 800 562-3974
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
ClinicalTrials.gov Identifier: NCT00428948    
Other Study ID Numbers: 156-04-251
2006-002768-24 ( EudraCT Number )
First Submitted: January 26, 2007
First Posted: January 30, 2007
Results First Submitted: March 29, 2017
Results First Posted: July 2, 2017
Last Update Posted: July 2, 2017