A Phase 2 interventional study of Tolvaptan in Polycystic Kidney, Autosomal Dominant, sponsored by Otsuka Pharmaceutical Development & Commercialization, Inc.. Completed at 11 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2017-07-02.
Sponsored by Otsuka Pharmaceutical Development & Commercialization, Inc. · Phase 2, Interventional, and Treatment
This study's purpose is to evaluate the long-term safety of open-label tolvaptan regimens to determine the maximally-tolerated dose and acquire pilot efficacy data in patients with autosomal dominant polycystic kidney disease (ADPKD).
Autosomal Dominant Polycystic Kidney Disease is a genetic disease classified by the formation of fluid-filled cysts in the kidneys. The accumulation of these cysts causes the kidneys to enlarge several times the normal size and leads to the eventual loss of renal function and ultimately results in renal failure in end-stage patients. This is a disease with life-threatening implications to those who have it, and their family members who may also be affected. Aside from early anti-hypertensive control and dietary protein restriction, which are presumed to offer a modest degree of protection, most surviving patients require renal replacement therapy (dialysis and transplant) and suffer from high morbidity and mortality.
A rationale for use of tolvaptan in these genetic disorders has been proven, in principle, through use of a variety of animal models. In these models, tolvaptan is effective in halting or reversing the progression of this renal disease.
The current study is being undertaken in order to evaluate whether tolvaptan, an oral vasopressin V2 receptor inhibitor, will maintain an adequate safety profile and show a potential clinical benefit by reducing total renal volume in the hopes of making an impact upon disease progression.
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This study's enrollment of 46 is below the median of 66 across 63 interventional studies indexed under Arthrogryposis.
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Exclusion Criteria:
Participants received tolvaptan 45 mg orally in the morning and 15 mg orally 8 hours later for up to 4 years.
Drug: Tolvaptan
Participants received tolvaptan 60 mg orally in the morning and 30 mg orally 8 hours later for up to 4 years.
Drug: Tolvaptan
Participants were titrated to either the tolvaptan 45/15 or 60/30 mg split-dose over a 2-month Titration Period. They received the titrated dose for 34 months during the Fixed-dose Period. Following a planned off-treatment period, participants had the option to enter an Extension Period for an additional 12 months. Tolvaptan was supplied as tablets.
Also known as: OPC-41061
Safety Assessments Based on Vital Signs, Electrocardiogram (ECG's), Clinical Laboratory Tests, Physical Examinations Are Reported as Adverse Events (AEs) Upon Study Physician Discretion.
An AE was defined as any new medical problem, or exacerbation of an existing problem, experienced by a participant while enrolled in a study , whether or not it was considered drug-related by the study physician. A treatment-emergent AE (TEAE) was defined as an AE that started after start of study drug treatment; or if the event was continuous from Baseline and was serious, study drug related, or resulted in death, discontinuation.
Time frame: AEs were recorded from screening (ICF was signed) until 7-Day follow-up
Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to First Daily Dose.
Spot urine osmolality at trough was determined for urine samples collected immediately prior to morning dosing for Day 1 (Baseline), Months 2, 6, 12, 24, 36 for all participants. Sample was taken after the first morning's void and was provided as a mid-stream, clean catch sample. During the titration period (Weeks 1, 2, 3 and 4) and at Month 6, additional samples were collected for the preceding day immediately preceding the 2nd daily dose and at bed-time. These samples allowed derivation of an average nadir of spot urine osmolality concentrations at each dose level and while at steady state during extended tolvaptan administration. At the Month 36 visit, participants were given a urine container and brought back the specimen at Extension Day 1. All participants were fasting.
Time frame: Baseline to Month 36
Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to Second Daily Dose.
Urine osmolality at steady state (after at least 4 days of dosing) including "absolute trough" prior to the second daily dose. Samples for this assessment were taken as closely coincident to PK blood sample as practical. During Weeks 1, 2, 3 and 4 of the Titration Period and at Month 6, additional samples were collected for the preceding day immediately preceding the second daily dose. These samples allowed derivation of an average nadir of spot urine osmolality concentrations at each dose level and while at steady state during extended tolvaptan administration.
Time frame: Baseline to Month 24
Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to Bedtime.
Urine osmolality at steady state (after at least 4 days of dosing) including "average of troughs" (the mean urine osmolality prior to bedtime). Samples for this assessment were to be taken as closely coincident to PK blood sample as practical. During Weeks 1, 2, 3 and 4 of the Titration Period and at Month 6, additional samples were collected for the preceding day at bedtime. These samples allowed derivation of an average nadir of spot urine osmolality concentrations at each dose level and while at steady state during extended tolvaptan administration.
Time frame: Baseline to Month 24
Percent Change From Baseline in Renal Volume.
Total Kidney Volume (TKV) was assessed by the central magnetic resonance imaging (MRI) rater.
Time frame: Baseline to Month 36
Change From Pre-dose Baseline in Renal Function Estimated by Glomerular Filtration Rate (GFR).
GFR was estimated using reciprocal serum creatinine formula. The formula does not adjust for body weight or height, but this may be done to normalize to body surface area. The formula for reciprocal Serum creatinine is: 1/Pcr. (Pcr = serum creatinine concentration \[mg/dL\]). Clinic weight scales were calibrated at least yearly.
Time frame: Baseline to Month 36
Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to First Daily Dose- Extension.
Spot urine osmolality at trough was determined for urine samples collected immediately prior to morning dosing for Day 1 (Baseline), Months 2, 6, 12, 24, 36, Extension Day 1, and Extension Month 12 for all participants. Sample was taken after the first morning's void and was provided as a mid-stream, clean catch sample. During the titration period (Weeks 1, 2, 3 and 4) and at Month 6, additional samples were collected for the preceding day immediately preceding the 2nd daily dose and at bed-time. These samples allowed derivation of an average nadir of spot urine osmolality concentrations at each dose level and while at steady state during extended tolvaptan administration. At the Month 36 visit, participants were given a urine container and brought back the specimen at Extension Day 1. All participants were fasting.
Time frame: Baseline to Months 2, 6, 12, 24, 36, Extension Day 1, Extension Month 12
Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to Second Daily Dose- Extension.
Urine osmolality at steady state (after at least 4 days of dosing) including "absolute trough" prior to the second daily dose. Samples for this assessment were taken as closely coincident to PK blood sample as practical. During Weeks 1, 2, 3 and 4 of the Titration Period and at Month 6, additional samples were collected for the preceding day immediately preceding the second daily dose. These samples allowed derivation of an average nadir of spot urine osmolality concentrations at each dose level and while at steady state during extended tolvaptan administration.
Time frame: Baseline to Month 24
Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to Bedtime- Extension.
Urine osmolality at steady state (after at least 4 days of dosing) including "average of troughs" (the mean urine osmolality prior to bedtime). Samples for this assessment were to be taken as closely coincident to PK blood sample as practical. During Weeks 1, 2, 3 and 4 of the Titration Period and at Month 6, additional samples were collected for the preceding day at bedtime. These samples allowed derivation of an average nadir of spot urine osmolality concentrations at each dose level and while at steady state during extended tolvaptan administration.
Time frame: Baseline to Month 24
Percent Change From Baseline in Renal Volume-Extension.
TKV was assessed by the central magnetic resonance imaging (MRI) rater.
Time frame: Baseline to Months 2, 12, 24, 36, Extension Day 1, Extension Month 12
Change From Pre-dose Baseline in Renal Function Estimated by GFR- Extension.
GFR was estimated using reciprocal serum creatinine formula. The formula does not adjust for body weight or height, but this may be done to normalize to body surface area. The formula for reciprocal Serum creatinine is: 1/Pcr. (Pcr = serum creatinine concentration \[mg/dL\]). Clinic weight scales were calibrated at least yearly.
Time frame: Baseline to Months 2, 6, 9, 12, 16, 20, 24, 28, 32, 36, Extension Day 1, Extension Month 12
Mean Change From Baseline in Systolic Blood Pressure (sBP) for Hypertension Assessment.
The participants were seated and resting systolic and diastolic BP for each scheduled assessment was recorded. At each assessment, participants were categorized (based on repeated blood pressure measurements as being normotensive (MAP \< 100 mm Hg and off therapy), high normal (sBP \> 129 and or dBP \> 84 mm Hg off therapy) or hypertensive (sBP \>140 and/or dBP \> 90 mm Hg). The mean arterial pressure (MAP) was derived from these values and were not recorded (MAP = diastolic pressure + \[1/3 x pulse pressure (ie systolic - diastolic pressure)\] in mm Hg).
Time frame: Baseline to Month 36
Mean Change From Baseline in Diastolic Blood Pressure (dBP) for Hypertension Assessment.
The participants were seated and resting systolic and diastolic BP for each scheduled assessment was recorded. At each assessment, participants were categorized (based on repeated blood pressure measurements as being normotensive (MAP \< 100 mm Hg and off therapy), high normal (sBP \> 129 and or dBP \> 84 mm Hg off therapy) or hypertensive (sBP \>140 and/or dBP \> 90 mm Hg). The mean arterial pressure (MAP) was derived from these values and were not recorded (MAP = diastolic pressure + \[1/3 x pulse pressure (ie systolic - diastolic pressure)\] in mm Hg).
Time frame: Baseline to Month 36
Mean Change From Baseline in Mean Arterial Pressure (MAP) for Hypertension Assessment.
The participants were seated and resting systolic and diastolic BP for each scheduled assessment was recorded. At each assessment, participants were categorized (based on repeated blood pressure measurements as being normotensive (MAP \< 100 mm Hg and off therapy), high normal (sBP \> 129 and or dBP \> 84 mm Hg off therapy) or hypertensive (sBP \>140 and/or dBP \> 90 mm Hg). The mean arterial pressure (MAP) was derived from these values and were not recorded (MAP = diastolic pressure + \[1/3 x pulse pressure (ie systolic - diastolic pressure)\] in mm Hg).
Time frame: Baseline to Month 36
Mean Change From Baseline in sBP for Hypertension Assessment- Extension.
The participants were seated and resting systolic and diastolic BP for each scheduled assessment was recorded. At each assessment, participants were categorized (based on repeated blood pressure measurements as being normotensive (MAP \< 100 mm Hg and off therapy), high normal (sBP \> 129 and or dBP \> 84 mm Hg off therapy) or hypertensive (sBP \>140 and/or dBP \> 90 mm Hg). The mean arterial pressure (MAP) was derived from these values and were not recorded (MAP = diastolic pressure + \[1/3 x pulse pressure (ie systolic - diastolic pressure)\] in mm Hg).
Time frame: Baseline to Months 2, 6, 9, 12, 16, 20, 24, 28, 32, 36, Extension Day 1, Extension Month 4, Extension Month 8, Extension Month 12
Mean Change From Baseline in dBP for Hypertension Assessment- Extension.
The participants were seated and resting systolic and diastolic BP for each scheduled assessment was recorded. At each assessment, participants were categorized (based on repeated blood pressure measurements as being normotensive (MAP \< 100 mm Hg and off therapy), high normal (sBP \> 129 and or dBP \> 84 mm Hg off therapy) or hypertensive (sBP \>140 and/or dBP \> 90 mm Hg). The mean arterial pressure (MAP) was derived from these values and were not recorded (MAP = diastolic pressure + \[1/3 x pulse pressure (ie systolic - diastolic pressure)\] in mm Hg).
Time frame: Baseline to Months 2, 6, 9, 12, 16, 20, 24, 28, 32, 36, Extension Day 1, Extension Month 4, Extension Month 8, Extension Month 12
Mean Change From Baseline in MAP for Hypertension Assessment- Extension.
The participants were seated and resting systolic and diastolic BP for each scheduled assessment was recorded. At each assessment, participants were categorized (based on repeated blood pressure measurements as being normotensive (MAP \< 100 mm Hg and off therapy), high normal (sBP \> 129 and or dBP \> 84 mm Hg off therapy) or hypertensive (sBP \>140 and/or dBP \> 90 mm Hg). The mean arterial pressure (MAP) was derived from these values and were not recorded (MAP = diastolic pressure + \[1/3 x pulse pressure (ie systolic - diastolic pressure)\] in mm Hg).
Time frame: Baseline to Months 2, 6, 9, 12, 16, 20, 24, 28, 32, 36, Extension Day 1, Extension Month 4, Extension Month 8, Extension Month 12
Mean Change From Baseline in Patient-assessed Renal Pain Scale.
Participants were asked the question to assess the relative level of pain attributed to their kidneys. This question was, "On a scale of 0 to 10, with zero represented no pain at all and 10 represented the worst pain ever experienced, what was the worst kidney pain experienced in the last 4 months?" If the latest assessment was less than 4 months prior, the question was substituted "since your last visit" for "in the last 4 months". The same interrogator designated to this task was used throughout the study for each participant.
Time frame: Baseline to Month 36
Mean Change From Baseline in Patient-assessed Renal Pain Scale- Extension.
Participants were asked the question to assess the relative level of pain attributed to their kidneys. This question was, "On a scale of 0 to 10, with zero represented no pain at all and 10 represented the worst pain ever experienced, what was the worst kidney pain experienced in the last 4 months?" If the latest assessment was less than 4 months prior, the question was substituted "since your last visit" for "in the last 4 months". The same interrogator designated to this task was used throughout the study for each participant.
Time frame: Baseline to Months 2, 6, 12, 24, 36, Extension Day 1, Extension Month 12
Mean Change From Baseline in Abdominal Girth Measurement.
The participant had a measurement of their abdominal girth recorded. The measurement will be taken with a tape measure extending around the abdomen at the level of the iliac crests laterally and the umbilicus anteriorly. The examiner should also palpate for each kidney and liver edge, noting presence or enlargement. (By definition if the kidneys are palpable they are enlarged, the liver edge may be palpable but not enlarged).
Time frame: Baseline to Month 36
Mean Change From Baseline in Abdominal Girth Measurement- Extension.
The participant had a measurement of their abdominal girth recorded. The measurement will be taken with a tape measure extending around the abdomen at the level of the iliac crests laterally and the umbilicus anteriorly. The examiner should also palpate for each kidney and liver edge, noting presence or enlargement. (By definition if the kidneys are palpable they are enlarged, the liver edge may be palpable but not enlarged).
Time frame: Baseline to Extension Day 1, Extension Month 12
A phase 2, multi-center, open-label trial, to determine the safety, tolerability, and efficacy study of split-dose oral regimens of tolvaptan tablets in a range of 30 to 120 mg/d in autosomal dominant polycystic kidney disease (ADPKD) participants.
| Milestone | Tolvaptan 45+15 mg | Tolvaptan 60+30 mg |
|---|---|---|
| Started | 22 | 24 |
| Completed | 18 | 21 |
| Not completed | 4 | 3 |
| Withdrew: Lost to follow-up | 1 | 1 |
| Withdrew: Adverse event | 2 | 1 |
| Withdrew: Met withdrawal criteria | 1 | 0 |
| Withdrew: Withdrew consent | 0 | 1 |
| Milestone | Tolvaptan 45+15 mg | Tolvaptan 60+30 mg |
|---|---|---|
| Started | 17 | 18 |
| Completed | 17 | 18 |
| Not completed | 0 | 0 |
An AE was defined as any new medical problem, or exacerbation of an existing problem, experienced by a participant while enrolled in a study , whether or not it was considered drug-related by the study physician. A treatment-emergent AE (TEAE) was defined as an AE that started after start of study drug treatment; or if the event was continuous from Baseline and was serious, study drug related, or resulted in death, discontinuation.
| participants | Tolvaptan 45+15 mg | Tolvaptan 60+30 mg |
|---|---|---|
| Participants with serious TEAEs | 3 | 8 |
| Participants with severe TEAEs | 6 | 10 |
| Participants discontinued due to AEs | 3 | 1 |
Spot urine osmolality at trough was determined for urine samples collected immediately prior to morning dosing for Day 1 (Baseline), Months 2, 6, 12, 24, 36 for all participants. Sample was taken after the first morning's void and was provided as a mid-stream, clean catch sample. During the titration period (Weeks 1, 2, 3 and 4) and at Month 6, additional samples were collected for the preceding day immediately preceding the 2nd daily dose and at bed-time. These samples allowed derivation of an average nadir of spot urine osmolality concentrations at each dose level and while at steady state during extended tolvaptan administration. At the Month 36 visit, participants were given a urine container and brought back the specimen at Extension Day 1. All participants were fasting.
| mOsm/kg | Tolvaptan 45+15 mg | Tolvaptan 60+30 mg |
|---|---|---|
| Month 2 (N= 21, 22) | -274.10 ± 223.14 | -228.00 ± 238.19 |
| Month 6 (N= 19, 23) | -288.42 ± 219.55 | -263.78 ± 221.05 |
| Month 12 (N= 17, 21) | -227.29 ± 226.63 | -178.43 ± 228.43 |
| Month 24 (N= 18, 20) | -170.17 ± 272.21 | -189.75 ± 229.33 |
| Month 36 (N= 18, 21) | -222.50 ± 229.91 | -208.90 ± 194.19 |
Urine osmolality at steady state (after at least 4 days of dosing) including "absolute trough" prior to the second daily dose. Samples for this assessment were taken as closely coincident to PK blood sample as practical. During Weeks 1, 2, 3 and 4 of the Titration Period and at Month 6, additional samples were collected for the preceding day immediately preceding the second daily dose. These samples allowed derivation of an average nadir of spot urine osmolality concentrations at each dose level and while at steady state during extended tolvaptan administration.
| mOsm/kg | Tolvaptan 45+15 mg | Tolvaptan 60+30 mg |
|---|---|---|
| Month 2 (N= 21, 21) | -263.95 ± 220.40 | -298.71 ± 257.53 |
| Month 6 (N= 19, 23) | -321.78 ± 242.53 | -294.13 ± 215.95 |
| Month 12 (N= 16, 20) | -288.20 ± 216.85 | -234.65 ± 238.82 |
| Month 24 (N= 1, 7) | -405.00 ± NA | -227.14 ± 334.13 |
Urine osmolality at steady state (after at least 4 days of dosing) including "average of troughs" (the mean urine osmolality prior to bedtime). Samples for this assessment were to be taken as closely coincident to PK blood sample as practical. During Weeks 1, 2, 3 and 4 of the Titration Period and at Month 6, additional samples were collected for the preceding day at bedtime. These samples allowed derivation of an average nadir of spot urine osmolality concentrations at each dose level and while at steady state during extended tolvaptan administration.
| mOsm/kg | Tolvaptan 45+15 mg | Tolvaptan 60+30 mg |
|---|---|---|
| Month 2 (N= 21, 22) | -275.00 ± 219.37 | -291.09 ± 194.88 |
| Month 6 (N= 19, 23) | -327.41 ± 217.15 | -301.83 ± 210.55 |
| Month 12 (16, 18) | -283.21 ± 230.81 | -245.83 ± 234.46 |
| Month 24 (N= 1, 7) | -263.00 ± NA | -246.00 ± 208.50 |
Total Kidney Volume (TKV) was assessed by the central magnetic resonance imaging (MRI) rater.
| Percentage change per month | Tolvaptan 45+15 mg | Tolvaptan 60+30 mg |
|---|---|---|
| Month 2 (N= 21, 24) | -1.0 ± 5.2 | -1.3 ± 5.3 |
| Month 12 (N= 18, 22) | 0.3 ± 6.0 | 2.4 ± 6.6 |
| Month 24 (N= 18, 21) | 4.6 ± 8.4 | 1.0 ± 8.3 |
| Month 36 (N= 18, 20) | 9.9 ± 11.8 | 5.3 ± 10.0 |
GFR was estimated using reciprocal serum creatinine formula. The formula does not adjust for body weight or height, but this may be done to normalize to body surface area. The formula for reciprocal Serum creatinine is: 1/Pcr. (Pcr = serum creatinine concentration \[mg/dL\]). Clinic weight scales were calibrated at least yearly.
| dL/mg | Tolvaptan 45+15 mg | Tolvaptan 60+30 mg |
|---|---|---|
| Month 2 (N= 22, 24) | -0.09 ± 0.11 | -0.05 ± 0.13 |
| Month 6 (N= 19, 21) | -0.03 ± 0.10 | -0.01 ± 0.12 |
| Month 9 (N= 18, 23) | -0.01 ± 0.12 | -0.03 ± 0.13 |
| Month 12 (N= 17, 22) | -0.03 ± 0.11 | -0.01 ± 0.18 |
| Month 16 (N= 18, 21) | -0.06 ± 0.12 | -0.02 ± 0.12 |
| Month 20 (N= 18, 21) | -0.06 ± 0.10 | -0.03 ± 0.15 |
| Month 24 (N= 18, 20) | -0.04 ± 0.10 | -0.02 ± 0.13 |
| Month 28 (N= 18, 21) | -0.07 ± 0.10 | -0.02 ± 0.14 |
| Month 32 (N= 18, 21) | -0.09 ± 0.14 | -0.06 ± 0.12 |
| Month 36 (N= 18, 21) | -0.07 ± 0.11 | -0.06 ± 0.13 |
Spot urine osmolality at trough was determined for urine samples collected immediately prior to morning dosing for Day 1 (Baseline), Months 2, 6, 12, 24, 36, Extension Day 1, and Extension Month 12 for all participants. Sample was taken after the first morning's void and was provided as a mid-stream, clean catch sample. During the titration period (Weeks 1, 2, 3 and 4) and at Month 6, additional samples were collected for the preceding day immediately preceding the 2nd daily dose and at bed-time. These samples allowed derivation of an average nadir of spot urine osmolality concentrations at each dose level and while at steady state during extended tolvaptan administration. At the Month 36 visit, participants were given a urine container and brought back the specimen at Extension Day 1. All participants were fasting.
| mOsm/kg | Tolvaptan 45+15 mg | Tolvaptan 60+30 mg |
|---|---|---|
| Month 2 (N= 17, 17) | -328.06 ± 207.05 | -176.88 ± 225.54 |
| Month 6 (N= 17, 18) | -270.94 ± 200.29 | -223.50 ± 211.61 |
| Month 12 (N= 16, 17) | -234.56 ± 232.01 | -155.65 ± 242.53 |
| Month 24 (N= 17, 17) | -164.06 ± 279.32 | -160.06 ± 196.50 |
| Month 36 (N= 17, 18) | -234.71 ± 230.90 | -196.33 ± 175.23 |
| Extension Day 1 (N= 17, 17) | -54.59 ± 236.96 | -157.18 ± 229.19 |
| Extension Month 12 (N= 17, 18) | -115.59 ± 278.19 | -202.44 ± 227.92 |
Urine osmolality at steady state (after at least 4 days of dosing) including "absolute trough" prior to the second daily dose. Samples for this assessment were taken as closely coincident to PK blood sample as practical. During Weeks 1, 2, 3 and 4 of the Titration Period and at Month 6, additional samples were collected for the preceding day immediately preceding the second daily dose. These samples allowed derivation of an average nadir of spot urine osmolality concentrations at each dose level and while at steady state during extended tolvaptan administration.
| mOsm/kg | Tolvaptan 45+15 mg | Tolvaptan 60+30 mg |
|---|---|---|
| Month 2 (N= 17, 17) | -281.63 ± 235.90 | -254.82 ± 217.14 |
| Month 6 (N= 17, 18) | -305.25 ± 223.90 | -261.61 ± 201.49 |
| Month 12 (N= 16, 16) | -288.20 ± 216.85 | -190.69 ± 201.16 |
| Month 24 (N= 1, 6) | -405.00 ± NA | -120.50 ± 196.05 |
Urine osmolality at steady state (after at least 4 days of dosing) including "average of troughs" (the mean urine osmolality prior to bedtime). Samples for this assessment were to be taken as closely coincident to PK blood sample as practical. During Weeks 1, 2, 3 and 4 of the Titration Period and at Month 6, additional samples were collected for the preceding day at bedtime. These samples allowed derivation of an average nadir of spot urine osmolality concentrations at each dose level and while at steady state during extended tolvaptan administration.
| mOsm/kg | Tolvaptan 45+15 mg | Tolvaptan 60+30 mg |
|---|---|---|
| Month 2 (N= 17, 17) | -322.27 ± 207.32 | -258.88 ± 174.51 |
| Month 6 (N= 17, 18) | -309.73 ± 225.40 | -264.50 ± 180.12 |
| Month 12 (16, 15) | -283.21 ± 230.81 | -206.00 ± 200.36 |
| Month 24 (N= 1, 6) | -263.00 ± NA | -187.50 ± 153.04 |
TKV was assessed by the central magnetic resonance imaging (MRI) rater.
| Percentage change per month | Tolvaptan 45+15 mg | Tolvaptan 60+30 mg |
|---|---|---|
| Month 2 (N= 17, 18) | -1.3 ± 5.4 | -1.4 ± 3.9 |
| Month 12 (N= 17, 18) | -0.7 ± 4.5 | 1.9 ± 5.7 |
| Month 24 (N= 17, 18) | 3.2 ± 6.0 | 0.2 ± 7.2 |
| Month 36 (N= 17, 18) | 7.9 ± 8.7 | 3.8 ± 7.4 |
| Extension Day 1 (N= 17, 18) | 14.1 ± 10.5 | 8.4 ± 7.9 |
| Extension Month 12 (N= 17, 18) | 15.7 ± 12.7 | 10.7 ± 10.4 |
GFR was estimated using reciprocal serum creatinine formula. The formula does not adjust for body weight or height, but this may be done to normalize to body surface area. The formula for reciprocal Serum creatinine is: 1/Pcr. (Pcr = serum creatinine concentration \[mg/dL\]). Clinic weight scales were calibrated at least yearly.
| dL/mg | Tolvaptan 45+15 mg | Tolvaptan 60+30 mg |
|---|---|---|
| Month 2 (N= 17, 18) | -0.09 ± 0.11 | -0.04 ± 0.15 |
| Month 6 (N= 17, 16) | -0.03 ± 0.11 | -0.00 ± 0.13 |
| Month 9 (N= 16, 18) | -0.01 ± 0.11 | -0.01 ± 0.14 |
| Month 12 (N= 16, 17) | -0.03 ± 0.12 | -0.00 ± 0.21 |
| Month 16 (N= 17, 16) | -0.06 ± 0.12 | -0.01 ± 0.13 |
| Month 20 (N= 17, 18) | -0.06 ± 0.10 | -0.02 ± 0.16 |
| Month 24 (N= 17, 17) | -0.04 ± 0.11 | -0.02 ± 0.14 |
| Month 28 (N= 17, 18) | -0.06 ± 0.10 | -0.02 ± 0.14 |
| Month 32 (N= 17, 18) | -0.09 ± 0.14 | -0.05 ± 0.12 |
| Month 36 (N= 17, 18) | -0.07 ± 0.11 | -0.05 ± 0.14 |
| Extension Day 1 (N= 17, 18) | -0.04 ± 0.13 | -0.01 ± 0.17 |
| Extension Month 12 (N= 17, 18) | -0.05 ± 0.17 | -0.04 ± 0.14 |
The participants were seated and resting systolic and diastolic BP for each scheduled assessment was recorded. At each assessment, participants were categorized (based on repeated blood pressure measurements as being normotensive (MAP \< 100 mm Hg and off therapy), high normal (sBP \> 129 and or dBP \> 84 mm Hg off therapy) or hypertensive (sBP \>140 and/or dBP \> 90 mm Hg). The mean arterial pressure (MAP) was derived from these values and were not recorded (MAP = diastolic pressure + \[1/3 x pulse pressure (ie systolic - diastolic pressure)\] in mm Hg).
| mmHg | Tolvaptan 45+15 mg | Tolvaptan 60+30 mg |
|---|---|---|
| Month 2 (N= 22, 24) | -3.2 ± 12.6 | -3.0 ± 15.4 |
| Month 6 (N= 19, 23) | -3.6 ± 10.8 | -5.0 ± 12.4 |
| Month 9 (N= 18, 23) | -4.6 ± 12.5 | -3.5 ± 12.5 |
| Month 12 (N= 18, 23) | -8.0 ± 14.6 | -3.5 ± 14.2 |
| Month 16 (N= 18, 23) | -6.2 ± 14.2 | -2.9 ± 12.6 |
| Month 20 (N= 18, 21) | -7.9 ± 11.4 | -10.0 ± 16.4 |
| Month 24 (N= 18, 21) | -2.1 ± 18.4 | -0.1 ± 14.7 |
| Month 28 (N= 18, 21) | -4.7 ± 14.2 | -4.1 ± 17.1 |
| Month 32 (N= 18, 21) | -7.3 ± 10.9 | -7.2 ± 14.8 |
| Month 36 (N= 18, 21) | -0.2 ± 13.2 | -5.4 ± 17.6 |
The participants were seated and resting systolic and diastolic BP for each scheduled assessment was recorded. At each assessment, participants were categorized (based on repeated blood pressure measurements as being normotensive (MAP \< 100 mm Hg and off therapy), high normal (sBP \> 129 and or dBP \> 84 mm Hg off therapy) or hypertensive (sBP \>140 and/or dBP \> 90 mm Hg). The mean arterial pressure (MAP) was derived from these values and were not recorded (MAP = diastolic pressure + \[1/3 x pulse pressure (ie systolic - diastolic pressure)\] in mm Hg).
| mmHg | Tolvaptan 45+15 mg | Tolvaptan 60+30 mg |
|---|---|---|
| Month 2 (N= 22, 24) | -4.0 ± 11.4 | -0.2 ± 9.8 |
| Month 6 (N= 19, 23) | -3.6 ± 8.2 | -2.5 ± 11.2 |
| Month 9 (N= 18, 23) | -4.8 ± 8.9 | -2.8 ± 11.4 |
| Month 12 (N= 17, 23) | -9.2 ± 12.6 | -1.1 ± 12.6 |
| Month 16 (N= 18, 23) | -5.6 ± 11.4 | -2.3 ± 10.7 |
| Month 20 (N= 18, 21) | -7.4 ± 9.8 | -5.6 ± 12.1 |
| Month 24 (N= 18, 21) | -3.1 ± 11.6 | -0.1 ± 12.4 |
| Month 28 (N= 18, 21) | -5.3 ± 10.6 | -2.2 ± 8.8 |
| Month 32 (N= 18, 21) | -4.6 ± 11.2 | -3.0 ± 10.9 |
| Month 36 (N= 18, 21) | -5.4 ± 10.0 | -4.0 ± 13.2 |
The participants were seated and resting systolic and diastolic BP for each scheduled assessment was recorded. At each assessment, participants were categorized (based on repeated blood pressure measurements as being normotensive (MAP \< 100 mm Hg and off therapy), high normal (sBP \> 129 and or dBP \> 84 mm Hg off therapy) or hypertensive (sBP \>140 and/or dBP \> 90 mm Hg). The mean arterial pressure (MAP) was derived from these values and were not recorded (MAP = diastolic pressure + \[1/3 x pulse pressure (ie systolic - diastolic pressure)\] in mm Hg).
| mmHg | Tolvaptan 45+15 mg | Tolvaptan 60+30 mg |
|---|---|---|
| Month 2 (N= 22, 24) | -3.7 ± 10.5 | -1.0 ± 10.5 |
| Month 6 (N= 19, 23) | -3.6 ± 7.4 | -3.3 ± 11.1 |
| Month 9 (N= 18, 23) | -4.7 ± 9.2 | -3.0 ± 10.8 |
| Month 12 (N= 18, 23) | -12.0 ± 18.9 | -1.8 ± 12.1 |
| Month 16 (N= 18, 23) | -5.8 ± 11.0 | -2.5 ± 10.6 |
| Month 20 (N= 18, 21) | -7.6 ± 9.7 | -7.0 ± 12.3 |
| Month 24 (N= 18, 21) | -2.7 ± 13.0 | -0.1 ± 12.0 |
| Month 28 (N= 18, 21) | -5.2 ± 11.2 | -2.7 ± 10.1 |
| Month 32 (N= 18, 21) | -5.6 ± 10.0 | -4.3 ± 11.2 |
| Month 36 (N= 18, 21) | -3.8 ± 9.6 | -4.4 ± 13.8 |
The participants were seated and resting systolic and diastolic BP for each scheduled assessment was recorded. At each assessment, participants were categorized (based on repeated blood pressure measurements as being normotensive (MAP \< 100 mm Hg and off therapy), high normal (sBP \> 129 and or dBP \> 84 mm Hg off therapy) or hypertensive (sBP \>140 and/or dBP \> 90 mm Hg). The mean arterial pressure (MAP) was derived from these values and were not recorded (MAP = diastolic pressure + \[1/3 x pulse pressure (ie systolic - diastolic pressure)\] in mm Hg).
| mmHg | Tolvaptan 45+15 mg | Tolvaptan 60+30 mg |
|---|---|---|
| Month 2 (N= 17, 18) | -1.6 ± 13.0 | -2.7 ± 15.0 |
| Month 6 (N= 17, 18) | -3.4 ± 11.4 | -5.6 ± 13.7 |
| Month 9 (N= 16, 18) | -4.1 ± 13.2 | -4.3 ± 13.7 |
| Month 12 (N= 17, 18) | -8.9 ± 14.5 | -3.3 ± 15.5 |
| Month 16 (N= 17, 18) | -6.5 ± 14.5 | -1.7 ± 13.9 |
| Month 20 (N= 17, 18) | -7.7 ± 11.7 | -9.3 ± 17.1 |
| Month 24 (N= 17, 18) | -1.8 ± 18.9 | 1.4 ± 15.2 |
| Month 28 (N= 17, 18) | -4.9 ± 14.6 | -3.4 ± 17.7 |
| Month 32 (N= 17, 18) | -7.6 ± 11.1 | -6.8 ± 16.0 |
| Month 36 (N= 17, 18) | -0.6 ± 13.5 | -5.4 ± 18.8 |
| Extension Day 1 (N= 17, 18) | -4.4 ± 11.8 | -5.1 ± 14.9 |
| Extension Month 4 (N= 17, 18) | -1.1 ± 16.1 | -8.7 ± 11.8 |
| Extension Month 8 (N= 17, 18) | 1.8 ± 13.1 | -7.3 ± 14.8 |
| Extension Month 12 (N= 17, 18) | -0.5 ± 13.5 | -7.1 ± 12.2 |
The participants were seated and resting systolic and diastolic BP for each scheduled assessment was recorded. At each assessment, participants were categorized (based on repeated blood pressure measurements as being normotensive (MAP \< 100 mm Hg and off therapy), high normal (sBP \> 129 and or dBP \> 84 mm Hg off therapy) or hypertensive (sBP \>140 and/or dBP \> 90 mm Hg). The mean arterial pressure (MAP) was derived from these values and were not recorded (MAP = diastolic pressure + \[1/3 x pulse pressure (ie systolic - diastolic pressure)\] in mm Hg).
| mmHg | Tolvaptan 45+15 mg | Tolvaptan 60+30 mg |
|---|---|---|
| Month 2 (N= 17, 18) | -5.5 ± 12.4 | 0.3 ± 9.7 |
| Month 6 (N= 17, 18) | -4.5 ± 8.2 | -2.4 ± 12.6 |
| Month 9 (N= 16, 18) | -5.3 ± 9.4 | -2.9 ± 11.8 |
| Month 12 (N= 16, 18) | -10.1 ± 12.4 | -1.9 ± 13.0 |
| Month 16 (N= 17, 18) | -6.9 ± 10.1 | -2.1 ± 12.0 |
| Month 20 (N= 17, 18) | -7.5 ± 10.0 | -6.1 ± 12.1 |
| Month 24 (N= 17, 18) | -3.9 ± 11.4 | -0.6 ± 12.7 |
| Month 28 (N= 17, 18) | -5.6 ± 10.8 | -2.9 ± 8.4 |
| Month 32 (N= 17, 18) | -5.4 ± 11.0 | -3.6 ± 11.4 |
| Month 36 (N= 17, 18) | -5.7 ± 10.2 | -4.8 ± 14.0 |
| Extension Day 1 (N= 17, 18) | -7.9 ± 7.3 | -4.0 ± 10.8 |
| Extension Month 4 (N= 17, 18) | -6.8 ± 10.6 | -6.1 ± 10.8 |
| Extension Month 8 (N= 17, 18) | -5.0 ± 7.9 | -6.7 ± 12.7 |
| Extension Month 12 (N= 17, 18) | -6.0 ± 8.9 | -5.6 ± 11.7 |
The participants were seated and resting systolic and diastolic BP for each scheduled assessment was recorded. At each assessment, participants were categorized (based on repeated blood pressure measurements as being normotensive (MAP \< 100 mm Hg and off therapy), high normal (sBP \> 129 and or dBP \> 84 mm Hg off therapy) or hypertensive (sBP \>140 and/or dBP \> 90 mm Hg). The mean arterial pressure (MAP) was derived from these values and were not recorded (MAP = diastolic pressure + \[1/3 x pulse pressure (ie systolic - diastolic pressure)\] in mm Hg).
| mmHg | Tolvaptan 45+15 mg | Tolvaptan 60+30 mg |
|---|---|---|
| Month 2 (N= 17, 18) | -4.1 ± 11.6 | -0.6 ± 10.0 |
| Month 6 (N= 17, 18) | -4.2 ± 7.7 | -3.4 ± 12.5 |
| Month 9 (N= 16, 18) | -4.8 ± 9.8 | -3.4 ± 11.5 |
| Month 12 (N= 17, 18) | -13.1 ± 18.9 | -2.3 ± 12.9 |
| Month 16 (N= 17, 18) | -6.8 ± 10.4 | -1.9 ± 11.8 |
| Month 20 (N= 17, 18) | -7.5 ± 10.0 | -7.2 ± 12.8 |
| Month 24 (N= 17, 18) | -3.1 ± 13.2 | 0.1 ± 12.6 |
| Month 28 (N= 17, 18) | -5.5 ± 11.4 | -2.9 ± 10.2 |
| Month 32 (N= 17, 18) | -6.2 ± 10.0 | -4.6 ± 12.0 |
| Month 36 (N= 17, 18) | -4.1 ± 9.8 | -5.1 ± 14.8 |
| Extension Day 1 (N= 17, 18) | -6.8 ± 7.8 | -4.4 ± 11.0 |
| Extension Month 4 (N= 17, 18) | -5.1 ± 10.7 | -6.9 ± 10.1 |
| Extension Month 8 (N= 17, 18) | -2.8 ± 8.6 | -6.8 ± 12.1 |
| Extension Month 12 (N= 17, 18) | -4.2 ± 9.3 | -6.0 ± 10.9 |
Participants were asked the question to assess the relative level of pain attributed to their kidneys. This question was, "On a scale of 0 to 10, with zero represented no pain at all and 10 represented the worst pain ever experienced, what was the worst kidney pain experienced in the last 4 months?" If the latest assessment was less than 4 months prior, the question was substituted "since your last visit" for "in the last 4 months". The same interrogator designated to this task was used throughout the study for each participant.
| Units on a scale | Tolvaptan 45+15 mg | Tolvaptan 60+30 mg |
|---|---|---|
| Month 2 (N= 22, 24) | 0.6 ± 3.1 | 0.0 ± 1.6 |
| Month 6 (N= 19, 23) | 0.4 ± 2.8 | -0.1 ± 1.7 |
| Month 12 (N= 18, 23) | 1.2 ± 3.3 | -0.1 ± 2.1 |
| Month 24 (N= 18, 21) | 0.2 ± 1.6 | 1.0 ± 3.3 |
| Month 36 (N= 18, 21) | 0.6 ± 2.3 | 0.5 ± 2.2 |
Participants were asked the question to assess the relative level of pain attributed to their kidneys. This question was, "On a scale of 0 to 10, with zero represented no pain at all and 10 represented the worst pain ever experienced, what was the worst kidney pain experienced in the last 4 months?" If the latest assessment was less than 4 months prior, the question was substituted "since your last visit" for "in the last 4 months". The same interrogator designated to this task was used throughout the study for each participant.
| Units on a scale | Tolvaptan 45+15 mg | Tolvaptan 60+30 mg |
|---|---|---|
| Month 2 (N= 17, 18) | 0.9 ± 2.7 | 0.3 ± 1.3 |
| Month 6 (N=17, 18) | 0.8 ± 2.5 | -0.2 ± 1.9 |
| Month 12 (N= 17, 18) | 1.2 ± 3.4 | -0.3 ± 2.0 |
| Month 24 (N= 17, 18) | 0.2 ± 1.6 | 0.8 ± 3.3 |
| Month 36 (N= 17, 18) | 0.6 ± 2.3 | 0.5 ± 2.4 |
| Extension Day 1 (N= 17, 18) | -0.3 ± 0.6 | 0.8 ± 2.1 |
| Extension Month 12 (N= 17, 18) | -0.4 ± 1.3 | -0.6 ± 2.2 |
The participant had a measurement of their abdominal girth recorded. The measurement will be taken with a tape measure extending around the abdomen at the level of the iliac crests laterally and the umbilicus anteriorly. The examiner should also palpate for each kidney and liver edge, noting presence or enlargement. (By definition if the kidneys are palpable they are enlarged, the liver edge may be palpable but not enlarged).
| cm | Tolvaptan 45+15 mg | Tolvaptan 60+30 mg |
|---|---|---|
| Month 2 (N= 22, 24) | 0.6 ± 5.0 | -2.3 ± 6.1 |
| Month 6 (N= 18, 23) | 1.4 ± 6.5 | 0.5 ± 4.6 |
| Month 12 (N= 18, 23) | 1.3 ± 4.7 | -2.8 ± 11.5 |
| Month 24 (N= 17, 21) | 2.0 ± 7.4 | -0.6 ± 6.7 |
| Month 36 (N= 18, 21) | 3.1 ± 7.2 | 0.3 ± 7.3 |
The participant had a measurement of their abdominal girth recorded. The measurement will be taken with a tape measure extending around the abdomen at the level of the iliac crests laterally and the umbilicus anteriorly. The examiner should also palpate for each kidney and liver edge, noting presence or enlargement. (By definition if the kidneys are palpable they are enlarged, the liver edge may be palpable but not enlarged).
| cm | Tolvaptan 45+15 mg | Tolvaptan 60+30 mg |
|---|---|---|
| Month 2 (N= 17, 18) | -0.8 ± 3.9 | -2.8 ± 7.0 |
| Month 6 (N= 16, 18) | 0.3 ± 5.6 | 0.3 ± 5.1 |
| Month 12 (N= 17, 18) | 1.1 ± 4.8 | -3.5 ± 12.9 |
| Month 24 (N= 17, 21) | 2.0 ± 7.4 | -1.1 ± 7.1 |
| Month 36 (N= 17, 18) | 2.5 ± 6.9 | 0.1 ± 7.7 |
| Extension Day 1 (N= 17, 18) | 4.2 ± 7.2 | 2.9 ± 7.9 |
| Extension Month 12 (N= 17, 18) | 4.6 ± 9.5 | 1.6 ± 6.1 |
Collected over AEs were recorded from screening (ICF was signed) until 7-days of safety follow-up. Participants with AEs in multiple system organ classes were counted only once towards the total.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Tolvaptan 45+15 mg | — | 3/22 (13.6%) | 20/22 (90.9%) |
| Tolvaptan 60+30 mg | — | 8/24 (33.3%) | 23/24 (95.8%) |
| Event | Tolvaptan 45+15 mg | Tolvaptan 60+30 mg |
|---|---|---|
| Atrial fibrillationCardiac disorders | 0/22 | 2/24 |
| CholelithiasisHepatobiliary disorders | 1/22 | 0/24 |
| Pituitary tumor benignNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 1/22 | 0/24 |
| Renal painRenal and urinary disorders | 1/22 | 1/24 |
| TachycardiaCardiac disorders | 0/22 | 1/24 |
| Polycystic liver diseaseCongenital, familial and genetic disorders | 0/22 | 1/24 |
| Abdominal painGastrointestinal disorders | 0/22 | 1/24 |
| Epiploic appendagitisGastrointestinal disorders | 0/22 | 1/24 |
| Chest painGeneral disorders | 0/22 | 1/24 |
| PyelonephritisInfections and infestations | 0/22 | 1/24 |
| Event | Tolvaptan 45+15 mg | Tolvaptan 60+30 mg |
|---|---|---|
| Renal painRenal and urinary disorders | 9/22 | 9/24 |
| DizzinessNervous system disorders | 6/22 | 3/24 |
| PolyuriaRenal and urinary disorders | 6/22 | 2/24 |
| Upper respiratory tract infectionInfections and infestations | 1/22 | 6/24 |
| Urinary tract infectionInfections and infestations | 1/22 | 6/24 |
| NocturiaRenal and urinary disorders | 5/22 | 2/24 |
| Abdominal painGastrointestinal disorders | 2/22 | 5/24 |
| FatigueGeneral disorders | 4/22 | 5/24 |
| ThirstGeneral disorders | 1/22 | 5/24 |
| Back painMusculoskeletal and connective tissue disorders | 4/22 | 3/24 |
| Age, Continuous(Years) | Tolvaptan 45+15 mg | Tolvaptan 60+30 mg | Total |
|---|---|---|---|
| Mean | 39.3 ± 8.4 | 43.9 ± 7.8 | 41.7 ± 8.3 |
| Sex: Female, Male(Participants) | Tolvaptan 45+15 mg | Tolvaptan 60+30 mg | Total |
|---|---|---|---|
| Female | 16 | 18 | 34 |
| Male | 6 | 6 | 12 |
This study is completed, as verified in May 2017. You cannot join it, but the record below documents what was studied.
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