Polycystic Kidney, Autosomal Dominant
Conditions
Keywords
ADPKD
Brief summary
The purpose of the trial was to evaluate and describe the long term safety of tolvaptan in participants with autosomal dominant polycystic kidney disease (ADPKD).
Detailed description
This was a Phase 3b trial to evaluate and describe the long term safety of tolvaptan treatment in ADPKD participants with chronic kidney disease (CKD). Eligible participants could enroll into Trial 156-13-211 after completing the follow-up visit(s) of their previous trial (156-13-210, 156-08-271, 156-04-251, or 156-09-290). Renal function was assessed during screening by using historical laboratory values for serum creatinine levels to calculate the estimated glomerular filtration rate (eGFR).
Interventions
DRUGTolvaptan
Tolvaptan tablets (15 or 30 mg) self-administered orally as split-dose regimens, once upon awakening and another approximately 8 to 9 hours later
Sponsors
Otsuka Pharmaceutical Development & Commercialization, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male and female participants ≥ 18 years with confirmed diagnosis of ADPKD (during participation in prior tolvaptan trials) who have completed and transferred from the double-blind Trial 156-13-210 (12-month period including post treatment follow-up, regardless of whether this was on-treatment or off-treatment), or completed Trial 156-08-271 or a prior tolvaptan trial, or interrupted or discontinued treatment in a prior tolvaptan ADPKD trial other than Trial 156-13-210. Participants may be enrolled with the medical monitor approval, and additional close monitoring may be required at the beginning of the trial. * eGFR ≥ 20 milliliter (mL)/minute (min)/1.73 meter squared (m\^2) within 3 months prior to the baseline visit. Participants who have an eGFR ≤ 20 mL/min/1.73 m\^2 may be enrolled with medical monitor approval.
Exclusion criteria
* Need for chronic diuretic use * Hepatic impairment based on liver function abnormalities other than that expected for ADPKD with cystic liver disease * Women of childbearing potential who do not agree to practice 2 different methods of birth control or remain abstinent during the trial and for 30 days after the last dose of investigational medicinal product (IMP) * Women who are breast-feeding and/or who have a positive pregnancy test result prior to receiving IMP. * Participants with contraindications to required trial assessments (contraindications to optional assessments, for example, magnetic resonance imaging \[MRI\] are not a limitation). * Participants who in the opinion of the investigator or the medical monitor, have a medical history or medical finding inconsistent with safety or trial compliance
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number Of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) | Baseline through end of treatment (up to 42 months) and follow-up 7 days posttreatment(+ 7 days) | An adverse event (AE) was as any untoward medical occurrence associated with the use of an investigational medicinal product (IMP), whether or not considered IMP related. A TEAE was an AE that started after trial drug treatment; or if the event was continuous from baseline and was serious, related to IMP, or resulted in death, discontinuation, interruption or reduction of trial therapy. A serious TEAE included any event that resulted in: death, life-threatening, persistent or significant incapacity, substantial disruption of ability to conduct normal life functions, required inpatient hospitalization, prolonged hospitalization, congenital anomaly/birth defect, or other medically significant events as per medical judgment, that jeopardized the participant and that required medical or surgical intervention. A severe TEAE was an inability to work or perform normal daily activity. A summary of serious and all other non-serious TEAEs, regardless of causality, is located in the AE section. |
Countries
Argentina, Australia, Belgium, Canada, Czechia, Denmark, Germany, Hungary, Israel, Italy, Netherlands, Norway, Poland, Romania, Russia, South Africa, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
Eligible participants could enroll into Trial 156-13-211 after completing follow-up visit(s) of their previous trial (156-13-210, 156-08-271, 156-04-251, or 156-09-290).
Pre-assignment details
One participant screened, but withdrew consent on the same day (prior to study drug treatment) and is not included in the study data. Starting doses depended on the participant's previous trial.
Participants by arm
| Arm | Count |
|---|---|
| Tolvaptan (From 156-13-210: Tolvaptan) Participants were previously treated with tolvaptan in Trial 156-13-210. Participants initiated on tolvaptan at a split-dose of 45/15 milligrams (mg) with upward titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to tolerability. | 506 |
| Tolvaptan (From 156-13-210: Placebo) Participants were previously treated with placebo in Trial 156-13-210. Participants initiated on tolvaptan at a split-dose of 45/15 mg with upward titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to tolerability. | 570 |
| Tolvaptan (From 156-08-271: Tolvaptan) Participants were previously treated with tolvaptan in Trial 156-08-271. Participants retained the last dose level of tolvaptan received in the trial (45/15 mg, 60/30 mg, or 90/30 mg) and started at that same dose in Trial 156-13-211. | 718 |
| Tolvaptan (From Other: Tolvaptan) Participants were previously treated with tolvaptan in Other Trials (156-04-251 and 156-09-290). Participants initiated on tolvaptan at a split-dose of 45/15 mg with upward titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to tolerability. | 6 |
| Tolvaptan (From Other: Placebo) Participants were previously treated with placebo in Other Trials (156-04-251 and 156-09-290). Participants initiated on tolvaptan at a split-dose of 45/15 mg with upward titration every 3 to 4 days to 60/30 mg or 90/30 mg per day according to tolerability. | 3 |
| Total | 1,803 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 23 | 60 | 28 | 0 | 0 |
| Overall Study | Lost to Follow-up | 5 | 6 | 4 | 0 | 0 |
| Overall Study | Physician Decision | 19 | 30 | 26 | 0 | 1 |
| Overall Study | Protocol Deviation | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 25 | 51 | 35 | 1 | 0 |
Baseline characteristics
| Characteristic | Tolvaptan (From 156-13-210: Tolvaptan) | Tolvaptan (From 156-13-210: Placebo) | Tolvaptan (From 156-08-271: Tolvaptan) | Tolvaptan (From Other: Tolvaptan) | Tolvaptan (From Other: Placebo) | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 48.9 Years STANDARD_DEVIATION 8.1 | 48.6 Years STANDARD_DEVIATION 8 | 45.5 Years STANDARD_DEVIATION 7.8 | 41.2 Years STANDARD_DEVIATION 11.4 | 47.0 Years STANDARD_DEVIATION 2.6 | 47.4 Years STANDARD_DEVIATION 8.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 27 Participants | 25 Participants | 49 Participants | 1 Participants | 0 Participants | 102 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 479 Participants | 545 Participants | 669 Participants | 5 Participants | 3 Participants | 1701 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 16 Participants | 16 Participants | 10 Participants | 0 Participants | 0 Participants | 42 Participants |
| Race (NIH/OMB) Black or African American | 19 Participants | 23 Participants | 6 Participants | 0 Participants | 0 Participants | 48 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 6 Participants | 6 Participants | 0 Participants | 0 Participants | 18 Participants |
| Race (NIH/OMB) White | 461 Participants | 525 Participants | 694 Participants | 6 Participants | 3 Participants | 1689 Participants |
| Sex: Female, Male Female | 234 Participants | 290 Participants | 343 Participants | 5 Participants | 2 Participants | 874 Participants |
| Sex: Female, Male Male | 272 Participants | 280 Participants | 375 Participants | 1 Participants | 1 Participants | 929 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 505 | 5 / 569 | 3 / 717 | 0 / 6 | 0 / 3 |
| other Total, other adverse events | 469 / 505 | 525 / 569 | 633 / 717 | 6 / 6 | 3 / 3 |
| serious Total, serious adverse events | 87 / 505 | 96 / 569 | 103 / 717 | 1 / 6 | 2 / 3 |
Outcome results
Primary
Number Of Participants Reporting Treatment-Emergent Adverse Events (TEAEs)
An adverse event (AE) was as any untoward medical occurrence associated with the use of an investigational medicinal product (IMP), whether or not considered IMP related. A TEAE was an AE that started after trial drug treatment; or if the event was continuous from baseline and was serious, related to IMP, or resulted in death, discontinuation, interruption or reduction of trial therapy. A serious TEAE included any event that resulted in: death, life-threatening, persistent or significant incapacity, substantial disruption of ability to conduct normal life functions, required inpatient hospitalization, prolonged hospitalization, congenital anomaly/birth defect, or other medically significant events as per medical judgment, that jeopardized the participant and that required medical or surgical intervention. A severe TEAE was an inability to work or perform normal daily activity. A summary of serious and all other non-serious TEAEs, regardless of causality, is located in the AE section.
Time frame: Baseline through end of treatment (up to 42 months) and follow-up 7 days posttreatment(+ 7 days)
Population: All participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tolvaptan (From 156-13-210: Tolvaptan) | Number Of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) | Deaths | 1 participants |
| Tolvaptan (From 156-13-210: Tolvaptan) | Number Of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) | Participants with serious TEAEs | 87 participants |
| Tolvaptan (From 156-13-210: Tolvaptan) | Number Of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) | Discontinued due to TEAEs | 33 participants |
| Tolvaptan (From 156-13-210: Tolvaptan) | Number Of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) | Participants with severe TEAEs | 74 participants |
| Tolvaptan (From 156-13-210: Tolvaptan) | Number Of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) | Participants with TEAEs | 473 participants |
| Tolvaptan (From 156-13-210: Placebo) | Number Of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) | Participants with serious TEAEs | 96 participants |
| Tolvaptan (From 156-13-210: Placebo) | Number Of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) | Discontinued due to TEAEs | 65 participants |
| Tolvaptan (From 156-13-210: Placebo) | Number Of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) | Participants with TEAEs | 531 participants |
| Tolvaptan (From 156-13-210: Placebo) | Number Of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) | Deaths | 5 participants |
| Tolvaptan (From 156-13-210: Placebo) | Number Of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) | Participants with severe TEAEs | 78 participants |
| Tolvaptan (From 156-08-271: Tolvaptan) | Number Of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) | Participants with severe TEAEs | 83 participants |
| Tolvaptan (From 156-08-271: Tolvaptan) | Number Of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) | Discontinued due to TEAEs | 38 participants |
| Tolvaptan (From 156-08-271: Tolvaptan) | Number Of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) | Deaths | 3 participants |
| Tolvaptan (From 156-08-271: Tolvaptan) | Number Of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) | Participants with serious TEAEs | 103 participants |
| Tolvaptan (From 156-08-271: Tolvaptan) | Number Of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) | Participants with TEAEs | 640 participants |
| Tolvaptan (From Other: Tolvaptan) | Number Of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) | Deaths | 0 participants |
| Tolvaptan (From Other: Tolvaptan) | Number Of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) | Participants with TEAEs | 6 participants |
| Tolvaptan (From Other: Tolvaptan) | Number Of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) | Participants with serious TEAEs | 1 participants |
| Tolvaptan (From Other: Tolvaptan) | Number Of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) | Participants with severe TEAEs | 2 participants |
| Tolvaptan (From Other: Tolvaptan) | Number Of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) | Discontinued due to TEAEs | 0 participants |
| Tolvaptan (From Other: Placebo) | Number Of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) | Discontinued due to TEAEs | 1 participants |
| Tolvaptan (From Other: Placebo) | Number Of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) | Participants with severe TEAEs | 1 participants |
| Tolvaptan (From Other: Placebo) | Number Of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) | Participants with serious TEAEs | 2 participants |
| Tolvaptan (From Other: Placebo) | Number Of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) | Participants with TEAEs | 3 participants |
| Tolvaptan (From Other: Placebo) | Number Of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) | Deaths | 0 participants |