Tolvaptan Open-label Pilot Efficacy, Tolerability, and Safety Study in Autosomal Dominant Polycystic Kidney Disease (ADPKD) (TEMPO 2:4)

Tolvaptan Open-label Pilot Efficacy, Tolerability, and Safety Study in Autosomal Dominant Polycystic Kidney Disease (ADPKD)

A Phase 2, Multi-center, Open-label Study to Determine Long-term Safety, Tolerability and Efficacy of Split-dose Oral Regimens of Tolvaptan Tablets in a Range of 30 to 120 mg/d in Patients With Autosomal Dominant Polycystic Kidney Disease

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.

Participants received tolvaptan 45 mg orally in the morning and 15 mg orally 8 hours later for up to 4 years.

Participants received tolvaptan 60 mg orally in the morning and 30 mg orally 8 hours later for up to 4 years.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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).

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).

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).

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).

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

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).

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

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).

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

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.

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.

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).

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).

Inclusion Criteria: Prior participation in designated tolvaptan ADPKD studies (156-04-248, 156-04-249). Able to give Informed Consent. Exclusion Criteria: Women who are breast feeding and females of childbearing potential who are not using acceptable contraceptive methods. In the opinion of the study investigator or sponsor may present a safety risk. Patients who are unlikely to adequately comply with study procedures. Patients who at Day 1 have an estimated glomerular filtration rate (GFR) below 30 mL/min or who anticipate renal-replacement therapy within one year of study entry. Patients having contraindications to magnetic resonance imaging (MRI) or gadolinium contrast will be eligible but will not be able to participate in MRI. Patients taking a diuretic within 1 week of enrollment or likely to need diuretic therapy prior to Month 2.

Gattone VH 2nd, Wang X, Harris PC, Torres VE. Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist. Nat Med. 2003 Oct;9(10):1323-6. doi: 10.1038/nm935. Epub 2003 Sep 21.

Torres VE, Wang X, Qian Q, Somlo S, Harris PC, Gattone VH 2nd. Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease. Nat Med. 2004 Apr;10(4):363-4. doi: 10.1038/nm1004. Epub 2004 Feb 29.

Higashihara E, Torres VE, Chapman AB, Grantham JJ, Bae K, Watnick TJ, Horie S, Nutahara K, Ouyang J, Krasa HB, Czerwiec FS; TEMPOFormula and 156-05-002 Study Investigators. Tolvaptan in autosomal dominant polycystic kidney disease: three years' experience. Clin J Am Soc Nephrol. 2011 Oct;6(10):2499-507. doi: 10.2215/CJN.03530411. Epub 2011 Sep 8.