E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Nocturia associated with nocturnal polyuria |
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E.1.1.1 | Medical condition in easily understood language |
Production of excessive volume and frequency of urine at night |
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E.1.1.2 | Therapeutic area | Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064016 |
E.1.2 | Term | Nocturnal polyuria |
E.1.2 | System Organ Class | 100000004857 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine the change in the number of nocturnal voids from baseline to the highest dose before hyponatremia occurs or the last dosing period
To determine the change in the duration of the first sleep period from baseline to the last highest dose before hyponatremia occurs or the last dosing period
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E.2.2 | Secondary objectives of the trial |
To determine the treatment responder rate, defined as the proportion of patients with at least 33% reduction from baseline in the number of nocturnal voids
To determine the change in nocturnal urine volume from baseline to the highest dose before hyponatremia occurs or the last dosing period
To determine the therapeutic ratio, defined as the ratio of the safe, highest effective dose not causing hyponatremia and the lowest dose meeting efficacy criteria
To investigate the safety and tolerability of ASP7035 in patients with nocturia associated with nocturnal polyuria
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. An institutional review board (IRB)/independent ethics committee (IEC)-approved written informed consent form including privacy language per national regulations must be obtained from the patient before any study related procedures (including withdrawal of prohibited medication, if applicable).
2. Patient is 60 to 85 years of age.
3. Patient has a mean ≥ 2.5 nocturnal voids at the end of the 2-week placebo run-in.
4. Patient has a mean ≥ 2.5 nocturnal voids for at least six months by history
5. 24-hour urine: urine output of < 3000mL/24 hr for patients weighing ≤79 kg and up to 3500 mL/24 hr for patients weighing > 79 kg.
6. Serum sodium concentration is > 135 mmol/L.
7. Serum triglycerides are < 400 mg/dL.
8. Female patients must be post-menopausal (one year or greater without menses), surgically incapable of childbearing (surgical removal of uterus and/or ovaries), or agreeable to practicing abstinence or two effective methods of birth control during the study period. Acceptable methods may include:
• Intrauterine device
• Spermicide
• Barrier contraception
• Hormonal contraception
9. If male, with female partners of child-bearing potential, the patient agrees to sexual abstinence or to use two highly effective methods of birth control (see criterion #8) during the study period and for 90 days after the last dose. Patient must not donate sperm during the study period and for 90 days after the last dose.
10. Patient is willing and able to sign informed consent and comply with the study requirements.
11. At least 33% of the patient’s total urine volume should be produced at night (patients who work during the night will not be eligible for the study).
12. Nocturia index is > 1.0 defined as:
nocturnal urine volume
functional bladder capacity (largest single volume voided)
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E.4 | Principal exclusion criteria |
1. Incontinence resulting in nocturnal enuresis (occasional stress or urge incontinence during the daytime is not exclusionary) or severe stress incontinence
2. Diabetes insipidus (central or nephrogenic
3. Uncontrolled diabetes mellitus (any Type I or II)
• Fasting blood glucose > 140 mg/dL
• Admitted to a hospital for treatment of diabetes or diabetes-related illness in the past 12 weeks
• Not under a physician care for diabetes mellitus
• Has not been on stable doses of oral hypoglycemic drug(s) and/or long acting insulin for 4 weeks prior to screening and < 8 weeks for oral thiazolidinedione (glitazones)
4. Congestive heart failure (New York Heart Association [NYHA] Class II, III, or IV
5. Polydipsia (> 3000 mL/24 hr for patients ≤ 79 kg and > 3500 mL/24 hr for patients > 79 kg) or thirst disorders
6. Uncontrolled hypertension (systolic > 165 mmHg, diastolic > 100 mm Hg), unstable angina or other unstable clinical finding or condition that, in the opinion of the investigator, would be negatively affected by the study medication or that would potentially affect the study outcomes.
7. Urinary retention (post void residual of > 100 mL assessed by ultrasound or catherization); assessed during the screening period
8. Evidence of hepatic insufficiency or inflammation (i.e., > 2 x upper limit of normal [ULN] for total bilirubin, unless the patient has a history of Gilbert’s syndrome or ≥ 2 x ULN for alanine transaminase [ALT] and aspartate aminotransferase [AST])
9. Evidence of renal insufficiency (glomerular filtration rate [GFR] < 50 mL/min/1.73m2) by Modification of Diet in Renal Disease (MDRD) calculation method
10. History of syndrome of inappropriate antidiuretic hormone (SIADH)
11. Nephrotic syndrome
12. History of urinary bladder or prostate surgery or pelvic radiation
13. Daytime urinary frequency of ≥ 12 voids/day; assessed during the placebo run-in phase
14. Use of steroids (except topical steroids) during the study
15. Females with pelvic prolapse greater than Stage II
16. Current or past malignancy (except cured basal or squamous carcinoma)
17. Patient has previously participated in a study with ASP7035, or trials for nocturia, BPH and OAB
18. Clinical evidence of urinary tract infection (UTI), microscopic or gross hematuria that has not been evaluated, bladder stone, bladder pain syndrome (BPS) or interstitial cystitis
19. Urinary bladder dysfunction of neurologic etiology that in the judgment of the investigator would interfere with study assessments
20. Multiple sclerosis, Parkinson’s disease or neurogenic detrusor over activity
21. Obstructive sleep apnea
22. Hyperkinetic limb disorders (e.g., restless leg syndrome) or other syndromes that disrupt sleep
23. Work or lifestyle that interferes with night time sleep (e.g., late night shift work)
24. Known alcohol or substance abuse within the last 24 months
25. Previous use of desmopressin
26. Receipt of blood products or donation of blood products within 30 days of screening
27. Positive for hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV Ab) or human immunodeficiency virus (HIV) by medical history
28. Patient with a prostate-specific antigen (PSA) of > 4.0 must have had a negative prostate biopsy within the last 6 months
29. Treatment with any investigational drug within 30 days or within five elimination half lives prior to screening, whichever is greater
30. Taking loop diuretics within 6 months of screening or planned used during treatment
31. An acute illness or medical condition that has resulted in a fluid/electrolyte imbalance within 60 days of screening
32. Any cardiopulmonary, renal or hepatic medical condition that in the judgment of the investigator would interfere with the assessments of the study
33. Concomitant use of strong/moderate CYP3A4/5 and/or P-gp inhibitors including food-based CYP3A4/5 inhibitors (i.e., grapefruit, grapefruit juice, and Seville oranges) during screening or during this study
34. Use of pharmaceutical sleep aids, other than those started 6 months prior to screening and maintained daily at a stable dosage (i.e., occasional use of sleep aids or changes in dose of chronic sleep aids are not permitted)
35. Refusal to drink only for thirst from 1 hour before bed time until waking up in the morning
36. Other medical conditions which in the judgment of the investigator would make participation in the study unacceptable
37. Known allergy or hypersensitivity to ASP7035 and/or any of its excipients
38. Patient is unable to report complete and accurate information in the diaries per the investigator’s assessment
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E.5 End points |
E.5.1 | Primary end point(s) |
The change in mean number of nocturnal voids from baseline to the last hyponatremia free dose
The change in average number of hours of first sleep duration (time to bed with intent to sleep to time of first waking for the purpose of voiding) from baseline to the last hyponatremia-free dose |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The timepoint for evaluation is from baseline to last hyponatremia-free dose. This duration is anywhere from 2 weeks (baseline) to 12 weeks (6 dose levels/2 weeks per level) |
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E.5.2 | Secondary end point(s) |
Descriptive analyses of the proportion of patients who had at least 33% reduction from baseline overall and at each escalation dose
The average urine volume and the change from baseline
The therapeutic ratio (ratio of the safe, highest effective dose not causing hyponatremia and the lowest dose meeting efficacy criteria) will be calculated for each patient and summarized
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The timepoint for evaluation is from baseline to last hyponatremia-free dose. This duration is anywhere from 2 weeks (baseline) to 12 weeks (6 dose levels/2 weeks per level) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 15 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 14 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 14 |