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 | 17.0 |
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 55 to 85 years of age. 3. Patient has a mean ≥ 2.5 nocturnal voids for at least six months by history 4. Serum sodium concentration is ≥ 135 mmol/L. 5. Serum triglycerides are < 400 mg/dL. 6. Female patients must be post-menopausal (two years 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 7. 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 #6) 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. 8. Patient is willing and able to sign informed consent and comply with the study requirements.
Randomization Criteria Patients must meet the following criteria at the end of the run-in period using data from the run-in diary and other measures in order to be randomized: 1.Compliance with diary on the last 7 days of the run-in period 2.Patient has a mean ≥ 2.5 nocturnal voids during the 2 week run-in period 3.24 hour urine: urine output of < 3000 mL/24 hr for patients weighing ≤ 79 kg and up to 3500 mL/24 hr for patients weighing > 79 kg (defined as any instance in a 24 hour period) 4.Mean of ≥ 33% of the patient's total urine volume produced at night (all urine produced after going to bed with the intent to sleep up to and including the first morning void) during the run-in period 5.Serum sodium concentration at the randomization visit, assessed at the local laboratory, must be ≥ 135 mmol/L 6.Absence of polydipsia (defined as 1 or more instances of fluid consumption >3000 mL/24 hour for patients ≤ 79kg and > 3500 mL/24 hour for patients > 79 k or thirst disorders as assessed by diary during the run-in period 7.Nocturia index is > 1.0 defined as: nocturnal urine volume / maximum single voided volume during a 24 hour period 8.Daytime urinary frequency of <12 voids/day during the run-in period 9.Reduction of <33% in frequency of nocturia and/or nocturnal urine volume during the run-in phase. Change in nocturia frequency and nocturnal urine volume is defined as a % change in the mean of the last three days of the run-in period compared to the mean of the first three days of the run-in period. 10.Study drug compliance at the end of run-in period: •Patients missed ≤3 doses during the run-in period AND •Patients took all of the last 4 consecutive doses in the run-in period 11.In Investigator's assessment, based on all run-in diary data, the patient DOES NOT have incontinence resulting in nocturnal enuresis (occasional stress or urge incontinence is not exclusionary) or severe stress incontinence
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E.4 | Principal exclusion criteria |
1.Incontinence resulting in nocturnal enuresis or severe stress incontinence 2.Diabetes insipidus 3.Uncontrolled diabetes mellitus 4.Congestive heart failure 5.Polydipsia or thirst disorders in medical history at screening 6.Uncontrolled hypertension , 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 assessed during the screening period 8.Evidence of hepatic insufficiency or inflammation 9.Evidence of renal insufficiency 10.History of syndrome of inappropriate antidiuretic hormone 11.Nephrotic syndrome 12.History of urinary bladder or prostate surgery or pelvic radiation 13.Daytime urinary frequency of ≥ 12 voids/day by history at screening 14.Current use of systemic glucocorticosteroids (except topical steroids) or planned at any time 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 one nocturia, BPH or OAB clinical study within the last 9 months or participated in more than one of these trials at any time will be excluded. 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.Planned used of desmopressin at any time during the study or use of desmopressin within the last 9 months in the setting of a clinical trial or in more than one clinical trial. 26. Previous use of desmopressin as prescribed by a physician not in the context of a clinical trial. 27. Receipt of blood products or donation of blood products within 30 days of screening or planned at any time during the study 28.Positive for hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV Ab) or human immunodeficiency virus (HIV) by medical history. For subjects who do not have a current sample (within 3 months of screening visit test) submission of sample to central lab is acceptable. 29.Patient with a prostate-specific antigen (PSA) of > 8.0 must have had a negative prostate biopsy within the last 6 months. For patients with a PSA between 4 and 8 the need for a negative prostate biopsy will be discussed on a case by case basis between the Investigator and the Sponsor. For inclusion of these patients without biopsy, both the Investigator and the Sponsor need to agree that based on other information available (e.g. time course of PSA elevations in the past) the likelihood of prostate cancer is low and that a biopsy would not be part of standard of care outside of the setting of this clinical trial. For patients who did not have PSA assessed in the past, for whom it is not possible to verify this criterion, PSA may be assessed locally during the screening period. 30.Treatment with any investigational drug within 30 days or within five elimination half lives prior to screening, whichever is greater (excluding additional criteria provided under exclusion #17 and #25) 31.Taking loop diuretics within 6 months of screening or planned used during treatment 32.An acute illness or medical condition that has resulted in a fluid/electrolyte imbalance within 60 days of screening 33.Any cardiopulmonary, renal or hepatic medical condition that in the judgment of the investigator would interfere with the assessments of the study 34.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 35.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) 36.Refusal to drink only for thirst from 1 hour before bed time until waking up in the morning 37.Other medical conditions which in the judgment of the investigator would make participation in the study unacceptable 38.Known allergy or hypersensitivity to ASP7035 and/or any of its excipients 39.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 | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
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 |