A Trial to Investigate Efficacy, Safety and Tolerability of FE 201836 for Nocturia Due to Nocturnal Polyuria in Adults

Phase 2CompletedNCT03201419

Ferring Pharmaceuticals302 enrolled

Overview

The purpose of this trial was to investigate the efficacy, safety and tolerability of different oral doses of FE 201836, with desmopressin as a benchmark, during 12 weeks of treatment for nocturia due to nocturnal polyuria in adults

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

302

Conditions

Nocturia

Interventions

FE 201836DRUG

Oral solution for daily intake

DesmopressinDRUG

Desmopressin Orally Disintegrating Tablet (ODT)

Placebo oral solutionDRUG

Manufactured to mimic experimental drug

Placebo ODT

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Adults ≥18 years of age (at the time of written consent) * Medical history of, or subject reported nocturia symptoms during the 6 months prior to Visit 1 * ≥2 nocturnal voids (an average over 3 days) as documented in the 3-day e-Diary prior to Visit 2 * The largest single voided volume must be ≥200 mL (at least 1 void ≥200 mL) as documented in the 3-day e-Diary prior to Visit 2 * Nocturnal polyuria, defined as Nocturnal Polyuria index \>33%, a ratio of Nocturnal Urine Volume in excess of 33% of total daily (24-hour) urine volume as documented in the 3-day e-Diary prior to Visit 2 * ≥20% decrease in the nocturnal diuresis rate (mL/min) (that was recorded at Visit 2) as documented in the 3-day e-Diary prior to Visit 3 Exclusion Criteria: * Current diagnosis of Obstructive Sleep Apnoea (OSA) * Restless Legs Syndrome (RLS) * Bladder Outlet Obstruction (BOO) or urine flow \<5 mL/s, as confirmed by uroflowmetry upon suspicion during screening prior to Visit 2 * Urinary incontinence defined as an average of \>1 episode/day in the 3-day e-Diary prior to Visit 2 (occasional urge incontinence during daytime or at night on the way to void is not necessarily exclusionary) * Any pelvic or lower urinary tract surgery and/or radio therapy or previous pelvic irradiation within the past 6 months prior to Visit 1. Including e.g., transurethral resection for Bladder Outlet Obstruction or Benign Prostatic Hyperplasia, hysterectomy or female incontinence procedures * Genito-urinary tract pathology that can in the investigator's opinion be responsible for urgency or urinary incontinence e.g., symptomatic or recurrent urinary tract infections, interstitial cystitis, bladder-related pain, chronic pelvic pain syndrome, or stone in the bladder or urethra causing symptoms * A history of cancer with the last date of disease activity/presence of malignancy within the last 12 months prior to Visit 1, except for adequately treated basal cell carcinoma of the skin * History of any neurological disease affecting bladder function or muscle strength (e.g., Multiple Sclerosis, Parkinson's, spinal cord injury, spina bifida) * Habitual (fluid intake \>3L per day) or psychogenic polydipsia * Uncontrolled hypertension, as judged by the investigator * Uncontrolled diabetes mellitus, as judged by the investigator * Central or nephrogenic diabetes insipidus * Known history of Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion * History of gastric retention * Suspicion or evidence of congestive heart failure, (New York Heart Association (NYHA) class II, III, IV) * Hyponatraemia: * Serum sodium level \<135 mmol/L at Visit 1(re-tested, with results available within 7 days) * Serum sodium level \<130 mmol/L at Visit 3 (re-tested, with results available within 7 days) * Use of any prohibited therapy listed below: * Current or former (within 3 months prior to screening) treatment with any other investigational medicinal product (IMP) * Unstable electrostimulation or behavioural bladder training program less than 3 months prior to screening (stable electrostimulation or behavioural bladder training program started at least 3 months before screening are acceptable) * Thiazide diuretics * Antiarrhythmic agents * V2-receptor antagonists/agonists (e.g., vaptans/desmopressin, vasopressin) * Loperamide * Botulinum toxin (cosmetic non-urological use is acceptable) * Valproate

Locations (72)

Outcomes

Primary Outcomes

Change From Baseline in Aggregated Mean Number of Nocturnal Voids During 12 Weeks of Treatment

Time frame: Baseline, during 12 weeks of treatment

Secondary Outcomes

Change From Baseline in Mean Number of Nocturnal Voids at Week 1

Nocturnal voids were defined as voids occuring from 5 minutes after bedtime until rising in the morning. The number of nocturnal voids at each visit was calculated as the average over the 3 consecutive 24 hour periods just prior to the respective visit. Adjusted visit-specific mean changes from baseline in nocturnal voids are estimated using a baseline value of 2. MMRM=Mixed Model for Repeated Measurements. For all visit-specific results, the tables present the number of subjects with an observation of the endpoints in question at the specific visit. All secondary analyses are performed using the observed-case approach based on repeated measurements for all subjects in the ITT-RT population. That is, these secondary analyses are based on all subjects with at least one non-missing post-baseline observation (with a baseline value if relevant).

Time frame: Baseline, Week 1

Change From Baseline in Mean Number of Nocturnal Voids at Week 4

Time frame: Baseline, Week 4

Data from ClinicalTrials.gov

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Manufactured to mimic experimental drug

Achieve Clinical Research, LLC

Birmingham, Alabama, United States

Coastal Clinical Research, an AMR company

Mobile, Alabama, United States

Clinical Trials Research

Lincoln, California, United States

Tri Valley Urology Medical Group

Murrieta, California, United States

San Diego Clinical Trials

San Diego, California, United States

Advanced Rx Clinical Research Group, Inc.

Westminster, California, United States

Downtown Women's Health Care

Denver, Colorado, United States

Genitourinary Surgical Consultants, P.C.

Denver, Colorado, United States

South Florida Medical Research

Aventura, Florida, United States

Women's Medical Research Group, LLC

Clearwater, Florida, United States

...and 62 more locations

Change From Baseline in Mean Number of Nocturnal Voids at Week 8

Time frame: Baseline, Week 8

Change From Baseline in Mean Number of Nocturnal Voids at Week 12

Time frame: Baseline, Week 12

Responder Rate in Nocturnal Voids at Week 1

Defined as 50% reduction in nocturnal voids from baseline. Adjusted visit-specific estimated odds of at least 50% in the reduction mean number of nocturnal voids are estimated using a baseline value of 2. The estimated odd equals the probability of response divided by the probability of non-response; these odds may vary between 0 and infinity. For example, if the probability of responding is 80%, the odd of responding is 4, as it is 4 times more likely to respond (80%) then it is not to respond (20%).

Time frame: Week 1

Responder Rate in Nocturnal Voids at Week 4

Defined as 50% reduction in nocturnal voids from baseline. Adjusted visit-specific estimated odds of at least 50% reduction in the mean number of nocturnal voids are estimated using a baseline value of 2. The estimated odd equals the probability of response divided by the probability of non-response; these odds may vary between 0 and infinity. For example, if the probability of responding is 80%, the odd of responding is 4, as it is 4 times more likely to respond (80%) then it is not to respond (20%).

Time frame: Week 4

Responder Rate in Nocturnal Voids at Week 8

Time frame: Week 8

Responder Rate in Nocturnal Voids at Week 12

Time frame: Week 12

Responder Rate in Nocturnal Voids During 12 Weeks of Treatment

Defined as 50% reduction in nocturnal voids from baseline. Estimated odds of at least 50% reduction in the aggregated mean number of nocturnal voids for a subject with 2 nocturnal voids at baseline are presented in this endpoint. The 95% credibility interval (2.5 and 97.5 percentiles of the posterior distribution) instead of confidence interval is presented for this endpoint. The estimated odd equals the probability of response divided by the probability of non-response; these odds may vary between 0 and infinity. For example, if the probability of responding is 80%, the odd of responding is 4, as it is 4 times more likely to respond (80%) then it is not to respond (20%).

Time frame: During 12 weeks of treatment

Change From Baseline in Mean NI Diary Total Score at Week 1

The NI Diary is a 12-item questionnaire with 11 core items (Q1-Q11) and an overall quality of life (QoL) impact question (Q12). The NI Diary Total Scores are calculated by summing the 11 core items.Responses are scored from 0 to 4 (lowest t o highest impact). The NI Diary Total is standardized from 0 to 100 (lowest to highest impact). The score at each visit was calculated as the average over the three consecutive 24 hour periods just prior to the respective visit. Adjusted visit-specific mean changes from baseline in NI Diary Total Score are estimated using a baseline value of 40.

Time frame: Baseline, Week 1

Change From Baseline in Mean NI Diary Total Score at Week 4

The NI Diary is a 12-item questionnaire with 11 core items (Q1-Q11) and an overall QoL impact question (Q12). The NI Diary Total Scores are calculated by summing the 11 core items. Responses are scored from 0 to 4 (lowest to highest impact). The NI Diary Total is standardized from 0 to 100 (lowest to highest impact). The score at each visit was calculated as the average over the three consecutive 24 hour periods just prior to the respective visit. Adjusted visit-specific mean changes from baseline in NI Diary Total Score are estimated using a baseline value of 40.

Time frame: Baseline, Week 4

Change From Baseline in Mean NI Diary Total Score at Week 8

Time frame: Baseline, Week 8

Change From Baseline in Mean NI Diary Total Score at Week 12

Time frame: Baseline, Week 12

Change From Baseline in Aggregated Mean NI Diary Total Score During 12 Weeks of Treatment

The NI Diary is a 12-item questionnaire with 11 core items (Q1-Q11) and an overall QoL impact question (Q12). The NI Diary Total Scores are calculated by summing the 11 core items. Responses are scored from 0 to 4 (lowest to highest impact). The NI Diary Total is standardized from 0 to 100 (lowest to highest impact). The score at each visit was calculated as the mean over the three consecutive 24 hour periods just prior to the respective visit. The visit-specific means were aggregated into a mean of current and preceding visits. Level estimated for baseline value of mean NI Diary Total Score equal to 40 is presented in this endpoint. The 95% credibility interval (2.5 and 97.5 percentiles of the posterior distribution) instead of confidence interval is presented for this endpoint.

Time frame: Baseline, during 12 weeks of treatment

Percentage of Nights With at Most One Nocturnal Void During 12 Weeks of Treatment

The percentages of nights during the treatment period with at most one nocturnal void are presented in this endpoint. Level estimated for baseline value of mean number of nocturnal voids equal to 2 is presented in this endpoint.

Time frame: During 12 weeks of treatment

Percentage of Nights With No Nocturnal Voids During 12 Weeks of Treatment

The percentages of nights during the treatment period with complete response, i.e. no nocturnal voids are presented in this endpoint. Level estimated for baseline value of mean number of nocturnal voids equal to 2 is presented in this endpoint.

Time frame: During 12 weeks of treatment

Change From Baseline in Mean NI Diary Overall Impact Score at Week 1

The NI Diary is a 12-item questionnaire with 11 core items (Q1-Q11) and an overall QoL impact question (Q12). For the overall impact question (Q12), response options range from 0 (not at all) to 4 (a great deal). The NI Diary Overall Impact Scores are standardized from 0 to 100 (lowest to highest impact). The score at each visit was calculated as the average over the three consecutive 24 hour periods just prior to the respective visit. Adjusted visit-specific mean changes from baseline in NI Diary Overall Impact Score are estimated using a baseline value of 40.

Time frame: Baseline, Week 1

Change From Baseline in Mean NI Diary Overall Impact Score at Week 4

Time frame: Baseline, Week 4

Change From Baseline in Mean NI Diary Overall Impact Score at Week 8

Time frame: Baseline, Week 8

Change From Baseline in Mean NI Diary Overall Impact Score at Week 12

Time frame: Baseline, Week 12

Change From Baseline in Aggregated Mean NI Diary Overall Impact Score During 12 Weeks of Treatment

The NI Diary is a 12-item questionnaire with 11 core items (Q1-Q11) and an overall QoL impact question (Q12). For the overall impact question (Q12), response options range from 0 (not at all) to 4 (a great deal). The NI Diary Overall Impact Scores are standardized from 0 to 100 (lowest to highest impact). The score at each visit was calculated as the average over the three consecutive 24 hour periods just prior to the respective visit. The visit-specific means were aggregated into a mean of current and preceding visits. Level estimated for baseline value of mean NI Diary Overall Impact Score equal to 40 is presented in this endpoint. The 95% credibility interval (2.5 and 97.5 percentiles of the posterior distribution) instead of confidence interval is presented for this endpoint.

Time frame: Baseline, during 12 weeks of treatment

Patient Global Impression of Improvement (PGI-I) Urinary Symptoms Scores at Week 1

The PGI-I is a 1-item questionnaire designed to assess the patient's impression of changes in urinary symptoms. The PGI-I was scored from 1 (very much better) to 7 (very much worse). Visit-specific PGI-I in urinary symptoms is presented in this endpoint.

Time frame: Week 1

Patient Global Impression of Improvement (PGI-I) Urinary Symptoms Scores at Week 4

Time frame: Week 4

Patient Global Impression of Improvement (PGI-I) Urinary Symptoms Scores at Week 8

Time frame: Week 8

Patient Global Impression of Improvement (PGI-I) Urinary Symptoms Scores at Week 12

Time frame: Week 12

Change From Baseline in Patient Global Impression of Severity (PGI-S) Scores at Week 1

The PGI-S is a 1-item questionnaire designed to assess patient's impression of disease severity. The PGI-S was scored from 1 (none) to 4 (severe). Change from baseline in visit-specific PGI-S is presented in this endpoint. Level estimated for baseline value of PGI-S equal to 3 is presented in this endpoint.

Time frame: Baseline, Week 1

Change From Baseline in PGI-S Scores at Week 4

Time frame: Baseline, Week 4

Change From Baseline in PGI-S Scores at Week 8

Time frame: Baseline, Week 8

Change From Baseline in PGI-S Scores at Week 12

Time frame: Baseline, Week 12

Change From Baseline in Hsu 5-point Likert Bother Scale at Week 1

The Hsu 5-point Likert Bother scale is a questionnaire designed to assess the subjective bothersomeness and functional disruptiveness of nocturia. The Hsu 5 point Likert Bother Scale was scored from 0 (not at all) to 4 (extremely). Change from baseline in visit-specific Hsu Bother is presented in this endpoint. Level estimated for baseline value of Hsu Bother equal to 3 is presented in this endpoint.

Time frame: Baseline, Week 1

Change From Baseline in Hsu 5-point Likert Bother Scale at Week 4

Time frame: Baseline, Week 4

Change From Baseline in Hsu 5-point Likert Bother Scale at Week 8

Time frame: Baseline, Week 8

Change From Baseline in Hsu 5-point Likert Bother Scale at Week 12

Time frame: Baseline, Week 12

Change From Baseline in ISI at Week 4

The ISI is a 7-item questionnaire which comprises of four 'sleep-related' items and three 'wake-related' items. Each item is rated on a 0-4 scale and the total score ranges from 0 to 28 (higher score suggests more severe insomnia). Change from baseline in visit-specific ISI is presented in this endpoint. Level estimated for baseline value of ISI equal to 15 is presented in this endpoint.

Time frame: Baseline, Week 4

Change From Baseline in ISI at Week 8

Time frame: Baseline, Week 8

Change From Baseline in ISI at Week 12

Time frame: Baseline, Week 12

Change From Baseline in Mean Duration of First Undisturbed Sleep Period (FUSP) at Week 1

The FUSP is defined as the time in minutes from the time of going to bed to the time of first nocturnal void, or time of awakening if no void occured. The duration of FUSP at each visit was calculated as the average over the 3 consecutive 24-hour periods just prior to the respective visit. Adjusted visit-specific mean changes from baseline in FUSP are estimated using a baseline value of 180 (min).

Time frame: Baseline, Week 1

Change From Baseline in Mean Duration of FUSP at Week 4

The FUSP is defined as the time in minutes from the time of going to bed to the time of first nocturnal void, or time of awakening if no void occurred. The duration of FUSP at each visit was calculated as the average over the 3 consecutive 24-hour periods just prior to the respective visit. Adjusted visit-specific mean changes from baseline in FUSP are estimated using a baseline value of 180 (min).

Time frame: Baseline, Week 4

Change From Baseline in Mean Duration of FUSP at Week 8

Time frame: Baseline, Week 8

Change From Baseline in Mean Duration of FUSP at Week 12

Time frame: Baseline, Week 12

Change From Baseline in Aggregated Mean Duration of FUSP During 12 Weeks of Treatment

The FUSP is defined as the time in minutes from the time of going to bed to the time of first nocturnal void, or time of awakening if no void occurred. The visit-specific means were aggregated into a mean of current and preceding visits. Level estimated for baseline value of mean duration of FUSP (minutes) equal to 180 is presented in this endpoint. The 95% credibility interval (2.5 and 97.5 percentiles of the posterior distribution) instead of confidence interval is presented for this endpoint.

Time frame: Baseline, During 12 Weeks of Treatment

Change From Baseline in Nocturnal Diuresis Rate Profiles at Week 1

The nocturnal diuresis rate (mL/min) is calculated as the mean of the nocturnal diuresis for each of the three nights, with the single-night nocturnal diuresis calculated as the ratio of NUV to total time in bed. Change from baseline in visit-specific mean nocturnal diuresis (mL/min) is presented. Level estimated for baseline value of mean nocturnal diuresis (mL/min) equal to 1.3 is presented in this endpoint.

Time frame: Baseline, Week 1

Change From Baseline in Nocturnal Diuresis Rate Profiles at Week 12

Time frame: Baseline, Week 12

Change From Baseline in Mean NUV in Week 1

The NUV is defined as the total urine volume from 5 minutes after bedtime with the intention to sleep including the first void within 30 minutes of rising in the morning. The NUV at each visit was calculated as the average over the 3 consecutive 24-hour periods just prior to the respective visit. Adjusted visit-specific mean changes from baseline in NUV are estimated using a baseline value of 750 (mL).

Time frame: Baseline, Week 1

Change From Baseline in Mean NUV at Week 12

Time frame: Baseline, Week 12