Nocdurna - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Nocdurna - Scientific Information

Manufacture: Ferring Pharmaceuticals
Country: Canada
Condition: Nocturnal Polyuria, Nocturnal Enuresis (Enuresis), Urination - excessive volume (Nocturnal Polyuria)
Class: Antidiuretic hormones
Form: Tablets
Ingredients: Gelatin, Mannitol, Anhydrous Citric Acid, Desmopressin

Pharmaceutical Information

Drug Substance

Proprietary Name: Desmopressin Acetate
Chemical names: 1-Desamino-8-D-arginine vasopressi
acetate trihydrate

1-(3-mercaptopropanoic acid)-8-D-arginine
vasopressin monoacetate (salt) trihydrate
Molecular formula and
molecular mass:
C48H74N14017S2 (acetate trihydrate)
MW = 1183.2
C46H64N14O12S2 (free base)
MW = 1069.2
Structural formula:
Physicochemical Properties: Desmopressin acetate is a white lyophilized powder which
is soluble in water, methanol, ethanol, and acetic acid,
and sparingly soluble in chloroform and ethyl acetate.
An aqueous solution of 1 mg/mL at 24°C has a pH of 4.8

Clinical Trials

NOCDURNA 25 µg in Females

The safety and efficacy of NOCDURNA 25 µg in females were evaluated in two Phase 3 studies, CS29 and CS31. CS29 was conducted in 2 parts. Part I was a double-blind, placebo-controlled, multi-center, randomized, parallel-group study investigating the efficacy and safety of 4 doses (10, 25, 50, and 100 µg) of NOCDURNA administered at bedtime for 28 days for the treatment of nocturia in male and female adults. A total of 757 subjects were included in the ITT population. Subjects on active drug continued into CS29 Part II for 1 to 6 months and those on placebo were blindly randomized to an active dose. 3, 4

The ITT population (n=757) across all treatment arms had an overall median age of approximately 64 years (range 20 to 89 years). The majority of subjects participating were Caucasian. The ethnic/racial distribution was 80.4% Caucasian, 15.3% black, 2.1% Asian, and 1.8% others. Subjects with following conditions were excluded from the trials: Neurogenic bladder dysfunction, severe OAB and BPH (low bladder capacity), urological malignancies gynaecological abnormalities, pregnancy, uncontrolled hypertension, uncontrolled diabetes mellitus, low baseline serum sodium, diabetes insipidus, SIADH secretion and polydipsia. 3

Durability of effect was assessed and confirmed for up to 96 weeks during CS29 Part II and the open-label extension study CS31. A total of 601 NOCDURNA-treated subjects (excluding placebo subjects) were included in the ITT population of CS29 and CS31 combined. 3, 4

The co-primary endpoints, measured from baseline to the final visit in CS29 Part I (Day 28), were the change in the mean number of nocturnal voids and the proportion of subjects with >33% reduction in the mean number of nocturnal voids. In addition to these co-primary endpoints, the change from baseline in the initial period of undisturbed sleep and nocturnal urine volume were also evaluated in CS29 Part I as well in the durability studies, CS29 Part II and CS31. 3, 4

At Day 28 the difference in the mean number of nocturnal voids and the proportion of subjects with >33% reduction in the mean number of nocturnal voids was statistically significant, favoring NOCDURNA 25 µg over placebo. The mean reductions in nocturnal voids were 1.22 voids in females receiving NOCDURNA 25 µg versus 0.88 voids for placebo (p=0.0200). The 33% responder rates were 62% in females receiving NOCDURNA 25 µg versus 42% for placebo (p=0.0197). Statistical analyses of the efficacy data, based on a linear model for change from baseline and logistic regression for 33% responder,with adjustment for nocturnal polyuria status, age group and baseline number of voids, for females treated with NOCDURNA 25 µg are presented in Table 1. 3

Table 1: Primary Efficacy results for Females treated with NOCDURNA 25 μg at Day 28 (CS29 Part I, ITT Analysis Dataset)
Co-primary efficacy endpoints NOCDURNA 25 μg
N=65
Placebo
N=66
Number of nocturnal voids    
Mean change from baseline (SD) -1.22 (1.060) -0.88 (1.008)
Adjusted mean treatment difference 1 (95% CI) -0.397 (-0.731, -0.063)
P=0.0200
 
33% responder status    
Proportion of patients achieving 33% reduction
from baseline in mean no. of nocturnal voids
62% 42%
Odds Ratio 2 (95% CI) 2.344 (1.154, 4.848)
p=0.0197
 

SD = standard deviation, CI = confidence interval

1 ANCOVA of change from baseline at Day 28, adjusted for age stratification group (<65, ≥65 years), absence/presence of nocturnal polyuria, and baseline nocturnal voids

2 Logistic regression of responder status at Day 28, adjusted for age stratification group (<65, ≥65 years), absence/presence of nocturnal polyuria, and baseline nocturnal voids

Durability of effect was indicated during long-term treatment. The primary efficacy results that had been observed in CS29 Part I were maintained, sometimes improved, with continued NOCDURNA treatment in CS29 Part II and CS31 (Table 2). 3, 4

Table 2: Change from Baseline in Mean Number of Nocturnal Voids and Proportion of Subjects with >33% Reduction in Mean Number of Nocturnal Voids in Females Receiving Long-term Treatment with NOCDURNA 25 μg (CS29 Part II, CS31)
Endpoints Mean Change in Nocturnal Voids
Mean (SD)
33% Responder Rate
28 Weeks (N=29)
-1.78 (1.138)
(N=29)
24 (83%)
52-56 Weeks (N=40)
-1.74 (1.126)
(N=40)
35 (87.5%)
72-76 Weeks (N=36)
-1.99 (1.235)
(N=36)
29 (80.6%)
92-96 Weeks (N=32)
-1.82 (1.068)
(N=32)
24 (75.0%)

In general, the initial period of undisturbed sleep increased in all treatment groups throughout study duration. Mean increases in the initial period of undisturbed sleep observed in CS29 Part I continued beyond 4 weeks After 1 year of treatment, the mean initial period of undisturbed sleep among females increased by approximately 2.5 hours in the NOCDURNA 25 µg group. After 92-96 weeks of treatment, the mean initial period of undisturbed sleep increased by approximately 3.3 hours, giving an average first uninterrupted sleep time of approximately 4.9 hours. 4

NOCDURNA 50 µg in Males

The safety and efficacy of NOCDURNA 50 µg in males were evaluated in the Phase 3 study, CS41. CS41 was a double-blind, placebo-controlled, multicenter, randomized trial consisting of 2 parts. Part I was a double-blind, randomized, placebo-controlled, parallel-group 3-month period designed to evaluate the clinical effect and safety of two doses of NOCDURNA for treatment of nocturia in adult males. A total of 395 subjects were randomized to 1 of 3 treatment groups (NOCDURNA 75 µg, NOCDURNA 50 µg, or placebo). After the first 3 months of treatment, all subjects switched to desmopressin 100 µg for a period of 1 month for further evaluation of safety in an open-label extension phase (Part II).5

Randomisation was stratified by age (< 65 years, ≥ 65 years). The mean age was 60.6 years (median age: 64 years), and age ranged from 20 to 87 years. The majority of subjects participating were Caucasian. The ethnic/racial distribution was 81% Caucasian, 17% black, 2 % Asian, and <1% others. 5

The co-primary endpoints were the change from baseline in the mean number of nocturnal voids and the proportion of subjects with >33% reduction from baseline in the mean number of nocturnal voids. Secondary endpoints included change from baseline in the initial period of undisturbed sleep and in nocturnal urine volume. Statistically significant differences, favoring both NOCDURNA 50 µg and 75 µg, were observed in these primary and secondary endpoints. 5

At each visit (Week 1, Month 1, Month 2, and Month 3) the differences in the mean number of nocturnal voids were statistically significant, favoring NOCDURNA 50 µg over placebo. The mean (adjusted) reductions in nocturnal voids during 3 months were 1.25 voids with NOCDURNA 50 µg and 0.88 voids with placebo (p=0.0003). 5

At each visit, the proportions of 33% responders were greater in males receiving NOCDURNA

50 µg compared to placebo. The (adjusted) odds of achieving a >33% responder status during the 3 months of treatment, as compared to placebo, was greater with NOCDURNA 50 µg (OR=1.98, p=0.0009). At Month 3, the 33% responder rate for NOCDURNA 50 µg was 67%. 5

Statistical analyses of the efficacy data for males treated with NOCDURNA 50 µg are presented in Table 3. 5

Table 3: Primary Efficacy results for Males treated with NOCDURNA 50 μg during 3 months of treatment (CS41, Part I Full Analysis Set)
Difference average over 3 months

Co-primary efficacy endpoints
NOCDURNA 50 μg
N=119
Placebo
N=142
Number of nocturnal voids    
Baseline mean (SD) 2.88 (0.864) 2.90 (0.807)
Adjusted mean change from baseline 1 -1.25 -0.88
Adjusted mean treatment difference 1 (95% CI) -0.37 (-0.57, -0.17)
P=0.0003
 
33% responder status    
Adjusted probability of achieving 33%
reduction from baseline in mean no. of
nocturnal voids
0.67 0.50
Odds Ratio 2 (95% CI) 1.98 (1.32, 2.96)
p=0.0009
 

SD = standard deviation, CI = confidence interval

1 Repeated measures ANCOVA of change from baseline at Week 1, Month 1, Month 2 and Month, Adjusted for Age stratification factor (<65, ≥65 years), visit, and baseline nocturnal voids

2 GEE Method for 33% responder status at Week 1, Month 1, Month 2 and Month 3. Adjusted for Age stratification factor (<65, ≥65 years), visit, and baseline nocturnal voids

The initial period of undisturbed sleep increased throughout study duration. At 3 months, mean increase in the initial period of undisturbed sleep was approximately 112 minutes (p = 0.0064) in the NOCDURNA 50 µg group, giving an average first uninterrupted sleep time of approximately 4.3 hours. 5 The mean increase in the initial period of undisturbed sleep in the placebo group was approximately 73 minutes, giving an average first uninterrupted sleep of approximately 3.6 hours. The decrease in Nocturnal Urine Volume with 50 µg NOCDURNA was -209 mL, a 78 mL larger volume decrease than in the placebo group (p = 0.0086).

QoL Responder Analysis

For the QoL assessments, pooled treatments for all subjects compared changes in key clinical endpoints between responders and non-responders. Two criteria were used to define responders. reduction of ≥2 nocturnal voids from baseline to Month 3 and increase of ≥2 hours in time to first nocturnal void from baseline to Month 3. For both definitions of responders, mean improvement (higher numbers) in NQoL scores was statistically significantly greater in subjects from pooled treatment groups who responded than in non-responders. Mean changes in quality of life, as measured by the global QoL score, bother/concern domain, and sleep/energy domain, are summarized longitudinally in Table 4.

Table 4: Exploratory Efficacy Endpoints NQoL NOCTURIA (Longitudinal Analysis–Full Analysis Set
  Responder vs. Non-responder
N-QoL Difference in Adjusted Means [95% CI] P-value
Responder Criteria: ≥2 voids reduction from baseline
Global Quality Score 5.73 [ 2.58; 8.87 ] 0.0004
Bother/Concern Domain 9.60 [ 6.04; 13.15 ] <.0001
Sleep/Energy Domain 9.26 [ 5.64; 12.88 ] <.0001
Responder Criteria: ≥2 hrs increase in time to first void 4.51 [ 1.60; 7.43 ] 0.0003
Global Quality Score
Bother/Concern Domain 9.06 [ 5.80; 12.33 ] <.0001
Sleep/Energy Domain 8.63 [ 5.31; 11.95 ] <.0001
Note: N-QoL is a scale of 0-100. Increased score means improved QoL

Treatment Change in Mean Nocturia Quality of Life (NQoL) Scores

Post-hoc longitudinal analyses (repeated measures ANCOVA adjusting for baseline as a covariate and age stratification factor, treatment, visit, and treatment-by-visit interaction term as factor) were conducted to investigate the treatment effect of desmopressin versus placebo on the change from baseline in N-QoL domain scores and total score. Results for CS41 are shown in Table 5.

Table 5: Adjusted treatment differences in mean change from baseline in N-QoL domain scores at Month 3 including treatment-by-visit interaction term (FAS using repeated measures ANCOVA)
  Adjusted Means Difference in Adjusted Means
Desmopressin Placebo Treatment
Contrast
95% CI p-value
CS41 N=103 N=127      
Total Score
(BC+SE)
18.37 13.88 4.49 [0.24, 8.74] 0.0385*
Bother/Concer
n Domain
18.13 15.2 2.92 [-1.58, 7.42] 0.2022
Sleep/Energy
Domain
18.67 12.56 6.11 [1.42, 10.80] 0.0108*
Overall
Quality of Life
10.70 3.49 7.21 [3.42, 11.00] 0.0002*

* Statistically significant difference versus placebo, p≤0.05.

Note: All scores are re-scaled to 0–100.

BC = bother/concern; SE = sleep/energy

At Month 3, significantly greater improvements were seen with desmopressin compared with placebo based on the total score. The absolute change from baseline due to desmopressin treatment was highly clinically relevant, but also the treatment contrast of approximately 5 in the total score is clinically relevant according to the suggested N-QoL values for clinical improvement. 18, 45, 46 The main driver of the treatment contrast was the sleep/energy domain. The change in the stand-alone overall QoL question was also significant.

Impact on Quality of Sleep

Clinical benefit was furthermore assessed through three sleep VAS scales included in the diary assessing different dimensions of sleep quality.

For the sleep quality assessments, pooled treatments for all subjects compared changes in key clinical endpoints between responders and non-responders. Two criteria were used to define responders, reduction of ≥2 nocturnal voids from baseline to Month 3 and Increase of ≥2 hours in time to first nocturnal void from baseline to Month 3. For both definitions of responders, mean improvement (higher numbers) in sleep quality was statistically significantly greater in subjects from pooled treatment groups who responded than in non-responders. Mean changes in sleep quality (how do you feel right now, rate how refreshed you feel, and quality of sleep last night) are summarized longitudinally in Table 6.

Table 6: Exploratory Sleep Endpoint Sleep Quality (Longitudinal Analysis – full Analysis Set Responders vs. Non-responders
Quality of Sleep Difference in Adjusted Means [95% CI] P-value
Responder Criteria: ≥2 voids reduction from baseline
Average of how you feel right now 0.48 [0.22; 0.74] 0.0003
Average of how refreshed 0.46 [0.20; 0.71] 0.0006
Average of quality of sleep last night 0.69 [0.41; 0.97] <.0001
Responder Criteria: ≥2 hrs increase in time to first void 0.40 [0.16; 0.64] 0.0013
Average of how you feel right now
Average of how refreshed 0.31 [0.07; 0.56] 0.0109
Average of quality of sleep last night 0.54 [0.28; 0.80] <.0001
Note: Sleep diary questions sleep rank 1-10. Increased score means improved quality of sleep.

Treatment Change in Sleep Quality

Post-hoc longitudinal analyses (repeated measures ANCOVA adjusting for baseline as a covariate and age stratification factor, treatment, visit, and treatment-by-visit interaction term as factor) were conducted to investigate the treatment effect of desmopressin versus placebo on the change from baseline in the 3 sleep VAS scales. Results are shown in Table 7.

Table 7: Adjusted treatment differences in mean change from baseline in sleep VAS at Month 3
  Adjusted Means Difference in Adjusted Means
Desmopressin Placebo Treatment
Contrast
95% CI p-value
CS41 N=102 N=125      
Mean of Q1:
How do you feel right now?
1.21 0.78 0.43 [0.05; 0.82] 0.0265*
Mean of Q2:
Rate how refreshed you feel
1.34 0.85 0.49 [0.11; 0.87] 0.0113*
Mean of Q3:
Rate the quality of your
sleep last night
1.69 1.33 0.36 [-0.03; 0.75] 0.0684

* Statistically significant difference versus placebo, p≤0.05.

At Month 3, significantly greater improvements were seen with desmopressin compared with placebo in 2 of the3 sleep VAS scales.

Increasing initial undisturbed sleep time to ≥4 hours is associated with clinically meaningful improvements in sleep quality scores.

Toxicology

Acute Toxicity

The i.v. acute toxicity of desmopressin acetate was studied in mice, rats and rabbits. Mice tolerated i.v. doses of 2 mg/kg. At doses of 30 µg/kg in rats and 50 µg/kg in rabbits, only transient changes in clinical behaviour were observed. 12, 13, 41

Subacute Toxicity

Results from 14-day studies show that the drug given intravenously to rats at 8 µg/kg/day and to rabbits at 6 µg/kg/day caused no biologically significant changes in hematological and clinical chemistry parameters. Post-mortem examinations did not reveal any abnormalities. 14, 15

Rats which received 5 mg/kg/day subcutaneously for 3 days did not show any significant changes in weight, blood count, or organ changes. 41

Chronic Toxicity

Subcutaneous Administration

Rat Studies

In a controlled 8-week experiment, 20 rats received 2 µg/kg/day desmopressin acetate subcutaneously. No increase in blood glucose or morphological or histological pancreatic changes occurred. 42

Rats (20 per group) which received doses of 5, 50 and 500 ng/kg/day, for six months did not show any significant changes in weight, blood values, or levels of transaminases. The weight of heart, lungs and kidneys decreased in female animals in the lower dose groups but not in the higher ones. In the male animals a decrease in non-esterified fatty acids was noted. 41

Rats were treated with dose levels of 0.1, 1 and 10 µg/kg/day by subcutaneous injection for 13 weeks. Anticipated pharmacological changes were observed in a series of urinary parameters mainly at the high dose: decreased urinary volume and pH; increased specific gravity and concentration of sodium, potassium, chloride and protein. Absolute and relative kidney weights were increased at all dose levels. There were no macroscopic observations at necropsy. Histopathology showed changes at the injection site, where the incidence and severity were slightly increased at the high dose level.

Dog Studies

Dogs (3 per group) which received subcutaneous doses of 10 and 100 ng/kg/day for 6 months did not show any significant changes in comparison with control groups in blood sugar or transaminases and did not show histological or morphological organ changes. 41

Intravenous Administration

Rat Studies

In rats treated intravenously with desmopressin at dose levels of 9.47, 47.4 or 238 μg/kg/day for 180 days, urinary specific gravity was increased and urinary volume was decreased in all desmopressin treated groups, thus showing the pharmacological effect of the compound. Absolute kidney weight was increased from the mid dose level while body weight related kidney weight was increased from the low dose level. There were no gross pathological changes at necropsy. Histopathological changes were confined to the kidneys and consisted of increased incidence of tubular protein casts from 47.4 μg/kg/day and hyaline droplet degeneration at the high dose level.

All changes were reversible after the 30-day reversibility period, except increased kidney weight, which showed incomplete reversibility. 15

Oral Administration

Rat Studies

Oral administration of desmopressin to rats (20 male and 20 females per group dosed at 25, 75 and 200 μg/kg/day) did not reveal any clinical findings related to desmopressin. Treated male and female rats were comparable to controls with respect to food consumption, body weight gain and water consumption. There were no drug-induced ocular abnormalities. 21

A dosage-related reduction was seen in levels of total circulating white blood cells, attributable to reduced neutrophil and lymphocyte counts in treated females, when compared with controls, at the week 13 and 26 investigations. Treated males were not affected. 21Reduced plasma Factor VIII levels were seen in treated females at week 14 and treated males at week 25 in comparison with controls. 21

The terminal studies revealed no morphological or histological changes related to treatment with desmopressin. 21

Dog Studies

When desmopressin was given orally to dogs (4 males and 4 females per group, at 0, 25, 75 and 200 μg/kg/day) all animals survived the 26-week period and no clinical signs were observed that were related to treatment. There were no adverse effects on body weight, food and water consumption and no ocular abnormalities. Hematological investigations revealed no treatment-related findings. 16

During weeks 6, 13 and 26 serum total protein concentrations of treated animals were increased due to an increase in the globulin fraction. However, there were no changes from the pre-dose values in males at 200 µg/kg/day after 13 and 26 weeks treatment and males at 75 µg/kg/day after 26 weeks treatment. 16

No organ morphological or histological changes were seen on autopsy which could be related to treatment with desmopressin. 16

Reproduction Studies

Subcutaneous Administration

Rat Studies

In a teratogenicity study in Wistar rats, neither teratologic nor embryotoxic effects were observed in 369 foetuses from 40 females dosed with up to 50 ng/kg/day desmopressin acetate subcutaneously during day 1 to day 20 of gestation. 40

Rabbit Studies

In a study of 78 Dutch belted rabbits which received subcutaneous doses of desmopressin acetate up to 10 µg/kg/day during day 6 and day 18 of pregnancy, neither teratogenic nor embryotoxic effects were observed in 296 fetuses. Weaning was unaffected. 39

Intravenous Administration

Rat Studies

A teratology study was performed in rats. Groups of 30 pregnant Slc:Wistar rats were treated daily from day 7 to day 17 of gestation by i.v. administration of desmopressin at dosage levels of 9.47, 47.4 and 238 g desmopressin/kg/day. A control group received the vehicle, physiological saline. Twenty females in each group were killed on day 20 of gestation to allow fetal examinations; the remaining 10 females were allowed to litter to determine any postnatal effects that might be attributable to prenatal treatment. There were no effects of treatment on the dams, and fetal survival, growth and morphology were also unaffected. Postnatal offspring survival, growth, development, behavior and reproductive performance also showed no effects of prenatal exposure to desmopressin. 22

Genotoxicity

The genotoxic potential of desmopressin was examined in 3 Ames tests and one mouse lymphoma assay all of which turned out to be negative. Desmopressin is therefore considered to be devoid of mutagenic potential under the condition tested. 22

Carcinogenesis

Studies with desmopressin acetate have not been performed to evaluate carcinogenic potential.