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Use of NPSP558 in the Treatment of Hypoparathyroidism (REPLACE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00732615
Recruitment Status : Completed
First Posted : August 12, 2008
Results First Posted : March 6, 2015
Last Update Posted : December 8, 2015
Sponsor:
Information provided by (Responsible Party):
Shire

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Hypoparathyroidism
Interventions Drug: Placebo
Drug: NPSP558
Enrollment 124
Recruitment Details 124 Subjects were enrolled between 12/2008 and 9/2011 at 28 clinical sites in North America, Western Europe and Hungary.
Pre-assignment Details

Subjects underwent a screening and stabilization period (optimization) of up to 16 weeks prior to enrollment.

Please note: Data for 10 subjects were excluded.

Arm/Group Title Placebo NPSP558
Hide Arm/Group Description Matching Placebo: Placebo for subcutaneous injection NPSP558: Recombinant Human Parathyroid hormone (rhPTH[1-84]) 50, 75, or 100 mcg subcutaneously daily
Period Title: Overall Study
Started 40 84
Completed 33 79
Not Completed 7 5
Reason Not Completed
Withdrawal by Subject             3             1
Lost to Follow-up             0             1
Adverse Event             0             2
Physician Decision             3             0
Non-Compliance, Subject/Physician Dec.             1             1
Arm/Group Title Placebo NPSP558 Total
Hide Arm/Group Description Matching Placebo: Placebo for subcutaneous injection NPSP558: Recombinant Human Parathyroid hormone (rhPTH[1-84]) 50, 75, or 100 mcg subcutaneously daily Total of all reporting groups
Overall Number of Baseline Participants 40 84 124
Hide Baseline Analysis Population Description
[Not Specified]
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 40 participants 84 participants 124 participants
< 45 years 13 35 48
45 to 64 years 23 45 68
> = 65 years 4 4 8
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 40 participants 84 participants 124 participants
Female
33
  82.5%
65
  77.4%
98
  79.0%
Male
7
  17.5%
19
  22.6%
26
  21.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 40 participants 84 participants 124 participants
Hispanic or Latino
0
   0.0%
2
   2.4%
2
   1.6%
Not Hispanic or Latino
40
 100.0%
82
  97.6%
122
  98.4%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 40 participants 84 participants 124 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
1
   2.5%
1
   1.2%
2
   1.6%
Native Hawaiian or Other Pacific Islander
0
   0.0%
1
   1.2%
1
   0.8%
Black or African American
0
   0.0%
1
   1.2%
1
   0.8%
White
39
  97.5%
80
  95.2%
119
  96.0%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
1
   1.2%
1
   0.8%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 40 participants 84 participants 124 participants
North America 21 43 64
Europe 12 25 37
Hungary 7 16 23
1.Primary Outcome
Title The Percentage of Subjects Who Met the Triple Efficacy Endpoint Criteria at Week 24.
Hide Description The triple efficacy endpoint criteria were defined as at least a 50% reduction from the baseline in oral calcium dose and at least a 50% reduction from the baseline in active vitamin D dose and an albumin-corrected total serum calcium concentration that was maintained or normalized compared to the baseline value (≥ 7.5 mg/dL) and did not exceed the upper limit of the laboratory normal range. The analysis of primary efficacy endpoint was based on investigator prescribed data.
Time Frame Week 24 of dosing
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to Treat (ITT) population, which includes all randomized subjects who received at least 1 dose of study drug and had at least 1 post-baseline efficacy assessment.
Arm/Group Title Placebo NPSP558
Hide Arm/Group Description:
Matching Placebo: Placebo for subcutaneous injection
NPSP558: Recombinant Human Parathyroid hormone (rhPTH[1-84]) 50, 75, or 100 mcg subcutaneously daily.
Overall Number of Participants Analyzed 40 84
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
2.5
(0.1 to 13.2)
54.8
(43.5 to 65.7)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, NPSP558
Comments The null hypothesis is that the % of subjects meeting primary efficacy endpoint criteria are the same for both tmt arms. The sample size was determined based on the assumption that 40% and 10% of subjects for NPSP558 and pbo arms would meet the endpt criteria, respectively. Based on 2-tailed test, alpha of 0.05 and 2-to-1 randomization ratio, 84 (56 NPSP558, 28 pbo) subjects who completing the study would achieve 80% statistical power. Adjusted for dropouts, planned enrollment was 110 subjects.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments A fixed sequence test procedure was used to control the study level type I error. Order of test sequence started with the primary efficacy endpoint and proceeded to the 3 secondary efficacy endpoints, in the order defined in the protocol.
Method Fisher Exact
Comments The 2-sided Fisher’s Exact test was utilized to test for difference between NPSP558 and the placebo treatment groups.
Method of Estimation Estimation Parameter Treatment difference
Estimated Value 52.3
Confidence Interval (2-Sided) 95%
40.6 to 64.0
Estimation Comments The above two sided asymptotic 95% confidence interval is based on normal approximation.
2.Secondary Outcome
Title Percentage Changes From Baseline in Daily Calcium Dose at Week 24.
Hide Description The analysis of this endpoint was based on investigator prescribed data.
Time Frame 24 Weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to Treat (ITT) population subjects with Baseline and Week 24 data
Arm/Group Title Placebo NPSP558
Hide Arm/Group Description:
Matching Placebo: Placebo for subcutaneous injection
NPSP558: Recombinant Human Parathyroid hormone (rhPTH[1-84]) 50, 75, or 100 mcg subcutaneously daily
Overall Number of Participants Analyzed 33 79
Mean (Standard Deviation)
Unit of Measure: percentage change from baseline
2.4  (38.37) -51.8  (45.71)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, NPSP558
Comments The null hypothesis is that there is no difference between the percentage changes from baseline for the two treatment arms.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments Following fixed sequence test procedure described in the primary endpoint section, statistical hypothesis testing was conducted for this secondary endpoint after the testing for the primary endpoint reached statistical significance.
Method ANCOVA
Comments ANCOVA analysis conducted using percentage change from baseline as dependent variable, treatment as factor, and baseline calcium dose as covariate.
3.Secondary Outcome
Title Proportion of Subjects Who Achieved Independence From Active Vitamin D and an Oral Calcium Dose of ≤ 500 mg/Day at Week 24.
Hide Description Subjects Who Achieved Independence from Active Vitamin D Usage and with Calcium Dose of 500 mg/day or less. This analysis was based on Investigator Prescribed Data.
Time Frame 24 Weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to Treat (ITT) population subjects with Baseline and Week 24 data.
Arm/Group Title Placebo NPSP558
Hide Arm/Group Description:
Matching Placebo: Placebo for subcutaneous injection
NPSP558: Recombinant Human Parathyroid hormone (rhPTH[1-84]) 50, 75, or 100 mcg subcutaneously daily
Overall Number of Participants Analyzed 33 79
Measure Type: Number
Unit of Measure: percentage of participants
6.1 43.0
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, NPSP558
Comments The null hypothesis is that there is no difference between the proportions of subjects (who achieved this secondary endpoint) from the two treatment arms.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments Following fixed sequence test procedure described in the primary endpoint section, statistical hypothesis testing was conducted for this secondary endpoint after the testing for the first secondary endpoint reached statistical significance.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 11.711
Confidence Interval (2-Sided) 95%
2.619 to 52.363
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Percentage of Subjects With Any Clinical Symptoms of Hypocalcemia During Weeks 16-24.
Hide Description Clinical symptoms were a selected group of adverse events that occurred during study weeks 16 through 24. The group of terms were defined by key opinion leaders and documented in study protocol.
Time Frame 8 Weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to Treat (ITT) population.
Arm/Group Title Placebo NPSP558
Hide Arm/Group Description:
Matching Placebo: Placebo for subcutaneous injection
NPSP558: Recombinant Human Parathyroid hormone (rhPTH[1-84]) 50, 75, or 100 mcg subcutaneously daily
Overall Number of Participants Analyzed 40 84
Measure Type: Number
Unit of Measure: percentage of participants
37.5 34.5
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, NPSP558
Comments The null hypothesis is that the percentages of subjects with any reported clinical symptoms for the two treatment arms are the same.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.747
Comments Following fixed sequence test procedure described in the primary endpoint section, statistical hypothesis testing was conducted for this secondary endpoint after the testing for the second secondary endpoint reached statistical significance.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.879
Confidence Interval (2-Sided) 95%
0.402 to 1.922
Estimation Comments [Not Specified]
Time Frame 28 weeks
Adverse Event Reporting Description 24 weeks on treatment plus 4 week follow-up period
 
Arm/Group Title Placebo NPSP558
Hide Arm/Group Description Matching Placebo: Placebo for subcutaneous injection NPSP558: Recombinant Human Parathyroid hormone (rhPTH[1-84]) 50, 75, or 100 mcg subcutaneously daily
All-Cause Mortality
Placebo NPSP558
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Hide Serious Adverse Events
Placebo NPSP558
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   4/40 (10.00%)      9/84 (10.71%)    
Gastrointestinal disorders     
Diarrhoea  1  0/40 (0.00%)  0 1/84 (1.19%)  1
Pancreatitis  1  0/40 (0.00%)  0 1/84 (1.19%)  1
Vomiting  1  0/40 (0.00%)  0 1/84 (1.19%)  1
Infections and infestations     
Diverticulitis  1  0/40 (0.00%)  0 1/84 (1.19%)  1
Erysipelas  1  0/40 (0.00%)  0 1/84 (1.19%)  1
Metabolism and nutrition disorders     
Hypocalcaemia  1  1/40 (2.50%)  1 2/84 (2.38%)  2
Hypercalcaemia  1  0/40 (0.00%)  0 2/84 (2.38%)  2
Dehydration  1  1/40 (2.50%)  1 0/84 (0.00%)  0
Musculoskeletal and connective tissue disorders     
Back pain  1  0/40 (0.00%)  0 1/84 (1.19%)  1
Nervous system disorders     
Cerebrovascular accident  1  0/40 (0.00%)  0 1/84 (1.19%)  1
Reproductive system and breast disorders     
Epididymal tenderness  1  1/40 (2.50%)  1 0/84 (0.00%)  0
Respiratory, thoracic and mediastinal disorders     
Asthma  1  1/40 (2.50%)  1 0/84 (0.00%)  0
Chronic obstructive pulmonary disease  1  1/40 (2.50%)  1 0/84 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (12.0)
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo NPSP558
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   38/40 (95.00%)      69/84 (82.14%)    
Gastrointestinal disorders     
Nausea  1  7/40 (17.50%)  9 17/84 (20.24%)  35
Diarrhoea  1  4/40 (10.00%)  4 10/84 (11.90%)  13
Vomiting  1  0/40 (0.00%)  0 10/84 (11.90%)  12
Paraesthesia oral  1  3/40 (7.50%)  6 7/84 (8.33%)  7
Abdominal pain upper  1  0/40 (0.00%)  0 7/84 (8.33%)  9
Gastrooesophageal Reflux Disease  1  3/40 (7.50%)  3 0/84 (0.00%)  0
General disorders     
Fatigue  1  8/40 (20.00%)  11 10/84 (11.90%)  25
Injection Site Haematoma  1  5/40 (12.50%)  6 0/84 (0.00%)  0
Pyrexia  1  3/40 (7.50%)  3 0/84 (0.00%)  0
Feeling Cold  1  2/40 (5.00%)  2 0/84 (0.00%)  0
Oedema Peripheral  1  2/40 (5.00%)  2 0/84 (0.00%)  0
Infections and infestations     
Upper respiratory tract infection  1  2/40 (5.00%)  2 8/84 (9.52%)  8
Sinusitis  1  2/40 (5.00%)  2 6/84 (7.14%)  6
Nasopharyngitis  1  5/40 (12.50%)  5 0/84 (0.00%)  0
Bronchitis  1  3/40 (7.50%)  3 0/84 (0.00%)  0
Cystitis  1  2/40 (5.00%)  2 0/84 (0.00%)  0
Herpes Zoster  1  2/40 (5.00%)  2 0/84 (0.00%)  0
Viral Infection  1  2/40 (5.00%)  2 0/84 (0.00%)  0
Injury, poisoning and procedural complications     
Contusion  1  2/40 (5.00%)  3 0/84 (0.00%)  0
Excoriation  1  2/40 (5.00%)  2 0/84 (0.00%)  0
Muscle Strain  1  2/40 (5.00%)  2 0/84 (0.00%)  0
Investigations     
Blood 25-hydroxycholecalciferol decreased  1  0/40 (0.00%)  0 5/84 (5.95%)  5
Urine Calcium Increased  1  2/40 (5.00%)  3 0/84 (0.00%)  0
Metabolism and nutrition disorders     
Hypocalcaemia  1  9/40 (22.50%)  10 33/84 (39.29%)  54
Hypercalcaemia  1  4/40 (10.00%)  4 14/84 (16.67%)  17
Tetany  1  4/40 (10.00%)  13 10/84 (11.90%)  24
Hypomagnesaemia  1  0/40 (0.00%)  0 5/84 (5.95%)  5
Musculoskeletal and connective tissue disorders     
Muscle spasms  1  12/40 (30.00%)  21 25/84 (29.76%)  41
Arthralgia  1  5/40 (12.50%)  5 10/84 (11.90%)  18
Pain in extremity  1  3/40 (7.50%)  3 9/84 (10.71%)  13
Back pain  1  7/40 (17.50%)  8 8/84 (9.52%)  8
Myalgia  1  3/40 (7.50%)  3 6/84 (7.14%)  13
Neck pain  1  0/40 (0.00%)  0 5/84 (5.95%)  5
Muscle Twitching  1  4/40 (10.00%)  5 0/84 (0.00%)  0
Muscle Tightness  1  2/40 (5.00%)  2 0/84 (0.00%)  0
Nervous system disorders     
Paraesthesia  1  10/40 (25.00%)  16 30/84 (35.71%)  69
Headache  1  10/40 (25.00%)  20 22/84 (26.19%)  56
Hypoaesthesia  1  5/40 (12.50%)  6 16/84 (19.05%)  24
Dizziness  1  3/40 (7.50%)  4 0/84 (0.00%)  0
Dysgeusia  1  2/40 (5.00%)  2 0/84 (0.00%)  0
Psychiatric disorders     
Anxiety  1  0/40 (0.00%)  0 5/84 (5.95%)  5
Renal and urinary disorders     
Hypercalciuria  1  0/40 (0.00%)  0 6/84 (7.14%)  7
Skin and subcutaneous tissue disorders     
Hypoaesthesia facial  1  0/40 (0.00%)  0 5/84 (5.95%)  5
Alopecia  1  2/40 (5.00%)  2 0/84 (0.00%)  0
Hyperhidrosis  1  2/40 (5.00%)  2 0/84 (0.00%)  0
Vascular disorders     
Hypertension  1  2/40 (5.00%)  2 5/84 (5.95%)  5
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (12.0)
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
 
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Executive Director, Clinical Development
Organization: NPS Pharmaceuticals
Phone: +1 908-450-5300
EMail: info@npsp.com
Layout table for additonal information
Responsible Party: Shire
ClinicalTrials.gov Identifier: NCT00732615    
Other Study ID Numbers: CL1-11-040
First Submitted: August 8, 2008
First Posted: August 12, 2008
Results First Submitted: February 20, 2015
Results First Posted: March 6, 2015
Last Update Posted: December 8, 2015