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Long-Term Study of Nitisinone to Treat Alkaptonuria

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ClinicalTrials.gov Identifier: NCT00107783
Recruitment Status : Completed
First Posted : April 8, 2005
Results First Posted : January 19, 2011
Last Update Posted : August 26, 2021
Sponsor:
Information provided by:
National Institutes of Health Clinical Center (CC)

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Single (Outcomes Assessor);   Primary Purpose: Treatment
Condition Alkaptonuria
Intervention Drug: Nitisinone (NTBC)
Enrollment 40
Recruitment Details Patients were enrolled at the NIH Clinical Center between April 2005 and March 2006.
Pre-assignment Details  
Arm/Group Title Control Nitisinone-treated
Hide Arm/Group Description No treatment Subjects received nitisinone 2 mg orally, once daily.
Period Title: Overall Study
Started 20 20
Completed 17 16
Not Completed 3 4
Reason Not Completed
Adverse Event             0             2
Death             0             1
Withdrawal by Subject             2             0
Second hip replacement             1             1
Arm/Group Title Control Nitisinone-treated Total
Hide Arm/Group Description No treatment Subjects received nitisinone 2 mg orally, once daily. Total of all reporting groups
Overall Number of Baseline Participants 20 20 40
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 20 participants 20 participants 40 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
20
 100.0%
19
  95.0%
39
  97.5%
>=65 years
0
   0.0%
1
   5.0%
1
   2.5%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 20 participants 20 participants 40 participants
51.3  (6.5) 52.2  (7.9) 51.7  (7.1)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 20 participants 20 participants 40 participants
Female
5
  25.0%
8
  40.0%
13
  32.5%
Male
15
  75.0%
12
  60.0%
27
  67.5%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 20 participants 20 participants 40 participants
20 20 40
Total Range of Motion (ROM) Worse Hip   [1] 
Mean (Standard Deviation)
Unit of measure:  Degrees
Number Analyzed 20 participants 20 participants 40 participants
46.4  (16.1) 39.0  (12.7) 42.7  (14.8)
[1]
Measure Description: The total (internal + external) range of motion (ROM) of the worse hip.
Schober's test   [1] 
Mean (Standard Deviation)
Unit of measure:  Cm
Number Analyzed 20 participants 20 participants 40 participants
11.42  (1.04) 10.86  (0.73) 11.14  (0.93)
[1]
Measure Description: Schober's test measures a patient's ability to flex his/her lower back. The examiner makes a mark at L5 (fifth lumbar vertebra) and places one finger 5 cm below and another finger 10 cm above this mark. The patient is asked to touch his/her toes. The examiner measures the increase in distance between the two fingers.
Functional Reach Assessment   [1] 
Mean (Standard Deviation)
Unit of measure:  Cm
Number Analyzed 20 participants 20 participants 40 participants
10.22  (2.92) 8.98  (3.10) 9.60  (3.04)
[1]
Measure Description: Functional reach assessment measures the difference between the length of a person's outstretched arm and their maximal reach forward, while maintaining balance.
Timed get up and go   [1] 
Mean (Standard Deviation)
Unit of measure:  Seconds
Number Analyzed 20 participants 20 participants 40 participants
7.56  (1.40) 9.70  (4.10) 8.63  (3.21)
[1]
Measure Description: In timed get up and go, the patient is asked to stand up from a standard chair and walk a distance of 3 meters, turn around and walk back to the chair and sit down. The examiner measures the time it takes for the patient to perform this series of tasks.
6 minute walk test   [1] 
Mean (Standard Deviation)
Unit of measure:  Ft
Number Analyzed 20 participants 20 participants 40 participants
1578  (205) 1336  (369) 1457  (319)
[1]
Measure Description: The 6MWT measures the distance that a patient can quickly walk on a flat hard surface in a period of six minutes.
1.Primary Outcome
Title Change in Total ROM Worse Hip
Hide Description Change from baseline in the total (external + internal) hip range of motion (ROM) in the worse hip at 36 months. The patient lies on exam table in the supine position. The patient flexes his/her hip and knee to 90 degrees. The examiner measures the patient's hip external rotation and hip internal rotation range of motion with a goniometer.
Time Frame Measured at baseline and at 36 months
Hide Outcome Measure Data
Hide Analysis Population Description
Intention to treat.
Arm/Group Title Control Nitisinone-treated
Hide Arm/Group Description:
No treatment
Subjects received nitisinone 2 mg orally, once daily.
Overall Number of Participants Analyzed 20 20
Mean (Standard Deviation)
Unit of Measure: degrees
-9.1  (24.7) 1.6  (21.8)
2.Secondary Outcome
Title Change in Schober's Test
Hide Description Change from baseline of Schober's test at 36 months. Schober's test measures a patient's ability to flex his/her lower back. The examiner makes a mark at L5 (fifth lumbar vertebra) and places one finger 5 cm below and another finger 10 cm above this mark. The patient is asked to touch his/her toes. The examiner measures the increase in distance between the two fingers.
Time Frame Measured at baseline and at 36 months
Hide Outcome Measure Data
Hide Analysis Population Description
In the control group, two patients who dropped out for personal reasons were not included in this analysis, and in the treated group one patient who died was not included in this analysis.
Arm/Group Title Control Nitisinone-treated
Hide Arm/Group Description:
No treatment
Subjects received nitisinone 2 mg orally, once daily.
Overall Number of Participants Analyzed 18 19
Mean (Standard Deviation)
Unit of Measure: cm
-0.06  (1.33) 0.12  (1.05)
3.Secondary Outcome
Title Change in Functional Reach Assessment
Hide Description Change from baseline of functional reach assessment at 36 months. Functional reach assessment measures the difference between the length of a person's outstretched arm and their maximal reach forward, while maintaining balance.
Time Frame Measured at baseline and at 36 months
Hide Outcome Measure Data
Hide Analysis Population Description
In the control group, two patients who dropped out for personal reasons were not included in this analysis, and in the treated group one patient who died was not included in this analysis.
Arm/Group Title Control Nitisinone-treated
Hide Arm/Group Description:
No treatment
Subjects received nitisinone 2 mg orally, once daily.
Overall Number of Participants Analyzed 18 19
Mean (Standard Deviation)
Unit of Measure: cm
-1.21  (3.81) -1.86  (3.59)
4.Secondary Outcome
Title Change in Timed Get up and go
Hide Description Change from baseline of timed get up and go at 36 months. In timed get up and go, the patient is asked to stand up from a standard chair and walk a distance of 3 meters, turn around and walk back to the chair and sit down. The examiner measures the time it takes for the patient to perform this series of tasks.
Time Frame Measured at baseline and at 36 months
Hide Outcome Measure Data
Hide Analysis Population Description
In the control group, two patients who dropped out for personal reasons were not included in this analysis, and in the treated group one patient who died was not included in this analysis.
Arm/Group Title Control Nitisinone-treated
Hide Arm/Group Description:
No treatment
Subjects received nitisinone 2 mg orally, once daily.
Overall Number of Participants Analyzed 18 19
Mean (Standard Deviation)
Unit of Measure: seconds
-0.54  (1.84) -1.33  (5.04)
5.Secondary Outcome
Title Change in 6 Minute Walk Test (6MWT)
Hide Description Change from baseline of the 6MWT at 36 months. The 6MWT measures the distance that a patient can quickly walk on a flat hard surface in a period of six minutes.
Time Frame Measured at baseline and at 36 months
Hide Outcome Measure Data
Hide Analysis Population Description
In the control group, two patients who dropped out for personal reasons were not included in this analysis, and in the treated group one patient who died was not included in this analysis.
Arm/Group Title Control Nitisinone-treated
Hide Arm/Group Description:
No treatment
Subjects received nitisinone 2 mg orally, once daily.
Overall Number of Participants Analyzed 18 19
Mean (Standard Deviation)
Unit of Measure: ft
22  (356) 169  (591)
Time Frame 36 months
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Control Nitisinone-treated
Hide Arm/Group Description No treatment Subjects received nitisinone 2 mg orally, once daily.
All-Cause Mortality
Control Nitisinone-treated
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Hide Serious Adverse Events
Control Nitisinone-treated
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/20 (0.00%)      6/20 (30.00%)    
Blood and lymphatic system disorders     
anemia † 1  0/20 (0.00%)  0 1/20 (5.00%)  1
Cardiac disorders     
atrial fibrillation * 1  0/20 (0.00%)  0 1/20 (5.00%)  1
Eye disorders     
keratitis * 1 [1]  0/20 (0.00%)  0 1/20 (5.00%)  3
Hepatobiliary disorders     
bile duct stone * 1  0/20 (0.00%)  0 1/20 (5.00%)  1
liver enzyme elevation † 1 [2]  0/20 (0.00%)  0 1/20 (5.00%)  1
Immune system disorders     
sarcoidosis † 1  0/20 (0.00%)  0 1/20 (5.00%)  1
Injury, poisoning and procedural complications     
accidental overdose † 1  0/20 (0.00%)  0 1/20 (5.00%)  1
muscle injury † 1  0/20 (0.00%)  0 1/20 (5.00%)  1
†
Indicates events were collected by systematic assessment
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (13.1)
[1]
corneal irritation due to tyrosine crystal deposition
[2]
High elevations of alanine transaminase (ALT); ALT > 123 U/L.
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Control Nitisinone-treated
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   10/20 (50.00%)      10/20 (50.00%)    
Ear and labyrinth disorders     
sensorineural hearing loss * 1  0/0  0 3/20 (15.00%)  3
Hepatobiliary disorders     
elevated liver enzymes † 1 [1]  6/20 (30.00%)  8 6/20 (30.00%)  8
Infections and infestations     
upper respiratory infection * 1  5/20 (25.00%)  6 2/20 (10.00%)  2
Psychiatric disorders     
depression * 1  2/20 (10.00%)  2 0/20 (0.00%)  0
Skin and subcutaneous tissue disorders     
skin rash † 1  3/20 (15.00%)  3 0/20 (0.00%)  0
†
Indicates events were collected by systematic assessment
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (13.1)
[1]
Mild elevations in alanine transaminase (ALT); ALT between 41 and 100 U/L.
Small number of patients involved in study and several patients dropped out; primary outcome parameter selection possibly inappropriate because hip joint damage that is already present may be irreversible.
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: William Gahl, MD/Clinical Director
Organization: NHGRI
Phone: 301-402-2739
EMail: gahlw@mail.nih.gov
Publications:
Layout table for additonal information
Responsible Party: William A. Gahl, M.D./National Human Genome Research Institute, National Institutes of Health
ClinicalTrials.gov Identifier: NCT00107783    
Other Study ID Numbers: 050076
05-HG-0076 ( Other Identifier: NHGRI )
First Submitted: April 7, 2005
First Posted: April 8, 2005
Results First Submitted: December 20, 2010
Results First Posted: January 19, 2011
Last Update Posted: August 26, 2021